What is a drug “tail,” and what does it have to do with long-acting PrEP?
BETA is reporting from the 2016 Conference on Retroviruses and Opportunistic Infections (CROI) this week in Boston—bringing you the latest news, updates, and research on HIV treatment and prevention.
“Why am I showing you a picture of a grumpy Komodo dragon? It’s because he’s got a very long tail. And, these drugs have very long tails,” said Ian McGowan, MD, PhD at a CROI 2016 Symposium session.
Drug “tails” are a hot topic at CROI 2016 as attendees wait to hear results from a long-acting cabotegravir PrEP injection study with HIV-negative men. (Return to BETA later this week to read results from the ÉCLAIR Phase 2A PrEP safety and pharmacokinetic study.) A few prominent researchers have already incorporated the issue of drug “tails” into their discussions of one potential downside to having a PrEP drug that stays in a person’s system for an extended length of time.
Here’s what we’ve learned about the issue so far.
Sharon Hillier, PhD, introduced the subject by explaining it in context to a long-acting drug already on the market: the hormonal contraceptive Depo-Provera.
“People talk a lot about how great Depo-Provera is. It’s a little bit forgiving as a contraceptive because after it’s given, it has a therapeutic range where it’s a very effective; then, it has a longer ‘tail’ where it’s not completely effective in everybody but there is still some level of drug present. So you actually still have the drug present, but it might work or might be sub-therapeutic. When we think about applying this to ARVs, I think there are some real strengths and some real weaknesses,” she said.
The problem, explained Hillier, is that people with a low level of an antiretroviral in their system—not enough to offer protection from HIV—that then become infected with HIV, may be more likely to develop a corresponding drug resistant mutation. Resistance mutations are a problem, because people who develop resistance ultimately have fewer options for HIV treatment.
“If you were exposed to HIV at a time when you were coming off a study or stopped using [an] injectable, and you were in a hyperendemic region, it’s probably—unfortunately—a distinct possibility that you might develop a class of resistance to a drug like rilpivarine. We’re not so sure about cabotegravir, but possibly,” said McGowan.
McGowan explained that this did happen in one instance to a participant enrolled in a long-acting rilpivarine study.
“The participant received a 300 mg dose [of rilpivarine]. On day 40 post-dose, she reported an exposure with an individual who was HIV-infected. That’s the point where she got infected. At that moment, she was hovering around the lower-limit of rilpivarine. And it got lower. And in that setting, she developed resistance.”
The participant developed a resistance mutation to rilpivarine and cross-resistance to etravirine, nevirapine, and efavirenz as well.
Clinical trials that test long-acting candidates for PrEP must take the drug tail into consideration by essentially “covering” the tail with oral PrEP after the study is over. In cabotegravir long-acting clinical trials, participants are exposed to drug through injection(s) that are effective for two to three months. Two to three months after the last study dose, participants take oral PrEP for an additional 12 months.
“The challenge here is that many of patients that are most-suited to the LA [long-acting] PrEP are the least likely ones to take oral PrEP. But then you’re using a strategy here that would require oral PrEP. So that is not ideal,” said McGowan.
What we need to think about, said Hillier, is how to counsel people who either take long-acting PrEP in a clinical trial or in a real-world setting at some point in the future. She said that people must know how long they will be protected from HIV, and how long they might have low-levels of drug that might not provide protection but could select for resistance in the advent of an infection.
Hillier, S. L. The rapidly changing landscape of HIV prevention. CROI 2016, Oral session W1.
McGowan, I. The promise and challenges of sustained delivery of PrEP. CROI 2016, Symposium Session S-4.