Studies have reported that one in six patients gain significant weight—at least 10% of their body weight—within two years after starting HIV treatment. This weight gain is more common in women, Black people, and people who had poorer health when starting treatment, but the reasons for weight gain are still unclear. Weight gain is strongly correlated with integrase inhibitors (INSTIs) and tenofovir alafenamide (TAF), particularly second-generation integrase inhibitors dolutegravir and bictegravir. Weight gain is a concern because it can increase the risk of diabetes, cardiovascular disease, and other comorbidities.
Mitigating weight gain was the topic of a lively discussion at IDWeek 2024 in Los Angeles in October, with two experts, Christine Erlandson, professor of medicine at the University of Colorado in Denver, and Cecile Lahiri, an associate professor at Emory University in Atlanta, each defending different strategies.
The case for switching medications
Lahiri started by listing the characteristics of a fictional (but typical) patient who has experienced weight gain: A 55-year-old cisgender Black woman who was on Atripla (efavirenz/tenofovir disoproxil fumarate/emtricitabine) for about a decade, then was switched to Odefsey (rilpivirine/tenofovir alafenamide/emtricitabine). She did well for five years, until two years ago, when her treatment was “modernized” to Biktarvy (bictegravir/tenofovir alafenamide/emtricitabine) and since then has gained about seven kilograms, or about 15 pounds; she is not happy with the added weight. She’s pre-diabetic, has hypertension, and a body mass index (BMI) of 34 (considered obese). She’s a non-smoker, has good renal functions and is on a statin drug to lower cholesterol.
“If this were your patient, what would you do?” Lahiri asked, providing six possible options:
- Continue the current regimen of BIC/TAF/FTC, and give some lifestyle modification counseling
- Switch back to RPV/TAF/FTC
- Start a new regimen of DOR/3TC/TDF
- Switch to long-acting CAB/RPV
- Switch to DRV/c/TAF/FTC
- Add a GLP-1 receptor agonist (the diabetes drugs also used for weight loss)
- Add a different agent
Making a case for changing the antiretroviral treatment (ART) regimen to reduce weight gain, Lahiri pointed to a 2022 study of women and Black and Hispanic people who discontinued INSTIs. “In a real-life scenario, we see that switching off of an INSTI might stabilize weight gain,” she said.
But it’s not all about integrase inhibitors, Lahiri said, pointing to a study looking at over 6,000 people in a Swiss cohort that was switched from TAF, in which the most pronounced weight change was in participants who were switched from TAF to TDF. “Whether [weight change] resulted from going off TAF or going on TDF, we don’t know, but switching from TAF to TDF may prove beneficial for weight loss.”
Lahiri said that some data will be coming from another clinical trial, ACTG A5391, aka the Do It study, a randomized clinical trial to look at doravirine for people who are obese and on integrase inhibitors and TAF. The Do It study has completed enrollment, and the primary endpoint, weight loss at 48 weeks, will be analyzed soon.
The case for not switching medications
Erlandson followed up by arguing that switching regimens can lead to toxicity. “Any time we're talking to our patients about weight, we need to also weigh the consequences of therapies that might decrease their bone density, might contribute to renal insufficiency, and as we know, efavirenz can cause cognitive impairments, even psychiatric effects and many other toxicities,” she said. Erlandson added that the regimens that Lahiri mentioned were primarily stabilizing weight, but didn’t lead to weight loss.
‘GLP-1 receptors can have numerous benefits, but almost 20% of people probably won’t have much of a weight change with GLPs, so they’re not a magic pill for everyone.’
Making the case for lifestyle recommendations and modifications, Erlandson pointed to studies showing that people with HIV (PWH) have experienced weight loss with nutritional counseling and supervised exercise.
“These lifestyle interventions can also have benefits well beyond weight reduction, in maintenance or things that we might see just with switching someone over to tenofovir or other therapies that might stabilize their weight,” Erlandson said. “We can see decreases in mortality, improvements in neurocognitive function, improvements in physical function, reduced inflammation and the risk for diabetes and ultimately decrease the use of additional medications, which is often a major concern in our patients as they're getting older with HIV.”
Acknowledging that some people won’t respond enough to a lifestyle intervention, Lahiri said weight loss meds, including glucagon-like (GLP)-1 receptor agonists, can be more effective for weight loss than changing an ART regimen. Recently the SLIM Liver Study showed that semaglutide not only reduced the severity of common liver disease in PWH, but participants also lost a significant amount of weight.
Erlandson also noted that metformin, which is approved for pre-diabetes, not weight loss, could nevertheless be a cost-effective option for losing weight, at least for PWH who are able to access it.
“Metformin is a very cheap medication, with potential benefits. As we think about our patients that are getting older, there's interest in looking at metformin as an anti-aging drug. It can improve cognitive function, decrease cancer risk, and have expanded lifespan. You hear of various people that are taking this on a daily basis to improve their longevity. And it has relatively few drug interactions with HIV medications.”
Consensus
Lahiri and Erlandson concluded by agreeing on several points. First, there are no current data supporting weight loss by changing ART, although switching regimens can stabilize weight in some people. “We both agree that everyone should have intensive counseling on nutrition and exercise with ongoing support, even in people that are receiving GLPs,” Lahiri said.
“GLPs are not going to change the entire face of weight loss without some lifestyle changes, in part because of the reversible effects as soon as someone stops these therapies,” she added. “GLP-1 receptors can have numerous benefits, but almost 20% of people probably won’t have much of a weight change with GLPs, so they’re not a magic pill for everyone.”
Both Lahiri and Erlandson agreed that food and housing insecurity can limit options for weight change in some populations, and that clinicians could work with patients to find preferable healthy food options that can also fit within budgets.
Erlandson concluded by saying clinicians should develop a unique treatment plan for each patient, using the combination of options that’s right for each individual.