Weight/fat gain is reported in integrase strand transfer inhibitors (INSTI)-exposed patients, raising concerns on possible deleterious clinical outcomes [1,2]. An increased incidence of obesity was observed in antiretroviral therapy (ART)-naïve young Black-African patients living with HIV (PLWH) who initiated dolutegravir than in those who initiated an efavirenz-based treatment with higher weight gain in women than men . In switch situations of ART-controlled PLWH, not all retrospective studies, including mainly men and white subjects, reported weight gain with INSTI [4,5]. Nevertheless, women and persons over 50 years experienced greater weight gain after vs. before switch to an INSTI . In the Women's Interagency HIV Study (WIHS), women who switched to or added an INSTI to ART experienced greater increase in body weight compared with women who did not .
The 96-week ANRS 163 ETRAL study (NCT02212379) evaluating the efficacy and safety of raltegravir (400 mg twice-daily)/etravirine (200 mg twice-daily) in individuals over 45 years on a protease inhibitor-containing regimen, demonstrated durable efficacy . We analyzed evolution of weight/fat and insulin sensitivity according to sex, and, in women, according to ovarian activity (n = 40, detectable level of the anti-Müllerian hormone, AMH, ELISA, Beckman-Coulter)  and menopausal status (12-month spontaneous amenorrhea). Body composition (total, trunk and limb mass, lean body mass) was measured using dual X-ray absorptiometry as previously published . Insulin sensitivity was evaluated by the HOmeostasis Model Assessment of Insulin Resistance (HOMA-IR) index, sex steroids by mass spectrometry .
Baseline values and percentage changes from baseline were compared between groups using Mann–Whitney and Kruskal–Wallis tests and Wilcoxon paired test for the change within group. Correlation between parameters used the Spearman test. Chi2 test was performed to compare categorical variables between groups.
There was no baseline difference between men (n = 117) and women (n = 48) in terms of personal and HIV-related parameters, except for race (35% Black-African women vs. 6% men) and CD8+ cell count (Supplemental Digital Content-1, http://links.lww.com/QAD/B795).
At baseline, BMI did not differ between men and women and increased similarly at 48 and 96 weeks, with a 1.5 and 2.8% increase in men (P < 0.0001) and a 1.6 and 1.8% increase in women (P = 0.04 and 0.01), respectively (Table 1). Both men and women experienced increases in total, trunk and limb fat. Fat gain affected both peripheral (limbs) and central (trunk, waist, hip) areas.
AMH was detectable in 12 women, indicating functional ovarian activity (group 1, 46 years), six nonmenopausal women had undetectable AMH (perimenopausal, group 2, 47 years) and 22 were postmenopausal (group 3, 54 years). Evolution of BMI, total and trunk fat differed between the three groups (Table 1) with no variation in group 1, contrasting with increased BMI, total and trunk fat in the perimenopausal and postmenopausal groups leading to homogeneous fat gain. BMI variation did not differ between white and Black-African women.
Regarding the level of the main sexual steroids at baseline and 48 weeks (Supplemental Digital Content-2, http://links.lww.com/QAD/B795), estrogen and progesterone levels markedly differed, as expected, between groups. Conversely, there was no difference in the levels of testosterone, Δ-4-androstenedione and dehydroepiandrosterone between groups at baseline and 48 weeks, and no association with BMI changes.
The variation in BMI was negatively associated with the AMH level at 48 weeks (R = −0.361, P = 0.02) with the same trend at baseline (R = −0.274, P = 0.08); 75% of women with detectable AMH at 48 weeks had stable or decreased BMI. Conversely, 71% of peri/postmenopausal women had increased BMI (Chi2P = 0.0065). The results obtained with baseline AMH were almost similar. This suggests that functional ovarian activity could protect against raltegravir/etravirine-induced weight gain.
HOMA-IR did not differ between men and women at baseline and increased at 48 weeks in men and in peri/postmenopausal women and at 96 weeks in men.
BMI and HOMA-IR variations between baseline and 96 weeks were corelated both in men (R = 0.348, P < 0.001) and women (R = 0.413, P = 0.004), in favor of increased insulin resistance partly resulting from weight gain.
We observed here that men increased weight/fat after switching to raltegravir/etravirine. This weight variation appears different from that related to aging in PLWH. In the Multicenter AIDS Cohort Study , BMI steadily increased between 40 and 60 years by 0.05 kg/m2/year (0.2%/year) and stabilized over 60 years, far less than the 1.5%/year observed in ETRAL men. While initiation of INSTI has been associated with weight gain in men , most studies on patient switched to INSTI were retrospective and report no or a mild weight gain [4–6] contrasting with the ETRAL results.
Women from the general population experience progressive fat mass increase with chronological aging, whereas changes in body composition with central fat distribution are primarily due to ovarian aging, reflected by the AMH level . However, PLWH from the WIHS aged 40–60 years undergoing the menopausal transition increased steadily annually their BMI by 0.06 kg/m2/year (0.2%) . The rate of fat gain was not increased during/after menopause by contrast to HIV-negative women who experienced increased BMI and waist circumference . In our study, postmenopausal women experienced an 2.1% increased BMI and 6.5% increased waist circumference after 96 weeks, far more than expected according to the data from the WIHS , further stressing for a global weight/fat gain related to raltegravir/etravirine, in addition to the hormonal status. Accordingly, specific weight gain related to switching to an INSTI has been reported in white and Black women from the AIDS Clinical Trials Group A5001/A5233 studies more than 50 years but not less than 40 years . In the WIHS , INSTI-treated women experienced a 2.4-kg increased body weight vs. 0.2 kg in the group receiving conventional ART. Weight gain was higher for women more than 50 years, again stressing for a possible role of the menopausal status in women switched to an INSTI. This contrasts with the INSTI-induced weight gain observed in young women initiating ART . This discrepancy remains to be addressed. Regarding ethnicity, we did not find differences between white or Black-African women, as observed in the ACTG follow-up study . Discrepant results have been reported regarding variations in insulin resistance after switching to an INSTI, with raltegravir either decreasing (SPIRAL) or increasing (ETRAL) insulin resistance.
Limitations are the single-arm design of study and the relatively small number of women included. Modifications in the dietary habits or exercise levels were not recorded.
Overall, men and women gained weight/fat when receiving raltegravir/etravirine. However, these changes differed markedly according to the women's hormonal status Functional ovarian activity prevented fat gain or higher insulin resistance. These findings might be important for the clinical management of these women.
C.R., S.F., J.-P.B., A.L. and D.F. have performed all the assays presented in this article and participated to their analysis. L.B. and L.A. have monitored the ETRAL study. L.A., D.C. and J.C. have performed the analysis of the data. C.K. has participated to the study as the PI of the ETRAL study. J.C., L.A. and D.C. have written the grant proposition. S.G. has reviewed all the legal and funding aspects. C.R. and B.F. have reviewed all the endocrine aspects. J.C. has written the first draft, B.F. and C.K. have participated to the redaction and all the authors have participated to the correction of the article.
Conflicts of interest
D.C. has received grants from MSD and Janssen and personal fees for lectures from Merck Switzerland, MSD, Gilead and Janssen; J.C. has received grants from ViiV healthcare and MSD, and personal fees for lectures from ViiV healthcare, MSD, Gilead, Janssen. For the remaining authors none were declared: The ANRS 163 ETRAL study was sponsored and funded by the French National Institute for Health and Medical Research (INSERM)–French National Agency for Research on AIDS and Viral Hepatitis (ANRS); the ETRAL study was also supported by MSD and Janssen. This study received a grant from MSD.
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