2 studies look at potential weight gain for women taking dolutegravir

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Women with HIV gained significantly more weight in the year after giving birth if they were taking dolutegravir rather than efavirenz, Aidsmap reports two studies in sub-Saharan Africa have found. But one of the studies found that although women gained more weight on dolutegravir, they gained no more weight than HIV-negative women of a similar age, suggesting that efavirenz may limit weight gain.

A third study, also carried out in South Africa, showed that people taking efavirenz who have a genetic predisposition to metabolise the drug slowly, leading to higher blood levels, gained less weight than people who processed efavirenz quickly or people taking dolutegravir.

Weight gain after pregnancy, especially when this weight is not lost in the months or years afterwards, is associated with an increased risk of long-term cardiometabolic changes such as raised glucose levels, type 2 diabetes and raised lipid levels.

In the Tshilo Dikotla observational cohort study in Botswana, researchers at the University of Cape Town and the Wits Reproductive Health and HIV Institute, recruited 122 HIV-negative pregnant women, and pregnant women with HIV who were receiving antiretroviral treatment with either dolutegravir/tenofovir disoproxil fumarate (TDF)/emtricitabine (170) or efavirenz/TDF/emtricitabine (114). The women were followed for 18 months after giving birth.

A second study, DolPHIN-2, carried out by researchers at Northwestern University, Ann & Robert H Lurie Children’s Hospital of Chicago, Harvard TH Chan School of Public Health, Botswana Harvard AIDS Institute Partnership, Botswana Ministry of Health, University of Hawaii and ICAP at Columbia University, in South Africa and Uganda, found that women with HIV who started dolutegravir-based treatment during pregnancy gained more weight postpartum than women taking efavirenz-based treatment.

While the ADVANCE study by researchers at University of Cape Town, Liverpool School of Tropical Medicine, Makerere University, University of Liverpool, Radboud University Medical Centre, Nijmegen and the Desmond Tutu HIV Foundation, compared three regimens, the CYP2B6 sub-study was restricted to participants in the two arms which included tenofovir disoproxil (TDF) in order to reduce confounding. The researchers compared 171 people receiving efavirenz/TDF/emtricitabine who consented to genotyping and 351 people taking dolutegravir/TDF/emtricitabine.

The study investigators suggest that further study of efavirenz’s impact on fat through mitochondrial toxicity is called for (efavirenz is known to cause mitochondrial toxicity in liver cells leading to disruptions in fat storage). They also draw attention to the neuropsychiatric effects of efavirenz on appetite.

Abstract 1
Two African trials reported more weight gain with dolutegravir (DTG) than efavirenz (EFV), especially in women. EFV is toxic to mitochondria and is associated with lipoatrophy. We hypothesised that CYP2B6 metaboliser genotype, which predicts EFV exposure, would determine amount of weight gained and fat distribution in patients starting EFV-based ART.
Participants enrolled in the EFV/TDF/FTC arm of the ADVANCE trial who consented to genetic testing were included. CYP2B6 metaboliser genotype was classified as extensive, intermediate, and slow. Outcomes included change in weight gain and trunk and limb fat on DXA from baseline to week 48 by CYP2B6 genotype. Weight gain was compared between CYP2B6 extensive metabolisers in the EFV/TDF/FTC arm and the DTG/TDF/FTC arm.
171 participants had genetic testing done. CYP2B6 metaboliser genotypes were 51 extensive, 74 intermediate, and 46 slow; median age 32 years (IQR 2837); 57% women; median BMI 23.7 kg/m2 (IQR 20.227.5); and median CD4 count 292 cells/uL (IQR 172406). The percentage change in weight from baseline over 48 weeks differed by CYP2B6 metaboliser genotype (p=0.004; Kruskal-Wallis), but differences were more marked in women over time (see figure). In men CYP2B6 metaboliser genotype was associated with percentage change in weight initially (week 12 p=0.007; week 24 p=0.053), but the effect attenuated over time. The percentage change in limb fat on DXA (n=148) from baseline to 48 weeks differed significantly by CYP2B6 metaboliser genotype in women (p=0.008), with highest percentage increase in extensive metabolisers, but not in men (p=0.680). Percentage change in trunk fat on DXA from baseline to 48 weeks was not significantly different by CYP2B6 metaboliser genotype in women (p=0.082) or men (p=0.732). The percentage change in weight from baseline to 48 weeks was similar between CYP2B6 extensive metabolisers in the EFV/TDF/FTC arm and the DTG/TDF/FTC arm (p=0.939).

In Africans starting EFV-based ART CYP2B6 metaboliser genotype was associated with weight gain and, in women, with changes in limb fat. The similar weight gain observed between CYP2B6 extensive metabolisers in the EFV/TDF/FTC arm and the DTG/TDF/FTC arm suggests off-target effects (e.g. mitochondrial toxicity) impairing weight gain in EFV slow/intermediate metabolisers could explain the greater weight gain observed with DTG in African trials.

