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CROI 2015: Putting On Too Much Weight After Starting ART Increases Chronic Inflammation

A return to normal weight after starting antiretroviral therapy (ART) can be beneficial for very sick, underweight individuals living with HIV -- but further weight gain appears to increase markers of inflammation associated with metabolic complications and poorer survival, according to a study reported at the 2015 Conference on Retroviruses and Opportunistic Infections (CROI) this week in Seattle.

Although CROI traditionally has been at least partly dedicated to opportunistic infections (OIs), the success of ART has made most of the OIs relatively rare occurrences, and the conference has increasingly focused on the complications and comorbidities that are still seen in people living with HIV, such as cancer and metabolic complications like heart disease, kidney disease, osteoporosis, and so on.

The metabolic complications of HIV are now thought to be due to the interplay between the host, the virus, and the immune response, and possibly to some antiretroviral drugs. In addition to the fact that populations with HIV are aging in both resource-rich and resource-poor settings, behavioral risks such as poor diet, smoking, and inactivity also contribute to the development of non-communicable diseases and to non-AIDS morbidity and mortality.

Obesity is another factor that increases the risk of complications -- and both obesity and untreated HIV infection are associated with inflammation and immune activation. Although treating HIV should decrease inflammation and immune activation, it is often also associated with weight gain, and little is known about the effects of body weight changes during ART initiation on the changes in markers of inflammation and immune activation.

One team of researchers, led by Kristine Erlandson from the University of Colorado, hypothesized that this weight gain could actually be associated with heightened inflammation and immune activation despite the initiation of ART -- particularly if people on treatment became or already were overweight or obese.

To find out, the researchers performed a nested case-control study within the randomized PEARLS (Prospective Evaluation of Antiretrovirals in Resource Limited Settings) trial, with roughly 30 participants randomly selected from 9 participating countries, including the U.S.

Participants were categorized as being underweight, normal weight, or overweight or obese at the start of HIV treatment, and changes in their body mass index (BMI) and markers of inflammation such as interleukin 6 (IL-6), gamma-interferon, tumor necrosis factor-alpha (TNF-alpha), C-reactive protein (CRP), IL-18, IP-10, and soluble CD14 (sCD14) were assessed after 48 weeks of treatment.

Characteristics of the Study Population

Half the study participants were women and the mean age was 35 years. About half (53%) were black, 11% were white, 23% were Asian, and 13% were of other race/ethnicity.

The median baseline CD4 T-cell count was 179 cells/mm³ (indicating relatively advance immune suppression), median viral load was 5.07 log, and hemoglobin and albumin levels were 12.4 and 4.0, respectively. ART regimens were about evenly divided between efavirenz/AZT/3TC (37%), atazanavir/ddI/emtricitabine (33%), and efavirenz/tenofovir/emtricitabine (30%).

Results

At baseline, 8% of the participants were underweight, 65% were normal weight, and 27% were overweight or obese. By week 48, there was an increase in the proportion of the overweight and obese subjects to 37%, and a decrease in those who were underweight down to 3%.

In multivariate models, which were adjusted for sex, age, country, baseline HIV viral load, and treatment arm, among underweight participants, each incremental gain in BMI was associated with a significant 9.3 mg/L decrease in CRP (a positive finding). There were similar trends with the other markers of inflammation and immune activation, however they did not reach statistical significance.

Among overweight/obese individuals, each incremental gain in BMI was associated with a significant 0.02 log increase in sCD14. Again, there were similar trends with the other markers of inflammation but they did not reach statistical significance.

Essentially, when ART helped sick individuals return to a normal healthy weight, there was a decrease in markers of inflammation, but becoming or remaining overweight or obese after going on ART was associated with heightened inflammation.

Erlandson noted that sCD14 has been found to be a marker of mortality during HIV treatment, so these data suggest that obesity may be associated with decreased survival. However, further studies are needed to investigate the impact of obesity on treatment outcomes.

2/24/15

Reference

KM Erlandson, N Gupte, JR Lama et al. Obesity and Inflammation in Resource-Diverse Settings of Antiretroviral Therapy Initiation. 2015 Conference on Retroviruses and Opportunistic Infections. Seattle, February 23-24, 2015. Abstract 778.