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Weight and metabolic changes after switching from tenofovir alafenamide (TAF)/emtricitabine (FTC)+dolutegravir (DTG), tenofovir disoproxil fumarate (TDF)/FTC+DTG and TDF/FTC/efavirenz (EFV) to TDF/lamivudine (3TC)/DTG
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Download the PDF here
CID, 15 December 2022
from Jules: what about kidney & bone function changes that might result from switching to TDF ?
Bronwyn Bosch (1), Godspower Akpomiemie (1), Nomathemba Chandiwana (1), Simiso Sokhela (1), Andrew Hill (2), Kaitlyn McCann (3), Ambar Qavi (3), Manya Mirchandani (3), Willem Daniel Francois Venter (1)
1Ezintsha, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.; 2Department of Pharmacology and Therapeutics, University of Liverpool, United Kingdom; 3Faculty of Medicine, Imperial College, London, UK
CHARACTERISE enrolled residents of inner-city Johannesburg from July-November 2022 who had previously been part of ADVANCE and were not pregnant at the time of screening.
Abstract
Participants randomised to first-line tenofovir alafenamide (TAF)/emtricitabine (FTC)+dolutegravir (DTG), tenofovir disoproxil fumarate (TDF)/FTC+DTG or TDF/FTC/efavirenz (EFV) for 192 weeks were then switched to TDF/lamivudine (3TC)/DTG for 52 weeks. Participants switching either TAF/FTC+DTG or TDF/FTC/EFV to TDF/3TC/DTG showed statistically significant reductions in weight, low density lipoprotein, triglycerides, glucose and glycated haemoglobin.
Weight
For women switching from TAF/FTC+DTG to TDF/3TC/DTG after week 192, there was a statistically significant reduction in weight (median: -1.6kg, p=0.0125). This change in weight was not significant in men (median: -0.2kg, p=0.2561). There was a statistically significant reduction in BMI for women (median: -0.57 kg/m2, p=0.0106) but not men (median: -0.08, p=0.2473).
Participants switching from TDF/FTC/EFV to TDF/3TC/DTG, showed a significant increase in body weight (median: +2.9, p=0.02) and BMI (median: +1.01, p=0.0225). This change in weight was significant for the subset of men (median: +2.3, p=0.0464) but not women (median: +2.9, p=0.1127).
For participants in the TDF/FTC+DTG arm switching to TDF/3TC/DTG, there was no significant change in weight and BMI for either women or men.
Lipids, glucose, blood pressure and hba1c
Participants switching from TAF/FTC+DTG to TDF/3TC/DTG after week 192 showed significant reductions in total cholesterol (p=0.0018), LDL (p<0.001), triglycerides (p=0.0254), glucose (p=0.0003) and HbA1C (p=0.0004). The reduction in HDL and increase in systolic and diastolic blood pressure was not significant. Participants switching from TDF/FTC/EFV to TDF/3TC/DTG showed significant decreases in total cholesterol (p=0.0113), LDL (p=0.0012), HDL (p=0.0495), triglycerides (p=0.0575) and HbA1C (p=0.0082). The reduction in glucose and increase in systolic and diastolic blood pressure was not significant. For participants switching from TDF/FTC+DTG to TDF/3TC/DTG, there was a significant increase in total cholesterol (p=0.0009), HDL (p=0.0209) and systolic blood pressure (p=0.0206). However, changes in LDL, triglycerides, glucose, HbA1C and diastolic blood pressure were not significant.
DISCUSSION
Millions of PLWH worldwide have switched from TDF/3TC/EFV or similar regimens, to TDF/3TC/DTG in the last five years. In the CHARACTERISE study, participants who switched from TDF/FTC/EFV to TDF/3TC/DTG gained a median 2.9kg. We also saw small improvements in LDL cholesterol, triglycerides, fasting glucose and HbA1C during the switches from TDF/FTC/EFV to TDF/3TC/DTG. Again, this change is expected, given the previously described metabolic effects of EFV [4].
Women who switched from TAF/FTC+DTG to TDF/3TC/DTG lost a median 1.6kg, and overall, this cohort had a slightly improved glucose and lipid profile. The results from CHARACTERISE are consistent with those seen in other observational studies from Finland and Germany in 292 and 385 participants, respectively [10, 11]. With weight gain persisting as a potentially major health complication with the use of all modern ART, risks for the development of long-term cardiac disorders remain of concern. A previously published analysis on the 5- and 10-year risks of cardiovascular disease (CVD) and diabetes was conducted on the same ADVANCE population at week 96 and demonstrated that participants on the TAF/FTC+DTG regimen had significantly greater risk scores for development of CVD or diabetes, driven by weight gain, in comparison to the TDF-containing groups [12]. A switch from TAF to TDF may be clinically justified in patients, especially women experiencing weight gain and those with glucose or lipid disorders, although it is unclear whether this weight loss will be maintained, or whether other weight loss measures will be required.
Limitations of the CHARACTERISE study include the open-label design and the relatively small sample size: only 16% of the original 1053 participants participated in the trial extension, so the statistical power to evaluate effects of switching in women and men is limited. There was low participation by men, reflective of attrition to HIV care of men in HIV programmes. There is potential for selection bias in those who chose to participate in CHARACTERISE versus those who did not. The trial was conducted in inner-city Johannesburg, with participants coming from across the region and recruited from routine patient care, factors which strengthen the generalisability of the study. This trial was also conducted in a region of highest global genetic diversity. However, this study should be repeated in Asian, Hispanic and Caucasian populations.
Current WHO recommendations for TDF/3TC/DTG as the preferred first-line regimen appear to be further substantiated by our study and are very reassuring for the participants switched from EFV-based regimens. Ultimately, countries such as Botswana that are moving away from TDF/3TC/DTG in favour of TAF/FTC+DTG, may want to consider preservation of TDF-containing regimens as an option for patients with ongoing, significant weight gain and metabolic disease, sadly a significant proportion, of this population.
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