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IAS 2017: First Protease Inhibitor Combo Pill Maintains Viral Suppression


The first once-daily single-tablet regimen containing a protease inhibitor maintained viral suppression in almost everyone who switched after achieving undetectable HIV RNA on a multi-pill regimen, according to a report at the 9th International AIDS Society Conference on HIV Science (IAS 2017) last month in Paris.

Recommended antiretroviral therapy (ART) for first-line HIV treatment often involves single-tablet regimens that are taken as 1 pill, once daily. Taking fewer pills can improve adherence, but there are fewer single-pill options for second-line or subsequent therapy. Many treatment-experienced people who have developed drug resistance may require a protease inhibitor, a drug class with potent and durable antiviral activity and a high barrier to resistance.

Jean-Michel Molina of the University of Paris reported results from the EMERALD study, a Phase 3 clinical trial evaluating a single-tablet regimen -- dubbed D/C/F/TAF -- containing the protease inhibitor darunavir (Prezista), cobicistat as a booster, and emtricitabine and tenofovir alafenamide (TAF) as a NRTI backbone.

EMERALD enrolled 1141 participants in the U.S., U.K., and Europe. More than 80% were men, 75% were white, and the median age was 46 years. They had had HIV for a median of 9 years and the median baseline CD4 count was approximately 630 cells/mm3. They had normal kidney function at baseline, with an estimated glomerular filtration rate (eGFR) averaging around 107.

Participants were required to have had a viral load below 50 copies/mL at for at least 2 months using a boosted protease inhibitor plus emtricitabine and the older tenofovir disoproxil fumarate (TDF). For just over 40% this was their first ART regimen. Most (about 70%) were already on boosted darunavir, 22% were on boosted atazanavir (Reyataz), and 8% were on lopinavir/ritonavir (Kaletra). About 15% were already using cobicistat, rather than ritonavir, as their booster. About 15% had a history of prior virological failure, but they could not have prior darunavir failure or evidence of darunavir resistance mutations.

Participants in this open-label studywere randomly assigned to either receive the new darunavir single-tablet regimen or stay on their current regimen for 48 weeks. Molina presented 24-week interim results. After the 48-week primary endpoint, all participants will continue on the combination pill through 96 weeks.

D/C/F/TAF was highly effective: 96% of participants who switched maintained undetectable viral load, matching the proportion who did so on their existing regimen. Virological rebound was rare in both study arms (1.8% vs 2.1%, respectively). Most rebounders regained viral suppression without changing therapy, and there were no confirmed rebounds above 200 copies/mL or treatment discontinuations due to virological failure. Among the 4 people who underwent genotypic testing (2 in each arm), none showed evidence of primary protease inhibitor or NRTI resistance mutations.

Treatment was generally safe and well-tolerated. There were few drug-related grade 3-4 adverse events (1.2% in the D/C/F/TAF arm and 0.5% in the continuation arm) or early discontinuations due to adverse events (1.3% vs 1.1%, respectively). The most common adverse events in both groups were nasopharyngitis, upper respiratory tract infections, and vitamin D deficiency.

The researchers focused on kidney and bone side effects, as TAF is easier on the kidneys and bones than TDF. Estimated GFR fell a bit more in the D/C/F/TAF group than in the continued therapy group. However, Molina explained that cobicistat has a known inhibitory effect on kidney tubule secretion of creatinine, which leads to a decrease in estimated GFR but has no effect on "real GFR." When GFR was measured using a different method, it rose slightly in the D/C/F/TAF arm while declining by about 1% in the continued therapy arm.

Bone mineral density at the hip and spine increased slightly in the D/C/F/TAF arm (by 0.6% and 1.2%, respectively), while falling by an even smaller amount in the continuation arm (-0.3% at both sites).

Based on these findings, the researchers concluded, "D/C/F/TAF combines the safety advantages of TAF and darunavir, with the known efficacy and high genetic barrier to resistance of darunavir, in a single-tablet regimen."



J Molina et al. Efficacy and safety of switching from boosted-protease inhibitor plus emtricitabine/tenofovir disoproxil fumarate regimens to the single-tablet regimen of darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) in virologically-suppressed, HIV-1-infected adults through 24 weeks: EMERALD study.9th International AIDS Society Conference on HIV Science.Paris, July 23-26, 2017. Abstract TUAB0101