AIDS INFORMATION NEWSLETTER Michael Howe, MSLS, Editor AIDS Information Center VA Medical Center, San Francisco (415) 221-4810 ext 3305 November 22, 1996 Antiretroviral Therapy (Part III) Editor's Note: In Part II (8 November 1996) part of the information following question number nine was lost during transmission. The question with the corrected response should be: 9. Okay! What drugs are available to me? The number of drugs available to people with HIV has increased dramatically over the past year. Nine drugs are now FDA-approved for the treatment of HIV, with several others in the pipeline. Five of these nine belong to a class of drugs called nucleoside analogue reverse transcriptase inhibitors, AZT, ddI, ddC, d4t, and 3TC. Three others belong to a class of drugs called protease inhibitors, saquinavir, ritonavir, indinavir; the most recently approved drug, nevirapine, belongs to a third class called non-nucleoside reverse transcriptase inhibitors (NNRTIs). ---------------------------------------------------------------- Nucleoside Analogs - Reverse Transcriptase Inhibitors AZT (Zidovudine, Azidothymidine, Retrovir) Approved March, 1987 Descriptive Information 1. Wilde MI and Langtry HD. Zidovudine: An Update of its Pharmacodynamic and Pharmacokinetics Properties, and Therapeutic Efficacy. Drugs. 1993;46(3):515-578. Abstract: Zidovudine remains the mainstay in the treatment of patients infected with human immunodeficiency virus (HIV). The drug delays disease progression to acquired immunodeficiency syndrome (AIDS) and to AIDS-related complex (ARC), reduces opportunistic infections, and increases survival in patients with advanced HIV infection. There is evidence to suggest that zidovudine also delays disease progression in patients with mild symptomatic disease. Although one study has shown zidovudine to have no significant beneficial effects on survival or disease progression in patients with asymptomatic HIV infection, several other studies have shown zidovudine to delay disease progression in this patient group. Results from related ongoing studies are awaited with interest. Zidovudine reduces the incidence of AIDS dementia complex (ADC) and appears to prolong survival in these patients, and improves other neurological complications of HIV infection. The drug also appears to enhance the efficacy of interferon-alpha in patients with Kaposi's sarcoma. Although zidovudine is widely used as postexposure prophylaxis following accidental exposure to HIV, its efficacy in preventing seroconversion is unclear. Whether zidovudine prevents vertical transmission also remains to be determined. The overall efficacy of zidovudine in the treatment of children with HIV infection appears similar to that in adults despite more rapid disease progression in younger patients. Zidovudine-resistant isolates can emerge as early as after 2 months' therapy, and primary infection with zidovudine-resistant strains has been documented. Both zidovudine resistance and the syncytium-inducing HIV phenotype appear to be associated with poor clinical outcome. However, zidovudine resistance may revert on drug withdrawal or switching to an alternative therapy. Zidovudine-associated haematotoxicity may be dose-limiting. Nonhaematological adverse events associated with zidovudine therapy are generally mild and usually resolve spontaneously. Dosages of approximately 500 to 600 mg/day appear to be at least as effective as dosages of 1200 to 1500 mg/day and are better tolerated in patients with less advanced disease. However, optimal dosage are unclear. Despite beneficial effects, zidovudine monotherapy is not curative. There is evidence to suggest that the concomitant administration of zidovudine with didanosine or zalcitabine is effective in patients with HIV disease progression despite receiving zidovudine monotherapy, and there is some evidence that concomitant zidovudine plus didanosine therapy is more effective than alternating monotherapy. However, results from studies of combination therapy in asymptomatic patients, and from comparative combination therapy studies are awaited. Cotherapy with agents that augment haematopoiesis allows the continuation of therapeutic zidovudine dosages. Therefore, at present, zidovudine remains the cornerstone in the treatment of HIV infection. In the near future, however, multiple agent zidovudine-containing