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  AIDS 2010
18th International AIDS Conference (IAC)
July 18-23 2010
Vienna, Austria
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Fatal Liver Failure Still 8 Times More Common With HIV in Large US Cohort
  XVIII International AIDS Conference, July 18-23, 2010, Vienna
Mark Mascolini
Compared with gender- and age-matched HIV-negative controls, adults with HIV had almost a 7 times higher risk of fatal liver failure from 2002 to 2007 and more than a 5 times higher risk of nonfatal liver failure in California's Kaiser-Permanente health group [1]. Relative risk of nonfatal failure dropped sharply in more recent years, but risk of fatal failure barely declined over the same period. Lower CD4 counts and lack of antiretroviral therapy favored a heightened risk of both fatal and nonfatal liver failure in people with HIV.
Kaiser-Permanente investigators matched 20,277 HIV-infected adults with 202,313 HIV-negative controls of the same gender and age. Kaiser physicians cared for the HIV-positive "cases" and the HIV-negative controls between 1996 and 2007. The researchers classified a death as liver failure if records showed liver failure as the primary or secondary cause of death or if a recent diagnosis of liver failure preceded death. Nonfatal cases of liver failure were established if (1) a patient's hospital discharge record showed liver failure, hepatic encephalopathy, or bleeding esophageal varices, or (2) if two thirds of certain liver-related lab values exceeded upper limits of normal. Follow-up continued until fatal or nonfatal hepatic failure, death, withdrawal from the Kaiser-Permanente system, or the end of the study.
Age of cases and controls averaged 40 years, and 90% were men. Follow-up averaged 4 years in the HIV group and 5 years in the non-HIV group. Half in the HIV group was white, 20% were Hispanic, and 17% were black. But racial comparisons with the control group are difficult because 44% of controls did not have a reported race or ethnicity. The HIV group had a higher proportion of people with a history of alcohol or drug use (19% versus 8%), hepatitis C (8% versus 1%), and hepatitis B (4% versus 1%), but not of diabetes (2% versus 3%) or lipid-lowering therapy (4% in both groups). Initial CD4 counts averaged 389 in the HIV group and initial viral load 50,000 copies. One third of people with HIV had taken antiretrovirals before the starting date for this analysis.
The Kaiser team built a multivariate statistical model that factored in age, gender, race/ethnicity, smoking, alcohol abuse, drug abuse, hepatitis B or C coinfection, hypertension, diabetes, and lipid-lowering therapy. Compared with HIV-negative controls, the HIV group had nearly a 7 times higher overall risk of fatal liver failure (adjusted hazard ratio [AHR] 6.7, 95% confidence interval [CI] 5.2 to 8.8, P < 0.0001) and more than a 5 times higher risk of nonfatal failure (AHR 5.6, 95% CI 4.8 to 6.5, P < 0.0001).
Fatal and nonfatal hepatic failure risk was higher in the HIV group both for men (AHR 5.4, 95% CI 4.6 to 6.2) and women (AHR 8.4, 95% CI 4.7 to 14.8)
. The heightened HIV-related risk of fatal liver failure barely declined from 1996-2001 (AHR 9.6) to 2002-2007 (AHR 8.1), and in both periods the difference from HIV-negative people remained highly statistically significant (P < 0.0001). In contrast, the higher HIV-related risk of nonfatal liver failure slipped from 9.9 in 1996-2001 to 3.6 in 2002-2007. But again the risk difference from HIV-negative people remained highly significant in both periods (P < 0.0001).
Taking antiretroviral therapy (ART) and having a higher CD4 count diminished the fatal and nonfatal risk difference between Kaiser patients with and without HIV. But only untreated people with a CD4 count above 500 no longer had a significantly increased risk of fatal liver failure than HIV-negative people.
Fatal liver failure
-- ART+ CD4s > 500: AHR 2.2, P < 0.05
-- ART- CD4s > 500: AHR 1.7, 95% CI 0.4 to 6.9, not significant
-- ART+ CD4s 201-499: AHR 3.8, P < 0.0001
-- ART- CD4s 201-499: AHR 5.4, P < 0.0001
-- ART+ CD4s < 200: AHR 21.9, P < 0.0001
-- ART- CD4s < 200: AHR 51.6, P < 0.0001
Nonfatal liver failure:
-- ART+ CD4s > 500: AHR 2.8, P < 0.0001
-- ART- CD4s > 500: AHR 3.3, P = 0.0052
-- ART+ CD4s 201-499: AHR 5.0, P < 0.0001
-- ART- CD4s 201-499: 5.6, P < 0.0001
-- ART+ CD4s < 200: 14.3, P < 0.0001
-- ART- CD4s < 200: 30.8, P < 0.0001
Notably, except in the 500+ CD4 brackets, the risk of fatal or nonfatal liver failure was always greater among people not taking antiretrovirals than among those on treatment. Risk of fatal or nonfatal liver failure was not significantly higher with nonnucleoside-based regimens than with protease inhibitor regimens. The Kaiser team did not analyze the impact of different nucleosides.
A recent CD4 count below 200 versus above 200 more than doubled the risk of fatal or nonfatal liver failure (AHR 2.5, 95% CI 2.0 to 2.3, P < 0.001). A nadir CD4 count under versus over 200 raised the risk of liver failure 1.5 times (95% CI 1.2 to 2.0, P = 0.003). Viral load above versus below 500 upped the liver failure risk 1.7 times (95% CI 1.4 to 2.1, P < 0.001). Alcohol or drug abuse at any time, hepatitis B or C, or diabetes also independently raised the risk of fatal or nonfatal liver failure. Factors not associated with liver failure risk were antiretroviral therapy, gender, race/ethnicity, hypertension, obesity, and lipid-lowering therapy.
The Kaiser investigators argued that the inverse correlation between CD4 count and risk of hepatic failure underscores the importance of avoiding low CD4 counts in preventing liver failure.
1. Towner W, Xu L, Silverberg M, et al. 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. July 18-23, 2010. Vienna. Abstract TUAB0102.