i g w The Protease Inhibition for Viral Evaluation (PROVE) 2 and PROVE 3 trials tested the efficacy of various egimens of telaprevir-combination therapy in treatmentaive and treatment-experienced patients.1,2 Both studies ncluded a ribavirin-free arm in which patients received elaprevir with peginterferon alone. The results were strikng. In the PROVE 2 study,2 patients who received only eginterferon and telaprevir had a sustained virologic esponse (SVR) rate of only 36%, significantly lower than n those treated with standard peginterferon and ribavirin SVR, 46%; P .003). In treatment-experienced patients, eplacement of ribavirin with telaprevir led to a very modst increase in SVR from 14% in the control group to only 4% in those treated with peginterferon plus telaprevir lone (P .02).1 The serine protease inhibitor therapy 1 (SPRINT 1) trial evaluated boceprevir combination therapy and included an arm with low-dose ribavirin.3 Similar o the telaprevir studies, ribavirin proved to be very imortant. Only 36% of patients randomized to receive lowose ribavirin achieved an SVR, a markedly worse outome than in those treated with either the standard of are or with boceprevir with peginterferon and full-dose ibavirin. These trials clearly demonstrated that ribavirin ill not disappear quite as quickly as some might have nticipated. A closer examination of the ribavirin-free or low-dose ibavirin arms of the PROVE and SPRINT trials offers ome important insights into the potential role of ribaviin in the era of DAAs.1–3 With both telaprevir and boceprevir, less than full-dose ribavirin was associated with lower rates of SVR, but, perhaps more importantly, less than full-dose ribavirin was associated with (1) viral breakthrough and (2) viral relapse after therapy. In the PROVE 2 study,2 during the initial 2 weeks of treatment, the viral ecline was rapid in all telaprevir-containing arms and as unaffected by the presence or absence of ribavirin Figure 1). However, beyond 2 weeks, differences emerged; iral breakthrough started to occur in the ribavirin-free rm. By week 12, breakthrough had occurred in 24% of atients in the ribavirin-free arm compared with just %–5% of patients who received ribavirin.2 Strikingly, but perhaps not surprisingly, all of the early viral breakthroughs were composed of predominantly telaprevir-resistant virus. Ribavirin also markedly affected the rate of viral relapse. Relapse occurred in 22 of the 46 (48%) patients in the ribavirin-free arm who had undetectable virus at the end of therapy compared with 14% to 30% in the ribavirin-containing arms.2 The somewhat surprising importance of ribavirin in the first DAA trials may be helpful in terms of thinking about its mysterious mechanism of action. Numerous theories have been proposed to explain the antiviral effects of ribavirin; however, despite some experimental evidence for each, none has proven entirely satisfactory.4 Ribavirin nhibits inosine monophosphate dehydrogenase, limiting eneration of guanosine triphosphate pools in the cell, hich are necessary for viral (and cellular) replication.4 The observation that more potent inosine monophosphate dehydrogenase inhibitors have little or no effect on hepatitis C virus (HCV) calls into question the importance of this mechanism.5 At high concentrations, ribavirin directly inhibits the RNA-dependent RNA polymerase of HCV, and, therefore in theory, it could be a DAA itself.6 However, this mechanism also seems unlikely. First, ribavirin has minimal effect on HCV when given as monotherapy.7 Second, even with long-term passage of HCV in the presence of low-dose ribavirin, truly ribavirin-resistant HCV has not been conclusively identified8: something some would argue is necessary to satisfy the definition of a DAA. In theory, ribavirin could act as a very weak DAA with a very high genetic barrier to resistance; however, the