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.