More Time on Dolutegravir Needed Before Drug Switch: Study

Most cases of virologic failure on dolutegravir treatment for HIV are likely due to adherence problems and more time on treatment is needed before switching to another drug, according to new data from the ADVANCE trial.

“What we saw was a faster time to re-suppression in the people followed-up long term on dolutegravir and also a higher percentage of people becoming suppressed when they remained on dolutegravir,” said Andrew Hill, MD, from the Department of Pharmacology and Therapeutics at the University of Liverpool, United Kingdom.

The new data was presented here at the International AIDS Society Conference on HIV Science (IAS) in Brisbane, Australia. The ADVANCE trial is a three-arm randomized study involving 1053 treatment-naive individuals comparing two triple-therapy combinations — dolutegravir, emtricitabine, and one of two tenofovir prodrugs — with a standard care regimen of tenofovir disoproxil fumarate, emtricitabine, and efavirenz.

Although the usual approach for someone in a clinical trial who experiences elevations in HIV RNA levels while on a dolutegravir-based treatment is to switch them to another therapy, the ADVANCE investigators opted for a different strategy.

“We actually continued treatment despite high viral load, and we didn’t have standard discontinuation preferences,” Hill said at the meeting. They instead provided counselling about adherence, which gave an opportunity to examine viral re-suppression rates in participants in both the dolutegravir and efavirenz arms.

This revealed that 95% of patients in the two dolutegravir arms of the study were able to achieve re-suppression of their viral load — defined as below 50 viral RNA copies per mL — without any emergence of resistance.

The Guidelines

Current World Health Organization guidelines recommend that anyone whose viral load goes above 1000 copies per mL who is on a non-nucleoside reverse transcriptase inhibitor such as efavirenz should be switched to an appropriate regimen.

Those who experience viremia on an integrase inhibitor such as dolutegravir should receive adherence counseling, have a repeat viral load test done in 3 months, and if their viral load is still elevated, be switched to another regimen.

Hill and his team were examining how this might play out in a clinical trial setting and they found that there were a similar number of episodes of initial virologic failure in both the dolutegravir and efavirenz groups.

But after adherence counseling, testing for resistance and — if no resistance was evident — continuation with treatment, they saw differences emerge between the two groups.

“What we saw was a faster time to re-suppression in the people followed-up long term on dolutegravir and also a higher percentage of people becoming suppressed when they remained on dolutegravir,” he said.

Time to Viral Re-suppression

At 24 weeks after restarting treatment, 88% of people in the dolutegravir group had re-suppressed their viral RNA compared with 46% of people in the efavirenz group. At 48 weeks, those figures were 95% and 66%, respectively.

Hill pointed out that a significant number of people were lost to follow-up after virologic failure, and genotyping was not performed at baseline.

We addressed the question of how much adherence counseling should be undertaken in people who experienced viremia while on dolutegravir therapy, Hill said, particularly as there were often very good reasons for lack of adherence, such as homelessness.

“If you can get through those difficult phases, people can go back on their meds,” he told Medscape Medical News. “It’s almost a sociological problem rather than a clinical issue.”

And with efavirenz and the lower rates of re-suppression observed in the study, Hill said it was a more fragile drug, so viremia therefore provided the opportunity for resistance to emerge, “and then once the resistant virus is there, you can’t get virus undetectable.”

Laura Waters, MD, a genitourinary and HIV medicine consultant at CNWL’s Mortimer Market Centre in London, who was not involved in the study, said the results support recommendations to give people on drugs such as dolutegravir, which have a high genetic barrier to resistance, more time to improve their adherence before switching to another therapy.

“Although it provides that reassuring proof of concept, it doesn’t negate the importance of having to continue to monitor, because nothing is infallible,” she told Medscape Medical News. “We’ve talked about high-barrier drugs in the past, and you do start seeing resistance emerge.”

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