Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
Correspondence: Professor Norifumi Kawada, Department of Hepatology, Graduate School of Medicine, Osaka City University Medical School, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan. Email: email@example.com
Erythropoietin is widely used in the USA and some other Western countries to maintain doses of ribavirin during peginterferon/ribavirin-based treatment for chronic hepatitis C virus (HCV) infection. However, the impact of erythropoietin on sustained virological response (SVR) is unclear. Here, we report the cases of three Japanese ribavirin-intolerant relapsed patients with HCV genotype 2 who achieved SVR from retreatment by adding erythropoietin. Three women aged 50, 64 and 68 years with chronic HCV genotype 2 received retreatment with peginterferon-α and ribavirin. During their prior therapy, HCV RNA became negative according to real-time polymerase chain reaction at weeks 4–8 in all three patients; however, the total dose of ribavirin was 18.1–30.6% lower than the planned dose, and HCV RNA relapsed post-treatment. At present, epoetin-β 24 000 IU was introduced at weeks 2 or 3 of dual-combination therapy, resulting in a less than 4.2% reduction in the total dose of ribavirin. HCV RNA became negative at weeks 4–8, and all patients achieved SVR. Until the next-generation antiviral treatments for HCV genotype 2 become available, the addition of erythropoietin to dual therapy can be a treatment of choice for ribavirin-intolerant relapsed patients.
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HEPATITIS C VIRUS (HCV) infection remains an important health problem and one of the main causes of liver-related morbidity worldwide. Triple therapy, which involves adding a specific inhibitor of the HCV non-structural (NS)3/4A serine protease (e.g. telaprevir and boceprevir) to peginterferon (PEG IFN)-α and ribavirin (RBV), for “difficult-to-cure” patients with genotype 1 infection has increased sustained virological response (SVR) rates to approximately 75%.[2, 3] In contrast, no effective alternative treatment is currently available for 20% of patients with genotype 2 who have not achieved SVR to PEG IFN-α and RBV dual therapy, because clinical investigations of novel direct-acting antiviral agents have been delayed for such patients.
For patients who have not achieved SVR and subsequently received retreatment, it is an imperative prerequisite to identify factors for relapse or non-response to previous treatments. In addition to viral factors (including core and NS5A mutations)[5-7] and host factors (including IL28B gene polymorphisms), adherence to PEG IFN-α or RBV is an important factor that can affect therapeutic outcome.[9, 10] Patients who adhere to less than 80% of the intended dose of either PEG IFN or RBV have significantly lower SVR rates than patients adhering to 80% or more of the intended doses of both drugs. The major dose-limiting toxicity of RBV is hemolytic anemia. Erythropoietic growth factor, erythropoietin, is widely used in the USA and some Western countries to increase hemoglobin level, maintain the doses of RBV and improve treatment compliance.[11-21]
However, the adjuvant use of erythropoietin in the setting of anti-HCV therapy has not been approved in Japan. In addition, the impact of erythropoietin administration on SVR remains unclear. We hypothesized that the addition of erythropoietin increases the chance of SVR from retreatment with PEG IFN-α and RBV in patients who have had rapid or early response to prior therapy but relapsed probably because of insufficient RBV dose. Here, we report the cases of three Japanese, RBV-intolerant relapsed patients with HCV genotype 2 who achieved SVR from retreatment by adding erythropoietin.
Patients and treatment regimen
OF THE 87 patients with chronic hepatitis C genotype 2 infection who received 24-week PEG IFN-α and RBV therapy at our hospital between January 2006 and June 2011, 68 (78%) achieved SVR (Fig. 1). RBV was reduced in nine of the 19 patients without SVR to 65.1 ± 18.8% of the total planned doses. Of the nine RBV-intolerant patients without SVR, seven had rapid/early virological response: two had rapid virological response defined as HCV RNA negative at week 4, and five had early virological response defined as HCV RNA positive at week 4 but negative at week 12. We considered these seven RBV-intolerant rapid/early responders to the prior therapy to be good candidates for adjuvant erythropoietin therapy. Three patients (Table 1) provided written informed consent to receive erythropoietin and undergo genome analysis.
Table 1. Baseline characteristics of patients
Time point of HCV RNA disappearance in the previous therapy (week)
aIL28B major type was defined as homozygosity for the major allele TT at rs8099917.
bITPA major type was defined as homozygosity for the major allele CC at rs1127354.
HCV, hepatitis C virus; IL28B, interleukin 28B; ITPA, inosine triphosphatase.
Patients received PEG IFN-α-2a (Pegasys; Chugai Pharmaceutical, Tokyo, Japan) 180 μg s.c. once per week and RBV (Copegus; Chugai) p.o. twice a day at a total daily dose of 600–1000 mg according to bodyweight for 24 weeks (Fig. 2). The dose of PEG IFN-α-2a was modified because of adverse events in accordance with the manufacturers’ recommendations. Epoetin-β (Epogin; Chugai) was started at a dose of 24 000 IU when hemoglobin fell below 12 g/dL and was administrated s.c. weekly six times followed by biweekly three times. Procedures of the study were in accordance with the Declaration of Helsinki of 1964 (2008 revision) and were approved by our hospital ethics committee.
A 50-year-old woman with chronic hepatitis C genotype 2a infection initiated retreatment with PEG IFN-α-2a 180 μg per week and RBV 600 mg/day in November 2010 (Fig. 3a). She had no history of blood transfusion. Approximately 2 years earlier, she had received PEG IFN-α and RBV therapy. In the previous therapy, HCV RNA became negative according to real-time polymerase chain reaction (PCR) at week 4, but the total dose of RBV was 30.6% lower than the planned dose and HCV RNA relapsed post-treatment. The laboratory values at the start of retreatment were as follows: aspartate aminotransferase (AST), 37 IU/L; alanine aminotransferase (ALT), 35 IU/L; γ-glutamyltransferase (GGT), 28 IU/L; endogenous erythropoietin, 12.0 IU/L (normal, 4.2–23.7); hemoglobin concentration, 13.4 g/dL; white blood cell count, 4000/mm3; and platelet count, 123 000/mm3. Epoetin-β was started at week 3 and administrated nine times according to the protocol, and the dose of RBV was not reduced. HCV RNA became negative at week 4, and she achieved SVR.
A 64-year-old woman with chronic hepatitis C genotype 2a infection initiated PEG IFN-α-2a 180 μg per week and RBV 600 mg/day in September 2012 (Fig. 3b). At the age of 11 years, she had undergone surgery for congenital hip dislocation with transfusion. In the preceding therapy approximately 2 years earlier, HCV RNA became negative according to real-time PCR at week 8, but the total dose of RBV was reduced by 18.1% and HCV RNA relapsed post-treatment. The laboratory values at the start of retreatment were as follows: AST, 16 IU/L; ALT, 11 IU/L; GGT, 14 IU/L; erythropoietin, 8.1 IU/L; hemoglobin, 14.5 g/dL; white blood cell, 4100/mm3; and platelet, 108 000/mm3. Epoetin-β was started at week 2 and administrated nine times, and the dose of RBV was not reduced. HCV RNA became negative at week 8, and she achieved SVR.
A 68-year-old woman with chronic hepatitis C genotype 2b infection started PEG IFN-α-2a 180 μg per week and RBV 600 mg/day in October 2010 (Fig. 3c). At 33 years of age, she underwent cardiac surgery for atrial septal defect closure with transfusion. In the preceding therapy approximately 4 years earlier, HCV RNA became negative according to real-time PCR at week 8, but the total dose of RBV was reduced by 19.4% and HCV RNA relapsed post-treatment. The laboratory values at the start of retreatment were as follows: AST, 32 IU/L; ALT, 52 IU/L; GGT, 16 IU/L; erythropoietin, 20.6 IU/L; hemoglobin, 14.5 g/dL; white blood cell, 5200/mm3; and platelet, 119 000/mm3. Epoetin-β was started at week 3 and administrated nine times, and the total dose of RBV was reduced only by 4.2%. HCV RNA became negative at week 4, and she achieved SVR.
Substantial Progress has been made in the development of anti-HCV therapies during the past few years. Many novel IFN-free antiviral regimens for HCV are now under clinical investigation.[23, 24] Some of these include RBV in combination with one or two direct-acting antiviral agents.[25, 26] RBV will remain a key drug for the treatment of chronic HCV infection in the forthcoming era of oral combination therapy. Therefore, it is critical to establish effective strategies for managing RBV-induced anemia, including the use of erythropoietin, and determine its optimal dose for Japanese patients.
