This article is part of TheBody.com's archive. Because it contains information that may no longer be accurate, this article should only be considered a historical document.
Initially used in salvage regimens, dual protease inhibitor therapy is now increasingly used earlier in treatment. (For discussions of dual protease inhibitors in salvage therapy, see Treatment Issues, "Salvage Therapy: Still More Intuition Than Data" January 1999 and "The Great Salvage Therapy Drug Juggle" April 1998.) The primary reasoning behind this strategy is that combining protease inhibitors can help overcome some of their shortcomings, such as poor biavailability and short half-lives. This is possible because they all are metabolized by the cytochrome P450 3A4 isoenzyme system. Ritonavir, in particular, inhibits this system, which means that administering ritonavir with other protease inhibitors can increase their blood levels. This allows lower or less frequent dosing and can remove food restrictions, resulting in fewer toxicities and improved adherence. Some combinations, such as ritonavir/saquinavir, and possibly ritonavir/indinavir, also appear to be very potent and long lasting. Nevertheless, federal guidelines do not recommend dual protease inhibitor therapy as first-line treatment, presumably due to concerns about side effects and drug-drug interactions, particularly since ritonavir interacts with a wide variety of drugs. There are also concerns that the use of two or more protease inhibitors could increase the risk of lipodystrophy and other metabolic toxicities. At this point, there are very little data on the long-term consequences of using dual protease inhibitor therapy.
Recent conferences have included several studies of dual protease inhibitor therapy in both treatment-naive and treatment-experienced populations, which are discussed below.
Results from ACTG 398 -- a study to determine whether a second protease inhibitor, combined with amprenavir, abacavir, efavirenz, and adefovir, would improve virologic response in protease inhibitor-experienced patients with a detectable viral load -- were presented as a Retrovirus late-breaker (Hammer, LB 7). Based on prior protease inhibitor experience, 481 patients were randomized to also receive saquinavir (1600 mg, twice daily), indinavir (1200 mg, twice daily), nelfinavir (1250 mg, twice daily), or a placebo. Median baseline viral load was 51,600 copies and CD4 count was 202 cells. At week 24, 35% in the saquinavir arm, 38% in the indinavir arm, and 39% in the nelfinavir arm had viral loads below 200 copies, compared to 28% in the placebo arm (p=0.02). Prior NNRTI use was significantly associated with virologic failure, but previous protease inhibitor use (one vs. two or more) was not. Also at week 24, seven percent of the patients had stopped treatment, 33% due to toxicity and 19% due to virologic failure. Grade three to four adverse events were similar in all four arms, with gastrointestinal symptoms, hypertriglyceridemia, and hypophosphatemia being the most common.
Two retrospective studies at the Third Salvage Therapy Workshop looked at indinavir (800 mg)/ritonavir (200 mg) in a salvage therapy setting. Grossman reported on 41 heavily pretreated patients (73% with NNRTI experience, 95% with prior indinavir or ritonavir experience) with a median viral load of 30,000 copies and CD4 count of 258 cells (abstract 27). At three, six, and nine months, 51%, 56%, and 62% of the patients, respectively, had viral loads below 400 copies. Median CD4 increase was about 75 cells at six months. Although there were no reports of kidney stones, nineteen of the 41 (46%) had adverse events, including nausea and vomiting (17% of the 41 patients), rash and dry skin (12%), diarrhea (5%), and paresthesia (3%).
In the second study, Campo provided results for 27 heavily pretreated patients who took at least one nucleoside analog and/or NNRTI in addition to the protease inhibitors (abstract 7). Fifteen patients (56%) attained viral suppression (<400 copies). In addition, four of four with baseline phenotypic resistance and ten of thirteen with baseline genotypic resistance to indinavir and ritonavir attained a viral load below 400 copies. Responders had higher initial CD4 counts (283 vs. 150) and lower viral loads (156,500 vs. 228,000). Of interest, however, baseline resistance to indinavir and ritonavir was associated with a better response to therapy. To explain this counter-intuitive result, Campo suggested that resistance could have be an indication of adherence. That is, those who were adherent on failing regimens developed resistance, and they were more likely to be adherent on the salvage regimen. Given the small numbers and retrospective nature of the study, however, it is difficult to draw any strong conclusions about the relationship between baseline resistance and adherence.
Also at the Salvage Therapy Workshop, researchers from Glaxo Wellcome proposed a salvage therapy regimen of amprenavir (600 mg), saquinavir (800), and ritonavir (100) twice daily, with or without other classes of antiretrovirals (Furfine, abstract 16). It is crucial to note that this proposal is currently theoretical: the pharmacokinetic interaction studies have not been carried out in humans, and what happens in the body can show great variance from what happens in a test tube. Nevertheless, there are several (again, theoretical) reasons to think the combination might be effective. First, laboratory tests have shown that amprenavir and saquinavir are synergistic. Second, there is little cross-resistance between amprenavir and saquinavir; in fact, in vitro studies show that the amprenavir I50V mutation is more susceptible to saquinavir. Moreover, when HIV with amprenavir-resistant mutations 46I/47V/50V is exposed to saquinavir, it develops the 84L mutation, but this quadruple mutation leads to greater susceptibility to amprenavir. Third, people who have failed nelfinavir or indinavir are often still sensitive to amprenavir and saquinavir. Finally, ritonavir enhances the blood levels of amprenavir and saquinavir.
Just as the benefits of this triple protease inhibitor combination are still unproven, the related adverse events are unknown. With some cooperation among the drug manufacturers, future drug interaction trials could shed some light on the feasibility of using this regimen in salvage therapy.
This article is part of TheBody.com's archive. Because it contains information that may no longer be accurate, this article should only be considered a historical document.
This article was provided by Gay Men's Health Crisis. It is a part of the publication GMHC Treatment Issues.
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