We Know the "Tail" Is Something to Track
After a single dose of CAB-LA or RPV, the slow fade of drug from the body means drug levels eventually fall beneath a concentration that shuts down HIV -- unless a person gets another shot in the prescribed time. In the ÉCLAIR trial, CAB-LA remained detectable in blood in 14 participants (17 percent) 52 weeks after the last injection. If someone taking CAB for PrEP forgets a shot long enough -- or just stops -- and keeps having sex, low CAB levels could permit HIV infection. And when HIV starts copying itself in the face of meager antiretroviral levels, it starts making resistant copies.
This is not a theoretical scenario. It already happened to a woman who got a single 300-mg intramuscular shot of RPV. She tested positive for HIV 84 days after the shot, and after 115 days the infecting virus carried a mutation that confers resistance to the whole nonnucleoside class. The researchers call this "a unique instance of infection with wild-type [nonmutant] HIV-1 and subsequent selection of resistant virus by persistent exposure to long-acting PrEP." To avoid repeating this misadventure, a person taking a long-acting injectable would have to have a clear HIV prevention plan for several months after the last shot -- some combination of complete condom use, behavior change or covering the slowly waning tail of the injectable with faithfully taken oral PrEP, like Truvada.
We Know the Trial Designs Are Complex
December 2016 saw the launch of HPTN 083, a 4500-person double-dummy, double-blind trial of injectable CAB-LA PrEP every eight weeks. The trial is enrolling MSM and TGW in countries in North and South America, Asia, as well as in South Africa. Researchers estimate it could take 3.5 years to complete HPTN 083 but note that the trial is "endpoint driven," meaning that the timing depends on the frequency with which new HIV diagnoses occur in participants. HPTN 084, a parallel CAB-LA PrEP trial in women, is also a double-dummy, double-blind trial and is expected to start later this year.
Does "double-dummy double-blind" sound familiar? It might not. This and other terms are relatively new in the biomedical HIV prevention field. But times have changed. The advent of daily oral PrEP as a WHO-recommended prevention strategy has propelled changes in trials of other prevention strategies -- including ARV-based and non-ARV based prevention alike. (AVAC has developed a plain language glossary of some of the commonly used terms HIV Prevention Trial Terms: An advocate's guide.)
The designs for HPTN 083 and 084 are examples of what efficacy trials look like in the "post-placebo" era. In a placebo-controlled trial, people are randomly assigned to receive either an active agent (like oral PrEP pills) or an identical "dummy" candidate (a sugar pill or a saline injection). Both groups receive the same HIV prevention package. HIV prevention trials involving people whose primary risk is sexual exposure all provide condoms, diagnosis and treatment of sexually transmitted infections and behavior change; some also now provide referrals for voluntary medical male circumcision, PrEP and partner testing and treatment.
For now, PrEP is not part of the standard prevention package in all HIV prevention trials (e.g., vaccine studies and more). It's being provided on referral in countries where PrEP is also part of the national policy. But this approach won't work for trials of long-acting injectable PrEP. Trial ethics require that a trial of a new method (an injectable PrEP) be compared to existing effective methods in the same category (daily oral PrEP).
For an in-depth look at HPTN 084 trial and the "lexicon" associated with such studies, check out AVAC's most recent issue of Px Wire.
To meet this ethical imperative and get a clear, usable answer, the trials have to ask a new kind of question: how does injectable PrEP compare to daily oral PrEP when it comes to reducing the risk of acquiring HIV?
Because of the way that statistics work, this question has to be phrased very precisely. Broadly speaking there are two questions PrEP trials can ask in the post-placebo era:
- Is this new experimental product better than a placebo or an existing product, e.g., is injectable CAB-LA better than daily TDF/FTC? A superiority trial asks this kind of question.
- Is this new experimental product equivalent to or not worse than the existing product, by a pre-specified margin? A non-inferiority trial asks this kind of question.
These weighty questions about injectable antiretroviral adherence, safety, and resistance will probably take a few years to answer because big efficacy trials have just started signing up recruits.
We Know That Clinical Trial Success Is Only One Step -- and Doesn't Always Translate to Impact
If injectable PrEP or treatment works in trials, there will still be lots to explore about delivery in the real world.
Most people with HIV see their provider every 4-6 months; most HIV-negative individuals who may be candidates for PrEP see their clinician much less often, if at all. That will have to change if providers intend to give people antiretroviral injections for treatment or prevention every two months. There will be many other questions too about who is willing to pay for long-acting ARVs, what types of programs these tools would belong in -- and more.
As we've learned from many strategies -- from HPV vaccine to oral PrEP -- if you wait until there is evidence of efficacy to begin addressing these questions, then you've waited too long. AVAC is working with CHAI as part of the Gates Foundation-funded HIV Prevention Market Manager project to frame and address key questions about long-acting PrEP. At the same time, we are working with many of our partners in civil society to ensure that the trial designs are ethical, the goals well understood, and the outcomes on track to achieve the ultimate goal -- a sustained end to epidemic levels of new HIV infections worldwide.
See the AVAC infographic on long-acting injectables for a nuts-and-bolts review of testing these agents for HIV treatment and prevention; see: HIV Prevention Trial Terms: An advocate's guide for definitions of many of the terms used in this article.
Mark Mascolini is a medical journalist who writes about HIV news, research and global policies for the International AIDS Society and many publications. Emily Bass is the director of strategy and content at AVAC.