A growing body of evidence continues to show that people who use the integrase inhibitor dolutegravir are more likely to gain weight after starting treatment, with the effect greater for women and hence a detrimental effect on pregnancy outcomes at the population level, according to reports presented last month at the International AIDS Conference (AIDS 2020:Virtual), reports POZ.
Weight gain after starting antiretroviral treatment has become a concern in recent years. People with advanced immune suppression and opportunistic illnesses often gain weight as they return to health after starting treatment, and some people with HIV develop lipohypertrophy, a specific type of weight gain that often involves accumulation of internal abdominal fat. But the weight gain that occurs among people who start treatment with modern antiretrovirals before they sustain serious immune system damage appears to be a different phenomenon.
Although weight gain can occur after starting any class of antiretroviral drug, it has most frequently been reported among those taking potent integrase inhibitors, including dolutegravir (Tivicay, also in the Triumeq, Juluca and Dovato coformulations), and tenofovir alafenamide (TAF), the newer version of the drug in Descovy and several other combination pills.
At AIDS 2020, Dr Julie Ake, of the US Military HIV Research Programme, presented findings from a study of weight gain and hyperglycaemia (high blood glucose) during the transition to dolutegravir in Africa.
Dolutegravir is one of the most effective antiretrovirals, and US and World Health Organisation guidelines recommend it for first-line treatment. The US President’s Emergency Plan for AIDS Relief (PEPFAR) has adopted dolutegravir, tenofovir disoproxil fumarate (TDF, the older version of the drug) and lamivudine as the preferred regimen for its funded global programmes.
The African Cohort Study (AFRICOS) enrolled nearly 2,000 HIV-positive participants between January 2013 and November 2019 at 12 PEPFAR-supported clinics in Kenya, Nigeria, Tanzania and Uganda.
Other studies presented at the conference also saw a link between dolutegravir and weight gain.
Dr Simiso Sokhela, of the University of the Witwatersrand in Johannesburg, reported the latest findings from the ADVANCE study, a large randomised trial that compared first-line treatment using dolutegravir/TAF/emtricitabine, dolutegravir/TDF/lamivudine or efavirenz/TDF/emtricitabine (the drugs in Atripla). The study enrolled more than 1,000 participants in South Africa. Almost all were Black, about 60% were women and the average age was 32.
Another research group performed a systematic review of adverse pregnancy outcomes related to obesity in an effort to estimate the impact of antiretroviral treatment. Based on the ADVANCE results, they calculated that for every 1,000 pregnant women, 140 of those treated with dolutegravir/TAF/emtricitabine and 80 of those treated with dolutegravir/TDF/emtricitabine for 96 weeks would develop obesity.
Taken together, these studies confirm prior research linking dolutegravir and weight gain, especially among women. Treatment-associated weight gain is still poorly understood – experts do not yet know what causes it or how best to manage it – but this is an active area of research, as overweight and obesity raise the risk of cardiovascular disease, diabetes and other health problems.
Abstract
Background: Clinical trials demonstrated weight gain upon initiation of dolutegravir-based regimens in sub-Saharan Africa, and reports of hyperglycemia have emerged during the programmatic rollout of TLD (tenofovir disoproxil fumarate/lamivudine/dolutegravir). We systematically examined the incidence of these conditions in the care and treatment setting.
Methods: The African Cohort Study (AFRICOS) enrolled HIV-infected and uninfected participants at twelve PEPFAR-supported clinics in Uganda, Kenya, Tanzania and Nigeria. BMI was assessed six-monthly and glucose annually. Overweight/obese was defined as BMI > 25 kg/m2. Hyperglycemia was defined as fasting glucose>99, any glucose >199 or taking hypoglycemic medication. Incidence rates of becoming overweight/obese and developing hyperglycemia were calculated overall and by HIV status and treatment groups. Among HIV-infected participants without the conditions of interest upon enrollment, Cox proportional hazards models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for TLD use and other potential risk factors for weight gain and hyperglycemia.
