A triple combination containing the new integrase inhibitor bictegravir proved just as effective as a dolutegravir-based combination in suppressing viral load over 96 weeks, but people taking bictegravir experienced significantly fewer adverse events related to treatment, Professor Hans-Jürgen Stellbrink of the University of Hamburg and researchers at the Infectious Diseases Unit, Hospital La Paz, Madrid, Spain, department of internal medicine, Mercer University School of Medicine, Macon, Georgia, US, reported at the International Congress on Drug Therapy in HIV Infection (HIV Glasgow 2018).
Bictegravir is a new integrase inhibitor. It received regulatory approval in the EU in July 2018 as part of a co-formulated, single-pill product called Biktarvy, combined with emtricitabine and tenofovir alafenamide. Biktarvy is also approved in the US.
The GS-1490 study presented at HIV Glasgow compared Biktarvy to a regimen of dolutegravir, tenofovir alafenamide and emtricitabine in previously untreated people. Participants in this blinded study received matching placebos so that everyone took the same number of pills.
The study recruited 645 participants in Europe and North America. People were eligible to join the study if they had normal-to-mildly impaired kidney function (eGFR > 30ml/min) and no previous history of antiretroviral treatment. People with hepatitis B or hepatitis C co-infection were eligible to join the study.
A primary endpoint analysis of the study was presented at the 9th International AIDS Society Conference on HIV Science (IAS 2017) in Paris in July 2017, showing no difference between the two regimens in rates of virological suppression after 48 weeks of treatment.
This week, Hans-Jürgen Stellbrink presented results of the secondary endpoint analysis of the study, rates of virological suppression at 96 weeks and adverse events.
Six hundred and fifty-seven participants were randomised and 645 began treatment in the study. Approximately one-third of study participants were black, a quarter were Hispanic or Latino and the remainder were white. The median baseline viral load was 4.43 log10 copies/ml in the bictegravir group and 4.45 log10 copies/ml in the dolutegravir group. The study population had relatively high baseline CD4 counts (a median of 440 cells/mm3), reflecting the trend towards earlier diagnosis.
The intent-to-treat analysis, covering everyone randomised to participate in the study, showed that after 96 weeks, 84.1% of those receiving Biktarvy and 86.5% of those receiving dolutegravir-based treatment had a viral load below < 50 copies/ml, a non-significant difference.
The per-protocol analysis, covering everyone who commenced treatment, showed that 100% of those receiving Biktarvy and 98.2% of those receiving dolutegravir-based treatment had a viral load below 50 copies/ml, a statistically significant difference (p = 0.03).
Five people taking dolutegravir-based treatment had detectable viral loads at week 96 but none had evidence of resistance to study drugs. Fourteen people in the bictegravir arm and seven in the dolutegravir arm discontinued treatment with a detectable viral load; in seven cases because they had no post-baseline visit, or because they did not wish to continue in the study, or due to pregnancy.
Participants randomised to dolutegravir had a significantly larger mean CD4 cell increase (+281 cells/mm3 vs 237 cells/mm3, p = 0.008), but Stellbrink noted that there was no significant difference in the absolute CD4 count at week 96 (733 cells/mm3 in the dolutegravir arm and 693 cells/mm3 in the bictegravir arm), nor in the change in CD4 cell percentage between the study arms.
Treatment-related adverse events were significantly more common in people receiving dolutegravir-based treatment than in the Biktarvy group (28 vs 20%, p = 0.02) but there was no difference in the rate of discontinuation due to adverse events (2%). The most common adverse events were nausea, diarrhoea and headache. No significant differences in the frequency of laboratory test abnormalities was observed.
Background: The once-daily STR D/C/F/TAF 800/150/200/10 mg is approved in the EU and under regulatory review in the US. In AMBER (NCT02431247), D/C/F/TAF was non-inferior versus D/C+F/TDF (control) (Week 48 VL<50 copies/mL: 91% vs. 88%, respectively; FDA Snapshot), with improved bone and renal biomarker safety, in
ART-naive, HIV-1-infected adults. Week 96 analysis of efficacy, safety and resistance results are presented.
Methods: AMBER is a Phase III, randomised, active-controlled, double-blind, international, multicentre, non-inferiority trial. ART-native, HIV-1-infected adults were randomised (1:1) to D/C/F/TAF or D/C+F/TDF over at least 48 weeks. After unblinding, patients randomised to D/C/F/TAF continued on open-label D/C/F/TAF and patients randomised to control were switched to D/C/F/TAF in the extension phase until Week 96.
Results: Seven hundred and twenty-five patients were randomised and treated (at baseline 18% VL≥100,000 copies/mL; median CD4+ count 453 cells/mm3). At Week 96, exposure to D/C/F/TAF was 626 patient-years in the D/C/F/TAF arm, and consecutively 512 to D/C+F/TDF and 109 to D/C/F/TAF in the control arm. A high proportion of
patients in the D/C/F/TAF arm (85%, 308/362) had virological suppression at Week 96 (VL<50 copies/mL; FDA Snapshot). A high Week 96 response rate (from baseline) was also observed in the control arm (84%, 304/363). VL≥50 copies/mL (VF category by FDA Snapshot) at Week 96 occurred in 20/362 (6%) patients in the D/C/F/TAF arm and 16/363 (4%) from baseline in the control arm. Increases from baseline to Week 96 in CD4+count (LS means, NC=F) were 229 cells/mm3 (D/C/F/TAF) and 227 cells/mm
3 (control). No darunavir, primary PI or tenofovir RAMs were seen post-baseline. In one patient in each arm an M184I and/or V RAM was detected (D/C/F/TAF arm Week 36; control arm Week 84). Few serious adverse events (SAEs) and AE-related discontinuations and no deaths occurred (Table 1). Improvements in renal and bone parameters were maintained in the D/C/F/TAF arm and seen in the control arm after switch, with a small change in TC/HDL-C ratio (Table 1).
Conclusions: High virological response and low failure rates were seen at Week 96 in both arms, with no development of resistance to darunavir or TAF. For D/C/F/TAF, safety findings at Week 96 were consistent with those at Week 48. Bone, renal and lipid safety were consistent with known TAF and cobicistat profiles. In the control arm, safety findings were consistent with those in the D/C/F/TAF arm. D/C/F/TAF combines the efficacy and high genetic barrier to resistance of darunavir with the safety benefits of TAF for ART-naive, HIV-1-infected patients.
H Stellbrink; J Arribas; J Stephens; H Albrecht; P Sax; F Maggiolo; C Creticos; C Martorell; X Wei; K White; S Collins; A Cheng; H Martin