Some 60% to 70% of cases of hepatitis C progress to chronic hepatitis, and then to cirrhosis and hepatocellular carcinoma over 20 years to 30 years. Following the 1986 report of Hoofnagle et al[23
] on the effects of interferon (IFN) on HCV infection in patients with chronic hepatitis, IFN therapy has been employed throughout the world to treat chronic hepatitis C. The treatment of choice for chronic hepatitis C is antiviral therapy using IFN[24,25
In Japan, many cases of hepatitis C have been treated with IFN since 1992, when treatment using IFN drugs became covered by the public health insurance system. IFN monotherapy, which was used initially, successfully resulted in low sustained HCV-negative condition of all cases treated[26
]. Sustained virological response (SVR) was gained in merely 6% of patients with HCV-1b in high viral loads when the practice of administering a 6-mo regimen of natural IFN was started in 1992; it increased to 20% with the 6-mo regimen of standard IFN combined with ribavirin (RBV) implemented in 2001[27,28
]. Finally, the introduction of the 12-mo regimen of pegylated IFN (PEG-IFN) and RBV approved in 2004 achieved SVR in 50%[29,30
The viral factors that affect the effectiveness of IFN therapy include HCV genotype and HCV-RNA quantity, and the host factors that do so include the histological condition of the liver, age and degree of fatness.
Generally, genotype Ib virus is more resistant to IFN than genotype IIa or IIb viruses. In Japan, genotype Ib in high viral loads accounts for more than 70% of HCV infections, making it difficult to treat patients with chronic hepatitis C[27,28
With regard to the effect of the combination therapy of oral administration of zinc with IFN for chronic hepatitis C, Nagamine et al[31
] reported on the roles of zinc and metallothionein in IFN-α therapy for hepatitis C in 1997. Takagi et al[32
] treated 68 cases of chronic hepatitis C with genotype Ib virus of an HCV-RNA quantity of at least 100 Kcopy/mL with a dose of 10 million units of IFN-α once daily for four weeks, and then the same dose three times weekly for the subsequent 20 wk, by intramuscular injection. They combined the IFN administration with an oral dose of 150 mg of polaprezinc (Promac；Zeria Pharmaceutical, Company Ltd., Tokyo, Japan) daily (equivalent to 34 mg of zinc) in 32 of the 68 cases. The effects of the treatment were evaluated six months after completion, with the criteria of complete response (CR) for disappearance of HCV-RNA and normal alanine aminotransferase (ALT) levels; incomplete response (IR) for HCV-RNA that did not disappear, but normal ALT levels; and non-responder for other cases. The IFN monotherapy group (IFN) was compared with the IFN and zinc combination group (IFN + Zn) in terms of those criteria, with the following results. The IFN group showed CR: 11.1% (4/36) and IR: 11.1% (4/36), totaling 22.2% (8/36), while the IFN + Zn group showed CR: 37.5% (12/32) and IR: 18.8% (6/32), totaling 56.3% (18/32). Thus, they concluded that the zinc combination group had a significantly higher effective rate[32
Murakami et al[33
] treated cases of chronic hepatitis C with a high virus quantity of genotype Ib with the PEG-IFN/RBV therapy, and analyzed the proportion of cases that became HCV-RNA negative after eight weeks of treatment by using groups with and without combination with zinc administration with an oral dose of 150 mg of polaprezinc (containing 34 mg of zinc) daily. They reported that the proportion of cases in whom ALT lowered to 35 U/L or less by the eighth week was 91% (10/11) in the zinc combination group and 58% (7/12) in the non-zinc administration group; however, the proportions of cases that became HCV-RNA negative were 18% (2/11) and 25% (3/12) respectively, showing no significant difference. Furthermore, they continued to observe the cases, and reported that all the cases (9/9) in the group with combination with zinc administration and 67% (8/12) of the cases in the group without combination with zinc administration showed normal ALT levels after 24 wk, and that all the cases (7/7) in the group with zinc and 60% (6/10) of the cases in the group without zinc did so after 48 wk. Interferon therapy for chronic hepatitis C has improved in many ways such as combination with ribavirin, and the rate of virus disappearance resulting from such therapy has increased conspicuously in comparison with the initial results. This therapy now achieves an SVR of approximately 50% even for cases with a high virus quantity of genotype Ib, and a viral clearance rate of nearly 90% for other cases. However, this therapy has shown poor results for cases with severe hepatic histological fibrosis or thrombocytopenia, or for elderly patients, so its combination with zinc administration should be attempted in refractory cases.