In the February 2020 issue of the journal AIDS, lead author Toby Pepperrell, M.B.B.S., submitted a research letter entitled, “Time to rethink endpoints for new clinical trials of antiretrovirals? Long-term re-suppression of HIV RNA with integrase inhibitors.”
Pepperrell is a fifth-year medical student at Imperial College London. He’s been working on access to medicine since his bachelor’s in global health, and he runs the Imperial chapter of Universities Allied for Essential Medicines. His research currently centers around the ADVANCE trial (a noninferiority trial comparing one new antiretroviral [ARV] regimen to the current global standard-of-care regimen) and equity in clinical trial recruitment and social determinants of suppression.
Terri Wilder: Can you start off by just telling me a little bit about why you and your colleagues decided to submit this research letter to the journal?
Toby Pepperrell: The ADVANCE trial has been going on for a number of years now. We’ve just had the week 96 results. This was a really important finding from the ADVANCE trial. We thought this was important information for clinicians to have on how dolutegravir compares to older first-line treatment, in terms of the ability of patients to reach suppression even after they’ve had low-level viremia.
TW: I’ve talked to several clinicians over the last several years. A lot of times, medical providers will scratch their heads when they have a patient with HIV that has low-level viremia. And they’re scratching their head because, should we keep them on the current regimen, or should we switch them to something else? I’m wondering if you can talk about what you and your colleagues laid out in the research letter that could help clinicians who might read this interview, or go back and look at your letter about what was your thesis and how it could help them, in terms of this quandary that they often have.
TP: Yes. That’s a really good point. I think that it is helpful in informing treatment on integrase inhibitors, but it has to be taken into account that these are the first—well, these are early findings—but perhaps yet to be followed in the ADVANCE trial at later time points. So this needs further support, but it currently indicates that this low-level viremia might not cause the levels of drug resistance that we see on older regimens, like efavirenz-based regimens; and actually that patients who are struggling with adherence or are struggling to keep their viral load down may not be getting this resistance on integrase inhibitors. And there’s the suggestion that they can reach long-term suppression even after having this low-level viremia. So, it could be really helpful to keep patients on their treatment rather than switching to more expensive regimens or regimens that have to be taken more than once daily, that might be more toxic than integrase inhibitors.
TW: As I was reading the article, you brought up that there are a number of different guideline bodies—like WHO [World Health Organization], Southern African HIV Clinicians Society, there are other U.S. guidelines—that have definitions about what viral suppression is. And I’m just wondering if—you know, do we need a new term for efficacy? Is it really virologic failure, if you will, to only be able to reach 50 copies?
TP: That’s a really good point, and that’s something that we considered when writing the article. I think that virological failure threshold is often too stringent, particularly with newer regimens that have the same or similar potency to older regimens, that don’t have the same resistance profile, and actually have a genetic barrier to resistance.
I think that the WHO guidelines of 1,000 copies/mL are maybe more practicable than the U.S. guidelines of 200, because patients staying below that 1,000 copies/mL threshold are able to reach suppression, as we’ve said. Also, it’s important to point out that efficacy in clinical trials does not equate to treatment effects in the real world. So, patients in clinical trials have a much better environment in order to adhere to their treatment and keep on with the regimen, and they will have more contact with clinicians, and are able to report adverse events and the like much more easily than patients just out in the real world who have to put up with adverse events.
TW: I’m also wondering if, instead of framing it as virological failure, if we really need to be framing it as: What is virological success?
TP: Yeah. That’s a good point. And I think that with regimens that have a lower-level drug-resistant profile, it should be possible to have a wider bracket to aim under, and at that point, suppression, I guess, could be termed a success too. It would be a lot easier for patients to kind of visualize that rather than such a clinical term as suppression.
TW: You obviously were, you and your colleagues were, kind of posing the question: Are we undervaluing our new agents?
TP: Yeah. I think that there’s been a lot of discussion of the genetic barrier to resistance of dolutegravir, but actually how that affects practice hasn’t necessarily been considered in great depth. And if these findings can be extrapolated to further results from ADVANCE, other clinical trials, and also case studies, then that could be really important in changing the way we look at this new era of medication.
