Weight gain in people with HIV starting antiretroviral therapy has been a source of concern for years. Recently, however, that concern has shifted to a more narrow focus on two areas: One is the relatively recent class of integrase strand inhibitors (INSTIs), and the other is the NRTI tenofovir alafenamide (TAF), which has generally been regarded as having a better long-term safety profile than tenofovir disoproxil fumarate (TDF, Viread).
This year’s IDWeek conference, which concluded on Oct. 25, saw a number of presentations on weight gain among people starting TAF. Although the mechanism and long-term implications remain unclear, these studies affirm that the effect is occurring—and that a person’s prior HIV treatment regimen may play a role.
TDF to TAF on Integrase Inhibitor Based Therapy
The most important presentation on this topic during IDWeek was a late-breaking oral presentation by Grace A. McComsey, M.D., a professor of pediatrics and medicine at Case Western Reserve University and the vice president of research at University Hospitals Cleveland Medical Center. McComsey and colleagues conducted a retrospective observational study based on clinical practice experience in the U.S.
They evaluated weight change in people with HIV who were virologically suppressed and who switched from an INSTI-based regimen containing either abacavir (ABC, Ziagen) or TDF to another INSTI-based regimen containing TAF. Their hypothesis as they embarked upon the study was that weight gain associated with switching to TAF might result from losing the weight-suppressive effect of TDF suggested by some earlier research.
Data for the study were derived from electronic medical records and prescription data from 10 HIV treatment centers that provided care to more than 42,000 people receiving antiretroviral therapy (ART) in the U.S. The study enrolled people living with HIV who were at least 18 years old and were virologically suppressed on ART. Neither the “switch from” regimen nor the “switch to” regimen could include a protease inhibitor (PI) or a NNRTI—this study was all INSTI, all the time.
The statistical analysis compared the two groups in terms of their risk of gaining 3% or more of their body weight, adjusting for age, gender, race, body mass index (BMI), and CD4 count.
Of 970 participants included in the study, 828 (85%) switched from a TDF-containing regimen to a TAF-containing regimen, and 142 (15%) switched from an ABC-containing regimen to a TAF-containing regimen. After a year, people who switched from TDF gained a mean of 1.4 kg, and the people who switched from ABC gained a mean of 0.2 kg (P = 0.039). There was a higher proportion of people who gained 3% or more of their baseline body weight among those who switched from TDF than among those who switched from ABC (40% vs 27%, P = 0.003).
Even after accounting for age, gender, race, baseline body mass index (BMI), CD4 count, and current use of either EVG or the INSTI dolutegravir (DTG, Tivicay), participants were at greater risk of a weight gain of 3% or more of their baseline body weight if they switched from TDF to TAF than if they switched from ABC to TAF.
Moreover, McComsey and colleagues concluded that the results of this study support their hypothesis that people gain weight when they switch from TDF to TAF because TDF has a weight-suppressive effect.
TAF Switch Not Tied to Short-Term Diabetes, Dyslipidemia, or Hypertension
Julia Darnell, Pharm.D., a pharmacy resident at the University of California-San Diego (UCSD), presented a poster summarizing her team’s study on how switching to a TAF-containing regimen affects weight gain, BMI, and metabolic side effects.
Darnell and colleagues conducted a single-center retrospective cohort study based on the clinical experience of people with HIV over the age of 18 who received care at the Owen Clinic, an HIV primary care center in San Diego associated with the UCSD of Medicine. The study compared a case group of 446 people who switched to a TAF-containing regimen to a control group of 162 people who remained on a non-TAF–containing regimen—specifically, abacavir/dolutegravir/lamivudine (brand name: Triumeq). The TAF-containing regimen of those in the case group could be INSTI-based or non-INSTI-based.
For cases, the switch date was considered the baseline; for controls, the date of their first available data within the study period was considered the baseline. Weight and BMI were collected over six-month intervals. Data regarding diagnosis of diabetes mellitus, hypertension, and dyslipidemia were based on participants’ first date of diagnosis using ICD-10 codes. The study also gathered Veterans Aging Cohort Study (VACS) Index scores—a composite of CD4 count, viral load, and general indicators of organ system injury that predicts all-cause mortality, cause-specific mortality, and other health outcomes among people with HIV.
