CHAPTER 89 THE ACQUIRED IMMUNODEFICIENCY SYNDROME
CHAPTER 89 THE ACQUIRED IMMUNODEFICIENCY SYNDROME
HOWARD A. LIEBMAN
TIMOTHY P. COOLEY
ALEXANDRA M. LEVINE
Definition and History
Origins of HIV
Etiology and Pathogenesis
Human Immunodeficiency Virus-1
Pathogenesis of HIV Infection
Diagnosis of HIV Infection
Laboratory Features of Disease Progression
Course and Prognosis
Acute Retroviral Syndrome
Early Asymptomatic HIV Disease
Advanced Symptomatic HIV Disease
Anemia in HIV Infection
Systemic Organ Abnormalities
Nucleoside Reverse Transcriptase Inhibitors
Nonnucleoside Reverse Transcriptase Inhibitors
Management of HIV in Pregnancy
Significant advances have recently been made in the area of HIV and AIDS in terms of the molecular aspects of the virus and immunopathogenesis of the disease. Mechanisms of HIV transmission have been elucidated, with specific means to decrease the transmission to health care workers and to children born to HIV-infected mothers. Detection of specific HIV RNA levels in the blood may both provide prognostic information and help guide treatment decisions. Use of highly active antiretroviral therapy has been associated with a marked decrease in new AIDS-defining illnesses and in mortality from AIDS. HIV may affect virtually all organ systems, with prominent abnormalities related to the marrow and blood. Malignancies associated with HIV include lymphoma, Kaposi sarcoma, and cervical cancer, among others. The pathogenesis of these neoplastic disorders has been elucidated in large part, with new treatment strategies attempting to address the various steps involved in the development of these tumors.
Acronyms and abbreviations that appear in this chapter include: AIDS, acquired immunodeficiency syndrome; ANC, absolute neutrophil count; AZT, zidovudine; bDNA, branched-chain DNA; bFGF, basic fibroblast growth factor; CDC, Centers for Disease Control and Prevention; cDNA, copy DNA; CFU-GEMM, colony-forming unit–granulocyte-erythroid-monocyte-macrophage; CNS, central nervous system; d4T, stavudine; DIC, disseminated intravascular coagulation; EBER, Epstein-Barr early region; EBV, Epstein-Barr virus; ELISA, enzyme-linked immunoassay; G-6-PD, glucose-6-phosphate dehydrogenase; G-CSF, granulocyte colony-stimulating factor; GI, gastrointestinal; GM-CSF, granulocyte-monocyte colony-stimulating factor; GP, glycoprotein; HAART, highly active antiretroviral therapy; HHV-8, human herpesvirus 8; HIV, human immunodeficiency virus; ICAM-1, intercellular adhesion molecule-1; Ig, immunoglobulin; IL, interleukin; IM, intramuscular; INF-a, interferon-a ITP, immune thrombocytopenic purpura; IV, intravenous; IVIG, intravenous gamma globulin; MAC, Mycobacterium avium complex; m-BACOD, methotrexate, bleomycin, cyclophosphamide, and etoposide combination chemotherapy; M-tropic, macrophage tropic; NK, natural killer; NNRTI, nonnucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; PEL, primary effusion lymphoma; PEP, postexposure prophylaxis; PGL, persistent generalized lymphadenopathy; PI, protease inhibitor; RT-PCR, reverse transcriptase polymerase chain reaction; SAIDS, simian acquired immunodeficiency syndrome; SIC, simian immunodeficiency virus; 3TC, lamivudine; TGF-b, transforming growth factor b, TNF-a, tumor necrosis factor a; TTP, thrombotic thrombocytopenic purpura; VCAM-1, vascular cell adhesion molecule 1; WHO, World Health Organization.
DEFINITION AND HISTORY
The definition of acquired immunodeficiency syndrome (AIDS) initially was based exclusively upon clinical symptoms and signs.1 As knowledge of the viral etiopathogenesis evolved, the case definition of AIDS underwent multiple revisions by the Centers for Disease Control and Prevention (CDC), with inclusion of additional clinical illnesses and/or a blood CD4 count of less than 200/µl [0.2(109/liter)] in a patient with serologic evidence of infection with the human immunodeficiency virus (HIV).2,3 and 4
While this expanded definition is employed in industrialized nations, the World Health Organization (WHO) adopted alternative case-definition systems for diagnosis of AIDS in underdeveloped countries where serologic and immunologic testing is not readily available (Table 89-1).5,6
TABLE 89-1 AIDS-DEFINING CLINICAL CONDITIONS FOR HIV-INFECTED ADOLESCENTS AND ADULTS
A formal classification system for HIV infection was adopted by the CDC in 1993 that utilized CD4+ cell count and symptoms to better characterize the earlier stages of HIV infection. However, the rapid development of sensitive technologies to quantify HIV in blood and tissues has rapidly supplanted these classification systems as the primary methods of staging and following patients with HIV infection.7,8
ORIGINS OF HIV
At approximately the same time that AIDS was first recognized in 1981, reports of a similar immunodeficiency syndrome, characterized by wasting and opportunistic infections, was described in several colonies of macaques housed at primate centers in the United States.9,10 The illness, known as simian immunodeficiency syndrome (SAIDS), was associated with infection by a retrovirus, termed simian immunodeficiency virus (SIV).11 Subsequent testing revealed that over 20 percent of all tested symptomatic African green monkeys or African mangabeys from the wild had serologic evidence of SIV infection.12,13 and 14 The SIV viral strain infecting these monkeys is related to HIV-2, a less virulent strain of human immunodeficiency virus, found primarily in West Africa.15 An immunodeficiency virus related to HIV-1 and infecting African chimpanzees was also identified.16 Recent evidence suggests that the subspecies of chimpanzee Pan troglodyte may have been the original reservoir of HIV-1.17
Based upon these observations, it is postulated that HIV originally may have been transmitted to humans from an African species of ape.14,17 By the mid- to late 1960s, political and societal circumstances were beginning to change dramatically in ways that were conducive to the rapid spread of this infection in humans. The movement of previously isolated African peoples from rural villages to large urban centers; a change in sexual habits, resulting in widespread exposure to increasing numbers of sexual partners; the worldwide epidemic of parenteral drug abuse; and the advent of commercial air travel all contributed to the current pandemic of HIV infection.
The WHO has estimated that over 30 million people had been infected by HIV worldwide by mid-1998,18 the majority infected by heterosexual contact, with homosexual contact and injection drug use the predominant modes of transmission in the United States and western Europe. Vertical transmission from infected mother to child is now decreasing in developed countries, although such transmission continues to increase in resource-poor regions of the world.
ETIOLOGY AND PATHOGENESIS
HUMAN IMMUNODEFICIENCY VIRUS-1
HIV-1 is a member of the primate Lentivirinae subfamily of retroviruses,19,20 RNA viruses that induce a chronic cellular infection by converting their RNA genome into a DNA provirus that is integrated into the genome of the infected cell. Infection by these lentiviruses is characterized by long periods of clinical latency followed by a gradual onset of disease-related symptoms.21,22 and 23
TRANSMISSION OF HIV
HIV may be transmitted by sexual contact with an infected partner, by parenteral drug use with a contaminated needle, by exposure to infected blood or blood products, and by perinatal exposure from an infected mother to her infant.
General Mechanisms of Sexual Transmission HIV-1 has been isolated from the semen of HIV-infected men24 as well as from cell-free seminal fluid25 and may be detected during the first 3 to 4 weeks after primary infection.27 Factors associated with increased viral burden in semen include more advanced symptomatic HIV disease, higher levels of HIV-RNA in blood, CD4 cell counts of less than 200/µl, and presence of seminal fluid leukocytosis. HIV infection has been reported after exposure to infected semen during artificial insemination.27
HIV has been recovered from cervical and vaginal secretions of HIV-infected women,28,29 and HIV-infected endothelial cells and macrophages have been detected in cervical biopsies.30 Factors that influence the levels of HIV-1 in female genital tract secretions include the stage of HIV disease, menstruation status, hormonal parameters, concomitant vaginal infection, age, HIV-1 RNA level in plasma, and antiviral therapy.31 Although female-to-female transmission of HIV has been reported,32,33 this appears to be relatively unusual.
HIV transmission may be facilitated by the presence of other sexually transmitted diseases, both with and without ulceration,34 and HIV has been isolated directly from genital ulcers.35 Prevention or treatment of sexually transmitted disease has been associated with a decrease in HIV-1 transmission.36
Transmission through Parenteral Drug Use Sharing needles and syringes is an important mode of transmission among parenteral drug users.37 The use of cocaine has been associated with a particularly high risk of HIV infection,38 presumably related to its short half-life and the resulting need for greater numbers of injections. Behavioral factors may lead to increased risk of HIV-1 transmission even among nonparenteral illicit drug users.
Transmission through Infected Blood Products The risk of infection with HIV after receiving 1 unit of infected blood approximates 90 percent.39 Transfusion of blood products derived from multiple units of pooled blood can also transmit HIV and accounted for the initially high prevalence of HIV infection among patients with hemophilia. Screening of all donated blood, beginning in March 1985, and the subsequent routine heat or solvent detergent treatment of clotting factor concentrates have resulted in a marked decrease in new transfusion-associated HIV infections. Guidelines for proper inactivation of HIV in clotting factor concentrates have been developed.40,41 Currently, the risk of acquiring HIV through receipt of a unit of blood that tests negative for antibodies to HIV-1 is approximately 1 in 493,000.42
Mother-to-Child Transmission The risk of infection from mother to infant differs in various parts of the world, ranging from approximately 15 percent in Europe to 15–30 percent in the United States and 40–50 percent in Africa.43,44 and 45 HIV-1 may be transmitted in utero,46,47 intrapartum (at the time of delivery);48,49 or postpartum, through ingestion of HIV-1 infected mother’s milk.50,51 Several factors predict an increased risk of perinatal transmission. In terms of the mother, more advanced HIV disease,52,53 higher HIV-1 viral load in the plasma,54,55 cigarette smoking,56 and active injection drug use57 have all been associated with increased risk of transmission. In terms of the details of delivery, premature rupture of the amniotic membranes (over 4 h),58,59 presence of chorioamnionitis,57 and vaginal delivery, as opposed to elective cesarean section,60,61 have each been associated with increased rates of transmission. In terms of the infant, breast-feeding, prematurity, and low gestational age are reported as risk factors.58,59,62 The CDC has recently made formal recommendations regarding the optimal care for HIV-1 infected pregnant women.63 These recommendations differ for resource-rich and resource-poor settings. In the United States, the use of antiretroviral agents in pregnancy and delivery, with subsequent administration to the infant for the first 6 weeks of life, has resulted in a dramatic reduction in the rate of transmission, from approximately 25 percent to 8 percent.64 With the further use of elective cesarean section and avoidance of breast feeding, transmission rates have dropped to approximately 2 percent.60 The efficacy of shorter courses of zidovudine or neviripine (a non–nucleoside reverse transcriptase inhibitor) have been demonstrated and may be more practically feasible in resource-poor regions of the world.65,66 The long-term toxicities of in utero exposure to antiretroviral agents are unknown. Nonetheless, their use during pregnancy resulted in a 43 percent decrease in the number of children with perinatally acquired HIV infection in the United States when comparing data from 1992 and 1996.67
HIV GENE PRODUCTS
HIV-1 has three structural genes necessary for replication: GAG, POL, and ENV.19 These viral genes encode proteins that are required for binding to the host cell, intracellular synthesis of provirus by reverse transcription, proviral integration into the host-cell genome, and viral assembly and release. The 9-kb genome of HIV-1 also contains at least six additional genes involved in the regulation of viral gene expression and cellular latency: VIF, VPU, VPR, TAT, REV, and NEF (Fig. 89-1).68
ENV HIV-1 is an icosahedral virion with a protein-rich envelope in a membrane derived from the host cell69 (see Fig. 89-1). The surface of the virus particle contains a 120-D glycoprotein (gp120) that is linked noncovalently to a 41-kD transmembrane protein (gp41). Both proteins are derived from a 160-kD precursor protein that is encoded by the ENV gene. The intracellular processing of gp160 involves the assembly of oligomeric trimer complexes, which are glycosylated and subsequently cleaved into the respective gp120 and gp41 in the Golgi apparatus of the host cell.70 HIV gp120 serves as a virion receptor for noninfected cells,71 first binding to the CD4 antigen and then to one or the other the chemokine receptors CCR5 and CXCR4.72,73 and 74 The CD4-binding domain of gp120 is located on the carboxyl terminal region of the molecule.75 Within the CD4-binding site of gp120 are a number of regions that display significant genetic variation between different viral isolates without compromising viral binding.76 The binding of CD4 results in a conformational transition in the V3 variable loop of gp120, exposing the chemokine receptor binding site of the viral molecule and increasing the affinity of gp120 binding to CCR5 by 10- to 100-fold.70,77 Complexing of gp120 with CD4 and chemokine molecules promotes a second conformational change, which exposes the HIV-1 transmembrane anchoring protein, gp41, ectodomain, which is necessary for fusion of the viral membrane with the membrane of the newly infected cell.77,78 These viral proteins are immunogenic. Consequently, antibodies against both gp120 and gp41 can be detected in serum of all individuals infected with HIV-179 (Fig. 89-2). However, antibodies capable of neutralizing HIV and preventing cellular infection appear to develop only after infection is well established. Further, these antibodies are not capable of efficiently controlling ongoing infection.70
FIGURE 89-1 A schematic representation of the genome and viral structure of HIV-1.
FIGURE 89-2 A Western blot analysis of antibodies against HIV viral proteins from the serum of a patient with AIDS.
GAG The GAG gene encodes a 54-kD precursor protein that is cleaved by a viral protease to form four viral core proteins: p24, p17, p9, and p7 (see Fig. 89-1). The 24-kD protein (p24) forms the shell of the nucleocapsid. The 17-kD myristylated matrix protein (p17) is located between the viral envelope and the nucleocapsid and functions to stabilize the virion and, as part of the p54 GAG-precursor protein, to assist in targeting viral assembly at the cell surface. The 7-kD protein (p7) and 9-kD protein (p9) are tightly associated with the viral RNA, stabilizing it in the viral ribonucleoprotein core.80
POL The POL gene encodes three critical viral proteins. The first, reverse transcriptase, is a 66-kD protein that generates a copy DNA (cDNA) from the viral RNA genome. The cDNA then is used as a template, generating a double-stranded DNA provirus, which then integrates into the host cellular genome.81 The POL gene also encodes a 31-kD integrase protein that is required for stable integration of proviral double-stranded DNA into host cellular DNA.82 The 5′ region of the POL gene encodes a viral protease that cleaves the p54 GAG precursor protein.83 A defective protease leads to the production of noninfectious virions.84
LIFE CYCLE OF HIV-1
HIV-1 gp120 binds to the CD4 surface membrane protein, resulting in a further high-affinity binding to the chemokine CCR5 receptor.70,85 Human helper-inducer (CD4) lymphocytes, monocytes-macrophages, Langerhans’ cells, follicular dendritic cells, megakaryocytes, and thymic cells express the CD4 and chemokine receptor molecules and are susceptible to infection by HIV-1. The structural diversity of the gp120 viral receptor has resulted in viral strains with selective or restricted patterns of infection, such as those that readily infect monocytes, while others are tropic for CD4 lymphocytes.76,86 Macrophage-tropic (M-tropic) strains of HIV use the CCR5 chemokine receptor to infect both macrophages and CD4+ lymphocytes.87,88 The T-tropic strains use the CXC4 chemokine receptor and may also use the CCR5 receptor.87,88 Additional chemokine receptors CCR2 and CCR3 have also been implicated as coreceptors for HIV infection of certain cell types.88,89
Upon binding to the CD4 protein on the host cell, the virus envelope fuses with the host cell membrane90 (Fig. 89-3). This fusion is mediated by a hydrophobic domain on the amino terminal portion of gp41.77 The internalized nucleocapsid then is destabilized and dissociates after binding to the cellular protein cyclophilin A,91 exposing the diploid viral RNA genome associated with reverse transcriptase.92 Reverse transcription proceeds by the synthesis of a single cDNA strand, followed by degradation of the viral RNA by the ribonuclease H activity of p66. Reverse transcriptase then acts as a DNA polymerase, forming a second DNA strand. This synthesis of the double-stranded DNA provirus must proceed rapidly to prevent the degradation of viral RNA by intracellular enzymes. The estimated rate of base substitution errors for HIV reverse transcriptase may be as high as 1 in 1700 to 1 in 2000.93,94 This results in 5 to 10 nucleoside mutations per virus for each replication cycle and explains the high degree of genomic diversity observed between viral isolates of HIV.95
FIGURE 89-3 The life cycle of HIV-1.
The integration of the provirus is necessary for stable infection of the cell. Viral integrase is capable of both cleaving host DNA and integrating a linear form of the provirus.96 Kinetic studies of HIV-1 infection have detected viral DNA present in the cytoplasm within 2 to 3 h of infection, while nuclear viral DNA has been detected by 24 h.97 The gene product of the VPR gene appears to assist in the transport of the preintegration viral DNA into the nucleus for subsequent integration.98,99 After successful integration of the viral genome, the HIV-1–infected cell may develop either a latent or a persistent form of infection.
The mechanism or mechanisms of viral latency remain poorly understood but appear to require activation of the infected cell, since HIV-1 does not replicate efficiently in resting lymphocytes or macrophages.100,101 Cellular transactivating proteins, such as NF-kB, are up-regulated in activated cells and enhance HIV proviral transcription.102
After integration, HIV-1 proviral transcription leads to the expression of regulatory proteins designated tat, rev, and nef.97,98 Tat is a small nuclear protein that is essential for HIV replication and, in conjunction with other cellular proteins, TAK (Tat-associated kinase) and CycT (cyclin T), assists in viral RNA elongation, resulting in a 1000-fold increase in HIV-1 expression by the infected cells.98,103,104
Rev is a viral protein that regulates nuclear export of unspliced viral RNA.98,105,106 Like tat, rev is essential for viral replication and must bind to a rev-responsive element located in the ENV gene. The other HIV-encoded proteins, designated nef and vpu, have a role in the modulation and down-regulation of the cellular receptor, CD4.98,107,108,109 and 110
The structural proteins of the GAG, POL, and ENV genes are expressed as precursor proteins and subsequently cleaved by viral protease to yield mature viral proteins. Proteolysis of proteins by the viral protease is essential for viral maturation and infectivity. The products of the ENV gene, gp120 and gp41, are transported to the cell membrane. The ribonucleoprotein core assembles in the cytoplasm of the host cell and subsequently moves to the membrane surface for budding. The efficient packaging of the viral RNA is dependent upon packaging signals present in the Gag region of the viral RNA.111 The budding of virus appears to be dependent upon the product of the VPU gene, which assists in membrane transport of ENV gene products.107,108,112 In addition, viral infectivity appears to require the gene product of the VIF gene.113
PATHOGENESIS OF HIV INFECTION
HIV infection results in aberrant immune regulation and immunodeficiency. The numerous in vitro and in vivo defects in cellular immune response observed with HIV infection include decreased lymphocyte proliferation to soluble antigens,114 decreased helper response in immunoglobulin (Ig) synthesis,115 impaired delayed hypersensitivity,1,2 decreased interferon-g production,116 and decreased T-cell–mediated cytotoxicity of virally infected cells.117
DEPLETION OF CD4+ T CELLS
Infection with HIV-1 results in a progressive loss of CD4-positive (CD4+) T lymphocytes, resulting from the direct cytopathic effect of HIV on CD4+ lymphocytes. Formation of syncytial multinucleated giant cells by a mechanism involving fusion of infected cells expressing viral gp120 with noninfected CD4+ T lymphocytes is another mechanism of CD4 depletion.118 The propensity of certain viral stains to form syncytia appears to be associated with an aggressive clinical course.117,118 More recent experimental data suggest that an HIV-1 phenotypic switch from an M-tropic (nonsyncytial) to a T-tropic (syncytial) virus may be the central event in acceleration of HIV-induced immunodepletion.119
The host immunologic response against HIV-infected lymphocytes also may contribute to the progressive loss of CD4+ lymphocytes by antibody-mediated and cytotoxic T-cell–mediated mechanisms.120,121 Noninfected lymphocytes may also become “innocent bystander” targets for immunologic destruction by binding free gp120 to their surface CD4 protein.
Defective production of immunostimulatory cytokines, such as interleukin-2 (IL-2),122,123 and 124 or exaggerated expression of inhibitors of T-lymphocyte proliferation, such as transforming growth factor-b (TGF-b),125 can contribute to the progressive decline in CD4 lymphocytes. High-level replication and budding of virus, resulting in membrane injury, has also been proposed as a mechanism for lymphocyte cytotoxicity.
Recent advances in combination antiretroviral therapy have resulted in marked suppression of viral replication, with resulting reductions of blood and tissue viral reservoirs.126,127 Efficient viral suppression has resulted in significant and prolonged immunologic reconstitution characterized by increased CD4+-lymphocyte numbers, reduced opportunistic infections, and prolonged survival.128,129 However, significant deficits in the immunologic repertoire persist, and complete immunologic reconstitution has not yet been attained.130,131
DEFECTS IN B-CELL IMMUNITY
A number of defects in humoral immunity have been associated with HIV infection. Pronounced polyclonal activation of B lymphocytes is common, resulting in polyclonal hypergammaglobulinemia.132,133 Spontaneous proliferation of B cells is observed in patients with advanced HIV infection.134 In contrast, antigen-specific B-cell proliferation and antibody production are decreased in patients with AIDS.135 This may result from the loss of helper T-lymphocyte activity.
The aberrant B-lymphocyte regulation in HIV infection is associated with a pronounced increase in autoimmune phenomena and an increased risk of B-cell lymphomas.136 In addition to an increased frequency of positive antiglobulin test results, antibodies against neutrophils,137,138 lymphocytes,139 and platelets140,141 and 142 also have been reported.
DEFECTS IN IMMUNE ACCESSORY CELLS AND NATURAL KILLER CELLS
Monocytes, macrophages, and follicular dendritic cells of the lymph nodes express CD4 antigen and can be infected by HIV.143,144 Monocytes and macrophages are resistant to HIV-induced cytotoxicity and serve as a chronic reservoir of HIV expression.143 While functional defects in the chemotaxis of HIV-infected monocytes have been reported,145 most studies have failed to demonstrate consistent defects.146,147 The follicular dendritic cells appear to play an important role in HIV clearance in early asymptomatic HIV disease. However, a progressive depletion of these cells is observed over time, resulting in increasing plasma viremia. The loss of follicular dendritic cells results in defective antigen processing in patients with advanced HIV disease.
