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School of Population Medicine
University of New South Wales
Senior Staff Specialist
South Eastern Sydney Local Health Network
Don Smith, MD, has reported that he has received consulting fees from Gilead Sciences, Janssen, and ViiV Healthcare and fees for research support from ViiV Healthcare.
New Aspects of ARV-Associated Weight Gain
Most people with HIV in Australia are now being treated with integrase inhibitor–based regimens that usually contain tenofovir alafenamide (TAF). Thus, possible TAF or integrase strand transfer inhibitor (INSTI)–based weight gain is a concern for us. The 2021 International AIDS Society Conference on HIV Science provided a few more pieces in the jigsaw puzzle of antiretroviral (ARV)-associated weight gain.
Most of the presentations started with the accepted wisdom that INSTIs and TAF are both associated with weight gain as a toxicity and went on to describe weight gain patterns and possible linkage with obesity complications. Hocqueloux and colleagues described 1184 patients in the Dat’AIDS cohort who were switched from tenofovir disoproxil fumarate to TAF and recorded only a 1.28-kg weight gain. Those with higher baseline weight gained the most.
Chan and colleagues looked at 243 patients receiving bictegravir/emtricitabine/TAF and noted that 28% had more than 10% weight gain. Fortunately, this did not seem to be associated with metabolic syndrome. However, the study results presented by Hamooya and colleagues suggested that dolutegravir (DTG)-based antiretroviral therapy (ART) in Zambia was associated with an increased risk of higher blood pressure, increased waist circumference, and lower high-density lipoprotein levels compared with those receiving nonnucleoside reverse transcriptase inhibitor (NNRTI)- or protease inhibitor–based ART.
The results presented by Dunn and colleagues suggested that TAF with boosted darunavir was not associated with metabolic syndrome or hepatic fibrosis. Yet, Dr.Trevillyan and colleagues summarized that ARV-associated weight gain is associated with increased inflammatory markers and that the combination of TAF with second-generation integrase inhibitors is now being aligned to cases of diabetes. For now, the underlying mechanism for this weight gain is unclear. Lagathu and colleagues expanded on their earlier work, which suggested DTG-induced fibrosis in adipocytes, to also look at beige fat and not just white or brown fat. They found evidence that DTG can damage mitochondrial function in these cells, which seem to be important for thermogenesis. It seems their hypothesis is that DTG inhibits the ability of beige fat cells to burn energy to maintain body temperature. Therefore, still more clarity is required.
Are these observations enough to dissuade us from using DTG/bictegravir or TAF as preferred therapy? My view is that their potency, tolerability, lack of other toxicity, and convenience still outweigh the potential downside.
Long-Acting Injectable ART
Long-acting injectable ART is not yet available in Australia, but patients are aware of it and asking about possible suitability. Dr. Chloe Orkin and colleagues updated the FLAIR study with Week 124 results showing continued suppression with cabotegravir/rilpivirine as initial therapy. More than 85% of subjects had HIV-1 RNA <50 copies/mL on injectable therapy. One additional patient had confirmed virologic failure with both NNRTI and INSTI mutations. Charpentier and colleagues consolidated these results within a summary of the FLAIR, ATLAS, and ATLAS-2M studies and evaluated baseline predictors of viral failure. It had previously been noted that baseline resistance associated mutations (RAMs) were associated with a nearly 40-fold increased risk of failure. Interrogating a database of more than 4000 clinical samples, they identified that 6% had rilpivirine RAMs but only 0.7% had cabotegravir RAMs. This would highlight the need to carefully check pretherapy genotypes before considering this regimen.
Long-Acting SC Lenacapavir in Heavily Treatment-Experienced Patients
The real standout of the meeting was the presentation by Dr. Molina and colleagues on the CAPELLA Week 26 results with the novel capsid inhibitor lenacapavir, which is given subcutaneously every 6 months. When stress testing the drug by using it as a new class agent in heavily resistant patients, 81% of patients achieved HIV-1 RNA <50 copies/mL at 6 months, with 89% of patients <200 copies/mL. These are impressive results, and I suspect that this drug might leapfrog over the other injectable agents in the near future.
What is your experience with ARV-associated weight gain, and how do you see lenacapavir fitting into the treatment landscape in your home country? Join the discussion by posting a comment sharing your experiences.