IDWeek 2017: Single-Tablet Protease Inhibitor Regimen Maintains Viral Suppression for a Year

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People who switched from a multi-pill antiretroviral regimen to the first 1-pill, once-daily regimen that includes a protease inhibitor maintained undetectable viral load for a year, according to a report at the IDWeek 2017 conference last week in San Diego.

Findings from the EMERALD study, also published in the October 6 online edition of The Lancet, showed that an all-in-1 coformulation containing darunavir (sold separately as Prezista), cobicistat as a booster, and emtricitabine and tenofovir alafenamide or TAF (the drugs in Descovy) was non-inferior to a standard regimen containing a boosted protease inhibitor plus emtricitabine and the older tenofovir disoproxil fumarate or TDF (the drugs in Truvada).

On September 26 the European Commission approved Janssen's new coformulation, to be marketed as Symtuza, for the treatment of HIV-positive adults and adolescents age 12 and older. U.S. Food and Drug Administration approval is still pending.

Recommended antiretroviral regimens for first-line HIV treatment often involve single-tablet regimens, which can potentially improve adherence, but there are fewer 1-pill, once-daily options for second-line therapy. Many treatment-experienced people who have developed drug resistance may need the potency, durability and high barrier to resistance offered by protease inhibitors.

EMERALD (NCT02269917) is a Phase 3 clinical trial evaluating the single-tablet regimen, known as D/C/F/TAF, as a switch option for people who have achieved undetectable viral load on a multi-pill regimen.

The study enrolled 1141 participants in the U.S., U.K., and Europe. More than 80% were men and the median age was 46 years. They had been HIV-positive for a median of 9 years and about 60% had used 5 or more previous antiretrovirals. At baseline they had a viral load below 50 copies/mL for at least 2 months. The median CD4 count was high, at approximately 630 cells/mm3. They had normal kidney function, which is a consideration because tenofovir -- especially the older TDF -- can cause kidney problems.

Most participants (about 70%) were already using boosted darunavir in their multi-pill regimen, while 22% were on boosted atazanavir (Reyataz) and 8% were on lopinavir/ritonavir (Kaletra). About 15% were already using cobicistat, while the rest were using ritonavir as a booster. Although 15% had a history of prior virological failure, they could not have prior darunavir failure or evidence of darunavir resistance mutations.

Participants in this open-label study were randomly assigned to either switch to the D/C/F/TAF single-tablet regimen or stay on their current combination regimen for 48 weeks. Jean-Michel Molina of the University of Paris reported 24-week interim results at the IAS Conference on HIV Science in July, and Joseph Eron of the University of North Carolina School of Medicine presented 48-week primary results at IDWeek.

At 48 weeks, 94.9% of people who switched to D/C/F/TAFmaintained an undetectable viral load, as did 93.7% of those who stayed on their baseline combination regimen. These response rates were statistically similar, showing that D/C/F/TAFwas non-inferior to the multi-pill regimens.

Virological rebound was rare in both study arms, 2.5% on D/C/F/TAFand 2.1% on the baseline regimen. Most people who rebounded were able to regain viral suppression by week 48 without changing therapy. Virological failure rates were also low and similar (0.8% and 0.5%, respectively) and there were no treatment discontinuations due to virological failure. Among participants who underwent genotypic testing, no mutations conferring resistance to any study drugs were observed.

Treatment was generally safe and well-tolerated. There were few serious adverse events (4.6% on D/C/F/TAFand 4.8% on the baseline regimen) or discontinuations due to adverse events (1.4% vs 1.3%, respectively). The most common adverse events were nasopharyngitis (nose and throat inflammation), upper respiratory tract infections, and diarrhea.

Renal and bone biomarkers were more favorable overall in the D/C/F/TAFgroup compared to the group that stayed on regimens containing TDF, confirming that the new version of tenofovir is easier on the kidneys and bones.

Estimated glomerular filtration rate (GFR), a common measure of kidney function, fell a bit more in the D/C/F/TAFarm, attributed to cobicistat's inhibitory effect on kidney tubule secretion of creatinine; however, the coformulation looked better when GFR was measured using a different method. Bone mineral density at the hip and spine increased slightly in the D/C/F/TAFarm while falling slightly in the baseline regimen arm. Blood lipid profiles were slightly less favorable with D/C/F/TAF.

"The findings from the EMERALD study bring us one step closer to being able to offer those who live with HIV and struggle with adherence an option that combines the efficacy and high genetic barrier to resistance of darunavir with the demonstrated safety profile of tenofovir alafenamide into a single tablet," Eron said in a Janssen press release.

D/C/F/TAF is also being studied for first-line therapy in the Phase 3 AMBER trial, with 48-week results to be presented at the European AIDS Conference in Milan later this month.

10/12/17

Sources

C Orkin, JM Molina, J Gallant, et al. Week 48 results of EMERALD: A phase 3, randomized, non-inferiority study evaluating the efficacy and safety of switching from boosted-protease inhibitors (bPI) plus emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF) regimens to the once daily (QD), single-tablet regimen (STR) of darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) in virologically-suppressed, HIV-1-infected adults.IDWeek. San Diego, October 4-8, 2017. Abstract 1689b.

C Orkin, JM Molina, E Negredo, et al. Efficacy and safety of switching from boosted protease inhibitors plus emtricitabine and tenofovir disoproxil fumarate regimens to single-tablet darunavir, cobicistat, emtricitabine, and tenofovir alafenamide at 48 weeks in adults with virologically suppressed HIV-1 (EMERALD): a phase 3, randomised, non-inferiority trial. The Lancet. October 6, 2017 (online ahead of print).