combination therapy is likely to be the optimal treatment strategy. Journal Articles - Historical Overview (Chronological Order) 1. Fischl MA et al. The Efficacy of Azidothymidine (AZT) in the Treatment of Patients with AIDS and AIDS-Related Complex: A Double-Blind, Placebo-Controlled Trial. NEJM. 1987;317(4):185- 91. Abstract: We conducted a double-blind, placebo-controlled trial of the efficacy of oral azidothymidine (AZT) in 282 patients with the acquired immunodeficiency syndrome (AIDS) manifested by Pneumocystis carinii pneumonia alone, or with advanced AIDS-related complex. The subjects were stratified according to numbers of T cells with CD4 surface markers and were randomly assigned to receive either 250 mg of AZT or placebo by mouth every four hours for a total of 24 weeks. One hundred forty-five subjects received AZT, and 137 received placebo. When the study was terminated, 27 subjects had completed 24 weeks of the study, 152 had completed 16 weeks, and the remainder had completed at least 8 weeks. Nineteen placebo recipients and 1 AZT recipient died during the study (P less than 0.001). Opportunistic infections developed in 45 subjects receiving placebo, as compared with 24 receiving AZT. The base-line Karnofsky performance score and weight increased significantly among AZT recipients (P less than 0.001). A statistically significant increase in the number of CD4 cells was noted in subjects receiving AZT (P less than 0.001). After 12 weeks, the number of CD4 cells declined to pretreatment values among AZT recipients with AIDS but not amonG AZT recipients with AIDS-related complex. Skin-test anergy was partially reversed in 29 percent of subjects receiving AZT, as compared with 9 percent of those receiving placebo (P less than 0.001). These data demonstrate that AZT administration can decrease mortality and the frequency of opportunistic infections in a selected group of subjects with AIDS or AIDS-related complex, at least over the 8 to 24 weeks of observation in this study. 2. Fischl MA et al. The Safety and Efficacy of Zidovudine (AZT) in the Treatment of Subjects with Mildly Symptomatic Human Immunodeficiency Virus Type 1 (HIV) Infection: A Double-Blind, Placebo-Controlled Trial. The AIDS Clinical Trials Group. Annals of Internal Medicine. 1990;112:727-37. Abstract: OBJECTIVE: To evaluate the efficacy and safety of zidovudine early in the treatment of human immunodeficiency virus type 1 (HIV) infection. DESIGN: A double-blind, randomized, placebo-controlled trial with subject stratification by pretreatment CD4 T lymphocyte counts. SETTING: Multicenter trial at AIDS Clinical Trial units. SUBJECTS: Seven hundred eleven subjects with mildly symptomatic HIV infection. INTERVENTION: Three hundred fifty-one subjects were assigned to placebo and 360 to zidovudine, 200 mg orally every 4 hours. The median duration of follow-up was 11 months. MEASUREMENTS AND MAIN RESULTS: Fifty-one subjects developed the acquired immunodeficiency syndrome (AIDS), advanced AIDS-related complex, or death as a first critical event. For the stratum of subjects with more than 200 but less than 500 CD4 T lymphocytes/mm3 before treatment, 34 events occurred in placebo recipients and 12 in zidovudine recipients (P = 0.0002; relative risk [RR] estimate, 3.23 [95% CI, 1.67 to 6.24]). For the stratum of subjects with 500 to 799 CD4 T lymphocytes/mm3 before treatment, 2 events occurred in placebo recipients and 3 in zidovudine recipients. Candidiasis at study entry independently increased the risk for having an event (P = 0.005; RR estimate, 2.3 [95% CI, 1.29 to 4.12]); HIV antigenemia at study entry also increased this risk (P = 0.01; RR estimate, 2.1 [95% CI, 1.2 to 3.8]). Significant differences between the treatment groups in CD4 T-lymphocyte counts occurred in subjects with more than 200 but less than 500 CD4 T lymphocytes/mm3 after 4 weeks of therapy (P = 0.002). Differences persisted through week 52. Less prominent changes occurred in subjects with 500 or more CD4 T lymphocytes/mm3. Serum levels of HIV antigen decreased significantly in zidovudine recipients. Serious anemia and neutropenia occurred in 5% and 4% of zidovudine recipients, respectively, and in 0% and 1% of placebo recipients, respectively. CONCLUSION: Zidovudine delayed progression of HIV disease and produced little toxicity in subjects with mildly symptomatic HIV disease and less than 500 CD4 T lymphocytes/mm3. 