More weight gain in people starting HIV treatment with newer integrase inhibitors or darunavir

A US study has concluded that weight gain is greater by around 2 to 4 kg in HIV-positive people taking bictegravir or dolutegravir as part of their first antiretroviral therapy (ART), compared to their counterparts using other drug regimens. A similar effect was reported in those using the protease inhibitor darunavir.

The study led by Dr Stephanie Ruderman of the University of Washington, published in the Journal of Acquired Immune Deficiency Syndrome, highlights the heterogeneity of weight gain between different antiretroviral regimens after people living with HIV start their first treatment.

Background

Integrase inhibitors are still a relatively recent class of antiretrovirals. There has been growing evidence of a link between their use and weight gain, as well as growing concerns about this outcome in the HIV community. However, most studies on the issue have had their limitations, including recruiting too few participants, not reflecting the diversity of people living with HIV, not including bictegravir, and not accounting for other weight-impacting medications taken by individuals, such as antipsychotic drugs.

Additionally, many studies have compared antiretroviral classes, rather than individual antiretroviral drugs. Also, some of them have assessed outcomes after participants already on treatment switched regimens, potentially allowing for effects from prior individual drugs.

Glossary

integrase inhibitors (INI, INSTI)

A class of antiretroviral drugs. Integrase strand transfer inhibitors (INSTIs) block integrase, which is an HIV enzyme that the virus uses to insert its genetic material into a cell that it has infected. Blocking integrase prevents HIV from replicating.

body mass index (BMI)

Body mass index, or BMI, is a measure of body size. It combines a person’s weight with their height. The BMI gives an idea of whether a person has the correct weight for their height. Below 18.5 is considered underweight; between 18.5 and 25 is normal; between 25 and 30 is overweight; and over 30 is obese. Many BMI calculators can be found on the internet.

boosting agent

Booster drugs are used to ‘boost’ the effects of protease inhibitors and some other antiretrovirals. Adding a small dose of a booster drug to an antiretroviral makes the liver break down the primary drug more slowly, which means that it stays in the body for longer times or at higher levels. Without the boosting agent, the prescribed dose of the primary drug would be ineffective.

nadir

Lowest of a series of measurements. For example, an individual’s CD4 nadir is their lowest ever measured CD4 count.

diabetes

A group of diseases characterized by high levels of blood sugar (glucose). Type 1 diabetes occurs when the body fails to produce insulin, which is a hormone that regulates blood sugar. Type 2 diabetes occurs when the body either does not produce enough insulin or does not use insulin normally (insulin resistance). Common symptoms of diabetes include frequent urination, unusual thirst and extreme hunger. Some antiretroviral drugs may increase the risk of type 2 diabetes.

These considerations brought Dr Ruderman and her colleagues to conduct a large retrospective cohort study. The objective was to evaluate weight change differences by antiretroviral regimen among people living with HIV, from the moment they started ART.

The study

The investigators used data from 3232 people who had started their first ART containing three or more antiretrovirals between 2012 and 2019. These data had been collected in eight US sites of the CNICS (Centres for AIDS Research Network of Integrated Clinical Systems) cohort.

Weight change was measured in individuals taking the eleven most common ART regimens during both the first six months on treatment and also at all follow-up visits.

Seven of the eleven regimens assessed included tenofovir disoproxil (TDF) and emtricitabine (FTC):

Efavirenz – EFV/TDF/FTC.
Rilpivirine – RPV/TDF/FTC.
Atazanavir boosted with ritonavir – ATVr/TDF/FTC.
Darunavir boosted with ritonavir – DRVr/TDF/FTC.
Raltegravir – RAL/TDF/FTC.
Elvitegravir boosted with cobicistat – EVGc/TDF/FTC
Dolutegravir – DTG/TDF/FTC.

The other four combinations assessed for weight gain were:

Dolutegravir with tenofovir alafenamide and emtricitabine – DTG/TAF/FTC.
Bictegravir with tenofovir alafenamide and emtricitabine – BIC/TAF/FTC.
Cobicistat-boosted elvitegravir with tenofovir alafenamide and emtricitabine – EVGc/TAF/FTC.
Dolutegravir with abacavir and emtricitabine – DTG/ABC/FTC.

Results

The mean age in the whole study was 37 years. There were only 505 women (16%) in the cohort. Average follow-up time on first ART regimen was 1.9 years.

The cohort was ethnically diverse: 1463 (45%) participants were Black, 1136 (35%) White, 402 (13%) Hispanic and 231 (7%) in the other category. Hepatitis B and C coinfection rates were 3% and 9%, respectively, while hepatitis C coinfection was more common in those taking the RAL/TDF/FTC (22%) and the ATVr/TDF/FTC (16%) regimens. Average nadir CD4 ranged from 295 to 432 depending on the regimen, indicating that this population had started ART with fairly high CD4 counts.

Average baseline weight was 79 kg and baseline Body Mass Index (BMI) was 26 kg/m².

Participants on all regimens gained weight after starting ART. Those beginning EFV/TDF/FTC gained + 0.71 kg in the first six months. By comparison with that regimen and after adjustment for other factors that could influence the results, weight gain in the first six months was greater with several other regimens:

DRVr/TDF/FTC: + 3.7 kg (95% CI: 2.1-5.2).
DTG/TDF/FTC: + 2.6 kg (95%: CI 1.3–3.9).
DTG/ABC/FTC: + 2.3 kg (95%: CI 1.1–3.5).
DTG/TAF/FTC: + 4.4 kg (95%: CI 2.1-6.6).
BIC/TAF/FTC: + 3.9 kg (95%: CI 2.2 – 5.5).
EVGc/TDF/FTC: + 1.8 kg (95%: CI 0.7–2.9).
EVGc/TAF/FTC: + 1.9 kg (95%: CI 0.6–3.2).

During longer follow-up, weight gain was also greater in participants on darunavir and INSTI-based regimens, compared to those on EFV/TDF/FTC. The overall pattern of weight change by regimen did not differ when adjusting for recent CD4 count. Weight changes were similar regardless of baseline BMI (above or below 25kg/m²), although small differences such as more weight gain on atazanavir/ritonavir in the lower BMI groups than in the higher BMI groups were observed.

Conclusions

“Return to health cannot fully explain the association between dolutegravir and bictegravir and weight gain.”

The study provides insights as to weight gain among people living with HIV outside of clinical trials. It highlights differences in weight gain between integrase inhibitors, with more weight gain on dolutegravir or bictegravir than on elvitegravir. Weight gain on darunavir was also statistically significant. Another finding of note is the greater weight gain in patients on TAF regimens, when compared to TDF regimens, which would be in line with what was found in a large South African clinical trial.

In their paper, the investigators discuss ‘return to health’ of individuals as a possible mechanism of weight gain after starting ART. It has been hypothesised that superior virologic benefits of integrase inhibitors are a factor of a faster return to health than other ARV classes, leading to weight gain. However, as per today’s HIV treatment recommendations, people with HIV should start treatment immediately, most of the time with fairly high CD4 counts as in this study, hopefully without too many HIV-induced health issues that return to health could reverse. Also, in the study, the finding that weight gained on dolutegravir and bictegravir was greater than weight gained on some other integrase inhibitors indicate that return to health cannot fully explain the association between these two drugs and weight gain.

Clearly, as Stephanie Ruderman and colleagues conclude, “long-term observation of people living with HIV taking integrase strand transfer inhibitors is warranted”.

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