Low-Level HIV Viral Load Linked to Gut Leakage and Inflammation

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Even low levels of HIV in the body are associated with microbial translocation, or leakage of bacteria from the gut, which can lead to excessive immune activation and inflammation, according to study published in the February 1, 2013, Journal of Acquired Immune Deficiency Syndromes

A growing body of evidence indicates that an inflammatory process begins at the earliest stages of HIV infection, and persistent inflammation appears to contribute to a host of non-AIDS conditions such as cardiovascular disease and cancer that occur earlier and more often in people with HIV.

While the mechanisms underlying this process are not fully understood, one contributor is leakage of bacteria as HIV damages lymphoid tissue in the gut. These escaping bacteria and the toxins they produce trigger a strong immune reaction. While this type of response is needed to fight acute infection, ongoing immune activation and inflammation can have detrimental effects throughout the body.

Sergio Reus from Hospital General Universitario de Alicante in Spain and colleagues looked at biomarkers of inflammation among people with very low virus levels. While research has shown that a decrease in HIV viral load is accompanied by a decrease in microbial translocation and chronic inflammation, they noted as background, it is not clear what happens in people with HIV RNA < 20 copies/mL, considered "undetectable" by viral load tests widely used in clinical practice.

The researchers conducted a cross-sectional observational study to determine whether strict control of HIV viral load is associated with microbial translocation and chronic inflammation.

The analysis included 52 people with HIV on combination antiretroviral therapy (ART) with viral load < 200 copies/mL for more than 6 months. About two-thirds were men and the median age was 45 years. The median CD4 T-cell count was high at 552 cells/mm3 (range 126-1640 cells/mm3). People with chronic liver disease, other active infections, or using antibiotics were excluded.

HIV viral load was measured using a third-generation assay with a limit of detection of 20 copies/mL. The primary study endpoint was molecular microbial translocation, as determined by detection in plasma of 16S ribosomal DNA sequences that act as bacterial signatures. Secondary variables included levels of lipopolysaccharide (LPS; a bacterial endotoxin that triggers immune response), soluble CD14 (a co-receptor for LPS), and the pro-inflammatory cytokines tumor necrosis factor alfa (TNF-alfa) and interleukin 6 (IL-6).

Results

Patients with HIV receiving treatment who have undetectable HIV viral load (< 20 copies/mL) show evidence of microbial translocation less frequently than people with low-level HIV viremia, the researchers concluded. "Microbial translocation is associated with higher levels of inflammation markers, independent of HIV viral load."

"Microbial translocation is caused by depletion of CD4 cells in the gut mucosa and the gut's increased permeability," they explained in their discussion. "ART induces a progressive decrease in plasma levels of microbial DNA, which stabilize after several weeks but do not normalize."

"[L]ow-level HIV viremia was not accompanied by increased inflammatory biomarkers in the absence of microbial translocation, suggesting that inflammation is produced by microbial translocation and not directly by HIV viremia," they noted. "Reductions in microbial translocation and inflammatory markers are broadly related to a decrease in HIV viral load. ART itself is probably beneficial even if it does not suppress HIV viremia."

"Patients in the SMART study who received episodic rather than continuous ART had higher mortality and morbidity rates (AIDS-related and cardiovascular diseases)," they continued. "Microbial translocation and inflammation markers have been implicated in [poor CD4 cell recovery] in response to treatment and also in much of the morbidity associated with HIV, such as dyslipidemia, cardiovascular disease, neurocognitive impairment, osteoporosis, non-HIV-related cancers, or kidney failure."

"The clinical significance of low-level viremia in terms of HIV progression and persistent inflammation is not known, nor is the source of the virus (possibly sanctuary sites)," the authors wrote. "The relevance of detectable HIV viral load under the detection threshold is not known, but some data suggest an increased risk of viral load rebound in the following year. For this reason, the current ART target of 50 [copies/mL] may need to be revised downward."

2/1/13

Reference

S Reus, J Portillo, J Sánchez-Payá , et al. Low-Level HIV Viremia Is Associated With Microbial Translocation and Inflammation. Journal of Acquired Immune Deficiency Syndromes 62(2):129-134. February 1, 2013.