HIV-related wasting in people on HAART may be a cytokine-mediated syndrome that results from residual HIV replication in monocytes and macrophages, even in individuals with long-term suppressed viral load, according to the results of a retrospective study to be published in the June 15th issue of Clinical Infectious Diseases. It was also published online on May 3rd.
The characteristics of HIV-related wasting have changed since the advent of HAART. Instead of the catastrophic weight loss once associated with advanced HIV disease, the process has become more subtle, and is more appropriately termed cachexia, which is characterised by a loss of lean body mass without severe weight loss. One post-HAART study found that over 50% of individuals with cachexia were receiving HAART at the time.
The currently available HAART does not fully prevent HIV replication in viral reservoirs or ‘sanctuary sites’. These include long-lived, infected immune cells, like monocytes and macrophages, as well as lymphatic tissue, the central nervous system, the thymus, and the testicles.
Researchers from the University of Hawaii hypothesised that the low-level weight loss seen since the advent of HAART may be due to persistent low-level HIV replication in two types of scavenger immune system cells: monocytes (large white blood cells) and macrophages (mature monocytes that migrate from the blood into tissues). They theorised that some of the intercellular chemical messengers, or cytokines, produced by these cells could speed up the body’s metabolism, resulting in weight loss.
The researchers conducted an exploratory analysis using a “convenience sample” of individuals already enrolled in a local longitudinal cohort study, the Hawaii Ageing with HIV Cohort. They found 70 individuals who had extra data on wasting in their files, 71% of whom were receiving HAART. These data included details of plasma cytokine levels, measurements of macrophage activation, and intracellular levels of HIV proviral DNA in peripheral blood mononuclear cells (PBMCs), which measures low-level ongoing viral replication.
At baseline, the cohort’s mean body mass index (BMI) was 25.4kg/m2. A BMI below 18.5kg/m2 is considered underweight, 18.5-25kg/m2 is considered a healthy weight, 25-30kg/m2 is considered overweight, and a BMI over 30kg/m2 is considered to be obese. Only 14.3% of the cohort had a BMI below 20kg/m2, whereas 20% had a BMI above 28kg/m2, suggesting that many in this cohort were overweight at baseline.
One year later, weight information was available for 57 participants. Over the year, 14% of individuals lost more than 10% of their weight; 15.8% lost between 5%–10%; 64.9% had stable weight; and 5.3% increased their weight by 5%–10%. However, the researchers provide no data on how many of those with a BMI below 20kg/m2 lost weight, or how much of the cohort’s weight loss was intentional. Consequently, it is not clear how many of these participants were truly wasting.
The researchers found differences neither in baseline viral load, nor in baseline or lowest-ever CD4 cell counts between those individuals who had lost weight and those who had gained weight or remained stable.
However, those who lost weight had significantly higher ongoing low-level HIV replication in PBMCs compared with those whose weight was stable or increased (8.9 vs. 0.9 HIV proviral DNA copies/106 PBMCs; p = 0.006). The researchers additionally analysed 19 individuals with plasma viral load below 50 copies/ml, and found that the median proviral DNA copy number was also higher in individuals with weight loss (8.9 vs. 0.5 HIV proviral DNA copies/106 PBMCs; p = 0.028).
No significant differences were seen between those who lost or gained weight, or remained stable in most of the cytokine levels measured. These included interleukin (IL)-6, IL-8, soluble TNF receptor (sTNFR) types I and II, and soluble Fas. However, a statistically significant correlation was found between weight change and macrophage chemotactic protein-1 (MCP1) level (r = 0.59; p = 0.01).
Although the researchers concede that there may be unrecognised biases when performing analyses on cohorts developed for other research interests, they suggest that this research supports their hypothesis. “To our knowledge, this is the first report detailing the association between wasting and intracellular HIV proviral DNA load,” they write.
They conclude by calling for studies that are explicitly designed to explore the link between persistent HIV infection in monocytes and macrophages and cytokine-mediated wasting.
If these studies agree with their initial findings, this may have an impact on future guidelines for antiretroviral therapy, they argue, since new antiretroviral regimens may be needed to obtain complete HIV eradication in monocytes and macrophages in order to prevent wasting in the future.
Shikuma CM et al. HIV-associated wasting in the era of Highly Active Antiretroviral Therapy: a syndrome of residual HIV infection in monocytes and macrophages. Clin Infect Dis 40, online edition, May 3rd, 2005.