The primary outcome was absolute change in weight at 12 months after switching to TAF; secondary outcomes included percent change in weight, absolute change in BMI after switching to TAF, change in BMI category, and development of diabetes mellitus, dyslipidemia, or hypertension after switching to TAF. Participants were also asked to report on their level of physical activity.
At 12 months, Darnell and colleagues found that the control group was older (average age 54 versus 49 years, P < 0.001), and had a higher proportion of African-American or Black participants (17.9% versus 11.4%, P = 0.04), as well as higher mean VACS Index scores (27 versus 18, P < 0.001). The control group also had fewer participants with reported physical activity (22% versus 30%, P = 0.04), but this finding was driven by a higher proportion of participants in the control group with unknown physical activity.
Overall, participants in the case group exhibited significantly more weight gain compared to those in the control group (2.02 kg versus 0.77 kg, P < 0.001). Increase in weight at 12 months varied depending on the overall composition of the pre-switch regimen:
- Those switching from a non-INSTI regimen to an INSTI-based regimen (n=96) gained a mean of 2.38 kg (95% confidence interval [CI] 1.48–3.27, P = 0.01).
- Those switching from a non-INSTI regimen to another non-INSTI regimen (n=106) gained a mean of 2.89 kg (95% CI 2.02–3.75, P < 0.001).
- Those switching from a TDF-containing regimen (n=362) gained a mean of 2.40 kg (95% CI 1.92–2.87, P < 0.001).
Weight gain among participants in the case group who had been on other pre-switch regimens (including INSTI to INSTI, INSTI to non-INSTI, and no TDF in pre-switch regimen) did not differ significantly from the control group.
There was a higher proportion of participants with increased BMI among those in the case group compared to the control group (18% versus 10%, P = 0.01). The case group had a significant increase in the proportion of patients with hypertension (36% pre-switch versus 44% post-switch, P = 0.02) and hyperlipidemia (8% pre-switch versus 18% post-switch, P < 0.00001), but not diabetes. Among participants in the control group, there was a significant increase in the proportion of those with hyperlipidemia (50% pre-switch versus 68% post-switch, P = 0.01), but not diabetes or hypertension.
Although BMI was higher after 12 months among the case group of people who switched to TAF than the control group, Darnell and colleagues did not find higher rates of diabetes, dyslipidemia, or hypertension in the case group compared to the control group.
B/F/TAF Switch Study: Higher BMI When Prior Regimen Had No INSTI
A poster presented by Daniel T. Vo, M.D., an infectious disease fellow at Washington University in Saint Louis, addressed weight change associated with switching to B/F/TAF, the fixed-dose combination of bictegravir, emtricitabine, and tenofovir alafenamide (sold under the brand name Biktarvy), among 156 people with HIV who were virologically suppressed on a previous regimen.
Among pre-switch regimens, 74% of participants had been on an INSTI-based regimen, 17% on an NNRTI-based regimen, and 16% on a PI-based regimen. The INSTIs used most frequently were elvitegravir (54.3%) and dolutegravir (41.7%).
Of the participants, 28% switched from TDF-containing regimens, and 50% switched from TAF-containing regimens—thus, this was not a study specifically focused on switching from non-TAF to TAF-containing regimens.
The analysis by Vo and colleagues found no significant shift in the mean BMI (P = 0.2) or BMI rate of change over time (P = 0.8) after switching. Of the participants, 19% had an increase in BMI of 10% or more. Compared to those with less than a 10% increase in BMI, factors significantly associated with weight gain among those with a 10% or more increase in BMI included younger age (42.8 versus 48.9 years, P = 0.036), switch from a non-PI based regimen (P = 0.004), and switch from a TDF-containing regimen (36.4% versus 12.6%, P < 0.001).
Importantly, in this study, significant increases in the rate of change of BMI was most evident among those switching from non-INSTI–based regimens; this study had less to say about switching from a non-TAF-containing regimen to a regimen containing TAF.
The issue of weight gain associated with TAF-containing regimens continues to be of concern to people with HIV and their health care providers alike. Future studies will no doubt further elucidate the scope of the problem, as well as explore the factors contributing to TAF-associated weight gain.
For now, it seems, the main takeaway is that TAF is clearly associated with some degree of weight gain in some patients. In addition, these studies all point to the ongoing issue of safety tradeoffs in ART: While regimens become ever more effective and convenient for a greater number of people living with HIV, emerging longer-term safety concerns, including weight gain and metabolic issues, may pose their own set of risks.