We carefully assessed an array of clinical and 
psychosocial risk factors and, not unexpectedly, found that never treated patients were older, more likely to engage in ongoing alcohol or other substance abuse, and to experience social instability compared with treatment nonresponders. We speculated that differing biobehavioral risk profiles were unlikely to account for the reduced incidence of cirrhosis in untreated patients since many of these would be predicted to increase, rather than reduce fibrosis progression. We used two alternative strategies to statistically adjust for these potential confounders in our Cox proportional hazards models. Using either adjustment method, treatment nonresponders were found to have a significantly greater hazard of developing cirrhosis than the never treated group�Ca finding that was observed in the both the SFVA and UCSF cohorts. Some differences between treated and never treated patients were identified that could not be completely corrected in our statistical models. Treated patients were followed for approximately 1.5 years longer than never treated patients and had, on average, one additional diagnostic procedure. Both the duration of follow-up and the number of diagnostic procedures were entered into predictive models, but were not found to be confounders for either outcome. It is still possible that unmeasured confounding factors linked to treatment failure may have biased the results, but rigorous data collection, robust statistical methods, and the stability of a significant hazard ratio for cirrhosis among nonresponders in both cohorts make a compelling case for the validity of these findings. Furthermore the congruence of the findings from two diverse patient populations�Cthe SFVA cohort comprised of comparably aged veterans with similar risk behavior histories and the more demographically diverse UCSF cohort�C suggest that these results may be generalizable. Our results suggest the possibility that treatment with IFNabased regimens without viral clearance may be associated with progressive liver disease. Although these data reflect the Alprostadil long-term outcomes for two entire patient cohorts at independent institutions, they should be interpreted with caution as they are derived from retrospective chart reviews. If confirmed, these results make a compelling case for the enhanced use of sensitive diagnostic and predictive tools, including recently described genetic tests, to identify patients most likely to benefit from IFNa-based treatment. Moreover, the potential for adverse outcomes should be considered in current and future studies examining HCV treatment using pegylated-IFNa/RBV in combination with newer agents such as HCV protease inhibitors, as a substantial proportion of null or partial responders with advanced fibrosis will emerge from these treatment groups. In particular, it may be advisable not to retreat these patients with IFNa, but to keep them under observation until IFNa-free regimens are available. Peroxisome proliferator-activated receptors are nuclear receptors that function as ligand-inducible transcription factors. Consistent with their regulation by fatty acids and eicosanoid metabolites, PPARs function as modulators of lipid metabolism and inflammatory responses. The three PPAR subtypes activate their target genes LOUREIRIN-B through binding to PPAR response elements as heterodimers with members of the retinoid X receptor family. Genome-wide analyses have identified PPRE-mediated repression as a major mechanism of transcriptional regulation by unliganded PPARb/d, and revealed that a subset of these repressed genes is activated by an agonist-mediated switch.