People living with HIV who put on extra pounds and develop metabolic syndrome or related disorders linked in part to certain antiretroviral agents remain a concern today, even as the drugs used to suppress HIV infection have evolved over the decades.
Linkage of HIV treatment with lipodystrophy and insulin resistance or diabetes began in the 1990s with protease inhibitors (Clin Infect Dis. 2000 Jun;30[suppl 2]:s135-42). Several reports over the years also tied any form of effective antiretroviral therapy to weight gain in HIV patients (Antivir Ther. 2012;17[7]:1281-9). More recently, reports have rattled the HIV-treatment community by associating alarmingly high levels of weight gain with a useful and relatively new drug, tenofovir alafenamide fumarate (TAF) – a nucleoside reverse transcriptase inhibitor (NRTI) approved for use in the United States in late 2016, as well as certain agents from an entirely different antiretroviral therapy (ART) class, the integrase strand transfer inhibitors (INSTIs). Both TAF and the INSTIs have come to play major roles in the HIV-treatment landscape, despite relevant and concerning recent weight gain observations with these drugs, such as in a 2019 meta-analysis of eight trials with 5,680 treatment-naive patients who started ART during 2003-2015 (Clin Infect Dis. 2019 Oct 14;doi: 10.1093/cid/ciz999).
“Weight gain is clearly seen in studies of dolutegravir [DTG] or bictegravir [BTG] with TAF,” wrote W.D. Francois Venter, PhD and Andrew Hill, PhD in a recent published commentary on the topic (Lancet HIV. 2020 Jun 1;7[6]:e389-400). Both DTG and BTG are INSTI class members.
“Excessive weight gain, defined as more than 10% over baseline, has recently been observed among people with HIV initiating or switching to regimens incorporating TAF, an INSTI, or both, particularly DTG,” wrote Jordan E. Lake, MD, an HIV specialist at the University of Texas Health Science Center at Houston, in a recent commentary posted online. Women and Black patients “are at even greater risk for excessive weight gain,” Dr. Lake added.
“In recent times, it has emerged that weight gain is more pronounced with the integrase inhibitor class of agents, especially dolutegravir and bictegravir, the so-called second-generation” INSTIs, said Anna Maria Geretti, MD, a professor of clinical infection, microbiology, and immunology at the University of Liverpool, England. ”The effect is more pronounced in women and people of non-White ethnicity, and is of concern because of the associated potential risk of metabolic syndrome, cardiovascular disease, etc.,” Dr. Geretti said in an interview.
The unprecedented susceptibility to weight gain seen recently in non-White women may in part have resulted from the tendency of many earlier treatment trials to have cohorts comprised predominantly of White men, Dr. Venter noted in an interview.
Alarming weight gains reported
Perhaps the most eye-popping example of the potential for weight gain with the combination of TAF with an INSTI came in a recent report from the ADVANCE trial, a randomized, head-to-head comparison of three regimens in 1,053 HIV patients in South Africa. After 144 weeks on a regimen of TAF (Vemlidy), DTG (Tivicay), and FTC (emtricitabine, Emtriva), another NRTI, women gained an averaged of more than 12 kg, compared with their baseline weight, significantly more than in two comparator groups, Simiso Sokhela, MB, reported at the virtual meeting of the International AIDS conference. The women in ADVANCE on the TAF-DTG-FTC regimen also had an 11% rate of incident metabolic syndrome during their first 96 weeks on treatment, compared with rates of 8% among patients on a different form of tenofovir, tenofovir disoproxil fumarate (TDF), along with DTG-FTC, and 5% among those on TDF–EFV (efavirenz, Sustiva)–FTC said Dr. Sokhela, an HIV researcher at Ezintsha, a division of the University of the Witwatersrand in Johannesburg, South Africa.
“We believe that these results support the World Health Organization guidelines that reserve TAF for only patients with osteoporosis or impaired renal function,” Dr. Sokhela said during a press briefing at the conference. The WHO guidelines list the first-line regimen as TDF-DTG-3TC (lamivudine; Epivir) or FTC. “The risk for becoming obese continued to increase after 96 weeks” of chronic use of these drugs, she added.
“All regimens are now brilliant at viral control. Finding the ones that don’t make patients obese or have other long-term side effects is now the priority,” noted Dr. Venter, a professor and HIV researcher at University of the Witwatersrand, head of Ezintsha, and lead investigator of ADVANCE. Clinicians and researchers have recently thought that combining TAF and an INSTI plus FTC or a similar NRTI “would be the ultimate regimen to replace the nonnucleoside reverse transcriptase inhibitors (NNRTIs)” such as EFV, “but now we have a major headache” with unexpectedly high weight gains in some patients, Dr. Venter said.
Weight gains “over 10 kg are unlikely to be acceptable in any circumstances, especially when starting body mass index is already borderline overweight,” wrote Dr. Venter along with Dr. Hill in their commentary. Until recently, many clinicians chalked up weight gain on newly begun ART as a manifestation of the patient’s “return-to-health,” but this interpretation “gives a positive spin to a potentially serious and common side effect,” they added.
More from ADVANCE
The primary efficacy endpoint of ADVANCE was suppression of viral load to less than 50 RNA copies/mL after 48 weeks on treatment, and the result showed that the TAF-DTG-FTC regimen and the TDF-DTG-FTC regimen were each noninferior to the control regimen of TDF-EFV-FTC (New Engl J Med. 2019 Aug 29;381[9]:803-15). Virtually all of the enrolled patients were Black, and 59% were women. Planned follow-up of all patients ran for 96 weeks. After 48 weeks, weight gain among the women averaged 6.4 kg, 3.2 kg, and 1.7 kg in the TAF-DTG, TDF-DTG, and TDF-EFV arms respectively. After 96 weeks, the average weight gains among women were 8.2 kg, 4.6 kg, and 3.2 kg, respectively, in new results reported by Dr. Sokhela at the IAC. Follow-up to 144 weeks was partial and included about a quarter of the enrolled women, with gains averaging 12.3 kg, 7.4 kg, and 5.5 kg respectively. The pattern of weight gain among men tracked the pattern in women, but the magnitude of gain was less. Among men followed for 144 weeks, average gain among those on TAF-DTG-FTC was 7.2 kg, the largest gain seen among men on any regimen and at any follow-up time in the study.
Dr. Sokhela also reported data on body composition analyses, which showed that the weight gains were largely in fat rather than lean tissue, fat accumulation was significantly greater in women than men, and that in both sexes fat accumulated roughly equally in the trunk and on limbs.
An additional analysis looked at the incidence of new-onset obesity among the women who had a normal body mass index at baseline. After 96 weeks, incident obesity occurred in 14% of women on the TAG-DTG-FTC regimen, 8% on TDF-DTG-FTC, and in 2% of women maintained on TDF-EFV-FTC, said Dr. Hill in a separate report at the conference.