July 9, 2002
Although already overshadowed by the "soon-to-come" 908-amprenavir-prodrug, amprenavir (APV or Agenerase) continues to be an important tool in the armamentarium for the treatment of HIV infection.
The addition of boosting 100 mg ritonavir (RTV) to APV has proven to increase APV levels by almost five-fold above those seen with APV alone, and thereby reducing pill burden from 16 capsules to a total of ten capsules a day.
Several clinical trials have been conducted to study the efficacy and tolerability of APV in naive and experienced populations, but there is limited data directly comparing the use of boosted APV with APV alone in these populations. Considering the advantages of boosting APV with ritonavir, a study that compares the efficacy and tolerability of these two regimens is welcome. That is precisely what investigators aimed toward in the design of this study.
Dr. Jeffrey Nadler, from the University of South Florida in Tampa, presented the results of a 24-week study comparing APV/RTV 600/100 mg BID to APV 1,200 mg BID. The study was designed to compare how tolerable and efficacious these two regimens are in both naive and experienced populations. The antiretroviral-experienced group was naive to APV but had evidence of susceptibility to APV and to at least two other antiretroviral agents.
Two hundred and eleven subjects (40 naive, 171 experienced) were randomized 3:1 to receive either APV/RTV vs. APV, both in combination with two other non-protease inhibitor (PI) agents. Both groups had similar demographic characteristics, including a median CD4 count around 315 cells and a HIV-RNA around 4.3 logs. There was a large percentage of patients in both groups (more than 30 percent) who discontinued their therapy due to various reasons, including adverse events and subjects lost to follow up, but only five patients discontinued their therapy due to insufficient viral load response.
In the naive group the rate of response, defined as achieving HIV-RNA less than 200 copies/mL, was 76 percent for the APV/RTV arm and 50 percent for the APV arm. In the experienced group, the response rate was 64 percent for the APV/RTV arm and 70 percent for the APV arm. The percentage of subjects with HIV-RNA less than 50 copies/mL at week 24 was statistically better in the APV/RTV arm than in APV arm. Also the mean increase from baseline CD4 cell counts for both groups was similar at around 46-49 percent. Statistically, the results of this study showed that the APV/RTV arm was at least as good as or better than the APV arm in virologic response at week 24.
The incidence of side effects in both arms was very similar with the exception of hyperlipidemia and increased liver transaminases seen in the APV/RTV arm and not seen in the APV arm.
The results of this study support others that have suggested a good tolerability and adequate efficacy of the APV/RTV combination, especially in the experienced population. Considering the distinctive APV resistance profile, it is important that we optimize its use in the PI-experienced population by guiding our selection of antiretroviral regimen with a baseline resistance testing.
Although this study did not include an arm switching from APV 1,200 mg to APV/RTV 600/100 mg, it emphasizes the potential advantages of switching from a non-boosted to a boosted APV regimen. On the other hand, the risks of hyperlipidemia and to a lesser extent, elevation in liver transaminases needs to be considered.
Today, the use of APV in the naive population has been relegated mainly as a curiosity in clinical trials. Despite its efficacy and tolerability, APV use in this population has always been hampered by the large pill burden. Even boosted APV is associated with significant side effects, as we observed in this study. With other regimens available -- equally effective and better tolerated -- I would feel uncomfortable recommending this regimen in the naive population.
Nevertheless, considering the role that APV/RTV continues to play in the management of experienced patients it is refreshing to see that studies continue to support the use of this combination.
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