Patients With Chronic HCV Who Need Early Treatment
Patients With Chronic HCV Who Need Early Treatment
We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations in conducting this systematic review. With the assistance of a medical research librarian, we performed serial literature searches for English and non-English articles. MEDLINE (via PubMed), EMBASE, Web of Science and Scopus were searched using the following keywords: 'cirrhosis' or 'liver cirrhosis' or 'fibrosis', 'hepatitis C' or 'hepatitis C, chronic' or 'chronic hepatitis C', 'disease progression' or 'progression' or 'decompensation'. Boolean operators and medical subject heading terms as well as other controlled vocabulary were used to enhance electronic searches. An example of specific search strategy details is shown in Table S1 http://onlinelibrary.wiley.com/store/10.1111/apt.12921/asset/supinfo/apt12921-sup-0001-TableS1-S6.docx?v=1&s=130e5a4e31352228b5691bb0dcf446af48e7576f.
All human subject studies published in full-text or abstract were eligible for inclusion. The search was limited to publications from 2003 to 2014 as this 10-year period contained the most contemporary and relevant data with respect to treatment and current practice. Additional studies of interest were identified by hand searches of bibliographies and cited reference tracking and consultation with clinical experts on the topic. The initial search was performed in October 2013 and the search was last updated on 2 June 2014.
Two authors (M.A.K. and A.S.L.) sequentially determined study eligibility. Studies were initially screened by the first author; decisions about study inclusion were made independently by both authors (M.A.K and A.S.L). Differences in opinion regarding study inclusion were resolved through consensus. Studies were included if they: (i) included human studies with participants 18 years of age or older; (ii) systematically evaluated predictors of fibrosis progression and/or clinical outcomes for patients with CHC; and (iii) used a longitudinal cohort study design. We focused on studies of untreated patients but also included studies with a mix of treated and untreated patients provided that <20% of the study population achieved SVR and results were stratified by treatment outcomes. For studies evaluating predictors of fibrosis progression, we selected studies only when paired biopsy was used to assess progression.
We excluded studies that enrolled (i) patients co-infected with hepatitis B (HBV) or human immunodeficiency virus (HIV); (ii) patients with additional causes of chronic liver disease; (iii) patients with prior liver transplantation and (iv) specific groups of patients (e.g. thalassaemia patients) only. These patient populations were excluded because they likely have different rates and risk factors for disease progression compared to the general population of patients with CHC. In addition, studies that evaluated HCC as the only outcome of interest were excluded as we were interested in broad clinical outcomes for patients with CHC, and predictors of HCC development alone may not be the same as predictors of disease progression in CHC in general. Lastly, studies that focused on predictors that are not readily available clinically (e.g. genetic or other serum markers for which commercial assays are not available, and experimental imaging techniques) were excluded given that they would not be relevant to current clinical practice.
Patients with CHC were defined as those with detectable HCV ribonucleic acid (RNA). We were interested in two outcomes: histological progression and clinical progression. The definition of histological progression was an increase of ≥1 METAVIR (range 0–4) or Ishak (range 0–6) fibrosis stage on follow-up liver biopsy. The definition of clinical progression encompassed the progression from compensated to decompensated cirrhosis, and liver-related or overall mortality. The definition of compensated cirrhosis was based on histology when available (Ishak fibrosis score ≥5 or METAVIR 4) or on the combined results of other noninvasive testing including laboratory tests and imaging. Decompensated cirrhosis was defined by the presence of any of the following: ascites, spontaneous bacterial peritonitis (SBP), variceal bleeding or hepatic encephalopathy (HE). The presence of HCC as defined by histology or American Association for Study of Liver Diseases radiological criteria was variably included as a clinical outcome.
Data from eligible studies were abstracted by two authors (M.A.K. and S.Y.) using a standardised template adapted from the Cochrane Collaboration. For all studies, we recorded: study design, sample size, patient population characteristics, duration of follow-up, predictor variables studied, outcomes measured, criteria used to define these outcomes and measures of association/predictiveness of risk for these outcomes. We accepted the outcome definitions as stated by each study without independently validating or reviewing their data. Study authors were directly contacted for additional, unpublished data.
Two authors (M.A.K and S.Y.) independently assessed the risk of study bias and study quality. Since all the included studies were nonrandomised cohort studies, the Newcastle-Ottawa scale was used to judge study quality as recommended by the Cochrane Collaboration. This scale uses a star system to assess the quality of a study based on three domains: selection of the study population, comparability of the study groups and method of outcomes assessment. For our review, given that no study had a comparison group, we excluded comparability components of the scale across all studies. Studies which received stars in every domain were assessed as being of high quality.
Given the substantial variation in the design, methods and inclusion/exclusion criteria within our included studies, meta-analysis was not performed. Two authors (M.A.K. and S.Y.) qualitatively synthesised the results of the included studies, focusing on the risk factors evaluated and their independent predictiveness in terms of the outcomes measured and patient populations studied. Studies were categorised according to the outcome of interest: predictors of histological progression, predictors of clinical outcomes or studies investigating both clinical and histological outcomes. All authors had access to the study data and had reviewed and approved the final manuscript.
