The use of highly active antiretroviral therapy (HAART) has greatly reduced AIDS-related death rates in North America, Western Europe and Australia. Yet HAART users can experience a range of side effects, including varying degrees of liver damage. Indeed, between 6% and 30% of people with HIV/AIDS can develop increased levels of liver enzymes in the blood — suggestive of liver damage — once they begin to use HAART. This problem occurs because HAART drugs often affect the liver, interferring with how this organ works.

It is possible that some drugs used in HAART regimens affect the liver more than others. To begin studying this, researchers in Baltimore, Maryland, compared the effect that two commonly used anti-HIV drugs — the non-nucleoside analogues (non-nukes) efavirenz (Sustiva, Stocrin) and nevirapine (Viramune) — have on the liver.

Study details

Between 1996 and 2001, researchers enrolled 568 HIV positive subjects who were prescribed combination anti-HIV therapy containing either nevirapine (256 subjects) or efavirenz (312 subjects). The subjects had the following profile:

• 71% male, 29% female
• an average CD4+ count of 150 cells
• an average viral load of 45,000 copies

Researchers divided subjects into two basic groups based on the drugs they used — nevirapine or efavirenz — and monitored them for an average of about 10 months.

Liver enzyme levels

Before starting their study medications, in general, researchers found that there were no differences in liver enzyme levels between the two groups of subjects. However, subjects co-infected with hepatitis C virus (HCV) had significantly higher liver enzyme levels than subjects who were not co-infected with HCV.

Results

After subjects entered the study and began using HAART, levels of liver enzymes in the blood remained near normal levels in the following proportion of subjects in each group:

• efavirenz users – 51%
• nevirapine users – 20%

This difference was statistically significant; that is, not likely due to chance alone.

Researchers detected severe liver toxicity — which they defined as liver enzyme levels greater than 3.5 times the upper limit of normal — in the following proportion of subjects:

• efavirenz – 8%
• nevirapine – 16%

This difference was also significant.

Hepatitis C

The researchers found that severe liver toxicity was most commonly detected in HCV co-infected subjects receiving nevirapine or efavirenz in combination with a protease inhibitor.

Nevirapine hypersensitivity

In a very small proportion of nevirapine users, a hypersensitivity reaction — fever, rash — can occur. In this study, hypersensitivity reaction occured in only one male user of nevirapine.

Unrelated factors

Researchers found that the following factors were not related to developing severe liver damage:

• race
• gender
• age
• viral load
• use of AZT, d4T (Zerit, stavudine) or ddI (Videx)

Deaths due to complications of liver damage

Three HCV positive subjects who received nevirapine and protease inhibitors required hospitalization because of complications from liver damage. Two of these subjects died. Among HCV positive subjects who received efavirenz and protease inhibitors, one required hospitalization and later died from complications due to liver damage. Overall, death occurred in the following proportion of subjects in each group:

• nevirapine – 23%
• efavirenz – 11%

Key points

• It is important to bear in mind that that the majority of subjects in this study did not develop severe liver damage.
• The risk of developing severe liver damage was twice as high among subjects co-infected with hepatitis-causing viruses
• 70% of cases of severe liver damage occurred among subjects who were co-infected with HBV (hepatitis B virus) or HCV
• Subjects who used protease inhibitors in addition to efavirenz or nevirapine were twice as likely to develop serious liver toxicity as subjects who did not use protease inhibitors

REFERENCE

Sulkowski MS, Thomas DL, Mehta SH, et al. Hepatotoxicity associated with nevirapine or efavirenz-containing antiretroviral therapy: role of hepatitis C and B infections. Hepatology 2002;35:182-189.

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