September 29, 2006
Fosamprenavir (FPV, 908, Lexiva, Telzir) is a potent protease inhibitor that was approved by the Food and Drug Administration in October 2003. Several studies have documented the safety and efficacy of once-daily fosamprenavir boosted with ritonavir (RTV, Norvir) in treatment-experienced patients, but better efforts were needed to demonstrate that fosamprenavir/ritonavir-based regimens are safe in antiretroviral-naive patients, particularly with regard to lipid changes and toxicity differences according to gender. There was also a need to perform studies that examined fosamprenavir/ritonavir efficacy in comparison with other drugs in order to demonstrate a compelling role for fosamprenavir/ritonavir in antiretroviral regimens.
In fact, it was recently reported at the XVI International Conference on AIDS, held in Toronto during August 2006, that fosamprenavir/ritonavir was as effective as lopinavir/ritonavir (LPV/r, Kaletra) at achieving significant reductions in viral load, according to results from the KLEAN trial (Kaletra twice daily versus Lexiva twice daily, both with Epivir and Abacavir one daily, in ART-Naive patients).1 In addition, the final 48-week results of KLEAN, by Joseph Eron, Jr., and colleagues, published in The Lancet, documented that the lipid profile changes observed in individuals who received fosamprenavir/ritonavir + abacavir/lamivudine (ABC/3TC, Epzicom, Kivexa) were similar to those observed in individuals who received the same two nucleosides together with lopinavir/ritonavir.2 Thus, reasonable equivalence was observed with regard to fosamprenavir/ritonavir and lopinavir/ritonavir in virtually all respects in the context of the KLEAN study.
An open-label, prospective, randomized pilot trial, termed ALERT, represents an attempt to compare fosamprenavir/ritonavir against atazanavir (ATV, Reyataz)/ritonavir, each in combination with a tenofovir/emtricitabine (TDF/FTC, Truvada) nucleos(t)ide backbone. All drugs are administered once daily, and the study population includes 106 antiretroviral-naive patients with a viral load above 1000 copies/mL. Preliminary 24-week results from the 48-week study were presented at the 2006 Interscience Conference on Antimicrobial Agents and Chemotherapy.3
According to the intent-to-treat analysis, 79% (42/53) of patients in the fosamprenavir/ritonavir arm, compared with 83% (44/53) of patients in the atazanavir/ritonavir arm, attained viral load suppression below 50 copies/mL after 24 weeks of treatment. On-treatment responses were slightly better for each arm, at 84% and 88%, respectively. Equivalent numbers of patients in each arm attained viral load reductions below 400 copies/mL whether by intent-to-treat (89%) or on-treatment analysis (94%).
In addition, no significant differences between the arms were reported with regard to lipid profiles.
Thus, it appears as though fosamprenavir/ritonavir is similar to atazanavir/ritonavir when given in combination with tenofovir/emtricitabine with regard to antiviral efficacy and safety. Of course, these are early results that extend to only 24 weeks of treatment. It will be interesting to observe whether these two regimens continue to demonstrate equivalence over longer periods of follow-up. It is unlikely that further data on this topic will be available before the summer of 2007.
One of the most salient questions that has remained unanswered about fosamprenavir/ritonavir-based therapies involves the potential for sex-related differences in treatment outcomes. Various reports suggest that women may achieve higher plasma and intracellular concentrations of certain antiretrovirals, which could translate into improved effectiveness, but also increased toxicity. Accordingly, Judith Currier, from the University of California, Los Angeles, and colleagues conducted a systematic review of three pivotal, randomized, controlled clinical trials that studied the use of fosamprenavir in treatment-naive and treatment-experienced patients in order to assess efficacy and safety according to sex.4
In general, no gender-based differences in treatment outcomes were observed. At week 48 equal percentages of males and females on fosamprenavir (with or without ritonavir) in the treatment-naive NEAT and SOLO studies attained viral load reductions below 400 copies/mL. In the treatment-experienced CONTEXT study, comparable levels of viral load suppression were found for men and women receiving fosamprenavir once daily or twice daily.
There was also no gender-based difference in the discontinuation rate of fosamprenavir in the NEAT and SOLO trials. In the CONTEXT trial, more females than males discontinued once-daily fosamprenavir/ritonavir before the end of the study (47% versus 22%).
In terms of adverse events, the incidence of grade 2-4 adverse events was similar for fosamprenavir-treated men and women across the three studies. The most common fosamprenavir-associated adverse events included rash and gastrointestinal complications such has diarrhea, nausea, vomiting and abdominal pain. Women generally reported lower rates of fosamprenavir-related grade 2-4 laboratory abnormalities in comparison with men, especially triglyceride elevations.
Based on this study, it appears that both fosamprenavir and fosamprenavir/ritonavir are safe and well tolerated in patients of both genders, without any major differences in toxicity or drug efficacy. Although these findings are reassuring, the investigators did note that the total number of women included in their analysis was too low to draw definitive conclusions about potential sex differences in fosamprenavir-related outcomes.