Peginterferon alfa-2b/Ribavirin(Merck & Co., Inc.)

Temozolomide (TMZ) is an oral alkylating agent used in the treatment of central nervous system neoplasms and metastatic melanoma. Preclinical and clinical data suggested that combining TMZ with interferon alpha-2b (IFN-alpha-2b) may result in increased anti-tumour efficacy.

This was a phase I, dose-escalation study to define the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of cyclical oral TMZ (days 1-7 and 15-21) in combination with pegylated IFN-alpha-2b (PEG-IFN-alpha-2b) in patients with advanced solid tumours.

We treated 19 patients (10 female and nine male), median age 58 years (range: 41-79 years). Ten patients tolerated TMZ at 100 mg/m² on days 1-7 and 15-21 plus PEG-IFN-alpha-2b at 1.5 mcg/kg/week on 28-day cycles which was the MTD of the combination. The pharmacokinetic parameters of PEG-IFN-alpha-2b were not altered by TMZ, at the MTD.

The MTD of cyclical oral TMZ was 100 mg/m² on days 1-7 and 15-21 when combined with weekly subcutaneous PEG-IFNα-2b at 1.5 mcg/kg/week on 28 days cycles. The PK of PEG-IFN-alpha-2b appeared consistent with those when it is used as monotherapy.

In the United States, dual therapy with pegylated interferon (Peg-IFN) and ribavirin had been the standard treatment for chronic hepatitis C virus genotype 1 (HCV-1) infection until recently, irrespective of viral load [1]. Since HCV NS3/4 serine protease inhibitors, such as telaprevir and boceprevir, became available, the standard treatment was replaced by triple therapy with a protease inhibitor, PegIFN, and ribavirin [2]. Guidelines proposed by the Japanese Study Group for the Standardization of Treatment of Viral Hepatitis [3] had recommended monotherapy with pegylated or non-pegylated IFN for treatment-naive patients with low HCV-1 loads (\5 log10 IU/mL), and dual therapy with Peg-IFN and ribavirin for patients with high HCV-1 loads (C5 log10 IU/mL) until the approval of telaprevir in 2011. We read the JSH Guidelines for the Management of Hepatitis C Virus Infection in a recent issue of the Journal of Gastroenterology [4]. The Guidelines recommend monotherapy for treatment-naive patients with low HCV-1 loads and triple therapy including telaprevir for patients with high HCV-1 loads. For example, the Guidelines recommend monotherapy if HCV RNA is 4.9 log10 IU/mL and triple therapy if HCV RNA is 5.0 log10 IU/mL. We wonder if there is a range of ‘middle’ viral loads for which dual therapy can be indicated. A phase III clinical trial in Japan showed that the rate of sustained virologic response (SVR) was higher with triple therapy than with dual therapy, but the difference did not reach statistical significance in the subgroup of patients with HCV RNA of 5.0–6.9 log10 IU/mL (74/100 vs. 26/45, P = 0.056) [5]. We retrospectively analyzed the relation between baseline HCV RNA loads and treatment outcomes in patients who received dual therapy in our hospital during several years before telaprevir was approved. Between December 2004 and May 2011, 183 treatmentnaive patients (75 men/108 women; 57 ± 11 years old) with high HCV-1 loads started dual therapy with Peg-IFN-a2b and ribavirin. The median laboratory values (interquartile range) at baseline were as follows: aspartate aminotransferase 45 (36–66) IU/L, alanine aminotransferase 52 (37–81) IU/L and platelet count 171 (134–204) 9 10/mm. Of the 169 patients who underwent liver biopsy, the stage of fibrosis was F1 in 125 (74 %), F2 in 28 (17 %), F3 in 12 (7.1 %), and F4 in 4 (2.4 %). Of the 141 patients who consented to genome analysis, the interleukin 28B genotype at rs8099917 was TT in 104 (74 %) and TG/GG in 37 (26 %) [6]. The SVR rate was 79 % in the 19 patients with HCV RNA of 5.0–5.4 log10 IU/mL, 47 % in the 34 with 5.5–5.9 log10 IU/mL, 51 % in the 110 with 6.0–6.9 log10 IU/mL, and 50 % in the 20 with C7.0 log10 IU/mL; the rate was significantly higher in the 19 patients with HCV RNA 5.0–5.4 log10 IU/mL than in the remaining 164 patients with HCV RNA C5.5 log10 IU/mL (P = 0.027). One possible explanation why the rate of SVR did not decline with an increase in viral loads when HCV RNA exceeded 5.4 log10 IU/mL is that the duration of treatment was extended from 48 to 72 weeks if a patient had a late virologic response, in accordance with the concept of ‘responseguided therapy.’ In summary, in patients with genotype 1 HCV RNA of 5.0–5.4 log10 IU/mL, the SVR rate was sufficiently high (about 80 %) in response to Peg-IFN and ribavirin. Dual An answer to this letter to the editor is available at doi:10.1007/s00535-013-0760-y.