DEFINE: A Prospective, Randomized, Phase 4 Trial to Assess a Protease Inhibitor-based Regimen Switch Strategy to Manage Integrase Inhibitor-related Weight Gain.

BACKGROUND: Integrase strand transfer inhibitor (InSTI)-based antiretroviral therapies have been associated with greater weight gain in people living with HIV versus on protease inhibitor (PI)-based regimens. The DEFINE study investigated whether switching from an InSTI- to a PI-based regimen could mitigate/reverse weight gain. METHODS: DEFINE (NCT04442737) was a randomized, 48-week, open-label, prospective, phase 4 study in virologically suppressed adults with HIV-1 and ≥10% weight gain on InSTI+tenofovir alafenamide (TAF)/emtricitabine (FTC) (<36 months pre-screening). Participants either switched immediately to darunavir/cobicistat/emtricitabine/TAF (D/C/F/TAF) or continued InSTI+TAF/FTC during Weeks 0-24 then switched to D/C/F/TAF for Weeks 24-48. The primary endpoint was least squares (LS) mean (95% confidence interval [CI]) percent weight change from baseline to Week 24. RESULTS: Overall, 103 adults were randomized (D/C/F/TAF, n=53; InSTI+TAF/FTC, n=50); 30% female; 61% Black/African American. No significant difference in weight change was observed at Week 24 (LS mean change: D/C/F/TAF, 0.63% [95%CI: -0.44, 1.70] vs InSTI+TAF/FTC, -0.24% [-1.35, 0.87]; p=0.24); however, a trend towards weight loss was observed with extended time post-ARV switch to D/C/F/TAF (baseline to Week 48, -0.36% [-1.77, 1.06]), particularly in subgroups at higher weight gain risk (eg, females, Black/African Americans). Metabolic endpoints paralleled weight change over time. D/C/F/TAF was well tolerated, with comparable virologic efficacy between arms. CONCLUSIONS: While no significant change in body weight was observed at 24 weeks after switching from InSTI+TAF/FTC to D/C/F/TAF among adults with weight gain, a trend towards weight loss emerged with longer time post-ARV switch, supporting further investigation of antiretroviral selection/switch for weight management.

Weight and BMI Changes Following Initiation of Emtricitabine/Tenofovir Alafenamide Co-Formulated with Darunavir or Co-Administered with Dolutegravir in Overweight or Obese, ART-Naïve People Living with HIV-1.

Introduction: Integrase strand transfer inhibitor-based regimens (eg, containing dolutegravir [DTG]) are associated with weight/body mass index (BMI) increases among people living with HIV-1 (PLWH). Assessing antiretroviral therapy (ART)-related weight/BMI changes is challenging, as PLWH may experience return-to-health weight gain as a result of viral suppression. This retrospective, longitudinal real-world study compared weight/BMI outcomes among overweight/obese (BMI ≥25 kg/m2; thus excluding return-to-health weight/BMI changes), treatment-naïve PLWH who initiated darunavir (DRV)/cobicistat (c)/emtricitabine (FTC)/tenofovir alafenamide (TAF) or DTG + FTC/TAF. Methods: Treatment-naïve PLWH with BMI ≥25 kg/m2 who initiated DRV/c/FTC/TAF or DTG + FTC/TAF (index date) had ≥12 months of baseline observation and ≥1 weight/BMI measurement in baseline and post-index periods in the Symphony Health IDV® database (07/17/2017-12/31/2021) were included. Inverse probability of treatment weighting (IPTW) was used to balance differences in baseline characteristics between cohorts. On-treatment time-to-weight/BMI increases ≥5% were compared between cohorts using weighted adjusted Cox models. Results: Post-IPTW, 76 overweight/obese DRV/c/FTC/TAF-treated (mean age = 51.2 years, 30.7% female, 35.6% Black, mean baseline BMI = 33.2 kg/m2) and 88 overweight/obese DTG + FTC/TAF-treated PLWH (mean age = 51.5 years, 31.4% female, 31.4% Black, mean baseline BMI = 32.7 kg/m2) were included. The median [interquartile range] time from ART initiation to weight/BMI increase ≥5% was shorter for the DTG + FTC/TAF cohort (21.8 [9.9, 32.3] months) than the DRV/c/FTC/TAF cohort (median and interquartile times not reached; Kaplan-Meier rate at 21.8 months = 20.8%). Over the entire follow-up, overweight/obese PLWH initiating DTG + FTC/TAF had a more than twofold greater risk of experiencing weight/BMI increase ≥5% compared to those initiating DRV/c/FTC/TAF (hazard ratio [95% confidence interval]=2.43 [1.02; 7.04]; p = 0.036). Conclusion: Overweight/obese PLWH who initiated DTG + FTC/TAF had significantly greater risk of weight/BMI increase ≥5% compared to similar PLWH who initiated DRV/c/FTC/TAF and had shorter time-to-weight/BMI increase ≥5%, suggesting a need for additional monitoring to assess the risk of weight gain-related cardiometabolic disease.

Adaption of an ongoing clinical trial to quickly respond to gaps in changing international recommendations: the experience of D2EFT.

A rapidly changing landscape of antiretrovirals and their procurement at scale has permitted the evaluation of new optimised second-line antiretroviral therapy (ART) in low- and middle-income countries. D2EFT is an open-label randomised controlled non-inferiority phase IIIB/IV trial in people living with HIV-1 (PWH) whose first-line non-nucleoside reverse transcriptase inhibitor (NNRTI)-based ART is failing. At inception, it compared a standard of care of boosted darunavir with two nucleos(t)ide reverse transcriptase inhibitors (NRTIs) to the novel NRTI-sparing regimen of boosted darunavir with dolutegravir. Implemented in 2017, participating sites were across Africa, Asia and Latin America. Around the time of implementation, the World Health Organization updated its treatment guidelines and recommended scaling up tenofovir disoproxil fumarate-lamivudine-dolutegravir (TLD). This situation pushed D2EFT investigators to consider the impact of the roll-out of TLD on the D2EFT research question. The protocol team agreed it was important to study TLD in second-line when an NNRTI regimen was failing, and focused on options to expedite the work by studying the question within the existing trial and network. All key issues (statistical, programmatic and financial) were reviewed to assess the benefits and risks of adding a third arm to the ongoing study, as opposed to developing a new randomised clinical trial with the same control arm and within the same network. The development of a new trial was deemed to be longer than adding a third arm, and to create a challenging situation with two competing clinical trials at the same sites which would slow down recruitment and impair both trials. On the other hand, adding a third arm would be demanding in terms of operationalisation, increased sample size and statistical biases to control. The optimal strategy was deemed to be the addition of a third arm, arriving retrospectively at a simplified multi-arm multi-stage clinical trial design to achieve statistical validity. The D2EFT study maintains additional value in a quickly evolving second-line ART strategy allowed by the progress in global access to ART.