July 9, 2002
There has been a growing concern about the risk of long-term complications from HIV therapy -- among these are mitochondrial injury, lipodystrophy and liver toxicity. The latter is the focus of this study, brought to recent attention by the fact that many HIV therapies are metabolized by the liver and the increasing recognition of the prevalence of co-infection with hepatitis B and C virus among many HIV-infected persons.
This study analyzed a large cohort of HIV-infected persons from four clinic sites across the United States, called the CHORUS cohort. Over 5,000 people are studied in the cohort, 1,237 of these were included in this analysis (those who initiated first three-drug HAART therapy and had baseline liver function testing).
The analysis compared different classes of treatment: nucleoside (triple nukes; NRTI), nucleoside + protease inhibitors (NRTI + PI); NRTI + non-nucleoside RT inhibitors (NNRTI); triple class regimens of NRTI + NNRTI + PI. There were differences in the baseline patient demographics, with NRTI patients having higher median CD4+ cell counts and lower viral loads than the other treatment groups; conversely, the triple class patients had greater prior pre-HAART therapy.
When the three classes of therapies were compared for the incidence of grade 2, 3 or 4 liver toxicity, there were no significant differences. Liver injury was low, with seven to nine events per 100 person years of therapy -- a rate roughly 10 percent per person year. The incidence of serious toxicity (grade 3) was expectedly even lower, about 5 percent and there were no cases of clinically evident hepatitis. However, when the data were adjusted for site, evidence of baseline liver function test abnormality, concurrent or past hepatitis, the later three factors appear to significantly increase the likelihood of having liver toxicity. Persons with baseline liver function test abnormality were nearly three-fold more likely to have treatment emergent liver toxicity; persons with concurrent hepatitis were 4.6-fold more likely to have liver toxicity (compared with persons receiving the triple nucleoside class regimen).
These data show that the absolute risk of serious liver injury is low in the real-world clinic population and apparently independent of the type of treatment used -- perhaps surprising because of anecdotal suggestion that the rates of liver toxicity are higher among persons receiving non-nucleoside RT inhibitor-based therapies.
The study conclusions are limited because of the lack of information about concurrent alcohol consumption and lack of documentation about the specific drugs used. The later point could be important if one member of the class produced toxicity while a second did not; the net effect could be to cancel out the ability of the analysis to detect an effect (for example nevirapine vs. efavirenz or single vs. boosted protease inhibitor). The finding of increased risk for liver toxicity among persons with baseline liver function test abnormality or history of hepatitis is clinically important, because these data provide a way for clinicians and patients to modify their counseling and monitoring while on therapy -- persons with these risk factors might be more carefully monitored while on therapy. Overall, as we accumulate additional information about the best (and less better) settings in which to use our medications, we can hopeful utilize this data to appropriately select patients who are more likely to have durable and least toxic responses to therapy.
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