To Switch or not to Switch: are there any Antiretroviral Strategies to Attenuate Weight Gain in People with HIV?

Integrase strand transfer inhibitor (INSTI)-based antiretroviral (ARV) therapies have been associated with greater weight gain in people with human immunodeficiency virus (HIV) versus those 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. 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 prescreening). Participants either switched immediately to darunavir/cobicistat/FTC/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. Overall, 103 adults were randomized (D/C/F/TAF, n = 53; INSTI + TAF/FTC, n = 50); 30% were female, and 61% were 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, -.44% to 1.70%] vs INSTI + TAF/FTC, -0.24% [95% CI, -1.35% to .87%]; P = .24); however, a trend toward weight loss was observed with extended time post-ARV switch to D/C/F/TAF (baseline to week 48, -0.36% [95% CI, -1.77% to 1.06%]), particularly in subgroups at higher weight gain risk (eg, female and Black/African American participants). Metabolic endpoints paralleled weight change over time. D/C/F/TAF was well tolerated, with comparable virologic efficacy between arms. 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 toward weight loss emerged with longer time post-ARV switch, supporting further investigation of ARV selection/switch for weight management. Clinical Trials Registration. NCT04442737.

Further investigations into the relationship between integrase strand transfer inhibitors (INSTIs) and weight gain are required, especially whether ceasing INSTI results in weight loss. We evaluated weight changes associated with different antiretroviral (ARV) regimens. A retrospective longitudinal cohort study was conducted using data extracted from the electronic clinical database at the Melbourne Sexual Health Centre, Australia, from 2011 to 2021. The association between weight change per time unit and ARV use in people living with HIV (PLWH) and the factors associated with weight changes when using INSTIs were estimated using a generalized estimated equation model. We included 1540 PLWH contributing 7476 consultations and 4548 person-years of data. ARV-naive PLWH initiating INSTIs gained an average of 2.55 kg/year (95% confidence interval 0.56 to 4.54; p = 0.012), while those using protease inhibitors and non-nucleoside reverse transcriptase inhibitors had no significant weight change. When switching off INSTIs, there was no significant weight change (p = 0.055). These weight changes were adjusted for age, gender, time on ARVs, and/or use of tenofovir alafenamide (TAF). Weight gain was the main reason PLWH ceased INSTIs. In addition, risk factors for weight gain in INSTI users were age younger than 60 years, male gender, and concomitant use of TAF. Weight gain was found among PLWH using INSTIs. After INSTI discontinuation, PLWH's weight stopped rising, but no weight loss was observed. Careful weight measurement after initiating INSTIs and early initiation of strategies to avoid weight gain will be important to prevent permanent weight gain and the associated morbidity.

We explored factors associated with weight gain among people with HIV (PWH) on antiretroviral therapy (ART) at The Ohio State University Wexner Medical Center (OSUWMC). This was a retrospective cohort study of adult PWH on ART for ≥3 months. Patients with CD4+ T cell count <200 cells/mm3, viral load >200 copies/mL, history of malignancy, or pregnancy were excluded. Eight hundred seventy patients met criteria. The primary outcome was percent weight change over the follow-up period (Δ = relative effects). The secondary outcome was the odds of ≥5 kg weight gain over the study period. The effects of concurrent medications, medical comorbidities, ART combinations, and lifestyle behaviors on these outcomes were modeled using mixed effects regression analyses. Over a mean follow-up of 1.86 years, the study population gained a mean percent weight of 2.12% ± 0.21% (p < .001) with the odds of ≥5 kg weight gain of 0.293 (p < .001). Males gained an average of 1.88% ± 0.22% over follow up, while females gained an average of 3.37% ± 0.51% over follow up (p = .008 for the difference). In regression models, combination therapy with tenofovir alafenamide (TAF) and integrase strand transfer inhibitor (INSTI) containing regimens was associated with an increase in weight over the study period (Δ = 2.14% ± 0.45%, p < .001 and Δ = 1.09% ± 0.39%, p = .005, respectively). Increasing age was significantly associated with a decrease in percent weight change over the study period (Δ = -0.68% ± 0.18% per year, p < .001). Self-reported improvement in diet was associated with a decrease in weight change (Δ = -1.99% ± 0.47%, p ≤ .001) and reduced odds of ≥5 kg weight gain (odds ratio = 0.70, 95% confidence interval = 0.50-0.97, p = .03). Factors associated with weight gain include therapy with TAF and INSTI. Diet may play an influential role in attenuating weight gain in PWH.

