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Long-acting antiretrovirals for HIV treatment and PrEP

, by Liz Highleyman

injectionLong-acting antiretrovirals that could be used for both HIV treatment and prevention were among the big news at the International AIDS Society Conference on HIV Science, held last month in Paris.

Long-acting injectable formulations of cabotegravir and rilpivirine, taken once every four or eight weeks, maintained viral suppression in most participants in the LATTE-2 trial. Injectable cabotegravir also looks promising as a long-acting pre-exposure prophylaxis (PrEP) option for HIV prevention.

Further back in the pipeline, a novel oral drug, MK-8591, which could potentially be taken once a week, showed good activity in an early HIV treatment trial. It also protected monkeys against rectal infection and may be a future PrEP candidate.

Modern antiretrovirals are highly effective for HIV treatment if taken as directed every day. Once-daily Truvada (tenofovir/emtricitabine) is the only PrEP regimen approved in the U.S. (although a French study showed that taking it before and after sex also works). Maintaining good adherence over the long term can be challenging, and long-acting drug formulations could offer an alternative.

Injectable Cabotegravir and Rilpivirine

Joseph Eron, MD (Photo: Liz Highleyman)

Joseph Eron, MD (Photo: Liz Highleyman)

Joseph Eron, MD, of the University of North Carolina at Chapel Hill presented the latest findings from LATTE-2, which is evaluating a maintenance regimen of injectable cabotegravir, an experimental integrase inhibitor, and rilpivirine, which is currently approved as an oral formulation (Edurant, also in the Complera combination pill).

The earlier LATTE-1 trial showed that a two-drug combination of oral cabotegravir and rilpivirine worked well as a simplified maintenance regimen for people who achieved undetectable viral load using standard three-drug antiretroviral therapy (ART). This set the stage for LATTE-2 trial, testing long-acting formulations of cabotegravir and rilpivirine given as intramuscular injections.

This open-label Phase 2b study enrolled 309 participants who were starting HIV treatment for the first time. More than 90% were men, about 80% were white, the median age was 35 years, and they had a median CD4 count of approximately 500 cells/mm3.

Participants initially started a three-drug induction regimen of oral cabotegravir plus abacavir/lamivudine (Epzicom). After 20 weeks, those with viral load below 50 copies/mL were randomly assigned to either stay on the same oral regimen or switch to cabotegravir and rilpivirine injections. The latter group received either 400 mg cabotegravir plus 600 mg rilpivirine administered every 4 weeks (Q4W), or 600 mg cabotegravir plus 900 mg rilpivirine given every 8 weeks (Q8W).

Last year researchers presented 32-week primary-endpoint results from LATTE-2, showing that 95% of participants who switched to the Q8W injectable combo and 94% of those who used the Q4W regimen maintained undetectable viral load, as did 91% of those who stayed on the oral regimen.

At this IAS meeting, Eron reported that most people maintained viral suppression through two years. At 96 weeks, 94% of people on the Q8W injectable combo and 87% on the Q4W regimen still had undetectable HIV RNA, as did with 84% of those on the continued oral regimen.

Injectable cabotegravir and rilpivirine were generally safe and well tolerated, and few people stopped treatment early due to adverse events. Injection site reactions were common, but mostly mild or moderate and usually temporary, lasting an average of three days. Only two people stopped treatment early for this reason. Overall, study participants said that they were satisfied with the long-acting therapy and would like to continue on it.

Both Q8W and Q4W injections maintained cabotegravir levels similar to those seen with oral dosing. Monthly dosing resulted in a slightly lower rate of virological failure at week 48, so this scheduled was selected for Phase 3 studies now underway. But Eron said that that with longer-term follow-up, the Q4W and Q8W regimens looked similarly effective, and a Phase 3 study of every-other-month dosing is being developed.

Long-acting injectable cabotegravir is also being studied for HIV prevention. Raphael Landovitz of the University of California at Los Angeles presented the first findings from the HPTN 077 study. This Phase 2a trial is looking at the safety, tolerability, and acceptability of injectable cabotegravir, but is not designed to evaluate prevention efficacy yet.

