Dolutegravir monotherapy and body weight gain in antiretroviral naïve patients

Rizzardo, Sebastiano; Lanzafame, Massimiliano; Lattuada, Emanuela; Luise, Dora; Vincenzi, Marcello; Tacconelli, Evelina; Vento, Sandro

doi:10.1097/qad.0000000000002245

Cited by 25 publications

(26 citation statements)

References 12 publications

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“…Among patients receiving INSTI‐based regimens, these findings corroborate our prior report from a smaller Southeastern US cohort in which we described greater weight gain associated with DTG‐based ART regimen use [14], as well as reports from other observational cohorts [15‐17]. Moreover similar disparities in weight gain by initial ART regimen type were noted in a recent 48‐week, open‐label, randomized trial conducted in South Africa comparing EFV/TDF/FTC versus DTG with TDF/FTC or with TAF/FTC, which reported greater increases over 48 weeks in weight and truncal fat among DTG compared to EFV recipients, particularly among persons also receiving TAF.…”

Section: Discussionsupporting

confidence: 89%

“…In a cohort from Brazil, PWH receiving RAL‐based regimens were sevenfold more likely to become obese (BMI ≥ 30kg/m 2 ) compared to those receiving NNRTI‐ or PI‐based regimens [13]. In other observational studies, INSTI‐based regimens generally, and particularly DTG‐based ART regimens [14‐17], were also associated with greater weight gain. In the prospective AIDS Clinical Trial Group (ACTG) study A5257, the use of RAL with tenofovir disoproxil fumarate and emtricitabine (TDF/FTC) as an initial ART regimen was associated with greater increases in waist circumference and increased odds of a >10% weight gain at 96 weeks, compared to ART regimens including ritonavir‐boosted darunavir or ritonavir‐boosted atazanavir, each combined with TDF/FTC [18,19].…”

Section: Introductionmentioning

confidence: 99%

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Weight gain among treatment‐naïve persons with HIV starting integrase inhibitors compared to non‐nucleoside reverse transcriptase inhibitors or protease inhibitors in a large observational cohort in the United States and Canada

et al. 2020

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Introduction: Weight gain following antiretroviral therapy (ART) initiation is common, potentially predisposing some persons with HIV (PWH) to cardio-metabolic disease. We assessed relationships between ART drug class and weight change among treatment-na€ ıve PWH initiating ART in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD). Methods: Adult, treatment-na€ ıve PWH in NA-ACCORD initiating integrase strand transfer inhibitor (INSTI), protease inhibitor (PI) or non-nucleoside reverse-transcriptase inhibitor (NNRTI)-based ART on/after 1 January 2007 were followed through 31 December 2016. Multivariate linear mixed effects models estimated weight up to five years after ART initiation, adjusting for age, sex, race, cohort site, HIV acquisition mode, treatment year, and baseline weight, plasma HIV-1 RNA level and CD4 + cell count. Due to shorter follow-up for PWH receiving newer INSTI drugs, weights for specific INSTIs were estimated at two years. Secondary analyses using logistic regression and all covariates from primary analyses assessed factors associated with >10% weight gain at two and five years. Results: Among 22,972 participants, 87% were male, and 41% were white. 49% started NNRTI-, 31% started PI-and 20% started INSTI-based regimens (1624 raltegravir (RAL), 2085 elvitegravir (EVG) and 929 dolutegravir (DTG)). PWH starting INSTI-based regimens had mean estimated five-year weight change of +5.9kg, compared to +3.7kg for NNRTI and +5.5kg for PI. Among PWH starting INSTI drugs, mean estimated two-year weight change was +7.2kg for DTG, +5.8kg for RAL and +4.1kg for EVG. Women, persons with lower baseline CD4 + cell counts, and those initiating INSTI-based regimens had higher odds of >10% body weight increase at two years (adjusted odds ratio = 1.37, 95% confidence interval: 1.20 to 1.56 vs. NNRTI). Conclusions: PWH initiating INSTI-based regimens gained, on average, more weight compared to NNRTI-based regimens. This phenomenon may reflect heterogeneous effects of ART agents on body weight regulation that require further exploration.

