The NEW ENGLAND JOtJRNAL of MEDICINE

11 EDI_TORI_ALs __ II

A New Era of Hepatitis C Therapy Begins Donald M. Jensen, M.D.

A new era of therapy for hepatitis C virus (HCV) phase before boceprevir (or placebo) was added. infection is dawning with the development of There were three treatment groups. The first re- two effective HCV protease inhibitors, bocepre- ceived a standard regimen of peginterferon and vir and telaprevir. In this issue of the Journal, ribavirin for 44 weeks after the lead-in period the results of two phase 3 trials involving bocepre- (control). The second received response-guided vir, in combination with peginterferon and riba- triple therapy consisting of boceprevir plus peg- virin, are presented: the SPRINT-2 (Serine Protease interferon-ribavirin for 24 weeks, after which Inhibitor Therapy 2) trial (ClinicaITrials.gov num- patients with undetectable HCV RNA levels be-, ber, NCT00705432), by Poordad and colleagues.' tween weeks 8 and 24 after the lead-in period and HCV RESPOND-2 (Retreatment with HeV could stop all treatment. The third received fixed- Serine Protease Inhibitor Boceprevir and Pegln- duration triple therapy for 44 weeks after the tron/Rebetol 2; NCT00708500), by Bacon and col- lead-in period. In both non black and black co- leagues." Both studies focused on patients in- horts, the use of boceprevir achieved a substan- fected with HCV genotype 1; the SPRINT-2 trial tial and significant increase in the rate of a sus- involved those who had not previously received tained virologic response. In the combined cohorts treatment, whereas HCV RESPOND-2 involved of black and nonblack patients, the rate of a those who had previously received treatment. sustained virologic response was 38% among What are the key background concepts to controls, 66% among patients receiving 48 weeks keep in mind when reading these two important of triple therapy, and 63% among patients receiv- studies? First, boceprevir, a competitive inhibitor ing response-guided triple therapy. Patients with of the nonstructural 3 (NS3) protease complex advanced fibrosis represented 7 to 11% of the of HCV genotype 1, does not have clinically sig- SPRINT-2 patients and had lower rates of a sus- nificant activitYIagainst other HCV genotypes.v" tained virologic response than those with less fi- Second, HCV has been shown to rapidly develop brosis. Anemia and dysgeusia were among the resistance when exposed to protease-inhibitor most common adverse events associated with bo- monotherapy, but the addition of interferon re- ceprevir, occurring in approximately 49% and 40% duces the rate of emergence of these resistant of boceprevir-treated patients, respectively. variants." Third, black patients respond less well In HCV RESPOND-2, boceprevir was tested in to antiviral therapy with peginterferon plus riba- patients with HCV genotype 1 infection who had virin than do nonblacks, in part because of the previously received treatment with peginterfer- decreased prevJlence among blacks of an inter- on-ribavirin, with an outcome of relapse or non- leukin-28B gen~ ClL28B) polymorphism associat- response. Importantly, the study excluded patients ed with interferon responsiveness." Finally, the in whom 12 weeks of the prior therapy resulted presence of cirrhosis has a negative impact on in a reduction in the HCV RNA level of less than response to therapy,' yet it affects a considerable 2 loglo IU per milliliter. Similar to the SPRINT-2 percentage o~atients awaiting treatment. study, HCV RESPOND-2 included a 4-week lead-in In the SP T-2 trial, all patients received peg- phase and studied both fixed-duration and re- interferon and ibavirin during a 4-week lead-in sponse-guided therapy. The most important find-