Natural killer (NK) cell activity is decreased in the blood of HIV-infected individuals.147,148 In combination with helper T-lymphocyte depletion, decreased NK activity results in defective clearance of virally infected cells. While the number of NK cells is reported to be normal,147,148 the defect in NK activity appears to result from a deficiency in the signals for cell activation. The addition of exogenous IL-2 can improve NK lymphocyte function.149
DIAGNOSIS OF HIV INFECTION
Like the clinical manifestations of acute (primary) HIV infection (“acute retroviral syndrome”), the laboratory markers are nonspecific, with frequent elevation of liver transaminase levels and erythrocyte sedimentation rate. However, HIV viremia is present during the acute illness and can be detected by molecular methods such as reverse transcription polymerase chain reaction (RT-PCR).
The primary diagnostic screening tool is detection of antibody via the enzyme-linked immunoassay (ELISA). However, since a positive ELISA result may not be specific for HIV-1 infection, all positive ELISA screening test results should be verified by immunoblotting HIV-1 antigens (see Fig. 89-2).
By ELISA and immunoblot techniques, the median time from initial infection to first detection of HIV antibody has been estimated to be 2.4 months, while 95 percent of cases are expected to seroconvert within 5.8 months (see Fig. 89-4).150 HIV infection for longer than 6 months without detectable antibody is extremely uncommon.151,152 and 153
FIGURE 89-4 The virologic, serologic, and clinical course of HIV infection. Antibodies against HIV can first be detected between 2 and 5 months after infection.
The presence of the p24 antigen or HIV RNA in serum or plasma may precede seroconversion by several weeks.154 This initial rise in p24 antigen correlates with the burst of viremia that occurs shortly after primary HIV infection.155 Despite these observations, p24 antigen screening of donated units of blood appears to provide no benefit over conventional ELISA and immunoblot techniques.156
LABORATORY FEATURES OF DISEASE PROGRESSION
With progression from the initial acute infection to the expected asymptomatic period, various laboratory parameters may be used to predict development of more advanced disease.7,8,157 Quantitation of plasma HIV RNA (viral load) and CD4+ lymphocyte count are the most useful parameters. The CD4+ lymphocyte count falls during the acute retroviral infection and then stabilizes during early asymptomatic infection and may appear relatively normal. The CD4+ count then decreases by approximately 40 to 80 µl/year in the absence of antiretroviral medications,158 although there is significant variability among patients.159
An initial measurement of plasma viral load by RT-PCR or branched-DNA (bDNA) methods provides important prognostic information that can be useful in determining when to start antiretroviral medications.7,8 The serial assessment of plasma HIV viral load also allows for rapid assessment of efficacy of antiretroviral medications. Changes in viral load usually precede significant alterations in CD4+ lymphocyte counts.8,128
Several nonspecific markers of disease progression have been defined, including b2-microglobulin160 and neopterin,161 each of which has independent predictive value in estimating the probability of progression to AIDS. However, each of these surrogate markers has been largely replaced by the more specific molecular assays to quantify plasma HIV viral load.
COURSE AND PROGNOSIS
HIV infection results in a progressive process characterized by gradual depletion of immune function and eventual development of rather nonspecific symptoms, followed by specific infections and/or neoplastic disease. Patients who develop AIDS generally experience relentless deterioration in physical health and ultimately succumb to one or more complications secondary to acquired immunodeficiency, organ dysfunction, and/or malignancy associated with HIV infection.
The recent use of monitoring by means of assessment of the quantity of HIV-1 RNA in the plasma has allowed a more rational basis upon which to predict the course of disease in individual patients. In a study performed through the Multicenter AIDS Cohort, a longitudinal cohort study of HIV disease in homosexual and bisexual men, the earliest, baseline level of HIV RNA in plasma was found to correlate significantly with prognosis over time. Thus, a viral load of 5,000 to 10,000 copies/µl was associated with an 8 percent risk of progression to clinical AIDS within the next 5 years, while a viral load in excess of 36,000 copies/µl was associated with a 62 percent 5-year risk of AIDS.7 In a subsequent study, use of both viral load and CD4+ cells was found to more accurately predict the prognosis of HIV-infected men.8
In addition to the use of viral load monitoring, the development of potent new antiretroviral agents, including the protease inhibitors,162,163 and 164 has recently led to a remarkable improvement in the natural history of HIV infection.129 The use of combinations of highly active antiretroviral therapies (HAART) was found to be associated with a 73 percent decrease in the incidence of new opportunistic infections and a 49 percent decrease in death due to AIDS when data from 1997–1998 were compared to data from 1994.129 Remarkable decreases in the incidence of cytomegalovirus disease, atypical Mycobacterium intracellularis infections, and other serious opportunistic infections have occurred as a consequence of HAART therapy,165 and improvement in immune function has also been documented.166 It may now be possible to discontinue the routine use of prophylaxis against Pneumocystis carinii in patients who have been successfully treated with HAART.167
ACUTE RETROVIRAL SYNDROME
An acute clinical illness is often associated with initial HIV infection, occurring in approximately 50 to 90 percent of individuals.155,168,169 This syndrome begins approximately 1 to 3 weeks (range 5 days to 3 months) after primary infection and usually lasts for 1 to 2 weeks. Prominent symptoms include significant fatigue and malaise; fever, which may be as high as 40°C (104°F); headache; photophobia; myalgias; and a morbilliform rash, seen in approximately 40 to 50 percent of patients. Generalized lymphadenopathy may occur toward the end of the acute illness. The symptoms are similar to those of other viral illnesses, such as infectious mononucleosis (see Chap. 90). All symptoms of this acute retroviral syndrome subside within several weeks. However, headache may persist as an intermittent complaint, as may the generalized lymphadenopathy, termed persistent, generalized lymphadenopathy (PGL), which occurs in approximately 75 percent of patients.155,169
EARLY ASYMPTOMATIC HIV DISEASE
After resolution of the acute retroviral syndrome, the patient usually returns to a state of well-being. During this period, the patient harbors HIV in blood and in genital secretions and may transmit the virus to others. This phase of asymptomatic infection persists for approximately a decade or more in the absence of therapy and appears similar in all racial and ethnic groups, all geographic areas, both genders, and all risk groups for HIV infection.170,171,172 and 173
ADVANCED SYMPTOMATIC HIV DISEASE
With time, more significant manifestations of disease occur, with more extensive fatigue, fevers, weight loss, night sweats, and the eventual development of opportunistic infections, neurologic symptoms, and/or neoplasms that are considered AIDS-defining conditions (see Table 89-1).
ANEMIA IN HIV INFECTION
INCIDENCE OF ANEMIA
Anemia is very common in HIV-infected individuals, occurring in approximately 10 to 20 percent at initial presentation and diagnosed in approximately 70 to 80 percent of patients over the course of disease.174,175 and 176 In an attempt to ascertain the precise incidence of anemia in the setting of HIV infection, Sullivan and colleagues evaluated data derived from the case records of 32,867 HIV-infected persons followed from 1990 through 1996.176 This cohort, termed the Multistate Adult and Adolescent Spectrum of HIV Disease Surveillance Project, consists of individuals who receive HIV care in hospitals and HIV clinics in nine U.S. cities. Using a hemoglobin level of less than 10 g/dl to define anemia, the 1-year incidence of anemia was 37 percent among patients with clinical AIDS; 12 percent among patients with immunologic AIDS, as defined by a CD4+ cell count pf less than 200 cells/ml; and 3 percent among HIV-infected individuals with neither clinical nor immunologic AIDS. These data confirm the high incidence of anemia among HIV-infected patients at all stages of disease.
ETIOLOGY OF ANEMIA
Numerous causes for anemia exist in HIV-infected patients (Table 89-2).
TABLE 89-2 CAUSES AND MECHANISMS OF ANEMIA IN HIV INFECTION
ANEMIA DUE TO DECREASED PRODUCTION OF RED BLOOD CELLS
A decrease in production of red blood cells may result from factors suppressing the CFU-GEMM, such as inflammatory cytokines or the HIV virus itself.174,175 In addition, a blunted production of erythropoietin has been documented in anemic HIV-infected patients, similar to the suppression seen in other states of chronic infection or inflammation.177 Infiltration of the marrow by tumor, such as lymphoma,178 or infection, such as Mycobacterium avium complex (MAC), may also lead to the decreased production of red cells. In addition, MAC may also be associated with cytokine-induced marrow suppression. Involvement of the gastrointestinal (GI) tract by various infections or tumors may lead to chronic blood loss, with eventual iron deficiency anemia. Another prominent cause of hypoproliferative anemia in patients with HIV infection is the common use of multiple medications, many of which may cause marrow and/or red cell suppression. Zidovudine (AZT), the first licensed antiretroviral agent, is uniformly associated with macrocytosis mean cell volume (MCV >100), which can be used as an objective indication that the patient has been compliant with this medication.179 It noteworthy that transfusion-dependent anemia (hemoglobin < 8.5 g/dl) has been reported in approximately 30 percent of patients with full-blown AIDS, receiving zidovudine at doses of 600 mg/day. However, the incidence of severe anemia is only 1 percent when the same dose of zidovudine is used in patients with asymptomatic HIV disease.180
Infection of the marrow by parvovirus B19 is another cause of hypoproliferative anemia in HIV-infected patients, resulting in specific infection of the pronormoblast.181,182 Thus, while marrow failure affecting all three lines has been described in association with parvovirus B19 infection, a pure red cell aplasia is the usual consequence. Parvovirus infection is usually acquired during childhood, leading to “fifth disease,” one of the common childhood exanthums. Exposure to the virus leads to an antibody response, with subsequent resistance to further infection. Approximately 85 percent of adults have serologic evidence of prior parvovirus infection. However, the seroprevalence of such antibodies among HIV-infected patients is only 64 percent. This would suggest that these individuals may have an ineffective immune response against newly acquired infection. The diagnosis of parvovirus B19 can be made on marrow examination, revealing giant pronormoblasts with clumped basophilic chromatin and clear cytoplasmic vacuoles; diagnosis can be confirmed by in situ hybridization using sequence-specific DNA probes for parvovirus B19. Therapy for parvovirus-induced red cell aplasia consists of infusions of intravenous (IV) gamma globulin that contain antibodies from plasma donors most of whom have been exposed to parvovirus. Relapse of parvovirus B19–induced red cell aplasia may occur, necessitating retreatment in these individuals.181,182
ANEMIA DUE TO INCREASED RED CELL DESTRUCTION
Increased red cell destruction may be seen in HIV-infected patients with G-6-PD deficiency who are exposed to oxidant drugs and in HIV-infected patients with disseminated intravascular coagulation (DIC) or thrombotic thrombocytopenic purpura (TTP);183 presence of fragmented red cells and thrombocytopenia on blood smear will be seen in the latter two conditions, and Heinz bodies will be seen in association with G-6-PD deficiency. Hemophagocytic syndrome has also been described in association with HIV infection. An additional cause of red cell destruction in HIV-infected patients is the development of autoantibodies, with resultant positive Coombs’ test result and shortened red cell survival. It is interesting to note that a positive direct Coombs’ test result has been reported in as many as 18 to 77 percent of HIV-infected patients, although the incidence of actual hemolysis is quite low. When present, anti-i antibody and antibody against auto-U antigens have been described, occurring in 64 percent and 32 percent of HIV-infected patients, respectively.184,185 and 186 A high incidence of positive direct Coombs’ test results has also been detected in patients with other hypergammaglobulinemic states, indicating that the positive Coombs’ test results in HIV may simply be secondary to the polyclonal hypergammaglobulinemia that is known to occur in the setting of HIV infection.187
ANEMIA DUE TO INEFFECTIVE PRODUCTION OF RED CELLS (B12 AND/OR FOLIC ACID DEFICIENCY)
Folic acid is absorbed in the jejunum and is responsible for one carbon transfer required in the synthesis of DNA. A deficiency of folic acid leads to a megaloblastic anemia, with large oval red cells in the blood, hypersegmented neutrophils, and a decrease in all three lines, with resultant anemia, neutropenia, and thrombocytopenia. Since tissue stores of folate are relatively small, a deficiency of folate in the diet lasting as little as 6 to 7 months may lead to anemia. It is thus apparent that HIV-infected patients who are ill and not eating properly, as well as those with underlying disease of the jejunum, may be unable to absorb sufficient folic acid. The classic changes of megaloblastic anemia will be detected upon examination of the bone marrow, while serum and red cell folate levels will be low.
Ineffective production of red cells, with pancytopenia in the blood, elevated indirect bilirubin level, and low reticulocyte count may also be seen in vitamin B12 deficiency. The absorption of B12 requires initial production of intrinsic factor by parietal cells in the stomach, with subsequent absorption of the complex of B12 and intrinsic factor within the ileum. Thus, malabsorption of B12 can occur in various disorders of the stomach (achlorhydria), by production of antibodies to intrinsic factor (“pernicious anemia”), or by various disorders of the small bowel and ileum (infection or Crohn’s disease). While B12 deficiency is highly unlikely on a dietary basis alone, patients with HIV infection appear to be prone to B12 malabsorption, presumably due to the myriad infections and other disorders that may occur in the small intestine. Negative vitamin B12 balance has been documented in approximately one-third of patients with AIDS, the majority demonstrating defective absorption of the vitamin.188 Diagnosis of B12 deficiency can be made by documenting low serum B12 levels, while the earliest indication of negative B12 balance is the finding of low B12 levels in blood in patients taking transcobalamin II.189 Monthly administration of parenteral B12 will correct the deficiency and the resultant anemia and pancytopenia in the peripheral blood. Since B12 deficiency may also cause neurologic dysfunction (subacute combined degeneration of the cord), with motor, sensory, and higher cortical dysfunction, the possibility of vitamin B12 deficiency should also be considered in HIV-infected patients with these neurologic symptoms.
CONSEQUENCES OF ANEMIA IN HIV INFECTION
The consequence of anemia in HIV-infected patients was addressed by the Multistate Spectrum of HIV Disease Surveillance Project, in which records from over 32,000 individuals were reviewed. In this study, anemia was defined as a hemoglobin level less than 10 g/dl. It is important to note that anemia was found to be associated with an increased risk of death in this cohort.176 Thus, the relative risk of death for anemic individuals who began the study with CD4+ counts above 200 cells/ml was 148 percent higher than for individuals at the same CD4+ strata without anemia, while the risk of death was increased by 58 percent for those who entered the study at CD4+ counts less than 200 cells/ml and developed anemia. It is interesting to note that the risk of death decreased in those patients who recovered from anemia, whatever its cause, while the risk of death remained 170 percent higher for patients who did not recover from anemia. A similar relationship between anemia and increased risk of death has also been noted by others.190
USE OF ERYTHROPOIETIN IN HIV-INFECTED PATIENTS WITH ANEMIA
A blunted response to erythropoietin is extremely common in the setting of HIV infection;171,190 it is caused by a posttranscriptional defect, since levels of kidney erythropoietin mRNA are normal. Multiple studies have now confirmed the beneficial effect of erythropoietin in HIV-infected patients with anemia, in whom marrow function has been suppressed as a result of HIV or of other chronic infectious or inflammatory diseases.190,191 and 193 Erythropoietin is also effective in treating the anemia due to zidovudine or other medications, including cancer chemotherapy, which may suppress the marrow.193 Patients with a baseline endogenous erythropoietin level of less than or equal to 500 IU/liter are expected to respond to erythropoietin therapy, while those with endogenous levels over 500 IU/liter are not. Erythropoietin is administered subcutaneously at a dose of 100 to 200 U/kg body weight three times weekly until normalization of the red cell count is achieved and then given approximately once every week or every other week to maintain the desired hemoglobin concentration. When erythropoietin is prescribed in this manner, statistical increases in the hematocrit are expected, with significant decreases in the number of red cell transfusions required and a significant increase in overall quality of life. Recent data from the Spectrum of Disease Study indicate that correction of anemia is also associated with prolongation of survival.171,190 Toxicity is uncommon, consisting primarily of local pain at the site of injection, mild fever, or rash. In those patients with endogenous erythropoietin levels less than 500 IU/liter who do not respond to the drug, a search for occult iron deficiency, serum B12 or folate deficiency, or other such causes should be made.
ETIOLOGY OF NEUTROPENIA AND DECREASED GRANULOCYTE FUNCTION IN HIV
Neutropenia is reported in approximately 10 percent of patients with early, asymptomatic HIV infection and in over 50 percent of those individuals with more advanced HIV-related immunodeficiency.174,175,193 As with other peripheral blood cytopenias in the setting of HIV infection, multiple etiologies may be present, either singly or in combination.194 Thus, decreased colony growth of the progenitor cell CFU-GM195 may lead to decreased production of both granulocytes and monocytes. Soluble inhibitory substances produced by HIV-infected cells have been noted to suppress neutrophil production in vitro.196 Decreased serum levels of G-CSF have been described in HIV-seropositive subjects with afebrile neutropenia (<1000 neutrophils/µl), indicating that a relative deficiency of this specific hematopoeitic growth factor may also contribute to persistent neutropenia.197 Finally, myelosuppression and neutropenia may result from any one of several medications that are commonly prescribed for HIV-infected patients.
Aside from absolute neutropenia, patients with HIV infection may also experience decreased function of granulocytes and monocytes. Thus, abnormal Fc processing by macrophages has been described, while decreased opsonization and intracellular killing of bacterial or fungal organisms by granulocytes has also been noted.198
RISK FACTORS FOR INFECTION IN NEUTROPENIC PATIENTS WITH HIV
In patients with cancer who receive chemotherapy, multiple studies have shown that the risk of bacterial infection rises when the absolute neutrophil count (ANC) falls below 1000 cells/dl and increases again when the ANC falls below 500 cells/µl.199 Several studies have confirmed the same relationships in patients with HIV infection. Thus, Moore and colleagues found that the risk of bacterial infection increased 2.3-fold for HIV-infected individuals with less than 1000 cells/µl and rose by 7.9-fold in those with ANC levels less than 500 cells/µl.200 Lower ANC counts are associated with increased risk of hospitalization for serious infection among HIV-infected patients, as shown by a review of 2047 HIV-positive patients. On multivariate analysis, the severity and duration of neutropenia were found to be significant predictors of the incidence of hospitalization for serious bacterial infections.201
In a recent study of 62 HIV-infected patients with ANCs less than or equal to 1000 cells/µl, 24 percent developed infectious complications, most commonly within 24 h after the onset of neutropenia.202 On multivariate analysis, the three factors independently associated with infectious complications included presence of a central venous catheter, neutropenia in the previous 3 months, and a lower nadir of granulocyte count (250 cells/µl in those with infections versus 622 cells/µl in those without). Among patients with medication-associated neutropenia, the most common cause was zidovudine, followed by trimethoprim-sulfamethoxazole, and ganciclovir; neutropenia was less likely to be associated with infection in these patients than in individuals who were neutropenic due to the use of cancer chemotherapy.202
USE OF GRANULOCYTE COLONY-STIMULATING FACTOR AND GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR IN NEUTROPENIC PATIENTS WITH HIV INFECTION
When administered subcutaneously to HIV-infected patients with neutropenia, granulocyte colony-stimulating factor (GM-CSF) results in dose-dependent increases in granulocytes, monocytes, and eosinophils.203,204
GM-CSF has been associated with augmentation in the replication of HIV, with increases in viral load, specifically seen in those HIV isolates that are monocyte/macrophage tropic. Thus, use of GM-CSF was associated with a 200-fold increase in HIV p24 levels over baseline when used to prevent neutropenia associated with chemotherapy for AIDS-related lymphoma.205 However, GM-CSF also increases the uptake and phosphorylation of zidovudine to its active triphosphate form, resulting in a greater antiretroviral effect. It is therefore recommended that antiretroviral therapy be employed in all patients receiving GM-CSF. When used with antiretroviral agents, GM-CSF is not associated with an increased HIV viral load.
Granulocyte colony-stimulating factor (G-CSF) has also been demonstrated to raise granulocyte counts in neutropenic patients with HIV in whom neutropenia has occurred as a consequence of cancer chemotherapy, antiretroviral therapy, and/or antiinfective therapy.193,206 A retrospective analysis of 152 neutropenic HIV-infected patients, including 71 who received G-CSF and 81 patients who never received G-CSF, was conducted during the years from 1991 to 1994.207 The two groups had similar baseline characteristics, including median CD4+ count of 37 and 40 cells/µl, respectively. In multivariate analysis, use of G-CSF was associated with a significantly decreased risk of bacteremia (p = .02). Further, multivariate analyses revealed a decreased risk of death in patients receiving G-CSF, as well as in those who received antiretroviral agents and/or prophylaxis for Pneumocystis carinii pneumonia.207
The early recommendations for dosing of G-CSF included an initial induction dose of 5 mg/kg/day given subcutaneously. Recent evidence would suggest, however, that much lower doses of G-CSF may be effective in HIV-infected persons. Thus, an initial dose of 1 mg/kg/day is often initiated and used until the neutrophil count rises to acceptable levels (>1000 cells/µl). This is followed by a titration of dosing, often requiring therapy only once or twice per week, as necessary to maintain the desired response.
G-CSF does not enhance HIV replication in vitro, and its use has not been associated with up-regulation of HIV in vivo. Toxicity of G-CSF has been rather minimal, consisting primarily of bone pain.
