A dramatic decline in AIDS mortality was noted in 1996, when deaths dropped 21%. This trend has continued into 1997, with AIDS deaths down 44%. This dramatic advance occurred because of a better understanding of HIV pathogenesis, the ability to measure and monitor HIV RNA (viral load), and the development of new antiretroviral therapies. With treatment, HIV infection has become a chronic disease. As of April 1998, 11 drugs have been approved to treat HIV infection. The drugs can be classified into three groups: nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors (PIs) (Table 90-1, Table 90-2).
Table 90-1. Antiretroviral drugs: generic and trade names, characteristics
Table 90-2. Other antiretroviral drugs
Antiretroviral therapy began in 1986, when zidovudine first became available. Zidovudine monotherapy was the standard treatment for patients with a CD4-cell count of less than 500/mm3. When this treatment was not tolerated or failed, another NRTI, such as didanosine or zalcitabine, was substituted for zidovudine. The development of resistance is the major problem with monotherapy, and the Concorde Trial findings, presented in 1993, pointed out this lack of efficacy when zidovudine was used alone over time. A new era in antiretroviral therapy began in late 1995, when the results of ACTG 175 and the European-Australian Delta trials showed increased survival with combination therapy for both symptomatic patients and asymptomatic patients with a CD4-cell count below 500/mm3. This new approach, presented in 1996 at the International AIDS Conference, has been termed highly active antiretroviral therapy (HAART). Guidelines for implementing this “hit-early, hit-hard” approach have been issued by the International AIDS Society U.S.A. and by the Department of Health and Human Services and the Henry J. Kaiser Family Foundation (Table 90-3). The recommendations contained in each document regarding initiation of therapy are almost identical.
Table 90-3. Indications for initiation of antiretroviral therapy
The recommended antiretroviral agents for starting therapy are listed in Table 90-4. For the patient naive to antiretroviral therapy, one should begin with a regimen that uses two NRTIs and one PI. An alternative regimen consists of ritonavir and saquinavir (soft-gel formulation) plus one or two NRTIs.
Table 90-4. Recommended antiretroviral agents for treatment of HIV infection
The National Institutes of Health sponsored a panel to define the principles of therapy for HIV infection. Eleven principles were defined as follows:
Active replication of HIV results in immune system damage and progression to AIDS in 98% of patients. For adults in industrialized countries, it takes about 10 years for AIDS to develop after the initial infection in the absence of therapy. In about 20% of persons, disease will progress rapidly, with development of AIDS within 5 years of infection.
Levels of HIV RNA (viral load) indicate the magnitude of HIV replication and the risk for disease progression. The viral load is usually measured by two techniques: branched-chain DNA (bDNA) and RNA reverse transcriptase-polymerase chain reaction (RT-PCR). To convert the number of copies of virus per milliliter obtained by the bDNA method, multiply the result by two to obtain the number of copies per milliliter for the RT-PCR method. The viral load can increase with an acute illness and after an immunization, so that testing of HIV RNA should be deferred for 1 month under these circumstances. It is preferable to retest the viral load in the same laboratory and with the same assay. The threshold of detection with the newer, ultrasensitive assays is as few as 20 copies per milliliter. A significant change in viral load is at least a threefold or a .5 log change. Before initiation of therapy, two specimens should be obtained for HIV RNA determination within 1 to 2 weeks to provide a baseline. It is recommended that the viral load be measured again 4 to 8 weeks after initiation or change of therapy. Measurement of CD4-cell counts is critical to determine the status of the immune system. Susceptibility to opportunistic infections correlates with CD4-cell levels, and recommendations for prophylaxis are based on threshold CD4-cell levels. At present, prophylactic drugs should be continued even when CD4-cell counts increase above the levels considered to be a threshold for prophylaxis.
Treatment decisions to initiate or change therapy should be based on the results of viral load tests and CD4-cell counts. A decrease in viral load of 1 log is associated with an increase in CD4-cell count of about 85/mm3.
The goal of combination therapy is to suppress the HIV RNA (viral load) to below levels of detection by the most sensitive assays. Drug resistance is likely to be present when HIV RNA levels are at or above 5,000 copies per milliliter.
