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Protease inhibitor regimen maintains viral suppression for a year

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

On 26 September the European Commission approved Janssen Pharmaceutical's new co-formulation, to be marketed as Symtuza, for the treatment of HIV for adults and adolescents aged 12 and older. US Food and Drug Administration (FDA) approval is still pending.

Findings from the EMERALD study showed that an all-in-one co-formulation 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).

Recommended antiretroviral regimens for first-time HIV treatment often involve single-tablet regimens, which can potentially improve adherence, but there are fewer one-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 is a phase 3 clinical trial evaluating the Symtuza single-tablet regimen as a switch option for people who have achieved undetectable viral load on a multi-pill regimen.

The study by researchers at Barts Health NHS Trust, London, the department of infectious diseases, Saint-Louis Hospital, Paris, Southwest CARE Centre, Santa Fe, New Mexico, Germans Trias i Pujol University Hospital, Badalona, Spain, Plaza Medical Centre, Houston, Texas, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina and Janssen Pharmaceutica, Beerse, Belgium, enrolled 1,141 participants in the UK, Europe and the US. More than 80% were men and the median age was 46 years. They had been living with HIV for a median of nine years and about 60% had used five or more previous antiretrovirals. At baseline, they had a viral load below 50 copies/ml for at least two 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 (Norvir) 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 Symtuza single-tablet regimen (also known as D/C/F/TAF) 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 Symtuza maintained 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 Symtuza was non-inferior to the multi-pill regimens.

Virological rebound was rare in both study arms, 2.5 vs 2.1%, respectively.

Most people who experienced rebound 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 Symtuza and 4.8% on the continued regimens) 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 diarrhoea.

Renal and bone biomarkers were more favourable overall in the Symtuza group 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 Symtuza arm, attributed to cobicistat's inhibitory effect on kidney tubule secretion of creatinine; however, the co-formulation looked better when GFR was measured using a different method. Bone mineral density at the hip and spine increased slightly in the Symtuza arm while falling slightly in the continued regimen arm. Blood lipid profiles were slightly less favourable with Symtuza.

"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.

Symtuza 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.

Abstract 1
Background: EMERALD is evaluating the efficacy and safety of switching from bPI + FTC/TDF regimens (control) to D/C/F/TAF 800/150/200/10mg in virologically suppressed, HIV-1-infected adults. We present Wk 48 primary results.
Method: EMERALD (NCT02269917) is a randomized, active-controlled, open-label, international, multicenter, parallel-group, non-inferiority trial. Virologically suppressed (viral load [VL]<50c/mL for ≥2months), HIV-1-infected adults were randomized (2:1) to switch to D/C/F/TAF or continue control. The FDA-stipulated primary endpoint was non-inferiority of D/C/F/TAF vs control regarding % virologic rebound (confirmed VL≥50c/mL or premature discontinuations with last VL≥50c/mL) cumulative through Wk 48 (4% margin). Result: 1141 patients were randomized and treated (N=763 D/C/F/TAF; N=378 control); median age 46; 18% women; 76% white; 58% on >2 previous ARVs (prior to screening regimen); 15% with previous non DRV virologic failure (VF).
Virologic rebound through Wk 48 was non-inferior for D/C/F/TAF (2.5%; n=19) vs control (2.1%; n=8) (D0.4%, 95%CI: –1.5%; 2.2%; p<0.001). Most rebounders (12/19 [63%] vs 4/8 [50%]) resuppressed by Wk 48 without change in therapy.
Wk 48 virologic suppression rates (VL<50c/mL; FDA Snapshot) were 94.9% vs 93.7% (D1.2%, 95%CI: −1.7%;4.1%) and VF rates (VL≥50c/mL; Snapshot) were 0.8% vs 0.5% (D0.3%, 95%CI: −0.7%;1.2%), with no discontinuations for VF. No resistance-associated mutations related to any study drug were observed.
Adverse events (AEs) were similar between arms: AE-related discontinuations (1.4% vs 1.3%); grade 3-4 AEs (6.8% vs 8.2%); serious AEs (4.6% vs 4.8%); and no deaths. Renal and bone parameters favored D/C/F/TAF vs control. TC and LDL-C slightly favored control vs D/C/F/TAF, with no clinically significant difference in TC/HDL-C ratio between arms (Table 1).
Conclusion: Percentage of virologic rebound after switching to D/C/F/TAF was non-inferior to control cumulative through Wk 48, with high suppression rates (94.9%), no resistance development, better bone and renal safety parameters and similar TC/HDL-C ratio. D/C/F/TAF maintains the high genetic barrier to resistance of darunavir with the safety advantages of TAF, even in patients with a history of non DRV VF.

