Dual PI therapy emerges as most viable combination
Dual PI therapy emerges as most viable combination
It could become standard of care in 98
Emerging data on the impact of dual protease inhibitor (PI) therapy indicate that this new strategy may have better results than standard triple-drug combinations, particularly as initial therapy in drug-naive patients. Choosing when to use two protease inhibitors instead of one and knowing which combinations work best can be difficult, but experts are providing some guidelines.
The promise of dual PI therapy generated much discussion at the recent Interscience Conference on Antimicrobial Agents and Chemo therapy (ICAAC) meeting in Toronto, where a separate session was devoted to the topic. Leading the rallying cry for dual PI therapy was John Mellors, MD, director of the HIV/AIDS program at the University of Pittsburgh and a leading researcher on protease inhibitors. After laying out the considerable benefits of using two protease inhibitors in combination therapy instead of one, Mellors predicted that the strategy would become the favored standard of care in 1998.
Other leaders in AIDS research are waxing positive about the concept.
"We are using it a lot," John Bartlett, MD, chief of infectious disease at Johns Hopkins University School of Medicine in Baltimore, tells AIDS Alert. "Most people are fairly excited about it because it doesn’t have a lot of side effects."
The accumulating data on dual PI therapy show that not only is it as well-tolerated as single PI combination therapy, but has greater viral suppression, requires fewer pills, and delays resistance.
"Whether this emerges as a new standard of care remains to be seen, but it is something that has become tremendously important," says Eugene Sun, MD, head of the antiviral venture at Abbott Laboratories, which manufactures ritonavir.
Some researchers, in fact, have questioned whether the new federal HIV treatment guidelines should be modified to reflect these new findings. The guidelines currently recommend that dual PI therapy should be limited to patients who have failed on other regimens, and yet the greatest benefits of dual PI therapy have been observed in patients in the early stages of infection.
Bartlett, who chaired the committee that developed the guidelines, says dual PI therapy should not be limited to late-stage patients, and that there shouldn’t be so much concern over using the so-called big guns of antiviral therapy up front.
"Everybody does something different, but I think that [ritonavir plus saquinavir] is an appropriate drug combination to start with," he explains. "If patients are going to get resistance to ritonavir, they are going to be in trouble anyway."
The most popular combination is ritonavir and saquinavir, he says, because it is well-tolerated, it’s the easiest for patients to comply with, and, in Mellors’ words, "it has as good antiretroviral activity as anything we have got." Although the ritonavir/saquinavir combination has been the most-studied regimen, most of its studies have involved drug-naive patients.
Most dual protease therapy has been given to patients who have failed on single protease combination therapy. Emerging data on dual PIs, some presented at ICAAC, indicate that dual PIs failed more often than not as salvage therapy, and that this treatment method is unpredictable, primarily because of adverse events and resistance profiles.
A four-drug combination that included ritonavir and saquinavir was tested in 51 patients from Australia, more than half of whom had been pretreated with protease inhibitors and 90% with nucleoside analogues. Although virus became undetectable in 63% of the patients, 41% had virological evidence of treatment failure by six months, suggesting the emergence of resistance, it was reported at ICAAC.1 A smaller study of ritonavir and saquinavir in patients from Spain who had previously failed on indinavir found only short-term improvement in less than half of them.2
In a Swiss study evaluating toxicity, efficacy, and mutations in patients with advanced HIV treated with ritonavir plus saquinavir, researchers found that the response to this dual therapy is unpredictable.3 Although six of 18 patients had a sustained response after 13 weeks, the majority of patients failed to respond or dropped out of the study because of side effects, patient choice, or death. Of the four patients who withdrew because of side effects, one experienced drug-induced hepatitis. Of the nine patients who completed the 13-week trial, six had drops in viremia exceeding 90%, and two had undetectable virus, noted the authors of the study, which was published in the October issue of AIDS.3
Not unexpectedly, seven patients had pre-existing mutations associated with protease inhibitor resistance. However, two compliant patients who did not respond to treatment developed new mutations within five weeks of therapy. "The rapid appearance of multiple mutations was unexpected in view of published results with saquinavir monotherapy for 24-48 weeks, and suggests that data obtained in moderately advanced HIV disease may not apply to very advanced HIV infection," the authors note.
