Analysis of severe hepatic events associated with nevirapine-containing regimens: CD4+ T-cell count and gender in hepatitis C seropositive and seronegative patients.
BACKGROUND
Nevirapine-containing regimens have been associated with a risk of significant elevations of liver transaminase levels. Higher risk in antiretroviral-naive populations has been related to gender and CD4+ T-cell count (women with CD4+ T-cell counts of > or =250/mm(3) or men with CD4+ T-cell counts of > or =400/mm(3), i.e. group at risk). However, recent studies do not confirm this association in HIV populations comprising patients who are antiretroviral-experienced. Moreover, the predictive value of gender and CD4+ T-cell count on the risk of raised transaminase levels has been poorly investigated in populations of patients co-infected with hepatitis C virus (HCV).


METHODS
Analysis of HIV-positive patients receiving nevirapine-containing regimens for the first time was conducted. Grade > or =III hepatotoxicity (i.e. > or =5 x upper limit of normal in alanine aminotranferase or aspartate aminotransferase levels) was the primary endpoint. Univariate and multivariable Cox proportional hazard regression models were separately conducted among HCV-antibody (Ab)-positive and HCV-Ab-negative patients.


RESULTS
Amongst 905 patients, 49% were HCV-Ab-positive and 79% were antiretroviral-experienced. Grade > or =III liver transaminase elevations developed in 7.1% of patients, accounting for an incidence of 2.47 (95% CI 1.97, 3.09) per 100 patient-years of follow-up. HCV-Ab reactivity was associated with a 3-fold increase in risk of developing relevant liver transaminase elevations (95% CI 1.75, 5.3; p < 0.001), whereas gender and CD4+ T-cell count did not impact significantly. When analysis was performed in HCV-Ab-negative patients, the outcome was independently correlated with the group at risk (hazard ratio [HR] 3.66; 95% CI 1.20, 11.14; p = 0.022). By contrast, in HCV-Ab-positive patients, the group at risk was not significantly associated with the outcome.


CONCLUSIONS
Most of the excess rates of relevant raised transaminase levels in patients prescribed nevirapine-containing regimens could be attributed to HCV co-infection. Gender and CD4+ T-cell count appeared to have a statistically significant impact on the risk of relevant transaminase level elevations in HCV-negative, but not in HCV-positive patients, probably due to a diluting effect of HCV. Incidence of hepatic events after nevirapine-containing regimens did not appear to be a major concern in our cohort of patients who were mainly antiretroviral-experienced and negative for HCV-Ab. Preferably, nevirapine should be avoided in HCV co-infected patients and in males with CD4+ T-cell counts of > or =400/mm(3) or females with CD4+ T-cell counts of > or =250/mm(3).
Torti
Carlo
C
School of Medicine, Institute for Infectious and Tropical Diseases, University of Brescia, Brescia, Italy. torti.carlo@libero.it
Costarelli
Silvia
S
De Silvestri
Annalisa
A
Quiros-Roldan
Eugenia
E
Lapadula
Giuseppe
G
Cologni
Giuliana
G
Paraninfo
Giuseppe
G
Castelnuovo
Filippo
F
Puoti
Massimo
M
Carosi
Giampiero
G
D000328:Adult; D000410:Alanine Transaminase / Q000097:blood; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D001219:Aspartate Aminotransferases / Q000097:blood; D018791:CD4 Lymphocyte Count; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology; D015331:Cohort Studies; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy / Q000276:immunology; D015497:HIV-1; D016174:Hepacivirus / Q000276:immunology*; D006526:Hepatitis C / Q000150:complications / Q000276:immunology; D018937:Hepatitis C Antibodies / Q000097:blood*; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008111:Liver Function Tests; D008297:Male; D019829:Nevirapine / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D012189:Retrospective Studies; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D012307:Risk Factors; D012737:Sex Factors
D019380:Anti-HIV Agents; D018937:Hepatitis C Antibodies; D018894:Reverse Transcriptase Inhibitors; D019829:Nevirapine; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase