Dolutegravir-based and low-dose efavirenz-based regimen for the initial treatment of HIV-1 infection (NAMSAL): week 96 results from a two-group, multicentre, randomised, open label, phase 3 non-inferiority trial in Cameroon

Calmy, Alexandra; Kouanfack, Charles; Perrineau, Ségolène; Wandji, Martial Lantche; Tata, Darius Tetsa; Bassega, Pierette Omgba; Bwenda, Thérèse Abong; Mercier, Noémie; Lemoing, Vincent; Reynes, Jacques; Sanchez, Tamara Tovar; Mpoudi-Etame, Mireille; Leroy, Sandrine; Lantche-Wandji, M; Tetsa-Tata, D; Omgba-Bassega, P; Abong-Bwenda, T; Varloteaux, Marie; Tongo, Marcel; Mpoudi‐Ngolé, Eitel; Montoyo, Alice; Peeters, Martine; Delaporte, Éric; Ayouba, Ahidjo; Agholeng, A; Butel, Christelle; Cournil, Amandine; Eymard-Duvernay, Sabrina; Granouillac, Bruno; Izard, S.R.; Lacroix, André; Serrano, Laëtitia; Vidal, Nicole; Fouda, P. Bilobi; ., R. Mougnoutou; Olinga, J; Omgba, Vincent; Tchokonte-Ngandé, SC; Ymele, B; Epoupa-Mpacko, CD; Fotso, Marie‐Jeannette; Moukoko, R; Nke, T.; Akamba, A; Lekelem, Skinner; Tongo-Fotack, SB; Ngono, S. A.; Tanga, M.; Ebong, Ewang Abraham; Edoul-Mbesse, G; Ciaffi, Laura; Koulla‐Shiro, Sinata; Manirakiza, G; Mimbé, ED; Boyer, Sylvie; Bousmah, Marwân-al-Qays; Maradan, Gwenaëlle; Nishimwe, ML; Spire, Bruno; Lê, M.P.; Peytavin, Gilles; Diallo, Alpha; Fournier, Isabelle; Rekacewicz, Claire; Casas, Carmen Pérez

doi:10.1016/s2352-3018(20)30238-1

Cited by 115 publications

(114 citation statements)

References 23 publications

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“…A large proportion of this gain is due to a return to good health; patients with a low CD4 and a high viral load gain the most weight during the first two years of ART. Nevertheless, this weight/fat mass gain is excessive in some individuals taking an INSTI [mainly dolutegravir (DTG) and bictegravir], especially in women (vs. men) and African ethnic groups (vs. Caucasians) (120,121). Weight gain is also observed in some ART-controlled patients who switch to an INSTI; female sex and older age are risk factors for this increase.…”

Section: Art-related Changes In Fat With Combinations Of Today's Arvs Descriptionmentioning

confidence: 99%

Contribution of Adipose Tissue to the Chronic Immune Activation and Inflammation Associated With HIV Infection and Its Treatment

et al. 2021

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White adipose tissue (AT) contributes significantly to inflammation – especially in the context of obesity. Several of AT’s intrinsic features favor its key role in local and systemic inflammation: (i) large distribution throughout the body, (ii) major endocrine activity, and (iii) presence of metabolic and immune cells in close proximity. In obesity, the concomitant pro-inflammatory signals produced by immune cells, adipocytes and adipose stem cells help to drive local inflammation in a vicious circle. Although the secretion of adipokines by AT is a prime contributor to systemic inflammation, the lipotoxicity associated with AT dysfunction might also be involved and could affect distant organs. In HIV-infected patients, the AT is targeted by both HIV infection and antiretroviral therapy (ART). During the primary phase of infection, the virus targets AT directly (by infecting AT CD4 T cells) and indirectly (via viral protein release, inflammatory signals, and gut disruption). The initiation of ART drastically changes the picture: ART reduces viral load, restores (at least partially) the CD4 T cell count, and dampens inflammatory processes on the whole-body level but also within the AT. However, ART induces AT dysfunction and metabolic side effects, which are highly dependent on the individual molecules and the combination used. First generation thymidine reverse transcriptase inhibitors predominantly target mitochondrial DNA and induce oxidative stress and adipocyte death. Protease inhibitors predominantly affect metabolic pathways (affecting adipogenesis and adipocyte homeostasis) resulting in insulin resistance. Recently marketed integrase strand transfer inhibitors induce both adipocyte adipogenesis, hypertrophy and fibrosis. It is challenging to distinguish between the respective effects of viral persistence, persistent immune defects and ART toxicity on the inflammatory profile present in ART-controlled HIV-infected patients. The host metabolic status, the size of the pre-established viral reservoir, the quality of the immune restoration, and the natural ageing with associated comorbidities may mitigate and/or reinforce the contribution of antiretrovirals (ARVs) toxicity to the development of low-grade inflammation in HIV-infected patients. Protecting AT functions appears highly relevant in ART-controlled HIV-infected patients. It requires lifestyle habits improvement in the absence of effective anti-inflammatory treatment. Besides, reducing ART toxicities remains a crucial therapeutic goal.

