| Alcohol
Consumption May Impair Response to HAART and Increase Risk of Liver Toxicity By
Liz Highleyman | Alcohol
consumption may interfere with immune restoration in HIV patients taking HAART,
and may also worsen protease inhibitor liver toxicity, according to 2 recent presentations. |
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. 6/23/09 References
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].
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. |
