My Take on Recent Data on the Metabolic Implications of Weight Gain Associated With ART

Princy N. Kumar, MD, FIDSA, MACP

Professor of Medicine and Microbiology
Chief,
Division of Infectious Diseases and Travel Medicine
Senior Associate Dean of Students
Georgetown University School of Medicine
Washington, DC


Princy N. Kumar, MD, FIDSA, MACP, has disclosed that she has served on an advisory board/panel or speakers bureau for Amgen, Gilead Sciences, GlaxoSmithKline, Merck, and Theratechnologies; has received grants or research support for Gilead Sciences, GlaxoSmithKline, and Merck; and has ownership interest in Gilead Sciences, GlaxoSmithKline, Merck, Pfizer, and Johnson & Johnson.


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Released: April 14, 2020

Although the COVID-19 pandemic forced the CROI 2020 committee to adopt a virtual meeting format, we were nevertheless able to gain important insights from several excellent presentations with valuable clinical implications. A specific focus of CROI 2020, and one that I would like to focus on here, was weight gain and associated metabolic complications with various ART regimens. I believe the following 3 presentations on this topic were particularly noteworthy.

ADVANCE: Risk of Cardiovascular Disease and Diabetes in Treatment-Naive Patients Initiating Dolutegravir- or Efavirenz-Based ART
ADVANCE was a randomized, open-label phase III noninferiority trial conducted in South Africa that investigated the efficacy and safety of dolutegravir (DTG) plus emtricitabine (FTC)/tenofovir alafenamide (TAF) vs DTG plus FTC/tenofovir disoproxil fumarate (TDF) vs efavirenz (EFV)/FTC/TDF as initial ART. It was previously observed that weight gain was higher for patients initiating DTG-based ART vs EFV/FTC/TDF and that weight gain was higher with TAF vs TDF and in women vs men. The analysis at CROI 2020 compared changes in the prevalence of metabolic syndrome, risk of cardiovascular disease (CVD), and risk of type 2 diabetes mellitus after 96 weeks of initial ART with DTG plus FTC/TAF vs DTG plus FTC/TDF vs EFV/FTC/TDF using standard risk equations.

The data presented confirmed more profound weight gain in the ADVANCE trial for women vs men at 96 weeks. Indeed, treatment-emergent obesity at 96 weeks was observed in 28% of women treated with DTG plus FTC/TAF, 17% treated with DTG plus FTC/TDF, and 12% treated with EFV/FTC/TDF, whereas treatment-emergent obesity at 96 weeks was observed in only 7% of men treated with DTG plus FTC/TAF, 5% treated with DTG plus FTC/TDF, and 3% treated with EFV/FTC/TDF. Moreover, weight continued to increase for women through Week 96.

Expanding on these data, investigators showed that DTG plus FTC/TAF was associated with significantly greater increases in visceral adipose tissue and subcutaneous adipose tissue vs either DTG plus FTC/TDF or EFV/FTC/TDF (visceral adipose tissue: P < .001 vs either arm; subcutaneous adipose tissue: P < .001 vs DTG plus FTC/TDF and P = .006 vs EFV/FTC/TDF), and a significantly higher prevalence of metabolic syndrome vs EFV/FTC/TDF (P = .031) at Week 96. The investigators also observed a significantly greater increase in the estimated 10-year risk of diabetes with DTG plus FTC/TAF vs DTG plus FTC/TDF using the QDIABETES equation. There was no increase in the predicted 10-year risk of myocardial infarction or coronary death using the Framingham Risk Equation. However, the increase in estimated 10-year risk of heart attack or stroke was higher with DTG plus FTC/TAF vs EFV/FTC/TDF (P = .027) according to the QRisk Equation. Taken together, these results show small but statistically significant differences that suggest TAF combined with a second-generation INSTI may have adverse metabolic effects.

ADVANCE Post Hoc Analysis: CYP2B6 Genotype Associated With Differential Weight Gain in ART-Naive Patients Initiating EFV-Based ART in South Africa
In a post hoc analysis of the ADVANCE study, investigators shed additional light on the hypothesis that loss-of-function single-nucleotide polymorphisms in CYP2B6, which are associated with higher EFV plasma concentrations, could impair weight gain in patients with HIV (PWH) receiving EFV-based ART. The results showed that weight gain differences between EFV and DTG were driven by impaired weight gain for patients with loss-of-function single-nucleotide polymorphisms in CYP2B6.

D:A:D: Risk of BMI Changes and CVD
Another study presented at CROI 2020 examined the effect of short-term BMI changes on the incidence of CVD and diabetes in D:A:D participants from 1999 to 2009 who were receiving ART and had at least 2 BMI measurements and at least 1 year of further follow-up from cohort entry. Investigators showed that an increase in BMI across all levels of baseline BMI were consistently associated with an increased risk of diabetes but not CVD.

Implications for Clinical Practice
INSTIs have a proven track record of efficacy and tolerability, both in clinical trials and in real-world experience, and are the preferred initial regimens in both the DHHS and IAS-USA guidelines. However, some clinicians and PWH are concerned about the potential for INSTIs, especially in combination with TAF, to cause weight gain and that this weight gain may not be just a return-to-health phenomenon. The consequences of progressive weight gain on morbidity and mortality has implications for PWH since, in the general population, there is progressively greater mortality as BMI increases above 25. Moreover, obesity is known to be a substantial risk factor for CVD and diabetes.

Until we fully understand the differing effects of various INSTIs and the contribution of the NRTI backbone, specially TAF, we, as clinicians, should obtain the weights of PWH at every visit in a consistent manner and track weights with the same rigor we have applied to HIV-1 RNA and CD4+ cell counts. In addition, counseling on the need for lifestyle changes, including healthier diets, exercise, and the cessation of smoking, should remain important aspects of patient care.

Your Thoughts
How do these results affect your choice of HIV therapy or the way in which you will monitor patients in your clinical practice? Join the discussion by posting a comment.

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