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Results
Number of Studies
A total of 172 relevant articles were identified using the search criteria detailed above. Twenty-one manuscripts were reviewed in full. After applying the inclusion criteria, six studies were used in the final analysis (Fig. 1). The six studies included a total of 443 cirrhotic patients. The median number of patients across each study was 62.5 (range 15–153).
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Figure 1.
Study selection – Algorithm depicting the literature search flow chart and why studies were included or excluded.
Diagnosis of Cirrhosis
Cirrhosis was diagnosed by liver biopsy in all studies. Biopsies were evaluated by Metavir score in five studies. The remaining study used the Ishak scoring method to evaluate cirrhosis. A Metavir score of F4 or an Ishak fibrosis score of ≥5 was used to define cirrhosis. All studies reported results for paired biopsies. One biopsy was taken prior to antiviral therapy and one biopsy was taken after antiviral therapy. Biopsy length was reported in five of the six studies. The time between each biopsy was listed for all studies (Table 1). A central pathologist was used for diagnosis in two of the six studies. These data were not reported in one study. The remaining studies used 2–3 independent reviewers.
Antiviral Therapy
All studies used interferon-based regimens. Five of the six studies treated patients using interferon or pegylated interferon with or without the addition of ribavirin. In Shiratori et al., patients were treated solely with interferon. Duration of therapy across studies varied from 8 to 48 weeks. Specific details regarding antiviral therapy and treatment duration for each study are noted in the table (Table 1). Many of the studies were retrospective analyses of prior randomized controlled trials comparing antiviral dosages and length of therapy (Table 1). The median number of patients achieving sustained virological response across studies was 34% (range 24–44%).
Regression of Cirrhosis
Regression of cirrhosis was defined as reduction in Metavir stage to ≤F3 or Ishak fibrosis score to ≤4. Median regression of cirrhosis in patients with SVR across studies was 55% (range 24–83%). Overall, a total of 73 patients with SVR had regression of cirrhosis of a total of 137 patients with SVR (53%). Of note, regression of cirrhosis in patients who did not achieve SVR was also observed. Median regression of cirrhosis in these patients was 19.5% (range 2–44). Risk ratios were calculated to compare regression of cirrhosis in patients with SVR against regression of cirrhosis in patients without SVR. Relative risk for regression of cirrhosis across all studies was 2.69 (95% CI 1.45–4.97, P < 0.01) (Fig. 2).
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Figure 2.
Meta-analysis overall result – Cirrhosis regression in patients with and without a sustained viral response.
Subgroup Analysis
A number of subgroup analyses were also performed. The relative risk ratio for studies that studied only cirrhotic or advanced fibrosis patients was 6.15 (95% CI: 3.18–11.91, P < 0.01). The relative risk ratio for studies utilizing a central pathologist to review liver biopsy slides as compared with studies without a central pathologist was 1.60 (95% CI: 1.20–2.13, P < 0.01) and 3.97 (95% CI: 1.51–10.45, P = 0.005) respectively. Studies in which the mean biopsy length or median biopsy length of liver samples was less than 15 mm had a relative risk ratio of 1.91 (95% CI: 1.18–3.09, P = 0.008), whereas studies that had mean biopsy length or median biopsy length greater than 15 mm had a relative risk ratio of 4.38 (95% CI: 0.95–20.25, P = 0.06) for regression of cirrhosis. Subgroup analyses were also performed comparing studies in which the mean time between liver biopsies or median time between liver biopsies was less than 36-month or greater than 36-month. The relative risk ratio for cirrhosis regression in these studies was 1.79 (95% CI: 1.26–2.29, P < 0.01) (Fig. 3) and 4.33 (95% CI: 1.1–17.0, P < 0.05) (Fig. 4) respectively.
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Figure 3.
Follow-up biopsy time mean or median <36-month subgroup analysis – Cirrhosis regression in patients with and without a sustained viral response in trials in which the follow-up biopsy had mean or median time of <36-month.
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Figure 4.
Follow-up biopsy time mean or median >36-month subgroup analysis – Cirrhosis regression in patients with and without a sustained viral response in trials in which the follow-up biopsy had a mean or median time of >36-month.
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