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) recently held in Paris, France.
Recommended antiretroviral therapy (ART) for first-line HIV treatment often involves single-tablet regimens that are taken as one pill, once daily. Taking fewer pills can improve adherence, but there are fewer single-pill options for second-line 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 nucleoside reverse transcriptase inhibitor (NRTI) backbone.
The single-tablet regimen has been recommended for approval by the scientific committee of the European Medicines Agency and will be marketed as Symtuza in the EU after formal marketing approval by the European Commission later this year.
EMERALD enrolled 1141 participants in the UK, Europe and the US. 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 two 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 study were 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 four people who underwent genotypic testing (two 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 (nose and throat inflammation), 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.”
Background: D/C/F/TAF, a once-daily, single-tablet regimen containing darunavir (D 800mg), cobicistat (C 150mg), emtricitabine (F 200mg) and tenofovir alafenamide (TAF 10mg), is undergoing investigation in two Phase 3 studies, EMERALD (NCT02269917) and AMBER (NCT02431247).
Methods: EMERALD, a randomized (2:1), open-label, international, multicenter, parallel-group, non-inferiority, 48-week study, is evaluating the efficacy and safety of switching to D/C/F/TAF vs continuing a boosted protease inhibitor plus emtricitabine/TDF (control) in patients who are virologically suppressed [viral load (VL)< 50c/mL] for ≥2 months. FDA-stipulated primary endpoint is proportion with cumulative virologic rebound (confirmed VL≥50c/mL or premature discontinuations, with last VL≥50c/mL) through Week 48 (non-inferiority margin=4%). Pre-planned Week 24 interim results are presented.
Results: 1141 patients were randomized and treated (N=763 D/C/F/TAF vs N=378 control). Baseline characteristics: median age 46; 18% women; 25% non-white (21% black); 10% CD4+< 350 cells/mm3; 71%, 22%, and 8% on darunavir, atazanavir and lopinavir, respectively (15% on cobicistat). Cumulative virologic rebound was 1.8% (n=14 D/C/F/TAF) vs 2.1% (n=8 control), of which 10/14 and 5/8 respectively, resuppressed (< 50c/mL) by Week 24; there were no confirmed rebounds ≥200c/mL. At Week 24, FDA snapshot analysis showed virologic suppression (VL< 50c/mL) was 96.3% (D/C/F/TAF) and 95.5% (control), and virologic failure occurred in 0.5% and 0.8%, respectively, with no discontinuations for virologic failure and no detected resistance to any study drug.
Safety was similar between arms through 24 weeks, with low incidences of Grade 3-4 adverse events (AEs) (D/C/F/TAF 4.5% vs control 4.5%), serious AEs (2.6% vs 3.2%), and treatment discontinuations (overall, 2.9% vs 2.9%; due to AEs, 1.4% vs 1.1%). The most common AEs (≥5% both arms) were: nasopharyngitis (7.6% vs 6.6%), URI (6.3% vs 6.3%), vitamin D deficiency (5.5% vs 5%). There were no deaths. Total cholesterol/HDL-cholesterol ratios were similar between arms, with minimal changes from baseline. Changes from baseline in renal safety parameters were consistent with known profiles of the individual D/C/F/TAF components; Mean ΔeGFR (cystatin-C clearance by CKD-EPI): +0.3mL/min/1.73m² (D/C/F/TAF) vs. -1.0mL/min/1.73m² (control).
Conclusions: In virologically suppressed adults, switching to once-daily D/C/F/TAF was well tolerated, resulted in a low cumulative virologic rebound rate, and a high virologic suppression rate through 24 weeks.
JM Molina, J Gallant, C Orkin, E Negredo, L Bhatti, J Gathe, E Van Landuyt, E Lathouwers, V Hufkens, S Vanveggel, M Opsomer