Authors
Rulan Griese, Gary Maartens, Simiso Sokhela, Godspower Akpomiemie, Willem D Venter, Michelle A Moorhouse, Phumla Sinxadi

Abstract 2
Postpartum weight retention impacts cardiometabolic risk. Recent studies show higher weight gain with dolutegravir (DTG)-based antiretroviral therapy (ART) compared to other ART. We assessed the association of DTG with postpartum weight over time in women with HIV (WHIV) in Botswana using comparator groups of women on efavirenz (EFV) and HIV-negative (HIV-) women.
The Tshilo Dikotla study enrolled pregnant HIV- women and WHIV on either tenofovir (TDF)/emtricitabine or lamivudine (XTC)/DTG or TDF/XTC/EFV initiated during or before pregnancy. This analysis included women with weight measurements 1 to 18 months postpartum. Mixed models were fit to assess the association between HIV/ART status and postpartum weight over time, adjusting for confounders. Interaction terms between time and HIV/ART group were evaluated to assess for differences in weight trajectories. Subgroup analysis was performed among WHIV to further assess the association of DTG vs EFV and postpartum weight, adjusting for HIV specific factors.

Of 406 women, 170 received DTG and 114 EFV. Women on DTG or EFV were older than HIV- women (median age 28 vs 33 vs 25 years respectively, p<0.01), and fewer had a college education (13.5% vs 4.4% vs 29.5% respectively, p<0.01). Average weight gain per week (wk) between 2nd and 3rd trimester was highest in HIV- women (0.3 vs 0.2 for DTG vs 0.1 kg/wk for EFV, p<0.01) as was breastfeeding duration (35.7 vs. 19.0 for DTG vs. 22.6 wks for EFV, p<0.01). No differences in income, gestational diabetes (GDM), gestational age at delivery, or BMI at 1 month postpartum were noted across groups. Among WHIV, no differences in CD4 or log viral load at enrollment were noted between ART group; more women on EFV were on their ART at conception (86% vs. 35.3%, p<0.01). Compared to HIV- women, WHIV on DTG had similar postpartum weight through 18 months but were on average 5 kg heavier postpartum than WHIV on EFV (=5.0, p<0.01) after adjusting for age, GDM, breastfeeding duration, and weight gain between 2nd and 3rd trimester. (Fig) No differences in slope trajectories were noted between groups. This association persisted in subgroup analysis of WHIV even after further adjusting for CD4, viral load, and ART at conception (=2.4 for DTG vs. EFV, p=0.04).
WHIV on DTG have persistently higher weight through 18 months postpartum than those on EFV in Botswana but similar weight to HIV- women. Further studies to assess mechanisms of postpartum weight retention are needed.

Authors
Jennifer Jao, Shan Sun, Justine Legbedze, Denise Jacobson, Keolebogile N Mmasa, Samuel W Kgole, Gosego Masasa, Joseph Makhema, Sikhulile Moyo

Abstract 3
There are growing concerns about weight gain with dolutegravir (DTG) use, with some suggestion of heterogeneity of effects across populations especially among women. However there are no data from pregnancy and the postpartum (PP) period.

DolPHIN-2 (NCT03249181) is an open label trial randomising (1:1) pregnant women from Uganda and South Africa (SA) initiating ART from 28w gestation to DTG vs efavirenz (EFV) plus 2 NRTIs. Maternal weights were measured using standardized procedures at enrolment, <14 days of delivery and at 6, 12, 24 and 48 weeks PP. For this secondary analysis we examined changes in PP weight and body mass index (BMI) between study arms.
Enrolment took place between Jan and Aug 2018, and follow-up data were censored Sept 2019; 230 women (mean age, 28y) were included with median follow-up of 60 months. At enrolment (median gestation, 31w) the mean weight and BMI was 74 kg and 28 kg/m2, respectively, with no differences between trial arms but higher third trimester weight in SA (mean, 81 kg) versus Ugandan (mean, 68 kg) sites. 73%, 61% and 3% of women reported breastfeeding the infant at 12, 24 and 48w PP, respectively, with no differences by arm. Across both arms and sites, mean change in weight from enrolment to 6w PP was -5.9 kg, with mean weight approximately constant from 6 to 48w PP. However this masked notable inter-site differences. In Uganda, there was a small non-significant decrease in mean weight from 6 to 48w PP that was more marked in the EFV arm (DTG: 63.6 to 63.2 kg; EFV: 60.6 to 59.8 kg; p=0.28). In SA, there was a notable but non-significant increase in mean weight over the same period that was more marked in the DTG arm (DTG: 76.1 to 78.3 kg; EFV: 73.0 to 73.7 kg; p=0.33). After adjusting for site and enrolment weight, the overall mean difference in weight change, 48w-6w PP for DTG-EFV, was 1.00 kg (95% CI -0.98 to 2.97; p=0.32). This difference was larger in SA (1.30 kg; 95% CI -2.21 to 4.80) than in Uganda (0.75 kg; 95% CI -1.48 to 2.97; p for interaction=0.82). Similar findings were observed for BMI throughout.
These randomised data show no differences in PP weight changes between DTG and EFV in women initiating ART late in pregnancy. Substantial PP weight gain among SA women points to potential heterogene
ity across populations that requires further investigation.

Authors
Thokozile R Malaba, Tao Chen, Kenneth Kintu, Christiana Papamichael, Helen Reynolds, J
esca Nakibuka, Catriona Waitt, Eva Maria Hodel, Angela Colbers

Full Aidsmap report

CROI 2020 abstract 1

CROI 2020 abstract 2

CROI 2020 abstract 3

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