Alcohol consumption may impair response to HAART and increase risk of liver toxicity

Effect on HAART Outcomes

In the May 18, 2009 advance online edition of Alcohol and Alcoholism, María José Míguez-Burbano and colleagues from Miami looked at differences in HAART effectiveness after 24 weeks of therapy according to amount and type of alcohol consumed.

The study cohort included 110 HIV positive participants who reported drinking only beer or wine and 55 who reported drinking hard liquor. The investigators evaluated changes in HIV viral load, CD4 T-cell count, naive lymphocyte count, and size of the thymus, a gland in the neck where T-cells mature.

Results

• 24 weeks after HAART initiation, both CD4 count (+12 cells/mm3) and thymus size (+0.7 mm3) increased in the beer/wine group.

• In contrast, both CD4 count (-4 cells/mm3) and thymus size (-0.6 mm3) decreased in the liquor group.

• Women who drank liquor had significantly lower CD4 cells counts (average 163 cells/mm3) and naive lymphocyte counts (178 cells/mm3) than liquor-drinking men (282 and 301 cells/mm3, respectively).

• In adjusted regression models, liquor-drinking participants had a significantly greater likelihood than the beer/wine group of maintaining a detectable HIV viral load (relative rate [RR] 1.35; P = 0.03), increased thymus volume (RR 3.8; P = 0.04), and replenished naive lymphocytes (RR 13; P = 0.02).

"Liquor was associated with thymus deterioration and thus with poorer viro-immune outcomes after HAART," the study authors concluded. "Subtyping participants by alcohol consumption patterns seems to be clinically relevant and needs to be accounted for in future studies."

Department of Public Health, Florida International University, Miami, FL; Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, Miami, FL; Department of Radiology, University of Miami Miller School of Medicine, Miami, FL.

Liver Toxicity

Heavy alcohol consumption is a well-known contributor to advanced liver disease, including cirrhosis and liver cancer, but its effect on antiretroviral-induced liver toxicity (hepatotoxicity) is not well studied.

At the recent Digestive Disease Week annual meeting (DDW 2009) in Chicago, Xudong Wu and colleagues presented findings from a study of the association between alcohol use and protease inhibitor (PI) liver toxicity.

Alcohol consumption has been linked to worsening of serious liver toxicity induced by HIV PIs, the investigators noted as background. Their previous research demonstrated that PI-induced stress on the endoplasmic reticulum (ER; an intracellular structure involved in protein and lipid synthesis) is associated with dysregulation of lipid metabolism in hepatocytes (liver cells). But the underlying mechanisms by which alcohol and PIs promote lipid abnormalities in the liver remain unclear. The researchers hypothesized that alcohol and PIs may synergistically induce hepatoxicity by activating the ER stress response, leading to an inflammatory response and disrupted lipid homeostasis in the liver.

The present analysis included a laboratory study in which hepatocytes from wild type (non-mutant) and CHOP-knockout (a genetic variation associated with reduced ER stress effects) mice were first exposed to PIs in the absence or presence of alcohol. The researchers assessed activation of the ER stress response, apoptosis (programmed cell death), and intracellular lipid accumulation.

They then exposed wild-type and CHOP-negative live mice to PIs at a dosage of 50 mg/kg, with or without alcohol (2 g/kg) for 1 week, and assessed serum lipid levels, apoptosis, and pathological liver injury.

Results

• In the laboratory study, alcohol and PIs synergistically induced ER stress and apoptosis in primary mouse hepatocytes.

• Alcohol also increased PI-induced up-regulation of expression of SREBP-1 (a transcription factor involved in fat metabolism) and lipid accumulation in hepatocytes.

• In live mice, alcohol increased PI-induced serum lipid elevations and promoted PI-related liver injury.

• Both alcohol-induced and PI-induced lipid accumulation and cell apoptosis were significantly reduced in CHOP-knockout liver cells.

• Similarly, alcohol-induced and PI-induced increases in serum lipid levels were ameliorated in CHOP-negative mice.

Based on these findings, the researchers concluded, "Activation of the ER stress response is a key cellular mechanism underlying alcohol and HIV PI-induced hepatoxicity."

"Inhibition of ER stress activation may represent a new strategy to prevent alcohol and HIV PI-associated hepatoxicity," they added.

Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA; Internal Medicine, McGuire VA Medical Center, Richmond, VA.

By Liz Highleyman

References
1. MJ Míguez-Burbano, JE Lewis, J Fishman, and others. The Influence of Different Types of Alcoholic Beverages on Disrupting HAART Outcome. Alcohol and Alcoholism. May 18, 2009 [Epub ahead of print].
2. X Wu, R Cao, L Sun, and others. Alcohol Promotes HIV Protease Inhibitor-Induced Hepatoxicity By Activating the ER Stress Response in Hepatocytes. Digestive Disease Week (DDW 2009). Chicago. May 30-June 4, 2009. Abstract S1589.

HIVandHepatitis.com

http://www.hivandhepatitis.com/

http://www.hivandhepatitis.com/2009icr/ddw/docs/062309_a.html

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