We followed 150 patients for 5 years after SVR after treatment of chronic hepatitis C infection and determined clinical, virologic, histologic, and biochemical outcomes. The median duration of follow-up was 65 months (range: 13-86 months). This is the largest and longest study of successfully treated chronic hepatitis C to date, and the largest database of long-term follow-up biopsies (3
). The population in this study differs from most prior studies in the higher percentage of women enrolled (49%) (12
). Otherwise, the patients in this study did not differ from an average cohort of patients with chronic hepatitis C in the United States with the exception of the low numbers of African Americans enrolled.
Overall, clinical outcomes were very favorable, similar to previous studies (3
). No patient developed decompensated liver disease though two patients developed HCC and received OLTs. None of the patients with advanced fibrosis (Ishak stage 4) pre-treatment progressed to histologic evidence of cirrhosis. In contrast, Pradat et al found that cirrhosis developed in 2 of 87 patients who were followed for at least 5 years after SVR (12
). Only one patient in our study died of liver-related causes (recurrent HCC after OLT), similar to previous studies (6
). However, two of the sixteen patients with pre-treatment cirrhosis developed HCC, a rate of 12.5%. This is a higher rate of HCC than reported in other studies (6
) and may be due to either sample size given the low number of patients in our study with cirrhosis pretreatment or to the long period of follow-up. Veldt et al reported 3 of 142 patients (2%) with SVR and Ishak stage 4-6 fibrosis pre-treatment developed HCC during follow-up, however these patients were only followed for a median of 1.1 years (interquartile range: 0.3-2.9 years) (6
). Other long-term follow-up studies of patients with SVR have also reported low numbers of patients developing HCC (14
), thus the risk of late development of HCC after SVR in patients with advanced fibrosis or cirrhosis pre-treatment is real, though difficult to quantify.
Neither patient who developed HCC in our study had evidence of virologic relapse in sera by RT-PCR or TMA testing; this strongly indicates that the mechanism(s) which mediated development of HCC in these patients were not directly related to ongoing HCV replication. While we cannot exclude low-level HCV replication in the liver of these patients after SVR, any substantial replication should have been detectable in serum. Both patients were the only patients in the cohort who had an increase in fibrosis scores between pre-treatment and long-term follow-up biopsy. While both patients already had clear histologic evidence of cirrhosis pre-treatment, the extent of parenchymal remodeling increased between pre-treatment and long-term follow-up biopsy, thus their Ishak fibrosis scores increased from 5 to 6. One of the patients who developed HCC improved his combined Ishak inflammation score from 7 pre-treatment to 3 in the non-tumor liver on long-term follow-up biopsy while the other patient’s combined inflammation score deteriorated from 2 pre-treatment to 12 in the non-tumor liver on long-term follow-up biopsy.
Despite extensive testing using two different methodologies, RT-PCR and TMA, no patient had conclusive evidence of serum virologic relapse. None of the 147 patients tested had detectable viral replication in serum by RT-PCR assay. This contrasts with prior studies which found a low rate of late virologic relapse by RT-PCR testing (3
). Many patients in these earlier studies were treated with interferon monotherapy while all our patients received ribavirin, which may account for the difference. Nine patients had one serum sample with detectable HCV RNA by TMA assay but all other serum samples from these patients tested negative. None of these patients had elevated mean ALTs, nor were their ALTs elevated at the time of collection of the TMA positive serum. These patients were infected pre-treatment with 4 different genotypes or sub-genotypes, thus transient TMA positivity during long-term follow-up did not correlate with pre-treatment infection with a particular genotype. As none of these nine patients had detectable HCV RNA by RT-PCR assay during long-term follow-up, we were unable to perform any post-treatment sequence analysis to determine if the transient TMA positivity represented infection with a new genotype. Four of the nine patients had long-term follow-up biopsies, none of which showed evidence of histologic progression of disease on review of the clinical pathology reports. In this study we did not find any clinical relevance of a single positive TMA assay after SVR.
