Editorial: New drugs for HIV: quo vadis?

Weight Gain After HIV Therapy Initiation: Pathophysiology and Implications

“…Two NRTIs formed the backbone of almost every ART regimen for decades, until very recently, with the rise of dual therapy and injectable ARVs ( 32 ). Currently, with older drugs implicated in lipoatrophy steadily falling out of use, only 2 cytosine analogues, lamivudine and emtricitabine, widely regarded as being indistinguishable from each other and having minimal effect on weight, and 2 tenofovir prodrugs TDF and TAF, and abacavir, are still advocated in guidelines for first-line therapy.…”

“…Mechanistic pathways have been proposed for INSTI-related weight gain, although current data are unconvincing ( 3 , 12 ). Limited qualitative and subjective data suggest that dolutegravir increases feelings of hunger ( 32 ), and in macaques, decreases levels of leptin ( 33 ). Dolutegravir could also drive increased capacity for energy harvest ( 34 ).…”

“…Many long-acting therapeutic agents are under investigation, partly as the current daily oral offerings are remarkably safe and effective, offering little room for improvement, and partly as patient preference studies have indicated strong preference for long-acting agents over conventional daily dosing ( 32 , 62 ). The first long-acting treatment offering, a dual injection of rilpivirine and cabotegravir given every 2 months as 2 separate injections, appears to be safe, effective, and weight-neutral when compared against a standard daily offering, and was recently registered by the US Food and Drug Administration based on noninferiority studies.…”

“…Lenacapavir is also being explored as preexposure prophylaxis, again with weight measurements, but the lymphocyte toxicity signal seen with higher doses of islatravir has meant that the oral and implant prophylaxis studies have been terminated. Favorable early efficacy and toxicity data with these 2 agents, using lower islatravir oral weekly dosing, suggests they may form part of the treatment landscape soon, meaning close attention on their effect on weight ( 32 , 62 ). While these early offerings have already had challenges during development, it is likely that long-acting ARVs will steadily become a major alternative, if not altogether replace, daily therapy in the future, with weight gain a major factor in agent selection.…”