Relevance of the Core 70 and IL-28B polymorphism and response-guided therapy of peginterferon alfa-2a ± ribavirin for chronic hepatitis C of Genotype 1b: a multicenter randomized trial, ReGIT-J study

Abstract

Background: We conducted a multicenter randomized clinical trial to determine the optimal treatment strategy against chronic hepatitis C virus (HCV) with genotype 1b and a high viral load (G1b/high).

Methods: The study subjects included 153 patients with G1b/high. Patients were initially treated with PEG-IFNα-2a alone and then randomly assigned to receive different treatment regimens. Ribavirin (RBV) was administered to all patients with HCV RNA at week 4. Patients negative for HCV RNA at week 4 were randomly assigned to receive PEG-IFNα-2a (group A) or PEG-IFNα-2a/RBV (group B). Patients who showed HCV RNA at week 4 but were negative at week 12 were randomly assigned to receive weekly PEG-IFNα-2a (group C) or biweekly therapy (group D). Patients who showed HCV RNA at week 12 but were negative at week 24 were randomly assigned to receive PEG-IFNα-2a/RBV (group E) or PEG-IFNα-2a/RBV/fluvastatin (group F).

Results: Overall, the rate of sustained virological response (SVR) was 46 % (70/153). The total SVR rate in the group (A, D, and F) of response-guided therapy was significantly higher than that in the group (B, C, and E) of conventional therapy [70 % (38/54) versus 52 % (32/61), p = 0.049]. Although IL28-B polymorphism and Core 70 mutation were significantly associated with efficacy, patients with rapid virological response (RVR) and complete early virological response (cEVR) achieved high SVR rates regardless of their status of IL-28B polymorphism and Core 70 mutation.

Conclusion: In addition to knowing the IL-28B polymorphism and Core 70 mutation status, understanding the likelihood of virological response during treatment is critical in determining the appropriate treatment strategy.

Fig. 1

Study design. After a lead-in therapy with PEG-IFNα-2a for 4 weeks, patients with negative HCV RNA at week 4 (RVR) were randomly assigned to receive PEG-IFNα-2a alone (group A) or PEG-IFNα-2a/RBV combination (group B). Patients with negative HCV RNA at week 12 (cEVR) were randomly assigned to receive weekly PEG-IFNα-2a/RBV combination (group C) or biweekly PEG-IFNα-2a/RBV combination (group D). Patients with negative HCV RNA at week 24 (LVR) were randomly assigned to receive PEG-IFNα-2a/RBV combination (group E) or PEG-IFNα-2a/RBV/fluvastatin (FLV) combination (group F)

Fig. 2

Flowchart of the study. PEG-IFNα-2a monotherapy was initiated in 153 patients, of whom 15 patients necessitated treatment discontinuation. A total of 115 patients with RVR, cEVR, or LVR were randomly assigned to treatment groups, while 23 patients remained positive for HCV RNA (non-virological response, NVR) at week 24 and were finally judged as non-SVR. Of 18 patients with RVR, 10 were assigned to group A (PEG-IFNα-2a monotherapy) and eight to group B (PEG-IFNα-2a/RBV combination); of 70 patients with cEVR, 39 were assigned to group C (weekly PEG-IFNα-2/RBV combination) and 31 to group D (biweekly PEG-IFNα-2/RBV combination); and of 27 patients with LVR, 14 were assigned to group E (PEG-IFNα-2a/RBV combination) and 13 to group F (PEG-IFNα-2a/RBV/FLV combination)

Fig. 3

The SVR and treatment discontinuation rate in the group (A + D + F) of treatment regimens modified according to response-guided therapy and in the group (B + C + E) of PEG-IFNα-2a/RBV combination therapy

Fig. 4

Treatment response to PEG-IFNα-2a with or without RBV according to the IL-28B single nucleotide polymorphisms (TT versus TG/GG genotype)

Fig. 5

Treatment response to PEG-IFNα-2a with or without RBV according to the Core 70 mutation (wild-type versus mutant Core 70)