Obesity is increasing in people with HIV (PWH). This review aims to summarise the recent evidence investigating the associations between the use of integrase inhibitors and tenofovir alafenamide (TAF) with weight gain and the mechanisms by which this may occur. Understanding the role that antiretroviral therapies play in promoting weight gain is critical in making informed treatment decisions. Weight gain is common with antiretroviral therapies and can lead to significant medical complications for PWH. Antiretroviral regimens containing an integrase inhibitor in conjunction with TAF are associated with the greatest degree of weight gain. This weight gain is greatest with dolutegravir and bictegravir compared with other integrase inhibitors. Some of the measured weight gain attributed to TAF may actually reflect a loss of weight suppressant effects of tenofovir disoproxil fumarate, and thus the exact proportional contribution of TAF remains to be seen. The mechanisms by which advent of antiretroviral therapy may be promoting weight gain is still being determined but underlying genetic risks factors and gender are very important determinants of the degree of weight gained. Integrase inhibitors and TAF contribute to weight gain in PWH. This places them at risk for potentially serious medical complications.

BackgroundThere is increasing evidence that integrase strand transfer inhibitors (INSTIs) are associated with more weight gain when compared to other antiretroviral (ART) classes. Thus, the primary objective of the study was to evaluate the difference in weight gain at 6 and 18 months among treatment-naïve patients started on an INSTI-based versus a non-INSTI-based ART regimen. MethodsThis was a retrospective cohort study of ART-naive adults who were initiated and maintained on INSTI and non-INSTI based regimens for at least 18 months at an HIV clinic in an inner-city hospital from January 2013 to June 2019. The non-INSTI-based regimens were darunavir (DRV) or rilpivirine (RPV)-based. Data collected included patient demographics, ART regimen, pre- and post-ART initiation weight in kilograms (kg), body mass index (BMI), CD4 count, and viral load. A two-tailed t-test was used to compare change in weight in INSTI-based versus non-INSTI-based regimens. Sub-group analyses were conducted using the ANOVA test.ResultsOut of 170 patients, 60% were initiated on an INSTI-based regimen, 7.1% on a DRV-based regimen, and 32.9% on a RPV-based regimen. Of the patients initiated on INSTI-based regimens, 73.5% were on elvitegravir (EVG),16.7% on dolutegravir, 8.8% on bictegravir, and 0.98% on raltegravir. The mean age at ART initiation was 38 years with majority of the patients described as Black. More male patients received an INSTI-based regimen compared to females (77.5% vs. 32%). The average change in weight at 6 and 18 months in the INSTI-based group vs non-INSTI-based group was +3.6 kg vs. +2.9 kg (95% CI -2.2-0.7, p=0.317) and +5.7 kg vs.+4.8 kg (95% CI -3.2-1.2, p=0.357) respectively. There was no significant average change in weight among the INSTI-based regimens (+3.6 kg), vs DRV (+5.3 kg), or RPV (+2.4 kg) based regimens at 6 months (p=0.108) and 18 months [(+5.7 kg) vs (+7.2 kg), vs (+4.3 kg) (p=0.186) respectively]. Among the INSTIs, EVG was associated with the highest increase in weight at both 6 and 18 months (+3.9 kg and +5.8 kg). Forty-six percent of patients in the INSTI group were on tenofovir alafenamide (TAF) while no patients received TAF in the non-INSTI groups. ConclusionWhen comparing INSTI-based to DRV or RPV-based regimens, there was no significant increase in average weight at 6 and 18 months.DisclosuresAll Authors: No reported disclosures

