We assessed the long-term clinical, biochemical and virological outcomes of 153 patients with CHC who achieved a SVR after PEG-IFN plus ribavirin combination therapy. This study showed that a SVR is associated with permanent undetectable HCV-RNA in serum during a long-term follow-up. Nevertheless, it is difficult to say whether the treatment per se
is important or whether a SVR is important because no controls were included. A late relapse of at least 0.8% after 4-5 years of follow-up has been reported[7-11
]; however, introduction of more sensitive PCR methods may contribute to reduce this late-relapse rate.
There are some studies of the long-term clinical outcome of CHC patients with a SVR[8,11-16,20-27
] but the majority analyzed patients treated with recombinant IFN as monotherapy or in combination with ribavirin. At present, only 4 studies have enrolled patients treated with PEG-IFN plus ribavirin as shown in Table : in the study by Veldt et al[15
], 83 patients were analyzed; Chavalitdhamrong et al[16
] studied 78 patients; George et al[14
] recently published the results of a long-term study of SVR patients including only 4 patients (3%) treated with PEG-IFN plus ribavirin; and Giannini et al[18
] included 231 patients treated with PEG-IFN plus ribavirin, but only 33.3% were genotype 1.
Comparative results of other studies analyzing long term outcomes in chronic hepatitis C patients who achieved a sustained virological response n (%)
It is noteworthy that we included only patients treated with PEG-IFN plus ribavirin with a high proportion being genotype 1 (75.8%), in contrast to other studies (Chavalitdhamrong et al[16
], where genotype 3 represented 62%; George et al[14
], genotype 1 represented 47%; and Giannini et al[18
] genotype 1 represented 66.6%).
Overall, our study showed that clinical events were rare in this population, indicating that SVR patients have an excellent prognosis, similar to previous studies[8,9,11,14-16,20,21,25-29
]. No patient developed decompensated liver disease. There were 5 (4.2%) patients with cirrhosis pre-treatment in this study. None of the patients with advanced fibrosis (F3) pre-treatment progressed to cirrhosis. Similar findings have been reported with PEG-IFN[10,14,25
]. In contrast, Pradat et al[27
] found that cirrhosis developed in 2 of 87 patients who were followed for at least 5 years after a SVR.
One patient with pre-treatment cirrhosis developed a HCC that represented a rate of 0.8%. This patient had no other risk factors such as obesity, alcohol intake or diabetes. This is a similar rate of HCC as reported in other studies[12,15,20,21,23,24,26,30
]. Veldt et al[21
] reported that 3/142 patients (2%) with a SVR and F3-F4 stage pre-treatment developed HCC during follow-up. Nevertheless, Japanese authors[31,32
] have reported a HCC rate of 0.02%-0.5% per year, slightly lower than our study. These data confirm that the risk of late development of HCC after a SVR is a real problem, and we must continue the follow-up of these patients for a long time. It is also important to take into account that HCV-RNA remains undetectable when HCC appears. Scientists speculate about the possibility of hepatocarcinogenesis, despite null replication of HCV, by other pathways[29,33,34
It is well-known that most patients with a SVR normalize their serum ALT, AST and total bilirubin, unless another liver disease is present[8,9,11,24
]. We found the same results in our study: 99% of patients had normal AST and ALT levels during the entire period of follow-up. The patient with HCC had persistently normal serum ALT values. Only one patient had elevated ALT and AST levels during follow-up period: a woman with fibromyalgia and relevant consumption of non-steroidal anti-inflammatory drugs. Nevertheless, ALP values were increased after treatment, but remained within the normal range (< 100 U/L). There is no explanation for this finding.
Limitations of our study are that not all patients had a period of follow-up greater than 5 years and, importantly, that analysis of outcomes of fibrosis (stability, improvement or progression) are of limited value as no paired pre-treatment and post-treatment biopsies were analyzed from each patient. However, a large European study[21
] clearly demonstrated that the 5-year survival rate of patients achieving a SVR was similar to the overall population and that a SVR was associated with a decrease in fibrosis score; the authors speculated that excellent prognosis of sustained virological responders “is likely to hold true in the era of PEG-IFN and ribavirin”. Our data confirm this important prognostic assumption. Moreover, extensive recent histological analyses have shown that most virological responders without cirrhosis had normalization of liver histology[13
]; that is, up to 82% had improved fibrosis scores[14
] and in addition to fibrosis stability/improvement in 88%, in 64% of patients (9 of 14) regression of cirrhosis was observed[35
]. Taken all together[13,14,21,35
], these data question the indication for a second liver biopsy in CHC patients with a SVR after antiviral combination therapy.
The long-term clinical outcome of patients with a SVR to PEG-IFN plus ribavirin is favorable. However, a risk of HCC development still remains, although it is very low, so we must clinically monitor SVR patients for a long time, even with undetectable HCV-RNA, normal ultrasonography, and normal aminotransferase and AFP levels after PEG-IFN plus ribavirin therapy.