Orkin C, Molina JM, Negredo E, et al; EMERALD Study Group. 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. Lancet HIV. 2018;5(1):e23-e34. doi: 10.1016/S2352-3018(17)30179-0.
The development of combination antiretroviral therapy has had an extremely positive effect on reducing mortality and morbidity in patients with HIV. Nevertheless, poor adherence to therapy and the development of antiretroviral resistance remain obstacles to sustained successful treatment. Regimens that require multiple pills and complex timing of administration can adversely affect treatment adherence, whereas single-tablet regimens taken once daily increase the likelihood of patient adherence. Antiretroviral resistance may be addressed by switching regimens.1
The agents darunavir, cobicistat, emtricitabine, and tenofovir alafenamide have been combined in a single-tablet, once-daily regimen—the only such regimen for the treatment of HIV-1 that includes a protease inhibitor, darunavir. Moreover, darunavir has genetic characteristics that substantially reduce its susceptibility to developing antiretroviral resistance. Tenofovir alafenamide, a tenofovir prodrug, also offers advantages over its prodrug predecessor, tenofovir disoproxil fumarate, with which it shares comparable efficacy at 10% of the dose, as the risk for renal toxicity and bone mineral density (BMD) changes is reduced with tenofovir alafenamide. US and European treatment guidelines endorse the use of darunavir and cobicistat in combination with 2 nucleoside or nucleotide analogue reverse transcriptase inhibitors (NRTIs), such as emtricitabine and tenofovir alafenamide, while tenofovir alafenamide is widely recognized as a preferred NRTI backbone in certain guidelines.1
In the phase 3, randomized, active-controlled, open-label, noninferiority EMERALD study, Orkin and colleagues sought to evaluate the efficacy and safety of switching to this single-pill combination treatment versus remaining on a regimen that contains a boosted protease inhibitor combined with emtricitabine and tenofovir disoproxil fumarate.1
EMERALD was conducted at 106 centers in 9 North American and European countries. Patients enrolled in the study were adults at least 18 years of age with HIV-1 infection who had been on treatment and had never experienced virological failure on a darunavir-based regimen (and did not possess darunavir resistance mutations if genotyping had been conducted). Participants included in the study had to have been receiving a stable antiretroviral treatment regimen for at least 6 months prior to screening, which included a boosted protease inhibitor (once-daily darunavir plus either ritonavir or cobicistat, once-daily atazanavir plus either ritonavir or cobicistat, or twice-daily lopinavir plus ritonavir), and had to be virologically suppressed based on a viral load of <50 copies/mL within 2 months prior to screening. All participants were permitted 1 viral load ≥50 and <200 copies/mL during the 12 months prior to screening.1
Patients were randomized in a 2:1 ratio to receive 1 of 2 treatment regimens: 1) the fixed-dose, single-pill combination of darunavir 800 mg, cobicistat 150 mg, emtricitabine 200 mg, and tenofovir alafenamide 10 mg once daily (study regimen); or 2) a boosted protease inhibitor plus emtricitabine and tenofovir disoproxil fumarate (control regimen). Administration of the control regimen was performed based on local prescribing information. The screening period of the trial was approximately 30 days (6-week maximum) and the treatment period was 48 weeks, after which time all patients were invited to receive the study regimen in an extension phase. Study visits occurred at baseline, weeks 2, 4, 8, and 12, and then every 12 weeks thereafter.1
Because patients were virologically suppressed at baseline, the FDA defined a novel primary efficacy endpoint of “…proportion of patients with virological rebound…cumulative through week 48,” with rebound being defined as viral load of ≥50 copies/mL. Participants who terminated the study early for any reason while having a viral load of ≥50 copies/mL were also considered rebounders. The primary outcome was noninferiority of the study regimen versus the control regimen based on the proportion of virological rebounders. Secondary and exploratory endpoints included safety and tolerability, assessment of antiviral activity (per FDA snapshot analysis at week 48), time to virological rebound, change from baseline in CD4 cell count, HIV-1 genotypic resistance, adherence to therapy, change in serum creatinine, and changes in BMD and bone biomarkers. Noninferiority was observed if the difference between the study and the control regimens was less than 4% for the primary outcome. The primary analysis was based on the intention-to-treat (ITT) population and included any randomized patient who received at least 1 dose of the study medication.1
