By Christopher J. Hoffmann, MD, MPH, Johns Hopkins University School of Medicine
Weight gain and metabolic complications are increasingly a concern for patients taking antiretroviral (ARV) medications. The connection with a specific class of ARVs was first described for integrase strand transfer inhibitors (INSTI) [Norwood J, Turner M, Bofill C, et al. J Acquir Immune Defic Syndr. 2017; 76:527]; subsequently, an association with tenofovir alafenamide (TAF) was reported [Venter W, Moorhouse M, Sokhela S, et al. N Engl J Med. 2019;381(9):803] was reported. Now there is a recently published analysis of the Swiss HIV Cohort Study that compares weight changes and metabolic outcomes among people on stable antiretroviral therapy (ART) who were switched from tenofovir disoproxil fumarate (TDF) to TAF [Surial B, Mugglin C, Calmy A, et al. Ann Intern Med. 2021 Mar 16; online ahead of print].
The researchers assessed for TAF-associated changes by comparing participants switched from TDF to TAF to those who remained on TDF. Follow-up started upon approval of TAF in Switzerland (January 2016) and continued through July 2019. Participants taking TDF were included if they either continued TDF or switched to TAF. In those who switched, the index visit was the date of the switch to TAF; a random sample of index dates was assigned to those who continued TDF to generate random index dates for those participants. Weight measurements from 2.5 years prior to the index date until the end of follow-up were included. Individuals with any follow-up time following the index date were included in the analysis. If TAF was discontinued, follow-up was censored at that time. Pregnant individuals and those switched to another nucleoside reverse transcriptase inhibitor along with the TDF to TAF switch were excluded.
The analytic population included 4,375 individuals with a median age of 50 years; 25% were women, and 50% were of normal body mass index at the index visit. Overall, 20% continued TDF until the end of observation, and 80% were switched to TAF. Those who were switched to TAF were more likely to be men, identify as gay, have a lower estimated glomerular filtration rate, and less likely to be of African origin. The median follow-up was 17 months with a median of 3 follow-up visits after the index visit.
Crude weight trajectories before the index visit were similar between individuals who continued TDF and those who switched to TAF. The switch to TAF was associated with increases in weight regardless of the third ART agent (INSTI, protease inhibitor, or nonnucleoside reverse transcriptase inhibitor). A switch to TAF was associated with a 1.8 kg increase compared to a 0.7 kg increase in those who remained on TDF 18 months after the index visit. This change was similar when limiting the analysis to those with persistently suppressed viral load. The difference in weight gain between TAF and TDF was most marked for women of African origin (1.5 kg), followed by women of non-African origin (1.4 kg), and men of non-Africa origin (1.1 kg). Men of African origin did not appear to have a difference in weight gain between TDF and TAF. Assessment of metabolic parameters for 18 months following the TAF switch found that TAF was associated with increased total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglyceride levels; switching to TAF was also associated with new-onset diabetes, with an adjusted incidence rate ratio of 1.3.
This study adds to the growing body of evidence of weight gain with selected ARVs. The strengths of this study are the relatively large sample size and the inclusion of only individuals on stable long-term ART. A limitation, as with all cohort studies, is that unmeasured factors may have influenced both the agent switch and weight change, leading to failure to identify a confounder that is the real reason for the observed differences. Another limitation is the relatively short follow-up up time. The Kaplan-Meier figures from the analysis appear to show that most of the differential in weight gain occurs in the first 6 months following the switch to TAF. This leads to questions of whether greater weight gain persists beyond the initial period on TAF and whether switching from TAF to another ARV following this initial weight gain would affect a patient’s future weight change trajectory.
Notably, individuals in both groups gained weight, developed obesity, and had new onset diabetes, all health conditions that should be prevented and managed among all people living with HIV, regardless of ART regimen.