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ARV-Associated Weight Gain
Australian Perspectives on New Data From CROI 2021: My Picks for Studies of Weight Gain With ART and Long-Acting Injectable Therapy

Released: April 20, 2021

Expiration: April 19, 2022

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Some of the most clinically relevant data presented at the Virtual 2021 Conference on Retroviruses and Opportunistic Infections (CROI 2021) included new findings on antiretroviral (ARV)-associated weight gain and longer-term results from studies investigating injectable long-acting cabotegravir (LA CAB) plus rilpivirine (RPV).

Weight Gain After Switching to Different INSTIs
A retrospective study by McComsey and colleagues investigated weight gain after switching to INSTIs. The study analyzed data from 2272 patients in the Trio Health HIV database who were switched to elvitegravir (EVG), bictegravir (BIC), dolutegravir (DTG), or raltegravir (RAL).

After 1 year on the respective integrase strand transfer inhibitors (INSTIs), the mean weight gain was +1.5 kg with EVG, +0.9 kg with BIC, +1.2 kg with DTG, and +1.9 kg with RAL; no differences were observed in the proportion of patients who gained at least 3%, 5%, or 10% of their body weight. However, the groups were not balanced at baseline for race, age, sex, or CD4+ cell count. Another possible confounding factor is that one of the single-tablet coformulations with EVG and the only single-tablet coformulation with BIC contain tenofovir alafenamide (TAF) (ie, EVG/cobicistat COBI/emtricitabine FTC/TAF and BIC/FTC/TAF), whereas the second single-tablet EVG-based coformulated regimen includes tenofovir disoproxil fumarate (TDF) (ie, EVG/COBI/FTC/TDF).

In a multivariate analysis, factors associated with a higher risk of gaining 3% or more weight at 1 year included: switching from TDF to TAF (adjusted risk ratio aRR: 1.22; 95% CI: 1.06-1.41; P =.006); having a CD4+ cell count nadir <200 cells/mm3 (aRR: 1.33; 95% CI: 1.02-1.73; P = .036); age younger than 50 years (aRR: 1.16; 95% CI: 1.03-1.3; P = .012); female sex (aRR: 1.11; 95% CI: .95-1.3; P = .176); Black race (aRR: 1.13; 95% CI: 1.0-1.28; P = .043); and low body mass index (aRR: 1.17; 95% CI: 1.04-1.31; P = .009). There was no difference in the risk of weight gain between the different INSTIs in the multivariate analysis that included adjustment for these factors. This finding suggests that patient genetics, the effects of HIV on CD4+ cell count, and body mass may be more important weight gain determinants than treatment choice.

DRV/COBI/FTC/TAF vs DTG/ABC/3TC for Initial Treatment in Adults With HIV
The question of the relative contributions of TAF vs INSTIs to antiretroviral therapy (ART)–associated weight gain was addressed in a study presented by Podzamczer and colleagues. This randomized trial compared darunavir (DRV)/COBI/FTC/TAF with DTG/abacavir (ABC)/lamivudine (3TC) for initial ART. The investigators reported that the proportion of intent-to-treat exposed patients (n = 306) who achieved HIV-1 RNA <50 copies/mL was 79% with DRV-based therapy and 82% with DTG-based therapy (difference: -2.4%; 95% CI: -11.3% to 6.6%; P = .706). The proportion of patients who achieved viral suppression was higher with DRV vs DTG in patients with baseline HIV-1 RNA ≥100,000 copies/mL (78% vs 73%) and with baseline CD4+ cell counts <200 cells/mm3 (88% vs 82%), but the number of participants in each group was too small for the differences to achieve statistical significance. The overall median weight gain in both treatment arms was +2.9 kg, suggesting that both TAF and the INSTI may contribute to weight gain to a similar degree.

Based on the various abstracts and presentations from CROI 2021, there is a general consensus that weight gain is common when starting ART. Women and Black persons are more likely to gain weight. People starting treatment with a low nadir CD4+ cell count are also more likely to gain weight, potentially as part of the return to health phenomenon. It is important to note that these weight findings in patients with HIV are occurring on a background of aggregate weight gain in the overall population in most countries. To date, the mechanism of weight gain associated with ART has yet to be elucidated, and it remains unclear how much blame can be attributed to any of the different ARVs. There seems to be some suggestion that the INSTIs and TAF are associated with greater weight gain, and there is room for more work to be done in this area.

