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New and Investigational Antiretrovirals: An Expert Interview With Dr. Cal Cohen


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Editor's Note:
In summer 2006 alone, 2 new antiretroviral therapies have gained FDA approval for HIV infection. One is a coformulation of 3 existing drugs that is given in 1 pill taken once daily, and one is a protease inhibitor (PI) developed specifically for highly treatment-experienced patients. Beyond these exciting recent approvals, the HIV drug pipeline is quite rich, with 64 compounds in various stages of development. At the International AIDS Conference in Toronto, Scott Williams, Editorial Director of Medscape HIV/AIDS, spoke with Calvin Cohen, MD, about this promising area of HIV medicine. Dr. Cohen is Clinical Instructor at Harvard Medical School and Research Director at both the Community Research Initiative of New England and Harvard Vanguard Medical Associates in Boston, Massachusetts.

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Medscape: Dr. Cohen, we'd like to hear your insights about some important recent advances in antiretroviral drug development and strategies, including data that we've seen this week in Toronto at the International AIDS Conference. Before we discuss data on investigational compounds, it's important to note that 2 new treatment options have gained FDA approval this summer, including the new triple-drug coformulation (Atripla) of efavirenz (Sustiva), tenofovir (Viread), and emtricitabine (Emtriva), and the new PI darunavir (Prezista). The approval of these agents may certainly have some effect on how HIV clinicians consider longer-term ART strategies for their patients.

On the earlier side of the treatment spectrum is the coformulation of efavirenz and tenofovir and emtricitabine, which is the first single-pill, once-daily treatment for HIV. Are there certain patients or patient populations for whom the combination pills may perform particularly well, or conversely, are there patients in whom this would be unsuitable? Did we see any data at the meeting that provide guidance in this regard?

Dr. Cohen: At this conference we saw data from a randomized study done by the AIDS Clinical Trials Group (ACTG),[2] and this study provides us some very important insights about the role of Atripla in treatment-naive patients.

This combination is thought of as something for treatment-naive patients, in part because the bulk of the data we have are in patients from the earlier lines of antiretroviral therapy. What we saw [in the ACTG study] are the 2 DHHS-recommended approaches compared head-to-head [eg, 2 NRTIs combined with efavirenz or lopinavir/ritonavir (Kaletra)].

That study did not use Atripla: Efavirenz could be combined with any of 3 different nucleoside combinations, but we've certainly seen data to suggest that the nucleosides are more similar than different, at least with regard to success, and so that study provides us some key insights that address the issue of who Atripla is right for.

After 2 years, the virologic response rate to efavirenz and 2 nucleosides was, in fact, superior in some ways of measuring response than were 2 nucleosides in combination with lopinavir/ritonavir. That is particularly notable if we look at the most stringent parameters of success: How well do we get to a viral load of < 50 copies/mL after 2 years, and how well do people tolerate the regimen? After 2 years, the efavirenz-and-2-nucleosides approach provided great outcomes with sustained virologic efficacy that was, in fact, a little bit better than what was observed with lopinavir/ritonavir.

So who is this the right combination for? Most likely anybody in whom those drugs would be reasonable, safe choices. Who is that not the case for? We know that efavirenz is still not recommended for women considering pregnancy because it is not considered a safe drug during pregnancy and we have better alternatives to use. There are circumstances in which tenofovir may not be the right choice. Certainly people with severely compromised renal function should not take tenofovir, at least at the standard dose of 1 pill a day, because it is clear that that's not the right dose for these patients.

So we were reminded at this meeting that clinicians can be encouraged about this combination for most of their patients. There have been convincing, compelling data for several years now, all of which suggested that for many first-line patients this combination would be difficult to beat.

Medscape: We saw pharmacokinetic (PK) data[1] this week on these agents given separately or as 1 pill, which has obviously been one of the key issues that doctors are looking for. What did we learn?

Dr. Cohen: What we've learned about the PK of Atripla is a very important piece of the puzzle to clinicians, because each drug on its own, when given separately [as part of a combination regimen], has been very, very successful in establishing virologic control, as well as doing it very safely. So it's the approach toward increasing convenience that's the focus of this PK analysis.