While patient survival has not increased as a consequence of G-CSF or GM-CSF,207 these drugs will allow safer administration of other necessary medications.204,207
Thrombocytopenia is relatively common during the course of HIV infection, occurring in approximately 40 percent of patients and serving as the first symptom or sign of infection in approximately 10 percent.208,209 Sullivan and colleagues209 recently evaluated the 1-year incidence of thrombocytopenia (<50,000/µl) in a group of 30,214 HIV-infected patients as part of the retrospective Adult and Adolescent Spectrum of Disease Project. The incidence of thrombocytopenia over 1 year was 8.7 percent in patients with clinical AIDS, 3.1 percent in patients with immunologic AIDS (CD4+ <200 cells/µl), and 1.7 percent in patients with neither. Development of thrombocytopenia was associated with clinical or immunologic AIDS, history of injection drug use, history of anemia or lymphoma, and African American race. After controlling for multiple factors (AIDS, CD4+ count, anemia, neutropenia, antiviral therapy, and receipt of prophylaxis against P. carinii), thrombocytopenia was significantly associated with shorter survival (risk ratio = 1.7, 95% confidence interval = 1.6–1.8).209
MECHANISMS OF THROMBOCYTOPENIA IN HIV-RELATED THROMBOCYTOPENIC PURPURA
Increased Platelet Destruction As in “de novo” immune thrombocytopenic purpura (ITP), HIV-infected patients with ITP also demonstrate increased platelet destruction via phagocytosis by macrophages in the spleen.210 In HIV-related ITP, however, several mechanisms for platelet-associated antibody have been described, often occurring simultaneously in a given patient. Thus, presence of platelet-specific antibodies, immunochemically characterized as anti-glycoprotein (GP)IIb and/or GPIIIa, have been detected in HIV-infected patients with ITP, indicating a mechanism similar to that described in “de novo” disease.211 However, cross-reactive antibody between HIV GP160/120 and platelet GPIIb/IIIa has also been demonstrated.212 Thus, Bettaieb and colleagues found that serum antibodies against HIV GP160/120 could be eluted from platelets of patients with HIV-related ITP and that these HIV-specific antibodies shared a common epitope with antibodies against platelet GPIIb/IIIa on the platelet surface. It is thus apparent that molecular mimicry between HIV GP160/120 and platelet GPIIb/IIIa may be operative in the immune destruction of platelets in some cases of HIV-related ITP. A further mechanism of antibody-induced destruction of platelets arises from the absorption of immune complexes against HIV onto the platelet Fc receptor, thus providing a “free” Fc portion for subsequent macrophage binding and phagocytosis.211
Decreased Platelet Production Kinetic studies of platelet production and destruction have been performed in patients with HIV-related ITP, with results compared to a group of normal control subjects and to a group of patients with “de novo” ITP.210 Mean platelet survival was found to be significantly decreased in patients with HIV ITP, occurring to the same extent in patients receiving zidovudine and in those who were untreated. It is interesting to note that the mean platelet survival was also significantly decreased in HIV-infected patients with normal platelet counts. In addition to this increased destruction of platelets, mean platelet production was found to be significantly decreased in patients with untreated HIV ITP, although those patients receiving zidovudine demonstrated a subsequent increase in platelet production, occurring even in zidovudine-treated HIV-infected individuals without thrombocytopenia. Thus, it is apparent that patients with HIV ITP, while experiencing a moderate increase in platelet destruction, are also faced with significant decreases in platelet production, which occur even in those individuals with normal platelet counts.210
Infection of the Megakaryocyte by HIV The cause for the reduced production of platelets in the setting of HIV infection may be direct infection of the megakaryocyte by HIV. Thus, Kouri and colleagues first demonstrated that human megakaryocytes bear a CD4+ receptor capable of binding HIV-1,213 while Zucker-Franklin et al. showed that HIV-1 could be internalized by human megakaryocytes.214 Wang and colleagues demonstrated the presence of the HIV-1 coreceptor, CXCR4, on megakaryocytic progenitors, megakaryocytes, and platelets.215 Further, employing in situ hybridization techniques and a 35S HIV riboprobe (antisense to an HIV ENV sequence), HIV transcripts have been detected in megakaryocytes of 5 of 10 patients with HIV ITP, indicating that the megakaryocyte had been infected by HIV in these cases.216 Expression of viral RNA was also detected in all 10 patients, using in situ hybridization techniques. Specific ultrastructural damage in the HIV-infected megakaryocytes has also been noted, consisting of blebbing and vacuolization of the surface membrane.217 The documentation of significant increases in platelet production after receipt of zidovudine218 would be consistent with the hypothesis that a major mechanism of this disorder is the direct infection of the megakaryocyte by HIV.
Recently, Harker and colleagues described three chimpanzees infected with HIV-1 who developed ITP associated with elevated levels of antibody against platelet GPIIIa. Use of recombinant pegylated human megakaryocyte growth and development factor was associated with a decline in antiplatelet antibodies in serum as well as an increase in peripheral blood platelet counts and an increase in the number of megakaryocytes and megakaryocyte progenitors in the marrow.219 These changes would imply that the mechanism of ITP in HIV-infected chimps includes insufficient compensatory increases in platelet production.
THERAPY FOR HIV-RELATED ITP
Zidovudine The Swiss Group for HIV Studies was the first to demonstrate the efficacy of zidovudine therapy in patients with HIV ITP.218 Ten seropositive patients, with platelet counts ranging from 20,000 to 100,000/µl, received zidovudine at a dose of 2 g/day for 2 weeks, followed by 1 g/day for 6 weeks. This was followed by 8 weeks of placebo. All 10 patients experienced an increase in platelet counts while on zidovudine, with a mean increase of 54,600/µl range (53,200–107,800/µl). In contrast, no patient experienced an increase in platelet count while on placebo. The time to onset of response was approximately 8 days, with full response achieved by day 30. These results were subsequently confirmed by others.220,221
The appropriate dose of zidovudine in HIV ITP was studied by Landonio et al., who compared a dose of 500 mg/day in 35 patients with 1000 mg/day in another group of 36 patients.222 The majority of patients in both groups were injection drug users, with similar mean platelet counts (»23,000/µl) and mean CD4+ counts (»400 cells/µl). A response rate of 57 percent was achieved in the low-dose group, with 11 percent experiencing complete response. In contrast, a response rate of 72 percent was achieved in those receiving 1000 mg zidovudine per day, with complete response in 39 percent. At month 6, a significant difference remained between the groups, with a mean platelet count of 56,000/µl in the low-dose group versus 98,200/µl in those receiving high-dose zidovudine. It is apparent from this study that high-dose zidovudine is advantageous in patients with HIV ITP.222
Other Antiretroviral Agents At the present time, very little is known about the efficacy of other reverse transcriptase inhibitors or protease inhibitors in the treatment of HIV ITP. Several case reports would suggest the efficacy of didanosine in both adults and children with HIV ITP, even in one patient who had been refractory to prior zidovudine. However, two additional patients who had been successfully treated with zidovudine subsequently developed relapse of ITP when didanosine was substituted for zidovudine.223 Recently, increases in platelet counts have been described in 22 patients with advanced HIV disease treated with the protease inhibitor indinavir.224 It would thus seem appropriate to consider use of other antiretroviral agents in patients with HIV ITP, although full information is still unavailable.224
Interferon-a A prospective, randomized, double-blind, placebo-controlled trial of IFN-a at a dose of 3 million units thrice weekly, given subcutaneously, was conducted in 15 patients with HIV-related ITP.225 A platelet response was documented in 66 percent, with a mean increase of 60,000/µl. The average time to response was 3 weeks. When interferon therapy was discontinued, platelet counts returned to baseline values within 3 months, indicating the necessity to maintain IFN-a therapy over time. In an attempt to ascertain the mechanisms by which IFN-a exerts its effects, Vianelli et al. demonstrated a prolongation in platelet survival, while no significant increase in platelet production was noted.226
High-Dose Intravenous Gamma Globulin Intravenous gamma globulin (IVIG), at a dose of 1000 to 2000 mg/kg, has been used effectively in pediatric and adult patients with “de novo” ITP, resulting in a significant rise in platelet counts within 24 to 72 h in the majority of individuals.227 Bussel and Haimi treated 22 patients with HIV-related ITP employing 1 to 2 g/kg during a 2- to 5-day period, depending upon the platelet response.228 The average platelet count prior to therapy was 22,000/µl, rising to a mean of 182,000/µl (range 10,000–404,000/µl) within 2 to 5 days. Only two patients did not respond, while 77 percent experienced an increase to over100,000/µl, and 86 percent had an increase to over 50,000/µl. However, when IVIG was discontinued, only 25 percent of patients maintained the increased platelet count, while the remainder required repeat infusions approximately every 21 days. The major problem with IVIG appears to be cost, which is quite significant. For this reason, IVIG is often reserved for use in patients who are acutely bleeding or require an immediate increase in platelet count, for example, prior to an invasive procedure.
Anti-Rh Immunoglobulin The use of anti-Rh IG in nonsplenectomized Rh-positive patients with HIV-related ITP represents another potential mode of therapy.229 Requirements for effective therapy with anti-Rh (D) include a baseline hemoglobin level adequate to permit a 1- to 2-g decrease, presence of Rh positivity in the patient, and presence of a spleen, the site at which red cells would be preferentially phagocytized. Oksenhendler et al. treated 14 patients with HIV ITP employing 25 mg/kg IV over 30 min on 2 consecutive days.230 Nine of 11 (83%) Rh-positive patients responded with a platelet count above 50,000/µl, with response first noted at a median of 4 days (range 3–12 days), and median response duration of 13 days (range 0–37 days). Maintenance therapy was administered at a dose of 13 to 25 mg/kg IV every 2 to 4 weeks, resulting in a long-term response (>6 months) in 70 percent of patients. Subclinical hemolysis occurred in all, with a drop of hemoglobin of 0.4 to 2.2 g. Gringeri et al. subsequently confirmed these results and also studied the use of intramuscular (IM) anti-D IG for maintenance treatment after successful induction therapy by the IV route.229 Patients self-administered the IM anti-Rh at a dose of 6 to 13 mg/kg/week. After induction, 83 percent of patients had achieved a platelet count above 50,000/µl, a response that was maintained in 85 percent over time. It is thus apparent that anti-Rh IG may be used safely and effectively in patients with HIV-related ITP, providing an alternative that in some institutions may be as little as one-tenth the cost of high-dose IVIG.229,230
Splenectomy Splenectomy has been used effectively in patients with “de novo” ITP who are refractory to corticosteroids. At the onset of the AIDS epidemic, several anecdotal case reports described a rapid progression to AIDS postsplenectomy, and the procedure was largely abandoned. More recently, Oksenhendler et al. reported long-term experience with splenectomy in a cohort of 185 patients with HIV ITP.231 Splenectomy was eventually performed in 68 such patients, at an average of 13 months from initial diagnosis of HIV ITP. The mean platelet count presplenectomy was 18,000/ml, rising to 223,000/ml postoperatively. A response was seen in 92 percent of patients, with complete response (platelet count >100,000/µl) in 85 percent. Maintenance of the elevated platelet count for longer than 6 months was documented in 82 percent. In comparing the survival or rate of progression to AIDS in the 68 splenectomized patients versus the 117 who did not undergo the procedure, no difference was found, indicating that splenectomy was not associated with more rapid progression of HIV disease. Similar conclusions were made by Kemeny et al.232 It is important to note, however, that 5.8 percent of patients undergoing splenectomy in Oksenhendler’s series did experience fulminant infection, consisting of Streptococcus pneumoniae meningitis in two and Haemophilus influenzae sepsis in one. It is thus apparent that patients must undergo prophylactic vaccination prior to splenectomy and that such surgery may ultimately be safer in those HIV-infected patients who can still achieve an appropriate antibody response to vaccination against S. pneumoniae or H. influenzae.
Corticosteroids Corticosteroids remain the initial therapy of choice in patients with “de novo” ITP and at a dose of 1 mg/kg/day are associated with an 80 to 90 percent response rate. Similar results have been documented in patients with HIV-related disease. However, the immunosuppressive effects of high-dose corticosteroids have made such therapy far from optimal in HIV-infected patients. Further, the potential development of fulminant Kaposi sarcoma (KS) in HIV-infected homosexual and bisexual men after use of corticosteroids has further dampened enthusiasm for this therapeutic modality.
SYSTEMIC ORGAN ABNORMALITIES
HIV infection can result in severe organ system dysfunction, involving the brain, peripheral nervous system, heart, lungs, kidneys, and other organs. These disease-related complications can result in significant morbidity and shortened survival but are not within the scope of this chapter.
Over 40 percent of all HIV-infected patients are eventually diagnosed with cancer.233 Furthermore, the spectrum of neoplastic disease appears to be wider than initially seen.233,234 and 235 Three cancers are currently considered AIDS-defining in HIV-infected persons: KS, associated with the epidemic from the onset in 1981; intermediate- or high-grade B-cell lymphoma, added to the case definition for AIDS in 1985; and cervical carcinoma, which became an AIDS-defining condition on January 1, 1993. Only AIDS-associated lymphoma and KS are discussed here.
Patients with AIDS have a risk of developing lymphoma that is nearly 100 times greater than that of the general population.235,236 and 237 The incidence of lymphoma increases with survival and may approach 20 percent for patients with prolonged, far-advanced immunodeficiency.238,239 The use of HAART has been associated with a significant decrease in the incidence of KS240 and opportunistic infections129 in HIV-infected patients. It remains unclear whether the use of HAART will lead to a decreased incidence of AIDS-related lymphoma, although early data have not shown a decreased incidence.240,241 In the large Swiss HIV Cohort Study, the incidence of new AIDS conditions fell from 157 events per 1000 person years in 1992–1994 to 35 events in 1997–1998, after widespread use of HAART. However, no decrease in the incidence of lymphoma was seen.242 Lymphoma occurs among all population groups infected with HIV, in all age groups, and in patients from diverse geographic regions.238,243 The clinical and pathologic characteristics of lymphoma appear similar among all groups.237,244,246
FIGURE 89-5 Schematic representation of the possible sequence of events resulting in the development of lymphoma in HIV disease. (Modified from Martin, et al.342)
ETIOLOGY AND PATHOGENESIS
The mechanism or mechanisms underlying the development of lymphoma in the setting of HIV are not fully understood. One factor may be immune suppression itself, which is associated with an increased incidence of lymphoma in certain congenital immunodeficiency diseases,247 autoimmune disorders,248 or chronic use of immunosuppressive drugs, as in the setting of organ transplantation.249,250 The lymphomas that develop in these settings are similar to the AIDS lymphomas in terms of the pathologic type, the high frequency of extranodal disease at presentation, and the relatively poor prognosis.
Infection by HIV is associated with myriad immunologic aberrations. These include functional and quantitative defects of CD4+ T cells125,132,251 and chronic antigenic stimulation of B lymphocytes by antigens, mitogens, or viruses, including Epstein-Barr virus (EBV)252 and HIV itself.134,253 Ongoing B-cell expansion and activation result in the development of reactive B-cell hyperplasia in lymphoid tissues, known as PGL,132,144,147,251 and in polyclonal hypergammaglobulinemia in the serum.133 Lymphomas may develop after acquisition of genetic errors occurring in the course of polyclonal B-cell proliferation in the setting of underlying immunodeficiency. This has been noted in a primate model, in which high-grade B-cell lymphoma develops between 5 and 15 months after infection with the SIV, coincident with development of severe immunodeficiency.254
Cytokine Networks Dysregulated expression of cytokines may contribute to the chronic B-cell proliferation that characterizes HIV disease. B-cell proliferation and maturation may be induced by several cytokines, including IL-4, IL-6, IL-10, tumor necrosis factor a (TNF-a), and others.255 B cells from HIV-infected patients with hypergammaglobulinemia constitutively express TNF-a and IL-6.256 High levels of IL-6 gene expression have been noted in multiple myeloma, chronic lymphocytic leukemia, and both HIV-positive and HIV-negative cases of immunoblastic and large-cell lymphoma, independent of EBV status.257,258 and 259 While not unique to AIDS lymphoma, then, IL-6 may play a role in the pathogenesis of diverse types of B-cell neoplasia. Moreover, elevated serum levels of IL-6 can be detected in sera of patients with symptomatic HIV infection who later develop large-cell lymphoma.239
In addition, IL-10 may play a role in the development of AIDS-related lymphoma. Constitutive expression of IL-10 has been shown in EBV-positive B-cell lines derived from patients with AIDS-related Burkitt lymphoma,260 and IL-10 has been shown to function as an autocrine growth factor in B-cell lines.261 HIV may induce aberrant expression of these cytokines,262 thus stimulating pathologic B-cell proliferation and differentiation, and allowing for the possibility of neoplastic transformation.
Epstein-Barr Virus EBV is implicated in the pathogenesis of at least a subset of AIDS lymphoma, perhaps related to the impaired immunosurveillance against EBV-infected cells.252 EBV DNA has been found in the affected lymph nodes of 35 percent of HIV-infected patients with reactive lymphadenopathy;263 these individuals were shown to have an increased incidence of lymphoma over time.263
Patients with large-cell or immunoblastic lymphoma primary to the brain uniformly have latent EBV infections.264 Epstein-Barr early region (EBER) protein can be detected in essentially all such patients and the latent membrane protein in 45 percent.264 Latent membrane protein has transforming and oncogenic properties.265
Approximately 40 to 60 percent of systemic AIDS lymphoma cases have detectable EBV DNA within tumor nuclei.266,267 Large-cell and immunoblastic lymphomas are most commonly EBV positive.268 Evidence for clonal EBV infection has been demonstrated in all cases examined, indicating that EBV integration occurred before clonal B-cell expansion.269 This indicates that EBV may play a role in the etiopathogenesis of these lymphomas.
Abnormal DNA Rearrangements During AIDS-related B-cell stimulation induced by HIV, EBV, and/or cytokines, genetic “errors” in Ig gene rearrangement and/or expression may occur, leading to chromosomal translocations involving the Ig heavy- or light-chain genes. There are specific chromosomal translocations that have been described in AIDS-related lymphoma, including t(8;14); t(8;22); or t(8;2).270,271 and 272
C-MYC Dysregulation Translocations involving chromosome 8 can result in dysregulation of the c-MYC oncogene. Dependent upon the specific breakpoint position on chromosome 8 and the antigen receptor locus on chromosome 14, 2, or 22, different mechanisms for c-MYC dysregulation might apply, as described in the distinct forms of Burkitt lymphoma and in distinct geographic regions of the world.273,274 However, c-MYC dysregulation is not seen in all cases of AIDS lymphoma. While activation of c-MYC was detected in 100 percent of small, noncleaved lymphomas in one series,269 such activation was found in only a minority of large-cell or immunoblastic lymphomas.275 Moreover, the specific mechanisms leading to c-MYC dysregulation appear diverse.269,276,277 Thus, HIV-1 infection of immortalized B-cell lines in itself can result in upregulation of c-MYC transcripts,278 while HIV also may affect cellular c-MYC gene expression directly.277 Whatever the mechanism, dysregulation of c-MYC may contribute to transformation of human B cells in vitro and may cause B-cell lymphoma in transgenic animals carrying Ig-MYC chimeric constructs.279,280
BCL-6 Dysregulation and Other Genetic Abnormalities In AIDS-related diffuse large-cell lymphoma, the primary molecular alteration involves mutations of BCL-6.281,282 While gross rearrangements of BCL-6 are usually absent, small mutations in the 5′ regions of the gene are detectable in as many as 60 percent of cases.281,282 and 283 While the function of these mutations is still unclear, BCL-6 mutations are markers of germinal center derivaton of B cells, indicating that diffuse large-cell lymphomas in AIDS are related to germinal center B cells.284
Aside from these genetic abnormalities, other molecular aberrations have been noted, including p53 mutations or deletions in as many as 60 percent of AIDS-related small, noncleaved lymphomas.275,285 In addition, mutations of RAS have been described in some cases of AIDS-related Burkitt lymphoma.275
It is clear that multiple diverse molecular mechanisms are responsible for the various types of AIDS-related lymphomas.284 Small, noncleaved lymphomas are most often associated with c-MYC aberrations, as well as mutations in p53 and occasionally RAS. Diffuse large-cell lymphomas are associated with mutations in the BCL-6 gene, while immunoblastic and large-cell lymphomas appear to be driven primarily by EBV.
B symptoms, such as fever, night sweats, or weight loss are present at diagnosis in 80 to 90 percent of patients with AIDS lymphoma,286,287 and 61 to 90 percent have far-advanced disease presenting in extranodal sites.286,288,289,290,291,292 and 293 This is in contrast to non–AIDS-related lymphoma, in which approximately 40 percent of individuals present with extranodal lymphomatous disease.294
Virtually any anatomic site may be involved.286 The more common sites of initial extranodal disease include the central nervous system (CNS; 17–42%), GI tract (4–28%), marrow (21–33%), and liver (9–26%).286,288,289,290,291,292 and 293
Staging evaluation should include computed tomographic scanning of the chest, abdomen, and pelvis; a gallium-67 scan295; marrow aspirate and biopsy; and other studies as clinically indicated. Lumbar puncture should routinely be performed, since approximately 20 percent of patients have leptomeningeal lymphoma, even in the absence of specific symptoms or signs.296 Intrathecal methotrexate or cytosine arabinoside is often given to prevent isolated CNS relapse.296
Primary Central Nervous System Lymphoma Approximately 75 percent of patients with primary CNS lymphoma have far-advanced HIV disease, with median CD4 cell counts less than 50/µl, and a prior history of AIDS.234,287,297,298 and 299 Initial symptoms and signs may be quite variable, with seizures, headache, and/or focal neurologic dysfunction noted in most. However, very subtle changes in behavior may be the only presenting complaint.297
Radiographic scanning reveals relatively large mass lesions (2–4 cm), which tend to be few in number (one to three lesions). Ring enhancement may be seen.300,301 There is no specific radiographic picture. Positron-emission tomography scanning may be useful in differentiating cerebral lymphoma from toxoplasmosis.302 In addition, thallium-201 single-photon emission computerized tomography scanning may be useful, with median T1 uptake index of greater than 1.5 and a lesion size of greater than 2.5 cm serving as independent predictors of primary CNS lymphoma.303
Pathologically, almost all such lymphomas are of diffuse large-cell or immunoblastic subtypes and are uniformly associated with EBV infection within malignant cells.304 Thus, presence of EBV DNA within spinal fluid may be used as a diagnostic criterion for primary CNS lymphoma.305
Optimal therapy for primary CNS lymphoma remains to be defined. Use of cranial radiation is associated with a complete remission rate of only 50 percent and median survival of only 2 or 3 months. While median survival times have not been prolonged with radiation, approximately 75 percent of patients experience an improvement in quality of life.306 No specific regimen of chemotherapy has yet proven efficacious, perhaps due to the serious level of immunocompromise in affected patients.
Primary Effusion Lymphoma Primary effusion lymphoma (PEL) is uncommon, representing only a small fraction of all AIDS lymphomas. PEL is associated with the newly discovered human herpesvirus, termed KS-associated herpesvirus or human herpesvirus type 8 (HHV-8).307,308 and 309 The disease has been reported in both HIV-positive and HIV-negative patients, although it appears more common in the former. It is interesting to note that PEL has also been diagnosed in a cardiac transplant recipient, whose explanted heart was found, retrospectively, to be infected by HHV-8.310 Morphologically, the malignant cell is large and appears anaplastic with immunoblastic features. The malignant cell usually lacks B-cell markers but is B lymphoid in origin, based upon presence of Ig gene rearrangement. HHV-8 is present within tumor cells, which often harbor EBV as well. Clinically, patients present with effusions in the pleura, pericardium, or peritoneal cavity. Most patients do not have mass lesions, although such masses have been reported. Despite therapeutic intervention, survival is extremely short, in the range of approximately 2 months.311
Eighty to 90 percent of lymphomas associated with AIDS are intermediate- or high-grade B-cell tumors,312 including immunoblastic or large-cell types, and small noncleaved lymphoma, which may be subclassified as either Burkitt or Burkitt-like. Approximately 80 to 90 percent of patients are diagnosed with one of these pathologic types,289,290,291,292 and 293 in sharp contrast to non–HIV-infected patients, in whom high-grade lymphomas are expected in only 10 to 15 percent.313
Occasionally, HIV-infected patients with low-grade B-cell lymphomas have been reported,288,289,293,314 as have relatively young individuals with multiple myeloma or solitary plasmacytoma.315 The natural history of low-grade lymphoma appears similar in the presence or absence of underlying HIV infection.314,316 These cases are not considered AIDS defining.
