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CROI 2016: Long-Acting Cabotegravir PrEP Injection Tolerable and Acceptable, but Dose Adjustment Needed

Attendees at the Conference on Retroviruses and Opportunistic Infections (CROI 2016)last week in Boston heard results from the first Phase 2 (safety, acceptability, and dose-finding) study of a long-lasting injectable formulation of the integrase inhibitor drug cabotegravir for use as pre-exposure prophylaxis (PrEP) in HIV-negative people. The previous day researchers also presented a study of the same injectable drug, plus another injectable, rilpivirine, used as treatment for people with HIV.

[Produced in collaboration with Aidsmap.com]

In the cabotegravir PrEP study, dubbed ÉCLAIR, a couple of surprises awaited the researchers. First, the rate of absorption of the drug into the body was faster than expected, meaning that an injection will probably have to be given every 8 weeks, instead of every 12 weeks as hoped. Second, the duration and severity of pain and other effects of the injections were greater than expected. However, few people dropped out of the study because of them, and three-quarters of participants said they would be happy to continue taking cabotegravir injections as PrEP should it become available.

The ÉCLAIR study lasted for 81 weeks altogether; presenter Martin Markowitz of the Aaron Diamond AIDS Research Center did not present final results, as the final follow-up phase of the study has just finished.

For the first 4 weeks, participants took a daily oral cabotegravir pill or a placebo pill (1 in 5 took the placebo). This oral phase was intended as a precaution to weed out any subjects who have unusual adverse reactions to cabotegravir -- since one of the drawbacks of an injectable formulation is that is cannot be suddenly stopped.

At weeks 5, 17, and 29, participants were given 3 doses of injectable cabotegravir or saline as placebo. These consisted of 800 milligrams of cabotegravir given as 2 injections of 2 milliliters each, one in each buttock. The injection phase was defined as lasting until week 41, or 12 weeks after the last injection. There was then a follow-up phase of 40 weeks until week 81; not all the data has yet been collected from this phase.

The study population consisted of men aged 18 to 64 defined as being at low risk of HIV infection (as this is largely a safety, not a prevention trial). Their average age was 30.5 years, 57% were white, 32% were African-American, and roughly 80% were gay and 20% heterosexual. A total of 126 men entered the trial, 105 allocated to cabotegravir and 21 to placebo.

During the first 4 weeks on the oral pill, 11 people withdrew from the study who were taking cabotegravir, and 1 who was taking placebo. During the injection period, a further 7 people, all on cabotegravir, withdrew, 4 of them due to intolerance of the injections.

Markowitz attributed the fact that more people withdrew during the oral phase to caution on the part of the investigators in ensuring that no one who showed any possibility of side effects went forward to the injection phase. In particular, 3 participants in the oral phase saw an increase in levels of creatine phosphokinase, an enzyme that can indicate injury to muscle tissue; although these were almost certainly not drug-related, the men were withdrawn from receiving intramuscular injections as a precaution.

In the injection phase, the primary adverse event was injection site reactions: these were almost universal among the subjects receiving cabotegravir, with 93% reporting them, as did 57% receiving placebo. Injection site reactions largely consisted of pain in the muscle at the injection site. Pain was generally mild in placebo recipients, but in cabotegravir recipients 37% defined it as "moderate" and 10% as "severe," and lasting, on average, for 5.4 days. Other injection site reactions included itching, swelling, and heat at the injection site. The only non-local side effect was fever, experienced by 7% of men receiving cabotegravir.

Despite this, 62% of people on cabotegravir said they were satisfied with their study medication, and 74% said they would be happy to continue receiving it. In fact, more people said they preferred the 12-weekly injection to having to take a daily tablet.

Drug level measurements of cabotegravir showed that it was absorbed by the body faster than expected. This meant that the peak level of drug in the bloodstream, just after the injection, was higher than expected, and the trough level, just before the next injection, was lower than expected.

A model had forecast that the peak level in blood would be 3 micrograms per milliliter (mcg/mL) when in fact the average level was 5-6 mcg/mL, and that the average trough level would be 1 mcg/mL when in fact it was 0.3-0.6 mcg/mL. This is of concern since it is close to the IC90 -- the level of drug that cuts 90% of viral replication -- and drug levels should be well above this to ensure efficacy. The proportion of trial subjects whose trough drug levels fell below the IC90 was 24% after the first injection, 31% after the second, and 15% after the third.

Markowitz said that the reason for the faster absorption was unknown, but it would probably mean that cabotegravir PrEP would have to be given every 2 months rather than every 3.

There were 2 cases of HIV infection in the study. One person receiving placebo tested HIV-positive at week 23. The other had received cabotegravir, but tested positive at week 53, nearly 6 months after his last cabotegravir injection. At this point he still tested HIV antibody-negative but had a viral load of over 3 million copies/mL, so it must have been a very recent infection. He had no detectable cabotegravir in his bloodstream at this point.

Markowitz concluded that these results indicate that cabotegravir injections were safe and, despite injection site reactions, relatively well-tolerated. A parallel trial is happening in women, and when this has concluded the final decision will be made about taking injectable cabotegravir PrEP forward into a full-fledged effectiveness trial, where it would be compared with oral tenofovir/emtricitabine (Truvada).

2/29/16

Reference

M Markowitz, I Frank, R Grant, et al. ÉCLAIR: Phase 2A Safety and PK Study of Cabotegravir LA in HIV-Uninfected Men. Conference on Retroviruses and Opportunistic Infections. Boston, February 22-25, 2016. Abstract 106.