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Focus on Hepatitis: Hepatitis Coinfection and LPV/RTV

By Michael Carter

October 2004

HIV-positive patients who are coinfected with hepatitis B virus (HBV) or hepatitis C virus (HCV) have a significantly increased risk of developing elevated liver enzyme levels when taking an antiretroviral regimen including lopinavir/ritonavir (LPV/RTV), according to a study published in the September 2004 HIV Medicine. The study's Italian investigators believe that the results emphasize the importance of testing patients for hepatitis coinfection at baseline and the importance of monitoring liver function before and during antiretroviral therapy.

A retrospective Canadian study, presented at the XV International AIDS Conference in Bangkok, found that the use of LPV/RTV by patients coinfected with HBV or HCV was significantly associated with the development of grade 3/4 elevations in alanine aminotransferase (ALT) levels.

It is well known that protease inhibitor (PI)-containing antiretroviral therapy regimens can cause liver toxicities. Two reasons for this side effect have been suggested: the intrinsic toxic effects of this class of drugs, and the recovery of cell-mediated immunity brought about by antiretroviral therapy leading to the damage of HBV- or HCV-specific liver cells.

Investigators in northern Italy wished to determine the incidence of, and risk factors for, elevations in liver enzymes in PI-experienced patients taking LPV/RTV as part of their antiretroviral therapy.

In a prospective study, a total of 782 patients were followed for 12 months, or until the appearance of elevated liver enzymes. Patients were taking the standard dose of LPV/RTV (400 mg LPV boosted by 100 mg RTV), unless they were also taking a nonnucleoside reverse transcriptase inhibitor (NNRTI), in which case the dose of LPV/RTV was increased (533 mg LPV with 133 mg RTV).

Alanine aminotransferase, aspartate aminotransferase (AST), lipid levels, CD4 count, and viral load were evaluated at baseline, one month after starting LPV/RTV, and then at three-month intervals. Tests were also performed for the presence of HBV and HCV.

Elevated liver enzymes were graded according to severity. Alanine aminotransferase levels 2.6 to five times the upper limit of normal were described as grade 2 toxicity, ALT levels five to 10 times the upper range of normal as grade 3 toxicity, and ALT levels over 10 times the upper limit of normal were described as grade 4 toxicity.

Of the 782 patients recruited to the study, a total of 269 (34 percent) had elevated liver enzymes at baseline, and elevated ALT and AST levels on entry to the study were significantly related to infection with hepatitis B or C (P<0.001).

The most common nucleoside reverse transcriptase inhibitor (NRTI) backbones taken with LPV/RTV were didanosine (ddI) and stavudine (d4T) (18 percent) and lamivudine (3TC) and d4T (13 percent). A total of 18 percent of patients were taking an NNRTI, and just under 10 percent were taking a second PI.

Median duration of follow-up was 349 days. A total of 185 patients (24 percent) discontinued LPV/RTV a median of 198 days after starting antiretroviral therapy. Of these patients, 88 stopped because of side effects, including 13 who experienced hepatic toxicities.

Across the study population, a total of 9 percent experienced elevations in liver enzymes during LPV/RTV therapy. Alanine aminotransferase levels increased significantly at months 3 (P = 0.006), 6 (P = 0.005) and 9 (P = 0.04). However, these increases were principally confined to coinfected patients, with a total of 16 percent of HBV- or HCV-infected patients developing elevated liver enzymes compared to only 3 percent of patients without these infections.

In the patients who did develop elevated liver enzymes, almost 75 percent had grade 2 toxicity, 20 percent grade 3 toxicity, and 5 percent grade 4 toxicity.

Thirteen patients stopped LPV/RTV, but continued with their other antiretroviral drugs, because of elevations in liver enzymes, and this led to a normalization of liver function in 11 patients. There were four hospitalizations and one death.

In multivariate analysis, the investigators found that coinfection with HBV or HCV (P<0.001), younger age (P = 0.005), elevated ALTs at baseline (P = 0.005), and concomitant use of efavirenz (EFV) (P = 0.008) were predictive for the development of increased liver enzymes during LPV/RTV-containing antiretroviral therapy.

The investigators conclude that hepatitis coinfection should be tested for prior to the initiation of antiretroviral therapy, and that liver function should be carefully and closely monitored during antiretroviral therapy. They also suggest that therapeutic drug level monitoring could prove a useful tool to enable physicians to adjust doses of drugs to prevent drug-related liver damage.

Editor's Note: Reprinted with permission from www.aidsmap.com (first e-published October 13, 2004).


References

  1. Meraviglia P, et al. Lopinavir/ritonavir treatment in HIV antiretroviral experienced patients: evaluation of risk factors for liver enzyme elevation. HIV Med 2004;5:334-351.

  2. Chihrin S, et al. Exposure to lopinavir/r is a risk factor for grade 3/4 elevation of ALT in HIV and hepatitis B (HBV) and/or C (HCV) coinfected patients. XV International AIDS Conference. July 13-16, 2004. Bangkok. [abstract MoPeB3281]




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