Greater weight gain in pregnancy linked to TAF-and-integrase inhibitor combinations

Women with HIV were more likely to experience excessive weight gain during pregnancy if they took an antiretroviral combination containing both tenofovir alafenamide and an integrase inhibitor, a study in the United States has found.

The study also found that treatment containing the old formulation of tenofovir, known as tenofovir disoproxil (TDF) may have a reduced risk of excessive weight gain during pregnancy. The findings add to the body of evidence suggesting that TDF suppresses weight gain in people taking antiretroviral therapy and pre-exposure prophylaxis.

Most people who start antiretroviral treatment gain weight in the first year, but some people gain more than others. People with low CD4 counts and high viral load tend to gain more, most likely because of a ‘return to health’ effect. But studies have also shown that some combinations of antiretroviral drugs are associated with greater weight gain, notably integrase inhibitors coupled with tenofovir alafenamide.

Substantial weight gain can increase the risk of diabetes, heart disease and some cancers.

Weight gain is a normal feature of pregnancy and for most women it does no harm. But for a minority of women who experience excessive weight gain, it raises the risk of complications of pregnancy including high blood pressure, pre-eclampsia and gestational diabetes. In turn, these maternal complications raise the risk of stillbirth and premature delivery.

Researchers at Emory University in Atlanta looked at weight gain during pregnancy according to antiretroviral regimen in women with HIV receiving treatment at Grady Memorial Hospital in Atlanta between 2011 and 2019. The retrospective analysis identified 303 women with at least six prenatal visits and who were adherent to antiretroviral treatment during their pregnancy.

The women were predominantly Black and non-Hispanic (80%) with a median age of 28 years at the time of their pregnancy. Seventy-five percent had given birth at least once before. The majority were classified as either overweight (26%) or obese (40%) prior to the pregnancy evaluated in this study.

Almost half (47%) did not begin antiretroviral treatment until after conception and half did not begin pre-natal care until after the first trimester of pregnancy.

Of the 303 women who took antiretroviral treatment during pregnancy, 38 took an integrase inhibitor and tenofovir alafenamide and 51 took an integrase inhibitor without tenofovir alafenamide. Just under half (149) took tenofovir disoproxil (TDF), the older formulation of tenofovir. There were no significant differences between the treatment groups except that women who initiated treatment after conception were less likely to take TDF (p<0.001).

Forty percent of women had an undetectable viral load at the first prenatal visit and 81% had a CD4 count above 200 (40% above 500).

Weight gain during pregnancy is known as gestational weight gain. Excessive gestational weight gain is defined according to body mass index – for a woman with a BMI less than 25 (normal weight), weight gain of more than 16kg is defined as excessive by the US Institute of Medicine. For women with a BMI between 25 and 30 (overweight), weigh gain of more than 11.5kg is defined as excessive and for women with BMI above 30, weight gain of more than 9kg is defined as excessive.

Twenty-nine percent of women in the study population experienced excessive gestational weight gain. Excessive weight gain occurred more frequently in women taking both TAF and an integrase inhibitor (53%) and least often in women not taking an integrase inhibitor (24%).

At each body mass level, from normal to obese, excess gestational weight gain was greatest in women taking TAF and an integrase inhibitor but the difference was most pronounced in women already classified as obese at baseline. Seventy-one percent of women in this weight category taking TAF and an integrase inhibitor experienced excessive weight gain compared to 35% taking an integrase inhibitor without TAF and 28% not taking an integrase inhibitor.

A model of relative risk which adjusted for pre-pregnancy body mass index and the presence of detectable viral load at baseline found that women taking TAF and an integrase inhibitor were 78% more likely to experience excessive weight gain compared to women not taking either drug (RR 1.78, 95% CI 1.18-2.68). Women taking an integrase inhibitor were 30% more likely to experience excessive weight gain compared to women not taking an integrase inhibitor but this difference in risk was not statistically significant.

The researchers also analysed the risk of excessive weight gain depending on whether women were exposed to TDF or not. Women taking TDF had a 36% lower risk of excessive weight gain (RR 0.64, 95% CI 0.41-0.99, P<0.05).

Although there was no difference between regimens in the development of gestational diabetes, hypertensive disorders of pregnancy including preeclampsia and eclampsia were more common in women exposed to an integrase inhibitor during pregnancy (20% vs 7%, p<0.001).

Find out more: Weight gain and HIV treatment

Maternal antiretroviral treatment was not associated with any differences in neonatal complications.

The study authors say their findings reinforce the need to monitor women with HIV for gestational diabetes and hypertension during pregnancy, as well as offering counselling on diet, nutrition, exercise and weight gain. More research is also needed to investigate the mechanisms leading to weight gain in people with HIV taking TAF and integrase inhibitors.

In a review of study findings on weight gain in people taking antiretroviral therapy published in Open Forum Infectious Diseases, Dr Brian Wood of the University of Washington and Dr Gregory Huhn of Rush University, Chicago, sum up the current evidence:

• There isn’t a biologically plausible mechanism to explain why people taking TAF gain more weight than people taking TDF. Instead, TDF and other nucleoside reverse transcriptase probably suppress weight gain.
• There are several biologically plausible mechanisms to explain why people might gain weight on integrase inhibitors, but more research is needed.
• The weight-suppressive effects of TDF and efavirenz – often taken together – have been underappreciated. When people switch from those drugs to combinations containing TAF and/or an integrase inhibitor and gain weight, some of the weight gain is likely to be due to removal of the weight-suppressive drugs.

The authors emphasise that further research is needed into the mechanisms and possible strategies for switching treatment in people who have experienced weight gain, but in the meantime, careful monitoring of the long-term cardiovascular and metabolic effects of weight gain is needed.