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

被引:12
作者
Mikl, Jaromir [1 ,2 ]
Sulkowski, Mark S. [3 ]
Benhamou, Yves [4 ]
Dieterich, Douglas [5 ]
Pol, Stanislas [6 ]
Rockstroh, Juergen [7 ]
Robinson, Patrick A. [2 ]
Ranga, Mithun [2 ]
Stern, Jerry O. [2 ]
机构
[1] SUNY Albany, Sch Publ Hlth, Rensselaer, NY USA
[2] Boehringer Ingelheim Pharmaceut Inc, Ridgefield, CT 06877 USA
[3] Johns Hopkins Univ, Sch Med, Div Infect Dis, Baltimore, MD 21205 USA
[4] Hop La Pitie Salpetriere, Serv Hepatogastroenterol, Paris, France
[5] Mt Sinai Sch Med, New York, NY USA
[6] Hop Necker Enfants Malad, AP HP, Unite Hepatol, Paris, France
[7] Univ Bonn, Dept Med 1, D-5300 Bonn, Germany
关键词
HUMAN-IMMUNODEFICIENCY-VIRUS; ACTIVE ANTIRETROVIRAL THERAPY; RISK-FACTORS; HIV-1-INFECTED PATIENTS; PROTEASE INHIBITORS; HEPATOTOXICITY; HIV; RITONAVIR; EFFICACY; COINFECTION;
D O I
10.1186/1471-2334-9-203
中图分类号
R51 [传染病];
学科分类号
100401 ;
摘要
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 <= 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/mm(3) 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/mm(3) at baseline.
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页数:11
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