The most effective means to achieve sustained suppression of HIV replication is to use combinations of antiretroviral drugs. Monotherapy is associated with a high risk for the emergence of viral resistance to the agent and the potential for development of cross-resistance to the drug class. For example, suppression of HIV replication is best accomplished by using two NRTIs in combination with a PI. An alternative combination regimen for antiretroviral-naive patients is two NRTIs combined with an NNRTI, such as nevirapine.
Antiretroviral drugs should be prescribed according to the recommended schedules and doses. Underdosing should be avoided to prevent the development of drug resistance. Also, combination therapy should be started simultaneously; the drugs should not be added sequentially. Because patient adherence to the drug regimen is critical to the success of therapy, select drugs and schedules taking into consideration the patient’s circumstances and lifestyle.
When antiretroviral drugs are changed, cross-resistance between drugs in a class must be considered. When a failing regimen is changed, it is important never to change a single drug. Because the number of drugs is limited and cross-resistance occurs commonly, it is important not to abandon a drug prematurely. When it is necessary to change therapy for reasons such as drug toxicity or intolerance, then one drug can be substituted for another while the other components of the regimen are continued.
Pregnancy is not a contraindication for antiretroviral therapy. Women already receiving antiretroviral therapy should continue therapy if they become pregnant. For patients who are pregnant and need to begin antiretroviral drugs, it is recommended that therapy be delayed until 14 weeks of gestation. Zidovudine has been shown to reduce perinatal HIV transmission and should be offered to all pregnant women regardless of their viral load.
The same principles of antiretroviral therapy apply to children and infants, although certain drug formulations and pharmacokinetic data are lacking for these groups.
Persons with acute primary HIV infection should be given combination antiretroviral therapy. Some experts recommend that by “hitting the HIV hard and early” with combination therapy, the HIV viral load will be reduced and the immune system preserved, with a lower HIV set point. It has been suggested that reduction of the viral set point is associated with a more favorable subsequent clinical course. There is no evidence that initiating therapy in a patient with acute seroconversion will lead to eradication of the virus. In the absence of treatment, the viral load declines by less than 1 log per month, and the viral set point is attained at about 4 months. With standard triple-drug therapy, HIV loads decline about 1 log per week.
All HIV-infected persons, even those with undetectable viral loads, should be considered infectious and should be counseled on how to avoid transmitting this virus.
Recommendations have been issued for changing an antiretroviral drug regimen in cases of suspected drug failure based on a significant increase in viral load and/or a declining number of CD4 cells. When the decision to change regimens is based on the determination of an increasing viral load, it is advisable to confirm the data with a repeated viral load test. Generally, it is recommended not to change a single drug or add a single drug to a failing regimen, but rather to use at least two new drugs or an entire new regimen. Although data are limited, it is probably of little use to restart a drug that the patient has previously received because resistance recurs rapidly. Also, avoid changing from ritonavir to indinavir or vice versa for drug failure because cross-resistance is likely. For the same reason, avoid switching from nevirapine to delavirdine or vice versa for drug failure. Table 90-5 lists some regimens for patients who have failed antiretroviral therapy. Clearly, more clinical trials are needed regarding selection of drugs for failing regimens or salvage therapy.
Table 90-5. Regimens for patients who have failed antiretroviral therapy
Resistance to antiretroviral agents develops because of the rapid replication rate of HIV and the high error rate of HIV reverse transcriptase. This leads to frequent mutations and loss of antiretroviral effect. Genotypic testing is commercially available and relatively inexpensive. Phenotypic testing is not standardized and is expensive and time-consuming. Genotypic testing may help distinguish between treatment failure and nonadherence by showing that the virus present is still wild-type (susceptible). Phenotypic testing indicates how the virus interacts with various antiretroviral drugs. At present, both genotypic and phenotypic analysis have only limited use in the care of HIV patients.
