Transaminitis After Interferon-Ribavirin Therapy in HIV/HCV
The 248 patients included in the cohort had been receiving antiretroviral therapy for a mean of 6.3 (± 3.2) years. Their clinical and biological characteristics at the end of the trial of interferon-based anti-HCV therapy (W72 SVR assessment) are summarized in Table 1. Most patients were men (75%), and mean age was 41 ± 5 years. Intravenous drug use was the risk factor for HCV transmission in 62% of cases. Current alcohol consumption was reported by 47% of patients. Significant fibrosis (METAVIR score F3 or F4) was present in 98 patients (40%). Seventy-one patients (29%) had a sustained HCV response. During follow-up, 66 patients (26.6%) received a second course of anti-HCV therapy (peg-interferon plus ribavirin) and 29 (44%) of them had an SVR.
Severe transaminitis occurred in 64 patients (26%), a median of 54.5 (IQR 25.3–66.6) months after their inclusion in the cohort. Median follow-up was similar in patients with and without transaminitis: 5.4 years (IQR 4.5–5.7) vs 5.1 years (IQR 3.7–5.7), P = 0.3.
The baseline ALT level was normal in 36% of patients with severe transaminitis and in 64% of patients without severe transaminitis (P < 0.0001). Serum levels of GGT and Alk Ph were not significantly different between the two groups. At the onset of liver toxicity, the mean ALT and AST levels were 4.3 ± 2.3 ULN and 4.2 ± 2.0 ULN, respectively.
In univariate analysis, patients with severe transaminitis were older than the other patients (42.3 ± 5 vs 40.5 ± 5 years, P = 0.02) and were less likely to have an HCV SVR at the end of the trial (2%vs 38%; P < 0.0001) (Table 1). The duration of antiretroviral therapy tended to be longer in patients with severe transaminitis (7.0 ± 3.3 vs 6.1 ± 3.1 years, P = 0.06). Patients with severe transaminitis were more likely to be on stavudine-based therapy (HR 1.8, 95% CI 1.1–3.1, P = 0.02) and less likely to be taking abacavir (HR 0.4, 95% CI 0.2–0.8, P = 0.008) or lopinavir (HR 0.5, 95% CI 0.3–0.9, P = 0.02) (Table 2). Seventy-nine patients (32%) received stavudine-based therapy, 94 (38%) abacavir-based therapy and 88 (35%) lopinavir-based therapy during follow-up. Severe transaminitis tended to be less frequent in patients receiving PIs (HR 0.6, 95% CI 0.34–1.0, P = 0.06), while 70% of patients received at least one PI during follow-up. In contrast, didanosine, zidovudine, lamivudine, tenofovir, atazanavir, efavirenz and nevirapine exposure did not influence the risk of severe transaminitis.
The following factors were also not associated with the risk of severe transaminitis: sex, body mass index, current alcohol consumption (yes/no), CD4 cell count, HIV viral load above 200 copies/mL, HCV transmission group, extensive fibrosis (Metavir score F3 or F4), HCV viral load and HCV genotype.
In multivariate analysis, no SVR (HR 33.33, 95% CI 4.54–222, P = 0.001) and stavudine-based therapy (HR 2.11, 95% CI 1.12–3.99, P = 0.018) remained significantly associated with severe transaminitis (Table 3). Stavudine exposure was similar in patients with SVR and in the others (P = 0.992). Severe transaminitis occurred in 22% of patients receiving stavudine and in 11.09% of the remaining patients (P = 0.008). In stratified analysis according to SVR achievement, stavudine remained associated with severe transaminitis among patients who did not achieve SVR (HR 2.19, CI 95% 1.16–4.14, P = 0.016). Only one patient with SVR experienced a severe cytolysis through follow-up. This patient received stavudine also.
Results
The 248 patients included in the cohort had been receiving antiretroviral therapy for a mean of 6.3 (± 3.2) years. Their clinical and biological characteristics at the end of the trial of interferon-based anti-HCV therapy (W72 SVR assessment) are summarized in Table 1. Most patients were men (75%), and mean age was 41 ± 5 years. Intravenous drug use was the risk factor for HCV transmission in 62% of cases. Current alcohol consumption was reported by 47% of patients. Significant fibrosis (METAVIR score F3 or F4) was present in 98 patients (40%). Seventy-one patients (29%) had a sustained HCV response. During follow-up, 66 patients (26.6%) received a second course of anti-HCV therapy (peg-interferon plus ribavirin) and 29 (44%) of them had an SVR.
Severe transaminitis occurred in 64 patients (26%), a median of 54.5 (IQR 25.3–66.6) months after their inclusion in the cohort. Median follow-up was similar in patients with and without transaminitis: 5.4 years (IQR 4.5–5.7) vs 5.1 years (IQR 3.7–5.7), P = 0.3.
The baseline ALT level was normal in 36% of patients with severe transaminitis and in 64% of patients without severe transaminitis (P < 0.0001). Serum levels of GGT and Alk Ph were not significantly different between the two groups. At the onset of liver toxicity, the mean ALT and AST levels were 4.3 ± 2.3 ULN and 4.2 ± 2.0 ULN, respectively.
In univariate analysis, patients with severe transaminitis were older than the other patients (42.3 ± 5 vs 40.5 ± 5 years, P = 0.02) and were less likely to have an HCV SVR at the end of the trial (2%vs 38%; P < 0.0001) (Table 1). The duration of antiretroviral therapy tended to be longer in patients with severe transaminitis (7.0 ± 3.3 vs 6.1 ± 3.1 years, P = 0.06). Patients with severe transaminitis were more likely to be on stavudine-based therapy (HR 1.8, 95% CI 1.1–3.1, P = 0.02) and less likely to be taking abacavir (HR 0.4, 95% CI 0.2–0.8, P = 0.008) or lopinavir (HR 0.5, 95% CI 0.3–0.9, P = 0.02) (Table 2). Seventy-nine patients (32%) received stavudine-based therapy, 94 (38%) abacavir-based therapy and 88 (35%) lopinavir-based therapy during follow-up. Severe transaminitis tended to be less frequent in patients receiving PIs (HR 0.6, 95% CI 0.34–1.0, P = 0.06), while 70% of patients received at least one PI during follow-up. In contrast, didanosine, zidovudine, lamivudine, tenofovir, atazanavir, efavirenz and nevirapine exposure did not influence the risk of severe transaminitis.
The following factors were also not associated with the risk of severe transaminitis: sex, body mass index, current alcohol consumption (yes/no), CD4 cell count, HIV viral load above 200 copies/mL, HCV transmission group, extensive fibrosis (Metavir score F3 or F4), HCV viral load and HCV genotype.
In multivariate analysis, no SVR (HR 33.33, 95% CI 4.54–222, P = 0.001) and stavudine-based therapy (HR 2.11, 95% CI 1.12–3.99, P = 0.018) remained significantly associated with severe transaminitis (Table 3). Stavudine exposure was similar in patients with SVR and in the others (P = 0.992). Severe transaminitis occurred in 22% of patients receiving stavudine and in 11.09% of the remaining patients (P = 0.008). In stratified analysis according to SVR achievement, stavudine remained associated with severe transaminitis among patients who did not achieve SVR (HR 2.19, CI 95% 1.16–4.14, P = 0.016). Only one patient with SVR experienced a severe cytolysis through follow-up. This patient received stavudine also.
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