HIV Clinical Research Highlights From AIDS 2020, the 23rd International AIDS Conference

We’ve been trying to get the magic eight ball to tell us what’s up with the intersection between HIV and the novel coronavirus since the scope of the COVID-19 pandemic first became apparent. While we’ve learned a lot over the past several months, we’re far from having any clear answers.

AIDS 2020 didn’t offer much in the way of new information specifically focusing on the effect of COVID-19 among people living with HIV. (A separate mini-conference on July 10, however, did extensively cover what we know to date about COVID-19 more generally, and where we might be headed.) A pair of oral abstract presentations yielded some of the largest case studies to date involving people living with HIV who were hospitalized due to COVID-19. But we still have no solid sense of whether HIV status has any real impact on COVID-19 severity, nor do we know with any degree of confidence what role HIV antiretrovirals may play in affecting that risk.

What we do know is that the COVID-19 pandemic has hit our health care system like a tsunami, affecting HIV education, prevention, treatment, and care services in ways we’re only beginning to grasp. In the U.S., that has meant a scramble to utilize telehealth and otherwise adapt services to keep the HIV care continuum intact, with a significant number of presentations offering examples of how these adjusted interventions might play out. Globally, we learned about imminent threats to the HIV drug supply chain that may disrupt therapy for millions.

In short: It’s a challenging time. There’s still so much we don’t know. But thousands of researchers and HIV workforce members keep pressing to find answers, and to carve out a new normal for HIV care and services in a time of stunning societal upheaval (on top of all of the other societal upheavals we see in most countries in any given year).

If there’s any sanity to find in a mad, mad world, it’s that new HIV clinical research findings still flow forth as copiously as they were a year ago. For instance, we continue to gain precision in our understanding of the metabolic effects of some newer antiretrovirals, particularly tenofovir alafenamide (TAF) and dolutegravir (Tivicay, DTG). AIDS 2020 brought a few noteworthy developments in this area.

An analysis of the OPERA study, in which virally suppressed treatment-experienced people were switched from a regimen containing tenofovir disoproxil fumarate (TDF, Viread) to a TAF-containing regimen, found a marked early increase in weight gain among TAF recipients that plateaued over time. Among participants whose only regimen change was to swap TDF for TAF, weight gain averaged 2.6 kg/year in the first nine months after switching, and 0.3 kg/year afterward.

Interestingly, participants whose background regimen included a boosted protease inhibitor appeared to experience slightly less weight gain (2.0 kg/year in the first nine months, and weight loss of 0.1 kg/year after) than those on an integrase inhibitor (2.6 kg/year initially, 0.3 kg/year after) or NNRTI (2.3 kg/year initially, 0.2 kg/year after).

Meanwhile, metabolic data from the TANGO study suggested that if a provider wanted to switch their patient off TAF due to metabolic concerns, they may want to be careful about what to switch to. In TANGO, which switched people from a stable TAF-based regimen to dolutegravir/lamivudine (we’ll have more on that two-drug regimen shortly), switching to the two-drug regimen tended to yield minor but statistically significant improvements in total cholesterol, LDL cholesterol, triglycerides, fasting insulin, and insulin resistance, but had no real impact on weight.

This association between the integrase inhibitor dolutegravir and weight gain also played out in data from the AFRICOS study, which examined body mass index (BMI) and hyperglycemia in the context of the rollout of dolutegravir/lamivudine/TDF in several African countries. The study found that people receiving the regimen were 85% more likely to become overweight (i.e., have a BMI of 25 kg/m2 or higher) and experienced higher incidence of hyperglycemia than people taking other antiretroviral regimens.

Long-term findings from the ADVANCE study, a first-line treatment trial in South Africa, suggest that the weight-increasing effects of dolutegravir and TAF may be particularly noticeable among women. Through 144 weeks, the study found markedly greater weight gain among women who received dolutegravir/lamivudine/TAF (12.3 kg on average) compared to women who received dolutegravir/lamivudine/TDF (7.4 kg) or efavirenz/lamivudine/TDF (5.5 kg). (That said, all three regimens were highly effective.)

All of this appears to be taking place within a broader trend of unhealthy weight gain among people living with HIV generally. A Kaiser Permanente study found that, over a 12-year span, BMI among people with HIV increased at a rate of 0.22 kg/m2 per year, compared to an increase of 0.06 kg/m2 per year for their HIV-negative counterparts—and that BMI increases were greater for people with HIV across baseline weight classifications, be they underweight, obese, or anything in between. We explore these data more deeply in a separate article.