TW: Great. One of the things that you and your coauthors talked about was adherence, and persistence appears to be more important than the specific regimen. I’m wondering—you talked about enhanced adherence counseling. I’m wondering if you could define that. What does that mean, to have enhanced adherence counseling, in terms of helping folks get to their virologic suppression goals?
TP: Enhanced adherence counseling is something that’s already in practice in high-income countries. Pretty much it’s where patients come in; they’ve got a high viral load. And in everyday practice, that means they’re booked in for another appointment very soon to just check that they can get below that level. There’s this counseling based on their lifestyle factors and any side effects they might be experiencing and trying to get their adherent level up—whereas, in resource-constrained settings, that happens a lot less.
This paper is obviously focused on the results in ADVANCE, which is centered in Johannesburg. It’s not necessarily standard to have patients coming in regularly for viremic titers. It’s far less likely that they’ll be able to see a clinician.
TW: When I was thinking about the phrase enhanced adherence counseling, many clinicians have very little time. They barely have time to get to what they need to get to as a presenting problem when the patient comes in. You know, maybe they come in for something completely different. And I’m just wondering, how are clinicians going to have time to engage in enhanced adherence counseling? Or are folks going to be more likely to have some of the other staff on the team actually help with that enhanced adherence counseling?
TP: Yeah, I see what you mean. In HIV care, I guess, one of the most important things about a follow-up visit is checking your viral load. It’s something that can be prioritized in a clinical setting.
Of course, patients will come in with many other complaints. But if that viral load is high, then that’s something that they should pay attention to. I think that focusing the discussion on lifestyle factors is hugely important. And I think the social element of HIV care can’t be overvalued. I think time needs to be provided in the clinical setting to help the patient overcome any lifestyle problems they could be having with their care.
TW: As I was reading the article, I couldn’t help think about the questions that you guys are posing, in terms of how are we defining virologic success versus virologic failure. What do you think the questions that you’re posing in your article—what do you think this means for future design of research?
TP: I think that if a drug like dolutegravir has been proven to have high barriers to resistance, then for future drugs in that class that come off dolutegravir, or elvitegravir, trials can be designed to keep patients on treatment, despite meeting low-level viremic thresholds. Pharmaceutical company control trials will discontinue patients from their regimen if they have repeated readings over 200 copies, which is a very low viremia. So, I think that these trials need to be redesigned for integrase inhibitors so you can keep patients on their treatments if the outcomes are this lower viremia they’ve been getting.
TW: There’s a global campaign around undetectable equals untransmittable (U=U). And I’m wondering if we rethink the endpoints in what means viral suppression, is there any chance that that would also shift what U=U means? Which, right now, means less than 200.
TP: It may sound like the letter is saying that if a virologic titer is detectable, that’s OK. That’s not necessarily what we’re posing. We’re saying that these patients may not fare any better if their regimen is switched. They just need adherence counseling in order to become undetectable.
So this is the point, with assistance on a regimen like integrase inhibitors, that if you are experiencing low-level viremia, the answer isn’t to switch from dolutegravir to efavirenz, for example; the answer is to assess the patient’s lifestyle factors and give them counseling in order to enable them to take their drugs and get below that threshold. Because we’re not seeing resistance developing. So these patients that are technically failing are still able to reach suppression and become undetectable and, therefore, untransmittable.
TW: Great. I guess my final question: Since your research really centers around the ADVANCE trial, are there other things that you’re looking at in the ADVANCE trial that would be of interest to our readers?
TP: There have been some very interesting findings in the ADVANCE trial. You can see them in a New England Journal of Medicine paper, which outlines some of the week 48 endpoints. A lot of my interest in ADVANCE comes from the fact that it’s using an intention-to-treat population for the primary analysis, so we can see the social effects on participants’ results. We have been able to draw correlations between treatment failure and younger age and unemployment in ADVANCE. So we can see that these social factors are actually a lot more important than the regimen that people are on, in terms of reaching suppression—which I think is important because so much money in HIV is directed at new pharmaceuticals and new technologies as ways to get patients undetectable, when actually a lot can be gained from a much simpler, broader-scale intervention like social protection.
So, yeah, I think the findings from ADVANCE could be really important in redirecting and prioritizing the progression towards 90% suppression rates globally.
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