BackgroundBackground: Excess weight gain with integrase strand transfer inhibitors (INSTIs) has been reported in some people with chronic HIV. In antiretroviral therapy (ART)-naïve people, greater weight gain over 18 months was reported with dolutegravir than other agents. We hypothesized that initiating an INSTI-based regimen during acute HIV infection (AHI) would result in more weight gain than a non-INSTI-based regimen, and INSTIs other than elvitegravir (EVG) would be associated with greater weight gain than EVG.MethodsMethods: We performed a retrospective, observational, single center chart review analysis of adults with AHI (Feibig Stages 1-5) who were initiated on ART and followed for 48 (+/- 12) weeks. Changes in weight between people on INSTI- vs non-INSTI regimens were compared, and in a subgroup analysis, EVG vs non-EVG and tenofovir alafenamide (TAF) vs non-TAF were compared. Chi-square, t-test, or Wilcoxon Rank Sum test were used, when appropriate.ResultsResults: Baseline characteristics of the 61 participants are shown in Table 1. Overall median (IQR) weight change was 4.53 (1.22-8.36; within-group P< 0.0001) kg (Figure 1). Median weight change in 58 people initiated on INSTI was 4.66 (1.22-8.43; P< 0.0001) kg vs 1.64 (-3.08-6.57; P=0.75) kg in 3 people not on INSTI (between-group P= 0.33). Median weight change on EVG was 4.40 (0.91-6.71; P< 0.0001) kg vs 7.10 (4.97-13.15; P= 0.0001) kg for non-EVG INSTIs (between-group P= 0.008, Figure 2). Median weight change on TAF (n=33) was 2.66 (0.81-7.53; P= 0.002) kg vs 5.31 (3.72-9.34; P < 0.0001) kg in non-TAF (n=25) recipients (between-group P= 0.06). Lower baseline CD4+ T cell count correlated with greater weight gain (P= 0.012). No association between weight gain and race (P= 0.930) or gender (P= 0.379) was noted.Baseline characteristics and median weight change (kg) from baselineWeight change in elvitegravir vs non-elvitegravir integrase inhibitor regimen.Overall weight gain seen over 48 weeks after initiation of antiretroviral therapy calculated using the Wilcoxon Rank Sum test.ConclusionPeople initiating ART during AHI gained weight over 48 weeks, with persons taking INSTIs gaining more weight, though this finding did not reach statistical significance due to small sample size. Amongst INSTI-treated persons, those not on EVG gained more weight than those on EVG. While the benefits of starting ART during AHI on immune system preservation and reservoir should not be underscored, risk and consequences of weight gain following ART initiation should be discussed when initiating ART during AHI.DisclosuresJordan Lake, MD, Gilead Sciences (Grant/Research Support, Scientific Research Study Investigator)

Integrase strand-transfer inhibitors (INSTIs) and tenofovir alafenamide have been associated with weight gain in several clinical trials and observational cohorts. However, whether weight gain associated with INSTIs and tenofovir alafenamide confers a higher risk of weight-related clinical events is unclear. We aimed to assess whether changes in BMI differentially increase hypertension or dyslipidaemia risk in people with HIV receiving INSTIs, tenofovir alafenamide, or both versus other contemporary regimens. This multicentre, prospective observational study analysed prospective data from RESPOND, an international consortium of HIV cohorts for which recruitment began in 2017 and is still ongoing from HIV clinics and hospitals in 37 European countries and Australia. Participants were eligible if they were aged 18 years or older, receiving INSTI-containing antiretroviral therapy (ART) regimens or a contemporary non-INSTI, did not have hypertension or dyslipidaemia at baseline, and had baseline and at least two follow-up BMI, lipid, and blood pressure measurements. We excluded participants without baseline CD4 or HIV RNA results and those receiving non-ART medications associated with weight changes, including antipsychotics and mood stabilisers, corticosteroids, insulin, and insulin secretagogues. They were followed up from baseline until the earliest hypertension or dyslipidaemia event, their last visit, or Dec 31, 2021, whichever was earlier. The primary outcomes were incidence of hypertension and dyslipidaemia, for which we used multivariable Poisson regression adjusted for time-updated BMI to determine unadjusted and adjusted incidence rate ratios (IRRs) of hypertension and dyslipidaemia in people receiving INSTIs, tenofovir alafenamide, or both, and tested for interaction between time-updated ART regimen and BMI. Of the 35 941 RESPOND participants, 9704 (7327 [75·5 %] male and 2377 [24·5%] female) were included in the hypertension analysis and 5231 (3796 [72·6%] male and 1435 [27·4%] female) were included in the dyslipidaemia analysis. In the univariable model, hypertension was more common in individuals receiving an INSTI with tenofovir alafenamide (IRR 1·70, 95% CI 1·54-1·88) or an INSTI without tenofovir alafenamide (1·41, 1·30-1·53) compared with those receiving neither INSTIs nor tenofovir alafenamide. Adjustment for time-updated BMI and confounders attenuated risk in participants receiving an INSTI with (IRR 1·48, 1·31-1·68) or without (1·25, 1·13-1·39) tenofovir alafenamide. Similarly, dyslipidaemia was more common in participants using tenofovir alafenamide with an INSTI (IRR 1·24, 1·10-1·40) and tenofovir alafenamide alone (1·22, 1·03-1·44) than in participants using neither INSTI nor tenofovir alafenamide. Adjustment for BMI and confounders attenuated the risk in participants receiving tenofovir alafenamide with an INSTI (adjusted IRR 1·21, 1·07-1·37), whereas the risk in those receiving tenofovir alafenamide alone became non-significant (1·15, 0·96-1·38). The associations between increasing BMI and risk of hypertension and dyslipidaemia did not differ between participants receiving different ART regimens (pinteraction=0·46 for hypertension; pinteraction=0·31 for dyslipidaemia). Although residual confounding cannot be entirely excluded, the use of INSTIs was associated with incident hypertension, and the use of tenofovir alafenamide was associated with dyslipidaemia, with the latter association partly mediated by weight gain. These results reiterate the need for hypertension and dyslipidaemia screening in people with HIV. The CHU St Pierre Brussels HIV Cohort, The Austrian HIV Cohort Study, The Australian HIV Observational Database, The AIDS Therapy Evaluation in the Netherlands national observational HIV cohort, The Brighton HIV Cohort, The National Croatian HIV Cohort, The EuroSIDA cohort, The Frankfurt HIV Cohort Study, The Georgian National AIDS Health Information System, The Nice HIV Cohort, The ICONA Foundation, The Modena HIV Cohort, The PISCIS Cohort Study, The Swiss HIV Cohort Study, The Swedish InfCare HIV Cohort, The Royal Free HIV Cohort Study, The San Raffaele Scientific Institute, The University Hospital Bonn HIV Cohort, The University of Cologne HIV Cohort, Merck Life Sciences, ViiV Healthcare, and Gilead Sciences.

