Hepatic profile analyses of tipranavir in Phase II and III clinical trials

Abstract

Background: The risk and course of serum transaminase elevations (TEs) and clinical hepatic serious adverse event (SAE) development in ritonavir-boosted tipranavir (TPV/r) 500/200 mg BID recipients, who also received additional combination antiretroviral treatment agents in clinical trials (TPV/r-based cART), was determined.

Methods: Aggregated transaminase and hepatic SAE data through 96 weeks of TPV/r-based cART from five Phase IIb/III trials were analyzed. Patients were categorized by the presence or absence of underlying liver disease (+LD or -LD). Kaplan-Meier (K-M) probability estimates for time-to-first US National Institutes of Health, Division of AIDS (DAIDS) Grade 3/4 TE and clinical hepatic SAE were determined and clinical actions/outcomes evaluated. Risk factors for DAIDS Grade 3/4 TE were identified through multivariate Cox regression statistical modeling.

Results: Grade 3/4 TEs occurred in 144/1299 (11.1%) patients; 123/144 (85%) of these were asymptomatic; 84% of these patients only temporarily interrupted treatment or continued, with transaminase levels returning to Grade < or = 2. At 96 weeks of study treatment, the incidence of Grade 3/4 TEs was higher among the +LD (16.8%) than among the -LD (10.1%) patients. K-M analysis revealed an incremental risk for developing DAIDS Grade 3/4 TEs; risk was greatest through 24 weeks (6.1%), and decreasing thereafter (>24-48 weeks: 3.4%, >48 weeks-72 weeks: 2.0%, >72-96 weeks: 2.2%), and higher in +LD than -LD patients at each 24-week interval. Treatment with TPV/r, co-infection with hepatitis B and/or C, DAIDS grade >1 TE and CD4+ > 200 cells/mm3 at baseline were found to be independent risk factors for development of DAIDS Grade 3/4 TE; the hazard ratios (HR) were 2.8, 2.0, 2.1 and 1.5, respectively. Four of the 144 (2.7%) patients with Grade 3/4 TEs developed hepatic SAEs; overall, 14/1299 (1.1%) patients had hepatic SAEs including six with hepatic failure (0.5%). The K-M risk of developing hepatic SAEs through 96 weeks was 1.4%; highest risk was observed during the first 24 weeks and decreased thereafter; the risk was similar between +LD and -LD patients for the first 24 weeks (0.6% and 0.5%, respectively) and was higher for +LD patients, thereafter.

Conclusion: Through 96 weeks of TPV/r-based cART, DAIDS Grade 3/4 TEs and hepatic SAEs occurred in approximately 11% and 1% of TPV/r patients, respectively; most (84%) had no significant clinical implications and were managed without permanent treatment discontinuation. Among the 14 patients with hepatic SAE, 6 experienced hepatic failure (0.5%); these patients had profound immunosuppression and the rate appears higher among hepatitis co-infected patients. The overall probability of experiencing a hepatic SAE in this patient cohort was 1.4% through 96 weeks of treatment. Independent risk factors for DAIDS Grade 3/4 TEs include TPV/r treatment, co-infection with hepatitis B and/or C, DAIDS grade >1 TE and CD4+ > 200 cells/mm3 at baseline.

Trial registration: US-NIH Trial registration number: NCT00144170.

Figure 1

Kaplan-Meier estimates for time-to-first Grade 3/4 ALT/AST elevations and to first hepatobiliary serious adverse events (SAEs) among TPV/r recipients by baseline risk group. Log-rank test p-value comparing -LD vs. +LD:. Incidence of Hepatic SAEs p = 0.0125. Incidence of DAIDS Grade 3/4 ALT/AST p = 0.0072. TPV/r +LD patients with Grade 3/4 ALT/AST = TPV/r patients co-infected with HBV/HCV or with baseline ALT/AST DAIDS >1, time-to-first DAIDS ὅ3 ALT/AST. TPV/r -LD patients with Grade 3/4 ALT/AST = TPV/r patients not co-infected with HBV/HCV and with baseline ALT/AST DAIDS ὄ1, time-to-first DAIDS ὅ3 ALT/AST. TPV/r +LD patients with hepatic SAE = TPV/r patients co-infected with HBV/HCV or with baseline ALT/AST DAIDS >1, time-to-first onset date of hepatic SAE. TPV/r -LD patients with hepatic SAE = TPV/r patients not co-infected with HBV/HCV and with baseline ALT/AST DAIDS ὄ1, time-to-first onset date of hepatic SAE. +LD = patients with underlying liver disease (baseline evidence of active HBV/HCV infection or ALT/AST DAIDS >1); -LD = patients with no apparent liver disease (absence of active HBV/HCV infection and ALT/AST Grade ≤ 1); ALT = alanine aminotransferase; AST = aspartate aminotransferase; DAIDS = Division of AIDS; HBV = hepatitis B virus; HCV = hepatitis C virus; TPV/r = ritonavir-boosted tipranavir.

Figure 2

Actions and outcomes of Grade 3/4 ALT/AST elevations among TPV/r recipients. TPV/r +LD patients = TPV/r patients co-infected with HBV/HCV or with baseline ALT/AST DAIDS >1. TPV/r -LD patients = TPV/r patients not co-infected with HBV/HCV and with baseline ALT/AST DAIDS ὄ1. +LD = patients with underlying liver disease (baseline evidence of active HBV/HCV infection or ALT/AST DAIDS >1); -LD = patients with no apparent liver disease (absence of active HBV/HCV infection and ALT/AST Grade ≤ 1); ALT = alanine aminotransferase; AST = aspartate aminotransferase; HBV = hepatitis B virus; HCV = hepatitis C virus; IQR = interquartile range; TPV/r = ritonavir-boosted tipranavir.