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Section: Art-related Changes In Fat With Combinations Of Today's Arvs Descriptionmentioning

confidence: 99%

Contribution of Adipose Tissue to the Chronic Immune Activation and Inflammation Associated With HIV Infection and Its Treatment

et al. 2021

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“…reported a weight gain of 1.3 kg amongst 198 virologically suppressed PWHIV 1 year after switching to a DTG‐based regimen, 8 while the Swiss HIV Cohort Study reported a weight gain of 0.7 kg/year in a large cohort ( n = 2186) of virologically suppressed PLWH switched to a DTG‐containing regimen 34 . More pronounced weight gain has been observed in studies focusing on antiretroviral‐naïve PWHIV, with values ranging from 4.3 to 7.1 kg, 96 weeks after treatment initiation 9,10 . This initial weight gain has historically been thought of as a return‐to‐health phenomenon 35,36 .…”

Section: Discussionmentioning

confidence: 95%

“…34 More pronounced weight gain has been observed in studies focusing on antiretroviral-naïve PWHIV, with values ranging from 4.3 to 7.1 kg, 96 weeks after treatment initiation. 9,10 This initial weight gain has historically been thought of as a return-to-health phenomenon. 35,36 As all PWHIV were virologically supressed for at least 24 weeks prior to inclusion in this study, it suggests that other mechanisms are implicated in the weight gain described in our population.…”

Section: Discussionmentioning

confidence: 99%

“…low CD4 nadir, high HIV RNA), female sex, African origin, older age and higher weight at baseline with weight gain during follow-up. [4][5][6][7][8][9][10] Furthermore, certain antiretroviral classes have been associated with weight gain. Evidence suggests that integrase strand transfer inhibitors (INSTIs) are associated with a higher risk of weight gain compared to other antiretroviral classes.…”

Section: Introductionmentioning

confidence: 99%

“…A number of recent studies have established a link between HIV disease (e.g. low CD4 nadir, high HIV RNA), female sex, African origin, older age and higher weight at baseline with weight gain during follow‐up 4–10 . Furthermore, certain antiretroviral classes have been associated with weight gain.…”

Section: Introductionmentioning

confidence: 99%

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Pharmacokinetic parameters and weight change in HIV patients newly switched to dolutegravir‐based regimens in SIMPL'HIV clinical trial

Courlet

Barbieux

Sculier

et al. 2021

Brit J Clinical Pharma

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This study aims to evaluate the association between dolutegravir (DTG) pharmacokinetic parameters and weight changes in treatment-experienced people with HIV (PWHIV) from the Simpl'HIV study newly switched to a dual DTG-based regimen.We used multivariable linear regressions to evaluate the association between DTG pharmacokinetic parameters at week 48 (derived using an established model) and weight change between week 0 and week 48. We adjusted our model for potential confounders including CD4 nadir, female sex, African origin, age, weight at week 0 and presence of a non-nucleoside reverse transcriptase inhibitor-based regimen before switch to DTG. The analysis included data from 39 PWHIV. An average significant weight gain of 2.4 kg was observed between baseline and week 48. DTG plasma exposure was not significantly associated with weight gain, even after adjusting for Perrine Courlet and Charlotte Barbieux contributed equally to the work. Laurent Arthur Decosterd and Alexandra Calmy contributed equally.

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Contraception use and HIV outcomes among women initiating dolutegravir‐containing antiretroviral therapy in Kenya: a retrospective cohort study

et al. 2022

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Introduction The rollout of dolutegravir (DTG) in low‐ and middle‐income countries was disrupted by a potential association reported with periconceptional DTG exposure among women living with HIV (WLHIV) and infant neural tube defects. This prompted countries to issue interim guidance limiting DTG use among women of reproductive potential to those on effective contraception. Data to understand the potential impact of such guidance on WLHIV are limited. Methods We conducted a retrospective cohort analysis of WLHIV 15–49 years initiating DTG‐containing antiretroviral treatment (ART) in Kenya from 2017 to 2020. We determined baseline effective (oral, injectable or lactational amenorrhea) and very effective (implant, intrauterine device or female sterilization) contraception use among women who initiated DTG before (Group 1) or during (Group 2) the interim guideline period. We defined incident contraception use in each group as the number of contraceptive methods initiated ≤180 days post‐guideline (Group 1) or post‐DTG initiation (Group 2). We determined the proportions of all women who switched from DTG‐ to non‐nucleoside reverse transcriptase inhibitor (NNRTI)‐ (efavirenz or nevirapine) containing ART ≤12 months post‐DTG initiation, compared their viral suppression (<1000 copies/ml) and conducted multivariable logistic regression to determine factors associated with switching from DTG to NNRTI‐containing ART. Results Among 5155 WLHIV in the analysis (median age 43 years), 89% initiated DTG after transitioning from an NNRTI. Baseline effective and very effective contraception use, respectively, by the group were: Group 1 (12% and 13%) and Group 2 (41% and 35%). Incident contraception use in each group was <5%. Overall, 498 (10%) women switched from DTG to an NNRTI. Viral suppression among those remaining on DTG versus switched to NNRTI was 95% and 96%, respectively (p = 0.63). In multivariable analysis, incident effective and very effective contraception use was not associated with switching. Conclusions Baseline, but not incident, effective contraception use was higher during the interim guideline period compared to before it, suggesting women already using effective contraception were preferentially selected to initiate DTG after the guideline was released. These findings reveal challenges in the implementation of policy which ties antiretroviral access to contraceptive use. Future guidance should capture nuances of contraception decision‐making and support women's agency to make informed decisions.

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Dolutegravir-based and low-dose efavirenz-based regimen for the initial treatment of HIV-1 infection (NAMSAL): week 96 results from a two-group, multicentre, randomised, open label, phase 3 non-inferiority trial in Cameroon

Cited by 115 publications

References 23 publications

Contribution of Adipose Tissue to the Chronic Immune Activation and Inflammation Associated With HIV Infection and Its Treatment

Contribution of Adipose Tissue to the Chronic Immune Activation and Inflammation Associated With HIV Infection and Its Treatment

Pharmacokinetic parameters and weight change in HIV patients newly switched to dolutegravir‐based regimens in SIMPL'HIV clinical trial

Contraception use and HIV outcomes among women initiating dolutegravir‐containing antiretroviral therapy in Kenya: a retrospective cohort study

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