Weight and Lipid Changes in Phase III LA CAB Plus RPV Trials
Another study by Patel and colleagues evaluated pooled data from 3 randomized phase II/III clinical trials (FLAIR, ATLAS, and ATLAS-2M) for weight and lipid changes at Week 48. They compared switch to LA CAB plus RPV every 4 weeks (n =918) vs switch to LA CAB plus RPV every 8 weeks (n = 327) vs continued oral ART (n = 591), and median weight gain was +1.20 kg, +1.25 kg and +1.00 kg in each treatment arm, respectively. Changes in lipid parameters were small and similar across regimens.

Week 96 Efficacy and Safety of LA CAB Plus RPV Every 2 Months: ATLAS-2M
LA CAB plus RPV is approved for 4-week dosing intervals in Canada and the United States and 8-week dosing intervals in Europe. The regimen is currently under review for approval in Australia with an anticipated decision within the next 2 months. ATLAS-2M compared 4-week to 8-week dosing intervals of LA CAB plus RPV in patients who were enrolled on the ATLAS study (LA CAB plus RPV arm or continued oral ART arm) and patients outside of the ATLAS study who were virologically suppressed on standard-of-care oral ART (N = 1045). The Week 96 data presented at CROI 2021 demonstrated continued noninferiority of LA CAB plus RPV administered every 8 weeks compared with every 4 weeks: 91.0% of patients and 90.2% of patients, respectively, had HIV-1 RNA <50 copies/mL.

The percentage of participants with HIV-1 RNA levels ≥50 copies/mL at 96 weeks, either because the virus was not controlled or due to missed injections, was 2.1% with injections every 8 weeks and 1.1% with injections every 4 weeks. Confirmed virologic response rates were 1.7% with injections every 8 weeks and 0.4% with injections every 4 weeks. It is becoming more and more important to ask what happens if patients experience virologic failure on injectable LA therapy. RPV resistance associated mutations (RAMs) occurred in 7 of 9 participants with confirmed virologic failure (CVF) in the 8-week dosing interval arm vs 1 of 2 participants in the 4-week dosing interval arm. INSTI RAMs occurred in 5 of 9 patients with CVF in the 8-week dosing interval arm vs 2 of 2 patients in the 4-week dosing interval arm. This has major clinical implications, as the risk of developing resistance mutations in the instance of CVF is reasonably high. Of note, 11 participants receiving injections every 4 weeks withdrew from the study for injection-related reasons vs 7 who were receiving injections every 8 weeks, suggesting the longer dosing interval may be more tolerable.

In summary, LA CAB plus RPV dosed every 8 weeks was noninferior to dosing every 4 weeks, but a small proportion of patients did not remain adequately virologically suppressed and most of those patients developed resistance mutations. The every-4-week dosing schedule was less likely to result in CVF but may be less acceptable to some patients. People would probably prefer to have a longer gap between the injections, but there is the risk that a small number of patients may not be adequately suppressed for that whole period.

I think the results of ATLA-2M raises concerns about how much monitoring may be needed for patients on injectable therapy, as the 6 months between clinic visits that is standard for patients who are stable on oral ART may be too long for monitoring patients on injectable therapy and this may vary based on dosing schedule.

LA CAB Plus RPV in Older Adults: Pooled Phase III Week 48 Results
Finally, a study by Benn and colleagues examined the pooled 48-week results from 3 different LA CAB plus RPV studies (ATLAS, FLAIR, and ATLAS-2M) for differences in response rates by age and differences in tolerability to injection-site reactions. The data showed that virologic outcomes and injection-site reactions were similar across treatment arms and age groups with virologic suppression rates ranging from 92% to 97% and virologic nonresponse rates of approximately 2%. Most injection-site reactions were grade 1 and lasted 7 days or less with few resulting in withdrawal. It has been suggested that persons who have been infected with HIV longer and experienced the adverse events of some of the earlier treatments may be more tolerable to toxicities, but that was not observed in this study. It is good to see that there are no apparent tolerability differences by age with this injectable regimen.

Your Thoughts
What is your experience with ARV-associated weight gain? If you practice in Australia, how do you see LA CAB plus RPV fitting into the treatment landscape if it is approved? Join the discussion by posting a comment sharing your experiences.

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