Editor’s Note: “Experiencing weight gain due to medication” is a common concern for many people living with HIV (PLWH). Some antiretroviral therapy (ART) regimens are associated with weight gain and related metabolic complications. In the field of endocrinology, newer antidiabetic medications like glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been used for weight management and have gained popularity. So, are these new weight loss treatments suitable for PLWH experiencing ART-related weight gain? At the 2023 Infectious Diseases Week (IDWeek 2023), two studies on the use of GLP-1 RAs in PLWH and one study of weight control using protease inhibitor switching were presented. Dr. Hongzhou Lu from Shenzhen Third People’s Hospital (The Second Hospital Affiliated with the School of Medicine, Southern University of Science and Technology) provides an introduction and commentary on these studies.
Dr. Hongzhou Lu
PhD in Internal Medicine, Professor of Treatment, Professor
Shenzhen Third People’s Hospital
GLP-1 Receptor Agonists Promote Weight Loss Among People with HIV (Abstract #1982)
Background: Weight gain and related metabolic complications are becoming increasingly common in people living with HIV (PLWH), especially in patients initiating treatment with second-generation integrase strand transfer inhibitors (INSTIs). Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are diabetes treatment drugs based on promoting intestinal insulin release and have been shown to significantly reduce weight. However, there is limited research on their effectiveness in PLWH. This study aimed to elucidate the prescription practices and clinical outcomes of PLWH using GLP-1 RAs.
Methods: A retrospective cohort study was conducted on PLWH who received GLP-1 RA treatment at the University of California, San Diego, from February 1, 2021, to February 1, 2023. Patients who had been prescribed GLP-1 RAs but never used them or had unavailable weight data after GLP-1 RA treatment were excluded. Baseline clinical data were collected, and changes in weight, body mass index (BMI), and glycated hemoglobin (A1C) were calculated before and during GLP-1 RA treatment. Logistic regression analysis was used to determine variables associated with significant weight loss (over 5%).
Results: A total of 227 patients met the inclusion criteria. Baseline characteristics are shown in the table below. Ninety-nine patients (43%) used GLP-1 RAs for weight management without concurrent diabetes. Patients received an average of 15.2 months of GLP-1 RA treatment, with 92 patients (40.5%) reaching the maximum GLP-1 RA dose. GLP-1 RA treatment resulted in an average weight loss of 5.4 kg for all patients, a 1.8 reduction in BMI, and a 0.5 decrease in A1C. Patients with baseline A1C >6.5 experienced a 1.2 kg/m² reduction in BMI. In multivariate analysis, higher baseline BMI (OR 1.07, 95% CI: 1.02-1.3) and longer duration of GLP-1 RA treatment (OR 1.04, 1.01-1.07) were more likely to be significantly associated with weight loss (>5%); compared to other GLP-1 RAs, receiving dulaglutide was associated with a lower likelihood of weight loss (>5%) (OR 0.33, 0.17-0.66). Factors such as age, gender at birth, race, ethnicity, ART regimen, baseline CD4 cell count, HIV viral load, and comorbid diabetes did not predict weight changes.
Conclusion: The use of GLP-1 RAs can improve weight, BMI, and glycated hemoglobin in PLWH, providing an additional strategy to address weight gain and related metabolic complications.
Opinion: GLP-1 RA formulations can effectively lower weight while reducing blood sugar. This study also demonstrates that they are still applicable in HIV-infected individuals. There is currently no direct evidence of significant interactions between these types of medications and the inherent HIV treatment. However, various formulations and routes of administration for these drugs exist; further research with large-scale, large-sample evidence is needed to support their application in HIV-infected individuals, especially regarding dosage, route of administration, and safety.
Effects of Semaglutide on Adipose Tissue in HIV-Associated Lipohypertrophy (Abstract #1984)
Background: Lipodystrophy (accumulation of central fat tissue [AT]) is a common and significant issue in people living with HIV (PLWH). The pathogenesis of this condition remains unclear, but AT abnormalities are a key driving factor in the development of cardiovascular metabolic complications in HIV. This study aimed to assess the impact of semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1 RA), on AT in PLWH with fat accumulation.
Methods: This was a randomized, double-blind, placebo-controlled trial that enrolled participants aged ≥18 years with a BMI ≥25 kg/m2 and subjective increases in waist circumference or waist-to-hip ratio who were non-diabetic and receiving stable antiretroviral therapy (ART). Patients were randomized in a 1:1 ratio to receive semaglutide (32 weeks of treatment with an 8-week titration followed by 24 weeks of weekly subcutaneous injections of 1.0 mg) or a matching placebo. Abdominal areas and densities (total [TAT], visceral [VAT], and subcutaneous [SAT]) and body composition (lean body mass [LBM], limb/trunk/total body fat [TBF]) were measured using computed tomography (CT) and whole-body dual-energy X-ray absorptiometry. The effects of semaglutide were estimated using generalized estimating equations or simultaneous quantile regression for outcome variables.
Results: A total of 108 patients were included (54 in the semaglutide group, with a median age of 52 years; 70% were male, 61% were Black, and 83% were taking integrase strand transfer inhibitors). Both groups were well-matched at baseline. In unadjusted models, the semaglutide group showed significant reductions in BMI, homeostatic model assessment of insulin resistance (HOMA-IR), trunk fat, TBF (in ≥75th percentile), TAT, and SAT (P < 0.05), with a decreasing trend in limb fat and VAT (P < 0.1). After adjusting for age, gender, CD4 cell count, and duration of ART, the impact of semaglutide on BMI, HOMA-IR, trunk fat, TAT, and VAT remained significant. Caloric intake was also significant when it was ≤50th percentile. There were no differences in lean body mass (LBM), AT density, or VAT/TAT ratio. Semaglutide was well-tolerated, and severe adverse events were infrequent.
Conclusion: Semaglutide significantly reduces central fat in PLWH with fat accumulation, primarily due to a decrease in VAT. Semaglutide offers an effective treatment method to reduce visceral obesity and lower the risk of associated comorbidities. Further research is needed to determine the mechanism of reducing visceral fat.
Opinion: This study confirms that semaglutide is effective not only for simple obesity but also for HIV-related obesity. The study provides evidence for the application of such drugs in HIV-related obesity. Although the mechanism is not entirely clear, we speculate that it shares commonalities with the drug’s mechanism in regular obese patients. To fully elucidate this mechanism, we must understand the underlying causes of HIV-related obesity.
A Prospective, Randomized Trial to Assess a Protease Inhibitor–based Regimen Switch Strategy to Manage Integrase Inhibitor–related Weight Gain (Abstract #1985)
Background: Compared to antiretroviral therapy (ARV) regimens based on non-nucleoside reverse transcriptase inhibitors (NNRTIs) or boosted protease inhibitors (bPIs), ARV therapy based on integrase inhibitors (INIs) is associated with greater weight gain, especially among Black and Hispanic individuals, and women. The potential mechanism behind this weight gain is still unclear, and there is a lack of prospective randomized data exploring the impact of switching ARV drug classes to mitigate or reverse ARV-related weight gain.
Methods: DEFINE (ClinicalTrials.gov: NCT04442737) is a randomized (1:1), prospective, 48-week, active-controlled, open-label, multicenter Phase 4 study aimed at evaluating the effects of switching to D/C/F/TAF (doravirine/lamivudine/tenofovir alafenamide/ emtricitabine) in virologically suppressed adults with HIV-1 infection compared to continuing INI+TAF/emtricitabine (FTC) regimens. The primary endpoint of the study is to assess the percentage change in weight from baseline to week 24 in both groups. Mixed-model analysis of repeated measurements is used to evaluate the primary endpoint in participants who received ≥1 dose of study drugs. Secondary endpoints include changes in BMI, waist circumference (WC), efficacy, and safety. The data at week 24 is reported here.
Results: A total of 103 adult patients were randomly assigned to receive D/C/F/TAF (n=53) or continue with INI+TAF/FTC (n=50), with 30% being female and 61% being Black/African American. The median duration of virological suppression for INI+TAF/FTC was 27.0 months. The dropout rates were low, and the two groups were similar. At week 24, there was no significant difference in the percentage change in weight from baseline between the D/C/F/TAF and INI+TAF/FTC groups (D/C/F/TAF group and INI+TAF/FTC group: 0.63 vs -0.24, P=0.02394). Most participants in each group had weight changes of ≤±3% and remained within their baseline BMI and WC ranges. The percentage change in weight for key subgroups is shown in the figure below. Switching to D/C/F/TAF was safe, well-tolerated, and maintained efficacy.
Conclusion:
These three studies summarized clinical strategies for managing HIV-related weight gain. The first two studies used GLP-1 receptor agonists, while the third one employed the new D/C/F/TAF regimen, all effectively controlling weight gain in HIV-infected individuals. Furthermore, GLP-1 receptor agonists appear to reduce the increase in visceral fat and do not produce toxic interactions with existing HIV treatments. These results provide new approaches and means to control HIV-related weight gain.
However, it’s important to note that the mentioned studies had limitations, such as one being a single-center study (Abstract No: 1982), and all studies had relatively small sample sizes. Therefore, we anticipate the conclusions of larger, multicenter randomized controlled trials (RCTs) for further validation.
