HIV and ID Observations

One thing about the COVID-19 pandemic — other important non-COVID ID news gets crowded out.

As a prime example, take HPTN 083, a major clinical trial in HIV prevention. The results are a big deal, and should have garnered more attention when they were released last week.

This randomized, double-blind pre-exposure prophylaxis (PrEP) study compared long-acting injectable cabotegravir (CAB), given every 2 months, with a control arm of daily TDF/FTC (brand name Truvada). The population was men who have sex with men and transgender women at high risk for HIV. The National Institute of Allergy and Infectious Diseases funded the study with the drug manufacturers (ViiV and Gilead, respectively) providing the study drugs.

In reviewing the results of the ongoing trial, a data safety and monitoring board (DSMB) found the data so compelling that they stopped the blinding and informed participants of their treatment assignment.

DSMB actions like this are generally big news — the same thing happened recently with the COVID-19 remdesivir study comparing it to placebo, showing a faster recovery time in the remdesivir arm. So let’s take a brief break from all-things-COVID and look in more detail at the HPTN 083 results.

The study enrolled 4570 participants with a mean age of 28 years; 12% were transgender women. Importantly, 50% of the U.S. enrollment identified as Black or African American, the group in this country at disproportionately high risk of HIV. Participants also came from Argentina, Brazil, Peru, Thailand, Vietnam, and South Africa.

During the study, 50 participants acquired HIV, for an overall incidence rate of 0.79%. Since the investigators predicted a background HIV incidence of 4.5%, these results show that both study arms were highly effective in preventing HIV.

But here’s where it gets really interesting — 38 of the infections came in the TDF/FTC arm (incidence, 1.21%), versus only 12 (incidence, 0.38%) in the CAB treatment group.

Let’s do the complicated math — there were about three times fewer HIV infections acquired by participants on CAB than on TDF/FTC.

Since there’s still no baseball, I’ll fill the gap by applying the appropriate metaphor — this most certainly is a home run for HIV prevention. And, if you prefer Greek epic poetry metaphors, it appears that injectable cabotegravir overcomes the Achilles heel of daily TDF/FTC, which is adherence.

Safety and tolerability of the two approaches were similar, though injection site reactions were more common in the CAB arm. Remember, though all received active drug, accompanying placebos were also administered — kudos to the study sites for pulling this off, that’s a lot of injections.

The press release stated that resistance testing is “in progress” — these data will be critical. If the failure of CAB leads to integrase resistance, this will be a substantial disadvantage to this otherwise very promising strategy.

An additional endpoint of some interest (also not yet reported) will be weight changes over time since TDF/FTC tends to suppress weight, while most integrase-based regimens in people with HIV lead to weight gain. No effect of cabotegravir on weight was observed in a small previous study, but there was no TDF/FTC control arm.

Importantly, HPTN 084, a parallel trial designed to evaluate CAB in comparison to daily oral TDF/FTC in women in sub-Saharan Africa, is ongoing. The results of both these studies will capture the populations at greatest risk of HIV globally, and fully round out our understanding of these two strategies of HIV prevention.

As noted here previously, the FDA delayed approval of long-acting cabotegravir and rilpivirine late last year, so as of today clinicians cannot prescribe cabotegravir for PrEP. But you can be sure these results will add urgency to completing the approval process, COVID-19 notwithstanding.

They also will amplify the importance of other long-acting PrEP studies in development, including the injectable capsid inhibitor GS-6207 and the nucleoside reverse transcriptase translocation inhibitor islatravir, which is also undergoing evaluation as an implant.

Before finishing, I offer this disclosure and a personal note. The protocol chair of HPTN 083 is Dr. Raphael (Raphy) Landovitz, a longtime friend and former colleague mentioned numerous times on this site. I first met him (many) years ago when he was in medical school, and noted him to be brilliant, opinionated, funny — and most emphatically (and refreshingly) not your typical stereotype of the successful academic.

When he left Boston for UCLA to work under the research mentorship of Dr. Judy Currier, the energy level of the country shifted noticeably westward. Our loss. Regardless, it has been enormously gratifying to watch him go from success to success, with HPTN 083 just the latest example.

And even though he and I don’t share hobbies — he’s passionate about Broadway musicals (hard pass for me) but can’t stand baseball — even I have to admit that this is very, very well done: