What Comes Next After Failure of Injectable HIV Medication?

While the injectable HIV treatment regimen cabotegravir/rilpivirine (Cabenuva) is an increasingly important option, including for people who have struggled with adherence to daily tablets, it comes with a caution that must be discussed with each patient.

Around 1.5% of people who switch to the injections experience virologic failure, often despite perfect adherence to the injection schedule. While this rate is not higher than for daily oral HIV regimens, failures are frequently accompanied by resistance-associated mutations.

Since cabotegravir is an integrase inhibitor — as are dolutegravir and bictegravir, the most frequently used anchor drugs in modern HIV treatment — the development of resistance to integrase inhibitors risks significantly limiting future HIV treatment options. Virologic failure on cabotegravir/rilpivirine is therefore considered “a low incidence, but high consequence event” (a phrase shared by Saye Khoo at the Conference on Retroviruses and Opportunistic Infections earlier this year). But there is limited data and a lack of guidance on the most effective regimens to use following failure associated with resistance.

“In reality, what people do in case of failures with cabotegravir/rilpivirine is that they base their therapy on genotypic results,” explained Pierre Giguère, MSc, clinical pharmacy specialist at the Ottawa Hospital, Ottawa, Ontario, Canada. “We like to go with agents for which there are no mutations that could predict treatment failure. And in situations with cabotegravir/rilpivirine, when you have dual-class resistance mutations, like in our cases, what’s left are the protease inhibitors.”

The protease inhibitor darunavir — typically boosted with cobicistat or ritonavir — has become “the pillar of therapy” in these situations, he said in an interview.

However, he and his colleagues reported an unusual case series of six patients at the International AIDS Society Conference on HIV Science this week. Each one was successfully treated with bictegravir/emtricitabine/tenofovir alafenamide (Biktarvy), a single-tablet daily regimen based on an integrase inhibitor.

All patients had major mutations associated with both integrase inhibitors and non-nucleoside reverse transcriptase inhibitors. Despite this, all achieved viral suppression to below 20 copies/mL after switching to the bictegravir-based regimen and have maintained this for between 6 and 18 months.

This approach emerged unexpectedly during clinical practice. The first patient was a woman who initially chose to switch to the bictegravir-based regimen because she could not tolerate the pain she experienced at the injection site. However, samples taken at the time of her switch subsequently revealed that she had a virologic breakthrough with resistance to integrase inhibitors (148R) and reverse transcriptase (101E).

Given that this regimen would not normally be recommended in these circumstances, her clinicians considered taking her off the bictegravir she had already started but decided against it as she was now virally suppressed. “What would be the motivation to change therapy in a patient who is currently on a simple regimen that is working?” asked Giguère. “So, the decision was to keep following this patient closely, making sure that she remains suppressed. And that was our patient zero.”

The next five patients to go on the regimen were the next five patients to experience virologic failure on cabotegravir/rilpivirine at the hospital. “We decided just to keep going with the Biktarvy, based on that n of one experience, which ended up being an n of two, and now is an n of six,” Giguère said.

Three of the subsequent patients had mutations at both positions 138 and 148. While cabotegravir frequently selects for these mutations, and they rapidly confer a significant loss of susceptibility to cabotegravir, that is not the case for bictegravir. “From an in vitro perspective, you would not suspect that these mutations would much impact bictegravir susceptibility,” Giguère said. “But what has been lacking has been clinical data.”

Laura Waters, MD, consultant physician in sexual health and HIV medicine at Central and North West London NHS Foundation Trust, London, England, described the approach as “brave.” She noted that while other cases of patients switching to integrase inhibitors after failure of cabotegravir/rilpivirine have been reported, they did not generally involve people who had integrase inhibitor resistance mutations.

“But as we’re learning more and more, resistance isn’t absolute, and both our second-generation integrase inhibitors have high inhibitory quotients, and so we would expect that virologic suppression would be possible for many individuals,” she told Medscape Medical News.

She said she would be worried about the durability of the response. For three of the five cases reported, follow-up was for less than 1 year, while the patient observed the longest had 20 months of follow-up.

“The concern is around forgiveness: What happens if somebody misses a dose? What happens if somebody takes a cation-containing treatment or supplement that reduces integrase concentrations further?”

For his part, Giguère stresses the importance of defining a safe approach that can be implemented when virologic failure on cabotegravir/rilpivirine occurs. “I think we have to be able to come up with a simple, well-tolerated backup regimen in the case of failure,” he said. 

For the moment, it’s not clear that the bictegravir-based regimen is the right one, but he hopes other clinicians will try to replicate the experience. “Time will tell if the effect is long-lasting, and we need more people to confirm it.”

The study received no funding. Giguère reported having no relevant financial relationships. Waters had received speaker and advisory fees from Merck Sharp & Dohme (MSD), ViiV Healthcare, Janssen Pharmaceuticals, and AbbVie. She is also an investigator on trials funded by Gilead Sciences, MSD, and ViiV Healthcare with funding provided to her institution.

Roger Pebody is a freelance journalist based in Paris, France.