1272 N ENGLJ MED 364;13 NEJM.ORG MARCH 3', 2011 EDITORIALS ings from HCV RESPOND-2 are the ·impressive continuing peginterferon-ribavirin without bo- increase in the rates of a sustain~d virologic re- ceprevir. The lead-in period also makes therapy sponse both in patients who had had a non- logistically more complex, since the measure- response to prior therapy (with rates of 7% in ment of the week 4 viral load may take a week the control group, 40% in the response-guided or longer to receive from the laboratory. boceprevir group, and 52% in the fixed-duration Anemia was common in both the SPRINT-2 boceprevir group) and in patients who had had a study and HCV RESPOND-2, with more than relapse after prior therapy (with rates of 29%, 40% of patients requiring erythropoietin admin- 69%, and 75%, respectively). Adverse effects as- istration for up to approximately 150 days. In sociated with boceprevir treatment included ane- HCV RESPOND-2, more than 8% of patients in mia, rash, dry skin, and dysgeusia, yet discon- the fixed-duration boceprevir group had a reduc- tinuation of boceprevir owing to these adverse tion in the hemoglobin level to less than 8.0 g per events occurred in only 8 to 12% of the patients. deciliter, and 9% required blood transfusions. The 4-week lead-in period of peginterferon- This rate of anemia poses concerns. Without ribavirin rherapy used in the SPRJNT-2 trial and erythropoietin, additional reduction in the dose of HCV RESPOND-2 is a major point of divergence boceprevir or ribavirin (or both) would be neces- from other studies and appears to have certain sary to manage anemia, which might reduce the key advantages, but also introduces some com- rate of sustained virologic response. plexities. In the SPRJNT-l study," Kwo and col- In summary, HCV protease inhibitors represent leagues demonstrated that the advantage of hav- a major advance in our ability to treat chronic ing a lead-in phase was modest at best in groups HCV infection. Future therapy will be more com- receiving treatment for 24 to 28 weeks (with a plex, not easier, but the improvement in the rate rate of sustained virologic response of 56% with a of sustained virologic response with boceprevir, lead-in phase and 54% without it) but was greater to nearly 70% in the SPRINT-2 trial and to more in groups receiving 48 weeks of therapy (in which than twice the rate in previously treated patients the rates of sustained virologic response were in HCV RESPOND-2, have been eagerly awaited. 75% with a lead-in phase vs. 67% without it). We will soon embark on a new era of successful However, the advantage of a lead-in period ex- HCV therapy. tended beyond the rate of a sustained virologic Disclosure forms provided by the author are available with the response: the rate of viral breakthrough during full text of this article at NEJM.org. the treatment phase was lower in the group re- From the Center for Liver Diseases, University of Chicago Med- ceiving 48 weeks of treatment, which incorporat- ical Center, Chicago. ed the lead-in period, than in the other groups.' 1. Poordad F, McCone J Ir, Bacon BR, et al. Boceprevir for un- In both the SPRINT-2 study and HCV treated chronic HCV genotype 1 infection. N Engl J Med 2011; RESPOND-2, the decline in viral load after 4 weeks 364:1195-206. 2. Bacon BR, Gordon SC, Lawitz E, et al. Boceprevir for previ- of lead-in therapy was indicative of the subse- ously treated chronic HeV genotype 1 infection. N Engl JMed quent therapeutic response. Should treatment be 2011;364:1207-17. discontinued in patients with a decline in the 3. Malcolm BA, Liu R, Lahser F, et al. SCH 503034, a mecha- nism-based inhibitor of hepatitis C virus NS3 protease, sup- HCV RNA level of less than 1 log., IU per mil- presses polyprotein maturation and enhances the antiviral activ- liliter at week 4? In the SPRINT-2 study, among ity of alpha interferon in replicon cells. Antimicrob Agents the 95 patients in the combined cohort who had Chemother 2006;50:1013-20. 4. Susser S, Welsch C, Wang Y, et al. Characterization of resis- a decline in the HCV RNA level of less than tance to the protease inhibitor boceprevir in hepatitis C virus 1 log., IU per milliliter at week 4, the rate of sus- infected patients. Hepatology 2009;50:1709-18. tained virologic response was 38%, which is ac- 5. Lin K, Kwong AD, Lin C. Combination of a hepatitis C virus NS3-NS4A protease inhibitor and alpha interferon synergisti- tually quite high for this subgroup. However, cally inhibits viral RNA replication and facilitates viral RNA this success comes at a cost. A total of 38 of 94 clearance in replicon cells. Antimicrob Agents Chemother 2004: patients (40%) showed the development of resis- 48:4784-92. 6. Ge D, FellayJ, Thompson AJ, et al. Genetic variation in IL28B tant variants. Clearly, patients with a reduction predicts hepatitis C treatment-induced viral clearance. Nature in the HeV RNA level of 1 log., IU per milliliter 2009;461:399-40l. or more should continue therapy, although an 7. McHutchison JG, Lawitz EJ, Shiffman ML, et al. Peginter- feron alfa-2b or aifa-2a with ribavirin for treatment of hepatitis argument could be made that those with unde- C infection. N Engl J Med 2009:361:580-93. [Erratum, N Engl J tectable levels at week 4 may do just as well by Med 20Cl9:361:1027.]

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