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  IAS 2023
July 23rd - 26th
12th IAS Conference on HIV Science
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A prospective, randomized trial to assess a protease inhibitor-based regimen switch strategy to manage integrase inhibitor-related weight gain
  Switch to PI Has No Impact on INSTI Weight Gain: 24-Week Trial Results
IAS 2023, July 23-26, 2023. Brisbane
Mark Mascolini
After 24 weeks in a trial randomizing HIV-positive adults to stay with their integrase inhibitor (INSTI) regimen or switch to the cobicistat-boosted protease inhibitor (PI) darunavir, switching had no impact on INSTI-related weight gain [1]. The trial is continuing for another 24 weeks, but primary week-24 results suggest that switching to a PI will not reverse weight gains with an INSTI.
Early research linked INSTI therapy to weight gain, but further work and deeper analysis suggest the added pounds seen with contemporary regimens can have several contributors, including other drugs a person is taking (which may be associated with raising or lowering weight), the antiretroviral regimen a person is switching from, genetics, comorbidities, and countless lifestyle and cultural variables [2-4]. And antiretroviral-naive people starting an INSTI or non-INSTI regimen sometimes have almost identical weight gains. For example, at IAS 2023 a phase 3 trial comparing (1) the INSTI bictegravir coformulated with emtricitabine and tenofovir alafenamide and (2) the nonnucleoside doravirine plus the nucleotide reverse transcriptase translocation inhibitor islatravir found average 48-week gains of 3.32 kg with the INSTI combination and 3.45 kg with the nonnucleotide/islatravir combination [5] (reviewed separately at NATAP). Results of several trials and cohort studies do indicate that unwanted and potentially dangerous weight gains seen with newly prescribed antiretrovirals disproportionately affect women, blacks, and Hispanics. Because no randomized trial has assessed whether switching from an INSTI can mitigate or reverse INSTI-associated weight gains, DEFINE researchers in the United States conducted this study [6].
The trial recruited adults with an undetectable viral load who had a 10% or greater increase in body weight within 36 months of starting an INSTI plus tenofovir alafenamide (TAF) and emtricitabine (FTC). DEFINE investigators randomized 103 people to stay with their INSTI regimen or swap it for cobicistat-boosted darunavir plus FTC and TAF (D/C/F/TAF) for 24 weeks. Then everyone takes D/C/F/TAF for the next 24 weeks. The study excluded people who began or stopped other medications because of substantial weight changes within 90 days of screening for DEFINE.
While women made up 30% of the study population, 61% were black and 16% Hispanic. The INSTI group was marginally older than the D/C/F/TAF group (median 49 vs 42) and had slightly higher body mass index (median 34.7 and 31.4 kg/m2) and weight (102.9 and 94.5 kg). More than three quarters of both groups were taking bictegravir/TAF/FTC.
A linear mixed model for repeated measures figured that least squares means percent change in body weight at week 24, the primary endpoint, did not differ significantly between the D/C/F/TAF group and the INSTI group (0.63%, 95% confidence interval -0.44 to 1.70, and -0.24%, 95% confidence interval -1.35 to 0.87, P = 0.2394). Findings remained consistent when researchers looked at body mass index and waist circumference. Regardless of study arm, most participants gained 3% or less body weight in 24 weeks. When the researchers looked at percent change in body weight at week 24 in notable subgroups, they also saw no significant difference between switching to a PI and sticking with an INSTI (obese, female, male, black/African American, nonblack/African American, black/African American female). DEXA scans revealed no difference between study arms in fat mass, lean body mass, or total mass from baseline to week 24.
Week 24 FDA snapshot analysis confirmed that both regimens maintained virologic efficacy through 24 weeks, although researchers counted 5 virologic failures (viral load at or above 50 copies) at week 24 in the INSTI group and none in the D/C/F/TAF group. CD4 counts remained stable and similar between study arms through 24 weeks.
Proportions of participants with gastrointestinal adverse events were 17% with D/C/F/TAF and 16% with the maintained INSTI. Median total cholesterol rose slightly in people randomized to D/C/F/TAF (179 to 211 mg/dL) while staying nearly flat in the INSTI arm (183 to 187 mg/dL). The same pattern held for median low-density lipoprotein cholesterol (108 to 133 mg/dL with D/C/F/TAF, and 108 to 109 mg/dL with the INSTI).
These 24-week findings indicating that INSTI-related weight gains may not be reversible by replacing an INSTI with an antiretroviral from another class, the DEFINE team cautioned, underline the importance of considering weight and metabolic issues when selecting a first regimen.
1. Short WR, Ramgopal M, Hagins DP, et al. A prospective, randomized trial to assess a protease inhibitor-based regimen switch strategy to manage integrase inhibitor-related weight gain. IAS 2023, July 23-26, 2023. Brisbane.
2. Guaraldi G, Bonfanti P, Di Biagio A, et al. Evidence gaps on weight gain in people living with HIV: a scoping review to define a research agenda. BMC Infect Dis. 2023;23:230. doi: 10.1186/s12879-023-08174-3. https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-023-08174-3
3. Dupont E, Cyr-Yombi J. Antiretroviral therapy and weight gain in antiretroviral treatment-experienced HIV patients: a review. AIDS Rev. 2023;25:54-64. doi: 10.24875/AIDSRev.22000026. https://pubmed.ncbi.nlm.nih.gov/36952658/
4. Dupont E, Cyr-Yombi J. Antiretroviral therapy and weight gain in naive HIV-1 infected patient: a narrative review. AIDS Rev. 2022;25:122-132. doi: 10.24875/AIDSRev.21000092. https://pubmed.ncbi.nlm.nih.gov/36343575/
5. Rockstroh JK, Paredes R, Cahn P, et al. DOR/ISL (100/0.75 mg) QD compared to B/F/TAF as initial HIV-1 treatment: 48 week results from a double-blind phase 3 trial. IAS 2023, July 23-26, 2023. Brisbane. 6. A study of darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) evaluated as a fixed dose combination regimen in participants switching from an integrase inhibitor who have experienced rapid weight gain (DEFINE). Clinicaltrials.gov identifier NCT04442737. https://clinicaltrials.gov/study/NCT04442737?
IAS: A Prospective, Randomized Trial to Assess a Protease Inhibitor-based Regimen Switch Strategy to Manage Integrase Inhibitor-related Weight Gain - (07/27/23)