Tuesday, November 28, 2023
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Editor's Note:
Highly active antiretroviral therapy (HAART) was introduced 10 years ago, and since the arrival of that ground-breaking therapeutic
advance, new agents and treatment strategies have continued to emerge to improve the prognosis and quality of life of people
with HIV. At the 13th Conference on Retroviruses and Opportunistic Infections (CROI) in Denver, Colorado, held February 5-8,
2006, Scott Williams, Editorial Director of Medscape HIV/AIDS, interviewed Paul Sax, MD, Associate Professor
at Harvard Medical School in Boston, Massachusetts, about new antiretroviral agents and coformulated therapies, as well as
novel compounds under investigation for the management of HIV infection.
Medscape: For highly experienced patients with protease inhibitor (PI)-resistant virus, tipranavir was approved in 2005, and TMC-114 (darunavir) is now in expanded access and on track for approval, most likely later this year. Most HIV specialists have many highly treatment-experienced patients who are candidates for treatment with one of these agents. In the absence of a head-to-head comparative trial, what do we know about the differences between them, in terms of resistance profiles and which patients are likely to benefit?
Dr. Sax: Both drugs show activity against highly PI-resistant virus that's greatly in excess of the other currently available PIs. In that way, they're quite similar, but there are differences. Some preliminary data presented here at CROI on the resistance aspects of TMC-114 showed that the patients who were treated with TMC-114 and experienced treatment failure actually had virus that retained susceptibility to tipranavir.[1] Although one always needs to be cautious about overinterpretation of in-vitro data, the data imply that one could potentially be treated with TMC-114 first, and if one did not respond to that, then still have tipranavir as an option. Now granted, that's all based on the phenotypic susceptibility, and there are no clinical data to prove it, but it's a very provocative result.
Medscape: How well do these agents combine with other antiretrovirals from various classes?
Dr. Sax: Tipranavir inhibits cytochrome P450, like other boosted PIs, but also it's a potent inducer of the p-glycoprotein system, so it's been very hard to predict how tipranavir will interact with other medications, both for HIV disease and other conditions. For example, at CROI this year there was an analysis of the interaction between tipranavir plus TMC-125,[2] which is an investigational nonnucleoside reverse transcriptase inhibitor (NNRTI). These data showed that tipranavir significantly lowers the levels of TMC-125. Given that, one could not really use those drugs in combination. By contrast, a separate study showed that TMC-114 can be combined with TMC-125 without only a small and probably not a clinically significant reduction in drug levels.[3]
Medscape: And these agents combine pretty well with other nucleoside reverse transcriptase inhibitors (NRTIs)?
Dr. Sax: In general, the NRTIs go very well with both tipranavir and with TMC-114. There is interaction between tipranavir and other protease inhibitors because of this induction effect that I mentioned. Tipranavir, as we know from studies that were presented at the 2004 International AIDS Conference in Bangkok, Thailand,[4] significantly lowers levels of other PIs, so double-boosted PIs that include tipranavir are not an option. By contrast, another study presented here showed that TMC114 could be added to a double-boosted PI regimen of lopinavir/r and saquinavir and induce only small reductions in lopinavir levels.[5]
Medscape: What about safety and tolerability of these 2 agents?
Dr. Sax: We have much more information on tipranavir, obviously, than we do on TMC-114. In that regard, it's a little bit premature to compare them, and they've never been compared head-to-head. We know that tipranavir was approved with a warning about potential hepatotoxicity, as well as the tendency for that drug to cause more lipid elevations than comparator PIs. That said, in highly treatment-experienced patients who need a PI with activity against PI-resistant viruses, it's still, overall, a safe choice, and if the patient really needs tipranavir, I wouldn't pull back because of that. Based on the data we have on TMC-114 from the POWER studies,[6] we don't see those particular adverse effects with that agent at quite the same rate. There's a suggestion that TMC-114 might have a higher rate of rash, however, and we certainly need to see the results of their phase 3 studies before we have a full sense of its tolerability profile.
Medscape: Gilead and Bristol-Myers Squibb have collaborated on a major advance in HIV therapeutics, the combination of the already-approved drugs tenofovir, FTC (emtricitabine), and efavirenz into 1 pill taken once-daily. Besides an effective preventive vaccine, the impending launch of a single-pill, triple-drug therapy is really one of the holy grails of HIV research. What are the final hurdles that this triple-drug combo has to conquer in order to gain approval?
Dr. Sax: It needs to show that it's bioequivalent to the 3 drugs given separately. If it shows that it is bioequivalent, I'm confident that approval is highly likely. Actually, the FDA [US Food and Drug Administration] motivated these 2 companies to work together on this. It's certainly unprecedented in HIV medicine, and I think unprecedented in all of medicine, that we have 2 different pharmaceutical companies collaborating to put their products together. It's a credit to them that they're doing it, because it's obviously for the benefit of patients. I hope it's a harbinger of more such cooperative agreements in the future.
Medscape: Do we expect that the bioequivalence data will be presented at a conference this year?
