Weight gain after starting antiretroviral treatment is not exclusive to dolutegravir-based treatment, but appears to be associated with newer, better tolerated drugs, a large meta-analysis of randomised trials published this month in Clinical Infectious Diseases has found.
People with low CD4 counts were at much greater risk of large weight increases after starting treatment, the meta-analysis showed, suggesting that weight gain is partly a ‘return to health’ effect after years of fighting a viral infection.
Greater weight gain associated with dolutegravir and other integrase inhibitors has been observed in several large randomised studies and cohort studies. Most recently, analysis of two large, randomised studies conducted in Africa showed that dolutegravir-based treatment was associated with greater weight gain compared to efavirenz-based treatment, that weight gain was most pronounced when dolutegravir was combined with tenofovir alafenamide (TAF) and that weight gain was greater in women.
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. Many BMI calculators can be found on the internet.
integrase inhibitors (INI, INSTI)
A class of antiretroviral drugs. Integrase strand transfer inhibitors (INSTIs) block integrase (see ‘integrase’). Blocking integrase prevents HIV from replicating.
HIV enzyme that the virus uses to insert its genetic material into a cell that it has infected.
The result of a statistical test which tells us whether the results of a study are likely to be due to chance and would not be confirmed if the study was repeated. All p-values are between 0 and 1; the most reliable studies have p-values very close to 0. A p-value of 0.001 means that there is a 1 in 1000 probability that the results are due to chance and do not reflect a real difference. A p-value of 0.05 means there is a 1 in 20 probability that the results are due to chance. When a p-value is 0.05 or below, the result is considered to be ‘statistically significant’. Confidence intervals give similar information to p-values but are easier to interpret.
When the statistical data from all studies which relate to a particular research question and conform to a pre-determined selection criteria are pooled and analysed together.
But is dolutegravir the cause of weight gain, or is weight gain after starting or changing antiretroviral therapy a more widespread phenomenon?
To answer this question, investigators on eight clinical trials sponsored by Gilead Sciences and Gilead researchers analysed the studies to look for relationships between demographic factors, antiretroviral drugs, HIV disease characteristics and weight gain in previously untreated people.
The eight trials included 5680 participants and were carried out between 2003 and 2015. Six studies used the older formulation of tenofovir (TDF) in combination with emtricitabine and four used the newer formulation (TAF), including two which compared the two. The third agents most commonly tested in these studies were the non-nucleoside reverse transcriptase inhibitor (NNRTI) efavirenz and the integrase inhibitors elvitegravir and bictegravir. Other studies included comparator arms in which participants received atazanavir/ritonavir, rilpivirine or dolutegravir.
The combined study population was predominantly male (88%) and white (62%). While 26% of participants were black men, black women were particularly under-represented in these studies, forming only 6% of the combined population. In all studies, a majority of participants were in the United States, with most others coming from other high-income countries.
The mean baseline viral load was 4.65 log (under 50,000 copies/ml) and 29% had a baseline viral load above 100,000 copies/ml. The mean CD4 count was 401 cells/mm3 and 15% had a CD4 cell count below 200. Nineteen per cent had symptomatic HIV disease or an AIDS diagnosis.
All studies collected baseline and longitudinal weight measurements and body mass index (BMI). The mean baseline BMI was 25.7, 16% were obese at baseline (BMI of 30 or above) and 31% were overweight (BMI of 25-29.99).
Weight gain was seen in all study arms. Participants gained a median of 2kg over 96 weeks, most of it during the first 48 weeks of treatment. Seventeen per cent gained at least 10kg in weight over 96 weeks but 30% lost weight. More weight was gained in the most recent studies and more weight was gained by people taking the investigational regimen in every study.
Risk factors for weight gain
Low CD4 count and injecting drug use were the factors associated with greatest weight gain over 96 weeks of follow-up, followed by black race and baseline viral load above 100,000 copies/ml.