T-cell lymphomas also have been described in HIV-infected individuals.286 Once again, these cases are not considered AIDS-defining, and their incidence has not increased.
PROGNOSIS AND THERAPY
Prognostic Factors Poor prognostic indicators for survival include a Karnofsky performance status of less then 70 percent, history of AIDS prior to lymphoma, less than 100 CD4 cells/ml,287,317 stage III or IV disease, elevated lactate dehydrogenase, history of injection drug use, and age over 35 years.317
Patients with primary CNS lymphoma have shorter survival than those with systemic disease.287 However, in patients with systemic lymphoma who also have leptomeningeal involvement, prognosis is not affected, provided that appropriate therapy to the CNS is given.287
Treatment At the outset of the AIDS epidemic, very dose-intensive regimens were employed. Unfortunately, low complete remission rates (20–33%) were achieved, and there were high rates of complicating opportunistic infections, leading to death in 28 to 78 percent of cases.298,299,318,319 and 320 While occasionally reports noted the efficacy of dose-intensive regimens, these were characterized by the chance inclusion of patients who had presented with good prognostic features.321
These observations led to the design and implementation of a low-dose modification of the methotrexate, bleomycin, cyclophosphamide, and etoposide combination chemotherapy (m-BACOD) regimen.296 A complete response was achieved in 46 percent of patients, with long-term, lymphoma-free survival in 75 percent. The median survival of complete responders was 15 months, while that of all evaluable patients was 6.5 months.296
In an attempt to clarify the value of low-dose therapy, the AIDS Clinical Trials Group embarked on a prospective, multicenter trial.322 Patients were stratified by baseline prognostic indicators and randomized to receive either the low-dose m-BACOD regimen discussed above or standard-dose m-BACOD with hematopoietic growth factor support (GM-CSF). With 192 patients evaluable for response, no statistically significant difference was observed in response rates. While patients with CD4 cell counts below 100/ml did not respond as well as those with higher CD4 cells, the low-dose regimen appeared equivalent to standard-dose m-BACOD in patients with either good risk or poor risk prognostic features. Toxicity was significantly higher in those patients assigned to standard-dose therapy, with grade 3 or 4 toxicity in 70 percent of those assigned to standard dose and 51 percent of those who received low-dose therapy (p < .008). This trial indicates that low-dose m-BACOD is preferable to standard-dose therapy in patients with AIDS lymphoma.322
A regimen of continuous infusion chemotherapy, termed CDE, was piloted by Sparano and colleagues.323 This regimen consists of a 96-h continuous infusion of cyclophosphamide, doxorubicin, and etoposide, which is repeated every 28 days times six. Initial results were excellent, with a complete remission rate of 58 percent and a median overall survival of 18.4 months.323 When this experience was recently expanded in a multi-institutional trial through the Eastern Cooperative Oncology Group, a complete remission rate of 46 percent was achieved, with median survival of 8.2 months.324
Investigators at the National Cancer Institute have recently reported on the EPOCH regimen, employed in 24 patients with newly diagnosed AIDS-lymphoma.325,326 A 96-h continuous infusion of etoposide, oncovin, and adriamycin was administered, along with a bolus of cyclophosphamide, which was dose adjusted based on patients’ CD4 cell count and nadir neutrophil counts. Oral prednisone was also given. A complete remission rate of 79 percent was achieved, and no responding patient has experienced relapse, with a median follow-up of approximately 2 years.
When multiagent chemotherapy is administered together with HAART, pharmacokinetic profiles appear similar to those described in the absence of HAART for adriamycin and indinavir, while the clearance rate for cyclophosphamide appears moderately prolonged. Nonetheless, no increase in clinical or laboratory toxicity was reported. However, the concomitant use of zidovudine with chemotherapy has been associated with significant myelosuppression.
ETIOLOGY AND PATHOGENESIS
The etiology and pathogenesis of KS is complex, only recently elucidated, and still not fully understood. Underlying immunosuppression clearly increases the risk of KS. Thus, the incidence of KS in organ transplant recipients receiving immunosuppressive therapy is 400- to 500-fold higher than that seen in the general population.327 Genetic factors may also play a role.328,329
In addition to these factors, the epidemiology of AIDS-related KS has always suggested the possibility that another sexually transmitted organism might be involved in the pathogenesis of disease, since the disorder is statistically more likely to occur in homosexual and bisexual men than in other population groups infected by HIV.330,331 and 332 The concept of KS as a sexually transmitted disease independent of HIV infection is also derived from studies of KS in young, sexually active, HIV-negative homosexual men in the United States.333,334 and 335
The identification of a newly described human herpesvirus, termed KS-associated herpesvirus or HHV-8,336 provided the anticipated link between KS and a previously unknown sexually transmitted virus. Genomic material from HHV-8 was subsequently found within essentially all KS tissue from virtually all types of KS, including that associated with AIDS, classic Mediterranean KS, endemic KS from Africa, and transplantation-associated KS.337,338,339 and 340
Subsequent work confirmed that seroconversion to HHV-8 occurred prior to the development of clinical KS341 and that seropositivity to the virus increased with increasing numbers of sexual contacts.342 However, the actual means by which HHV-8 is transmitted and the clinical illness associated with initial HHV-8 infection remain speculative at this time.343
HHV-8 is a B-lymphotropic g-DNA herpesvirus with tropism for endothelial cells and keratinocytes.344 Multiple genes have recently been identified that encode various latent or lytic gene products. Two of these genes, ORF K3 and K5, may decrease major histocompatibility complex expression on the surface of infected cells, thereby enabling escape from immune control.345 Expression of a viral IL6 homolog (vIL6) has been shown to correlate with development of KS.346 vIL6 has been shown to induce proliferation of B cells and HIV replication in HIV-infected U1 monocyte cell lines.347 It is important to note that the lytic gene product, HHV-8 G protein–coupled receptor, which is expressed in the lytic phase of HHV-8, has been shown to transform cells through inflammatory cytokine signaling pathways while also serving as a chemokine homolog and serving to trigger other factors involved in angiogenesis.
In the setting of AIDS-related KS, HHV-8 has been shown to infect endothelial cells, inducing a change in the spindle cell morphology that is characteristic of the disease. These spindle cells then produce numerous autocrine and paracrine growth factors that stimulate both KS and blood vessel proliferation, including basic fibroblast growth factor (bFGF), vascular endothelial growth factor, platelet-derived growth factor, TGF-b, IL-6, IL-8, GM-CSF, and others.348,349,350,351 and 352
HHV-8–encoded gene products thus have the capability of inducing the multiple aberrations that are found within KS tissues. Nonetheless, while the virus appears necessary for development of KS, it is not sufficient in itself. The further addition of immunosuppression and an environment conducive to inflammatory and angiogenic signals is apparently also required.
Aside from inducing the necessary immunosuppression required for development of clinical KS, the HIV TAT gene product is also operative in the pathogenesis of disease. Thus, the Tat protein has been shown to increase the proliferation of KS derived spindle cells.353,354 Tat also activates the expression of tumor necrosis factor a (TNF-a), IL-6, and various adhesion molecules, such as E-selectin, ICAM-1, and VCAM-1. Tat synergizes with other inflammatory cytokines to stimulate endothelial cells and the invasion of KS spindle cells.
By inducing a mileau of inflammatory cytokines, such as IL-1, TNF-a, IL-6, and others, HIV further indirectly increases the proliferation of the KS lesion, while these inflammatory cytokines also serve to increase the production of various angiogenic factors, such as bFGF.355,356 and 357
The full pathogenesis of AIDS KS is thus complex, and the very designation of the tumor as a true malignancy is under question. Nonetheless, it is apparent that the full expression of disease requires several components. These include HIV-1 itself, which induces the requisite immunosuppression, as well as the TAT gene product, and a mileau of inflammatory cytokines and angiogenic factors. HHV-8 may induce the initial transforming event as well as myriad gene products that contribute to the cascade of angiogenic and inflammatory cytokines, which induce further growth of the lesion. Conceptually, then, the KS lesion is driven by factors that induce the three components that are integral to the disease: cell proliferation, inflammation, and angiogenesis. These newly recognized concepts will be critical to the development of new methods of treating patients with AIDS KS.
Changing Epidemiology of Kaposi Sarcome in the Era of Highly Active Antiretroviral Therapy The use of HAART has been associated with a significant decrease in the incidence of KS240 and opportunistic infections129 in HIV-infected patients. In the Multicenter AIDS Cohort Study, rates of KS fell by 66 percent between 1989–1994 and 1996–1997,240 coincident with the widespread use of HAART in the United States.
KS lesions appear as discrete, irregular reddish to violaceous or brown nodules, macules, or plaques and may be symmetrically arranged. They may be several centimeters in circumference or quite small and easy to overlook. Suspicious lesions should undergo biopsy, since many other conditions, such as bacillary angiomatosis, may be confused with KS, even by the experienced observer.
The lesions of KS may occur in any site,358 although CNS involvement is quite rare. Involvement of the mucous membranes of the mouth is quite common, and, approximately 50 percent of the time, oral KS is associated with KS elsewhere in the GI tract. KS may involve any area of the GI tract. Although usually asymptomatic, GI KS may produce symptoms of retrosternal, epigastric, or rectal pain; blood loss; diarrhea; abdominal cramps; and/or weight loss.359 Patients suspected of having KS in the GI tract should be evaluated by endoscopy,360 since barium studies often miss the flat lesions of KS.
Patients with pulmonary KS may have shortness of breath, fever, cough, hemoptysis, and/or chest pain. Occasionally, patients with pulmonary KS are asymptomatic.361 The radiographic appearance is varied and not specific. Survival in the setting of pulmonary KS is usually short, and systemic therapy is indicated.361,362
Patients with KS may present with lymphadenopathy alone, even in the absence of skin or mucous membrane involvement. The diagnosis requires lymph node biopsy.363 Patients also may present with lymphedema, even in the absence of overlying skin disease. The edema is presumably secondary to capillary leak in the local mileau of inflammatory cytokine and angiogenic factors.
THERAPY, COURSE, AND PROGNOSIS
Antiviral Therapy to Treat KS With the sharp decline in KS incidence coincident with the widespread use of HAART therapy, the efficacy of HAART as a specific treatment for KS has been discussed. At this time, no prospective trials addressing this issue have been completed. However, anecdoctal reports of KS regression while on HAART alone have been published.364
Of further interest is the possible use of antiviral agents directed against HHV-8 as a means of treating KS. Studies of in vitro drug sensitivity have shown that HHV-8 is very sensitive to cidofovir, moderately sensitive to ganciclovir and foscarnet, and weakly sensitive to acylovir.365 A recent prospective randomized trial aimed at determining optimal maintenance therapy for cytomegalovirus (CMV) retinitis in patients with AIDS has also provided information to suggest that treatment of HHV-8 may prevent development of KS.366 After initial systemic therapy of CMV disease, patients were randomized to receive either a ganciclovir retinal implant alone or the implant with systemic ganciclovir in addition. It is very interesting to note that patients randomized to receive systemic ganciclovir had a statistically decreased risk of progression to KS.366 The concept that one could treat lytic HHV-8 infection with ganciclovir and in so doing positively affect the development of a tumor is clearly intruiging, and a great deal of further work in this area is expected over the next several years.
Local Therapies KS is a multicentric disease at presentation and is inherently disseminated. Nevertheless, numerous local therapies have been used efficaciously, including surgical excision, liquid nitrogen cryotherapy, and argon laser therapy.367,368 and 369 Recently, the topical use of cisretinoic acid has proven efficacious in the local therapy of KS and has been licensed in the United States for this purpose.370,371 Injections of vinblastine, vincristine, or IFN-a directly into the lesion also have been effective.372,373 and 374 These injections may be associated with local pain as the lesion ulcerates and then resolves. Hypo- or hyperpigmented areas may remain. Local radiation therapy also may be effective. Depending upon the indication, complete remission may be achieved in 20 to 70 percent of cases, although postradiation hyperpigmentation has been reported in 20 percent or more, and local relapse may occur.375,376 Single doses of 800 cGy have been associated with good responses,377 albeit of short duration in some.378 Lesions in the oral cavity can be particularly troubling, producing pain or difficulty in eating. Although responses to radiation are expected in the majority, severe confluent mucositis, salivary gland dysfunction with dry mouth, and altered taste for food have been described in patients who were irradiated with as little as 1200 to 1800 cGy to the midline of the oral cavity.375
Biologic Response Modifiers Patients with more extensive disease may benefit from therapy with IFN-a, which has been shown to have antiretroviral effects in vitro379 that correlate with its antitumor efficacy.380 It is interesting to note that INF-a inhibits angiogenesis, which may be its primary mechanism of activity in KS. Although high doses of IFN-a were initially used to treat AIDS KS, recent studies have confirmed the efficacy of lower doses, from 1 to 10 million units/day, when combined with antiviral therapy.381,382 and 383 Response rates of approximately 40 percent have been reported,381,382 and 383 and maximal response may take up to 3 months.381,382 Response to IFN-a is associated with enhanced survival.384
Systemic Chemotherapy Systemic chemotherapy may be required for patients with rapidly progressive disease, symptomatic visceral disease, pulmonary KS, and/or lymphedema. Multiple single agents have activity in KS, including doxorubicin, vinblastine, vincristine, bleomycin, and etoposide.385,386,387 and 388 Single-agent use of liposomal daunomycin (DaunoXome) or doxorubicin (Doxil) has been associated with response rates of 40 to 50 percent with acceptable toxicity.389,390 Taxol, given every 2 or 3 weeks at a dose of 100 to 135 mg/m2, has also been associated with major response in 55 percent of relapsed or refractory patients.391
Combination chemotherapy regimens, such as ABV, consisting of doxorubicin (20 mg/m2), bleomycin (10 mg/m2), and vincristine (2 mg),388 or vincristine and bleomycin (VB) may also be useful.392 However, discontinuation of chemotherapy eventually results in relapse.
Antiangiogenesis Compounds and Drugs to Decrease the Cascade of Inflammatory Cytokines for Treatment of AIDS KS With the evolving understanding that the KS lesion requires a mileau rich in inflammatory cytokines and angiogenic factors, the possible blockade of these factors has been discussed as a means to treat the disease. In this regard, INF-a has known activity and serves as a potent inhibitor of angiogenic factors.382,383 A sulfated polysaccharide peptidoglycan (SP-PG) has been shown to inhibit angiogenesis associated with induction of KS-like lesions in vitro.393 A fumagillin analog with potent antiangiogenesis activity has shown evidence of clinical efficacy in patients with AIDS KS.394 Multiple additional angiogenesis inhibitors are currently in phase II trial, including IL-12, thalidomide, IM-862, and others. Retinoids have been shown to down-regulate IL-6 and other cytokines that are involved in the pathogenesis of KS, and recent trials have proven some efficacy with the use of oral 9-cis retinoic acid.395 Future directions in the therapy of AIDS KS will clearly involve testing and use of compounds that decrease the cascade of inflammatory cytokines and angiogenic factors that contribute to the pathogenesis of the disease.
Antiretroviral therapy has undergone significant and rapid change over the last several years. In addition to the emergence of an increasing number of effective antiretroviral agents, the development of sensitive assays for the quantitative determination of viral replication and the characterization of mechanisms of viral drug resistance has resulted in more logical and clinically effective therapeutic strategies. However, the rapidity with which HIV therapy has developed and the intensive investigative efforts currently being undertaken suggest that any recommendations made in the context of this chapter will be subject to significant modification, and clinicians should therefore avail themselves of the most current literature regarding HIV antiretroviral therapy.
While controversies exist regarding the optimal time to initiate antiretroviral therapy, current recommendations include treatment of all patients with symptomatic HIV disease or asymptomatic HIV-infected people with CD4 counts lower than 500/µl or plasma HIV RNA greater than 10,000 copies per milliliter by the branched-chain bDNA assay or more than 20,000 copies per milliliter by RT-PCR.396,397 and 398 There are both advantages and disadvantages to initiating early therapy in asymptomatic patients. Early intervention usually results in more effective control of viral replication, with rapid reduction of viral burden and maintenance of near normal immunologic function.399 An important benefit of rapid and maximal suppression of viral replication is the reduction of viral genomic mutations, which can result in the development of viral drug resistance and the emergence of more aggressive cytopathic viral strains.400,401 and 402 An additional, although theoretical, advantage is that reduced concentrations of virus in body fluids may decrease the risk of viral transmission.
The potential risks of early intervention include reduction in quality of life from drug toxicities, unexpected drug interactions, and an excessive pill burden. In addition, there is growing evidence that some antiretroviral drugs or combinations may have unexpected long-term toxicities, including diabetes, accelerated atherosclerosis, and persistent peripheral neuropathies. Early exposure to antiretroviral medications, especially if associated with poor patient compliance, may lead to early viral drug resistance and a subsequent reduction in therapeutic options due to viral cross-resistance to closely related drugs.403,404,405,406,407,408 and 409
The emergence of drug-resistant viral strains has complicated HIV therapy. Well-characterized genomic mutations have been reported in association with viral resistance to certain medications. In addition, some mutations may result in cross-resistance with other antiretroviral agents.404,405 and 406 Transmission of these drug-resistant viral strains has now been reported and therefore may complicate therapy for patients who are apparently therapy naive.410 Both phenotypic and genotypic assays of drug resistance have been developed.406,411,412 However, at present these assays are not routinely available.
Viral load should fall at least 1 log in the first 4 weeks after initiation of antiretroviral therapy and should be undetectable by 3 to 6 months.396,397 and 398 Current assays can detect viral RNA to a level of less than 50 copies per milliliter. Data suggest that lowering the viral load to less than 50 copies per milliliter is associated with more complete and durable viral suppression than are levels of 50 to 500 copies per milliliter.402 Viral load testing should be used to assess the efficacy of treatment and to assist in determining the need modify antiretroviral therapy.
NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS
Nucleoside reverse transcriptase inhibitors (NRTIs) continue to serve as the foundation for most multidrug antiviral regimens. After cellular uptake, NRTIs are converted by cellular kinases to their triphosphate form. The triphosphate form then competes with the natural substrate of HIV reverse transcriptase, which is not present in uninfected human cells. The phosphorylated NRTIs are incorporated into the DNA strand, causing premature termination of the HIV intermediate.413
In addition to convenience, the choice of which NRTI combination to use should also be based on efficacy, ability to penetrate the CNS, and effects that one NRTI may have on another. Several studies have found no significant differences among combinations of NRTIs.414
Among currently available NRTIs, AZT appears to be the most successful at crossing the blood-brain barrier and has been shown to substantially reduce the risk of developing HIV brain disease.415,416 Abacavir also effectively crosses the blood-brain barrier and is currently being evaluated as a treatment option for HIV dementia.417 In the era of triple therapy combinations, including nonnucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs) that can suppress HIV in the CNS, the absolute need for AZT in an initial regimen may no longer be apparent.
Resistance to lamivudine (3TC) emerges rapidly, especially in patients in whom viral load remains detectable.417,418 Paradoxically, the mutation that confers 3TC resistance may reverse resistance to AZT by suppressing the effect of AZT mutations at codons 215 and 70.419 However, this benefit is likely to be transient with the emergence of other mutations that will confer AZT resistance.420 Response to stavudine (d4T) in people previously treated with AZT may be impaired, sinces chronic AZT therapy may render cells less efficient in phosphorylating other NRTIs.406
NONNUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS
NNRTIs bind directly and noncompetitively to reverse transcriptase downstream from the active catalytic site to inhibit production of viral DNA, acting at different sites than NRTIs. They do not require phosphorylation for activation.421 The primary advantages of their use are the ability to delay use of PIs and their relatively easier dosing schedules. NNRTs are not cross-resistant with the NRTIs.421 However, resistance to this class of drugs can easily develop from a single mutation.422 In vitro mutations common to all NNRTI-resistant reverse transcriptases include codons 103, 106, 108, 181, and 190.411,421 Codon 236 mutation appears unique to resistance to delavirdine.423
PIs represent the most potent antiviral agents available, with the ability to suppress viral replication by 2 logs or more.396,397 and 398,424 PIs prevent HIV from being successfully assembled and released from the infected CD4 cell by inhibiting the viral protease enzyme that cleaves the large viral polyproteins into small functional units.424 There is clear evidence of durable virologic and immunologic effects with associated improvements in clinical outcome for patients treated with PIs.424,425,426,427,428,429,430,431,432,433,434 and 435 The introduction of PIs into clinical practice in 1996 accounts for the significant improvement in outcome for patients with HIV disease. Despite the potent antiviral effect of PIs, problems with their use include bioavailability, drug interactions, significant toxicity, and the emergence of resistance.435,436,437,438,439,440,441,442,443 and 444 Because of concerns for cross-resistance between the drugs in this class, the choice of which drug to use first becomes important because of the potential effect on future treatment options.396,397 and 398,424 Whether these drugs should be used as first-line therapy or reserved for use in people with virologic failure on other regimens is currently under evaluation.
Adverse reactions to PIs have become more apparent with long-term use, and drug-drug interactions are numerous.398,424,435,436,437,438,439,440,441,442,443 and 444 One newly recognized toxicity of PIs is the “lipodystrophy syndrome,” which may occur in 30 to 70 percent of PI-treated patients.441,442 Clinical features of the lipodystrophy syndrome include increased abdominal girth; loss of subcutaneous fat in the trunk, with increased visceral fat; development of dorsocervical fat pads; and loss of subcutaneous fat pads in the face.441 Other components of the lipodystrophy syndrome include the development of pseudo-Cushingoid appearance, hyperglycemia due to development of insulin resistance, and hypercholesterolemia with premature coronary artery disease.435,436,437,438,439,440,441,442,443 and 444 These toxicities may result from a cross-reaction between the PIs and enzymes for lipid metabolism, including lipoprotein receptor-like protein and cis-retinoic binding protein type1,441 although the precise mechanism for this toxicity is not yet known.
At present, indications for beginning antiretroviral therapy include (1) symptomatic HIV disease, (2) asymptomatic patients with CD4 count less then 500/µl and viral load greater than 10,000 copies of bDNA per milliliter or greater than 20,000 copies of RNA per milliliter, (3) acute retroviral syndrome or within 6 months of HIV seroconversion, (4) postexposure prophylaxis, and (5) prevention of perinatal transmission.396,397 and 398
Once a decision has been made to start antiretroviral therapy, the preferred initial regimens at present are a combination of two NRTIs with a PI, NNRTI alone, or two PIs.396,397 and 398
It is estimated that only 40 to 80 percent of treatment-naive patients will obtain complete virologic suppression with currently available standard regimens.396,397 and 398,445 New studies are attempting to determine whether long-term virologic suppression can be obtained in a higher proportion of patients when they are given a four-drug regimen that incorporates two NRTIs in combination with either two PIs or an NNRTI and a PI.