Methods
Data Sources and Search Strategy
We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations in conducting this systematic review. With the assistance of a medical research librarian, we performed serial literature searches for English and non-English articles. MEDLINE (via PubMed), EMBASE, Web of Science and Scopus were searched using the following keywords: 'cirrhosis' or 'liver cirrhosis' or 'fibrosis', 'hepatitis C' or 'hepatitis C, chronic' or 'chronic hepatitis C', 'disease progression' or 'progression' or 'decompensation'. Boolean operators and medical subject heading terms as well as other controlled vocabulary were used to enhance electronic searches. An example of specific search strategy details is shown in Table S1 http://onlinelibrary.wiley.com/store/10.1111/apt.12921/asset/supinfo/apt12921-sup-0001-TableS1-S6.docx?v=1&s=130e5a4e31352228b5691bb0dcf446af48e7576f.
All human subject studies published in full-text or abstract were eligible for inclusion. The search was limited to publications from 2003 to 2014 as this 10-year period contained the most contemporary and relevant data with respect to treatment and current practice. Additional studies of interest were identified by hand searches of bibliographies and cited reference tracking and consultation with clinical experts on the topic. The initial search was performed in October 2013 and the search was last updated on 2 June 2014.
Study Eligibility and Selection Criteria
Two authors (M.A.K. and A.S.L.) sequentially determined study eligibility. Studies were initially screened by the first author; decisions about study inclusion were made independently by both authors (M.A.K and A.S.L). Differences in opinion regarding study inclusion were resolved through consensus. Studies were included if they: (i) included human studies with participants 18 years of age or older; (ii) systematically evaluated predictors of fibrosis progression and/or clinical outcomes for patients with CHC; and (iii) used a longitudinal cohort study design. We focused on studies of untreated patients but also included studies with a mix of treated and untreated patients provided that <20% of the study population achieved SVR and results were stratified by treatment outcomes. For studies evaluating predictors of fibrosis progression, we selected studies only when paired biopsy was used to assess progression.
We excluded studies that enrolled (i) patients co-infected with hepatitis B (HBV) or human immunodeficiency virus (HIV); (ii) patients with additional causes of chronic liver disease; (iii) patients with prior liver transplantation and (iv) specific groups of patients (e.g. thalassaemia patients) only. These patient populations were excluded because they likely have different rates and risk factors for disease progression compared to the general population of patients with CHC. In addition, studies that evaluated HCC as the only outcome of interest were excluded as we were interested in broad clinical outcomes for patients with CHC, and predictors of HCC development alone may not be the same as predictors of disease progression in CHC in general. Lastly, studies that focused on predictors that are not readily available clinically (e.g. genetic or other serum markers for which commercial assays are not available, and experimental imaging techniques) were excluded given that they would not be relevant to current clinical practice.
Definition of Variables and Outcomes
Patients with CHC were defined as those with detectable HCV ribonucleic acid (RNA). We were interested in two outcomes: histological progression and clinical progression. The definition of histological progression was an increase of ≥1 METAVIR (range 0–4) or Ishak (range 0–6) fibrosis stage on follow-up liver biopsy. The definition of clinical progression encompassed the progression from compensated to decompensated cirrhosis, and liver-related or overall mortality. The definition of compensated cirrhosis was based on histology when available (Ishak fibrosis score ≥5 or METAVIR 4) or on the combined results of other noninvasive testing including laboratory tests and imaging. Decompensated cirrhosis was defined by the presence of any of the following: ascites, spontaneous bacterial peritonitis (SBP), variceal bleeding or hepatic encephalopathy (HE). The presence of HCC as defined by histology or American Association for Study of Liver Diseases radiological criteria was variably included as a clinical outcome.
Data Abstraction and Validity Assessment
Data from eligible studies were abstracted by two authors (M.A.K. and S.Y.) using a standardised template adapted from the Cochrane Collaboration. For all studies, we recorded: study design, sample size, patient population characteristics, duration of follow-up, predictor variables studied, outcomes measured, criteria used to define these outcomes and measures of association/predictiveness of risk for these outcomes. We accepted the outcome definitions as stated by each study without independently validating or reviewing their data. Study authors were directly contacted for additional, unpublished data.
Assessment of Risk of Bias and Study Quality
Two authors (M.A.K and S.Y.) independently assessed the risk of study bias and study quality. Since all the included studies were nonrandomised cohort studies, the Newcastle-Ottawa scale was used to judge study quality as recommended by the Cochrane Collaboration. This scale uses a star system to assess the quality of a study based on three domains: selection of the study population, comparability of the study groups and method of outcomes assessment. For our review, given that no study had a comparison group, we excluded comparability components of the scale across all studies. Studies which received stars in every domain were assessed as being of high quality.
Data Synthesis and Analysis
Given the substantial variation in the design, methods and inclusion/exclusion criteria within our included studies, meta-analysis was not performed. Two authors (M.A.K. and S.Y.) qualitatively synthesised the results of the included studies, focusing on the risk factors evaluated and their independent predictiveness in terms of the outcomes measured and patient populations studied. Studies were categorised according to the outcome of interest: predictors of histological progression, predictors of clinical outcomes or studies investigating both clinical and histological outcomes. All authors had access to the study data and had reviewed and approved the final manuscript.