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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Weight gain among treatment‐naïve persons with HIV starting integrase inhibitors compared to non‐nucleoside reverse transcriptase inhibitors or protease inhibitors in a large observational cohort in the United States and Canada

et al. 2020

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“…The marked increase in weight immediately following TAF initiation observed in OPERA was in line with results in ART-na€ ıve PLWH in clinical trials [10,12] and in the CFAR Network of Integrated Clinical Systems (CNICS) cohort [31]. While multiple studies have shown greater weight gains with InSTI-based regimen overall [11,12,[17][18][19][20][21][22][23][24][25][26] or specifically with dolutegravir, bictegravir or raltegravir [10][11][12]18,19,22,[25][26][27][28][29][30][31][35][36][37] compared to other regimens, most did not account for the role of TAF. In OPERA, the estimated rates of weight gain were numerically slightly higher in the first nine months of TAF when maintaining an InSTI, elvitegravir/cobicistat or dolutegravir, and when switching to bictegravir or dolutegravir, although differences between groups were not tested directly, and confidence intervals overlapped.…”

Section: Discussionsupporting

confidence: 63%

“…Greater weight gain has also been reported with integrase strand transfer inhibitors (InSTI), compared to other core classes [11,12,[17][18][19][20][21][22][23][24][25][26], specifically with dolutegravir or bictegravir, compared to other agents [12,18,19,22,[25][26][27][28][29][30]. In the ADVANCE trial, weight increases were greater with dolute-gravir+TDF/emtricitabine, compared to the South African standard of care of efavirenz+TDF/emtricitabine.…”

Section: Introductionmentioning

confidence: 99%

Weight gain before and after switch from TDF to TAF in a U.S. cohort study

Mallon

Brunet²,

Hsu

et al. 2021

J. Intern. AIDS Soc.

102

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Introduction Although weight gain has been reported with the use of integrase strand transfer inhibitors (InSTI), concurrent use of tenofovir alafenamide (TAF) has been implicated in recent studies. This study examined weight changes in people living with HIV (PLWH) who switched from tenofovir disoproxil fumarate (TDF) to TAF, to clarify the relative contribution to weight gain of core agents versus TDF to TAF switch. Methods Antiretroviral‐experienced, virologically suppressed PLWH in the U.S. OPERA cohort were included if they switched from TDF to TAF (5NOV2015‐28FEB2019) and either maintained all other antiretrovirals or switched from a non‐InSTI to an InSTI. Linear mixed models were used to assess weight changes before/after the switch to TAF (restricted cubic splines on time) and rates of change over time (linear splines on time, based on the shape of the weight change curves). Changes in weight on TDF or TAF were assessed among those who maintained other antiretrovirals (overall, by core class), and those who maintained an InSTI or switched to an InSTI (by core agent). All models were adjusted for age, sex, race, (age‐sex, race‐sex interactions), BMI, CD4 cell count, endocrine disorders and concurrent medications that could affect weight. Results A total of 6908 PLWH were included, with 5479 maintaining all other antiretrovirals (boosted protease inhibitor: 746, non‐nucleoside reverse transcriptase inhibitor: 1452, InSTI: 3281) and 1429 switching from a non‐InSTI to an InSTI (elvitegravir/cobicistat: 1120, dolutegravir: 174, bictegravir: 129). In adjusted models, modest weight gain was observed over time on TDF for most (0.24 to 0.71 kg/year); raltegravir was the exception with weight loss. Switching to TAF was associated with early, pronounced weight gain for all (1.80 to 4.47 kg/year). This effect with TAF switch was observed both in PLWH maintaining other antiretrovirals and those switching to an InSTI, regardless of which InSTI agent was used. Weight gain tended to slow down or plateau approximately nine months after switch to TAF. Conclusions In this large, diverse U.S. cohort of PLWH, switching from TDF to TAF was associated with pronounced weight gain immediately after switch, regardless of the core class or core agent, suggesting an independent effect of TAF on weight gain.