If therapy is to be discontinued for any reason (e.g., early pregnancy), it is advisable that all drugs be stopped simultaneously to prevent the probable emergence of drug resistance to any one drug when used as monotherapy.446 Early data from a subgroup of patients in the EARTH study who stopped therapy after 1 year showed a rebound in viral load in all patients. Although all responded to reintroduction of the same regimen used prior to discontinuation, there were declines in CD4 percentages during the period of no treatment.447 Thus, the concerns with “drug holidays” are related to the potential emergence of viral resistance and also to the adverse effect on immune function.
Indications to change antiretroviral therapy include (1) drug failure, defined as a failure to decrease HIV RNA by more than 0.5 to 0.75 log after 4 weeks of treatment, less than a 1-log reduction by 8 weeks, or a failure to obtain undetectable RNA levels within 4 to 6 months, (2) recurrence of detectable viral RNA from a previously undetectable level, suggesting the development of resistance, (3) significant increase of 0.5 to 0.75 log from nadir viral RNA not attributable to concurrent infection or vaccination, (4) persistently declining CD4 cell counts, (5) clinical deterioration, such as the development of a new major opportunistic infection, (6) toxicity, and (7) nonadherence.396,397 and 398
It is advisable to base any decision to change therapy on two separate tests of viral load and CD4 counts.396,397 and 398 The decision to change antiretroviral therapy needs to be balanced to include available treatment options, issues of cross-resistance, potential toxicities, and drug interactions. HIV RNA level monitoring should take precedence over CD4 counts in determining the need to switch therapy.
Viral resistance, altered pharmacokinetics, or poor patient adherence may cause failure of a specific regimen. It is essential to differentiate drug failure from drug intolerance, since in the latter situation it may be necessary to change the one offending drug rather than the whole regimen. In contrast, in a failing regimen it is essential to substitute for the old regimen at least two new drugs and preferably an entirely new regimen. For patients with advanced disease and a history of exposure to multiple antiretroviral drugs, it may be necessary to start a regimen that would be deemed suboptimal for initial therapy but that may be a reasonable choice for these patients.
MANAGEMENT OF HIV IN PREGNANCY
Various interventions have recently been explored in an attempt to decrease perinatal HIV-1 transmission. Use of zidovudine in pregnancy, beginning at week 14 and continuing throughout delivery, has been studied by the Pediatric AIDS Clinical Trials Group. A three-part regimen, beginning at week 14 of pregnancy, with IV infusions of zidovudine throughout labor and delivery and subsequent use of oral zidovudine by the infant resulted in a decrease in transmission rate by approximately 70 percent, from 25 percent to 8 percent.64 More abbreviated courses of zidovudine have also been shown effective, with a 9.3 percent transmission rate in infants who received the drug within 48 h of birth even though their mothers never received it.65 Short-term toxicity of zidovudine appears acceptable in terms of both mother and infant. However, cancers have developed in offspring of pregnant rodents and monkeys given zidovudine during pregnancy, and much longer follow-up will be required to ascertain the true toxicity of the drug in humans. Preliminary data from Uganda have demonstrated the efficacy of two doses of nevirapine in preventing HIV transmission to the infant. One dose (200 mg) was given orally to the mother at the time of delivery, and the second was given to the newborn within the first 72 h of life.66 This intervention, if confirmed, would be practically and financially feasible in resource-poor regions of the world. Current recommendations for prevention of perinatal HIV-1 transmission in the United States include use of combination antiretroviral therapy, as would ordinarily be indicated for the mother’s own care, with addition of zidovudine.67 The ultimate decision regarding use of antiretroviral agents in pregnancy must reside with the woman herself, after careful and nonjudgmental discussion with her hea lth care providers. Additional means of decreasing perinatal transmission include avoidance of breast feeding, avoidance of premature rupture of the membranes during delivery, and delivery by elective cesarean section.51,56,58 Each of these interventions poses particular problems in resource-poor regions of the world.
The guidelines for the management of postexposure prophylaxis (PEP) were outlined in a consensus statement from the CDC in 1998.448 Recommendations for PEP stem from animal studies and anecdotal human experience, since placebo-controlled clinical trials have not been performed. The risk for acquisition of HIV from a needle-stick exposure from an AIDS patient is 0.4 percent. Risk is increased with a deep injury, presence of visible blood on the device causing the injury, injury with a needle that has been placed in the source patient’s artery or vein, terminal illness in the source patient, and lack of use of zidovudine PEP. Based on these risk factors, the recent guidelines have divided PEP regimens into basic and expanded groups. This stratification of risk assessment is fraught with practical problems that are the focus of current debate. Concern for the acquisition of drug-resistant virus has led to the recommendation of the addition of a drug from a class to which the source patient has not been exposed in cases where resistance is known or clinically suspected. In heavily pretreated source patients, this may not be an option. At a minimum, PEP prophylaxis to health care workers should include zidovudine (300 mg orally twice daily) and lamuvidine (150 mg twice a day). These drugs should be started as quickly as possible after the needle stick and should be continued for 4 weeks. If the exposure occurred greater than 72 h from the time of evaluation, antiretroviral drug intervention is not recommended. Attention is currently being focused on the feasibility of extrapolating these recommendations to cases of sexual exposure and on publishing guidelines for the use of PEP in this setting.
Centers for Disease Control: Case definition of acquired immunodeficiency syndrome. MMWR 30:250, 1981.
Centers for Disease Control: Revision of the case definition of acquired immunodeficiency syndrome for national reporting. MMWR 34:373, 1985.
Centers for Disease Control: Revision of the CDC surveillance case definition for acquired immunodeficiency syndrome. MMWR 36(1S):1, 1987.
Centers for Disease Control: New case definition of HIV/AIDS. MMWR 41:RR17, 1992.
Colebunders R, Francis H, Izaley L: Evaluation of a clinical case-definition of acquired immunodeficiency syndrome in Africa. Lancet 2:492, 1987.
Pan American Health Organization: Working group on AIDS case definition. Epidemiol Bull PAHO 10:9, 1990.
Mellors JW, Rinaldo CR Jr, Gupta P, White RM, Todd JA, Kingsley LA: Prognosis in HIV-1 infection predicted by the quantity of virus in plasma. Science 272:1167, 1996.
Mellors JW, Munoz A, Giorgi J, et al: Plasma viral load and CD4+ lymphocytes as prognostic markers of HIV-1 infection. Ann Intern Med 126:946, 1997.
Letvin NL, Eaton KA, Aldrich WR, et al: Acquired immunodeficiency syndrome in a colony of macaque monkeys. Proc Natl Acad Sci USA 80:2718, 1983.
Henrickson RV, Maul DH, Osborn KG, et al: Epidemic of acquired immunodeficiency in rhesus monkeys. Lancet 1:338, 1983.
Kanki PJ, McLane MF, King NW Jr, et al: Serologic identification and characterization of a macaque T-lymphotropic retrovirus closely related to human T-lymphotropic retroviruses (HTLV) type III. Science 228:1199, 1985.
Kanki PJ, Kurth R, Becker W, et al: Antibodies to simian T-lymphotropic virus type III in African green monkeys and recognition of STLV-III viral proteins by AIDS and related sera. Lancet 1:1330, 1985.
Kanki PJ, Alroy J, Essex M: Isolation of T-lymphotropic retrovirus related to HTLV-III/LAV from wild-caught African green monkeys. Science 230:951, 1985.
Essex M: Origin of AIDS, in AIDS: Etiology, Diagnosis, Treatment and Prevention, 3rd ed, edited by VT DeVita Jr, S Hellman, SA Rosenberg, p 3. Lippincott, Philadelphia, 1992.
Kanki PJ, Barin F, Mboup S, et al: New human T-lymphotropic retrovirus related to simian T-lymphotropic virus type IIIAGM (STLV-IIIAGM). Science 232:238, 1986.
Huet T, Cheynier R, Meyerhaus A, et al: Genetic organization of a chimpanzee lentivirus related to HIV-1. Nature 345:356, 1990.
Gao F, Balles E, Robertson DL, et al: Origin of HIV-1 in chimpanzee Pan troglodytes troglodytes. Nature 397:436, 1999.
Chin J: Present and future dimensions of the HIV/AIDS pandemic. Plenary presentation, 7th International Conference on AIDS, Florence, June 17, 1991.
Varmus H: Retroviruses. Science 240:1427, 1988.
Sharp PM, Robertson F, Gao F, Hahn B: Origins and diversity of human immunodeficiency viruses. AIDS 8 (suppl 1):S27, 1994.
Gonda MA, Wong-Staal F, Gallo RC, et al: Sequence homology and morphologic similarity of HTLV-III and visna virus, a pathogenic lentivirus. Science 227:173, 1985.
Daniel MD, Letvin NL, King NW, et al: Isolation of T-cell tropic HTLV-III-like retrovirus from macaques. Science 228:1201, 1985.
Overbaugh J, Donahue PR, Quackenbush SL, et al: Molecular cloning of a feline leukemia virus that induces fatal immunodeficiency disease in cats. Science 239:906, 1988.
Ho DD, Schooley RT, Rota TR, et al: HTLV-III in the semen and blood of a healthy homosexual man. Science 226:451, 1984.
Levy JA: Human immunodeficiency viruses and the pathogenesis of AIDS. JAMA 261:2997, 1989.
Tindall B, Evans L, Cunningham P, et al: Identification of HIV-1 in semen following primary HIV-1 infection. AIDS 6:949, 1992.
Chiasson MA, Stoneburner RI, Joseph SC: Human immunodeficiency virus transmission through artificial insemination. J AIDS 3:69, 1990.
Vogt MW, Witt DJ, Craven DE, et al: Isolation of HTLV-III/LAV from cervical secretions of women at risk for AIDS. Lancet 1:525, 1986.
Wofsy C, Cohen J, Hauer I, et al: Isolation of AIDS associated retrovirus from genital secretions of women with antibodies to the virus. Lancet 1:527, 1986.
Pomerants RJ, de la Monte SM, Donegan SP, et al: Human immunodeficiency virus (HIV) infection of the uterine cervix. Ann Intern Med 108:321, 1988.
Anderson DA, Voeller B: AIDS and contraception, in Clinical Perspective in Obstetrics and Gynecology, edited by F Haseltine, D Shoupe, p192. Springer, New York, 1993.
Marmor M, Weiss LR, Lyden M, et al: Possible female to female transmission of human immunodeficiency virus. Ann Intern Med 105:969, 1986.
Monzon OT, Capellan JM: Female to female transmission of HIV. Lancet 2:40, 1987.
Stamm WE, Handsfield HH, Rompalo AM, et al: The association between genital ulcer disease and acquisition of HIV infection in homosexual men. JAMA 260:1429, 1988.
Kreiss JK, Coombs R, Plummer F, et al: Isolation of human immunodeficiency virus from genital ulcers in Nairobi prostitutes. J Infect Dis 160:380, 1989.
Grosskurth H, Mosha F, Todd J, et al: Impact of improved treatment of sexually transmitted diseases on HIV infection in rural Tanzania: Randomized controlled trial. Lancet 356:530, 1995.
Sasse H, Salmaso S, Conti S: First Drug User Multicenter Study Group: Risk behaviors for HIV-1 infection in Italian drug users: Report from a multicenter study. J AIDS 2:486, 1989.
Chaisson RE, Bacchetti P, Osmond D, et al: Cocaine use and HIV infection in intravenous drug users in San Francisco. JAMA 261:561, 1989.
Donegan E, Stuart M, Niland JC, et al: Infection with human immunodeficiency virus type 1 (HIV-1) among recipients of antibody-positive blood donations. Ann Intern Med 113:733, 1990.
Centers for Disease Control: Safety of therapeutic products used for hemophilia patients. MMWR 37:441, 1988.
Pierce GF, Lusher JM, Brownstein AP, et al: The use of purified clotting factor concentrates in hemophilia: Influence of viral safety, cost and supply on therapy. JAMA 261:3434, 1989.
Schreiber GB, Busch MP, Kleinman SH, Korelitz JJ: The risk of transfusion transmitted viral infections. N Engl J Med 334:1685, 1996.
Goedert JJ, Mendez H, Drummond JE, et al: Mother to infant transmission of human immunodeficiency virus type 1: Association with prematurity or low anti-gp 120. Lancet 2:1351, 1989.
Hira SK, Kamanga J, Bhat GJ, et al: Perinatal transmission of HIV-1 in Zambia. Br Med J 299:1250, 1989.
European Collaborative Study: Risk factors for mother-to-child transmission of HIV-1. Lancet 339:1007, 1992.
Courgnaud V, Laure F, Brossard A, et al: Frequent and early in utero HIV-1 infection. AIDS Res Hum Retroviruses 7:337, 1991.
Rouzioux C, Costagliola D, Burgard M, et al: Timing of mother-to-child HIV-1 transmission depends on maternal status: The HIV infection in newborns French Collaborative Study Group. AIDS 7(suppl 2):S49, 1993.
Burgard M, Mayaux MJ, Blanche S, et al: The use of viral culture and p24 antigen testing to HIV infection in neonates: The HIV infection in newborns French Collaborative Study Group. N Engl J Med 327:1192, 1992.
Ehrns A, Lindgren S, Dictor M, et al: HIV in pregnant women and their offspring: Evidence for late transmission. Lancet 337:203, 1991.
van de Perre P, Simonon A, Msellati P, et al: Postnatal transmission of human immunodeficiency virus type 1 from mother to infant: A prospective cohort study in Kigali, Rwanda. N Engl J Med 325:593, 1991.
Dunn DT, Newell ML, Ades AE, Peckham CS: Risk of human immunodeficiency virus type 1 transmission through breast-feeding. Lancet 340:585, 1992.
European Collaborative Study: Risk factors for mother-to-child transmission of HIV-1. Lancet 339:1007, 1992.
Mayzux M-J, Blanche S, Rouzioux C, et al: Maternal factors associated with perinatal HIV-1 transmission: The French cohort study, seven years of follow-up observation. J AIDS 8:188, 1995.
Fang G, Burger H, Grimson R, et al: Maternal plasma human immunodeficiency virus type 1 RNA level: A determinant and projected threshold for mother-to-child transmission. Proc Natl Acad Sci USA 92:12100, 1995.
Weiser B, Nachman S, Tropper P, et al: Quantitation of human immunodeficiency virus type 1 during pregnancy: Relationship of viral titer to mother-to-child transmission and stability of viral load. Proc Natl Acad Sci USA 91:8031, 1994.
Burns DN, Landesman S, Muenz LR, et al: Cigarette smoking, premature rupture of membranes, and vertical transmission of HIV-1 among women with low CD4 levels. J AIDS 7:718, 1994.
Nair P, Alger L, Hines S, Seiden S, Hebel R, Johnson JP: Maternal and neonatal characteristics associated with HIV infection in infants of seropositive women. J AIDS 6:298, 1993.
Landesman SH, Kalish LA, Burns DN, et al: Obstetrical factors and the transmission of human immunodeficiency virus type 1 from mother to child. N Engl J Med 334:1617, 1996.
Simonds RJ, Steketee R, Nesheim S, et al: Impact of zidovudine use on risk and risk factors for perinatal transmission of HIV. AIDS 12:301, 1998.
The International Perinatal HIV Group: The mode of delivery and the risk of vertical transmission of human immunodeficiency virus type 1: A meta-analysis of 15 prospective cohort studies. N Engl J Med 340:977, 1999.
European Collaborative Study: Caesarean section and the risk of vertical transmission of HIV-1 infection. Lancet 343:1464, 1994.
Stratton P, Tuomala RE, Abboud R, et al: Obstetric and newborn outcomes in a cohort of HIV-infected pregnant women: A report of the Women and Infants Transmission Stuidy. J Acquir Immune Defic Syndr Hum Retroviol 20:179, 1999.
Centers for Disease Control and Prevention: Public Health Service Task Force recommendations for the use of antiretroviral drugs in pregnant women infected with HIV-1 for maternal health and for reducing perinatal HIV-1 transmission in the United States. MMWR 47:1, 1998.
Connor EM, Sperling RS, Gelver R, et al: Reduction of maternal-infant trnasmission of human immunodeficiency virus type 1 with zidovudine treatment. N Engl J Med 331:1173, 1994.
Shaffer N, Chauchoowong R, Mock PA, et al: Short-course zidovudine for perinatal HIV-1 transmission in Bangkok, Thailand: A randomized controlled trial. Lancet 353:773–780, 1999.
Jackson B, Fleming TR: Executive Summary, HIVNET 012. http://www.niaid.nih.gov/newsroom/simple/exec.htm. July 14, 1999.
Centers for Disease Control and Prevention: Update: Perinatally acquired HIV/AIDS—United States, 1997. MMWR 46:1086, 1997.
Gelderblom HR, Hausmann EHS, Ozel M, et al: Fine structure of human immunodeficiency virus (HIV) and immunolocalization of structural proteins. Virology 156:171, 1987.
Kowalski M, Potz J, Basiripour L, et al: Functional regions of the envelope glycoprotein of human immunodeficiency virus type 1. Science 237:1351, 1987.
Wyatt R, Sodroski J: The HIV-1 envelope glycoproteins: Fusogens, antigens and immunogens. Science 280:1884, 1998.
Dalglesh AG, Beverley PCL, Clapham PR, et al: The CD4 (T4) antigen is an essential component of the receptor for the AIDS retrovirus. Nature 312:763, 1984.
Klatzmann D, Champagne E, Chamaret S, et al: T-lymphocyte T4 molecule behaves as the receptor for human retrovirus LAV. Nature 312:767, 1984.
Choe H, Farazan M, Sun Y, et al: The beta-chemokine receptors CCR3 and CCR5 facilitate infection by primary HIV isolates. Cell 85:1135, 1996.
Berberian L, Goodglick L, Kipps TJ, Braun J: Immunoglobulin VH3 gene products: Natural ligands for HIV gp120. Science 261:1588, 1993.
Cordonnier A, Montagnier L, Emerman M: Single amino acid changes in HIV envelope affect viral tropisms and receptor binding. Nature 340:571, 1989.
McKeating JA, Willey RL: Structure and function of the HIV envelope. AIDS 3(suppl):S35, 1989.
Lapham CK, Ouyang J, Chandrasakhar B, et al: Evidence for cell-surface association between fusion and CD4-gp120 complex in human cell lines. Science 274:602, 1996.
Bullough PA, Hughson F, Skehel J, et al: Structure of influenza haemagglutinin at pH of membrane fusion. Nature 371:37, 1994.
Sarngadharan MG, Popovic M, Bruch L, et al: Antibodies reactive with human T-lymphotropic retroviruses (HTLV-III) in the serum of patients with AIDS. Science 224:506, 1984.
Mervis RJ, Ahmad N, Lillehoj EP, et al: The gag gene products of human immunodeficiency virus type-1: Alignment with the gag open reading frame, identification of post-translational modifications and evidence for alternative gag precursors. J Virol 62:3993, 1988.
Mizrahi V: Analysis of the ribonuclease H activity of HIV-1 reverse transcriptase using RNA-DNA hybrid substrates derived from the gag region of HIV-1. Biochemistry 28:9088, 1989.
Wlodawer A, Miller M, Jaskolski M, et al: Conserved folding in retroviral proteases: Crystal structure of a synthetic HIV-1 protease. Science 245:616, 1989.
Peng C, Ho BK, Chang TW, Chang NT: Role of human immunodeficiency virus type-1–specific protease in core protein maturation and viral infectivity. J Virol 63:2550, 1989.
Arthros J, Dean KC, Chalkin MA, et al: Identification of the residues in human CD4 critical for the binding of HIV. Cell 57:469, 1989.
Fisher AG, Ensoli B, Looney D, et al: Biologically diverse molecular variants within a single HIV-1 isolate. Nature 334:444, 1988.
Stein BS, Gowda SD, Lifson SD, et al: pH-independent HIV entry into CD4-positive T cells via virus envelope fusion to plasma membrane. Cell 49:659, 1987.
Berger EA, Doms RW, Fenyo EM, et al: A new classification for HIV-1 [letter]. Nature 391:240, 1998.
Cairns JS, D’Souza MP: Chemokines and HIV-1 second receptors: The therapeutic connection. Nature Med 4:563, 1998.
Smith MW, Dean M, Carrington M, et al: Contrasting genetic influence of CCR2 and CCR5 variants on HIV-1 infection and disease progression. Science 277:959, 1997.
Varmus HE, Swanstrom R: Replication of retroviruses, in RNA Tumor Viruses, suppl, edited by R Weiss, N Teich, H Varmus, J Coffin, p 75. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, 1985.
Luban J: Absconding with the chaperone: Essential cyclophin-Gag interaction in HIV-1 viron. Cell 87:1157, 1996.
Preston BD, Poiesz BJ, Loeb LA: Fidelity of HIV-1 reverse transcriptase. Science 242:1108, 1988.
Roberts JD, Bebenek K, Kunkel TA: The accuracy of reverse transcriptase of HIV-1. Science 242:1171, 1988.
Hahn BH, Gonda MA, Shaw GM, et al: Genomic diversity of the acquired immune deficiency syndrome virus HTLV-III: Different viruses exhibit greatest divergence in their envelope genes. Proc Natl Acad Sci USA 82:4813, 1985.
Ellis J, Bernstein A: Retrovirus vectors containing an internal attachment site: Evidence that circles are not intermediates to murine retrovirus integration. J Virol 63:2629, 1989.
Kim S, Byrn R, Groopman J, Baltimore D: Temporal aspects of DNA and RNA synthesis during human immunodeficiency virus infection: Evidence for differential gene expression. J Virol 63:3708, 1989.
Schnittman SM, Psallidopoulos MC, Lane HC, et al: The reservoir for HIV-1 in human peripheral blood is a T cell that maintains expression of CD4. Science 245:305, 1989.
Emerman M, Malim MH: HIV-1 regulatory/assessory genes: Keys to unraveling viral and host cell biology. Science 280:1880, 1998.
Popov S, Rexach M, Zybarth G, et al: Viral protein R regulates nuclear import of the HIV-1 pre-integration complex. EMBO J 17:909, 1998.
Nabel G, Baltimore D: An inducible transcription factor activates expression of human immunodeficiency virus in T cells. Nature 326:711, 1987.