3. Volberding PA et al. Zidovudine in Asymptomatic Human Immunodeficiency Virus Infection: A Controlled Trial in Persons with Fewer than 500 CD4-Positive Cells per Cubic Millimeter. NEJM. 1990;;322(14):941-49. Abstract: Zidovudine (AZT) is a potent inhibitor of the replication of the human immunodeficiency virus (HIV), and it has been shown to improve survival in advanced HIV disease. We conducted a randomized, double-blind trial in adults with asymptomatic HIV infection who had CD4+ cell counts of fewer than 500 per cubic millimeter on entry into the study. The subjects (92 percent male) were randomly assigned to one of three treatment groups: placebo (428 subjects); zidovudine, 500 mg per day (453); or zidovudine, 1500 mg per day (457). After a mean follow-up of 55 weeks (range, 19 to 107), 33 of the subjects assigned to placebo had the acquired immunodeficiency syndrome (AIDS), as compared with 11 of those assigned to receive 500 mg of zidovudine (P = 0.002; relative risk, 2.8; 95 percent confidence interval, 1.4 to 5.6) and 14 of those assigned to receive 1500 mg of zidovudine (P = 0.05; relative risk, 1.9; 95 percent confidence interval, 1.0 to 3.5). In the three treatment groups, the rates of progression (per 100 person-years) to either AIDS or advanced AIDS-related complex were 7.6, 3.6, and 4.3, respectively. As compared with those assigned to placebo, the subjects in the zidovudine groups had significant increases in the number of CD4+ cells and significant declines in p24 antigen levels. In the 1500-mg zidovudine group, severe hematologic toxicity (anemia or neutropenia) was more frequent than in the other groups (P less than 0.0001). In the 500-mg zidovudine group, nausea was the only toxicity that was significantly more frequent (in 3.3 percent) than in the placebo group (P = 0.001). We conclude that zidovudine is safe and effective in persons with asymptomatic HIV infection and fewer than 500 CD4+ cells per cubic millimeter. Additional study will be required to determine whether such treatment will ultimately improve survival for persons infected with HIV. 4. Collier AC et al. A Pilot Study of Low-Dose Zidovudine in Human Immunodeficiency Virus Infection. NEJM. 1990;323(15):1015-21. Abstract: BACKGROUND. Zidovudine delays the progression of human immunodeficiency virus (HIV) infection but is associated with hematologic toxicity at high doses. Regimens are needed that preserve or enhance efficacy and reduce toxicity. Acyclovir has been reported to potentiate the effect of zidovudine on HIV in vitro. METHODS. We conducted a Phase II open-label, dose-escalating trial to evaluate the clinical and antiviral effects of zidovudine at low (300 mg daily, 28 subjects), medium (600 mg, 24 subjects), and high (1500 mg, 15 subjects) doses, either with or without acyclovir (4.8 g) by random assignment. The subjects had the acquired immunodeficiency syndrome (AIDS)-related complex, but not AIDS. All of them had either HIV p24 antigenemia or plasma viremia and CD4-lymphocyte counts of 200 to 500 per cubic millimeter when they began treatment. RESULTS. Performance scores and fatigue improved the most in the low- and medium-dose zidovudine groups (both P less than or equal to 0.025). Those assigned to low-dose zidovudine gained the most weight and had the greatest improvement in the mean CD4-lymphocyte count (from 321 per cubic millimeter at base line to 412 per cubic millimeter after 12 weeks, P = 0.01). The proportion of subjects in whom HIV antigenemia resolved, the decrease in the level of antigenemia, and the reduction in the plasma virus titers were similar at all three doses. Subjects assigned to receive the low or medium dose who subsequently crossed over to the 1500-mg dose (n = 19) did not have an increase in CD4-cell counts or a decline in levels of HIV antigen, but they did have dose-related toxicity. The addition of acyclovir to zidovudine was well tolerated, but it did not enhance any of zidovudine's antiretroviral effects. CONCLUSIONS. In this pilot study a very low dose of zidovudine (300 mg) had clinical and virologic effects similar to those of higher daily doses (600 and 1500 mg). The minimal effective dose of zidovudine for the treatment of HIV infection has yet to be determined, and further studies of very low daily doses are warranted. 