Dr. Sax: There's a very good chance that bioequivalence data will be presented at a conference or that the data that they're submitting to the FDA will be released in a different public format, such as a press release and a letter to HIV clinicians. And once bioequivalence is demonstrated, it will not take long for approval since this combination is already widely used and highly effective. You don't have to show antiviral efficacy comparable to existing drugs if you show that they're bioequivalent. For example, the new formulation of Kaletra was approved just based on its pharmacokinetics data, not based on efficacy.
Medscape: What real-world effect do you think the development might have on the management of people with HIV, in terms of adherence, overall success rates, use in resource-limited settings, or other issues?
Dr. Sax: Clearly, patients prefer fewer pills. The other thing that's interesting is that I think we clinicians underestimated this point. Many patients ask for fewer pills, and one of the more common questions that HIV clinicians get is, "What about the 'combination medicines'?" When Trizivir was approved, it was one of the first drugs that patients literally asked for, and it wouldn't surprise me if the same thing happens with this triple combination, the name of which is still to be determined but has engendered some very amusing candidate names from HIV treaters.
Medscape: Obviously, for women who want to get pregnant it's not going to be an option, but what about the other possible limitations of this coformulated pill?
Dr. Sax: From the medical standpoint, 2 other groups of patients who will not be able to take advantage of the coformulation come to mind. The first is those with resistance to NNRTIs, either from transmission or acquired from prior failed treatment with this class of drugs. Second, it will definitely need to be used with caution -- if at all -- in those with underlying renal insufficiency. Tenofovir has a very important dose reduction for patients with renal insufficiency, and while there are guidelines for dose reduction in coformulated tenofovir/emtricitabine (Truvada), there's no recommended reduced dose for efavirenz, so that's a problem.
A nonmedical challenge that it will face is in people who are already stable on their current regimen. Some people feel like switching is never a good strategy if things are working, and this view has some validity. However, one thing always to remember is that if virologic suppression has been achieved, often you can make a switch, and if things don't work out, you always go back to what you were on before.
Another challenge that the triple combination will face is the availability of generic NRTIs. There's already generic AZT and ddI, but when there's generic 3TC, which is not yet available but is coming soon, it might be harder from a cost standpoint to justify the triple combination. But from the standpoint of patient satisfaction, tolerability, and adherence, it may be very easy to justify. I think that there's going to be some tension around this in a couple of years, depending on the price of the triple combination and the position taken by the major payors of healthcare.
Medscape: Many expect that the next major advance in antiretroviral therapy might be the CCR5 antagonists. By the end of 2005, at least 2 of these agents experienced serious difficulties: Aplaviroc development was halted because of hepatotoxicity, and vicriviroc showed suboptimal virologic efficacy in naive patients. Now the once-daily arm in a study of maraviroc has been discontinued, although twice-daily is still continuing. Given these developments, what are the expectations for this drug class?
Dr. Sax: The vicriviroc study in ART-naive patients was just presented here at CROI,[7] and we were able to see the data for the first time. Vicriviroc (at 3 different doses) plus Combivir was compared with efavirenz plus Combivir. Clearly, the 2 lower doses of vicriviroc they tested were inferior to efavirenz, and the highest dose they tested was also inferior, although not statistically significantly inferior. There might have been some issues in study design that led to a higher rate of failure. For example, there was a monotherapy lead-in of 2 weeks, and that certainly might have contributed to resistance. We don't yet know the mechanism of resistance of these drugs. Nonetheless, it really gives one pause about using a CCR5 antagonist in treatment-naive patients, not just because of the results of this vicriviroc study but also because this is a cellular target, not a viral target; we already have excellent available treatments for treatment-naive patients. Another notable finding in this study was the development of resistance to 3TC (the M184V mutation) in all of the treatment failures on vicriviroc plus
That said, the treatment-experienced study using vicriviroc and 3 maraviroc studies are all going forward. The maraviroc studies include patients with dual-tropic virus that has been fully enrolled, a study in treatment-experienced patients with CCR5-tropic virus, and finally another study in naive patients. Even though the maraviroc once-daily treatment arm of the naive study has been stopped, they're going on with the twice-daily arm.
Medscape: Something I think that we're all now very excited about (although its development has waxed and waned over the years) is the integrase inhibitor class of drugs. Now we have some important candidates under study, including one by Merck and one by Gilead at slightly different phases of development. What do we know so far about the safety and activity of these compounds or any in-vitro resistance data?
