Coinfection

Elevated ALT Liver Enzymes in HIV Patients without Hepatitis B or C Are Linked to High Viral Load, Obesity, Alcohol, and Some NRTIs

Among HIV positive individuals without coexisting hepatitis C virus (HCV) or hepatitis B virus (HBV) infection, the incidence of persistent elevated ALT levels was 3.9 cases per 100 person-years, researchers reported in the February 15, 2010 issue of Clinical Infectious Diseases. The risk of ALT elevation was greater in people with high HIV RNA levels, higher body mass index (BMI), heavy alcohol use, and prolonged use of stavudine (d4T; Zerit) or zidovudine (AZT; Retrovir).

As people with HIV live longer thanks to effective antiretroviral therapy (ART), deaths due to AIDS-defining opportunistic illnesses have fallen while mortality due to non-AIDS conditions has increased.

In the combination ART era, liver disease has become a leading cause of sickness and death for HIV positive people in wealthy countries. This is often attributable to hepatitis B or C, but drug toxicity and other factors may also play a role.

In the present study, Helen Kovari from University Hospital in Zurich, Switzerland, and colleagues analyzed incidence and risk factors for chronic ALT elevation among participants in the Swiss HIV Cohort Study without HBV or HCV coinfection who were seen during 2002-2008. A majority (66%) were men and the median age was 38 years. The median current CD4 count was 426 cells/mm³ (with a nadir or lowest-ever level of 249 cells/mm³) and 56% were receiving ART.

ALT (alanine transaminase) is a liver enzyme released when the liver is damaged and serves as a biomarker for liver inflammation. It is typically measured in people receiving ART to monitor for liver drug toxicity (hepatotoxicity). In this study, chronic ALT elevation was defined as levels greater than the upper limit of normal at 2 consecutive semi-annual visits.

Results

• 2365 participants contributed a total 9972 person-years of follow-up.
• 385 participants (16%) developed chronic elevated ALT, for an incidence of 3.9 cases per 100 person-years.
• The incidence of chronic ALT elevation decreased significantly over time:
• 5.6 cases per 100 PY during 2002-2003;
• 4.5 cases per 100 PY during 2004-2005;
• 2.8 cases per 100 PY during 2006-2008.
• In a multivariate analysis controlling for potentially confounding factors, chronic elevated ALT was associated with the following:

o   HIV RNA level > 100,000 copies/mL: incidence rate ratio (IRR) 2.23, or more than twice the risk;

o   BMI indicating overweight (25-29.9): IRR 1.56;

o   BMI indicating obese (30 or higher): IRR 1.70;

o   "severe" alcohol use (> 40 g/day for women or > 60 g/day for men): IRR 1.83;

o   stavudine use: IRR 1.12 per year of exposure;

o   zidovudine use: IRR 1.04 per year of exposure.

• Associations with cumulative exposure to any combination ART, nucleoside reverse-transcriptase inhibitors (NRTIs) as a class, and unboosted protease inhibitors as a class were no longer statistically significant after adjusting for stavudine exposure.
• Other risk factors for non-alcoholic fatty liver disease (NAFLD) including abdominal obesity (IRR 1.66), lipoatrophy (IRR 1.50), lipohypertrophy (IRR 1.79), elevated cholesterol (IRR 1.63), and elevated triglycerides (IRR 1.75) were linked to elevated ALT in univariate but not multivariate analysis.
• Black race/ethnicity was associated with a decreased risk of chronic ALT elevation (IRR 0.52, or about half the risk).
• Interestingly, treatment outcomes and mortality rates did not differ between patients with and without chronic elevated ALT (5-year mortality 0.3% vs 1.6%, respectively; P = 0.14).

"Our results confirm that the main causes of chronic liver disease in HIV-infected patients without hepatitis B and C coinfections are alcohol consumption, non-alcoholic fatty liver disease (NAFLD) and antiretroviral drugs," the study authors wrote. High BMI is a risk factor for steatosis, or fatty liver.

"Besides those factors classically recognized as predisposing to hepatic steatosis in HIV-negative individuals, such as being overweight and having elevated alcohol consumption, high HIV RNA levels and exposure to stavudine and zidovudine were associated with chronic elevated ALT levels," they elaborated.

While various antiretroviral drugs can cause liver injury by different mechanisms, this study pointed to stavudine and zidovudine, which are thought to cause liver damage related to mitochondrial toxicity. Stavudine is no longer recommended for first-line ART for this reason, and AZT is falling out of favor. The researchers noted that the incidence of ALT elevation decreased over time, as stavudine use became less common. This analysis did not find a significant association with nevirapine -- which can cause liver toxicity related to hypersensitivity -- after adjusting for stavudine use.

The association between high HIV viral load and elevated ALT is consistent with other studies, and may be related to system inflammation triggered by HIV, they suggested.

Previous studies of both HIV positive and HIV negative individuals have found an association between elevated ALT and increased mortality, which was not observed in this study, with its relatively short follow-up period. The investigators suggested that "long-term follow-up is needed to assess whether chronic elevation of ALT levels will result in increased morbidity or mortality."

Finally, they recommended, "Early recognition and management of metabolic factors (eg, being overweight or having dyslipidemia), prevention or treatment of severe alcohol use, early initiation of combination ART if the HIV RNA level is high, and avoidance of stavudine and zidovudine are recommended in patients with chronically elevated ALT levels."

Division of Infectious Diseases and Hospital Epidemiology, University Hospital, Zurich, University of Zurich; Division of Infectious Diseases and Hospital Epidemiology, University Hospital, Basel; University Clinic of Infectious Diseases, University Hospital Berne; University of Berne, Berne; Division of Infectious Diseases, University Hospital, Geneva; Division of Infectious Diseases, University Hospital, Lausanne; Division of Infectious Diseases, Cantonal Hospital, St. Gall; Ospedale Regionale, Lugano, Switzerland.

1/26/10

Reference

H Kovari, B Ledergerber, M Battegay, and others. Incidence and Risk Factors for Chronic Elevation of Alanine Aminotransferase Levels in HIV-Infected Persons without Hepatitis B or C Virus Co-Infection. Clinical Infectious Diseases 50(4): 502–511(Abstract). February 15, 2010.