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Weight Loss or Gain Predictors Hard to
Find in INSTI-to-PI Switch Trial
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IDWeek 2023, October 11-15, 2023, Boston
Mark Mascolini
Switching from an integrase inhibitor (INSTI) regimen to a protease inhibitor (PI) combination for 24 weeks did not reverse 10% or greater weight gains during INSTI therapy in the DEFINE trial [1]. At IDWeek 2023, DEFINE researchers detailed results of post hoc analyses of their trial data, reporting that neither shorter time taking an INSTI nor length of time with weight gain before the trial began predicted weight loss in the first 24 weeks of DEFINE [2]. The investigators did find six baseline factors more often in trial participants who lost 3% or more weight in 24 weeks.
Prior research by other investigators scrutinizing eight randomized trials of first-line regimens demonstrated how many-layered the causes of weight change can be in people taking antiretrovirals [3]. Multivariate modeling assessing weight changes in more than 5000 trial participants linked greater weight gains to dolutegravir or bictegravir versus elvitegravir/cobicistat; to rilpivirine versus efavirenz; to tenofovir alafenamide (TAF) versus tenofovir disoproxil (TDF), abacavir, or zidovudine; and to baseline demographics including lower CD4 count, higher viral load, no injection drug use, female sex, and black race.
The post hoc analysis (an analysis not planned before the study began) explored week-24 DEFINE results according to pretreatment variables including length of INSTI exposure before switching to a PI, how quickly a person gained weight after starting an INSTI regimen, and how recently prestudy weight was gained. The DEFINE team also explored baseline factors in people who lost weight, regardless of study arm.
DEFINE enrolled 103 adults with an undetectable viral load and 10% or greater weight gain within 36 months while taking an INSTI plus TAF/FTC. Researchers randomized them to continue that regimen for 24 weeks or switch to dolutegravir (DTG)/cobicistat/TAF/FTC. At week 24 people who had continued their INSTI switched to the DTG regimen and everyone will continue that combination for another 24 weeks. The trial excluded people who started or stopped a drug linked to substantial weight changes within 90 days of screening for DEFINE.
When the trial began median age was similar in the 53-person DTG switch group and the 50 people staying with their INSTI: 42 and 49. Median body mass index in the DTG and INSTI groups was 31.4 and 34.7 kg/m2, while median weight stood at 94.5 and 102.9 kg. Overall proportions of women, blacks, nonblacks, and Hispanics were 30%, 61%, 39%, and 16%. At study week 24 more than 90% of participants remained in the trial. Because of the small size of the trial, each post hoc analysis described below included 31 or fewer people in each study arm.
After 24 weeks percent change from baseline body weight did not differ significantly in the steady-INSTI arm and the DTG-switch arm (-0.24% and +0.63%, P = 0.2394). Weight changes through 24 weeks proved consistent in gender and racial subgroups.
The first post hoc analysis involved people randomized fewer than or more than 24 months after starting their baseline INSTI. Those on an INSTI under 24 months averaged a 1.5% weight gain in both study arms, whereas those on an INSTI more than 24 months at baseline had almost no weight change at week 24 (-0.27% with DTG switch, -0.23% with steady INSTI). Regardless of study arm, the likelihood of gaining 3% or more weight was higher in those taking an INSTI fewer than 24 months at baseline than in those taking an INSTI longer (31% vs 10%).
People who gained weight within 12 months of starting their INSTI continued to gain weight during the first 24 weeks of study (1.57% with DTG switch, 1.00% with steady INSTI). In contrast, people randomized 12 months or longer after starting their INSTI had stable weight or shed a tiny amount during the first 24 weeks of DEFINE (+0.12% with DTG switch, -1.36% with steady INSTI).
Time to DEFINE randomization after weight gain (fewer versus more than 12 months) did not affect weight changes in 24 weeks of study, which were minimal (within 1% up or down) in both trial arms. In people who gained weight within 12 months after starting an INSTI, their earlier switch to a PI did not favor weight loss. Weight rose minimally in both the DTG switch group (1.8%) and the steady INSTI group (1.24%).
Regardless of study arm, six baseline factors proved more frequent in 16 people who lost 3% or more weight in DEFINE's first 24 weeks: higher baseline CD4 count, longer treatment with INSTIs or TAF, less education, lower baseline weight, lower percentage weight gain at baseline, and slower baseline weight gain after starting an INSTI.
The DEFINE team underlined the finding that people who gained weight during the first 12 months of INSTI therapy continued to add weight or maintained their increased weight. They suggested this pattern may be a predictive signal. They believe the six baseline factors found more often in people who lost 3% or more weight during DEFINE's first 24 weeks merit further study. But the main conclusion of DEFINE so far is that "INSTI-related weight gain may not be reversible through [an] antiretroviral switch," and that finding "reinforce[s] the importance of including the potential for weight gain as a pretreatment consideration."
References
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. https://www.natap.org/2023/IAS/IAS_125.htm
2. 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: post hoc analysis. IDWeek 2023, October 11-15, 2023, Boston.
3. Sax PE, Erlandson KM, Lake JE, et al. Weight gain following initiation of antiretroviral therapy: risk factors in randomized comparative clinical trials. Clin Infect Dis. 2020;71:1379-1389. doi: 10.1093/cid/ciz999. https://academic.oup.com/cid/article/71/6/1379/5586728
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