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CHAPTER 89 THE ACQUIRED IMMUNODEFICIENCY SYNDROME

CHAPTER 89 THE ACQUIRED IMMUNODEFICIENCY SYNDROME
Williams Hematology

CHAPTER 89 THE ACQUIRED IMMUNODEFICIENCY SYNDROME

HOWARD A. LIEBMAN
TIMOTHY P. COOLEY
ALEXANDRA M. LEVINE

Definition and History

Definition

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
Hematologic Abnormalities

Anemia in HIV Infection

Neutropenia

Thrombocytopenia
Systemic Organ Abnormalities
HIV-Associated Malignancies

AIDS-Related Lymphoma

Kaposi Sarcoma
Antiretroviral Therapy

Nucleoside Reverse Transcriptase Inhibitors

Nonnucleoside Reverse Transcriptase Inhibitors

Protease Inhibitors

Clinical Guidelines
Management of HIV in Pregnancy
Postexposure Prophylaxis
Chapter References

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
DEFINITION
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).
HEMATOLOGIC ABNORMALITIES
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.
NEUTROPENIA
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
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.
HIV-ASSOCIATED MALIGNANCIES
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.
AIDS-RELATED LYMPHOMA
EPIDEMIOLOGY
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.
CLINICAL FEATURES
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
PATHOLOGY
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.
KAPOSI SARCOMA
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.
CLINICAL FEATURES
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
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
PROTEASE INHIBITORS
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.
CLINICAL GUIDELINES
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.
POSTEXPOSURE PROPHYLAXIS
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.
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Books@Ovid
Copyright © 2001 McGraw-Hill
Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn
Williams Hematology

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5 comments on “CHAPTER 89 THE ACQUIRED IMMUNODEFICIENCY SYNDROME

  1. Retrovirus: An RNA virus (a virus composed not of DNA but of RNA). Retroviruses have an enzyme called reverse transcriptase that gives them the unique property of transcribing RNA (their RNA) into DNA. The retroviral DNA can then integrate into the chromosomal DNA of the host cell to be expressed there. The human immunodeficiency virus (HIV), the cause of AIDS, is a retrovirus.

  2. Although the tests for detecting HIV infection continue to improve, they still require that people volunteer for testing. It is estimated that approximately 20% of those infected with HIV in the United States are unaware of their infection because they have never been tested. In order to decrease the number that are unaware of their HIV infection status, in 2006, the Centers for Disease Control and Prevention recommended that all people between the ages of 13 and 64 years be provided HIV testing whenever they encounter the health-care system for any reason. In addition, resources are available to facilitate people finding local HIV testing centers ( http://www.hivtest.org ).

  3. Whether Gallo or Montagnier deserve more credit for the discovery of the virus that causes AIDS has been a matter of considerable controversy . Together with his colleague Françoise Barré-Sinoussi , Montagnier was awarded one half of the 2008 Nobel Prize in Physiology or Medicine for his “discovery of human immunodeficiency virus”.

  4. The human immunodeficiency virus (HIV) is a retrovirus, which, like many other viruses, stores its genetic information as RNA rather than as DNA (most other living things use DNA). When HIV enters a human cell, it releases its RNA, and an enzyme called reverse transcriptase makes a DNA copy of the HIV RNA. The resulting HIV DNA is integrated into the infected cell’s DNA. This process is the reverse of that used by human cells, which make an RNA copy of DNA. Thus, HIV is called a retrovirus, referring to the reversed (backward) process. Other RNA viruses (such as polio, influenza, or measles), unlike retroviruses, do not make DNA copies after they invade cells. They simply make RNA copies of their original RNA.

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