Switch to dolutegravir raises the risk of potentially harmful weight gain, four-country African study finds

Image: World Obesity Federation

People taking dolutegravir-based antiretroviral treatment have a substantially higher risk of becoming overweight or obese compared to other people with HIV and almost one in ten put on enough weight to be classified as overweight or obese, a prospective study in four African countries has shown.

The findings were presented at the 23rd International AIDS Conference (AIDS 2020: Virtual) by Dr Julie Ake of the US Military HIV Research Program at Walter Reed Army Institute of Research.

A study of adolescents switching to dolutegravir from another antiretroviral regimen in Eswatini also showed greater odds of weight gain as time on the drug increased, but researchers cautioned that more research is needed with adolescents with HIV before drawing conclusions.

Dolutegravir transition and weight gain in sub-Saharan Africa

The World Health Organization recommended dolutegravir-based treatment as its preferred option in 2017 and strongly recommended it for all adults in 2019, encouraging all countries to update their guidelines and transition to dolutegravir-based treatment as quickly as possible.

Dolutegravir-based treatment has the potential to be cost-saving, better tolerated – leading to better retention in care – and more potent, meaning that fewer people will need to switch to more costly second-line regimens.

PEPFAR committed to transitioning to a single regimen of tenofovir, lamivudine and dolutegravir during 2019 in all its funded programmes. Although this process was somewhat delayed due to concerns in some countries regarding a raised risk of neural tube defects associated with dolutegravir, the transition has been largely achieved.

Substantial weight gain has been observed in two large clinical trials in Africa in people taking dolutegravir. For example, the ADVANCE study showed that weight gain was greater in women and greatest in women taking dolutegravir with tenofovir alafenamide. Weight gain may place people with HIV at higher risk of cardiovascular disease, diabetes and high blood pressure.

To monitor the impact of introducing dolutegravir on weight in routine clinical care, the investigators enrolled people with HIV at 12 PEPFAR-supported treatment sites in Kenya, Nigeria, Tanzania and Uganda.

The study compared 742 people who began treatment with tenofovir, lamivudine and dolutegravir with 1212 people who had not started antiretroviral therapy or who received a non-dolutegravir antiretroviral regimen.

Investigators analysed the incidence of body mass index (BMI) of 25 kg/m2 or above during follow-up and the risk of weight gain leading to a BMI above 25, which indicates that the person is overweight or obese. They also analysed the development of hyperglycaemia (high blood sugar) (fasting glucose > 99 mg/dL, any glucose > 199 mg/dL or hypoglycaemic medication), as changes in metabolism have been proposed as a cause of weight gain and observed in some populations after starting antiretroviral treatment.

Owing to restrictions on the use of dolutegravir by women of child-bearing potential due to concerns about neural tube defects, men and older people were significantly more likely to be taking dolutegravir than women or younger people (both p < 0.001). Dolutegravir recipients were more likely to report depressive symptoms (p = 0.030), to have CD4 counts above 200 cells (p < 0.001) and to have a viral load below 1000 copies/ml (p < 0.001).

People took dolutegravir for a median of 255 days and during the follow-up period, 451 participants became overweight or obese. The incidence of overweight or obesity was 72 cases per 1000 people overall and 98 cases per 1000 people in dolutegravir recipients.

After adjusting for study site, gender, age, and depression, people who were prescribed dolutegravir had an 85% higher rate of becoming overweight or obese than people taking a non-dolutegravir regimen (hazard ratio 1.85, 95% CI 1.24-2.76). People not taking antiretroviral treatment had a 55% lower rate of becoming overweight or obese compared to participants on a non-dolutegravir regimen (HR 0.45, 95% CI 0.28-0.74).

Hyperglycaemia developed more frequently in people taking antiretroviral therapy but the analysis did not show an increased risk in people taking dolutegravir. Untreated people with HIV were at almost 80% lower risk of developing hyperglycaemia (HR 0.22, 95% CI 0.12-0.43).

Adolescent weight gain after switching to dolutegravir

Adolescents form a growing proportion of those receiving antiretroviral treatment in sub-Saharan Africa but there has been no information about weight patterns after starting antiretroviral treatment.

Weight gain was observed in a cohort of 605 adolescents aged 10-19 switching to dolutegravir at the Baylor Children’s Foundation clinic in Mbabane, Eswatini. All had been in care for at least a year and had suppressed viral load (< 200 copies/ml).

Glossary

body mass index (BMI)

Body mass index, or BMI, is a measure of body size. It combines a person's weight with their height. The BMI gives an idea of whether a person has the correct weight for their height. Below 18.5 is considered underweight; between 18.5 and 25 is normal; between 25 and 30 is overweight; and over 30 is obese. Many BMI calculators can be found on the internet.

hyperglycaemia

An excess of glucose (sugar) in the bloodstream. It may occur in a variety of diseases, including diabetes, due to insufficient insulin in the blood and excessive intake of carbohydrates.

prospective study

A type of longitudinal study in which people join the study and information is then collected on them for several weeks, months or years. 

retention in care

A patient’s regular and ongoing engagement with medical care at a health care facility. 

glucose

A simple form of sugar found in the bloodstream. All sugars and starches are converted into glucose before they are absorbed. Cells use glucose as a source of energy. People with a constant high glucose level might have a disease called diabetes.

The cohort was evenly balanced between male and female patients. Thirty per cent were aged 10-12 years, 46% aged 13-16 years and 24% 17-19 years. The majority were switching from nevirapine (73%) and the remainder from efavirenz (27%). Tenofovir/lamivudine was used as the backbone with dolutegravir by 88% of participants; the remainder used abacavir/lamivudine (12%).

After switching to dolutegravir, boys gained an average of 0.64kg/m2 in body mass per year and girls gained an average of 0.55kg/m2. Adjusting for other covariates, adolescents taking tenofovir/lamivudine/dolutegravir had a BMI 0.660 kg/m2 higher, on average, than those taking abacavir/lamivudine/dolutegravir (p < 0.001). Females had a BMI 1.371 kg/m2 higher, on average, than males (p < 0.001).

After switching to dolutegravir the odds of becoming overweight or obese increased by approximately 1% every day. This rate of increase was largely explained by greater body mass index change in adolescents who were categorised as thin prior to dolutegravir initiation. In the light of this finding, the increased risk of becoming overweight in adolescents needs to be interpreted cautiously, the investigators say. Further research is needed on risk factors for becoming overweight or obese after starting dolutegravir in adolescents.

References

Ake J et al. Weight gain and hyperglycemia during the dolutegravir transition in Africa. 23rd International AIDS Conference, abstract 3328, 2020.

Kay A et al. Optimization to dolutegravir-based ART in a cohort of virally suppressed adolescents is associated with an increase in the rate of BMI change and odds of becoming overweight. 23rd International AIDS Conference, abstract 8794, 2020.