Every-Other-Month Injectable HIV Treatment Works

Heather Boerner

March 10, 2020

BOSTON — HIV can be suppressed when the long-acting combination of cabotegravir plus rilpivirine (Cabenuva, ViiV Healthcare) is administered every 8 weeks, according to data from the ATLAS-2M study, presented at the virtual Conference on Retroviruses and Opportunistic Infections (CROI) 2020.

The ATLAS trial, presented at CROI last year, showed that viral suppression was similar in participants who received the two-drug injection every 4 weeks and those who took daily pills. At the time, the trial was hailed as a "landmark" in the advancement of HIV treatment.

"It can be challenging logistically for our patients to make it to the clinic, and giving them an every-2-month option will make this more broadly appealing," said Jonathan Li, MD, from Brigham and Women's Hospital in Boston.

Still, some signals on drug resistance are raising concern among clinicians, who wonder whether early signs of resistance and the 48-week trial design will be enough to sway practice change.

A World of Options

During the 20-week lead-in period in the ATLAS trial, participants took the two drugs orally until they become virally suppressed so that any adverse effects that would make the injections impractical could be detected, said Turner Overton, MD, from the University of Alabama at Birmingham.

In the ATLAS-2M open-label extension, 391 ATLAS participants who were still receiving monthly injections and 654 participants new to injections, many of whom had been in the pill group in the original trial, were randomized, half to 8-week injections and half to 4-week injections.

In the study cohort, 73% of participants were men and 29% were nonwhite.

ATLAS-2M doses of cabotegravir were higher in the 8-week group than in the 4-week group (600 vs 400 mg), as were doses of rilpivirine (900 vs 600 mg).

At 48 weeks, viral suppression rates were similar in the 8-week and 4-week groups (94.3% vs 93.5%). For context, viral suppression rates in ATLAS were 93.0% in the 4-week injection group and 95.0% in the pill group.

"The adjusted treatment difference is 0.8%," said Overton. This demonstrates that the "8-week dosing strategy is noninferior to 4-week dosing."

Resistance and Treatment Failure

However, six of the participants who met the criteria for treatment failure at 48 weeks were in the 8-week group, whereas only two were in the 4-week group.

All six participants who failed treatment in the 8-week group had markers of rilpivirine resistance, and five showed resistance to integrase inhibitors.

One of the participants in the 8-week group who failed treatment had a record of integrase mutations, but neither of the two who failed treatment in the 4-week group did.

Often, there are no punches pulled during the question and answer session that follows a presentation, but the virtual nature of this year's conference meant that there was no real-time discussion of the findings. Still, Overton reported that the questions he received by email and on Twitter were focused on the 10 people who experienced treatment failure.

And although previous studies have shown a surprising correlation between HIV A subtypes and treatment-resistant mutations to non-nucleoside reverse-transcriptase inhibitors (NNRTIs) and protease inhibitors, no such correlation was seen in ATLAS-2M.

"There were two people with subtype A HIV viruses," he said. "But the rest are a smorgasbord, a mixture of subtype B and C and others. So this time, a more diverse population had treatment failure."

The researchers have not determined whether sex or body mass index has any effect on response to the 8-week regimen, and they have not had a chance to analyze the background rate of resistance mutations. Future analyses will likely address these questions, Overton told Medscape Medical News.

These topics are exactly what Laura Waters, MD, chair of the British HIV Association, said she's concerned about.

https://twitter.com/drlaurajwaters/status/1237019012023926784

Going 8 weeks between treatments without answers to those questions is a nonstarter, said Waters, who noted that there have been previous concerns about new two-drug regimens.

The long-acting injection is "clearly a very effective switch option" for people who do well on current treatment, she told Medscape Medical News. But it's too early — both in terms of analysis of the data and in terms of the number of weeks they've followed participants so far — to put these findings into practice.

"For me, these findings mean I'm not yet close to confident enough to recommend 2-month doses for anybody," she said.

The combination injection for the treatment of HIV has not been approved by the US Food and Drug Administration.

Conference on Retroviruses and Opportunistic Infections (CROI) 2020: Abstract OA-34. Presented March 9, 2020.

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