It's taken some time, but finally the group at Gilead and Bristol-Myers Squibb was able to figure out a coformulated tablet that allows essentially similar exposures compared with when the drugs are given separately. The advances are important for us to consider because part of what we as clinicians have been focused on for the past several years has been not simply the issues around virologic success and even drug safety, but convenience. That matters for a couple of reasons, not the least of which is to minimize the risk for errors, such as "I forgot 1 pill at home; I guess I'll just take these two."

Although those are not necessarily common errors, they do occur. So this coformulated tablet allows us to take some of the best combination products we have in the marketplace and now make them as simple as treatment can be.

Medscape: Can you tell us a little bit about the obstacles that had to be overcome to achieve this? Weren't there a couple of stumbling blocks along the way?

Dr. Cohen: As I understand it, the development of this product had a couple of stumbling blocks along the way. One of the reasons had to do with the fact that they initially tried mixing efavirenz, tenofovir, and emtricitabine into the tablet in a mixture. For reasons that I'm sure they could explain better than I can, there was a difference in the PK exposure in that approach. So the successful approach is a bilayer tablet in which efavirenz is on one end and tenofovir/emtricitabine (Truvada) is the other half. Then they press these two together, create a film coating, and now we have a single tablet with the 2 halves, essentially 3 drugs now formulated in a way that mimics the PK exposure when given separately.

Medscape: Let's talk about the other end of the treatment spectrum in terms of recently approved antiretrovirals. New clinical data on darunavir were presented at this meeting. Please tell us what clinicians should know.

Dr. Cohen: Darunavir is the most recent FDA-approved PI, which was developed largely with a focus on treatment-experienced, and particularly PI-experienced, patients. The need was greatest for those patients for whom current PIs just were not successful.

The POWER studies, which compared darunavir vs any other comparator PI that was FDA-approved at the time, were updated to week 48 at this conference.[3] The durability of the initial suppression that we observed last year is an important piece of the puzzle that gives clinicians the confidence and the data that they need to understand a key question: What is the long-term success of darunavir in a background of the best possible regimen we can construct?

Fortunately, the news was reassuring. What we saw, last year, for example, was that darunavir was superior to any other PI we could pick in reestablishing control in our PI-experienced patients. At this meeting, we saw that the response at week 24 is durable to week 48; the percentage of people whose viral load was < 50 copies/mL at week 24 is essentially the same at week 48, which is a very reassuring piece of information.

We also learned about the limits of response to this drug. In whom might this drug not be a fully effective choice? The good news is that darunavir is successful at overcoming the vast majority of PI-resistance patterns that we see. Through either genotypic or phenotypic rules, we can certainly now understand when darunavir is likely to work, when darunavir is a bit at risk, and when darunavir is unlikely to work, which allows us to look to a pipeline of some future drug options even for those patients.

Medscape: On the topic of second-generation PIs, tipranavir is also a relatively recent addition to the PI class, but certainly there's been no head-to-head trial with tipranavir and darunavir at this point. In the absence of that and given your clinical expertise, what are the similarities or differences between these agents in terms of efficacy, safety, or resistance profiles that have been observed?

Dr. Cohen: Comparing tipranavir to darunavir on the basis of available data is a bit difficult. We certainly don't have head-to-head trials that allow us to make the most informed judgments, so we have to rely on our ability to compare different studies.

There were some similarities between the studies of who enrolled. At the British HIV Association meeting, Andrew Hill and Graham Moyle presented an analysis[4] comparing tipranavir results to darunavir results by first asking the question: Are these studies similar enough in who enrolled to allow us to compare the response of the 2 drugs? Their analysis of the data suggested that the patient populations were reasonably similar at baseline, which allows us to at least suggest the possibility that a cross-study comparison has validity until a head-to-head trial is done. In their analysis they were able to show that darunavir had a superior virologic outcome as compared to tipranavir. That was seen for a variety of subsets: if we looked at the rest of the regimen, if enfuvirtide was used or not. Ultimately, they were able to conclude that darunavir looks like a more successful drug in the majority of patients with PI-resistant virus. In terms of efficacy, darunavir likely has more activity than does tipranavir against PI-resistant HIV.

