Obesity following ART initiation is common and influenced by both traditional and HIV-/ART-specific risk factors

Bakal, David R; Coelho, Lara E.; Luz, Paula M.; Clark, Jesse L; Boni, Raquel Brandini De; Cardoso, Sandra Wagner; Veloso, Valdiléa G.; Lake, Jordan E.; Grinsztejn, Beatriz

doi:10.1093/jac/dky145

Cited by 154 publications

(149 citation statements)

References 29 publications

(31 reference statements)

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“…INSTI‐based ART regimens are now the recommended first‐line treatment for most PWH [12], but several recent studies, primarily from single sites or cohorts, report greater weight gain among persons receiving INSTI‐based ART regimens for initial therapy as compared to protease inhibitor (PI) and non‐nucleoside reverse transcriptase inhibitor (NNRTI)‐based regimens. 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.…”

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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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: 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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“…Interestingly women had greater VAT gain on raltegravir vs PI than men, and black vs nonblack individuals [8]. The association between dolutegravir or raltegravir vs elvitegravir use and weight gain was confirmed in observational cohorts of PLWH initiated with ART [9,10,11]. Weight gain following ART initiation could be attributable in part to a "return to health" phenomenon, but is also clearly associated with individual INSTI and with personal factors as sex and ethnicity [12].…”

Section: Role Of Instimentioning

confidence: 99%

Metabolic complications affecting adipose tissue, lipid and glucose metabolism associated with HIV antiretroviral treatment

Lagathu

Béréziat

Gorwood

et al. 2019

Expert Opinion on Drug Safety

112

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Introduction: Efficient antiretroviral-treatment(ART) generally allows control of HIV infection. However, persons-living-with-HIV(PLWH), when ageing, present a high prevalence of metabolic diseases. Area covered: Altered adiposity, dyslipidemias, insulin resistance, diabetes and their consequences are prevalent in PLWH and could be partly related to ART. Expert opinion: At first, personal and lifestyle factors are involved in the onset of these complications. The persistence of HIV in tissue reservoirs could synergize with some ART and enhance metabolic disorders. Altered fat repartition, diagnosed as lipodystrophy, has been related to first-generation nucleoside-reverse-transcriptase-inhibitors(NRTIs) (stavudine zidovudine) and some protease inhibitors(PIs). Recently, use of some integraseinhibitors(INSTI) resulted in weight/fat gain, which represents a worrisome unresolved situation.Lipid parameters were affected by some first-generation NRTIs, non-NRTIs(efavirenz) but also PIs boosted by ritonavir, with increased total and LDL-cholesterol and triglycerides.Insulin resistance is common in aging PLWH, often associated with abdominal obesity.Diabetes incidence, high with first-generation-ART (zidovudine, stavudine, didanosine, indinavir) has declined with contemporary ART close to that of the general population.Metabolic syndrome, a dysmetabolic situation with central obesity and insulin resistance, and liver steatosis are common in PLWH and could indirectly result from ART-associated fat gain and insulin resistance. All these dysmetabolic situations increase the atherogenic cardiovascular risk.Before 2000, PLWH received first-generation ART, as nucleoside analogue reverse transcriptase inhibitors (thymidine NRTIs, stavudine, zidovudine, didanosine) and protease inhibitors (PI, indinavir, ritonavir, nelfinavir) responsible for marked adverse events on lipid and glucose metabolism and on adipose tissue. These ART were replaced by newer molecules presenting a markedly lower metabolic toxicity.However, some PLWH, previously treated with first-generation NRTIs, present long-lasting fat alterations with metabolic consequences [1]. Some contemporary ART as integrase inhibitors (INSTI), considered as metabolic-friendly, were recently associated with weight/fat gain. Therefore, there are remaining and evolving concerns regarding the effect of ART on metabolism and adipose tissue in PLWH.As a consequence of the metabolic effects of some ART, increased prevalence of cardiovascular diseases (CVD), particularly atherosclerotic CVD[2] and diabetes, has been reported, but differ according to the calendar years and the geographic area. It is important to consider the metabolic profile of each patients to adapt ART. If required, classical lipid and glucose-lowering medications are prescribed.

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“…Several studies have reported an increasing prevalence of being overweight and obese in PWH, and have demonstrated that weight gain occurs in many PWH after initiating antiretroviral therapy (ART) [1][2][3][4]. Factors associated with weight gain in PWH include demographic factors (such as sex and race), HIV disease-related factors (such as disease stage and viral load), and ART-associated factors (specific antiretroviral drugs) [2,3,[5][6][7][8][9]. These observations have led to several non-exclusive mechanistic hypotheses for ART-associated weight gain, including a mirroring of societal trends, a return-to-health effect of ART, improved tolerability of ART regimens, and off-target effects of antiretroviral drugs.…”

Section: Introductionmentioning

confidence: 99%

“…Among the antiretroviral drugs, the integrase strand transfer inhibitors (INSTIs) have specifically been associated with weight gain in studies of treatment-naïve PWH and in PWH switching to INSTI-based therapy [2,7,8,10]. Whether this association is causative is unknown, and no mechanism to explain the association has been demonstrated.…”

Section: Introductionmentioning

confidence: 99%

Lack of an association between clinical INSTI-related body weight gain and direct interference with MC4 receptor (MC4R), a key central regulator of body weight

et al. 2020

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An increasing prevalence of overweight and obesity in people living with HIV has been associated with initiation of antiretroviral therapy with integrase strand transfer inhibitors (INSTIs). An off-target inhibition of the endogenous ligand binding to the human melanocortin 4 receptor (MC4R) has been suggested as a potential mechanism for clinical body weight gain following initiation of dolutegravir, an INSTI. In this study, we interrogated several INSTIs for their capacity for antagonism or agonism of MC4R in an in vitro cell-based assays including at concentrations far exceeding plasma concentrations reached at the recommended dosages. Our results indicate that while INSTIs do exhibit the capacity to antagonize MC4R, this occurs at concentrations well above predicted clinical exposure and is thus an implausible explanation for INSTI-associated weight gain. OPEN ACCESS Citation: McMahon C, Trevaskis JL, Carter C, Holsapple K, White K, Das M, et al. (2020) Lack of an association between clinical INSTI-related body weight gain and direct interference with MC4 receptor (MC4R), a key central regulator of body weight. PLoS ONE 15(2): e0229617. https://doi.

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Obesity following ART initiation is common and influenced by both traditional and HIV-/ART-specific risk factors

Abstract: Obesity following ART initiation is frequent among HIV-infected adults. Key risk factors include female sex, HIV disease severity and INSTI use. Further research regarding the association between INSTIs and the development of obesity is needed.

Cited by 154 publications

References 29 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

Metabolic complications affecting adipose tissue, lipid and glucose metabolism associated with HIV antiretroviral treatment

Lack of an association between clinical INSTI-related body weight gain and direct interference with MC4 receptor (MC4R), a key central regulator of body weight

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