Hepatic profile analyses of tipranavir in Phase II and III clinical trials.
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.
Mikl
Jaromir
J
SUNY at Albany, School of Public Health, Rensselaer NY, USA. jmikl1@nycap.rr.com
Sulkowski
Mark S
MS
Benhamou
Yves
Y
Dieterich
Douglas
D
Pol
Stanislas
S
Rockstroh
Jürgen
J
Robinson
Patrick A
PA
Ranga
Mithun
M
Stern
Jerry O
JO
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
D019380:Anti-HIV Agents; D011725:Pyridines; D011753:Pyrones; D013449:Sulfonamides; D000637:Transaminases; D019438:Ritonavir; C107201:tipranavir