PI-naive patients respond better
Dual PI therapy has provided the most beneficial response in patients in the earlier stages of infection. Indeed, a Canadian study of ritonavir/saquinavir in both naive and PI-experienced patients found that patients who had no previous treatment with protease inhibitors were 4.5 times more likely to suppress their viral load than those who had previously used a PI. Previous use of nucleoside analogues was not predictive of a response, however.4
The most recent, unpublished data for ritonavir/saquinavir therapy in PI-naive patients showed that 90% of 141 patients had undetectable plasma levels after nearly a year of therapy.
The regimen was well-tolerated, with tingling of the mouth, diarrhea, fatigue, and nausea the most common adverse reactions, Sun says.
A significant finding of the ritonavir/saquinavir combination is that it appears to penetrate the central nervous system, a potential reservoir for the virus. Cerebral spinal fluid levels in 12 of 13 biopsied patients showed undetectable levels of HIV, Abbott reported. According to the Centers for Disease Control and Prevention, central nervous system complications make up about 8% of AIDS-defining diseases, and cause dementia in as much as 15% of AIDS patients.
Another Swiss study combined ritonavir and saquinavir with stavudine (d4T), which was added because of its ability to penetrate the central nervous system, its convenient dosing, and favorable tolerability.5 In this study, which treated patients who had no previous experience with PIs, 49 of 56 patients showed viral load decreases by nearly 2.5 logs after nine weeks. Fewer than 10% of the 56 patients discontinued the study because of adverse events.
"These promising data justify further study of triple combination regimens that include two protease inhibitors and a nucleoside analog," says Manuel Battegay, MD, the study’s principal investigator and AIDS researcher at University Hospital in Basel, Switzerland.
The unique ability of ritonavir to enhance drug levels of other protease inhibitors makes it especially attractive with saquinavir, which has relatively low penetration on its own. In the Swiss triple-drug study, for example, saquinavir concentrations increased by 10 to 100 times, researchers note. Other studies have shown that ritonavir enhances drug levels for the new formulation of saquinavir as well, Sun says.
Because of this enhancing interaction, more favorable drug regimens have been possible when ritonavir is combined with saquinavir or indinavir so that the drugs can be given twice daily, instead of three or more times a day.
"Many patients feel these improved regimens are absolutely critical for long-term compliance," he adds.
With four PIs approved in the United States and several others in human trials, there are numerous possible combinations from which to choose. However, only the ritonavir/saquinavir combination has been widely studied. And while Mellors and others expect similar results to ritonavir and saquinavir, they will not be known until later this year. In addition, no study has run long enough to determine the long-term clinical implications of sustained viral load suppression. Other dual PI therapy studies under way include the combinations of indinavir, ritonavir, and saquinavir with nelfinavir.
References
1. Kaufmann G, Duncombi C, Beveridge A, et al. Efficacy of a four-drug combination therapy including two protease inhibitors in patients with advanced HIV-1 illness. Presented at a meeting of the Interscience Conference on Antimicrobial Agents and Chemotherapy. Abstract No. I-200. Toronto; 1997.
2. Puig I, Bonjoch A, Ruiz I, et al. Usefulness of ritonavir and saquinavir combination therapy for HIV-advanced patients failing on indinavir. Presented at a meeting of the Interscience Conference on Antimicrobial Agents and Chemotherapy. Abstract No. I-201. Toronto; 1997.
3. Lorenzi P, Yerly S, Abderrakin K, et al. Toxicity, efficacy, plasma drug concentrations and protease mutations in patients with advanced HIV infection treated with ritonavir plus saquinavir. AIDS 1997; 11:F95-F99.
4. Rhone S, Hogg R, Yip B, et al. The antiviral effect of ritonavir and saquinavir among HIV infected adults: Preliminary results from a community based study. Presented at a meeting of the Interscience Conference on Antimicrobial Agents and Chemotherapy. Abstract No. 207. Toronto; 1997.
5. Battegay M, Bernasconi E, Flepp M, et al. A pilot study of saquinavir in combination with ritonavir and d4T in patients with advanced HIV disease. Presented at a meeting of the Interscience Conference on Antimicrobial Agents and Chemotherapy. Abstract No. I-203. Toronto; 1997.
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