Long-term Outcome of Chronic Hepatitis C After Sustained Virological Response to Interferon-based Therapy

C. Koh; T. Heller; V. Haynes-Williams; K. Hara, X. Zhao; J. J. Feld; D. E. Kleiner; Y. Rotman; M. G. Ghany; T. J. Liang; J. H. Hoofnagle


Aliment Pharmacol Ther. 2013;37(9):887-894. 

In This Article


Among 262 patients treated in five clinical research protocols between 1984 and 2003, 103 had an SVR and comprised the analysis cohort for this study. These patients were followed up for a median time of 7.5 years (6 months to 23 years) after SVR and 89 were seen and evaluated after 2007. The duration of follow-up after SVR was less than 5 years in 27 patients, 5–10 years in 58 patients, and greater than 10 years in 12 patients. Of this cohort, three patients were found to be HCV RNA positive at the time of follow-up and were considered late relapsers. The estimated time to relapse was 0.67, 6.3 and 6.5 years after stopping therapy. Thus, the relapse free rate was 96% at an average of 7.6 years after therapy (Figure 1). The three HCV RNA positive patients appeared to have suffered a relapse rather than re-infection, as the recurrent virus was almost identical to the pre-treatment sequence strains (Supplemental Table S1, published online).[34] None had ongoing risk factors for hepatitis C or a clear predisposition for relapse (i.e. corticosteroids, chemotherapy or immunosuppression).

Figure 1.

Kaplan–Meier analysis of proportion of patients without virological relapse. Three of 103 patients became HCV RNA positive after having achieved an SVR after interferon-based therapy. At 7.2 years, the relapse free rate was 96%.

The remaining 100 patients included 56 men and 44 women, 88 whites, 4 African Americans and 8 Asians, with an average age of 55.6 years (Table 1). Twenty-one received standard interferon alone, 55 interferon and ribavirin and 24 peginterferon and ribavirin.

In follow-up, six of the 100 patients died but only one died of a HCV-related cause, hepatocellular carcinoma resulting in death 12.5 years after SVR. This patient had biopsy proven cirrhosis before the course of therapy with interferon and ribavirin that led to an SVR. The causes of death in the remaining five patients included Huntington's chorea, cerebrovascular disease, septicaemia from chronic osteomyelitis, pneumonia and cardiac arrest all of which occurred more than a year after therapy and none of which were considered related to hepatitis C or its treatment. No patient developed decompensated liver disease, jaundice, ascites, variceal haemorrhage, hepatic encephalopathy or required liver transplantation.

Follow-up testing was available from all patients 12–264 months after completion of therapy. Serum ALT levels were normal in 90% and the average value was 27 U/L, which was significantly less than before therapy (152 U/L) (Table 2 and Table 3). Of the remaining 10% of patients with abnormal follow-up ALT levels, values were minimally or modestly elevated and were less than twice the upper limit of the normal range in nine. All 10 patients with ALT elevations had gained weight; four were overweight and five were obese. Abdominal ultrasound demonstrated steatosis in all six who underwent imaging during follow-up (Supplemental Table S2, published online).

At the time of final follow-up there were also significant improvements in mean AST (87–24 U/L), alkaline phosphatase (78–69 U/L), IgG (1463–1113 mg/dL), alpha-fetoprotein (4.6–2.9 ng/mL), GGT (47–28 U/L), platelet count (209 000–239 000/μL) and rheumatoid factor (38–19% positive). Based on sensitivity analysis using regression models, patients with longer duration of follow-up had greater mean changes of ALT, AST, total and direct bilirubin, IgG and albumin values between baseline and follow-up (data not shown). Serum total bilirubin and albumin levels did not change appreciably, but were largely normal even before therapy. Direct bilirubin improved slightly although not significantly overall. Before therapy, 47% of patients had a direct bilirubin level of greater than 0.2 mg/dL (range: 0.0–0.4 mg/dL); at the time of last follow-up testing, only 26% had abnormal values (range: 0.1–0.4 mg/dL) (Table 3). On follow-up evaluation, no patient had an abnormal prothrombin time. Because the methodology and normal range for the prothrombin time varied over the period of observation, a comparison of initial and final values was not possible.

The calculated APRI was elevated (>0.8) in 53% of patients before treatment and averaged 1.31. In follow-up, the APRI was normal in all patients and averaged 0.33, which was significantly less than pre-treatment values (P < 0.001) (Figure 2).

Figure 2.

Mean platelet counts (a) and AST-to-platelet ratio index values (APRI: b) before therapy (Pre-Tx) and at the time of last follow-up evaluation in 100 patients with a sustained virological response stratified by degree of hepatic fibrosis on pre-treatment liver biopsy. Patients were categorised into three groups based upon pre-treatment Ishak fibrosis scores of 0–2 (no fibrosis to portal fibrosis only), 3–4 (bridging hepatic fibrosis) and 5–6 (early and complete cirrhosis).

Transient elastography was attempted in 75 patients at follow-up, but was successful in only 69 (Table 4). In this group, 59% had stiffness scores of ≤7.0 kPA (considered normal), 32% had values between 7.1 and 13.8 (suggestive of moderate to advanced fibrosis), and 9% had values above 13.8 kPA (suggestive of cirrhosis).

Liver biopsy had been performed on 97 patients before therapy and demonstrated cirrhosis (Ishak fibrosis 5–6) in 10, bridging fibrosis (Ishak 3–4) in 25 and no fibrosis or portal fibrosis only (Ishak 0–2) in 62. Analysis of TE stiffness values by initial hepatic fibrosis scores demonstrated that most patients (6 of 7) with pre-treatment cirrhosis had high TE values at follow-up 3.1–23 years after an SVR. In contrast, abnormal TE values were found in only 38% of those with minimal fibrosis and 29% with bridging fibrosis before treatment.

Platelet counts were low (<160 000/μL) in 24% of patients before therapy including 80% of those with cirrhosis. In follow-up, the average platelet count in the 100 patients increased (from 209 000 to 239 000/μL) and was in the normal range in 90% (Table 2 and Table 3). Platelet counts were generally normal in patients with no or mild fibrosis before therapy but even in these individuals, the average platelet count increased after SVR. Improvement in platelet count was most marked in patients with cirrhosis (123 000–164 000/μL) and also increased similarly in those with moderate to advanced fibrosis (204 000–241 000/μL) (Figure 2a). Importantly, the platelet count at the time of TE evaluation correlated with liver stiffness scores. Thus, the average platelet count in patients with normal TE scores was 219 902/μL, compared with 212 455/μL in those with TE scores between 7.1–13.8 and 147 333/μL in those with TE scores in the cirrhotic range of >13.8 kPA (P = 0.0248). In contrast, the APRI values correlated with the degree of hepatic fibrosis as assessed by liver biopsy before treatment, but were within the normal range in all patients at the time of follow-up evaluation regardless of initial Ishak scores or follow-up TE values (Figure 2b).