The mechanism of RBV-induced hemolytic anemia is not completely understood. In erythrocytes, RBV is converted into mono-, bi- and finally triphosphate forms. The active forms of RBV accumulate in red blood cells because of a lack of phosphatases required to hydrolyze them, probably leading to hemolysis. Fellay et al. show that genetic variants near the inosine triphosphatase (ITPA) gene protect against hemolytic anemia in HCV-infected patients receiving RBV. One possible explanation for this finding is that ITPA deficiency caused by the ITPA gene variation leads to an accumulation of inosine triphosphate, which can compete with the triphosphate form of RBV in red blood cells, thereby protecting cells from the lytic effects of the active form. Ochi et al. report that 75.1% of Japanese patients with chronic hepatitis C are homozygous for the major allele CC at rs1127354. All three patients in the present report had the ITPA major type associated with treatment-induced anemia (Table 1).
Erythrocyte-stimulating agents epoetin-α and epoetin-β are the two forms of human recombinant erythropoietin; both are synthesized in Chinese hamster ovary cells, which are commonly used to treat anemia in chronic kidney disease. Although there are some differences in the glycosylation of the polypeptide in post-translational processing, epoetin-α and epoetin-β essentially have the same clinical efficacy. A higher dose of erythropoietin is required to maintain hemoglobin levels in chronic hepatitis C patients with preserved production of endogenous erythropoietin than in patients with chronic kidney disease. Most clinical studies conducted in the USA used epoetin-α at a dose of 40 000–60 000 IU once weekly. In their preliminary dose-finding study, Kanai et al. report that 24 000–36 000 IU epoetin-β appears to be the optimal dose for Japanese patients with chronic HCV infection. Accordingly, we adopted 24 000 IU epoetin-β. Biweekly dosing of erythropoietin is commonly used in clinical practice to treat anemia in chronic kidney disease as a maintenance therapy if hemoglobin level is elevated by weekly dosing. Therefore, we administrated epoetin-β weekly six times followed by biweekly three times. No significant reductions in the dose of RBV were required after initiation or discontinuation of the biweekly epoetin-β dosing (Fig. 3). Moreover, the biweekly maintenance and tapering of erythropoietin appears cost-effective. There are few reports regarding the use of a long-acting erythropoietin analog, darbepoetin-α, in the setting of anti-HCV therapy. Although darbepoetin-α requires less frequent dosing, its disadvantages include relatively slow therapeutic effects.
Adherence to RBV therapy is important for the outcome of combination therapy. Among the 87 genotype 2 patients who received dual therapy at our hospital, the SVR rate of the 31 patients with RBV dose reduction was 71%, which is lower than the 82% response rate of the 56 patients without dose reduction, although the difference was not statistically significant (P = 0.28). However, the impact of adjuvant erythropoietin use on SVR to PEG IFN-α and RBV therapy remains controversial. A randomized clinical trial by Shiffman et al. did not find a significant difference in the SVR rate between erythropoietin and RBV dose reduction, in contrast to other trials.[18, 19] Most subjects included in the previous studies were treatment-naïve genotype 1 patients. Because approximately 50% of patients may achieve SVR without erythropoietin use and 20% of patients designated null responders may not achieve SVR despite erythropoietin use, the benefit of erythropoietin remains unclear. Therefore, we included only RBV-intolerant patients with HCV genotype 2 who relapsed after rapid/early response to prior therapy. Although the number of patients in the present report is quite small, adherence to RBV during treatment with erythropoietin use was significantly higher than that during the prior therapy without erythropoietin use (P = 0.046, Fig. 4b).
The potential benefits of erythropoietin use on anti-HCV treatment must be weighed against its considerable cost and potential side-effects. Although none of the present patients reported any adverse events attributable to erythropoietin, hypertension, headache, seizures, cardiovascular and thrombotic events, and antibody-mediated pure red-cell aplasia are rare complications of erythropoietin treatment. An alternative strategy for maintaining RBV dose would be extending the therapy duration.
In summary, we reported the cases of three Japanese RBV-intolerant relapsed patients with HCV genotype 2 who achieved SVR from retreatment with PEG IFN-α and RBV plus erythropoietin. We consider genotype 2 patients who exhibited rapid or early response to prior therapy but relapsed probably because of insufficient RBV dose to be good candidates for adjuvant erythropoietin therapy. Until the next-generation antiviral treatments for HCV genotype 2 become available, the addition of erythropoietin to dual therapy can be a treatment of choice for such patients.