Clinical, virologic, histologic, and biochemical outcomes after successful HCV therapy: a 5-year follow-up of 150 patients

Abstract

One hundred fifty patients with sustained virologic response (SVR) after treatment of chronic hepatitis C were enrolled in a long-term clinical follow-up study; patients were followed for 5 years for liver-related outcomes and evidence of biochemical or virologic relapse. Patients with stage 2 or greater fibrosis on pretreatment biopsy were invited to undergo a long-term follow-up biopsy after their fourth year of follow-up. One hundred twenty-eight patients (85%) were followed through their fourth year, and long-term follow-up biopsies were obtained from 60 patients (40%). Forty-nine patients had paired pretreatment and long-term follow-up biopsies blindly rescored. Forty of these patients (82%) had a decrease in fibrosis score, and 45 (92%) had a decrease in combined inflammation score. Ten patients (20%) had normal or nearly normal livers on long-term follow-up biopsy. Two patients with pretreatment cirrhosis developed hepatocellular carcinoma (HCC), and one died. All the other patients with pretreatment cirrhosis or advanced fibrosis had improved fibrosis scores on long-term follow-up biopsy. No patient had conclusive evidence of virologic relapse. Three patients had persistently elevated alanine aminotransferase levels; two of these had new liver disease.

Conclusion: In a cohort of 150 patients with SVR followed for 5 years, the majority of patients had good outcomes. Serum virologic relapse was not seen, but two patients with pretreatment cirrhosis developed HCC, and one died. In a blind rescoring of 49 paired pretreatment and long-term follow-up biopsies, 82% improved fibrosis scores and 92% improved at least one component of inflammation. A minority of patients had normal or nearly normal liver tissue on long-term follow-up biopsy. Patients with cirrhosis pretreatment are at a low but real risk of HCC after SVR.

Figure 1

147 patients had sera available for testing in the Bayer TMA assay and nine had detectable HCV RNA in one sample. All positive samples were reconfirmed by repeat testing at least once. All stored sera from the nine patients with a positive TMA test were also tested by TMA assay. Positive test results are denoted by a + and negative results by a -. The ALT values (normal range: 5-45 U/L) on the date the sample was collected are shown next to the result (+ or -) of the TMA assay of the serum sample collected on that date.

Figure 2

146 patients had pre-treatment liver biopsies. 116 patients had fibrosis scores of 2 or greater pre-treatment on clinical pathology reports using the Scheuer system and were eligible for a long-term follow-up biopsy after their 4^th year of follow-up. Sixty patients had long-term follow-up biopsies and 49 had paired pre-treatment and long-term follow-up histopathological material available for pathologist review and blind rescoring using Ishak.

Figure 3

Forty-nine paired pre-treatment and long-term follow-up biopsies were blindly reviewed and re-scored for fibrosis using the Ishak system (scored as stage 0-6). Paired pre-treatment and long-term follow-up biopsy fibrosis scores of patients are shown connected by a line and the number of patients with each outcome is shown next to the line. *These patients developed HCC. A: Patients with pre-treatment fibrosis scores of 4 or greater. B: Patients with pre-treatment fibrosis scores of 3 or less.

Figure 3

Forty-nine paired pre-treatment and long-term follow-up biopsies were blindly reviewed and re-scored for fibrosis using the Ishak system (scored as stage 0-6). Paired pre-treatment and long-term follow-up biopsy fibrosis scores of patients are shown connected by a line and the number of patients with each outcome is shown next to the line. *These patients developed HCC. A: Patients with pre-treatment fibrosis scores of 4 or greater. B: Patients with pre-treatment fibrosis scores of 3 or less.

Figure 4

Forty-nine paired pre-treatment and long-term follow-up biopsies were blindly reviewed and rescored using the Ishak system for periportal hepatitis, necrosis, and portal inflammation (each graded on a scale of 0-4). Paired pre-treatment and long-term follow-up biopsy scores are connected by a line and the number of patients with each outcome is shown next to the line. *Indicates a patient who developed HCC. A and B: Paired pre-treatment and long-term follow-up biopsy periportal hepatitis scores: A) patients with grade 3-4 inflammation pre-treatment, B) patients with grade 0-2 inflammation pre-treatment. C and D: Paired pre-treatment and long-term follow-up biopsy necrosis scores: C) patients with grade 3-4 inflammation pre-treatment, D) patients with grade 0-2 inflammation pre-treatment. E and F: Paired pre-treatment and long-term follow-up biopsy portal inflammation scores: E) patients with grade 3-4 inflammation pre-treatment, F) patients with grade 0-2 inflammation pre-treatment.