Landovitz reported that cabotegravir injections given every 8 weeks produced high enough drugs levels in both men and women to offer protection against HIV, although a larger dose given every 12 weeks fell short of this threshold. Read more about these findings here.

Long-acting injectable rilpivirine did not fare so well as a solo PrEP candidate, failing to consistently reach high levels enough to offer protection against HIV in a Phase 1 study. Development of injectable rilpivirine was therefore stopped at the Phase 2a stage. 

MK-8591: An antiretroviral in a new class of medication

Researchers also presented results from early-stage studies of a long-acting antiretroviral in a novel drug class. MK-8591, also known as EFdA, is a nucleoside reverse transcriptase translocation inhibitor that prevents HIV from replicating by binding to the polymerase active site of HIV’s reverse transcriptase enzyme.

Randolph Matthews from Merck presented findings from a Phase 1b study of the antiviral activity and tolerability of single doses of MK-8591 over seven to ten days. This open-label study enrolled 30 HIV-positive participants who had not yet started ART. They received a single administration of MK-8591, at doses of 0.5 mg, 1 mg, 2 mg, 10 mg, or 30 mg.

Single doses of MK-8591 across the range of tested doses led to “rapid and robust” viral load reductions, the researchers reported. At 168 hours after administration, mean viral load declines ranged from -1.18 log using the 0.5 mg dose to -1.57 log using the 30 mg dose.

Treatment was generally safe and well tolerated at all doses. Most participants experienced some treatment-related symptoms, but there were no serious adverse events. The most common drug-related adverse events were mild to moderate headache, diarrhea, and skin rash.

“The antiviral potency, human pharmacokinetics, and physical properties of MK-8591 have the potential to open new paradigms for extended duration HIV treatment and prophylaxis approaches,” the researchers concluded.

Pre-clinical research showed that MK-8591 had good distribution to rectal and vaginal tissues in monkeys, indicating potential suitability for PrEP. Martin Markowitz of the Aaron Diamond AIDS Research Center presented results from a study evaluating whether it could protect monkeys from rectal infection with a simian-human hybrid virus known as SHIV. 

Sixteen male macaques were given either MK-8519 at an oral dose of 3.9 mg/kg, or a placebo, at the start of the study, on day 7, and weekly thereafter up to 14 doses. They were rectally exposed to SHIV on day 6 and weekly thereafter for a maximum of 12 challenges.

None of the eight monkeys treated with MK-8591 became infected over the course of 12 viral exposures. They showed no evidence of HIV RNA in blood plasma, proviral DNA, or antibody seroconversion. In contrast, all eight monkeys in the placebo group became infected, mostly after one or two viral exposures. This worked out to a 42-fold lower risk of infection.

Taken together, these studies offer promising evidence that long-acting HIV treatment and PrEP may become available in the not-too-distant future.


Eron J et al. Safety and efficacy of long-acting CAB and RPV as two drug IM maintenance therapy: LATTE-2 week 96 results. IAS 2017. Abstract MOAX0205LB.

Landovitz R et al. Safety, tolerability and pharmacokinetics of long-acting injectable cabotegravir in low-risk HIV-uninfected women and men: HPTN 077. IAS 2017. Abstract TUAC0106LB.

McGowan I et al. An open-label multiple dose phase 1 assessment of long-acting rilpivirine. IAS 2017. Abstract TUAC0103.

Matthews RP et al. Single doses as low as 0.5 mg of the novel NRTTI MK-8591 suppress HIV for at least seven days. IAS 2017. Abstract TUPDB0202LB.

Markowitz M et al. Weekly oral MK-8591 protects male rhesus macaques against repeated low dose intrarectal challenge with SHIVC109P3. IAS 2017. Abstract MOAX0203LB.

Liz Highleyman is a freelance medical writer and editor of HIVandHepatitis.com.


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