Kawakami C, Scheidereit C, Roeder RG: Identification and purification of a human immunoglobulin enhancer binding protein NF-k B that activates transcription from a human immunodeficiency virus promoter in vitro. Proc Natl Acad Sci USA 85:4700, 1988.
Dayton AI, Sodroski JG, Rosen CA, et al: Transactivator gene of the human T cell lymphotropic virus type III is required for replication. Cell 44:941, 1986.
Laspia M, Rice A, Mathews MB: HIV-1 tat protein increases transcriptional initiation and stabilizes elongation. Cell 59:283, 1989.
Sodroski J, Goh WC, Rosen C, et al: A second post-transcriptional transactivator gene required for HTLV III replication. Nature 321:412, 1986.
Malim MH, Bohnlein S, Hauber J, Cullen BR: Functional dissection of the HIV-1 rev transactivation: Derivation of a trans-dominant repressor of rev function. Cell 58:205, 1989.
Schubert U, Anton LC, Bacik I, et al: CD4-glycoprotein degradation induced by human immunodeficiency virus type 1 Vpu protein requires the function of proteosomes and the ubiquitin conjugating pathway. J Virol 72:2280, 1998.
Margottin F, Bour SP, Durand H, et al: A novel WD protein, h-beta TrCp, that interacts with HIV-1 Vpu connects CD4 to the ER degradation pathway through F-box motif. Mol Cell 1:565, 1998.
Greenberg ME, Bronson S, Lock M, et al: Co-localization of the HIV-1 Nef with the AP-2 adaptor protein complex correlates with Nef-induced CD4 down-regulation. EMBO J 16: 6964, 1997.
Foti M, Mangasarian A, Piguet V, et al: Nef-mediated clathin-coated pit formation. J Cell Biol 139:37, 1997.
Jacks T, Power MD, Masiarz FR, et al: Characterization of ribosomal frameshifting in HIV-1 gag-pol expression. Nature 331:280, 1987.
Klimkait T, Strebel K, Hoggan MD, et al: The human immunodeficiency virus type-1-specific protein vpu is required for efficient virus maturation and release. J Virol 64:621, 1990.
Strebel K, Daugherty D, Clouse K, et al: The HIV “A” (sor) gene product is essential for virus infectivity. Nature 328:728, 1987.
Murry HW, Welte K, Jacobs JL, et al: Production of and in vitro response to interleukin 2 in the acquired immunodeficiency syndrome. J Clin Invest 76:1959, 1985.
Pahwa SG, Quilop MTJ, Lane M, et al: Defective B-lymphocyte function in homosexual men in relation to the acquired immunodeficiency syndrome. Ann Intern Med 101:757, 1984.
Murry HW, Rubin BY, Masur H, Roberts RB: Impaired production of lymphokines and immune (gamma) interferon in the acquired immunodeficiency syndrome. N Engl J Med 310:883, 1984.
Rook AH, Masur H, Lane HC, et al: Interleukin-2 enhances the depressed natural killer and cytomegalovirus-specific cytotoxic activities of lymphocytes from patients with the acquired immunodeficiency syndrome. J Clin Invest 72:398, 1983.
Tersmette M, de Goede REY, Al BJM, et al: Differential syncytium-inducing capacity of human immunodeficiency virus isolates: Frequent detection of syncytium-inducing isolates in patients with acquired immunodeficiency syndrome (AIDS) and AIDS-related complex. J Virol 62:2026, 1988.
Pantaleo G, Graziosi C, Demarest JF, et al: HIV infection is active and progressive in lymphoid tissue during the clinically latent stage of disease. Nature 362:355, 1993.
Glushakova S, Grivel J-C, Fitzgerald W, et al: Evidence for the HIV-1 phenotype switch as a causal factor in acquired immunodeficiency. Nature Med 4:346, 1998.
Walker BD, Chakrabarti S, Moss B, et al: HIV-specific cytotoxic T lymphocytes in seropositive individuals. Nature 328:345, 1987.
Tsuchiya S, Imaizumi M, Minegishi M, et al: Lack of interleukin-2 production in a patient with OKT4+ T-cell deficiency. N Engl J Med 308:1294, 1983.
Ebert EC, Stoll DB, Cassens BJ, et al: Diminished interleukin production and receptor generation characterize the acquired immunodeficiency syndrome. Clin Immunol Immunopathol 37:283, 1985.
Prince HE, Kermani-Arab V, Fahey J: Depressed interleukin-2 receptor expression in acquired immune deficiency and lymphadenopathy syndromes. J Immunol 133:1313, 1984.
Kekow J, Wachsman W, Gross WL, et al: Transforming growth factor-beta and suppression of humoral immune responses in HIV infection. J Clin Invest 87:1010, 1991.
Ammann AJ, Abrams D, Conant M, et al: Acquired immune dysfunction in homosexual men: Immunologic profiles. Clin Immunol Immunopathol 27:315, 1983.
Wong JK, Gunthard HF, Havir DV, et al: Reduction of HIV-1 in blood and lymph nodes following potent antiretroviral therapy of HIV-1 infection. Proc Natl Acad Sci USA 94:2574, 1997.
Cavert W, Notermans DW, Staskus K, et al: Kinetics of response in lymphoid tissues to antiretroviral therapy of HIV-1 infection. Science 276:960, 1997.
Hammer SM, Squires KE, Hughes MD, et al: A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. N Engl J Med 337:725, 1997.
Palella FJ Jr, Delaney KM, Moorman AC et al: Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N Engl J Med 338:853, 1998.
Connors M, Kovacs JA, Krevat S, et al: HIV infection induces changes in CD4+ T-cell phenotype and depletions within the CD4+ T-cell repertroire that are not immediately restored by antiviral or immune-based therapies. Nature Med 3:533, 1997.
Gorochov G, Neumann AU, Kereveur A, et al: Perturbation of CD4+ and CD8+ T-cell repertoire during progression to AIDS and regulation of the CD4+ repertoire during antiviral therapy. Nature Med 4:215, 1998.
Chess Q, Daniels J, North E, et al: Serum immunoglobulin elevations in the acquired immunodeficiency syndrome (AIDS): IgG, IgA, IgM, and IgD. Diagn Immunol 2:148, 1984.
Lane HC, Masur H, Edgar LC, et al: Abnormalities of B-cell activation and immunoregulation in patients with the acquired immunodeficiency syndrome. N Engl J Med 309:453, 1983.
Pahwa S, Pahwa R, Saxinger C, et al: Influence of the human T-lymphotropic virus/lymphadenopathy–associated virus on functions of human lymphocytes: Evidence for immunosuppressive effects and polyclonal B-cell activation by banded viral preparations. Proc Natl Acad Sci USA 82:8198, 1985.
Kopelman RG, Zolla-Pazner S: Association of human immunodeficiency virus infection and autoimmune phenomena. Am J Med 84:82, 1988.
Walsh CM, Nardi MA, Karpatkin S: On the mechanism of thrombocytopenic purpura in sexually active homosexual men. N Engl J Med 311:635, 1984.
van der Lelie J, Lange JMA, Vos JJE, et al: Autoimmunity against blood cells in human immunodeficiency virus infection. Br J Haematol 67:755, 1987.
Stricker RB, McHugh TM, Moody D, et al: An AIDS-related cytotoxic autoantibody reacts with a specific antigen on stimulated CD4+ cells. Nature 327:170, 1987.
Rossi G, Goria R, Stellini R, et al: Prevalence, clinical, and laboratory features of thrombocytopenia in HIV-infected individuals. AIDS Res Hum Retroviruses 6:261, 1990.
Murphy MF, Metcalfe P, Waters AH, et al: Incidence and mechanism of neutropenia and thrombocytopenia in patients with human immunodeficiency virus infection. Br J Haematol 66:337, 1987.
Ballem PJ, Belzberg A, Devine DV, et al: Kinetic studies of the mechanism of thrombocytopenia in patients with human immunodeficiency virus infection. N Engl J Med 327:1179, 1992.
Gartner S, Markovits P, Markovitz DM, et al: The role of mononuclear phagocytes in HTLV-III/LAV infection. Science 233:215, 1986.
Armstrong GA, Horne R: Follicular dendritic cells and virus-like particles in AIDS-related lymphadenopathy. Lancet 2:370, 1984.
Poli G, Bottazzi B, Acero R, et al: Monocyte function in intravenous drug abusers with lymphadenopathy syndrome and in patients with the acquired immunodeficiency syndrome: Selective impairment of chemotaxis. Clin Exp Immunol 62:136, 1985.
Murry HW, Gellene RA, Libby DM, et al: Activation of tissue macrophages from AIDS patients: In vitro response of alveolar macrophages to lymphokines and interferon-gamma. J Immunol 135:1501, 1985.
Kleinerman ES, Ceccorulli LM, Zwelling LA, et al: Activation of monocyte-mediated tumoricidal activity in patients with acquired immunodeficiency syndrome. J Clin Oncol 3:1005, 1985.
Creemers PC, Stark DF, Boyko WJ: Evaluation of natural killer cell activity in patients with persistent generalized lymphadenopathy and acquired immunodeficiency syndrome. Clin Lab Immunol 14:114, 1984.
Klatzman M, Lederman MM: Defective postbinding lysis underlies the impaired natural killer activity in factor VIII–treated human T lymphotropic virus type III seropositive hemophiliacs. J Clin Invest 45:406, 1986.
Reddy MM, Chinoy P, Grieco MH: Differential effects of interferon alpha and interleukin-2 on natural killer cell activity in patients with the acquired immune deficiency syndrome. J Biol Res Mod 3:379, 1984.
Horsburgh CR Jr, Ou CY, Jason J, et al: Duration of human immunodeficiency virus infection before detection of antibody. Lancet 2:637, 1989.
Imagawa DT, Lee MH, Wolinsky SM, et al: HIV-1 infection in homosexual men who remain seronegative for prolonged periods. N Engl J Med 320:1458, 1989.
Brettler DB, Somasundaran M, Forsberg AF, et al: Silent human immunodeficiency virus type 1 infection: A rare occurrence in a high-risk heterosexual population. Blood 80:2396, 1992.
Read S, Cassol S, Coates R, et al: Detection of incident HIV infection by PCR compared to serology. J AIDS 5:1075, 1992.
Goudsmit J, Lange JM, Krone WJ, et al: Pathogenesis of HIV and its implications for serodiagnosis and monitoring of antiviral therapy. J Virol Methods 17:19, 1987.
Tindall B, Cooper DA, Donovan B, et al: Primary human immunodeficiency virus infection: Clinical and serologic aspects. Infect Dis Clin North Am 2:329, 1988.
Alter HJ, Epstein JS, Swensen SG, et al: Prevalence of human immunodeficiency virus type 1 p24 antigen in U.S. blood donors: An assessment of the efficacy of testing in donor screening. N Engl J Med 323:1312, 1990.
Phillips AN: Studies of prognostic markers in HIV infection: Implications for pathogenesis. AIDS 6:1391, 1992.
Munoz A, Carey V, Saah AJ, et al: Predictors of decline in CD4 lymphocytes in a cohort of homosexual men infected with human immunodeficiency virus. J AIDS 1:396, 1988.
Malone JL, Simms TE, Gray GC, et al: Sources of variability in repeated T-helper lymphocyte counts from human immunodeficiency virus type 1 infected patients: Total lymphocyte count fluctuations and diurnal cycle are important. J AIDS 3:144, 1990.
Anderson RE, Lang W, Shiboski S, et al: Use of beta 2 microglobulin level and CD4 lymphocyte count to predict development of acquired immunodeficiency syndrome in persons with human immunodeficiency virus infection. Arch Intern Med 150:73, 1990.
Melmed RN, Taylor JMG, Detels R, et al: Serum neopterin changes in HIV infected subjects: Indicator of significant pathology, CD4 T cell changes, and the development of AIDS. J AIDS 2:70, 1989.
Hammer SM, Squires KE, Hughes MD, et al: A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200/mm3 or less. N Engl J Med 337:725, 1997.
Centers for Disease Control and Prevention: Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. MMWR, May 5, 1999.
Egger M, Hirschel B, Francioli P, et al: Impact of new antiretroviral combination therapies in HIV infected patients in Switzerland: Prospective multicentre study. BMJ 315:1194, 1997.
Tural C, Romeu J, Sirera G, et al: Long lasting remission of cytomegalovirus retinitis without maintenance therapy in human immunodeficiency virus infected patients. J Infect Dis 177:1080, 1998.
Li TS, Tubiana R, Katlama C, Calvez V, Mohand A, Autran B: Long-lasting recovery in CD4 T cell function and viral load reduction after highly active antiretroviral therapy in advanced HIV-1 disease. Lancet 351:1682, 1998.
Furrer H, Egger M, Opravil M, et al: Discontinuation of primary prophylaxis against Pneumocystis carinii pneumonia in HIV-1 infected adults treated with combination antiretroviral therapy. N Engl J Med 340:1301, 1999.
Cooper DA, Maclean P, Finlayson R, et al: Acute AIDS retrovirus infection. Lancet 1:537, 1985.
Fox R, Eldred LJ, Fuchs EJ, et al: Clinical manifestations of acute infection with human immunodeficiency virus in a cohort of gay men. AIDS 1:35, 1987.
Lemp GF, Payne SF, Rutherford GW, et al: Projections of AIDS morbidity and mortality in San Francisco. JAMA 263:1497, 1990.
Moss AR, Bacchetti P: Editorial review: Natural history of HIV infection. AIDS 3:55, 1989.
Schoenbaum EE, Hartel D, Friedland G: HIV infection and intravenous drug use. Curr Opin Infect Dis 3:80, 1990.
Volberding P: Clinical spectrum of HIV disease, in AIDS: Etiology, Diagnosis, Treatment and Prevention, 3rd ed, edited by VT DeVita Jr, S Hellman, SA Rosenberg, p 123. Lippincott, Philadelphia, 1992.
Mitsuyasu R: AIDS Clin Review 1993/4. Marcel Dekker, New York, 1993, p189.
Zon LI, Arkin C, Groopman JE: Hematologic manifestations of the human immunodeficiency virus (HIV). Semin Hematol 25:208, 1988.
Sullivan PS, Hanson DL, Chu SY, Jones JL, Ward JW: Epidemiology of anemia in human immunodeficiency virus infected persons: Results from the Multistate Adult and Adolescent Spectrum of HIV Disease Surveillance Project. Blood 91:301, 1998.
Spivak JL, Barnes DC, Fuchs E, Quinn TC: Serum immunoreactive erythropoietin in HIV infected patients. JAMA 261:310, 1989.
Seneviratne LS, Tulpule A, Mummaneni M, et al: Clinical, immunological and pathologic correlates of bone marrow involvement in 253 patients with AIDS-related lymphoma. Blood 92:244A, 1998.
Walker RE, Parker RI, Kovacs JA, et al: Anemia and erythropoiesis in patients with the acquired immunodeficiency syndrome (AIDS) and Kaposi sarcoma treated with zidovudine. Ann Intern Med 108:372, 1988.
Richman DD, Fischl MA, Grieco MH, et al: The toxicity of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex: A double-blind, placebo-controlled trial. N Engl J Med 317:192, 1987.
Anderson LJ: Human parvoviruses. J Infect Dis 161:603, 1990.
Frickhofen N, Abkowitz JL, Safford M, et al: Persistent B19 parvovirus infection in patients infected with human immunodeficiency virus type 1 (HIV-1): A treatable cause of anemia in AIDS. Ann Intern Med 113:926, 1990.
Rarick MU, Espina B, Mocharnuk R, Trilling Y, Levine AM: Thrombotic thrombocytopenic purpura in patients with human immunodeficiency virus infection: A report of three cases and review of the literature. Am J Hematol 40:103, 1992.
Telen MJ, Roberts KB, Bartlett JA: HIV associated autoimmune hemolytic anemia: Report of a case and review of the literature. AIDS 3:933, 1990.
McGinniss MH, Macher AM, Rook AH, Alter HJ: Red cell autoantibodies in patients with acquired immune deficiency syndrome. Transfusion 26:405, 1986.
Gupta S, Licorish K: The Coombs’ test and the acquired immunodeficiency syndrome. Ann Intern Med 100:462, 1984.
Toy PTCY, Reid ME, Burns M: Positive direct antiglobulin test associated with hyperglobulinemia in AIDS. Am J Hematol 19:145, 1985.
Harriman GR, Smith PD, Horne MK, et al: Vitamin B12 malabsorption in patients with acquired immunodeficiency syndrome. Arch Intern Med 149:2039, 1989.
Herbert V, Fong W, Gulle V, Stopler T: Low holotranscobalamin II is the earliest serum marker for subnormal vitamin B12 (cobalamin) absorption in patients with AIDS. Am J Hematol 34:132, 1990.
Moore RD, Keruly JC, Chaisson RE: Anemia and survival in HIV infection J Acquir Immune Defic Syndr Hum Retrovirol 19:29, 1998.
Henry DH, Beall GN, Benson CA, et al: Recombinant human erythropoietin in the treatment of anemia associated with human immunodeficiency virus (HIV) infection and zidovudine therapy: Overview of four clinical trials. Ann Intern Med 117:739, 1992.
Demetri G, Wade J, Cella D: Epoetin alfa improves quality of life in cancer patients receiving cytotoxic treatment independent of disease response: Prospective clinical trial results. Blood 90:175a, 1997.
Miles SA: The use of hematopoietic growth factors in HIV infection and AIDS-related malignancies. Cancer Invest 9:229, 1991.
Murphy M, Metcalfe P, Waters A: Incidence and mechanism of neutropenia and thrombocytopenia in patients with human immunodeficiency virus infection. Br J Haematol 66:337, 1987.
Bagnara GP, Zauli G, Giovannini M, Re MC, Furlini G, La Placa M: Early loss of circulating hemopoietic progenitors in HIV-1 infected subjects. Exp Hematol 18:426, 1990.
Leiderman I, Greenberg M, Adelsberg B, et al: A glycoprotein inhibitor of in vitro granulopoiesis associated with AIDS. Blood 70:1267, 1987.
Mauss S, Steinmetz HT, Willers R, et al: Induction of granulocyte colony-stimulating factor by acute febrile infection but not by neutropenia in HIV seropositive individuals. J Acquir Immune Defic Syndr Hum Retrovirol 14:430, 1997.
Elis M, Gupta S, Galant S, et al: Impaired neutrophil function in patients with AIDS or AIDS-related complex: A comprehensive evaluation. J Infect Dis 158:1268, 1988.
Bodey GP, Buckley M, Sathe US, et al: Qualitative relationships between circulating leukocytes and infection in patients with acute leukemia. Ann Intern Med 64:328, 1966.
Moore RD, Keruly J, Chaisson RE, et al: Neutropenia and bacterial infection in acquired immunodeficiency syndrome. Arch Intern Med 155:1965, 1995.
Jacobson MA, Cohen PT, Liu RC, et al: Risk of hospitalization for serious bacterial infection associated with neutropenia severity in patients with HIV [abst 231]. 11th International Conference on AIDS, Vancouver, Canada, 1996.
Meynard J-L, Guiguet M, Arsac S, et al: Frequency and risk factors of infectious complications in neutropenic patients infected with HIV. AIDS 11:995, 1997.
Groopman JE, Feder D: Hematopoietic growth factors in AIDS. Semin Oncol 19:408, 1992.
Groopman JE, Mitsuyasu RT, DeLeo MJ, et al: Effect of recombinant human granulocyte-macrophage colony stimulating factor on myelopoiesis in the acquired immunodeficiency syndrome. N Engl J Med 317:593, 1987.
Kaplan L, Kahn J, Crowe S, et al: Clincial and virologic effect of GM-CSF in patients receiving chemotherapy for HIV associated non-Hogkin’s lymphoma: Results of a randomized trial. J Clin Oncol 9:929, 1991.
Kimura S, Matsuda J, Ikematsu S, et al: Efficacy of recombinant human granulocyte colony-stimulating factor on neutropenia in patients with AIDS. AIDS 12:1251, 1990.
Keiser P, Higgs E, Scanton J: Neutropenia is associated with bacteremia in patients with HIV. Am J Med Sci 312:118, 1996.
Pechere M, Samii K, Hirschel B: HIV related thrombocytopenia. N Engl J Med 328:1785, 1993.
Sullivan PS, Hanson DL, Chu SY, Jones JL, Ciesielski CA: Surveillance for thrombocytopenia in persons infected with HIV: Results from the multistate Adult and Adolescent Spectrum of Disease Project. J Acquir Immune Defic Syndr Hum Retrovirol 14:374, 1997.
Ballem PJ, Belzberg A, Devine DV, et al: Kinetic studies of the mechanism of thrombocytopenia in patients with human immunodeficiency virus infection. N Engl J Med 327:1779, 1992.
Walsh CM, Nardi MA, Karpatkin S: On the mechanism of thrombocytopenic purpura in sexually active homosexual men. N Engl J Med 311:635, 1984.
Bettaieb A, Fromont P, Louache F, et al: Presence of cross-reactive antibody between human immunodeficiency virus (HIV) and platelet glycoproteins in HIV related immune thrombocytopenic purpura. Blood 80:162, 1992.
Kouri Y, Borkowsky W, Nardi M, Karpatkin S, Basch RS: Human megakaryocytes have a CD4+ molecule capable of binding human immunodeficiency virus-1. Blood 81:2664, 1993.
Zucker-Franklin D, Seremetis S, Heng ZY: Internalization of human immunodeficiency virus type I and other retroviruses by megakaryocytes and platelets. Blood 75:1920, 1990.
Wang J-F, Liu Z-Y, Groopman JE: The alpha-chemokine receptor CXCR4 is expressed on the megakaryocytic lineage from progenitor to platelets, and modulates migration and adhesion. Blood 92:756, 1998.
Zucker-Franklin D, Cao Y: Megakaryocytes of human immunodeficiency virus-infected individuals express viral RNA. Proc Natl Acad Sci USA 86:5595, 1989.
Zucker-Franklin D, Termin CS, Cooper MC: Structural changes in the megakaryocytes of patients infected with the human immunodeficiency virus (HIV-1). Am J Pathol 134:1295, 1989.
Swiss Group for Clinical Studies on AIDS: Zidovudine for the treatment of thrombocytopenia associated with HIV: A prospective study. Ann Intern Med 109:718, 1988.
Harker LA, Marzec UM, Novembre F, et al: Treatment of thrombocytopenia in chimpanzees infected with HIV by pegylated recombinant human megakaryocyte growth and development factor. Blood 91:4427, 1998.
Oksenhendler E, Bierling P, Farcet JP, et al: Response to therapy in 37 patients with HIV related thrombocytopenic purpura. Br J Haematol 66:49, 1987.
Oksenhendler E, Bierling P, Ferchal F, Clauvel J-P, Seligmann M: Zidovudine for thrombocytopenic purpura related to human immunodeficiency virus (HIV) infection. Ann Intern Med 110:365, 1989.