Figure 4

Forty-nine paired pre-treatment and long-term follow-up biopsies were blindly reviewed and rescored using the Ishak system for periportal hepatitis, necrosis, and portal inflammation (each graded on a scale of 0-4). Paired pre-treatment and long-term follow-up biopsy scores are connected by a line and the number of patients with each outcome is shown next to the line. *Indicates a patient who developed HCC. A and B: Paired pre-treatment and long-term follow-up biopsy periportal hepatitis scores: A) patients with grade 3-4 inflammation pre-treatment, B) patients with grade 0-2 inflammation pre-treatment. C and D: Paired pre-treatment and long-term follow-up biopsy necrosis scores: C) patients with grade 3-4 inflammation pre-treatment, D) patients with grade 0-2 inflammation pre-treatment. E and F: Paired pre-treatment and long-term follow-up biopsy portal inflammation scores: E) patients with grade 3-4 inflammation pre-treatment, F) patients with grade 0-2 inflammation pre-treatment.

Figure 4

Forty-nine paired pre-treatment and long-term follow-up biopsies were blindly reviewed and rescored using the Ishak system for periportal hepatitis, necrosis, and portal inflammation (each graded on a scale of 0-4). Paired pre-treatment and long-term follow-up biopsy scores are connected by a line and the number of patients with each outcome is shown next to the line. *Indicates a patient who developed HCC. A and B: Paired pre-treatment and long-term follow-up biopsy periportal hepatitis scores: A) patients with grade 3-4 inflammation pre-treatment, B) patients with grade 0-2 inflammation pre-treatment. C and D: Paired pre-treatment and long-term follow-up biopsy necrosis scores: C) patients with grade 3-4 inflammation pre-treatment, D) patients with grade 0-2 inflammation pre-treatment. E and F: Paired pre-treatment and long-term follow-up biopsy portal inflammation scores: E) patients with grade 3-4 inflammation pre-treatment, F) patients with grade 0-2 inflammation pre-treatment.

Figure 4

Forty-nine paired pre-treatment and long-term follow-up biopsies were blindly reviewed and rescored using the Ishak system for periportal hepatitis, necrosis, and portal inflammation (each graded on a scale of 0-4). Paired pre-treatment and long-term follow-up biopsy scores are connected by a line and the number of patients with each outcome is shown next to the line. *Indicates a patient who developed HCC. A and B: Paired pre-treatment and long-term follow-up biopsy periportal hepatitis scores: A) patients with grade 3-4 inflammation pre-treatment, B) patients with grade 0-2 inflammation pre-treatment. C and D: Paired pre-treatment and long-term follow-up biopsy necrosis scores: C) patients with grade 3-4 inflammation pre-treatment, D) patients with grade 0-2 inflammation pre-treatment. E and F: Paired pre-treatment and long-term follow-up biopsy portal inflammation scores: E) patients with grade 3-4 inflammation pre-treatment, F) patients with grade 0-2 inflammation pre-treatment.

Figure 4

Forty-nine paired pre-treatment and long-term follow-up biopsies were blindly reviewed and rescored using the Ishak system for periportal hepatitis, necrosis, and portal inflammation (each graded on a scale of 0-4). Paired pre-treatment and long-term follow-up biopsy scores are connected by a line and the number of patients with each outcome is shown next to the line. *Indicates a patient who developed HCC. A and B: Paired pre-treatment and long-term follow-up biopsy periportal hepatitis scores: A) patients with grade 3-4 inflammation pre-treatment, B) patients with grade 0-2 inflammation pre-treatment. C and D: Paired pre-treatment and long-term follow-up biopsy necrosis scores: C) patients with grade 3-4 inflammation pre-treatment, D) patients with grade 0-2 inflammation pre-treatment. E and F: Paired pre-treatment and long-term follow-up biopsy portal inflammation scores: E) patients with grade 3-4 inflammation pre-treatment, F) patients with grade 0-2 inflammation pre-treatment.