The introduction of PIs has made HIV a chronic disease. The various antiretroviral regimens are complex, and failure to adhere to them results in viral resistance and drug failure. Adherence is defined as the extent to which a patient’s behavior corresponds to the medical recommendations. The term adherence has replaced the term compliance because it is considered less pejorative. Measures to increase adherence are listed in Table 90-6. (N.M.G.)
Table 90-6. Methods to achieve optimal adherence
Bartlett JA, Benoit SL, Johnson VA. Lamivudine plus zidovudine compared with zalcitabine plus zidovudine in patients with HIV infection. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 1996;125:161–172.
Use of lamivudine (300 mg/d) plus zidovudine (600 mg/d) was as effective and better tolerated than higher-dose lamivudine plus zidovudine.
BHIVA Guidelines Co-ordinating Committee. British HIV Association guidelines for antiretroviral treatment of HIV-seropositive individuals. Lancet 1997;349:1086–1092.
Guidelines for therapy. Always add at least two new drugs.
CAESAR Coordinating Committee. Randomised trial of addition of lamivudine or lamivudine plus loviride to zidovudine-containing regimens for patients with HIV-1 infection: the CAESAR trial. Lancet 1997;349:1413–1421.
A significant reduction in progression to AIDS and death in patients given lamivudine plus zidovudine compared with zidovudine alone.
Carpenter CC, et al. Antiretroviral therapy for HIV infection in 1997. Updated recommendations of the International AIDS Society USA Panel. JAMA 1997;277:1962–1969.
Treatment guidelines of the International AIDS Society USA Panel. Treat all symptomatic HIV-infected persons and asymptomatic persons with a viral load greater than 5,000 copies per milliliter.
Carpenter CC, et al. Antiretroviral therapy for HIV infection in 1998. Updated recommendations of the International AIDS Society USA Panel. JAMA 1998;280:78–86.
Guidelines for when to initiate therapy, monitor response, and change drugs.
Centers for Disease Control and Prevention. Report of the NIH panel to define principles of therapy of HIV infection and guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. MMWR Morb Mortal Wkly Rep 1998;47 (RR5):1–82.
Guidelines (see also Ann Intern Med 1998;128:1057–1100, republished from MMWR).
Collier AC, et al. Treatment of human immunodeficiency virus infection with saquinavir, zidovudine, and zalcitabine. N Engl J Med 1996;334:1011–1017.
Use of two nucleoside analogs plus saquinavir was effective in reducing viral loads and increasing CD4-cell counts.
Concorde Coordinating Committee. Concorde: MRC/ANRS randomised double-blind controlled trial of immediate and deferred zidovudine in symptom-free HIV infection. Lancet 1994;343:871–881.
Monotherapy with zidovudine was not effective.
Condra JH, Emini EA. Preventing HIV-1 drug resistance. Sci Med 1997;4:1–11.
Mutations occur about once in every 10,000 nucleosides copied, or about once every time a viral genome is copied.
Delta Coordinating Committee. Delta: a randomised, double-blind, controlled trial comparing combinations of zidovudine plus didanosine or zalcitabine with zidovudine alone in HIV-infected individuals. Lancet 1996;348:283–291.
Use of zidovudine plus didanosine or zalcitabine improved survival and delayed disease progression in comparison with zidovudine alone.
Eron JJ, et al. Treatment with lamivudine, zidovudine, or both in HIV-positive patients with 200 to 500 CD4+ cells per cubic millimeter. N Engl J Med 1995; 333:1662–1669.
A combination of zidovudine and lamivudine was better than either drug alone.
Finzi D, et al. Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. Science 1997;278:1295–1300.
A reservoir of latent virus in CD4 cells was found in patients responding to highly active antiretroviral therapy.
Flexner C. HIV-protease inhibitors. N Engl J Med 1998;338:1281–1292.
Gulick RM, et al. Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy. N Engl J Med 1997;337:734–739.
Ninety percent of the group on triple therapy including indinavir had undetectable HIV-1 RNA (<500 copies per milliliter) at 24 weeks, compared with 43% of the group on indinavir monotherapy and none of the group on the lamivudine-zidovudine regimen.
