The Body PRO Covers: The 8th Conference on Retroviruses and Opportunistic Infections

Clinical Trials of HIV-1 Protease Inhibitors

February 6, 2001

  • Indinavir/Ritonavir Versus Indinavir in Combination with AZT/3TC for Treatment of HIV in Nucleoside-Experienced Patients: a Randomized, Open-Label Trial (Poster 335)
    Authored by M. Boyd, C. Duncombe, M. Newell, C. Ungsedhapand, K. Ruxrungtham, M. Khongphattanayothin, E. Hassink, S. Ubolyam, T. Chuenyam, J. Lange, D. Cooper, and P. Phanuphak
    View the original abstract

Administering indinavir with ritonavir as pharmacokinetic booster has several advantages, including elimination of indinavir's empty-stomach requirement as well as raising the between-dose drug trough levels. As a result, this method of dosing indinavir has become the de facto standard of care in many practices, despite the fact that there are no published studies that compare ritonavir-enhanced indinavir with standard every-eight-hour dosing.

In this study, conducted in Thailand, 106 patients (who all had received at least three months of AZT therapy) were given AZT/3TC and then randomly assigned to either indinavir 800mg three times daily (TID) or indinavir 800mg/ritonavir 100mg twice daily (BID). At baseline, the mean viral load was 4.0 log (10,000), and CD4 cell count 168. After 48 weeks of therapy, there were no differences between the TID and BID group in terms of viral load decline (2.0 and 1.6 log for TID and BID respectively), proportion with <50 copies/mL (70% vs. 66%), or CD4 cell increases (+57 vs. +70). Adverse effects, however, were somewhat more common in the BID group, in particular nausea and dry mouth, and there was a trend toward more kidney stones in the BID group (17% vs 22%, p=.08). This increased rate of side effects did not contribute to a higher cessation rate in the twice daily group.

The investigators conclude that BID indinavir/ritonavir is as effective as TID indinavir, and that it is a more convenient dosing regimen. However, this study underscores a commonly-seen theme in various ritonavir/indinavir studies -- namely, that the addition of ritonavir adds to the overall toxicity of indinavir-containing regimens. This is likely due both to ritonavir toxicity and to the greater overall exposure to indinavir that occurs when the drugs are co-administered, with indinavir-specific side effects including kidney stones, dry mouth and (in practice) dry skin and hair. Despite these problems, so convincing are the pharmacokinetic data on the indinavir/ritonavir combination that the latest Department of Health and Services Guidelines (released February 5, 2001) endorsed it in as one of the first-line protease inhibitor combination when used with nucleoside analogues. Questions remain as to the optimal dosing of both agents, with the most widely used regimens the one used in this study, 800mg indinavir with 200mg ritonavir both twice daily, and 400mg twice daily of both agents. A current ACTG study is examining this dosing question through intensive pharmacokinetic analysis.

This article was provided by TheBodyPRO. It is a part of the publication The 8th Conference on Retroviruses and Opportunistic Infections.

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