Weight gain in people with HIV on antiretroviral treatment – especially integrase inhibitors – may reflect a return towards a weight that's normal in the wider society, but physicians should be watching out for the most extreme cases, as these people are most likely to suffer weight-related complications in the future, Professor Andrew Carr of St Vincent’s Hospital, Sydney, told the HIV Glasgow 2020 virtual conference on Monday.
Weight gain on HIV treatment has become a concern for people with HIV and their doctors. Clinical trials and cohort studies have shown varying rates of weight gain in people taking integrase inhibitors, especially together with tenofovir alafenamide (TAF). In contrast, there is some evidence that tenofovir disoproxil fumarate (TDF) and efavirenz inhibit weight gain.
General population studies show that a 5kg/m2 increase in body mass index significantly increases the risk of death. Even a weight increase that places a person in the overweight category (BMI 25-29.9) may be enough to raise the risk of death substantially. “There’s no biological reason to believe that obesity in HIV-positive adults will not incur the same risk as it does in the general population,” said Carr.
Over a 13-year follow-up, the Global BMI Mortality Collaboration found that the increased risk of death at higher weights was greater in men – 50% versus 30% raised risk in women for each 5kg/m2 increase. Substantial weight gain before the age of 50 raised the risk by 52%.
Obesity raises the risk of non-communicable diseases, notably diabetes, cardiovascular disease, chronic kidney disease and cancer. Globally, deaths due to these causes increased by 20-30% between 2007 and 2017 and the burden of deaths due to non-communicable diseases is highest in lower-income countries.
However, speaking in the opening plenary of HIV Glasgow 2020, Carr urged caution in thinking about changes in body fat, pointing out that younger HIV-negative adults in the United States gain up to 1kg a year. Both the Kaiser Permanente cohort and the ADVANCE study in South Africa have reported that over several years, people with HIV on antiretroviral treatment gain weight – but their weight gain only returns them to the societal norm.
Reporting at AIDS 2020, Dr Michael Silverberg of Kaiser Permanente Northern California showed that although people with HIV gained weight three times faster than matched HIV-negative controls over 12 years of follow-up, by the end of the period they had similar body mass to the HIV-negative controls (both groups were overweight).
In the ADVANCE study, which compared two dolutegravir-based combinations to efavirenz-based treatment, participants who received dolutegravir gained weight, especially if they received TAF too. But the amount of weight they gained meant that after two years they weighed the same as HIV-negative counterparts, according to findings from two general population studies in South Africa (the South African NHANES study and South African weight data from 2016 reported by the World Health Organization).
Furthermore, several large trials have shown that the median weight gain in people starting integrase inhibitor treatment is in line with average annual weight gain for the population. Mean weight gain, on the other hand, can be much higher in these studies, distorted by a minority of outliers who have the greatest weight gain.
“These are going to be the patients at higher risk of complications due to weight gain,” Carr said.
Studies in different populations have observed big differences in weight gain too. Whereas participants in the GEMINI 1 & 2 studies who received dolutegravir gained an average of 2kg over 96 weeks, participants in the ADVANCE study receiving the same regimen gained an average of 5kg over the same period. Whether this difference is driven by outliers in the populations or factors affecting the population as whole, such as diet, is unclear.
But to achieve weight gain that might place them at increased risk of death, people with HIV in the normal weight range would need to gain upwards of 15kg, an order of magnitude higher than the gains in weight seen in most clinical trials and cohort studies.
As for reducing weight gain, “the way you lose fat is to metabolise fat with oxygen to carbon dioxide and water, so my simple message to patients is anything that makes them breathe more rapidly is going to be helping them to lose weight. Telling people to watch their diet is an ineffective way to address weight. In all the studies you lose less than a kilogram at six months.”
"Studies of people changing antiretroviral regimen or taking PrEP are more likely to identify drug effects."
Reminding delegates that it took over five years to show that lipoatrophy could be prevented by avoiding thymidine nucleoside analogues in randomised trials, Carr appealed to colleagues in academic centres to help answer questions about causes of weight gain by designing studies that could tease out the contributions of individual drugs.
Comparisons between sexes, ages and races are also needed, he said.
Studies of people changing antiretroviral regimen or taking PrEP are more likely to identify drug effects. Studies in previously untreated people may show return to health effects and interpreting weight changes is complicated by the fact that drugs are given in combination. Switch and PrEP trials have shown much smaller weight gains that are in line with normal changes in body weight over time.
A consensus definition of weight gain is also needed, experts agreed in a discussion after Carr’s plenary. Dr Giovanni Guaraldi of the University of Modena, Italy, said that fat tissue distribution and density is more important than total fat gain in determining the risk of cardiovascular disease and metabolic disorders and may be a more important outcome to measure in clinical trials.
Carr A. HIV and obesity. HIV Glasgow 2020, abstract KL1.