Incidence and risk factors for liver enzyme elevation during highly active antiretroviral therapy in HIV-HCV co-infected patients: results from the Italian EPOKA-MASTER Cohort

Abstract

Background: The risk of hepatotoxicity associated with different highly active antiretroviral therapy (HAART) regimens (containing multiple-protease inhibitors, single-protease inhibitors or non nucleoside reverse transcriptase inhibitors) in HIV-HCV co-infected patients has not been fully assessed.

Methods: Retrospective analysis of a prospective cohort of 1,038 HIV-HCV co-infected patients who commenced a new HAART in the Italian MASTER database. Patients were stratified into naïve and experienced to antiretroviral therapy before starting the study regimens. Time to grade > or =III hepatotoxicity (as by ACTG classification) was the primary outcome. Secondary outcome was time to grade IV hepatotoxicity.

Results: Incidence of grade > or =III hepatotoxicity was 17.71 per 100 patient-years (p-yr) of follow up in naïve patient group and 8.22 per 100 p-yrs in experienced group (grade IV: 4.13 per 100 p-yrs and 1.08 per 100 p-yrs, respectively). In the latter group, the only independent factors associated with shorter time to the event at proportional hazards regression model were: previous liver transaminase elevations to grade > or =III, higher baseline alanine amino-transferase values, and use of a non nucleoside reverse transcriptase inhibitor based regimen. In the naive group, baseline aspartate transaminase level was associated with the primary outcome.

Conclusion: Use of a single or multiple protease inhibitor based regimen was not associated with risk of hepatotoxicity in either naïve or experienced patient groups to a statistically significant extent. A cautious approach with strict monitoring should be applied in HIV-HCV co-infected experienced patients with previous liver transaminase elevations, higher baseline alanine amino-transferase values and who receive regimens containing non nucleoside reverse transcriptase inhibitors.

Figure 1

Time-to-development of grade ≥III hepatotoxicity among naïve (1a) and experienced (1b) patient groups stratified by type of antiretroviral treatment regimens prescribed. Continuous lines represent patients prescribed HIV-1 non nucleoside reverse transcriptase inhibitors; dotted lines represent patients prescribed single HIV-1 protease inhibitor regimens; dashed lines represent patients prescribed multiple HIV-1 protease inhibitor regimens. P: 0.16 for comparison across antiretroviral naïve patients prescribed different regimens (see panel 1a); P: 0.027 for comparison across antiretroviral experienced patients prescribed different regimens (panel 1b).

Figure 2

Results of the multiple proportional hazards regression analysis performed (end-point: grade III LFTs elevation) in experienced patient group. Circles represent hazard ratio; orizontal lines represent 95% confidence interval. The following abbreviations were used: IFN = interferon; LFT = liver function test; ALT = alanine amino-transferase, AST = aspartate amino-transferase; DDX = dideoxynucleoside reverse transcriptase inhibitors (i.e., didanosine, stavudine, zalcitabine); PI = protease inhibitor; NNRTI = non nucleoside reverse transcriptase inhibitor. Initial models have been run using variables whose data were available for all patients. Results for these variables are reported in the present figure. Further separate models have been performed imputing variables whose data were not available in some patients, however predictive values of variables whose data set was complete did not differ from those obtained through the initial models performed.