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 HIV and Coverage of the
XVIII International AIDS Conference
(AIDS 2010)  July 18 - 23, 2010, Vienna, Austria
People with HIV Have Higher Rate of Severe Liver Disease, Antiretroviral Therapy Cuts Risk

SUMMARY: People with HIV have a higher rate of both fatal and non-fatal liver failure compared with HIV negative individuals, according to a large analysis of members of the Kaiser Permanente health system presented this week at the XVIII International AIDS Conference in Vienna. The risk of liver failure increased as CD4 cell count rose -- an association seen even at high CD4 levels -- and antiretroviral therapy appeared to have a protective effect.

By Liz Highleyman

Numerous studies have found that liver problems are common among people with HIV, and that liver-related death is one of the major causes of mortality in the combination antiretroviral therapy (ART) era. Liver damage in this population may be due to chronic hepatitis B or C coinfection, drug-related toxicity, heavy alcohol use, persistent systemic inflammation, or other factors.

William Towner and colleagues performed an observational cohort study comparing rates and risk factors for liver failure among 20,277 HIV positive adult Kaiser Permanente health plan members in Northern and Southern California over the period 1996-2007, comparing them with 202,313 HIV negative members matched according to sex, age, year, and medical center.

Most study participants (90%) were men and the average age was 40 years. Within the HIV positive group, 51% were white, 20% were Hispanic, 17% were black, 4% were Asian, and 9% were of unknown race/ethnicity; among the control subjects, the corresponding percentages were 27%, 15%, 7%, 8%, and 44%.

As is true overall in California, a majority of HIV positive Kaiser members are gay or bisexual men. The mean baseline CD4 count in this group was 389 cells/mm3 and the average HIV viral load was approximately 50,000 copies/mL. HIV positive people were more than twice as likely to have a history of alcohol or drug abuse (19% vs 8%) and were much more likely to have hepatitis B or C (4% for B and 8% for C, compared with 1% each in the HIV negative group).

Liver problems in people with HIV are often identified based on alanine and aspartate aminotransferase levels (ALT and AST), biomarkers of liver inflammation that may not accurately predict subsequent liver failure, the investigators noted as background. Fulminant or acute liver failure has been less well studied than progressive liver fibrosis in HIV positive people.

For this analysis, fatal hepatic failure was defined as having a primary or secondary liver-related cause of death, or death preceded by a recent diagnosis of liver failure. The researchers identified cases of non-fatal liver failure by searching for mentions of hepatic failure, hepatic encephalopathy, or bleeding esophageal varices in hospital discharge databases, as well as laboratory tests showing elevated levels of ammonia (> upper limit of normal [ULN]), INR (> 1.2), or AST/ALT (> 5 x ULN).


Overall, there were 159 cases of fatal hepatic failure in the HIV positive group compared with 126 in the much larger HIV negative group (186 vs 12 cases per 100,000 person-years), for an adjusted hazard ratio (aHR) of 6.7 -- nearly 7 times higher risk.
There were 455 cases of non-fatal liver failure in the HIV positive group and 433 in the HIV negative group (540 vs 44 cases per 100,000 person-years), for an adjusted HR of 5.6.
Among the HIV positive patients, liver failure (fatal and non-fatal combined) was less common in the latter half of the study period, while it rose in the HIV negative group:
1996-2001: 695 vs 30 cases per 100,000 person-years (aHR 10.5);
2002-2007: 453 vs 50 cases per 100,000 person-years (aHR 3.6).
HIV positive people with lower CD4 counts and those not on ART were at greater risk of liver failure relative to HIV negative people:
CD4 < 200 cells/mm3, untreated: aHR 51.6 for fatal, 30.8 for non-fatal hepatic failure;
CD4 < 200 cells/mm3, on ART: aHR 21.9 for fatal, 14.2 for non-fatal;
CD4 201-499 cells/mm3, untreated: aHR 5.4 for fatal, 5.6 for non-fatal;
CD4 201-499 cells/mm3, on ART: aHR 3.8 for fatal, 5.0 for non-fatal;
CD4 > 500 cells/mm3, untreated: aHR 1.7 for fatal, 3.3 for non-fatal;
CD4 > 500 cells/mm3, on ART: aHR 2.2 for fatal, 2.8 for non-fatal.
ART more than halved the risk of liver failure for people with < 200 cells/mm3, while the differences were small at the 2 higher CD4 cell levels; none of these differences, however, was statistically significant after adjusting for other factors.
Liver failure risk did not differ significantly between HIV positive patients taking protease inhibitors vs NNRTIs.
Looking at fatal and non-fatal hepatic failure combined, significant risk factors included:
Recent CD4 cell count < 200 vs > 200 cells/mm3: aHR 2.5 -- more than double the risk;
Nadir (lowest-ever) CD4 cell count < 200 vs > 200 cells/mm3: aHR 1.5;
HIV viral load > 200 vs < 500 copies/ml: aHR 1.7;
History of alcohol or drug abuse: aHR 1.6;
Diabetes: aHR 1.9;
Hepatitis B or C: aHR 5.3.

"Adjusted risk for both hepatic failure and death increased in HIV positive vs. HIV negative persons," the Kaiser investigators concluded. "Risk [was] lower in the more recent ART era."

The association with recent CD4 cell count "suggests that hepatic failure is at least partially immune related," they continued. "Earlier treatment with antiretrovirals may reduce risk by preventing CD4 decline."

ART did not increase the likelihood of hepatic failure or liver-related death, indicating that drug-related liver toxicity is unlikely to be a major concern in the modern ART era.

Reducing T-cell decline may mitigate some of the detrimental effects of viral hepatitis coinfection, Towner suggested. While the link between ART and reduced liver failure risk did not reach statistical significance, he nevertheless said these findings support early use of ART as a primary intervention to reduce hepatic failure and liver-related death.

Kaiser Permanente, Infectious Diseases, Los Angeles, CA; Kaiser Permanente, Research and Evaluation, Pasadena, CA; Kaiser Permanente, Division of Research, Oakland, CA; Kaiser Permanente, Infectious Diseases, Hayward, CA.


W Towner, L Xu, M Silverberg, and others. Fatal and non-fatal hepatic failure (HF) in HIV-infected versus HIV-uninfected persons enrolled in Kaiser Permanente California (KP), a large managed care organization. XVIII International AIDS Conference. Vienna, July 18-23, 2010. Abstract TUAB0102.












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