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Antiretroviral Therapy

By Janine R. Maenza, M.D.

September 1996

Reports on advances in antiretroviral therapy played a prominent role at the Vancouver Conference. Throughout the week, optimism was generated by the developments of the past year. As discussed in the opening plenary session, this progress includes proof of the clinical benefit of combination therapy, a demonstrated survival benefit from treatment of asymptomatic patients with CD4 counts between 200 - 500/mm3, the development of new agents, the beginning of the protease-inhibitor era, and the benefits of treating primary infection. Selected studies highlighting these developments are described here.

Combinations of Nucleoside Reverse Transcriptase Inhibitors:

NUCA 3001/3002: AZT/3TC was compared to AZT or 3TC monotherapy in AZT-naive patients and to AZT/ddC in AZT-experienced patients. Patients on AZT/3TC had greater declines in viral RNA and greater increases in CD4 counts than other groups. In addition, a clinical benefit to AZT/3TC combination therapy was demonstrated. This is the first report of a clinical benefit from 3TC therapy.

ddI and d4T: An ongoing dose-ranging study is evaluating the combination of ddI and d4T in antiretroviral-naive patients with CD4 counts of 200 - 500/mm3. After one year, viral RNA remains suppressed by 1 - 2 log, and CD4 counts show sustained elevation. Only 1 of 94 patients has developed grade 2 peripheral neuropathy.

ddI and Hydroxyurea: Short-term results (Canadian trial): ddI-experienced patients received 500 or 1000 mg/d of hydroxyurea for one month in addition to continued ddI therapy. Among patients receiving 1000 mg/d, 50% showed a decline in viral RNA (.5 log copies/ml), compared with only 15% in the group receiving 500 mg/d. Long-term results (French trial): Antiretroviral-naive patients with CD4 counts >200/mm3 received ddI (200 mg bid) and hydroxyurea (500 mg bid). At one year 10 of 20 patients had undetectable viral RNA with CD4 count increases of approximately 100/mm3. Leukopenia developed in 4 patients.

Combinations Including Non-Nucleoside Reverse Transcriptase Inhibitors :

INCAS Trial: Combinations of AZT, ddI, and nevirapine were evaluated in antiretroviral-naive, asymptomatic patients with CD4 counts 200 - 600/mm3. Triple therapy (AZT/ddI/nevirapine) had a greater effect on viral RNA and CD4 count than either AZT/ddI or AZT/nevirapine: 60% of patients on the triple combination had undetectable viral RNA (<200 copies/ml) at 1 year.

Rash was common: 7 of 98 patients taking nevirapine had to discontinue therapy because of this side effect. (Note: nevirapine was approved by the FDA in June and should only be used as part of combination therapy with nucleoside analogs.)

Ongoing Delavirdine Trials:

Pharmacia and Upjohn Protocol 0021: Dose-ranging combinations of delavirdine (200, 300, or 400 mg bid) and AZT were compared to AZT monotherapy in patients with CD4 counts of 200 - 500/mm3. On delavirdine doses of 300 - 400 mg bid (in combination with AZT), CD4 counts showed a sustained increase of 20-30/mm3 (35-70 cells higher than AZT monotherapy), and viral load remained suppressed by .5 -.6 log at 60 weeks. Rashes occurred frequently but rarely led to medication discontinuation.

Pharmacia and Upjohn Protocol 0017: In AZT-experienced patients with CD4 counts of 0 - 300/mm3, delavirdine (400 mg bid)/ddI was compared with ddI alone. The delavirdine group showed sustained CD4 increases of 10-15/mm3 and viral RNA decreases of .5 log at 1 year.

Combinations Including Protease Inhibitors:

NV14256: AZT-experienced patients with CD4 counts of 50 - 300/mm3 received ddC, saquinavir, or the combination of these agents. The combination reduced the risk of disease progression or death by 53% and the risk of death by 72% compared with ddC alone. (There were no differences between the two monotherapy arms.)

Advanced HIV Ritonavir study group: Patients with CD4 counts <100 mm3 and >9 months of prior antiretroviral therapy were randomized to placebo or ritonavir (600 mg bid) in addition to continuing any nucleoside analog therapy prescribed by their primary medical provider. Open-label ritonavir was provided for the development of a clinical endpoint after 4 months. With longer follow-up data available now than when first reported in Washington in January (average follow-up now 9 months), there is a 50% reduction in disease progression or death in the ritonavir group.

Merck protocol 035: AZT-experienced patients with CD4 counts 50 - 400/mm3, were randomized to AZT/3TC, indinavir, or AZT/3TC/indinavir. Data were previously presented to 24 weeks. Updated information, with follow-up now 44 weeks, shows viral RNA was undetectable (<500 copies/ml) in 83% of the patients on triple therapy, in 22% on indinavir monotherapy, and in 0% on AZT/3TC. Nine of 97 patients developed nephrolithiasis.

Agouron protocol 520: Nelfinavir/d4T was compared with d4T monotherapy in patients with CD4 counts >200/mm3, HIV RNA >15,000 copies/ml, and no prior d4T or protease inhibitor therapy. After 2 months of combination therapy, viral RNA decreased by 1.7 - 2.4 log (on 500 - 1000 mg tid of nelfinavir), and CD4 increases were >100/mm3. This study only included 33 patients; larger phase II/III studies of nelfinavir are now ongoing. Nelfinavir may have a different resistance pattern than currently available protease inhibitors.

Therapy in Early Infection: Dr. Martin Markowitz presented information on 12 patients with early (within 90 days of seroconversion) HIV infection who were treated with AZT, 3TC, and ritonavir. Of the eight patients who have continued therapy (for up to 10 months to date), HIV RNA is undetectable, and cultures for HIV are negative. The CD4/CD8 ratio has normalized in all these patients, and CD4 counts have increased by about 200 cells.




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