Elsevier

The Lancet HIV

Volume 8, Issue 11, November 2021, Pages e711-e722
The Lancet HIV

Articles
Contemporary antiretrovirals and body-mass index: a prospective study of the RESPOND cohort consortium

https://doi.org/10.1016/S2352-3018(21)00163-6Get rights and content

Summary

Background

Weight gain effects of individual antiretroviral drugs are not fully understood. We investigated associations between a prespecified clinically significant increase (>7%) in body-mass index (BMI) and contemporary antiretroviral use.

Methods

The International Cohort Consortium of Infectious Diseases (RESPOND) is a prospective, multicohort collaboration, including data from 17 well established cohorts and over 29 000 people living with HIV. People with HIV under prospective follow-up from Jan 1, 2012, and older than 18 years were eligible for inclusion. Each cohort contributed a predefined minimum number of participants related to the size of the specific cohort (with a minimum of 1000 participants). Participants were required to have CD4 cell counts and HIV viral load measurement in the 12 months before or within 3 months after baseline. For all antiretroviral drugs received at or after RESPOND entry, changes from pre-antiretroviral BMI levels (baseline) were considered at each BMI measurement during antiretroviral treatment. We used logistic regression to identify individual antiretrovirals that were associated with first occurrence of a more than 7% increase in BMI from pre-antiretroviral BMI. We adjusted analyses for time on antiretrovirals, pre-antiretroviral BMI, demographics, geographical region, CD4 cell count, viral load, smoking status, and AIDS at baseline.

Results

14 703 people were included in this study, of whom 7863 (53·5%) had a more than 7% increase in BMI. Compared with lamivudine, use of dolutegravir (odds ratio [OR] 1·27, 95% CI 1·17–1·38), raltegravir (1·37, 1·20–1·56), and tenofovir alafenamide (1·38, 1·22–1·35) was significantly associated with a more than 7% BMI increase, as was low pre-antiretroviral BMI (2·10, 1·91–2·31 for underweight vs healthy weight) and Black ethnicity (1·61, 1·47–1·76 vs White ethnicity). Higher CD4 count was associated with a reduced risk of BMI increase (0·97, 0·96–0·98 per 100 cells per μL increase). Relative to lamivudine, dolutegravir without tenofovir alafenamide (OR 1·21, 95% CI 1·19–1·32) and tenofovir alafenamide without dolutegravir (1·33, 1·15–1·53) remained independently associated with a more than 7% increase in BMI; the associations were higher when dolutegravir and tenofovir alafenamide were used concomitantly (1·79, 1·52–2·11, and 1·70, 1·44–2·01, respectively).

Interpretation

Clinicians and people with HIV should be aware of associations between weight gain and use of dolutegravir, tenofovir alafenamide, and raltegravir, particularly given the potential consequences of weight gain, such as insulin resistance, dyslipidaemia, and hypertension.

Funding

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 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 and The University of Cologne HIV Cohorts, ViiV Healthcare, and Gilead Sciences.

Introduction

Weight gain in people living with HIV has been associated with exposure to integrase strand transfer inhibitors, particularly dolutegravir, in observational studies1, 2, 3, 4, 5, 6, 7 and randomised trials.8, 9, 10, 11, 12, 13 Evidence suggests that, among those receiving integrase strand transfer inhibitors, weight gain is more prevalent in women2, 4, 6, 7 and among those of Black ethnicity.6, 7, 14 Emerging evidence suggests that the nucleoside analogue reverse transcriptase inhibitor tenofovir alafenamide might have an additional effect on weight gain, particularly when co-administered with dolutegravir.8, 15, 16, 17, 18, 19, 20

Research in context

Evidence before this study

We searched PubMed for observational and randomised studies on weight gain among people living with HIV who were receiving contemporary antiretrovirals, focusing on integrase inhibitors and tenofovir alafenamide, using the search terms “tenofovir alafenamide”, “TAF”, “dolutegravir”, “DTG”, “raltegravir”, “RAL”, “integrase inhibitors”, “INSTIs”, AND (“weight” OR “BMI”). Searches were limited to studies published before March 1, 2020, in English. Abstracts from proceedings at conferences from the last 3 years and additional articles suggested by study group members were also included. Evidence collated suggested that there was an association between use of tenofovir alafenamide and dolutegravir and weight gain. However, previous studies have generally been small, limited to a single country, and assessed regimens in which tenofovir alafenamide and dolutegravir were used concomitantly rather than assessing the individual effects of these antiretrovirals. Furthermore, comparator regimens have often contained antiretrovirals with a known impact on body-mass index (BMI).