Background Integrase inhibitor (INI)–based antiretroviral (ARV) therapies are associated with greater weight gain than non-nucleoside reverse transcriptase inhibitor– or boosted protease inhibitor–based regimens, disproportionately affecting Black and Hispanic individuals and women. The mechanisms underlying this weight gain are unknown, and there are no prospective, randomized data exploring the impact of switching ARV 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 evaluating switching to darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) versus continuing INI+TAF/emtricitabine (FTC) in virologically-suppressed HIV-1–infected adults who had ≥10% weight gain while on the INI-based regimen. The primary objective was to assess percent change in body weight from baseline to Week 24 in both arms. The primary endpoint was analyzed using a mixed model for repeated measures in the intent-to-treat set of randomized participants who had received ≥1 dose of study drug. Secondary endpoints included change in body mass index (BMI), waist circumference (WC), efficacy, and safety. Data through Week 24 are reported. Results Overall, 103 adults were randomized to D/C/F/TAF (n=53) or continued INI+TAF/FTC (n=50); 30% were female and 61% were Black/African American, with median 27.0 months virologic suppression on INI+TAF/FTC (Table 1). Discontinuation rates were low and similar between arms. At Week 24, there was no significant difference in percent change in body weight from baseline between the D/C/F/TAF and INI+TAF/FTC arms (Figure). Most participants in each arm had body weight changes of ≤±3% and remained within baseline BMI and WC categories. Percent body weight changes for key subgroups are shown in Table 2. Switching to D/C/F/TAF was safe and well tolerated, and efficacy was maintained.Table 1.Demographics and Baseline Characteristics (ITT Set)BMI, body mass index; D/C/F/TAF, darunavir/cobicistat/emtricitabine/tenofovir alafenamide; FTC, emtricitabine; INI, integrase inhibitor; ITT, intent-to-treat; TAF, tenofovir alafenamide. *One participant in the D/C/F/TAF arm did not have available data. Percent Change From Baseline in Body Weight Over Time for Participants Who Switched to D/C/F/TAF and Those Who Continued Their Current INI+TAF/FTC Regimen (ITT Set) D/C/F/TAF, darunavir/cobicistat/emtricitabine/tenofovir alafenamide; FTC, emtricitabine; INI, integrase inhibitor; ITT, intent-to-treat; LS, least-squares; TAF, tenofovir alafenamide. LS means percent changes in body weight were calculated in the ITT set of randomized participants who had received ≥1 dose of study drug using a mixed model for repeated measures, in which the dependent variable was percent change from baseline in body weight; independent variables were treatment, baseline body mass index, sex, and race (Black/African American vs non–Black/African American); and visits were repeated measures. Participants in the ITT set with baseline records and ≥1 postbaseline record were included. Conclusion There was no significant difference in weight change through 24 weeks after switching from an INI-based regimen to D/C/F/TAF in adults with INI-related weight gain. Additional analyses are ongoing, including follow up through Week 48 and evaluation of changes in biomarkers and body composition (DEXA).Table 2.Percent Change From Baseline in Body Weight at Week 24 Among Key Subgroups (ITT Set)BMI, body mass index; D/C/F/TAF, darunavir/cobicistat/emtricitabine/tenofovir alafenamide; FTC, emtricitabine; INI, integrase inhibitor; ITT, intent-to-treat; TAF, tenofovir alafenamide. Disclosures William R. Short, MD, Gilead Sciences: Advisor/Consultant|ViiV: Advisor/Consultant|ViiV: Honoraria Moti Ramgopal, MD, FACP, FIDSA, AbbVie: Honoraria|Gilead Sciences, Inc.: Advisor/Consultant|Gilead Sciences, Inc.: Honoraria|Janssen Pharmaceuticals: Advisor/Consultant|Janssen Pharmaceuticals: Honoraria|Merck: Advisor/Consultant|ViiV Healthcare: Advisor/Consultant|ViiV Healthcare: Honoraria Debbie P. Hagins, MD, FAPCR, AAHIVS, Janssen Pharmaceuticals: Advisor/Consultant Johnnie Lee, MD, Janssen Pharmaceuticals: Employee|Janssen Pharmaceuticals: Stocks/Bonds Richard Bruce Simonson, BS, Janssen Pharmaceuticals: Employee|Janssen Pharmaceuticals: Stocks/Bonds Tien-Huei Hsu, PhD, Janssen Pharmaceuticals: Employee|Janssen Pharmaceuticals: Stocks/Bonds Ping Xu, PhD, Janssen Pharmaceuticals: Employee|Janssen Pharmaceuticals: Stocks/Bonds David Anderson, MD, Janssen Pharmaceuticals: Employee|Janssen Pharmaceuticals: Stocks/Bonds

