Simplified Antiretrovirals Outperform Typical HIV Treatment

Pam Harrison

October 19, 2015

For treatment-experienced HIV patients resistant to at least two drug classes, outcomes to 48 weeks were better with a simplified antiretroviral regimen, according to results from a new study.

The once-daily regimen consists of a single-tablet combination of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide (Stribild, Gilead Sciences), plus darunavir.

"I think treating clinicians should have the confidence and reassurance that patients on complicated regimens who have been through multiple failures, but who are doing well on darunavir, can be safely switched to a two-pill regimen to maintain virologic control," said Gregory Huhn, MD, from the Ruth M. Rothstein CORE Center in Chicago.

"And we were able to demonstrate that cobicistat — which is not an active antiretroviral but is the boosting agent in this regimen — actually boosts both elvitegravir and darunavir, which was important as well," he told Medscape Medical News.

The study results were presented at IDWeek 2015 in San Diego.

Virologic Suppression

Patients involved in the study were taking an antiretroviral regimen containing darunavir and were virologically suppressed at baseline. All had failed at least two previous regimens and were resistant to at least two classes of antiretroviral agents.

More than 70% were resistant to two antiretroviral drug classes, and approximately one-fifth to one-quarter were resistant to three classes of antiretroviral therapy.

At baseline, median estimated glomerular filtration rate was approximately 100 mL/min in the study cohort. Participants were taking a median of five pills a day, and 65% were on a twice-daily dosing, at minimum.

After randomization, 89 patients were switched to the simplified regimen, and the 46 who remained on their baseline regimen served as the control group.

The primary objectives were efficacy at week 23 and safety and tolerability at weeks 24 and 48.

Virologic suppression, defined as an HIV-1 RNA level below 50 copies/mL, was more common in the simplified group than in the control group at week 24 (97% vs 91%) and at week 48 (94% vs 76%).

When a more stringent threshold for virologic suppression — an HIV-1 RNA level below 20 copies/mL — was used, the simplified regimen was still better than the baseline regimens (90% vs 72%; P = .012).

Drug-related adverse events were more common in the simplified group than in the control group (15% vs 0%). There was one grade 3/4 drug-related adverse event in the simplified group, but none in the control group.

However, no patients in either group discontinued treatment because of an adverse event, and there were no serious adverse events related to the study drug.

At week 48, no patients in the simplified group developed resistance, but one patient in the control group did.

Switching to the simplified regimen "also improved proximal tubular proteinuria without a change in eGFR," Dr Huhn reported.

Specifically, the change in the median beta-2-microglobulin to creatinine ratio was significantly different between the simplified and control groups (–35% vs +11%; P < .001), as was the change in the median urine retinol-binding protein to creatinine ratio (–17% vs +13%; P = .019). Both are markers of proximal tubular proteinuria.

At week 48, more patients in the simplified group than in the control group reported an improvement in overall satisfaction with their HIV treatment regimen (27% vs 20%; P < .001).

Strategic Simplification

"Strategic simplification of an antiretroviral regimen with a high pill burden and dosing frequency is a priority for treatment-experienced patients with multidrug resistance to maintain effective virologic suppression," said Dr Huhn.

"And by simplifying therapy from approximately five pills a day to a once-daily, two-pill regimen, we were able to provide efficacious plasma exposure to all active drugs, and potentially improve the long-term safety features of the regimen, especially as they relate to renal side effects," he added.

Data demonstrating a successful switch in antiretroviral-experienced HIV-infected patients with virologic suppression are important for several reasons, said Frank Palella Jr, MD, from the Northwestern University Feinberg School of Medicine in Chicago.

By simplifying therapy from approximately five pills a day to a once-daily, two-pill regimen, We were able to provide efficacious plasma exposure to all active drugs, and potentially improve the long-term safety.

"First, antiretroviral therapy modification is now most often undertaken for reasons of safety, tolerability, and simplification, rather than for issues regarding efficacy," Dr Palella told Medscape Medical News.

However, most of the antiretroviral switch studies undertaken to date have not focused on patients whose viral isolates possess known resistance to antiretrovirals.

"This increases the relevance of the study," Dr Palella explained.

Moreover, the fact that the simplified regimen meant a reduction in overall pill burden from five to two pills a day has potential adherence implications, Dr Palella said.

The inclusion of tenofovir alafenamide fumarate in the four-drug tablet also resulted in reductions in kidney toxicity, as evidenced by urine biomarkers, which is important for long-term safety, particularly in patients with competing comorbidities related to aging, he added.

And the study showed that cobicistat, a pharmaco-enhancer, can boost both darunavir and elvitegravir, with demonstrated good bioavailability for all drugs in the regimen.

Because the study involved an ethno-demographically diverse group of patients, it has important implications for the generalizability of its findings, Dr Palella said.

This study was funded by Gilead Sciences. Dr Huhn reports serving as a consultant for Gilead and ViiV, and receiving grants from Gilead, ViiV, GlaxoSmithKline, Janssen, and Merck.

IDWeek 2015: Abstract 726. Presented October 9, 2015.


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