Added value of this study

We investigated factors associated with weight gain among people with HIV in the RESPOND cohort. RESPOND is a large multinational heterogeneous cohort with data from real-life settings and with a focus on newer drugs. Use of this cohort allowed enough power for the study to detect associations between use of specific antiretrovirals and BMI increases compared with lamivudine (a weight-neutral control antiretroviral), rather than between antiretroviral regimens and BMI increases. Furthermore, we were able to assess these associations in several sensitivity analyses, including in individuals who were antiretroviral therapy-naive, in individuals with high pretreatment CD4 cell counts, and in individuals with high pre-antiretroviral BMI. Previous explanations for associations seen include the comparator drug being a weight suppressive. However, by comparing to a weight-neutral drug, lamivudine, those explanations do not hold.

Implications of all the available evidence

In line with smaller studies, we found that use of dolutegravir, raltegravir, and tenofovir alafenamide was associated with a clinically meaningful more than 7% BMI increase when comparing pre-antiretroviral BMI with current BMI. People with HIV and clinicians prescribing antiretrovirals should be aware of these associations before making the decision to start either dolutegravir or tenofovir alafenamide. Further research on the consequences of antiretroviral-related weight gain is planned.

Weight gain, particularly in people with HIV starting antiretroviral therapy (ART), can reflect a general improvement in overall health with reduced catabolic and inflammatory activity and improved appetite, also known as return to health. However, the impact of ART on bodyweight might differ according to the specific regimen used. The ADVANCE trial showed that people with HIV on tenofovir alafenamide plus dolutegravir had a greater increase in trunk or limb fat mass compared with those receiving other regimens9 and metabolic syndromes were also more prevalent in those receiving dolutegravir plus tenofovir alafenamide. However, there was no evidence of incidental diabetes among those receiving dolutegravir in the NAMSAL trial.12

Given that dolutegravir and tenofovir alafenamide are recommended antiretrovirals in first-line regimens,21, 22, 23 the effects of these individual antiretrovirals on weight gain need to be understood. Since both antiretrovirals can be prescribed concomitantly, it is unclear which, if any, has the largest effect on weight gain. Furthermore, the observational studies that have investigated this question have to date been small, with short follow-up, few people on integrase strand transfer inhibitors, and comparators are commonly antiretrovirals with known negative impact on weight, such as efavirenz.1, 2, 3, 4, 5, 6, 7 Weight gain has generally been assessed from a pre-regimen or current value, and associations between individual antiretrovirals and weight gain could not be identified.

Although a standardised definition of weight gain does not exist in the HIV field, an increase of more than 7% is standardised in research looking at, for example, the effect of antipsychotic drugs on weight gain.24, 25, 26 Using this standardised definition of a more than 7% increase in body-mass index (BMI), we investigated factors associated with weight gain among people in the RESPOND cohort, focusing particularly on contemporary antiretrovirals, such as dolutegravir and tenofovir alafenamide.

Section snippets

Study design and participants

The International Cohort Consortium of Infectious Diseases (RESPOND) is a prospective, multicohort collaboration, including data from 17 well established cohorts and over 29 000 people with HIV. Participants under prospective follow-up from Jan 1, 2012, and older than 18 years were eligible for inclusion. Each cohort contributed a predefined minimum number of participants related to the size of the specific cohort (with a minimum of 1000 participants). Participants were required to have CD4

Results

14 703 (76·7%) of 19 176 people from cohorts with routine height and weight measurements were eligible for these analyses and contributed at least one row of data (appendix p 3). Compared with the 4473 people who were excluded, those included in the analyses were more likely to be from western Europe (8822 [60·0%] of 14 703 people vs 1776 [39·7%] of 4473 people; p<0·0001) and a higher proportion of included individuals were receiving an integrase strand transfer inhibitor-based regimen at

Discussion

In the large, heterogeneous RESPOND cohort consortium, use of dolutegravir, raltegravir, and tenofovir alafenamide (compared with lamivudine) was independently associated with a BMI increase of more than 7% from pre-antiretroviral BMI to on-antiretroviral BMI. In analyses restricted to use of dolutegravir without tenofovir alafenamide, and tenofovir alafenamide without dolutegravir, both antiretrovirals remained significantly associated with a BMI increase of more than 7%. Similar results were

Data sharing

The RESPOND Scientific Steering Committee (SSC) encourages the submission of concepts for research projects. Online research concepts (please see https://chip.dk/Research/Studies/RESPOND/Study-documents) should be submitted to the RESPOND secretariat ([email protected]). The secretariat will direct the proposal to the relevant scientific interest group, where the proposal will initially be discussed for scientific relevance before being submitted to the SSC for review. All data

Declaration of interests

JMM received a personal 80:20 research grant from Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain, during 2017–21. JMM also reports grants and personal fees from AbbVie, Angelini, Contrafect, Cubist, Genentech, Gilead Sciences, Jansen, Lysovant, Medtronic, MSD, Novartis, Pfizer, and ViiV Healthcare, outside the submitted work. DLB reports honoraria from ViiV Healthcare, Gilead Sciences, and Merck, outside the submitted work. OK reports personal fees from

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