Background Weight gain among persons with HIV (PWH) on integrase strand transfer inhibitors (INSTIs) is highly variable. Given the importance of the melanocortin-4 receptor (MC4R) in obesity, we examined associations between MC4R gene variants and weight gain following switch to INSTI-containing antiretroviral therapy (ART) among PWH in ACTG observational cohort studies A5001 and A5322. Methods Eligible participants switched to their first INSTI-containing ART from 2005-2018 and had available genetic and weight data. Imputed genotypes were from genome-wide data. Linear models assessed associations between MC4R variants and weight change, including 20 variants previously associated with weight/obesity in populations without HIV. Analyses adjusted for age, sex at birth, genetic principal components, time after switch, and body mass index, CD4 count and virologic control at switch; separate models were stratified by race/ethnicity, sex and baseline BMI category. Results Among 530 PWH, median age was 50 (IQR 42, 57) years, 29% were non-Hispanic Black, 22% were cis-gender female, 62% were overweight or obese at INSTI switch, and 73% switched from a protease inhibitor. INSTIs were raltegravir (62%), dolutegravir (21%), elvitegravir (17%), and bictegravir (1%). The switch regimen included tenofovir alafenamide (TAF) in 9%. Overall median weight gain after switch was 1.25 kg (IQR -1.2, 4.0). Of 20 MC4R variants previously associated with weight/obesity, three were nominally associated (p&amp;lt; 0.05) with weight change after switch in all participants or in subgroups. One (rs11873305) was associated with weight gain in all participants (p=0.01), and male (p=0.004) and White (p=0.02) subgroups. Of 507 additional MC4R variants, the lowest p-value among all participants was for rs56758444 (p=0.001). After Bonferroni correction, no variant was significant in MC4R or in exploratory genome-wide analysis. Conclusion Among PWH, MC4R variants were nominally associated with weight change after switch to INSTI-based ART. These findings are consistent with the known importance of melanocortins in appetite and weight, and suggest a neuroendocrine contribution to INSTI-related weight gain. Additional studies with newer INSTIs and TAF are needed. Disclosures Kristine M. Erlandson, MD MS, Gilead: Advisor/Consultant|Gilead: Grant/Research Support|ViiV: Advisor/Consultant Sara H. Bares, MD, Gilead Sciences: Expert Testimony|Janssen: Grant/Research Support|ViiV Healthcare: Grant/Research Support Todd T. Brown, MD, PhD, EMD Serono: Advisor/Consultant|Janssen: Advisor/Consultant|Merck: Advisor/Consultant|ViiV Healthcare: Advisor/Consultant|ViiV Healthcare: Honoraria Jordan Lake, MD, Merck: Advisor/Consultant|Theratechnologies: Advisor/Consultant Grace A. McComsey, MD, Gilead, Merck, GSK: Advisor/Consultant John R. Koethe, MD, Gilead Sciences: Advisor/Consultant|Gilead Sciences: Grant/Research Support|Merck &amp; Co.: Advisor/Consultant|Merck &amp; Co.: Grant/Research Support

Several studies have reported weight gain after switching to integrase strand transfer inhibitor (INSTI)-based antiretroviral therapy (ART). Debate persists if weight gain also occurs when switching from tenofovir disoproxil fumarate (TDF) to tenofovir alafenamide (TAF)-based ART. We performed a retrospective chart review of virally suppressed HIV-infected patients who were switched from non INSTI- to INSTI-based ART (INSTI switch group) as well as patients switched from TDF- to TAF-based ART (TAF switch group), and compared the mean weight change in these groups to the mean change in weight in patients maintained on NNRTI-based regimens (control group). 329 patients were identified. 256 patients in the INSTI switch group gained a mean 2.4kg over 17months compared to 0.5kg in 54 patients in the control group over the same period (p = 0.008). 161 patients in the TAF switch group gained a mean 2.8kg over 17months compared to 0.5kg in the control group (p = 0.003). There was no statistical difference in weight gain between the INSTI and TAF switch groups. Although the highest mean weight gain of 3.2kg was seen in those 90 patients switched from both TDF- to TAF-based and non INSTI- to INSTI-based ART (TAF/INSTI switch group), this weight gain was not statistically different compared with the INSTI switch or TAF switch groups. Our study suggests that weight gain is associated with both switching HIV regimens from non INSTI- to INSTI-based ART and TDF- to TAF-based ART.

Disclosure: S. Hudson: None. J. Aurora: None. K. Grossman: None. L. Kogelman: None. A.G. Pittas: None. Background: Antiretroviral therapy (ART) containing bictegravir (BIC), a second-generation integrase strand transfer inhibitor (INSTI), is a first-line treatment for HIV. There are mixed reports of INSTIs causing adverse metabolic effects, such as weight gain and hyperglycemia. There are cases of BIC causing hyperglycemia and diabetic ketoacidosis (DKA) within weeks to months following initiation; however, this has not been reported in clinical trials (1). It is unclear whether discontinuing BIC resolves hyperglycemia. We report a case of a patient with prediabetes who developed severe hyperglycemia after switching to a BIC-containing ART. The discontinuation of BIC resulted in significant improvement in glycemia, leading to the de-escalation of diabetes pharmacotherapy. Clinical Case: A 36-year-old woman with obesity was diagnosed with HIV during pregnancy, which was complicated by gestational diabetes mellitus. After pregnancy, she had prediabetes. Her initial ART was darunavir/cobicistat/emtricitabine/tenofovir alafenamide. Due to intolerable GI side effects, six years later, she was switched to bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF). Laboratory tests four months before starting BIC/FTC/TAF were consistent with prediabetes (HbA1c 6.4%, non-fasting blood glucose of 118 mg/dL). After one month, she was started on metformin when her HbA1c increased to 9.1% with a non-fasting blood glucose of 332 mg/dL. Another month later, HbA1c increased to 12.8% with a non-fasting blood glucose of 685 mg/dL without DKA. She was hospitalized for diabetes management. There were no significant changes in weight, viral load, or CD4 count. A search for secondary causes of hyperglycemia (diabetogenic medications, hypercortisolism, and autoimmune diabetes) was not revealing. She was discharged on metformin and insulin glargine. Her HIV regimen was switched to FTC/TAF and doravirine due to suspicion of BIC-induced hyperglycemia. After five months, she developed symptoms of hypoglycemia, and her estimated HbA1c by continuous glucose monitoring was 6.3%. Insulin glargine was discontinued. While on metformin, HbA1c three months later was 6.3%. Two years later on metformin and linagliptin: HbA1c was 6.1% and beta-cell function did not reveal insulin deficiency or resistance (non-fasting blood glucose 96 mg/dL, insulin 13.5 uIU/mL [RR 2.6-24.9 mIU/mL], C-peptide 3.7 ng/mL [RR 1.1-4.4 ng/mL]). Conclusion: Patients with HIV and a history of obesity and/or dysglycemia who are switched to a BIC-containing ART regimen should be educated and monitored for acute hyperglycemia. This may be due to impaired beta-cell function and/or insulin resistance; however, further research is needed to understand the mechanism. An alternative ART regimen should be considered if hyperglycemia develops. Reference: 1. Nolan NS, et al. Open Forum Infect Dis. 2021;16;8(5): ofab077. Presentation: 6/3/2024