Landonio G, Cinque P, Nosari A, et al: Comparison of two dose regimens of zidovudine in an open, randomized, multicenter study for severe HIV related thrombocytpenia. AIDS 7:209, 1993.
Piketty C, Gilquin J, Kazatchkine MD: Successful treatment of HIV related thrombocytopenia with didanosine (ddI). J AIDS 7:521, 1994.
Tozzi V, Narcisco P, Sebastiani G, Frigiotti D, D’Amato C: Effects of indinavir treatment on platelet and neutrophil counts in patients with advanced HIV disease. AIDS 11:1067, 1997.
Marroni M, Gresele P, Landonio G, et al: Interferon-a is effective in the treatment of HIV-1 related, severe, zidovudine-resistant thrombocytopenia: A prospective, placebo-controlled, double-blind trial. Ann Intern Med 121:423, 1994.
Vianelli N, Catani L, Gugliotta L, et al: Recombinant alpha-interferon 2b in the treatment of HIV related thrombocytopenia. AIDS 7:823, 1993.
Imbach P, d’Apuzzo V, Hirt A, et al: High dose intravenous gammaglobulin for idiopathic thrombocytopenic purpura in childhood. Lancet 1:1228, 1981.
Bussel JB, Saimi JS: Isolated thrombocytopenia in patients infected with HIV: Treatment with intravenous gammaglobulin. Am J Hematol 28:79, 1998.
Gringeri A, Cattaneo M, Santagostino E, Mannucci PM: Intramuscular anti-D immunoglobulins for home treatment of chronic immune thrombocytopenic purpura. Br J Hematol 80:337, 1992.
Oksenhendler E, Bierling P, Brossard Y, et al: Anti-Rh immunoglobulin therapy for human immunodeficiency virus-related immune thrombocytopenic purpura. Blood 71:1499, 1988.
Oksenhendler E, Bierling P, Chevret S, et al: Splenectomy is safe and effective in human immunodeficiency virus related immune thrombocytopenia. Blood 82:29, 1993.
Kemeny MM, Cooke V, Melester TS, et al: Splenectomy in patients with AIDS and AIDS-related complex. AIDS 7:1063, 1993.
Peters BS, Beck EJ, Coleman DG, et al: Changing disease patterns in patients with AIDS in a referral center in the United Kingdom: The changing face of AIDS. Br Med J 302:203, 1991.
Pluda JM, Yarchoan R, Jaffe ES, et al: Development of non-Hodgkin’s lymphoma in a cohort of patients with severe human immunodeficiency virus (HIV) infection on long-term antiretroviral therapy. Ann Intern Med 113:276, 1990.
Gail MH, Pluda JM, Rabkin CS, et al: Projections of the incidence of non-Hodgkin’s lymphoma related to acquired immunodeficiency syndrome. J Nat Cancer Inst 83:695, 1991.
Rabkin CS, Biggar RJ, Horm JW: Increasing incidence of cancers associated with the human immunodeficiency virus epidemic. Int J Cancer 47:692, 1991.
Beral V, Peterman T, Berkelman R, Jaffe H: AIDS-associated non-Hodgkin lymphoma. Lancet 337:805, 1991.
Biggar RJ, Rabkin CS: The epidemiology of acquired immunodeficiency syndrome-related lymphomas. Curr Opin Oncol 4:883, 1992.
Pluda JM, Vanzon D, Tosato G, et al: Factors which predict for the development of non-Hodgkin’s lymphoma in patients with HIV infection receiving antiretroviral therapy. Blood 78:285a, 1991.
Jacobson LP: Impact of highly effective anti-retroviral therapy on the incidence of malignancies among HIV infected individuals [abst S5]. J Acquir Immune Defic Syndr Hum Retrovirol 17:A39, 1998.
Buchbinder SP, Bittinghoff E, Colfax G, Holmberg S: Declines in AIDS incidence associated with highly active anti-retroviral therapy are not reflected in KS and lymphoma incidence [abst S7]. J Acquir Immun Defic Syndr Hum Retrovirol 17:A39, 1998.
Ledergerber B, Telenti A, Egger M: Risk of HIV related Kaposi’s sarcoma and non-Hodgkin’s lymphoma with potent antiretroviral therapy: Prospective cohort study. BMJ 319:23, 1999.
Roithmann S, Tourani JM, Andrieu JM: AIDS-associated non-Hodgkin’s lymphoma. Lancet 338:884, 1991.
Levine AM, Meyer PR, Begandy MK, et al: Development of B cell lymphoma in homosexual men: Clinical and immunologic findings. Ann Intern Med 100:7, 1984.
Monfardini S, Vaccher E, Tirelli U: AIDS associated non-Hodgkin’s lymphoma in Italy: Intravenous drug users versus homosexual men. Ann Oncol 1:208, 1990.
Ragni M, Kingsley L, Duzyk A, Obrams I: HIV associated malignancy in hemophiliacs: Preliminary report from the Hemophilia Malignancy Study (HMS). Blood 74:38a, 1988.
Purtilo DT: Opportunistic non-Hodgkin’s lymphoma in X-linked recessive immunodeficiency and lymphoproliferative syndromes. Semin Oncol 4:335, 1977.
Levine AM, Taylor CR, Schneider DR, et al: Immunoblastic sarcoma of T cell versus B cell origin: I. Clinical features. Blood 58:52, 1981.
Penn I: Tumors of the immunocompromised patient. Annu Rev Med 39:63, 1988.
Swinnen LJ, Costanzo-Nordin MR, Fisher SG, et al: Increased incidence of lymphoproliferative disorder after immunosuppression with the monoclonal antibody OKT3 in cardiac transplant recipients. N Engl J Med 323:1723, 1990.
Pantaleo G, Graziosi C, Fauci AS: Mechanisms of disease: The immunopathogenesis of human immunodeficiency virus infection. N Engl J Med 328:327, 1993.
Birx DI, Redfield RR, Tosato G: Defective regulation of Epstein-Barr virus infection in patients with acquired immunodeficiency syndrome (AIDS) or AIDS-related disorders. N Engl J Med 314:874, 1986.
Shear GM, Salahuddin SZ, Markham PD, et al: Prospective study of cytotoxic T lymphocyte responses to influenza virus and antibodies to human T lymphotropic virus-III in homosexual men: Selective loss of influenza-specific human leukocyte antigen-restricted cytotoxic lymphocyte response to human T lymphotropic virus-III positive individuals with symptoms of acquired immunodeficiency syndrome. J Clin Invest 76:1699, 1985.
Feichtinger H, Rutkonen P, Parravicini C, et al: Malignant lymphomas in Cynomolgus monkeys infected with simian immunodeficiency virus. Am J Pathol 137:1311, 1990.
Jelinek DF, Lipsky PE: Enhancement of human B cell proliferation and differentiation by tumor necrosis factor-alpha and interleukin 1. J Immunol 139:2970, 1987.
Fauci A, Schnittman SM, Poli G, et al: Immunopathogenetic mechanisms in human immunodeficiency virus (HIV) infection. Ann Intern Med 114:678, 1991.
Kawano M, Hirano T, Matsuda T, et al: Autocrine generation and requirement of BSF-2/IL-6 for human multiple myelomas. Nature 332:83, 1988.
Biondi A, Rossi V, Bassan R, et al: Constitutive expression of IL-6 gene in chronic lymphocytic leukemia. Blood 73:1279, 1989.
Emillie D, Coumbaras J, Raphael M, et al: IL-6 production in high grade B lymphomas: Correlation with presence of malignant immunoblasts in AIDS and in HIV-seronegative patients. Blood 80:498, 1992.
Benjamin D, Knobloch TJ, Abrams J, Dayton MA: Human B cell IL-10: B cell lines derived from patients with AIDS and Burkitt’s lymphoma constitutively secrete large quantities of IL-10. Blood 78:384a, 1991.
Masood R, Bond M, Scadden D, et al: Interleukin-10: An autocrine B cell growth for human B-cell lymphomas and their progenitors. Blood 80:115a, 1992.
Poli G, Fauci AS: The effect of cytokines and pharmacologic agents on chronic HIV infection. AIDS Res Hum Retroviruses 8:191, 1992.
Shibata D, Weiss LM, Nathwani BN, et al: Epstein-Barr virus in benign lymph node biopsies from individuals infected with the human immunodeficiency virus is associated with concurrent or subsequent development of non-Hodgkin’s lymphoma. Blood 77:1527, 1991.
MacMahon EME, Glass JD, Hayward SD, et al: Epstein-Barr virus in AIDS-related primary central nervous system lymphoma. Lancet 338:969, 1991.
Wang D, Liebowitz D, Kieff E: An EBV membrane protein expressed in immortalized lymphocytes transforms established rodent cells. Cell 43:831, 1985.
Subar M, Neri A, Inghirami G, et al: Frequent c-myc oncogene activation and infrequent presence of Epstein-Barr virus genome in AIDS-associated lymphoma. Blood 72:667, 1988.
Shibata D, Weiss LM, Hernandez AM, et al: Epstein-Barr virus–associated non-Hodgkin’s lymphoma in patients infected with the human immunodeficiency virus. Blood 81:2102, 1993.
Hamilton-Dutoit SJ, Raphael M, Audouin M, et al: In situ demonstration of Epstein-Barr virus small RNAs (EBER 1) in AIDS related lymphomas: Correlation with tumor morphology and primary site. Blood 82:619, 1993.
Neri A, Barriga F, Inghirami G, et al: Epstein-Barr virus infection precedes clonal expansion in Burkitt’s and acquired immunodeficiency associated lymphoma. Blood 77:1092, 1991.
Chaganti RSK, Jhanwar SC, Koziner B, et al: Specific translocations characterize Burkitt’s-like lymphoma of homosexual men with the acquired immunodeficiency syndrome. Blood 61:1269, 1983.
Peterson JM, Tubbs RR, Savage RA, et al: Small noncleaved B cell Burkitt-like lymphoma with chromosome t(8;14) translocation and Epstein-Barr virus nuclear associated antigen in a homosexual man with acquired immunodeficiency syndrome. Am J Med 78:141, 1985.
Rechavi G, Ben-Bassat M, Berkowicz U, et al: Molecular analysis of Burkitt’s leukemia in two hemophilic brothers with AIDS. Blood 70:1713, 1987.
Pelicci PG, Knowles DM, McGrath IT, Dalla-Favera R: Chromosomal breakpoints and structural alterations of the c-myc locus differ in endemic and sporadic forms of Burkitt lymphoma. Proc Natl Acad Sci USA 83:2984, 1986.
Shiramizu B, Barriga F, Neequaye J, et al: Patterns of chromosomal breakpoint locations in Burkitt’s lymphoma: Relevance to geography and Epstein-Barr virus association. Blood 77:1516, 1991.
Ballerini P, Gaidano G, Gong JZ, et al: Molecular pathogenesis of HIV-associated lymphomas. AIDS Res Hum Retroviruses 8:731, 1992.
Pelicci PG, Knowles DM II, Arlin ZA, et al: Multiple monoclonal B cell expansions and c-myc oncogene rearrangements in acquired immune deficiency syndrome-related lymphoproliferative disorders: Implications for lymphomagenesis. J Exp Med 164:2049, 1986.
Pauza CD, Galindo J, Richman DD: Human immunodeficiency virus infection of monoblastoid cells: Cellular differentiation determines the pattern of virus replication. J Virol 62:3558, 1988.
Laurence J, Astrin SM: Human immunodeficiency virus induction of malignant transformation in human B lymphocytes. Proc Natl Acad Sci USA 88:7635, 1991.
Lombardi L, Newcomb EW, Dalla-Favera R: Pathogenesis of Burkitt lymphoma: Expression of an activated c-myc oncogene causes the tumorigenic conversion of EBV infected human B lymphoblasts. Cell 46:161, 1987.
Adams JM, Harris AW, Pinkert CA, et al: The c-myc oncogene driven by immunoglobulin enhancers induces lymphoid malignancy in transgenic mice. Nature 318:553, 1985.
Gaidano G, Lo Coco F, Ye BH, et al: Rearrangements of the BCL-6 gene in AIDS associated non-Hodgkin’s lymphoma: Association with diffuse large cell subtype. Blood 84:397, 1994.
Gaidano G, Carbone A, Pastore C, et al: Frequent mutatiuons of the 5′ noncoding region of the BCL-6 gene in acquired immuodeficiency syndrome-related non-Hodgkin’s lympomas. Blood 89:3755, 1997.
Gaidano G, Dalla-Favera R: Biologic aspects of human immunodeficiency virus-related lymphoma. Curr Opin Oncol 4:900, 1992.
Gaidano G, Carbone A, Dalla-Favera R: Pathogenesis of AIDS-related lymphomas: Molecular and histogenetic heterogeneity. Am J Pathol 152:623, 1998.
Gaidano G, Ballerini P, Gong JZ, et al: p53 mutations in human lymphoid malignancies: Association with Burkitt lymphoma and chronic lymphocytic luekemia. Proc Natl Acad Sci USA 88:5413, 1991.
Levine AM: Acquired immunodeficiency syndrome-related lymphoma [review]. Blood 80:8, 1992.
Levine AM, Sullivan-Halley J, Pike MC, et al: HIV-related lymphoma: Prognostic factors predictive of survival. Cancer 68:2466, 1991.
Levine AM, Gill PS, Meyer PR, et al: Retrovirus and malignant lymphoma in homosexual men. JAMA 254:1921, 1985.
Ziegler JL, Beckstead JA, Volberding PA, et al: Non-Hodgkin’s lymphoma in 90 homosexual men: Relation to generalized lymphadenopathy and the acquired immunodeficiency syndrome. N Engl J Med 311:565, 1984.
Kaplan LD, Abrams DI, Feigal E, et al: AIDS-associated non-Hodgkin’s lymphoma in San Francisco. JAMA 261:719, 1989.
Knowles DM, Chamulak GA, Subar M, et al: Lymphoid neoplasia associated with the acquired immunodeficiency syndrome (AIDS): The New York University experience with 105 cases during 1981 through 1986. Ann Intern Med 108:744, 1988.
Lowenthal DA, Straus DJ, Campbell SW, et al: AIDS-related lymphoid neoplasia: The Memorial Hospital experience. Cancer 61:2325, 1988.
Ioachim HL, Dorsett B, Cronin W, et al: Acquired immunodeficiency syndrome associated lymphomas: Clinical, pathological, immunologic and viral characteristics of 111 cases. Hum Pathol 22:659, 1991.
Jones SE, Fuks Z, Bellm M, et al: Non-Hodgkin’s lymphoma: IV. Clinicopathologic correlation of 405 cases. Cancer 31:806, 1973.
Podzamczer D, Ricat I, Bolao F, et al: Gallium-67 scan for distinguishing follicular hyperplasia from other AIDS associated diseases in lymph nodes. AIDS 4:683, 1990.
Levine AM, Wernz JC, Kaplan L, et al: Low dose chemotherapy with central nervous system prophylaxis and azidothymidine maintenance in AIDS-related lymphoma: A prospective multi-institutional trial. JAMA 266:84, 1991.
Gill PS, Levine AM, Meyer PR, et al: Primary central nervous system lymphoma in homosexual men: Clinical, immunologic and pathologic features. Am J Med 78:742, 1985.
Goldstein JD, Dickson DW, Moser FG, et al: Primary central nervous system lymphoma in acquired immunodeficiency syndrome: A clinical and pathologic study with results of treatment with radiation. Cancer 67:2756, 1991.
Baumgartner JE, Rachlin JR, Beckstead JH, et al: Primary central nervous system lymphomas: Natural history and response to radiation therapy in 55 patients with acquired immunodeficiency syndrome. J Neurosurg 73:206, 1990.
Gill PS, Graham RA, Boswell W, et al: A comparison of imaging, clinical and pathologic aspects of space occupying lesions within the brain in patients with acquired immunodeficiency syndrome. Am J Physiol Imaging 1:134, 1986.
Ciricillo SF, Rosenblum ML: Use of CT and MR imaging to distinguish intracranial lesions and to define the need for biopsy in AIDS patients. J Neurosurg 73:720, 1990.
Hoffman JM, Waskin HA, Schifter T, et al: PDG-PET in differentiating lympoma from nonmalignant central nervous system lesions in patients with AIDS. J Nucl Med 34:567, 1993.
Alcaide FG, Lomena F, Cruceta A, et al: Predictive value of thallium-201 SPECT in the diagnosis of primary central nervous system lymphoma in AIDS patients [abstr 22291]. 12th World AIDS Conference, Geneva, Switzerland, 1998.
MacMahon EME, Glass JD, Hayward SDC, et al: Epstein-Barr virus in AIDS related primary central nervous system lymphoma. Lancet 338:969, 1991.
Cinque P, Brytting M, Vago L, et al: Epstein-Barr virus DNA in cerebrospinal fluid from patients with AIDS related primary lymphoma of the central nervous system. Lancet 342:398–401, 1993.
Baumgartner JE, Rachlin JR, Beckstead JH, et al: Primary central nervous system lymphoma: Natural history and response to radiation therapy in 55 patients with AIDS. J Neurosurg 73:206, 1990.
Nador RG, Cesarman E, Chadburn A, et al: Primary effusion lymphomas: A distinct clinicopathologic entity associated with the Kaposi’s sarcoma-associated herpes virus. Blood 88:645, 1996.
Chang Y, Cesarman E, Pessin MS, et al: Identification of herpesvirus-like DNA sequences in AIDS associated Kaposi’s sarcoma. Science 266:1865, 1994.
Cesarman E, Chang Y, Moore PS, Said JW, Knowles DM: Kaposi’s sarcoma associated herpesvirus like DNA sequences in AIDS-related body cavity based lymphomas. N Engl J Med 332:1186, 1995.
Jones D, Ballestas ME, Kaye KM, et al: Primary effusion lymphoma and Kaposi’s sarcoma in a cardiac transplant recipient. N Engl J Med 339:444, 1998.
Nador RG, Cesarman E, Chadburn A, et al: Primary effusion lymphoma: A distinct clinicopathologic entity associated with the Kaposi’s sarcoma-associated herpes virus. Blood 88:645, 1996.
Centers for Disease Control: Revision of the case definition of acquired immunodeficiency syndrome for national reporting: United States. Ann Intern Med 103:402, 1985.
Lukes RJ, Parker JW, Taylor CR, et al: Immunologic approach to non-Hodgkin’s lymphomas and related leukemias: Analysis of the results of multiparameter studies of 425 cases. Semin Hematol 15:322, 1978.
Levine AM, Burkes RL, Walker M, et al: Development of B cell lymphoma in two monogamous homosexual men. Arch Intern Med 145:479, 1985.
Carbone A, Tirelli U, Vaccher E, et al: A clinicopathologic study of lymphoid neoplasms associated with human immunodeficiency virus infection in Italy. Cancer 68:842, 1991.
Horning SJ, Rosenberg SA: The natural history of initially untreated low grade non-Hodgkin’s lymphomas. N Engl J Med 311:1471, 1984.
Straus DJ, Huang J, Testa MA, Levine AM, Kaplan LD: Prognostic factors in the treatment of human immunodeficiency virus-associated non-Hodgkin’s lymphoma: Analysis of AIDS Clinical Trials Group protocol 142: Low dose versus standard dose m-BACOD plus granulocyte-macrophage stimulating factor. J Clin Oncol 16:3601, 1998.
Dugan M, Subar M, Odajnyk C, et al: Intensive multiagent chemotherapy for AIDS related diffuse large cell lymphoma. Blood 68:124a, 1986.
Odajnyk C, Subar M, Dugan M, et al: Clinical features and correlates with immunopathology and molecular biology of a large group of patients with AIDS associated small non-cleaved lymphoma (SNCL). Blood 68:1331a, 1986.
Gill PS, Levine AM, Krailo M, et al: AIDS-related malignant lymphoma: Results of prospective treatment trials. J Clin Oncol 5:1322, 1987.
Bermudez M, Grant KM, Rodvien R, Mendes F: Non-Hodgkin’s lymphoma in a population with or at risk for acquired immunodeficiency syndrome: Indications for intensive chemotherapy. Am J Med 86:71, 1989.
Kaplan LD, Straus DH, Testa MA, et al: Low dose compared with standard dose m-BACOD chemotherapy for non-Hodgkin’s lymphoma associated with human immunodeficiency virus infection. N Engl J Med 336:1641, 1997.
Sparano JA, Wiernik PH, Strack M, Leaf A, Becker N, Valentine ES: Infusional cyclophosphamide, doxorubicin, and etoposide in HIV and HTLV-I related non-Hodgkin’s lymphoma: A highly active regimen. Blood 81:2810, 1993.
Sparano JA, Lee S, Chen M, et al: Phase II trial of infusional cyclophosphamide, doxorubicin and etoposide (CDE) in HIV associated non-Hodgkin’s lymphoma: An Eastern Cooperative Oncology Group trial (E1494) [abstr 41]. Proc ASCO 18:12a, 1999.
Wilson WH, Bryant G, Bates S, et al: EPOCH chemotherapy: Toxicity and efficacy in relapsed and refractory non-Hodgkin’s lymphoma. J Clin Oncol 11:1573, 1993.
Little RF, Pearson D, Steinberg S, et al: Dose adjusted EPOCH chemotherapy in previously untreated HIV associated non-Hodgkin’s lymhoma [abstr 33]. Proc ASCO 18:10a, 1999.
Penn I: The changing pattern of posttransplant malignancies. Transplant Proc 23:1101, 1991.
Brunson ME, Balakrishnan K, Penn I: HLA and Kaposi’s sarcoma in solid organ transplantation. Hum Immunol 29:56, 1990.
Mann DL, Murray C, O’Donnell M, et al: HLA antigen frequencies in HIV-1 related Kaposi’s sarcoma. J AIDS 3:51, 1990.
Jaffe HW, Choi K, Thomas PA, et al: National case-control study of Kaposi’s sarcoma and Pneumocystis carinii pneumonia in homosexual men: I. Epidemiologic results. Ann Intern Med 99:145, 1983.
Beral V, Bull D, Darby S, et al: Risk of Kaposi’s sarcoma and sexual practices associated with faecal contact in homosexual or bisexual men with AIDS. Lancet 339:632, 1992.
Beral V, Peterman TA, Berkelman RL, Jaffe HW: Kaposi’s sarcoma among persons with AIDS: A sexually transmitted infection? Lancet 335:123, 1990.
Afrasiabi R, Mitsuyasu R, Nashanian P: Characterization of a distinct subgroup of high risk persons with Kaposi’s sarcoma and good prognosis who present with normal T4 cell number and T4;T8 ratio and negative HTL VIII/LAV serologic test results. Am J Med 81:969, 1986.