The ITT population comprised a total of 1141 patients—763 in the study group and 378 in the control group. Baseline demographic, health, and previous treatment characteristics were well balanced between the 2 groups, with most patients being white and male with an average age of 46 years. Overall, 70% of the participants were receiving boosted darunavir at screening, whereas 58% had received at least 5 previous antiretrovirals, 41% had received at least 2 protease inhibitors, and 15% had experienced prior antiretroviral virological failure.1
Table 1 illustrates the outcome for the primary end point and Table 2 displays the results of the FDA snapshot analysis at week 48.1 As shown in Table 1, for the primary end point, the proportion of patients with confirmed virological rebound cumulative through week 48 was 2.5% with the study regimen and 2.1% with the control regimen—a significant treatment difference of 0.4% (95% CI, −1.5% to 2.2%; 1-sided noninferiority P <.0001).1 Since the threshold of noninferiority was 4%, this outcome demonstrates noninferiority of the study regimen compared with the control regimen. Of those experiencing virological rebound, 63% (12 of 19) in the study group and 50% (4 of 8) in the control group attained virological suppression (ie, viral load of <50 copies/mL) by week 48 without any treatment adjustment. Three study regimen patients experienced viral load rebounds of ≥200 copies/mL, compared with no rebounds among those receiving the control regimen. Time from baseline to virological rebound was evenly distributed across the 48 weeks and was similar between the 2 treatment groups. The FDA snapshot analysis (Table 2) also demonstrated close similarity for rates of virological success between the study regimen (94.9%) and the control regimen (93.7%), with a treatment difference of 1.2% (95% CI, —1.7% to 4.1%) that favored the study regimen.1
Glomerular filtration rate based on serum cystatin C (eGFRcyst) declined in the control regimen group and remained stable in the study group, a difference that was significant at week 48 (P = .034). Both hip and lumbar spine BMD also decreased in the control group while increasing in the study regimen group; these differences were significant in both instances at week 48 (P <.0001 for each).1
Discontinuation rates were similar for patients receiving the study regimen (4.5%) and those receiving the control regimen (5.3%), with most discontinuations due to adverse events (AEs; 1% in each group) or withdrawn consent, but none due to insufficient efficacy, according to the investigator.1
The rates of AEs and serious AEs (SAEs) of any kind were similar for both groups (82% and 5%, respectively), although the rate of AEs associated with treatment was higher among those receiving the study regimen (18%) compared with those receiving the control regimen (7%). Grade 3 or 4 AEs occurred at a similar rate: 7% with the study regimen versus 8% with the control regimen, and no deaths were reported during the study. The most common AEs included nasopharyngitis and upper respiratory tract infection. Most AEs occurred at similar rates between the 2 groups, with the exception of grade 3 or 4 changes in cholesterol, which were more common among the study regimen patients. A small, but statistically significant, difference was observed in median change from baseline in the ratio of total cholesterol to high-density lipoprotein cholesterol: 0.2% (study regimen) versus 0.1% (control regimen); P = .01. A single SAE (pancreatitis, which was reported in the study group) was deemed to be possibly related to the study treatment regimen.1
The main conclusion derived from the EMERALD study is that in treatment-experienced, virologically suppressed adults with HIV-1 infection, the single-tablet, once-daily formulation of darunavir, cobicistat, emtricitabine, and tenofovir alafenamide demonstrated noninferiority to a regimen containing a boosted protease inhibitor plus emtricitabine and tenofovir disoproxil fumarate over a 48-week treatment period.1 EMERALD was an atypical switching study, in that it had less stringent inclusion criteria that permitted the enrollment of patients with a diversity of previous treatment experiences, as long as they were virologically suppressed, had not experienced virological failure on a darunavir-based regimen, and did not have any darunavir resistance-associated mutations if historical genotypes were available. This may better reflect a real-world patient population who might be candidates for switching, relative to previous switching studies that tended to exclude patients who exhibited signs of resistance to any component of a study regimen. Ultimately, the inclusion of this broader patient population did not appear to adversely affect positive treatment outcomes with the single-tablet formulation.1
1. Orkin C, Molina JM, Negredo E, et al; EMERALD Study Group. 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. Lancet HIV. 2018;5(1):e23-e34. doi: 10.1016/S2352-3018(17)30179-0.