BackgroundInitiation of antiretroviral therapy (ART) often leads to weight gain. While some of this weight gain may be an appropriate return-to-health effect, excessive increases in weight may lead to obesity. We sought to explore factors associated with weight gain in several randomized comparative clinical trials of ART initiation.MethodsWe performed a pooled analysis of weight gain in 8 randomized controlled clinical trials of treatment-naive people living with human immunodeficiency virus (HIV) initiating ART between 2003 and 2015, comprising >5000 participants and 10 000 person-years of follow-up. We used multivariate modeling to explore relationships between demographic factors, HIV disease characteristics, and ART components and weight change following ART initiation.ResultsWeight gain was greater in more recent trials and with the use of newer ART regimens. Pooled analysis revealed baseline demographic factors associated with weight gain including lower CD4 cell count, higher HIV type 1 RNA, no injection drug use, female sex, and black race. Integrase strand transfer inhibitor use was associated with more weight gain than were protease inhibitors or nonnucleoside reverse transcriptase inhibitors (NNRTIs), with dolutegravir and bictegravir associated with more weight gain than elvitegravir/cobicistat. Among the NNRTIs, rilpivirine was associated with more weight gain than efavirenz. Among nucleoside/nucleotide reverse transcriptase inhibitors, tenofovir alafenamide was associated with more weight gain than tenofovir disoproxil fumarate, abacavir, or zidovudine.ConclusionsWeight gain is ubiquitous in clinical trials of ART initiation and is multifactorial in nature, with demographic factors, HIV-related factors, and the composition of ART regimens as contributors. The mechanisms by which certain ART agents differentially contribute to weight gain are unknown.

BackgroundPersons living with human immunodeficiency virus (PLWH) have a higher incidence of developing obesity, diabetes, and cardiovascular disease. TAF, a newer formulation of tenofovir, has favorable effects on renal function and bone mineral density compared to TDF. However, recent evidence suggests TAF may have a higher propensity for weight gain over TDF. The purpose of this study is to evaluate weight change in patient switched from TDF to TAF, keeping constant the other components of their antiretroviral therapy.MethodsThis retrospective observational cohort study evaluated adult PLWH who were followed for 12 months pre and post TDF to TAF therapy switch holding all other ART constant. Patients were excluded if not on TDF or TAF therapy for a minimum of 12 months, if there were additional changes to their ART, or if there was inadequate documentation of weight defined as less than 2 weight records pre and post TAF switch. Data collected included height, weight, HIV RNA, CD4 count, and presence of any current opportunistic infections or chronic comorbid conditions. The primary endpoint was change in weight after TAF switch. All variables were evaluated using linear mixed effect models over time.Results466 patient charts were reviewed and 55 patients met study criteria and were included in the analysis. The median age (SD) of patients included was 45.9 (12.6) years with most patients being male (67%) and black (73%). Patients had an HIV diagnoses for a mean (SD) of 10 (6.6) years with a mean (SD) CD4 count of 544 (246.8). Full baseline characteristics are recorded in Table 1. Notably, most patients had either an INSTI or PI in their baseline ART regimen (Table 1). The estimated overall marginal mean weight gain was 1.91 kg (95% CI 0.25-3.57, p=0.024). The estimated overall gain in BMI was 0.63 kg/m2 (95% CI 0.08-1.18). Significant predictors of weight gain included female gender (3.09, 95% CI 0.54 – 5.65) and use of both integrase and protease inhibitors at baseline (6.97 kg, 95% CI 3.02 – 10.92).ConclusionIn a predominantly black, male population, there was a statistically significant change in weight after a TAF switch.As this is the only data highlighting weight changes following tenofovir formulation change, more data is needed to elucidate the extent of weight-gain in patients on TAF-based regimens.DisclosuresAll Authors: No reported disclosures