Friedman-Kien AE, Saltzman BR, Cao YZ, et al: Kaposi’s sarcoma in HIV-negative homosexual men [letter]. Lancet 335:168, 1990.
Garcia Muret MP, Pujol RM, Puig I, et al: Disseminated Kaposi’s sarcoma not associated with HIV infection in a bisexual man. J Am Acad Dermatol 23:1035, 1990.
Chang Y, Cesarman E, Pessin ME, et al: Identification of herpes virus-like DNA sequences in AIDS-associated Kaposi’s sarcoma. Science 266:1865, 1994.
Moore PS, Chang Y: Detection of herpesvirus-like DNA sequences in Kaposi’s sarcoma in patients with and those without HIV infection. N Engl J Med 332:1181, 1995.
Huang Y-Q, Li JJ, Kaplan MH, et al: Human herpesvirus-like nucleic acid in various forms of Kaposi’s sarcoma. Lancet 345:759, 1995.
Dupin N, Grandadam MN, Calvez V, et al: Herpesvirus-like DNA sequences in patients with Mediterranean Kaposi’s sarcoma. Lancet 345:761, 1995.
Su I-J, Hsu Y-S, Chang Y-C, Wang I-W: Herpesvirus-like DNA sequences in Kaposi’s sarcoma from AIDS and non-AIDS patients in Taiwan. Lancet 345:722, 1995.
Gao S-J, Kingsley L, Hoover DR, et al: Seroconversion to antibodies against Kaposi’s sarcoma-associated herpesvirus-related latent nuclear antigens before the development of Kaposi’s sarcoma. N Engl J Med 335:233, 1996.
Martin JN, Ganem DE, Osmond DH, et al: Sexual transmission and the natural history of human herpesvirus 8 infection. N Engl J Med 338:948, 1998.
Oksenhendler E, Sazals-Hatem D, Schultz TF, et al: Transient angiolymphoid hyperplasia and Kaposi’s sarcoma after primary infection with HHV8 in a patient with HIV infection. N Engl J Med 338:1585, 1998.
Cerimele E, Cesarman E, Curreli G, et al: In vitro infection of primary human keratinocytes by Kaposi’s sarcoma associated herpesvirus [abstr 73]. 3rd National AIDS Malignancy Conference, Bethesda, MD, 1999.
Ganem D: KSHV/HHV8 infection and the pathogenesis of AIDS-related neoplasms: An overview [abstr S7]. 3rd National AIDS Malignancy Conference, Bethesda, MD, 1999.
Chadburn A, Hyjek E, Ying L, et al: KSHV/HHV8 interluekin 6 (vIL6) expression in HIV related lymphadenopathy correlates with development of Kaposi’s sarcoma and survival [abstr 47]. 3rd National AIDS Malignancy Conference, Bethesda, MD, 1999.
Breen EC, Gage JR, Magpantay L, et al: Biological effects of the HHV8-encoded IL-6 homologue (v IL6). [abstr 42]. 3rd National AIDS Malignancy Conference, Bethesda, MD, 1999.
Ensoli B, Nakamura S, Salahuddin SZ, et al: AIDS-Kaposi’s sarcoma derived cells express cytokines with autocrine and paracrine growth effects. Science 243:223, 1989.
Miles S, Rezai A, Magpantay L, et al: Oncostatin-M is a potent mitogen for AIDS-Kaposi’s sarcoma (AIDS-KS) cell lines. Science 255:1434, 1991.
Brown TJ, Rowe JM, Liu JW, Shoyab M: Regulation of IL-6 expression by oncostatin M. J Immunol 147:2175, 1991.
Miles SA, Rezai AR, Salazar-Gonzalez JF, et al: AIDS Kaposi’s sarcoma derived cells produce and respond to interleukin-6. Proc Natl Acad Sci USA 87:4068, 1990.
Huang YQ, Li JJ, Nicolaides A, et al: Fibroblast growth factor 6 gene expression in AIDS-associated Kaposi’s sarcoma. Lancet 339:1110, 1992.
Vogel J, Hinrichs SH, Reynolds RK, et al: The HIV tat gene induces dermal lesions resembling Kaposi’s sarcoma in transgenic mice. Nature 335:606, 1988.
Ensoli B, Barillari G, Salahuddin SZ, et al: Tat protein of HIV-1 stimulates growth of cells derived from Kaposi’s sarcoma lesions of AIDS patients. Nature 345:84, 1990.
Albini A, Fontanini G, Masiello L, et al: Angiogenic potential in vivo by KS cell free supernatants and HIV-1 tat product: Inhibition of KS like lesions by tissue inhibitor of metalloproteinase-2. AIDS 8:1237, 1994.
Breen EC, Rezai AR, Nakajima K, et al: Infection with HIV is associated with elevated IL-6 levels and production. J Immunol 144:480, 1990.
Molina JM, Scadden DT, Byrn R, et al: Production of tumor necrosis factor alpha and interleukin 1 beta by monocytic cells infected with human immunodeficiency virus. J Clin Invest 84:733, 1989.
Friedman-Kien AE, Laubenstein LJ, Rubinstein P: Disseminated Kaposi’s sarcoma in homosexual men. Ann Intern Med 96:693, 1982.
Friedman SL, Wright TL, Altman DF: Gastrointestinal Kaposi’s sarcoma in patients with acquired immunodeficiency syndrome. Gastroenterology 89:102, 1985.
Rose HS, Balthazar EJ, Megiobow AJ, et al: Alimentary tract involvement in Kaposi’s sarcoma: Radioscopic and endoscopic findings in homosexual men. Am J Radiol 13:661, 1982.
Gill PS, Akil B, Colletti P, et al: Pulmonary Kaposi’s sarcoma: Clinical findings and results of therapy. Am J Med 87:57, 1989.
Garay SM, Belenko M, Fazzini E, et al: Pulmonary manifestation of Kaposi’s sarcoma. Chest 91:39, 1987.
Levine AM, Meyer PR, Gill PS, et al: Results of diagnostic lymph node biopsy in homosexual men with generalized lymphadenopathy. J Clin Oncol 4:165, 1985.
Robles R, Lugo D, Gee L, Jacobson MA: Effect of antiviral drugs used to treat cytomegalovirus end-organ disease on subsequent course of previously diagnosed Kaposi’s sarcoma in patients with AIDS. J Acquir Immune Defic Syndr Hum Retrovirol 20:34, 1999.
Medveczky MM, Horvath E, Lund T, Medveczky PG: In vitro antiviral drug sensitivity of the Kaposi’s sarcoma-associated herpesvirus. AIDS 11:1327, 1997.
Martin DF, Kuppermann BD, Wolitz RA, et al: Oral ganciclovir for patients with cytomegalovirus retinitis treated with a ganciclovir implant. N Engl J Med 340:1063, 1999.
Serfling U, Hood AF: Local therapies for cutaneous Kaposi’s sarcoma in patients with acquired immunodeficiency syndrome. Arch Dermatol 127:1479, 1991.
Tappero JW, Berger TG, Kaplan LD, et al: Cryotherapy for cutaneous Kaposi’s sarcoma (KS) associated with acquired immune deficiency syndromen (AIDS): A phase II trial. J AIDS 4:839, 1991.
Wheeland RG, Bailin PL: Argon laser photocoagulation therapy of Kaposi’s sarcoma: A clinical and histological evaluation. J Dermatol Surg Oncol 11:1180, 1985.
Bodsworth N: Topical 9-cis retinoic acid gel as treatment of cutaneous AIDS-related Kaposi’s sarcoma: Interim results of an international, placebo-controlled trial [abstr 22277]. 12th World AIDS Conference, Geneva, Switzerland, 1998.
Friedman-Kien A, Conant M: North American phase III study (protocol L105T-31) of Panretin gel for cutaneous AIDS-related Kaposi’s sarcoma [abstr 22283]. 12th World AIDS Conference, Geneva, Switzerland, 1998.
Epstein JB, Lozada-Nur F, McLeod A, Spinelli J: Oral Kaposi’s sarcoma in the acquired immunodeficiency syndrome: Review of management and report of the efficacy of intra-lesional vinblastine. Cancer 64:2424, 1989.
Newman S: Treatment of epidemic Kaposi’s sarcoma with intralesional vinblastine injection [abstr]. Proc Am Soc Clin Oncol 7:5, 1988.
Sulis E, Florio C, Sulis ML, et al: Interferon administered intralesionally in skin and oral cavity lesions in heterosexual drug addicted patients with AIDS-related KS. Eur J Cancer Clin Oncol 25:759, 1989.
Chak LY, Gill PS, Levine AM, et al: Radiation therapy for acquired immunodeficiency syndrome-related Kaposi’s sarcoma. J Clin Oncol 6:863, 1988.
Cooper JS, Steinfeld AD, Lerch I: Intentions and outcomes in the radiotherapeutic management of epidemic Kaposi’s sarcoma. Int J Radiat Oncol Biol Phys 20:419, 1991.
Berson AM, Quivey JM, Harris JW, Wara WM: Radiation therapy for AIDS-related Kaposi’s sarcoma. Int J Radiat Oncol Biol Phys 19:569, 1990.
De Wit R, Smith WG, Veenhof KH, et al: Palliative radiation therapy for AIDS associated Kaposi’s sarcoma by using a single fraction of 800 cGy. Radiother Oncol 19:131, 1990.
Stiehm ER, Kronenberg LH, Rosenblatt HM, et al: Interferon: Immunobiology and clinical significance. Ann Intern Med 96:80, 1982.
Mitsuyasu RT: Interferon alpha in the treatment of AIDS-related Kaposi’s sarcoma. Br J Haematol 79:69, 1991.
Rozenbaum W, Gharakhanian S, Navarette MS, et al: Long-term follow-up of 120 patients with AIDS-related Kaposi’s sarcoma treated with interferon alpha-2a. J Invest Dermatol 95:161S, 1990.
Evans LM, Itri LM, Campion M, et al: Interferon-alpha 2a in the treatment of acquired immunodeficiency syndrome-related Kaposi’s sarcoma. J Immunother 10:39, 1991.
Krown SE, Gold JW, Niedzwiecki D, et al: Interferon-alpha with zidovudine: Safety, tolerance, and clinical and virologic effects in patients with Kaposi’s sarcoma associated with the acquired immunodeficiency syndrome. Ann Intern Med 112:812, 1990.
Krown S, Niedzwiecki D, Bhalla RB, et al: Relationship and prognostic value of endogenous interferon-alpha, b2 microglobulin, and neopterin serum levels in patients with Kaposi’s sarcoma and AIDS. J AIDS 4:871, 1991.
Lassoued K, Clauvel JP, Katlama C, et al: Treatment of the acquired immune deficiency syndrome-related Kaposi’s sarcoma with bleomycin as a single agent. Cancer 66:1869, 1990.
Laubenstein LJ, Krigel RL, Odajynk CM, et al: Treatment of epidemic Kaposi’s sarcoma with etoposide or a combination of doxorubicin, bleomycin, and vinblastine. J Clin Oncol 2:1115, 1984.
Volberding PA, Abrams DI, Conant M, et al: Vinblastine therapy for Kaposi’s sarcoma in the acquired immunodeficiency syndrome. Ann Intern Med 103:335, 1985.
Gill PS, Rarick MU, McCutchan JA, et al: A systemic treatment of AIDS-related Kaposi’s sarcoma: Results of a randomized trial. Am J Med 90:427, 1991.
Gill PS, Espina B, Cabriales S, et al: Liposomal daunorubicin (Daunoxome), an effective agent in the treatment of advanced AIDS-related Kaposi’s sarcoma. Blood 80:328a, 1992.
Northfelt DW, Dezube BJ, Thommes JA, et al: Pegylated-liposomal doxorubicin versus doxorubicin, bleomycin and vincristine in the treatment of AIDS-related Kpaosi’s sarcoma: Results of a randomized phase III clinical trial. J Clin Oncol 16:2445, 1998.
Gill PS, Tulpule A, Espina BM, et al: Taxol for advanced AIDS-related Kaposi’s sarcoma. J Clin Oncol 17:1876, 1999.
Gill PS, Rarick MU, Bernstein-Singer M, et al: Treatment of advanced Kaposi’s sarcoma using a combination of bleomycin and vincristine. Am J Clin Oncol 13:315, 1990.
Nakamura S, Sakurada S, Salahuddin SZ, et al: Inhibition of development of Kaposi’s sarcoma-related lesions by a bacterial cell wall complex. Science 255:1437, 1992.
Dezube BJ, Von Roenn JH, Holden-Wiltse J, et al: Fumagillin analog in the treatment of Kaposi’s sarcoma: A phase I CIDS Clinical Trial Group Study. J Clin Oncol 16:1444, 1998.
Miles S, Dezube B, Lee J, et al: Anti-tumor activity of oral 9-cis retinoic acid in AIDS related Kaposi’s sarcoma: AIDS Malignancy Consortium Study 002 [abstr 22276]. 12th World AIDS Conference, Geneva, Switzerland, 1998.
Carpenter C, Fischl M, Hammer S, et al: Updated recommendations of the International AIDS Society Panel: USA Panel. JAMA 277:1962, 1997.
1998 revision to the British HIV Association guidelines for antiretroviral treatment of HIV seropositive individuals. Lancet 352:314, 1998.
Department of Health and Human Services: Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. http://www.hivatis.org.
Ho D: Time to hit HIV early and hard. N Engl J Med 333:450, 1995.
O’Brien W, Hartigan P, Daar E, et al: Changes in plasma HIV-1 RNA and CD4 lymphocyte counts predict both response to antiretroviral therapy and therapeutic failure: Veterans Affairs Co-operative Study Group on AIDS. Ann Intern Med 126: 933, 1997.
Perelson A, Essunger Y, Cao Y, et al: Decay characteristics of HIV-1–infected compartments during combination therapy. Nature 387:188, 1997.
Raboud J, Montaner J, Conway B, et al: Suppression of plasma viral load below 20 copies/mL is required to achieve a long-term response to therapy. AIDS 12:1619, 1998.
Wit F, vanLeeuwen R, Weverling G, et al: Outcome and predictors of failure of highly active antiretroviral therapy: One-year follow-up of a cohort of human immunodeficiency virus type 1-infected persons. J Infect Dis 179:790, 1999.
Mayers D: Prevalence and incidence of resistance to zidovudine and other antiretroviral drugs. Am J Med 102:70, 1997.
Richman D: Antiretroviral drug resistance: Mechanism, pathogenesis, clinical significance. Adv Exp Med Biol 394: 383, 1996.
Moyle G: Current knowledge of HIV reverse transcriptase mutations selected during nucleoside analogue therapy: The potential to use resistance data to guide clinical decisions. J Antimicrob Chemother 40:765, 1997.
Williams A, Friedland G: Adherence, compliance and HAART. AIDS Clin Care 9:51, 1997.
Ickovics J, Meisler A: Adherence in AIDS clinical trials: A framework for clinical research and clinical care. J Clin Epidemiol 50:385, 1997.
Haynes R, McKibbon K, Kanani R: Systematic review of randomised trials of interventions to assist patients to follow prescriptions for medications. Lancet 348:383, 1996.
Hecht FM, Grant RM, Petropoulos CJ, et al: Sexual transmission of an HIV-1 variant resistant to multiple reverse-transcriptase and protease inhibitors. N Engl J Med 339:307, 1998.
Hirsh M, Conway B, D’Aquila R, et al: Antiretroviral drug resistance testing in adults with HIV infection: Implications for clinical management. International AIDS Society: USA Panel. JAMA 279:1984, 1998.
Rodriguez-Rosado R, Briones C, Soriano V: Introduction of HIV drug resistance testing in clinical practice. AIDS 12:1007, 1999.
Yarchoan R, Mitsuya H, Myers C, et al: Clinical pharmacology of a 3′-azido-2′,3′-dideoxythymidine and related didexynucleosides. N Engl J Med 321:726, 1989.
Molina J-M, Journot V, Ferchal F, et al: ALBI (ANRS 070): A randomized controlled trial to evaluate the efficacy and safety of AZT/3TC vs. alternating d4T/ddI and AZT/3TC vs. d4T/ddI [abstr 12227]. 12th World AIDS Conference, Geneva, 1998.
Yarchoan R, Berg G, Brouwers P, et al: Response of HIV associated neurological disease. Lancet 1:132, 1987.
Sidtis J, Gatsonis C, Price R, et al: Zidovudine treatment of the AIDS dementia complex: Results of a placebo-controlled trial. Ann Neurol 33:343, 1993.
Bew B, Brown S, Catalan J, et al: Phase III, randomized, double-blind, placebo controlled, multicentre study to evaluate the safety and efficacy of abacavir (ABC, 1592) in HIV-1 infected subjects with AIDS dementia complex (CNA3001) [abstr 39192]. 12th World AIDS Conference, Geneva, 1998.
Van Leeuwen R, Katlama C, Kitchen V, et al: Evaluation and safety of 3TC (lamivudine) with asymptomatic or mildly symptomatic HIV infection: A phase III study. J Infect Dis 171:116, 1995.
Larder B, Kemp S, Harrigan P: Potential mechanism for sustained antiretroviral efficacy of AZT-3TC combination therapy. Science 269:696, 1995.
Kemp S, Shi C, Bloor C, et al: A novel polymorphism at codon 333 of HIV type 1 reverse transcriptase can facilitate dual resistance to AZT and 3TC. J Virol 72:5093, 1998.
DeClercq E: The role of non-nucleoside reverse transcriptase inhibitors (NNRTIs) in the therapy of HIV-1 infection. Antiviral Res 153, 1998.
Saag M, Emini E, Larkin O, et al: A short-term clinical evaluation of L-697,661, a non-nucleoside inhibitor of HIV-1 reverse transcriptase. N Engl J Med 329:1065, 1997.
Feimuth WL: Delavirdine mesylate, a potent non-nucleoside HIV-1 reverse transcriptase inhibitor. Ann Exp Med Biol 394:279, 1996.
Flexner C: Drug therapy: HIV-protease inhibitors. N Engl J Med 338:1281, 1998.
Collier A, et al: Treatment of human immunodeficiency virus infection with saquinavir, zidovudine, and zalcitabine: AIDS Clinical Trials Group. N Engl J Med 334:1011, 1996.
Hammer S, Squires K, Hughes M, et al: A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 counts of 200 per cubic millimeter or less: AIDS Clinical Trials Group 320 Study Section. N Engl J Med 337:725, 1997.
Gulick R, Mellors J, Havlir D, et al: Treatment with indinavir, zidovudine and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy. N Engl J Med 337:734, 1997.
Gulick R, Mellor J, Havlir D: Simultaneous vs. sequential initiation of therapy with indinavir, zidovudine, and lamivudine for HIV-1 infection: 100-week follow-up. JAMA 280:35, 1998.
Cameron D, Heath-Chiozzi M, Danner S: Randomised placebo-controlled trial of ritonavir in advanced HIV-1 disease: The Advanced HIV Disease Ritonavir Study Group. Lancet 351:543, 1998.
Hsu A, Granneman F, Bertz R: Ritonavir: Clinical pharmacokinetics and interactions with other anti-HIV drugs. Clin Pharmacokinet 35:275, 1998.
Cameron D, Japour A, Xu Y: Ritonavir and saquinavir combination therapy for the treatment of HIV infection. AIDS 13:213, 1999.
Workman C, Musson R, Dyer W, et al: Novel double protease combinations containing indinavir with ritonavir: Results from first study [abstr 22372]. 12th World AIDS Conference, Geneva, 1998.
Pedneault L, Fetter A, Hanson C, et al: Amprenavir (141W94, APV): Review of overall safety profile [abstr 386]. 6th Conference on Retroviruses, Chicago, 1999.
Haubrich R: Phase 2 study or amprenavir, a novel protease inhibitor, in combination with zidovudine/3TC [abstr 12321]. 12th World AIDS Conference, Geneva, 1998.
Eron J, Haubrich R, Richman D: Safety and efficacy of amprenavir in combination with other HIV protease inhibitors [abstr 84]. 4th International Congress on Drug Therapy in HIV Infection, Glasgow, 1998.
Reports of diabetes and hyperglycemia in patients receiving protease inhibitors for the treatment of human immunodeficiency virus (HIV): FDA Public Health Advisory. JAMA 278:379, 1997.
Dube M, Johnson D, Currier J, et al: Protease inhibitor-associated hyperglycemia [letter]. Lancet 50:713, 1997.
Visnegarwala F, Krause K, Musher D: Severe diabetes associated with protease inhibitor therapy [letter]. Ann Intern Med 127:947, 1997.
Eastone J, Deckler C: New-onset diabetes mellitus associated with the use of protease inhibitor. Ann Intern Med 127:948, 1997.
Lo J, Mulligan K, Tai V, et al: Buffalo hump in men with HIV-1 infection. Lancet 351:867, 1998.
Carr A, Samarras K, Chisholm D, et al: Pathogenesis of HIV-1 protease inhibitor-associated peripheral lipodystrophy, hyperlipidemia and insulin resistance. Lancet 351:1881, 1998.
Gharakhanian S, Salhi Y, Nguyen H, et al: Frequency of lipodystrophy and factors associated with glucose/lipid abnormalities in a cohort of 650 patients treated by protease inhibitors [abstr 642]. 6th Conference on Retroviruses, Chicago, 1999.
Tsiodras S, Mantzoros C, Hammer S, et al: Effects of protease inhibitor use on hyperglycemia and hyperlipidemia: A five year analysis [abstr 643]. 6th Conference on Retroviruses, Chicago, 1999.
Henry K, Melroe H, Huebsch J et al: Severe premature coronary artery disease with protease inhibitors [letter]. Lancet 351:1328, 1998.
Lucas GM, Chaisson RE, Moore RD: Highly active antiretroviral therapy in a large urban clinic: Risk factors for virologic failure and adverse drug reactions. Ann Intern Med 131:81, 1999.
Wit F, vanLeewen G, Weverling S, et al: Determinants of failure of highly active antiretroviral therapy (HAART) [abstr 12271]. 12th World AIDS Conference, Geneva, 1998.
Garcia F, Romeu I, Grau M, et al: An open randomized study comparing the influence of difference therapeutic strategies: No treatment vs. double therapy (ZDV/d4T + 3TC) vs. triple therapy (d4T + 3TC + indinavir) in the progression of chronic HIV-1 infected patients in very early stages (Spanish Early Antiretroviral Therapy in HIV: Spanish EARTH-2 study) [abstr 12238]. 12th World AIDS Conference, Geneva, 1998.
Centers for Disease Control and Prevention: Public Health Service recommendations for the management of health-care worker exposures to HIV and recommendations for postexposure prophylaxis. MMWR 47(RR-7):1998.
Copyright © 2001 McGraw-Hill
Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn