Selecting an Initial ART Regimen: Lessons From ACTG 5257

Paul E. Sax, MD; Raphael J. Landovitz, MD


April 11, 2014

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The Need for ACTG 5257

Paul E. Sax, MD: Hello. This is Dr. Paul Sax from Brigham and Women's Hospital and the Harvard Medical School. Welcome to this Medscape interview.

Today I'm pleased to introduce the person I will be discussing our topic with: Dr. Raphael Landovitz (or Raphy Landovitz), who is Associate Professor of Medicine at UCLA, a former colleague, and a good friend.

Today's topic will be selecting an initial antiretroviral therapy (ART) regimen for people with HIV. The reason that it is particularly notable that we are going to have Dr. Landovitz on today's interview is that he recently was asked to present the results of a major HIV clinical trial [at the 2014 Conference on Retroviruses and Opportunistic Infections (CROI)].

Raphy, let's discuss that clinical trial and at least discuss the rationale. It is called ACTG 5257.[1] What was the reason behind doing this comparative clinical study?

Raphael J. Landovitz, MD: Thank you, Paul, and thanks for inviting me to this conversation.

ACTG 5257 was borne out of the observation that although tenofovir/emtricitabine/efavirenz (TDF/FTC/EFV) is the most commonly prescribed antiretroviral combination worldwide, there is not an insignificant number of patients for whom it is not actually recommended or is intolerable.

This includes women of childbearing potential, particularly if other options are available, and people with some comorbid mental health issues, and a lot of drug-drug interactions preclude its use. Perhaps most provocatively, it is not recommended in people who have themselves been infected with virus that is resistant to some of the components of this combination, which can happen in up to around 15% of new infections.[2]

So the question was, given the list of other first-line antiretroviral regimes that are recommended in the US Department of Health and Human Services guidelines,[2] is there one that would be preferable if the efavirenz-based combination could not be used? We wanted to see not just a short-term follow-up comparison but long-term clinical outcomes with all of the components that are important for a comprehensive evaluation of those regimens, including metabolic complications, tolerability, and, of course, virologic efficacy of the regimens.

Dr. Sax: Can you be specific? Which regimens were compared? How did people end up on them? Was it open-label, was it blinded, etc.?

Dr. Landovitz: Yes, obviously these are critical things to know in interpreting the results of any clinical trial. The 3 regimens that were compared were all in combination with TDF/FTC, and they were ritonavir-boosted atazanavir (ATV/r), raltegravir, and ritonavir-boosted darunavir (DRV/r), given open-label.

HIV-infected, treatment-naive individuals were randomly assigned, in equal proportions, to each of those 3 treatment arms and were followed for 96 weeks, or almost 2 years, after the final participant was enrolled. We enrolled about 1800 people, which took about 2 years to do, so the people who enrolled right up front actually had almost 4 years of follow-up.

Dr. Sax: That is substantially sized for an HIV study. The cholesterol researchers would probably still think it is pretty small, but for an HIV initial therapy trial, it is large. Why such a large sample size?

Dr. Landovitz: We were interested in having statistical power to answer some very specific questions. These were questions involving what we call pair-wise comparisons for each of those 3 treatment arms. Even though we had 3 arms, we wanted to look at every possible combination and be able to say something about how each one compared to the others with regard to a number of endpoints, such as how well it suppressed the virus for our virologic efficacy endpoint and how well it was tolerated.

Then we looked at a combination of those 2 endpoints, which we called a composite endpoint of virologic failure and tolerability. We thought this was actually the most relevant endpoint for clinicians and patients because it took into account the 2 most important things that clinicians and patients were interested in: How well does it work, and does it make people have side effects?

Noticeable Focus on Female Participants

Dr. Sax: Let's now skip to the results. I am going to ask you about the baseline characteristics, and I am going to focus on something that was quite noticeable when you presented the data at CROI: The study had about 25% females, which is much, much higher than other prospective clinical trials comparing initial regimens that we have seen recently.

It was done in the United States, so this was about the same proportion of women with HIV in the country. Congratulations to the study team for doing it. But how did you do that?

Dr. Landovitz: You are very kind for thinking that that is something worth noting. We were really focused at the beginning on enrolling a third of the participants as women. That was our original plan. We noted the results of other studies within the ACTG, and without, about some really important differences in tolerability of regimens and even some apparent differences in efficacy in women in both US-based and international initial treatment studies.[3] So we really thought that having enough women to be able to make statements about this -- whether these results were going to be different in women -- was important.

It is challenging to enroll women in clinical trials, at least within the HIV realm in the United States. People have thought of all sorts of reasons why that might be, but I don't think anyone knows for sure. Historically, we haven't done a great job of engaging women in the clinical trials process and communicating to them why it is important that they participate. They have other competing priorities, such as childcare, and a lot of these patients are single moms trying to juggle life.

Dr. Sax: Also, they are in a substantially lower socioeconomic group, on average, in the United States than are the men with HIV. It is just a very stark difference. But back to my question: How did you do it?

Dr. Landovitz: We focused all the sites on enrolling women from the start. But we lagged very far behind and it became clear that unless we made a push for doing so, we weren't going to be able to enroll a substantial portion of women.

So we put limits on the sites. We said, "In order to enroll your next man participant, you need to enroll a woman participant." Eventually, we had to close the study to male enrollment and just allow enrollment to women in order to get about a quarter of participants, which is what we got in the end.

Dr. Sax: Again, congratulations to the study team. It is very important that you did this, and I will also note that you ended up enrolling the study still within the time that you had predicted. So, good work.

Tolerability Drives the Difference

Dr. Sax: Now on to the results and the virologic, tolerability, and composite results. Tell us what you found. Focus first on the virology.

Dr. Landovitz: We designed this as an equivalence study. What that meant is that if 2 regimens have virologic suppression rates within ±10% of each other, it was clinically going to be an equivalent result. So we defined equivalence as the point estimate for virologic failure falling within ±10% for the difference of any pair-wise comparison as equivalent.

And we found all 3 regimens to be equivalent in regard to virologic efficacy. That was exciting. The rates of virologic suppression at our primary endpoint of 96 weeks were very similar and outstanding for all 3 arms -- 88% to 94% were suppressed.

Dr. Sax: It is safe to say that probably most of the nonsuccess in using these modern regimens was due to nonadherence or other factors, not specific drug factors, correct?

Dr. Landovitz: That is probably right, yes.

Dr. Sax: So how about the other results? Not the same story, is it?

Dr. Landovitz: It isn't, and this was a little bit of a surprise. In regard to the tolerability endpoint, the ATV/r arm was inferior to both other arms -- it was inferior to DRV/r and inferior to raltegravir. The DRV/r and raltegravir arms, in regard to tolerability, were equivalent.

The driving force of that result appeared to be a jaundice syndrome that was associated with elevated bilirubin levels, but the people who stayed on the ATV/r regimen and the people who found that intolerable didn't have vastly different rates of elevated blood chemistry testing for bilirubin. There were more extremely high elevations of bilirubin in the people who did stop than in those who didn't, but it was very interesting, and this was a notable difference to other studies that have used ATV/r.

As you well know, a number of studies have found fairly low rates of people stopping ATV/r for this jaundice/hyperbilirubin syndrome. We thought a lot about why our study might have been different, and you and I have talked about this. We've surmised that maybe it's because our study design allowed people to switch to other really good, well-tolerated regimens within the confines of the study. And that, perhaps, set a lower bar for people being willing to discontinue their ATV/r treatment when they knew other drugs were available very easily through the study and they wouldn't be asked to discontinue the study.

Dr. Sax: As we have mentioned (and I am going to underline one of the things you said), there are other very good options out there, and 2 of them were within the study that you were conducting. So a person who experienced hyperbilirubinemia and may have thought it a mild cosmetic problem had very little reason not to switch, as opposed to back in the early 2000s when atazanavir came out and there weren't as many good options.

So you have this effect, and the composite results (I am just going to summarize) showed the same thing: Raltegravir worked better than both of them. It was a little bit better than DRV/r in the viral outcome and a little bit better than DRV/r in tolerability. So who is the real winner in this study?

Dr. Landovitz: If I can extrapolate the results, it is the integrase inhibitor class that was the winner. Clearly, our results only used raltegravir so I can't necessarily generalize to other agents. But it is clear that, from a tolerability and virologic efficacy perspective, when both are considered together, the raltegravir-based arm did the best. It was sort of compelling and it was a little bit of a surprise on 2 counts: first, that there was so much worse tolerability with the ATV/r arm; and second, as you mentioned, in the composite endpoint, that the more subtle differences between raltegravir and DRV/r in regard to both virologic efficacy and potency translated into a superiority of raltegravir over both protease inhibitor-containing arms.

I found that compelling and a little surprising, but not inconsistent with our clinical experience.

Dr. Sax: Exactly. One of the really nice things about this study is that it does have direct clinical applicability to people who are practicing.

I am going to ask you about a couple of other things that were in ACTG 5257, and then after that I am going to broaden the questions a bit. First, lipids; second, bone. Tell me about results in this study.

Dr. Landovitz: The boosted protease inhibitor arms both had greater increases in fasting low-density lipoproteins and triglycerides, which was not a surprise. Perhaps the only surprise in the lipids was that DRV/r and ATV/r were not different from each other in this large, well-powered study.[4] Other work has suggested that there might be differences between those, so we were surprised at that.

Bone changes were more subtle, but the raltegravir arm also had less bone mineral density loss,[5] so that was a win for raltegravir as well.

Dr. Sax: I guess the only place where you might say that boosted protease inhibitors still reign supreme is resistance outcomes, right?

Dr. Landovitz: Right. That is a good point. When we presented the data, we didn't get a lot of opportunity to discuss the resistance results.

It is important to remember that there were very few people who failed all 3 of the arms virologically. The fewest failures were in the raltegravir arm. But of those who did fail virologically, raltegravir failures were more likely to have resistance -- not only to that third agent (in that case, raltegravir) but also to the nucleoside backbone that went with it.

That is important to note. You are not going to fail frequently, but if you do, it can compromise the backbone; in the protease inhibitor arms, it didn't.

Dr. Sax: It is remarkable. It is a consistent finding that we have seen in studies ever since that class started being used widely: Resistance simply does not develop, or does very rarely, in patients who get a boosted protease inhibitor plus 2 nucleosides.

Looking Broadly and Looking Ahead

Dr. Sax: Now let's broaden the discussion a bit. As you are aware, the Department of Health and Human Services updated their guidelines for initial therapy when dolutegravir was approved, and they did so to include, essentially, all of the integrase-based regimens, which are now listed as preferred regimens.[6] You have TDF/FTC/raltegravir; you have the single tablet of TDF/FTC/elvitegravir/cobicistat; you have TDF/FTC/dolutegravir; and you have abacavir/lamivudine/dolutegravir.

When you look at the list of preferred regimens, there are now 4 choices for integrase inhibitor-based therapy. Would you say that your study supports that change, and if so, can you comment about these a bit more? Or is it beyond the scope of the study?

Dr. Landovitz: Our study supports the inclusion of raltegravir-based regimens in the first-line preferred list. You didn't ask this, but it raises the question about whether ATV/r is going to retain its preferred first-line status, particularly when it was less well tolerated than DRV/r. That is going to be very interesting to see when the revised guidelines come out.

Our study obviously does not address the question of the elvitegravir or the dolutegravir regimens. But other head-to-head comparisons that have already been done and were presented -- between DRV/r and dolutegravir, between the elvitegravir combination and ATV/r, and between raltegravir and dolutegravir -- do make it likely that these results are going to be generalizable to the other integrase agents. Of course, the once-daily dosing and the smaller pill burden do make them attractive.

It is important to remember, though, that some of the tolerability gain of the integrase inhibitor is probably from the absence of the ritonavir booster, and I know there has been some experience with cobicistat having some of those same side effects. In our study, the DRV/r main discontinuation driver was a gastrointestinal syndrome.

It does probably suggest that -- although we haven't proven this yet -- that the dolutegravir-based regimens are going to have a leg up from a tablet perspective, a dosing perspective, and a lack of cobicistat perspective.

Dr. Sax: Raphy, this is a really interesting study. I wonder whether you had any further data coming down the pike from this study. I know the answer to that question is undoubtedly yes. One doesn't invest all of this time and energy in a study of this size and then stop with the first series of presentations. So, what is to come from ACTG 5257?

Dr. Landovitz: Thank you for that headliner of coming attractions. As you alluded to in our opening, we invested an enormous amount of time, energy, and resources in making sure we had adequate representation of women in this clinical trial, so one of our first analyses is going to be looking at the impact of gender effect on all of these treatment outcomes in order to better clarify some of the conflicting results that have been seen in other first-line treatment trials in regard to tolerability and efficacy in women.

We are also going to look carefully at results by race and ethnicity, as virologic suppression rates have been notably different across race and ethnicity groups in ACTG trials of initial therapy and other studies. We want to delve into that more. And we are also going to do a careful adherence analysis.

Paul, as you are well aware, one of my personal interests is HIV prevention and treatment as prevention. We did a behavioral analysis in this study that is looking at what happens to people's transmission risk behavior as they initiate treatment. In other words, does the fact that they are on treatment and now becoming virologically suppressed -- and given our new understanding of what that means for the transmissibility of the virus -- what does that do to people's sexual risk behaviors? We have both a baseline analysis, which we have already presented[7] (and which I am sure you have seen), as well as a longitudinal analysis.

And then there is a large metabolic substudy of ACTG 5257 which has another complicated number, ACTG 5260S, that looked very carefully at some biomarkers of early cardiovascular and cerebrovascular disease, a flow-mediated vasodilation parameter, and a lot of bone markers and inflammatory markers that may predict some of these longer-term metabolic outcomes in which we are concerned about mitigating the clinical effects in HIV treatment over the long term.

There are a lot more data to come that may modify these initial results in regard to how dogmatic we are about changes in guidelines or about which regimen is best, but certainly there will be a lot more detail, particularly for different subgroups.

Dr. Sax: Raphy, I want to thank you very much for spending the time to talk about this study specifically and also about its implications more broadly.

Again, this is Dr. Paul Sax. I have been talking with Dr. Raphael Landovitz about initial therapy for HIV. Thank you very much for your attention.


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