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“…Indeed, in a large analysis of more than 22,000 treatment-naive PLWH in the multi-site NA-ACCORD, individuals who initiated INSTI-based regimens gained an estimated mean 5.9 kg after 5 years of treatment, compared with 3.7 kg among individu als receiving NNRTI-based regimens and 5.5 kg for those receiving PI-based regimens 69 . Smaller observational studies have also reported a greater weight gain in PLWH initiating INSTI-containing regimens than in those initiating NNRTI or PI regimens, which generally has been greater in women, black individuals, and in those with lower weight and CD4 + T cell counts before starting ART 65,66, 68,70 . The aetiology of weight gain with INSTIs is unclear and may include effects on thermogenesis, appetite or energy regulation, or perhaps reflect a direct effect or a greater antiretroviral efficacy of these drugs in adipose tissue 71,72 or other metabolically active tissue.…”

Section: Generalized Fat Gain and Obesitymentioning

confidence: 99%

HIV and antiretroviral therapy-related fat alterations

Koethe

Lagathu

Lake

et al. 2020

Nat Rev Dis Primers

153

144

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Adipose tissue accounts for ~20-30% of total body weight in non-obese or overweight persons and for up to 50% in individuals with obesity and is a primary energy store with important endocrine and immunomodulatory functions. Most adipose tissue depots are comprised of white fat, which is responsible for energy storage and release in response to food intake and energy demand. In humans, brown and beige fat are minor components of adipose tissue and can dissipate energy as heat. White adipocytes sequester dietary lipids in adipose tissue depots to serve as energy stores during periods of fasting and prevent toxic lipid accumulation in other tissues such as muscle, liver, pancreas and heart 1. In addition, white adipocytes have a role in glucose and lipid metabolism and respond differentially to physiological cues or metabolic stresses by releasing adipokines and lipokines that regulate energy expenditure, appetite control, glucose homeostasis, insulin sensitivity, inflammation, immune function and tissue repair 2. Although adipose tissue is mainly comprised of adipocytes, it also contains mesenchymal stem cells (which can differentiate into adipocytes, myoblasts, osteoblasts and chondroblasts), immune cells (including M1 and M2 phenotype macrophages, CD4 + T cells and CD8 + T cells) and fibroblasts, in addition to blood vessels and nerves. Fat expands owing to excess energy supply either through hypertrophy (increased size of existing adipocytes) or hyperplasia (the formation of new adipocytes from mesenchymal stem cells in adipose tissue). In obesity, hypertrophic adipocytes have different biochemical properties to smaller adipocytes, including increased lipolysis, inflammatory cytokine production and reduced secretion of anti-inflammatory adipokines, such as adiponectin, that are also involved in insulin sensi tivity 1. Such alterations in fat depots predispose to ectopic lipid accumulation and the development of comorbidities, including type 2 diabetes mellitus (T2DM), non-alcoholic fatty liver disease (NAFLD), sarcopenia, atherosclerosis and heart failure 2. During physiological ageing, fat is lost from lower limbs and increases in the trunk, alongside accumulation of senescent adipocytes that have altered adipogenic potential and increased secretion of proinflammatory cytokines 3. Fat alteration became a major concern in Western countries in the mid-1990s, when people living with HIV (PLWH) receiving combination antiretroviral therapy

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Dolutegravir monotherapy and body weight gain in antiretroviral naïve patients

Cited by 25 publications

References 12 publications

Weight gain among treatment‐naïve persons with HIV starting integrase inhibitors compared to non‐nucleoside reverse transcriptase inhibitors or protease inhibitors in a large observational cohort in the United States and Canada

Weight gain among treatment‐naïve persons with HIV starting integrase inhibitors compared to non‐nucleoside reverse transcriptase inhibitors or protease inhibitors in a large observational cohort in the United States and Canada

Weight gain before and after switch from TDF to TAF in a U.S. cohort study

HIV and antiretroviral therapy-related fat alterations

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