But there's one other piece of the puzzle, and that is, of course, safety. We have learned recently of an FDA warning about the possibility of intracranial hemorrhage associated with tipranavir use that hasn't yet been reported with other PIs, including darunavir. The future will yield other information we may not yet know. But in addition, the package insert does caution us that tipranavir has been associated with elevated liver function tests, or hepatitis, and we don't see that warning with darunavir. In fact, in the case of darunavir, the FDA has given us information to suggest that the drug is safe to use even in patients coinfected with hepatitis B or C, whereas tipranavir has a particular caution about coinfected patients and the risk for hepatitis (drug-associated being even greater). In terms of safety, we do see some clear distinctions between the 2 products.

Medscape: Let's briefly talk about other promising categories of drugs that are directed towards novel targets. There's been a lot of buzz around integrase inhibitors, and it's made people very excited about the compounds that are in the pipeline. Did you see any notable data this week about the 2 compounds that are in the most advanced development?

Dr. Cohen: At this meeting we saw some very interesting information about the Merck integrase inhibitor,[5] and this was a follow-up of a study presented in 2005 at the Dublin meeting. This study was a randomized study of 4 different doses of the Merck integrase inhibitor. It's a small study but nevertheless the results were very provocative.

If we take a look at the design, the Merck integrase inhibitor was given as monotherapy for 2 weeks, and then the nucleosides were added; this was compared with a standard approach of 2 nucleosides and efavirenz given for 24 weeks. The extraordinary result is that the time of virologic suppression to < 50 copies/mL was faster on the nucleosides plus integrase inhibitor than we observed with the nucleosides plus efavirenz approach, which is something we've not seen in a very long time. Indeed, in other studies comparing efavirenz with other drugs, efavirenz has been the fastest one yet in this regard, but this is even faster. Does that matter? It's not really clear how much that predicts virologic durability and other factors, but nevertheless the intrinsic potency of stopping virus replication has been among the most impressive aspects of this trial.

In addition, about 90% of patients got to < 50 copies/mL, uniformly potent at a very high degree of success out to week 24. So on those 2 metrics, that's an extraordinary showing for this drug. And what's more, few, if any, toxicities were reported. Very few adverse events were reported and certainly were comparable to any other drug that we use, at least after 24 weeks. I think these results confirm why that buzz may be deserved.

Medscape: What about CCR5 antagonists? There have obviously been problems with this drug class. Did we see any data at this meeting that suggest that these issues are moving towards resolution?

Dr. Cohen: At this meeting we saw updated data on 2 CCR5 inhibitors, maraviroc and vicriviroc.[6,7] The maraviroc study was done in patients with dual-tropic HIV, meaning that the virus in those patients would use the CCR5 (R5) pathway, as well as the CXCR4 (X4) pathway. In some ways, it's predictable that what was observed after 24 weeks was minimal response, if any, to the addition of maraviroc to a background regimen, in part because these patients had virus that would use another pathway. The study was done, perhaps as a long shot, to see whether this approach could work, and it didn't.

But it did provide us one other important clue, which is the safety of this drug in a patient with dual-tropic [R5/X4] virus who, perhaps because screening tests aren't perfect, would be exposed to a drug like maraviroc for 24 weeks. And the good news is that while the R5-tropic virus was suppressed, there's perhaps a little bit of an enrichment of X4-tropic virus in those patients. Nevertheless, the CD4 counts improved on maraviroc vs placebo, which is a very, very important piece of the puzzle, because the concern is that if we give an R5 inhibitor to somebody who has X4-tropic virus and we don't detect that at baseline, will the X4-tropic virus do more harm? The reassuring piece of the puzzle from this study is that there is no evidence from 24 weeks that that's the case.

With the vicriviroc, we saw the opposite set of data. We saw what happens when we give an R5 inhibitor to people who screen for having only R5-tropic virus, and after 24 weeks we've got some very reassuring data. The drug exhibits virologic suppression of at least a 1.5 log copies/mL, Also, about a third of the patients achieved virologic suppression with a regimen that included vicriviroc and ritonavir plus an optimized background. This was certainly superior to what was observed in the absence of vicriviroc. So the results for vicriviroc were pretty reassuring in terms of potency.

The other issue that's come up for this particular drug was an announcement a few months ago about the safety of this compound, particularly because of a cluster of carcinomas or malignancies that were observed in the study.

Here we saw in public for the first time some of the data specifically about what happened. There were some people who did have a malignancy, but there was no clustering of a specific type of malignancy. For example, there were cases of Hodgkin's lymphoma and non-Hodgkin's lymphoma. One person had a gastric adenocarcinoma. And indeed, there were 2 cases of squamous cell carcinomas on the control arm, which suggests that at least currently there's no evidence that this CCR5 inhibitor is associated with an increased risk for malignancy. Certainly caution is advised, which is why we do studies. But right now these data were actually pretty reassuring for lack of a safety concern based on the data we've seen to date.

Medscape: What about TMC125, which is a second-generation nonnucleoside? Did we see any data on that compound at this meeting?

Dr. Cohen: With regard to new nonnucleoside development, we did see some new data on TMC125,[8] which now has the generic name of etravirine. We have some evidence now of the durability of response, even in patients with nonnucleoside resistance.

The concern with a new nonnucleoside has always been virologic durability. Will the resistance mutations that underlie nonnuke resistance undermine the activity of any new nonnucleoside? That's been certainly our history to date. And once again, we have pretty reassuring data. Last year we saw some 24-week data showing that etravirine created a 1-log additional response compared with an active control arm. At week 48, that 1-log difference is maintained. We saw data to suggest to us that patients with few NNRTI mutations do the best. But even in those with 2 or 3 mutations, this agent can exhibit a virologic effect even against some pretty heavily NNRTI-resistant isolates. The news was actually pretty reassuring that this drug does have prolonged durable activity, and fortunately some phase 3 studies are well under way to fully define this activity in a much larger cohort.

Medscape: Were there any other investigational compounds at this meeting for which particularly notable data were presented?

Dr. Cohen: For the first time at this meeting we saw some 48-week data about the Tanox compound,[9] which is a humanized monoclonal antibody directed against the CD4 receptor. The concept is very simple: If we can block viral entry by blocking the CD4 receptor, perhaps we can maintain a much lower viral load as a result of blocking that receptor. The challenge for this drug is that it's given by intravenous infusions every 2 weeks as a maintenance therapy.

But what about the data from this meeting? We saw about a 1-log additional viral load drop in those receiving the Tanox compound, and that was reasonably durable for the year's period of time, and then superior to what was observed with the placebo arm. A couple of different doses were studied and both had similar activity. There is also no evidence of a safety concern based on week-48 data. How well an IV infusion drug can be incorporated into current clinical life is the challenge that many of us discuss about the compound. Nevertheless, we now have a reason to discuss it. The drug clearly does have activity, and hopefully different doses and schedules will fully flesh out the profile so that we can understand what this drug can bring to the clinical setting.

Medscape: To shift gears as we conclude, a major focus of this meeting was emerging biomedical strategies around HIV prevention. This includes the investigation of novel interventions such as topical microbicides or preexposure prophylaxis using tenofovir with or without other antiretrovirals to prevent HIV. Did you see any data in this area to show that we're making progress towards any of these novel interventions?

Dr. Cohen: The topic of pre- or postexposure prophylaxis continues to be one of the more controversial discussions that we have in our field, in part because the urgency is real. We don't have a vaccine. It's not clear in the next decade whether we will get a vaccine, though the search does go on.

Nevertheless, we also do have data from animal studies to support that our standard antiretrovirals, well tolerated as they are in people with HIV, have potential to prevent HIV infection in those exposed to HIV. And so studies are under way, and at this meeting there were presentations, mostly focused on safety, not yet on efficacy, of these approaches in HIV-negative cohorts. The good news, not surprisingly, is that these same drugs are very well tolerated. Tenofovir underwent a large randomized study, which was presented as a late-breaker,[10] and it was as well tolerated in this population as it is in HIV-positive populations. Very few, if any, adverse events were reported, no significant laboratory abnormalities were observed, and so it was very reassuring that the drug could be used safely in a larger population.

Did it work? Well, the punch line is that there were so few seroconversions overall that it's difficult to be certain. Nevertheless, there were 2 seroconversions in the tenofovir-receiving group and 6 in the control arm. That doesn't definitively prove anything, but it certainly suggests that larger trials are warranted because we do have safety confirmed and we have a reason to proceed.

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