Although we’ve had brief dalliances with the idea of simplified antiretroviral therapy in the roughly two decades since three- (and four-) drug regimens became the gold standard, no regimen consistently proved hardy enough to maintain long-term viral suppression among a broad swath of people—that is, until relatively recently. In late 2019, dolutegravir/lamivudine earned a heralded spot in the recommended first-line therapy list maintained by the U.S. Department of Health and Human Services, marking the beginning of a new era in HIV treatment options.

AIDS 2020 featured several presentations that further cast two-drug antiretroviral regimens in a complimentary light. Though these studies were usually funded or led by the pharmaceutical companies developing the drugs, most nonetheless generally offered encouraging data, although with one notable blip on the radar in the form of inflammation markers.

The focus at this meeting was on two regimens: dolutegravir/lamivudine and islatravir/doravirine, an experimental regimen currently in phase 3 study. The overall thrust of the dolutegravir/lamivudine studies supported their real-world efficacy and safety through upwards of two years of follow-up, both among people who received the regimen as initial therapy and those who switched regimens. Although research continues to suggest a relationship between dolutegravir use and weight gain (as we noted earlier), other metabolic parameters (including limb and trunk fat) don’t appear to follow suit.

On the islatravir/doravirine front, we received a deep dive into virologic failures within the combo’s phase 2 study, which suggested it may be hyperbolic to even term the few viral load increases that occurred as “failures,” given that in no case did viral load exceed 80 copies/mL. We also learned more about the regimen’s safety profile, with a plethora of common and mild adverse effects punctuated with a trend toward weight gain.

We’ve got more on all of these findings in this deeper dive into AIDS 2020 research on two-drug regimens.

Even as a signal strengthens regarding the effect of dolutegravir use on body weight (especially in women), an even more concerning signal—the potential for birth defects—has grown progressively weaker over time, but still persists.

AIDS 2020 brought new results from the Tsepamo trial, which two years ago generated considerable alarm after finding a substantially higher rate of neural tube defects in infants when the birth parent had taken a dolutegravir-based regimen relative to non-dolutegravir therapy (0.94% versus 0.12%). Since then, a number of studies—including the IMPAACT 2010 trial and updated Tsepamo results—slightly tempered those concerns, with 2019 Tsepamo data finding that neural tube defects occurred 0.3% of the time among birth parents who took dolutegravir versus 0.1% of those who did not.

The newly presented Tsepamo findings provide an additional year’s worth of data. In that year, the incidence of neural tube defects among dolutegravir recipients dropped further relative to non-dolutegravir recipients; as of April 2020, the risk was 0.19% among birth parents who were taking dolutegravir at the time of conception and 0.04% among those who took the drug during pregnancy. By comparison, neural tube defect rates were 0.12% among HIV-negative birth parents, 0.09% among birth parents living with HIV who were not taking dolutegravir at conception, and 0.12% among birth parents taking efavirenz (Sustiva, Stocrin).

In other words: The heightened risk is still there, but it has grown much smaller—and it does not apply to treatment considerations while the birth parent is pregnant. This would seem to support the World Health Organization’s 2019 decision to recommend dolutegravir for pregnant patients—but still leaves behind a highly individualized decision about what treatment is right for a person living with HIV who is able to conceive.

Although it was branded as one of the top science presentations by AIDS 2020 organizers, the revelation that we may have a new HIV remission case—in a person who received only an array of oral medications, not a stem-cell transplant—may have left as many questions as answers about its significance.

The case derives from a small study in Sao Paulo, Brazil, involving 30 people living with HIV who had long-term viral suppression while on antiretroviral therapy. Researchers divided participants into six study arms, with five people each, and tested a different type of treatment intensification in each arm, in an effort to draw out and eradicate latent HIV within viral reservoirs.

At AIDS 2020, lead researcher Ricardo S. Diaz, M.D., Ph.D., presented findings on the only study participant who appeared to show signs of HIV remission. In 2015, on top of the participant’s existing antiretroviral regimen, Diaz et al added three medications: the antiretroviral dolutegravir (which prior research has indicated may affect viral replication in HIV reservoirs), the antiretroviral maraviroc (Selzentry, which some research has suggested may have latency reversal properties), and the dietary supplement nicotinamide (which has shown some potential in preventing T cells from entering latency).

The patient took this additional regimen for one year, then continued on regular antiretroviral therapy until March 2019, at which point he began a monitored treatment interruption. Since then, his viral load has remained suppressed off therapy, and his HIV antibody levels dropped to a point where at least one rapid HIV test came back negative.

Importantly, thorough examinations have not yet been performed that would certify whether HIV DNA is present in areas known to harbor HIV reservoirs, including the lymph nodes and gut. And no other participant in the study—including the other four people who received the same intervention as this man—was able to retain viral suppression afterward. So, at present, this case remains a hopeful curiosity, with no immediate clinical takeaways (e.g., patients need not stock up on nicotinamide).