People with CD4 counts below 200 gained more weight than people with higher CD4 counts (+2.97kg, 95% CI 2.81-3.13, p0.001) and gains in weight closely tracked gains in CD4 count over time. A CD4 count below 200 was also the strongest risk factor for a weight gain of at least 10% of baseline weight (odds ratio 4.36, 95% CI 3.6-5.27, p0.001).
People who injected drugs gained more weight than those who did not (+1.41kg, 95% CI 0.97-1.85, p0.001).
People with symptomatic HIV or AIDS at baseline gained 0.51kg (95% CI 0.36-0.65, p0.001) more than people who were asymptomatic.
Race was associated with greater weight gain than gender. Longitudinal modelling showed that black women gained more weight than black men (+1.12kg, 95% CI 0.25-1.99, p=0.011) or white women (+2.72kg, 1.68-3.77, p0.001) over 96 weeks.
Antiretrovirals and weight gain
“The trend towards greater weight gain with newer regimens may be a consequence of better gastrointestinal tolerability and less nausea.”
All antiretroviral drug classes were associated with weight gain but people receiving an integrase inhibitor (elvitegravir, dolutegravir or bictegravir) gained significantly more weight (+3.24kg) than people taking either an NNRTI (efavirenz or rilpivirine; +1.93kg) or a protease inhibitor (atazanavir/ritonavir; +1.6kg).
Bictegravir and dolutegravir were associated with greater weight gain than elvitegravir, and rilpivirine was associated with greater weight gain than efavirenz. People who received bictegravir or dolutegravir had higher odds of a weight gain of more than 10% from baseline (OR 1.82, 1.24-2.66, p=0.002). Elvitegravir/cobicistat was also associated with higher odds of more than 10% weight gain (OR 1.32, 1.04-1.78, p=0.026) compared to efavirenz.
Tenofovir alafenamide (TAF) was associated with greater weight gain than tenofovir disoproxil (TDF) (4.25kg vs 2.07kg) and abacavir was associated with greater weight gain than TDF (3.08kg vs 2.07kg). TAF was the only nucleoside reverse transcriptase inhibitor associated with higher odds of 10% weight gain, when compared to zidovudine (AZT), abacavir or TDF.
Metabolic impact of weight gain
Some researchers have suggested that substantial weight gain after starting antiretroviral treatment could lead to a higher risk of cardiovascular disease or diabetes. For this analysis, researchers looked for an association between 10% weight gain and the onset of diabetes or hyperglycaemia but found no association. People who gained greater than 10% of body weight had slightly higher total cholesterol to HDL cholesterol ratios after 96 weeks (3.7 vs 3.5) but the difference is unlikely to be clinically meaningful.
Explanations for weight gain
The study authors suggest that the trend towards greater weight gain with newer regimens may be a consequence of better gastrointestinal tolerability and less nausea associated with integrase inhibitors and TAF. Although there is some evidence that dolutegravir might interact with a hormonal signalling system that influences calorie intake and energy use, more research is needed to determine if this explains the association between the drug and weight gain.
However, the strongest association detected in the study was between low CD4 count and weight gain, suggesting that weight gain represents a `return to health` phenomenon in this group of people. Advanced HIV disease causes weight loss and increases metabolic demands, so stopping viral replication will lead to lower energy requirements and subsequent weight gain if food intake stays the same or increases.
Analysis of trials in which people with suppressed viral load switch medications might disentangle the extent of ‘return to health’ weight gain and weight gain associated with new drugs, the authors suggest.
The study authors note that greater weight gain in black women needs to be considered in the context of a higher prevalence of obesity in black women living with HIV.
Although pre-existing obesity was not a risk factor for weight gain in the studies analysed, the structural factors – poverty, diet, food choices – that lead to a higher prevalence of obesity in some populations are also likely to contribute to weight changes after starting antiretroviral treatment.The meta-analysis was not able to look at diet or other non-HIV related factors that might influence weight.
In an accompanying editorial commentary, Dr Sara Bares notes that future studies should look at calorie intake and make more efforts to recruit women, especially black women, if we are to learn more about the drivers of weight gain.