Dr. Sax: As you mentioned, Merck has led the way in development of integrase inhibitors, and they presented their monotherapy data and 10-day monotherapy study at EACS [European AIDS Clinical Society conference] of MK-0518 in late 2005: a viral load reduction of approximately 2 log10 copies/mL after 10 days of monotherapy in all the doses they checked.[8] In a late-breaker at this meeting,[9] we saw a study in treatment-experienced patients where, again, 3 different doses of the MK-0518 were compared with placebo plus an optimized background regimen, and again the integrase-treated patients had a phenomenal response. It was a only a 16-week interim result, so we don't know about the durability, and we can't say much about safety, because there weren't that many patients in the study (about 40 patients per arm). Nonetheless, about 70% of patients achieved viral loads < 400 copies/mL and almost 60% achieved viral loads < 50 copies/mL. These are really exciting responses for an investigational agent.. We didn't see the breakdown between those who got T20 and those who didn't, and one can assume, based on the question-and-answer session at CROI, that the people who got T20 did better. But such a response really kind of catapults the integrase inhibitor class into the next big thing, much more so than the CCR5 antagonists, because of the bumps in the road with those agents.
Right after that presentation, new data were reported on the Gilead integrase inhibitor GS-9137,[10] which differs a bit because it's metabolized by cytochrome P450, and so it can be boosted by ritonavir. In both a pharmacokinetic and a 10-day antiviral study of this agent, the pharmacokinetics of 50 mg of the Gilead integrase inhibitor plus 100 mg a day of ritonavir showed excellent pharmacokinetic properties over 24 hours, so it's likely to be dosed once daily, and the viral load reduction was about 2 log10 copies/mL, which is very similar to the antiviral response of the Merck integrase inhibitor in their 10-day study.
Medscape: So if drug-interaction studies pan out, it might end up combining well with ritonavir-boosted PIs?
Dr. Sax: Yes, it could potentially combine well with boosted PIs, and it could be a nice once-daily option. By contrast the Merck drug is twice daily. You have to weigh the benefits that the Merck drug has in that it's not part of the CYP3A4 pathway, so it has fewer drug interactions, vs the ability to give the Gilead integrase inhibitor once daily. So it's really a very exciting area, and fortunately, both drugs are moving forward in their next phase of studies.
Medscape: Any other important data that popped out here at CROI about investigational drugs?
Dr. Sax: There was a very nice pharmacokinetic analysis of the maturation inhibitor PA-457.[11] We saw the antiviral effect presented at EACS where, in a dose-dependent fashion, the highest dose had the greatest antiviral effect. The one thing that's unusual about this drug is that in addition to having a novel mechanism of action, it has a half-life of about 70 hours Efavirenz has a half-life of about 60 hours, and certainly efavirenz is incredibly effective. So that is a good property of the drug. The analysis modeled the dose, plasma levels, and antiviral response, and what it was able to show is that the maximal effective dose had not been reached. So even though 200 mg a day was tested, it's likely that a dose of 250 mg or even over 300 mg would have even greater antiviral effect.
The drug is now going into phase 2 testing. One thing about this drug that has raised questions is that in the highest-dose cohort, there were 2 patients who didn't have much of an antiviral response at all. One of them apparently had very low drug levels, and that might explain the lack of response; but the other one had adequate levels and still didn't get much of a response. The full explanation for this phenomenon is being investigated.
Medscape: For a long time, a hot issue in the activist and clinical research communities has been simultaneous testing of 2 or more investigational agents. While this is of potential benefit to some trial participants, it has obvious challenges for investigators in teasing out the efficacy of the individual agents. But now Tibotec is sponsoring a study of TMC-114 and TMC-125 called the DUET study, in patients with multidrug-resistant HIV. What are your thoughts about the need for these types of trials and how they might be designed and conducted to both benefit patients and provide data that can be interpreted?
Dr. Sax: It's such a good question, because there's really no easy answer. One thing that is clear is that we, as clinical investigators and clinicians, feel uncomfortable enrolling patients into studies of investigational agents, doing what I call "playing the T20 card," and then not having anything to back it up. So if you're going to choose to put someone on T20 who has no other active agents -- say they get randomized to the placebo arm of an investigational study -- it's sort of a sinking feeling, because then you've lost this very important treatment option for highly treatment-experienced patients. On the other hand, there is no other way to get access to the investigational drug.
The nice thing about the DUET study, at least for patients who are T20-naive, is that they will potentially get 2 new active agents even if they don't get TMC-125, because they'll get both TMC-114 and T-20; there's even a good chance they'll get 3 active agents. So there's a bit of a safety net there for those randomized to placebo. However, let's say that they've already received T20 and they have resistance to it; these individuals may get only TMC114 as their only active agent. While this is better than no new active drugs, clinicians and patients will need to consider carefully whether this is the right choice for them at this time.
One thing that's clear is that we need to do much more intensive studies early on to measure viral kinetics so that we can then go quickly from there to larger studies that provide at least 2 active drugs. The paradigm of using at least 2 active drugs to maximize the chance of virologic response has been proven again and again since T20 came out.
Drug-drug interactions are also really important, and these must be sorted out early on in HIV-negative individuals. For them, of course, getting serial treatment with one antiretroviral drug at a time is of no consequence from the perspective of viral resistance. And so working out the drug-drug interactions in HIV-negative subjects before initiating studies in people with HIV would be a really smart thing to do, as it would enable us to combine antiretroviral drugs more safely in larger clinical trials.