It is well-known that most patients with an SVR normalize their serum ALT, AST, and total bilirubin shortly after discontinuing treatment unless other liver disease is present (3
). This was confirmed in our study: 91% of our patients had biochemical evaluations three years or more after SVR and only three had persistently elevated ALT values. Of these, one developed HCC, one was diagnosed with autoimmune hepatitis on subsequent biopsy, and the third has had no adverse liver-related outcomes to date.
We obtained 60 long-term follow-up biopsies from the 150 patients. The biopsies were obtained an average of 62 months from EOT (range: 48-78 months), making this the largest dataset of late histologic outcomes evaluated after SVR to date. Forty-nine patients, including eight patients with cirrhosis and four with advanced fibrosis pre-treatment, had paired pre-treatment and long-term follow-up biopsies available for blind rescoring. Liver biopsies are inherently small samples of large organs and estimation of collagen deposition and architectural changes can vary even between experienced pathologists (15
). In this study, biopsies were considered acceptable for analysis by the pathologist and potential bias was minimized by randomly sorting the coded slides. Forty of 49 patients (82%) had decreased fibrosis scores and 45 (92%) had decreased inflammation scores on long-term follow-up biopsies. Declines in periportal hepatitis (94%) and portal inflammation (82%) were more frequent than declines in necrosis (69%) scores. In comparison, prior studies reported decreases in fibrosis in paired pre-treatment and post-treatment biopsies in 29% (14
), 44% (18
), and 59% (13
) of patients with SVR. The mean time in these studies between biopsies was 1.6 years (14
), 2.5 years (18
), and 3.7 years (13
), respectively. As we found 82% of patients with paired biopsies obtained a mean of 5.2 years apart had decreased fibrosis, the percentage of patients with SVR who have decreased fibrosis post-treatment may increase over time. These studies also reported 87% (18
) and 89% (13
) of patients had decreased inflammation on paired biopsies, similar to our study.
Of the 12 patients with advanced fibrosis or cirrhosis pre-treatment in the rescored dataset, ten (83%) had decreased fibrosis scores on long-term follow-up biopsy; two-thirds had a two-point or greater decrease in fibrosis score. Cirrhosis was no longer histologically noted in six of eight patients; the other two patients developed HCC. Two of the forty-nine long-term follow-up biopsies were “normal” based on scores of 0 for fibrosis, periportal hepatitis, necrosis, and portal inflammation. One of these had had stage 3 fibrosis pre-treatment. Eight additional patients had nearly normal liver tissue on long-term follow-up biopsy based on having a score of 0 in 3 of the 4 measured outcomes and a score of 1 in the remaining outcome. Thus recovery of normal or nearly normal liver tissue was seen in 10 of 49 (20%) blindly rescored paired biopsies. Other studies have also reported recovery of normal or near-normal liver tissue after SVR (18
In summary, we enrolled 150 patients with SVR after therapy for chronic HCV in a long-term clinical follow-up study. The majority of patients did very well but two patients with cirrhosis pre-treatment developed HCC two or more years after SVR and one died from recurrent liver cancer after OLT. This represents a 12.5% risk of HCC and a 6.25% risk of death from liver cancer in patients who had cirrhosis pre-treatment. No other late complications of liver disease were seen. All other patients with cirrhosis or advanced fibrosis pre-treatment had improved fibrosis scores on long-term follow-up. No definite serum virologic relapse was seen despite extensive testing. A persistently elevated ALT after SVR was indicative of new liver disease (HCC and autoimmune hepatitis) in two patients. Long-term follow-up biopsies were obtained from 60 patients a mean of 62 months after end of treatment and all but the two patients who developed HCC had evidence of histologic improvement in inflammation, fibrosis, or both. In conclusion, the clinical, virologic, biochemical, and histologic outcomes of patients followed 5 years after SVR is favorable and recovery of normal or nearly normal liver architecture is possible. However patients with cirrhosis pre-treatment remain at risk for late development of HCC.