title: 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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  US-NIH Trial registration number: NCT00144170.
authors.affiliation: SUNY at Albany, School of Public Health, Rensselaer NY, USA. jmikl1@nycap.rr.com
authors.forename: Jaromir
authors.initials: J
authors.lastname: Mikl
authors.forename: Mark S
authors.initials: MS
authors.lastname: Sulkowski
authors.forename: Yves
authors.initials: Y
authors.lastname: Benhamou
authors.forename: Douglas
authors.initials: D
authors.lastname: Dieterich
authors.forename: Stanislas
authors.initials: S
authors.lastname: Pol
authors.forename: Jürgen
authors.initials: J
authors.lastname: Rockstroh
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Robinson
authors.forename: Mithun
authors.initials: M
authors.lastname: Ranga
authors.forename: Jerry O
authors.initials: JO
authors.lastname: Stern
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019380:Anti-HIV Agents / Q000009:adverse effects* / Q000627:therapeutic use; D005260:Female; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy; D006525:Hepatitis, Viral, Human / Q000150:complications / Q000188:drug therapy; D006801:Humans; D053208:Kaplan-Meier Estimate; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D017093:Liver Failure / Q000139:chemically induced*; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D016016:Proportional Hazards Models; D011725:Pyridines / Q000009:adverse effects* / Q000627:therapeutic use; D011753:Pyrones / Q000009:adverse effects* / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic; D012307:Risk Factors; D019438:Ritonavir / Q000009:adverse effects / Q000627:therapeutic use; D013449:Sulfonamides; D000637:Transaminases / Q000097:blood*; D055815:Young Adult
chemical_list: D019380:Anti-HIV Agents; D011725:Pyridines; D011753:Pyrones; D013449:Sulfonamides; D000637:Transaminases; D019438:Ritonavir; C107201:tipranavir