Figure 4

Forty-nine paired pre-treatment and long-term follow-up biopsies were blindly reviewed and rescored using the Ishak system for periportal hepatitis, necrosis, and portal inflammation (each graded on a scale of 0-4). Paired pre-treatment and long-term follow-up biopsy scores are connected by a line and the number of patients with each outcome is shown next to the line. *Indicates a patient who developed HCC. A and B: Paired pre-treatment and long-term follow-up biopsy periportal hepatitis scores: A) patients with grade 3-4 inflammation pre-treatment, B) patients with grade 0-2 inflammation pre-treatment. C and D: Paired pre-treatment and long-term follow-up biopsy necrosis scores: C) patients with grade 3-4 inflammation pre-treatment, D) patients with grade 0-2 inflammation pre-treatment. E and F: Paired pre-treatment and long-term follow-up biopsy portal inflammation scores: E) patients with grade 3-4 inflammation pre-treatment, F) patients with grade 0-2 inflammation pre-treatment.

Figure 5

Representative liver biopsies obtained pre-treatment and during long-term follow-up from three patients. A: Top: pre-treatment biopsy: Trichrome stain with Ishak stage 3 fibrosis (portal-to-portal bridging). Bottom: Long-term follow-up biopsy obtained from the same patient 57 months after EOT: Trichrome stain with Ishak stage 1 fibrosis. B: Top: pre-treatment biopsy: Trichrome stain showing Ishak stage 4 fibrosis (portal-to-portal as well as portal-to-central bridging). Bottom: Long term follow-up biopsy obtained from the same patient 67 months after EOT. Trichrome stain showing Ishak stage 0 fibrosis. C: Top: Pre-treatment biopsy: H and E stain with Ishak combined inflammation score of 6: grade 3 periportal hepatitis, grade 1 necrosis, grade 2 portal inflammation. Bottom: Long term follow-up biopsy obtained from the same patient 49 months after EOT. H and E stain with Ishak combined inflammation score of 1: grade 0 periportal hepatitis, grade 1 necrosis, grade 0 portal inflammation.

Figure 5

Representative liver biopsies obtained pre-treatment and during long-term follow-up from three patients. A: Top: pre-treatment biopsy: Trichrome stain with Ishak stage 3 fibrosis (portal-to-portal bridging). Bottom: Long-term follow-up biopsy obtained from the same patient 57 months after EOT: Trichrome stain with Ishak stage 1 fibrosis. B: Top: pre-treatment biopsy: Trichrome stain showing Ishak stage 4 fibrosis (portal-to-portal as well as portal-to-central bridging). Bottom: Long term follow-up biopsy obtained from the same patient 67 months after EOT. Trichrome stain showing Ishak stage 0 fibrosis. C: Top: Pre-treatment biopsy: H and E stain with Ishak combined inflammation score of 6: grade 3 periportal hepatitis, grade 1 necrosis, grade 2 portal inflammation. Bottom: Long term follow-up biopsy obtained from the same patient 49 months after EOT. H and E stain with Ishak combined inflammation score of 1: grade 0 periportal hepatitis, grade 1 necrosis, grade 0 portal inflammation.

Figure 5

Representative liver biopsies obtained pre-treatment and during long-term follow-up from three patients. A: Top: pre-treatment biopsy: Trichrome stain with Ishak stage 3 fibrosis (portal-to-portal bridging). Bottom: Long-term follow-up biopsy obtained from the same patient 57 months after EOT: Trichrome stain with Ishak stage 1 fibrosis. B: Top: pre-treatment biopsy: Trichrome stain showing Ishak stage 4 fibrosis (portal-to-portal as well as portal-to-central bridging). Bottom: Long term follow-up biopsy obtained from the same patient 67 months after EOT. Trichrome stain showing Ishak stage 0 fibrosis. C: Top: Pre-treatment biopsy: H and E stain with Ishak combined inflammation score of 6: grade 3 periportal hepatitis, grade 1 necrosis, grade 2 portal inflammation. Bottom: Long term follow-up biopsy obtained from the same patient 49 months after EOT. H and E stain with Ishak combined inflammation score of 1: grade 0 periportal hepatitis, grade 1 necrosis, grade 0 portal inflammation.