Hepatotoxicity Associated with Protease inhibitor-based Regimens with or without Concurrent Ritonavir

The risk of hepatoxicicty among HIV monoinfected and HIV-HCV coinfected individuals using HIV protease inhibitors with or without concurrent ritonavir (Norvir) continues to be a concern.

In the current study, researchers sought to determine the incidence of significant liver enzyme elevations following the initiation of protease inhibitor (PI)-based antiretroviral therapy (ART) with or without pharmacokinetic boosting with ritonavir (RTV), and to define the role of chronic viral hepatitis in its development.

This was a prospective, cohort analysis of 1161 PI-naive, HIV-infected patients receiving RTV-boosted lopinavir (Kaletra), indinavir (Crixivan) and saquinavir (Invirase) and unboosted PI-based ART (indinavir, nelfinavir [Viracept]) that had at least one liver enzyme measurement before and during therapy.

The incidence of grade 3 and 4 liver enzyme elevations among persons with and without hepatitis B and/or C co-infection treated with PI-based ART were compared. Severe hepatotoxicity was defined as an increase in serum liver enzyme >= 5-times the upper limit of the normal range or 3.5-times an elevated baseline level.

Results

The incidence of grade 3 or 4 elevations among PI-naive patients was: nelfinavir, 11%; lopinavir/RTV (200 mg/day), 9%; indinavir, 13%; indinavir/RTV (200-400 mg/day), 12.8%; and saquinavir/RTV (800 mg/day), 17.2%.

The risk was significantly greater among persons with chronic viral hepatitis (63% of cases); however, the majority of hepatitis C virus (HCV)-infected patients treated with nelfinavir (84%), saquinavir/RTV (74%), indinavir, 86%, indinavir/RTV (90%) or lopinavir/RTV (87%) did not develop hepatotoxicity.

Conclusions

The authors conclude, “Our data suggest that the lopinavir/RTV is not associated with a significantly increased risk of hepatotoxity among HCV-infected and uninfected patients compared with an alternative PI-based regimen, nelfinavir. Accordingly, other medication-related factors (e.g., efficacy and non-hepatic toxicity) should guide individual treatment decisions.”

Discussion

In the current study, the incidence of grade 3 or 4 liver enzyme elevations in patients prescribed the lopinavir/RTV was similar to the incidence observed among those taking nelfinavir, as well as the incidence previously reported among patients receiving efavirenz.

In addition, the risk of hepatotoxicity observed with low-dose RTV-boosted PI regimens was substantially lower than the risk seen with higher dose RTV either alone or in combination with saquinavir.

Furthermore, although hepatitis C co-infection was independently associated with the development of significant liver enzyme elevations during therapy with PI-based regimens, the majority of co-infected patients taking PI-based HAART did not experience significant hepatotoxicity.

The authors write, “Taken together, our data suggest that the risk of hepatotoxicity does not substantially differentiate between lopinavir/RTV-based regimen and alternative PI (e.g., nelfinavir) or NNRTI-based regimens (e.g., efavirenz); accordingly, other medication-related characteristics (e.g., efficacy, resistance and non-hepatic adverse effects) should guide individual treatment decisions.”

“Finally, randomized, controlled studies will be necessary to directly compare the risk of liver injury with PI- and NNRTI-based regimens, including novel PIs and/or dosing regimens, and to further define the mechanism of interaction between drug-induced hepatotoxicity and chronic viral hepatitis.”

01/05/05

Reference
M S Sulkowski and others. Hepatotoxicity associated with protease inhibitor-based antiretroviral regimens with or without concurrent ritonavir. AIDS 18(17): 2277-2284, November 19, 2004.