Serum gamma-glutamyl transferase (GGT) levels are frequently elevated in HIV/hepatitis C virus (HCV)-coinfected patients but the significance of this abnormality is unclear. In HIV-monoinfected patients, liver toxicity is one of the most problematic adverse effects of antiretroviral therapy . In HCV-monoinfected patients, the GGT level has been linked to the hepatocyte growth factor level, which rises as fibrosis progresses and has been implicated in fibrogenesis . The aim of this study was to determine the prevalence of markedly elevated GGT levels [>5 upper limit of normal (ULN)] in 395 HIV/HCV-coinfected patients, and to examine possible interactions with host factors, viral factors, and antiretroviral treatment.
The patients were stratified into two groups according to their GGT level (≤5 and >5 ULN). The chi-square test or Fisher's exact test was used to analyze qualitative variables, and the Mann–Whitney test was used for quantitative variables. Logistic regression models were used to test possible associations between a high GGT level (outcome variable) and baseline characteristics (input variables). Characteristics with P-values below 0.05 in univariate analysis were included in multivariate models on the basis of a backward elimination procedure. All statistical tests were two-sided, with a type I error of 5%.
The demographic and biological characteristics of the 395 patients are shown in Table 1 according to the GGT level (≤5 ULN, n = 332; > 5 ULN, n = 63). Three hundred and twenty-five patients (82.3%) were receiving antiretroviral therapy, for a mean of 4.4 ± 3.3 years. The mean GGT level was 8.2 ± 3.5 ULN in patients with GGT levels higher than 5 ULN and 1.9 ± 1.2 ULN in the other patients. The mean alkaline phosphatase level was also higher in the patients with high GGT levels but it remained within the normal range. Serum levels of alanine aminotransferase, aspartate aminotransferase and bilirubin were not significantly different in the two groups, and bilirubin levels were also in the normal range.
Univariate analysis showed that a high GGT level was significantly associated with the following baseline variables: HCV genotype 4, HIV viral load below 400 copies/ml, nucleoside reverse transcriptase inhibitor (NRTI), protease inhibitor and nonnucleoside reverse transcriptase inhibitor (NNRTI) exposure. Among the NRTIs, didanosine and abacavir were significantly associated with high GGT levels. The following factors were not associated with high GGT levels: age, sex, BMI, the mean duration of HIV and HCV infection, AIDS status, the baseline CD4 cell count, the mean duration of antiretroviral treatment, the HCV transmission group, the mean METAVIR scores for necroinflammation and fibrosis, the presence of cirrhosis and steatosis, and HCV viral load.
In multivariate analysis, HCV genotype 4 [odds ratio (OR) = 4.02, 95% confidence interval (CI) = 1.86–8.70; P = 0.0004], NNRTIs (OR = 6.75, 95% CI = 3.65–12.48; P < 0.0001) and abacavir (OR = 2.75 95% CI = 1.24–6.11; P = 0.0129) remained significantly associated with high GGT levels.
GGT levels exceeded five times the normal upper limit in 63 (15.9%) of the 395 HIV/HCV-coinfected patients enrolled in this study. These patients were more likely to have HCV genotype 4 infection and to be receiving NNRTI-containing or abacavir-containing antiretroviral regimens. The GGT level was high in 34.0% of the 123 patients receiving NNRTI-containing regimens and in 28.8% of the 45 patients receiving abacavir-containing regimens. High GGT levels were similarly frequent in patients receiving nevirapine (NVP) (30.1%)-containing and efavirenz (EFV) (36.5%)-containing regimens.
GGT, a membrane-bound enzyme, participates in glutathione metabolism and is indirectly involved in drug metabolism . When levels of other cholestasis marker enzymes are normal, increased GGT serum activity is probably because of enzyme induction. A two- to three-fold increase in GGT levels has been observed in patients starting antiretroviral therapy with NVP or switching from protease inhibitor to NVP or to EFV [4,5]. A significantly higher NVP concentration has been observed in patients with elevated GGT level . We were unable to confirm this finding, as serum drug levels were unavailable in our study. Regarding protease inhibitors, a correlation between high plasma lopinavir and GGT levels has been noted . Elsewhere, plasma levels of NNRTI are higher in HIV/HCV co-infected patients than in HIV-monoinfected patients . Chronic liver disease may affect the activities of the various CYP isoforms, and NNRTIs are differentially metabolized by CYP isoforms, implying that hepatic dysfunction could affect NNRTI pharmacokinetics . Abacavir is metabolized by UDP-glucuronyltransferases and by cytosolic alcohol dehydrogenase, the activity of which can be affected by liver disease .
The independent link observed in our study between HCV genotype 4 and elevated GGT level has not previously been reported: 29.4% of the 51 patients with this genotype had high GGT levels, compared with only 16% of patients with genotype 1 and 10.4% of patients with genotype 2 or 3 infection. The only significant differences between patients with HCV genotype 4 and other genotypes were a lower mean METAVIR fibrosis score (2.03 ± 0.79 versus 2.37 ± 1.02; P = 0.03).
These findings have implications for the use of noninvasive liver fibrosis biomarker scoring systems that include GGT (fibrotest, forns, fibrometer and hepascore) , as their performance in HIV/HCV-coinfected patients could be affected by NNRTI or abacavir therapy.
This study was supported by Agence Nationale de Recherche sur le SIDA and SIDACTION.
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