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CYP2B6 Genotype and Weight Gain Differences
Between Dolutegravir and Efavirenz
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Rulan Griesel,1,2, Gary Maartens,1,2, Maxwell Chirehwa,1 Simiso Sokhela,3 Godspower Akpomiemie,3 Michelle Moorhouse,3 Francois Venter,3 and Phumla Sinxadi1,2 1Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa, 2Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa, and 3Ezintsha, Wits Reproductive Health and HIV Institute, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
Weight Change Following Antiretroviral Therapy Switch in People With Viral Suppression: Pooled Data from Randomized Clinical Trials - (09/02/21)

Dolutegravir is associated with more weight gain than efavirenz. Loss-of-function polymorphisms in CYP2B6 result in higher efavirenz concentrations, which we hypothesized would impair weight gain among people living with human immunodeficiency virus (HIV; PLWH) starting efavirenz-based antiretroviral therapy (ART).
We studied ART-naive participants from the ADVANCE study randomized to the efavirenz /emtricitabine/tenofovir disoproxil fumarate (TDF) and dolutegravir/emtricitabine/TDF arms. We compared changes in weight and regional fat on DXA from baseline to week 48 between CYP2B6 metabolizer genotypes in the efavirenz arm, and with the dolutegravir arm.
There were 342 participants in the dolutegravir arm and 168 in the efavirenz arm who consented to genotyping. Baseline characteristics were similar. Weight gain was greater in women than men. In the efavirenz arm CYP2B6 metaboliser genotype was associated with weight gain (P = .009), with extensive metabolizers gaining the most weight, and with changes in regional fat in women, but not in men. Weight gain was similar in CYP2B6 extensive metabolizers in the efavirenz arm and in the dolutegravir arm (P = .836). The following variables were independently associated with weight gain in all participants: baseline CD4 count, baseline human immunodeficiency virus type 1 (HIV-1) RNA, and CYP2B6 metaboliser genotype.
CYP2B6 metaboliser genotype was associated with weight gain in PLWH starting efavirenz-based ART. Weight gain was similar between CYP2B6 extensive metabolizers in the efavirenz arm and in the dolutegravir arm, suggesting that impaired weight gain among CYP2B6 slow or intermediate metabolizers could explain the increased weight gain on dolutegravir compared with efavirenz observed in ADVANCE and other studies.
We found that CYP2B6 metaboliser genotype was strongly associated with weight gain over 48 weeks in the efavirenz arm: extensive metabolizers gained the most weight, whereas slow metabolizers lost weight. CYP2B6 extensive metabolizers in the efavirenz arm had similar weight gain to participants in the dolutegravir arm. These findings suggest that the greater weight gain reported on dolutegravir-based ART compared with efavirenz-based ART could be due to impaired weight gain in PLWH with CYP2B6 intermediate or slow metaboliser genotypes, who likely had increased efavirenz concentrations causing toxicity, rather than off target effects of dolutegravir affecting appetite or metabolism. There were striking sex differences in weight changes on ART: women gained more weight than men and CYP2B6 metabolizer genotype was associated with central and peripheral fat changes on DXA over 48 weeks in women but not in men.
Our finding that weight gain was similar in CYP2B6 extensive metabolizers in the efavirenz arm and the dolutegravir arm, with CYP2B6 intermediate and slow metabolizers gaining less weight, are consistent with an observational study of PLWH on efavirenz-based ART switching to InSTI-based ART: CYP2B6 slow and intermediate metabolizers gained more weight than CYP2B6 extensive metabolizers after switching [13]. The large weight gain differences observed between dolutegravir-based ART and efavirenz-based ART observed in the NAMSAL and ADVANCE studies could be explained by the higher prevalence of CYP2B6 slow metabolizers in people of African ancestry [17]. Our finding that baseline CD4 count and HIV-1 RNA were strongly associated with weight gain is in keeping with findings from a pooled analysis of 8 trials in ART-naive participants [1]. Our finding that women gained more weight on ART than men is well established [1, 18]. We also found that the trajectories of weight gain differed by sex, with women gaining weight linearly and men reaching a plateau, which is consistent with an observational cohort study showing that women gained weight linearly over 3.5 years whereas men gained weight linearly over 6–12 months, followed by more gradual weight gain [18].
Rates of virologic suppression were similar in all groups in our study (Supplementary Figure 5), so the weight differences we observed were not due to ART failure. We explored the possibility that impaired weight gain in participants in the efavirenz arm with loss-of-function polymorphisms in CYP2B6 could be explained by an increased incidence of self-reported treatment-emergent gastrointestinal or neuropsychiatric adverse events due to high efavirenz concentrations. Although we found a higher proportion of self-reported nausea and vomiting among CYP2B6 slow metabolizers, none of the selected treatment-emergent adverse events were significantly associated with weight change at week 48 on univariate linear regression.
The association between CYP2B6 metaboliser genotype and fat distribution in women was more marked peripherally (SAT and limb fat) than centrally (VAT and trunk fat). We hypothesize that these differences in regional fat deposition could be due to the mitochondrial toxicity and impaired adipocyte differentiation of efavirenz, both of which are concentration dependent [10, 19]. Efavirenz has deleterious effects on adipogenesis (inhibiting the expression of genes controlling adipogenesis and lipid accretion and reducing the release of adipokines) and increases release of pro-inflammatory cytokines, which are catabolic [10, 20]. Our observation that changes in regional fat by CYP2B6 metaboliser genotype in the efavirenz arm was limited to women could be contributed to by higher efavirenz plasma concentrations in women [21, 22]; larger studies with longer follow-up may show similar findings in men.
Our study had limitations. First, only about half the participants in the efavirenz arm of ADVANCE agreed to genotyping. However, their baseline characteristics were similar to participants who did not agree to genotyping. Second, ours is a post hoc analysis of the ADVANCE study, with no formal sample size calculation to ensure adequate power, which increases the risk of chance findings. Third, our findings were in an African population of ART-naive participants and may not be generalizable to other populations. Fourth, we only had weight data over 48 weeks; longer term data will be important to determine the consequences of weight gain and weight trajectories over a longer period. Fifth, we did not perform CYP2B6 genotyping on participants in the dolutegravir arm to explore potential associations with weight gain. Finally, isoniazid was prescribed as tuberculosis preventive therapy for most participants in ADVANCE for the first 48 weeks. Isoniazid has an inhibitory effect on the metabolism of efavirenz among CYP2B6 slow metabolizers, resulting in about a 50% increase in efavirenz exposure [23, 24], which would accentuate concentration dependent toxicity. Strengths of our study include the randomized trial design of ADVANCE, the use of the same dual nucleoside/nucleotide reverse transcriptase inhibitors in both arms, and the use of DXA to evaluate longitudinal changes in regional fat.
In conclusion, CYP2B6 metaboliser genotype was associated with weight gain among all participants starting efavirenz-based ART and with fat distribution in women but not in men. Our finding that weight gain was similar in CYP2B6 extensive metabolizers in the efavirenz arm and in the dolutegravir arm, together with the finding by Sax et al [1] that newer and safer antiretrovirals are associated with more weight gain than older antiretrovirals, suggests that weight gain on newer ART regimens is a return to health phenomenon rather than off target effects of newer antiretrovirals from different classes on appetite or metabolism.

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