Hammer SM, Katzenstein DA, Hughes MD. A trial comparing nucleoside monotherapy with combination therapy in HIV-infected adults with CD4-cell counts from 200 to 500 per cubic millimeter. N Engl J Med 1996;335:1081–1090.
Improved survival in patients with CD4-cell counts of 200 to 500/mm3 given zidovudine plus didanosine, ziduvudine plus zalcitabine, or didanosine alone.
Hammer SM, et al. A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4-cell counts of 200 per cubic millimeter or less. N Engl J Med 1997;337:725–733.
A three-drug combination containing indinavir was superior to two nucleoside drugs in patients with AIDS (ACTG 320).
Hughes MD, Johnson VA, Hirsch MS. Monitoring plasma HIV-1 RNA levels in addition to CD4+ lymphocyte count improves assessment of antiretroviral therapeutic response. Ann Intern Med 1997;126:929–938.
Disease progression was noted in patients who had less than a 2.5-fold decrease in HIV-1 RNA levels from baseline at 8 weeks after the start of treatment.
deJong MD, et al. High-dose nevirapine in previously untreated human immunodeficiency virus type 1-infected persons does not result in sustained suppression of viral replication. J Infect Dis 1997;175:966–970.
Adverse effects with nevirapine included rash (25%) and fever (20%). Twenty percent of patients discontinued treatment.
Kovacs JA, et al. Controlled trial of interleukin-2 infusions in patients infected with the human immunodeficiency virus. N Engl J Med 1996;335:1350–1356.
CD4-cell counts increased in patients given interleukin-2 if their initial cell counts were above 200/mm3.
Luzuriaga K, et al. Combination treatment with zidovudine, didanosine, and nevirapine in infants with human immunodeficiency virus type 1 infection. N Engl J Med 1997;336:1343–1349.
A three-drug regimen of zidovudine, didanosine, and nevirapine was effective and well tolerated in maternally infected infants and children.
Mayaux MJ, et al. Maternal virus load during pregnancy and mother-to-child transmission of human immunodeficiency virus type 1: the French Perinatal Cohort Studies. J Infect Dis 1997;175:172–175.
HIV-1 was transmitted during pregnancy in 12% of cases with a viral load below 1,000 copies per milliliter, and in 29% of cases with a viral load above 10,000 copies per milliliter.
Medical Letter. Drugs for HIV infection. Med Lett 1997;39:111–116.
Mellors JW, et al. Prognosis in HIV-1 infection predicted by the quantity of virus in plasma. Science 1996;272:1167–1170.
HIV-1 RNA load is the best surrogate marker of disease progression and death.
Montaner JSG, et al. A randomized, double-blind trial comparing combinations of nevirapine, didanosine, and zidovudine for HIV-infected patients. JAMA 1998; 279:930–937.
Fifty-eight percent of patients taking nevirapine plus two nucleoside analogs (zidovudine plus didanosine) had undetectable viral loads (.5 log) and CD4-lymphocyte count.
Palella FJ, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N Engl J Med 1998;338:853–860.
The death rate declined (from 29.4/100 person-years in 1995 to 8.8 in 1997) and the number of opportunistic infections decreased in patients treated with combination therapy containing a protease inhibitor.
Panel on Clinical Practices for Treatment of HIV Infection. Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. Department of Health and Human Services and the Henry J Kaiser Family Foundation, December 1, 1998:1–46.
Guidelines for therapy.
Saravolatz LD, et al. Zidovudine alone or in combination with didanosine or zalcitabine in HIV-infected patients with the acquired immunodeficiency syndrome or fewer than 200 CD4 cells per cubic millimeter. N Engl J Med 1996;335:1099–1106.
In patients with AIDS, combination therapy with zidovudine and either didanosine or zalcitabine is not superior to zidovudine alone.
Volberding PA, et al. A comparison of immediate with deferred zidovudine therapy for asymptomatic HIV-infected adults with CD4-cell counts of 500 or more per cubic millimeter. N Engl J Med 1995;333:401–407.
Zidovudine was of no benefit in asymptomatic HIV-infected patients with a CD4-cell count above 500/mm3.