To evaluate the relationship between the gut microbiota composition and significant weight gain in virologically-suppressed people with HIV (PWH) on antiretroviral therapy. This 5-year prospective longitudinal study included virologically-suppressed PWH receiving regimens based on the integrase strand transfer inhibitors (INSTIs) or non-nucleoside reverse transcriptase inhibitors (NNRTIs). Body weight was measured annually, with significant weight gain defined as a ≥10% increase between consecutive measurements or compared to baseline. Gut microbiota profiling was conducted using 16S rRNA sequencing (V3-V4 regions) via the Illumina MiSeq platform. 202 participants were recruited, with 169 completing the 240-week follow-up. Among these, 63 remained on INSTI-based, 79 on NNRTI-based and 27 on NNRTI + INSTI-based regimens. Median (interquartile range (IQR)) 5-year weight gain was 1.3 (-2.8 to 4.5) kg. Significant weight gain occurred in 70 (34.7%) participants, including 20 (9.9%) with ≥10% gain between consecutive measurements and 50 (24.8%) from baseline. No significant differences were observed in adjusted α- and β-diversity indices between groups defined by weight gain. Adjusted analysis of compositions of microbiomes with bias correction 2 model showed that weight gain was associated with the genera Dialister and Tyzzerella_4, whereas Phascolarctobacterium was enriched in those without significant weight gain. While overall weight gain did not differ between INSTI-based and NNRTI-based groups, participants on INSTIs-based regimens showed higher relative abundances of bacteria linked to weight gain, like Tyzzerella_4 (0.05% versus 0.02%, P = 0.017) and Lactobacillus (0.29% versus 0.22%, P = 0.009). Significant weight gain in the PWH is associated with distinct gut microbiota profiles. The enrichment of weight gain-associated taxa, such as Tyzzerella_4 and Lactobacillus, in individuals on INSTI-based regimens suggests a potential microbiota-mediated mechanism modulating metabolic outcomes.

BackgroundWeight gain after the initiation of antiretroviral therapy (ART) is becoming a major clinical issue in treatment-naïve people living with human immunodeficiency virus (PLWH). However, limited data exist for the Asian populations. We aimed to investigate changes in weight after the initiation of ART therapy in treatment-naïve Asian patients.MethodsWe evaluated adult, treatment-naïve Asian PLWH who started integrase strand transfer inhibitor (INSTI)-, protease inhibitor (PI)-, or nonnucleoside reverse transcriptase inhibitor (NNRTI)-based ART at AIDS Clinical Center, Tokyo, between January 2005 and February 2019. They were followed up until October 2019. Multivariate linear mixed-effects models were used to generate marginal predictions of weight over time. Predicted weight by ART class (INSTI, PI, and NNRTI), each key drug (dolutegravir [DTG], elvitegravir [EVG], raltegravir [RAL], and darunavir [DRV]), and each key drug with or without the use of tenofovir alafenamide (TAF)/emtricitabine (FTC) was reported at 3-month intervals until censoring or 5 years.ResultsAmong the 1,579 study patients, 610 (38.6%), 929 (58.8%), and 40 (2.5%) started INSTI-, PI-, and NNRTI-based ART. After 5 years, PLWH who initiated DTG- (5.3 kg), DRV- (4.0 kg), and EVG-based treatment (4.6 kg) gained more weight than those who initiated RAL-based treatment (1.8 kg). PLWH who initiated DTG plus TAF/FTC (6.7 kg) gained the largest weight.ConclusionIn the Asian PLWH population, ART-associated weight gain continues to increase for 5 years after treatment initiation. DTG plus TAF/FTC was associated with the largest weight gain.DisclosuresAll Authors: No reported disclosures