5. Fischl MA et al. A Randomized Controlled Trial of a Reduced Daily Dose of Zidovudine in Patients with the Acquired Immunodeficiency Syndrome. NEJM. 1990;323(15):1009-14. Abstract: BACKGROUND. The initially tested dose of zidovudine for the treatment of patients with advanced disease caused by the human immunodeficiency virus type 1 (HIV) was 1500 mg. Although this dose is effective, it is associated with substantial toxicity. METHODS. To evaluate the efficacy and safety of a reduced dose, we conducted a randomized controlled trial in 524 subjects who had a first episode of Pneumocystis carinii pneumonia. The subjects were assigned to receive zidovudine in either a dose of 250 mg taken orally every four hours (the standard-treatment group, n = 262) or a dose of 200 mg taken orally every four hours for four weeks and thereafter 100 mg taken every four hours (the low-dose group, n = 262). RESULTS. The median length of follow-up was 25.6 months. At 18 months the estimated survival rates were 52 percent for the standard-treatment group and 63 percent for the low-dose group (P = 0.012 by the log-rank test). At 24 months the estimated survival rates were 27 percent for the standard-treatment group and 34 percent for the low-dose group (P = 0.033). In both groups, 82 percent of the subjects had another opportunistic infection, and the length of time to that infection was similar in the two groups (P = 0.56 by the log-rank test). CD4 T-lymphocyte counts improved transiently in both groups, and serum levels of HIV antigen decreased in the subjects with antigenemia. The hemoglobin level declined to less than 5 mml per liter (80 g per liter) in 101 subjects in the standard-treatment group and in 77 in the low-dose group (39 vs. 29 percent, P = 0.0009 by the log-rank test). The neutrophil count declined to less than 0.750 x 10(9) per liter in 134 subjects in the standard-treatment group and in 96 in the low-dose group (51 vs. 37 percent, P = 0.0001). CONCLUSIONS. The reduced daily dose of zidovudine used in this study was at least as effective as the standard dose and was less toxic; however, with the use of a four-week induction period with a high dose followed by low-dose treatment, severe anemia and neutropenia were common complications of treatment with zidovudine. 6. Hamilton JD et al. A Controlled Trial of Early Versus Late Treatment with Zidovudine in Symptomatic Human Immunodeficiency Virus Infection. NEJM. 1992;326(7):437- 43. Abstract: BACKGROUND. Zidovudine is recommended for asymptomatic and early symptomatic human immunodeficiency virus (HIV) infection. The best time to initiate zidovudine treatment remains uncertain, however, and whether early treatment improves survival has not been established. METHODS. We conducted a multicenter, randomized, double-blind trial that compared early zidovudine therapy (beginning at 1500 mg per day) with late therapy in HIV-infected patients who were symptomatic and had CD4+ counts between 0.2 x 10(9) and 0.5 x 10(9) cells per liter (200 to 500 per cubic millimeter) at entry. Those assigned to late therapy initially received placebo and began zidovudine when their CD4+ counts fell below 0.2 x 10(9) per liter (200 per cubic millimeter) or when the acquired immunodeficiency syndrome (AIDS) developed. RESULTS. During a mean follow-up period of more than two years, there were 23 deaths in the early-therapy group (n = 170) and 20 deaths in the late-therapy group (n = 168) (P = 0.48; relative risk [late vs. early], 0.81; 95 percent confidence interval, 0.44 to 1.59). In the early-therapy group, 28 patients progressed to AIDS, as compared with 48 in the late-therapy group (P = 0.02; relative risk, 1.76; 95 percent confidence interval, 1.1 to 2.8). Early therapy increased the time until CD4+ counts fell below 0.2 x 10(9) per liter (200 per cubic millimeter), and it produced more conversions from positive to negative for serum p24 antigen. Early therapy was associated with more anemia, leukopenia, nausea, vomiting, and diarrhea, whereas late therapy was associated with more skin rash. CONCLUSIONS. In symptomatic patients with HIV infection, early treatment with zidovudine delays progression to AIDS, but in this controlled study it did not improve survival, and it was associated with more side effects. Note: This historical overview of AZT will continue with Part IV.