Cabotegravir-LA Safe in Women, Challenges Remain

Heather Boerner

July 28, 2017

PARIS — The long-acting injectable cabotegravir (ViiV Healthcare), previously shown to be safe and effective for the prevention of HIV in men, is also safe and effective in women, new data show.

However, the issue of the "long tail" of cabotegravir remains unresolved, leading some to wonder how well the first generation of these formulations will serve patients.

"This is the first incremental advance," said Raphael Landovitz, MD, from the UCLA Center for Clinical AIDS Research and Education in Los Angeles, who presented data from the HIV Prevention Trials Network (HPTN) 077 study here at the International AIDS Society 2017 Conference.

But there will be more. "No one is going to stop with this," he told Medscape Medical News.

In the phase 2a safety and pharmacokinetic study, 199 people at low risk for HIV, 132 of whom were women, were divided into two cohorts. But that wasn't the original plan.

Learning From ÉCLAIR

Initially, the 41-week HPTN 077 study mirrored ÉCLAIR, a phase 2a trial of long-acting cabotegravir in men.

All ÉCLAIR participants received 4 weeks of daily oral cabotegravir to identify any adverse effects, and were then randomized to received six injections of cabotegravir 800 mg or saline 12 weeks apart (two injections per visit).

However, after ÉCLAIR data showed that 12 weeks of cabotegravir at 800 mg was insufficient to maintain therapeutic levels of the drug, recruitment in HPTN 077 was paused, and the 110 already-enrolled participants became the first cohort.

The second cohort — the subsequently enrolled 89 participants — received the same 4-week oral dosing ramp-up to check for safety, and were then randomized to five injections of cabotegravir 600 mg or saline administered 8 weeks apart.

And when ÉCLAIR data revealed that 17% of participants experienced a so-called long tail of detectable drug after administration of the final dose — for up to 52 weeks — HPTN 077 follow-up was extended from 52 to 76 weeks.

Consistently Safe

The full course of injections was completed by at least 75% of participants in the first and second cohorts. Although 91% of participants who received cabotegravir experienced adverse effects, they were "overwhelmingly mild to moderate," and declined as the study went on, Dr Landovitz reported.

Adverse effects included neurologic events, such as neuropathy and headaches, rashes, and one case of gastrointestinal distress. One woman with a history of seizure had a seizure during the study, and one person in the cabotegravir group discontinued treatment.

"There's no difference in safety between men and women," said Dr Landovitz. "It's very reassuring."

One woman experienced seroconversion 48 weeks after her final injection, when drug levels were undetectable. Single-gene sequencing for resistance is still underway.

Sex Difference in Drug Levels and the Long Tail

As expected, the shorter 8-week dosing schedule was better than the 12-week schedule for maintaining therapeutic drug levels.

The 8-week dose "consistently met prespecified pharmacokinetic targets," Dr Landovitz reported, with one exception. For women in the 8-week cabotegravir group, drug concentration levels were only 79% of target after the first injection, but they equalized after that.

The women also had lower peak drug concentrations directly after administration than the men studied in ÉCLAIR, and higher troughs toward the end of the dosing period.

This might mean longer, more consistent drug absorption for women, which would be good news, but it might also mean something else, Dr Landovitz said.

Women absorbed the drug 50% slower than men in the study and, in general, "we do expect the tail to be longer in females than in males," he told Medscape Medical News.

"The final results of HPTN 077 will tell us how much longer females would be expected to have levels," he added.

Anticipation and Concern

Patients have already started asking for injectables, so these data are welcome, said Tristan Barber, MD, from Chelsea and Westminster Hospital in London, who treats primarily gay and bisexual men, but also treats some transgender and nontransgender women.

"They ask about implants, they ask about injectables — anything that they wouldn't be able to forget," he told Medscape Medical News.

Long-acting cabotegravir is "clearly the lead product for PrEP at this time" because long-acting rilpivirine was discontinued for prevention, said Ian McGowan, MD, from the University of Pittsburgh, who noted that it continues to be used in combination with cabotegravir for injectable antiretroviral therapy for people infected with HIV.

But that doesn't mean patients and providers won't struggle with the 8-week dosing. "If you've got a PrEP clinic with 2000 people, it can be a huge burden," he told Medscape Medical News.

There is also concern that the long tail might mean that patients — the very patients who don't want to take pills — will have to take oral PrEP for a year or more after finishing their final dose of long-acting cabotegravir, he added.

Dr Landovitz said he is well aware of the limitations of this particular formulation and this drug, and has heard a lot about implants and other drugs that can be removed if there is a problem.

I don't have a crystal ball, he said, but I wonder if the future will really be in long-acting drugs, or whether it will be in extended release for short-acting drugs.

HPTN 077 was funded by the National Institutes of Health. ViiV Healthcare provided study product. Dr Barber reports receiving fees from Gilead Sciences, ViiV Healthcare, and GlaxoSmithKline. Dr McGowan has disclosed no relevant financial relationships.

International AIDS Society (IAS) 2017 Conference: Abstract TUAC01. Presented July 25, 2017.

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