Results: From January 2013-November 2019, 3,514 participants were enrolled including 2,043 (58%) females and 2,927 (83%) living with HIV with median age 38 (Interquartile range 31-46) years. Incidence for becoming overweight/obese was 72.33 (CI 66.22-78.99) cases/1,000PY overall (n=2,545) and 98.6 (CI 63.6-152.8) cases/1,000PY among participants on TLD (n=528). Hyperglycemia incidence was 52.01 (CI 47.28-57.21) cases/1,000PY overall (n=3,045) and 121.30 (CI 71.84-204.82) cases/1,000PY among participants on TLD (n=373). For each condition, those taking TLD consistently demonstrated the highest incidence across sites, ART naïve participants had the lowest incidence, and the geographically highest rates were observed in Nigeria. In time-to-event analysis, 436 participants became overweight/obese and 380 developed hyperglycemia. Those taking TLD had increased rates of becoming overweight/obese compared to those taking non-TLD ART (HR 2.73; CI 1.67-4.48) after adjusting for site, gender, age and depression. While participants on TLD had an increased HR compared those on non-TLD ART in the unadjusted model (1.81; CI 1.04-3.14), this difference was not statistically significant (HR 1.12; CI 0.65-1.93) after adjustment for site, gender, age and enrollment BMI.
Conclusions: TLD use was associated with increased incidence of weight gain and hyperglycemia in this cohort. We observed regional differences in both conditions and an independent effect of TLD on becoming overweight/obese.
Authors
Julie Ake
Abstract 2
Background: In low- and middle-income countries, most treatment-naïve people living with HIV (PLWH) take tenofovir disoproxil fumarate (TDF) with emtricitabine FTC (or lamivudine (3TC)) and efavirenz (EFV). Dolutegravir (DTG) and tenofovir alafenamide (TAF) are recommended in international guidelines, but clinical experience with these ARVs in sub-Saharan Africa is limited. In South Africa, over 10% of patients have transmitted NNRTI drug resistance.
Methods: We conducted a 96-week, open-label randomised trial in South Africa, comparing TAF/FTC+DTG, TDF/FTC+DTG and TDF/FTC/EFV. Inclusion criteria included age '¥12 years, no prior ART >30 days, creatinine clearance >60 mL/min (>80 mL/min if <19 years), and HIV-1 RNA >500 copies/mL. Pregnancy and tuberculosis (TB) were exclusion criteria. There was no screening for baseline drug resistance, consistent with South African treatment guidelines. The primary treatment failure endpoint was 96-week HIV-1 RNA >50 copies/mL, discontinuation or missing data (Intent-to-treat population, non-inferiority margin -10%, significance level p=0.017, adjusted for multiple comparisons). We report 96-week efficacy and safety data.
Results: We randomised 1053 PLWH between February 2017 and May 2018: 99% black, 59% female, mean age 32 years, with mean CD4 336 cells/uL. At week 96, the percentage of participants with HIV RNA <50 copies/mL was 78.6% for TAF/FTC+DTG, 78.3% for TDF/FTC+DTG and 73.5% for TDF/FTC/EFV. In the on-treatment analysis, 96% of participants on TAF/FTC+DTG, 95.7% on TDF/FTC+DTG and 95.5% on TDF/FTC/EFV had HIV RNA <50 copies/mL at Week 96. Both DTG arms demonstrated non-inferior efficacy versus the EFV arm. Overall, 206/244 (84%) of treatment failures were from discontinuation. Clinical adverse events and laboratory abnormalities were similar between treatment arms.
Conclusions: In the ADVANCE study, TAF/FTC+DTG and TDF/FTC+DTG demonstrated non-inferior efficacy versus TDF/FTC/EFV, with low rates of virologic failure in all three arms despite country-level background NRTI/NNRTI resistance.
Authors
Simiso mandisa Sokhela
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[link url="https://cattendee.abstractsonline.com/meeting/9289/Presentation/83"]AIDS 2020 abstract[/link]
[link url="https://cattendee.abstractsonline.com/meeting/9289/presentation/3498"]AIDS 2020 abstract[/link]