Gaining Insights on ART Tolerability Challenges: A Focus on Weight Gain

Key Takeaways

• It remains unclear why weight gain is seen more with second-generation INSTIs (eg, DTG, BIC) and TAF/FTC than with other ARV medications.
• The consequences of possible ARV medication–related weight gain are still being investigated.
• Data are lacking to support switching ART regimens when weight gain is observed; instead, healthcare professionals should try to reduce cardiovascular risks in people with HIV, including getting a detailed medical and family history.

When caring for people with HIV (PWH), we need to work with our patients to come up with the simplest, safest, and most effective therapy that is well tolerated and fits their lifestyle. Luckily, except for a small number of patients with complex resistance histories, finding simple and effective therapy is not too difficult. Even among patients who have been treated for up to 30 years, the vast majority are on a simple regimen of 1 or 2 combination pills once daily.

Unlike some past therapies, our current antiretroviral (ARV) medications are not associated with acute, highly morbid, or life-threatening adverse effects (AEs). The days of drug-related pancreatitis, peripheral neuropathy, marked anemia or neutropenia, lipoatrophy, or hypersensitivity reactions are in the distant past. Instead, we are faced with more subtle or long-term AEs or tolerability challenges that play out over years or decades instead of days or months.

ARV Medication–Related Weight Gain
If you had told me 25 years ago that we would be obsessed with too much weight gain in our PWH, I would have thought you were crazy. Yet here I am in clinic trying to decide if the weight gain I see is ARV medication related, a return to health, or an unexplained alteration in metabolism caused by the drugs. Theoretically, it may even be the result of a combination of preexisting metabolic risk exacerbated by HIV-related inflammatory changes—changes that persist in PWH but had been hidden by older ARV medications.

Based on current data, it is clear that second-generation integrase strand transfer inhibitors (INSTIs; eg, bictegravir [BIC] or dolutegravir [DTG]) and tenofovir alafenamide (TAF)/emtricitabine (FTC) are more associated with weight gain compared with previous preferred regimens such as efavirenz (EFV)/tenofovir disoproxil fumarate (TDF)/FTC, especially in specific patient populations (eg, Black women). We are still struggling with the “why” and figuring out what to do about it. 

TDF, and almost certainly EFV, is a weight suppressant, as seen in the ADVANCE study. Weight gain from a “return to health” was expected, but in men receiving EFV/TDF/FTC at Week 48, only a 0.5 kg weight gain was observed, as compared with 4.7 kg in the TAF-based DTG regimen arm.

TDF and TAF Changes
Multiple studies have compared switches from TDF to TAF, and vice versa, including several published this summer and presented at the AIDS 2022 meeting. When switching from TDF to TAF, we see weight increases of approximately 1-2 kg, and the opposite occurs when going from TAF to TDF. TAF may be contributing to weight gain; however, in several randomized and retrospective studies, when PWH transitioned off TAF to a regimen without tenofovir (eg, 2 drug regimens such as DTG/lamivudine or DTG/rilpivirine), weight either trends up similarly over time in the randomized comparative trials or modestly in the retrospective analyses. However, when TDF is removed, we observe increases in weight; this was observed in a substantial proportion of patients in a recent retrospective analysis by Nasreddine and colleagues.

Weight Loss Consequences
This weight loss observed with TDF may have adverse consequences. For example, in the IMPAACT 2010 study of pregnant persons with HIV receiving antiretroviral therapy (ART), infant outcomes were worse in mothers receiving TDF compared with TAF. This may have been because of better weight gain observed on TAF-containing therapy; inadequate weight gain in pregnancy can result in preterm birth or infants being small for their gestational age.

Another patient population in which weight loss may not be beneficial is adult PWH with low CD4+ cell counts. Patients with a CD4+ cell count of <200 cell/mm³ who were maintained on TDF in a study by Martinez-Sanz and colleagues actually lost weight over time, while a modest weight gain resulted in those switched to TAF regimens.

INSTIs and Cardiometabolic Toxicities
How to think about our second-generation INSTIs and weight gain is a little murkier. Data are lacking to support switching off DTG or BIC to a different ARV backbone that results in sustained weight loss.

There are potential consequences to weight gain; most evident has been a small, increased risk of diabetes mellitus as demonstrated by O’Halloran and colleagues. A short-term increase in cardiovascular events has been observed in a large observational study, the RESPOND trial, and possibly corroborated in a retrospective study presented at the AIDS 2022 meeting by Riberio and colleagues. Why such an effect would be transient is hard to explain, but it needs to be studied further.

My Approach
In my practice, I am no longer considering a switch to TDF as a weight-loss strategy. If a person with HIV needs a medication for weight loss, there are more effective alternatives, with even better ones coming.

There is no evidence supporting switching off a TAF-containing regimen to a non-tenofovir 2-drug regimen to promote weight loss. In fact, as seen in the TANGO study, 2-drug regimensare highly effective at controlling HIV, but demonstrating a favorable metabolic or tolerability benefit has been a challenge.

Second-generation INSTIs remain my anchor in ART regimens for most treatment-naive PWH. They have allowed me to simplify therapy for so many patients who have a history of extensive protease inhibitor and nucleoside reverse transcriptase inhibitor resistance who were on complex regimens containing boosting agents.

To address their potential effects, I do spend a substantial amount of time talking to PWH about the risks of weight gain, and I have redoubled my efforts in getting a detailed medical history to assess cardiovascular risk factors, as well as a complete family history including obesity in the absence of diabetes mellitus or cardiovascular disease.

Future Needs
We need to carefully explore the metabolic and cardiovascular consequences of long-term treated HIV infection—and of the medications we use to achieve sustained HIV-1 RNA suppression. These consequences and their pathogenesis need to be better understood to decrease long-term risk among PWH and to bring their life expectancy in line with people without HIV.

Your Thoughts?
How do you approach possible ARV medication–related weight gain? Join the conversation by posting in the discussion section.