Long-term clinical, histological and virological outcomes after sustained virologic response in patients with chronic hepatitis C

Successful antiviral treatment of chronic hepatitis C (HCV), resulting in Sustained Virologic Response (SVR) has been shown to reduce the risk for liver related complications, hepatocellular carcinoma (HCC) and death. Several studies have also shown that liver histology improves after achieved SVR. In a small sub-set of patients, however, liver fibrosis will persist and sometimes even progress to cirrhosis after SVR. Furthermore, a risk to develop HCC seems to remain many years after SVR has been achieved. The aim of this thesis was to study the long-term effect of sustained virologic response on clinical, histological and virological outcomes, and to identify risk factors associated with persisting advanced fibrosis and a continued risk to develop HCC after SVR.

In study I we investigated the effect of antiviral treatment on liver-related complications, HCC and death. We included 351 patients with HCV related cirrhosis in a prospective cohort study. Mean follow-up time was 5.3 years. The risk to develop liver-related complications, HCC, and liver-related and all-cause mortality was 0.9, 1.0, 0.7 and 1.9 per 100 person years for patients with achieved SVR, compared to 4.9, 4.0, 4.5 and 5.1 per 100 person years for patients never treated for HCV. In study II we investigated the prevalence and clinical implications of occult hepatitis C. In a cross-sectional study, 54 patients with all stages of pre-treatment liver fibrosis and SVR 5-20 years prior to inclusion were tested for HCV RNA using a highly sensitive method. Three patients (6%) tested positive for HCV RNA in peripheral blood mononuclear cells (PBMCs), but this did not correlate to clinical, histological or immunological evidence of persisting liver disease. In study III we investigated the long-term risk and risk factors for the development of HCC after achieved SVR. In this cohort study we included 399 patients with SVR and pre-treatment advanced fibrosis or cirrhosis. Median follow-up time was 7.8 years. The incidence rate of HCC was 0.15 and 0.95 per 100 person years for patients with advanced fibrosis and cirrhosis respectively. The main risk factor for the development of HCC was pre-treatment cirrhosis, low serum albumin and diabetes mellitus. The risk to develop HCC diminished with longer follow-up time. In study IV we investigated fibrosis regression and risk factors for persisting advanced fibrosis after achieved SVR. In a cross-sectional study 269 patients were examined with transient elastography. Median follow-up time was 7.7 years. A majority of patients regressed to a lower fibrosis stage at follow-up, but 24% had persisting advanced fibrosis. This proportion, however, diminished over time. Risk factors associated with persisting advanced fibrosis were pre-treatment cirrhosis, higher age and high body mass index.

Our studies have contributed to the growing evidence of the positive effects of SVR in chronic HCV. With long follow-up time, we were also able to show that disease regression continues over time. We identified established cirrhosis and co-morbidity with metabolic disease as important risk factors for persisting advanced fibrosis and a continued risk to develop HCC after SVR has been achieved.

List of scientific papers

I. Aleman S, Rahbin N, Weiland O, Davidsdottir L, Hedenstierna M, Rose N, Verbaan H, Stal P, Carlsson T, Norrgren H, Ekbom A, Granath F, Hultcrantz R. A risk for hepatocellular carcinoma persists long-term after sustained virologic response in patients with hepatitis C-associated liver cirrhosis. Clin Infect Dis. 2013 Jul;57(2):230-6.
https://doi.org/10.1093/cid/cit234

II. Hedenstierna M, Weiland O, Brass A, Bankwitz D, Behrendt P, Uhnoo I, Aleman S, Cardell K, Fryden A, Norkrans G, Eilard A, Glaumann H, Pietschmann T, Sallberg M, Brenndorfer ED. Long-term follow-up of successful hepatitis C virus therapy: waning immune responses and disappearance of liver disease are consistent with cure. Aliment Pharmacol Ther. 2015 Mar; 41(6):532-43.
https://doi.org/10.1111/apt.13096

III. Hedenstierna M, Nangarhari A, Weiland O, Aleman S. Diabetes and Cirrhosis Are Risk Factors for Hepatocellular Carcinoma After Successful Treatment of Chronic Hepatitis C. Clin Infect Dis. 2016 Sep 15;63(6):723-9.
https://doi.org/10.1093/cid/ciw362

IV. Hedenstierna M, Nangarhari A, El-Sabini A, Weiland O, Aleman S. Cirrhosis, high age and body mass index are risk factors for persisting advanced fibrosis after sustained virologic response in chronic hepatitis C. [Submitted]