Authors
Chloe Orkin, Jean-Michel Molina, MD, Joel Gallant, Eugenia Negredo, Joseph Gathe, Joseph Eron Jr, Erika Van Landuyt, Erkki Lathouwers, Veerle Hufkens, Romana Petrovic, Magda Opsomer

Summary
Background: Simplified regimens with reduced pill burden and fewer side-effects are desirable for people living with HIV. We investigated the efficacy and safety of switching to a single-tablet regimen of darunavir, cobicistat, emtricitabine, and tenofovir alafenamide versus continuing a regimen of boosted protease inhibitor, emtricitabine, and tenofovir disoproxil fumarate.
Methods: EMERALD was a phase-3, randomised, active-controlled, open-label, international, multicentre trial, done at 106 sites across nine countries in North America and Europe. HIV-1-infected adults were eligible to participate if they were treatment-experienced and virologically suppressed (viral load <50 copies per mL for ≥2 months; one viral load of 50–200 copies per mL was allowed within 12 months before screening), and patients with a history of virological failure on non-darunavir regimens were allowed. Randomisation was by computer-generated interactive web-response system and stratified by boosted protease inhibitor use at baseline. Patients were randomly assigned (2:1) to switch to the open-label study regimen or continue the control regimen. The study regimen consisted of a fixed-dose tablet containing darunavir 800 mg, cobicistat 150 mg, emtricitabine 200 mg, and tenofovir alafenamide 10 mg, which was taken once per day for 48 weeks. The primary outcome was the proportion of participants with virological rebound (confirmed viral load ≥50 copies per mL or premature discontinuations, with last viral load ≥50 copies per mL) cumulative through week 48; we tested non-inferiority (4% margin) of the study regimen versus the control regimen in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT02269917.
Findings: The study began on April 1, 2015, and the cutoff date for the week 48 primary analysis was Feb 24, 2017. Of 1141 patients (763 in the study group and 378 in the control group), 664 (58%) had previously received five or more antiretrovirals, including screening antiretrovirals, and 169 (15%) had previous virological failure on a non-darunavir regimen. The study regimen was non-inferior to the control for virological rebound cumulative through week 48 (19 [2·5%] of 763 patients in the study group vs eight (2·1%) of 378 patients in the control group; difference 0·4%, 95% CI −1·5 to 2·2; p<0·0001). No resistance to any study drug was observed. Numbers of discontinuations related to adverse events (11 [1%] of 763 patients in the study group vs four [1%] of 378 patients in the control group) and grade 3–4 adverse events (52 [7%] patients vs 31 [8%] patients) were similar between the two groups. There was a small non-clinically relevant but statistically significant (0·2 [SD 1·1] vs 0·1 [1·1], p=0.010) difference between the two groups in change from baseline in total cholesterol to HDL-cholesterol ratio. Only one serious adverse event (pancreatitis in the study group) was deemed as possibly related to the study regimen.
Interpretation: Our findings show the safety and efficacy of single-tablet darunavir, cobicistat, emtricitabine, and tenofovir alafenamide as a potential switch option for the treatment of HIV-1 infection in adults with viral suppression.

Authors
Chloe Orkin, Jean-Michel Molina, Eugenia Negredo, José R Arribas, Joseph Gathe, Joseph J Eron, Erika Van Landuyt, Erkki Lathouwers, Veerle Hufkens, Romana Petrovic, Simon Vanveggel, Magda Opsomer

[link url="http://www.aidsmap.com/iSymtuzai-protease-inhibitor-regimen-maintains-viral-suppression-for-a-year/page/3178747/"]Aidsmap material[/link]
[link url="https://idsa.confex.com/idsa/2017/webprogram/Paper67485.html"]IDWeek 2017 abstract[/link]
[link url="http://www.thelancet.com/journals/lanhiv/article/PIIS2352-3018(17)30179-0/fulltext"]The Lancet article summary[/link]

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