A Systematic Review and Meta-analysis
A. Probst; T. Dang; M. Bochud; M. Egger; F. Negro; P.-Y. Bochud
Posted: 11/14/2011; J Viral Hepat. 2011;18(11):749-755. © 2011 Blackwell Publishing
Abstract and Introduction
Abstract
The progression of liver fibrosis in chronic hepatitis C has long been considered to be independent from viral genotypes. However, recent studies suggest an association between Hepatitis C virus (HCV) genotype 3 and accelerated liver disease progression. We completed a systematic review and meta-analysis of studies evaluating the association between HCV genotypes and fibrosis progression. PubMed, Embase and ISI Web of Knowledge databases were searched for cohort, cross-sectional and case–control studies on treatment-naïve HCV-infected adults in which liver fibrosis progression rate (FPR) was assessed by the ratio of fibrosis stage in one single biopsy to the duration of infection (single-biopsy studies) or from the change in fibrosis stage between two biopsies (paired biopsies studies). A random effect model was used to derive FPR among different HCV genotypes. Eight single-biopsy studies (3182 patients, mean/median duration of infection ranging from 9 to 21 years) and eight paired biopsies studies (mean interval between biopsies 2–12 years) met the selection criteria. The odds ratio for the association of genotype 3 with accelerated fibrosis progression was 1.52 (95% CI 1.12–2.07, P = 0.007) in single-biopsy studies and 1.37 (95% CI 0.87–2.17, P = 0.17) in paired biopsy studies. In conclusion, viral genotype 3 was associated with faster fibrosis progression in single-biopsy studies. This observation may have important consequences on the clinical management of genotype 3-infected patients. The association was not significant in paired biopsies studies, although the latter may be limited by important indication bias, short observation time and small sample size.
Introduction
The hepatitis C virus (HCV) chronically infects ~170 millions of persons worldwide, which represents ~3% of the world's population.[1] The important morbidity and mortality associated with chronic hepatitis C result mainly from the development of liver fibrosis and its evolution towards cirrhosis and hepatocarcinoma.[2] The identification of factors affecting fibrosis progression is critical for the optimal management of infected patients.[3] Factors associated with rapid progression include demographic characteristics (such as older age at infection and male sex), host genetic factors, viral co-infections (with the hepatitis B [HBV] or the human immunodeficiency virus [HIV]), metabolic features (such as steatosis, insulin resistance or iron overload) and exposure to toxic agents (alcohol, tobacco or cannabis).[4] Risk factors identification for fibrosis progression was first based on fibrosis stage. However, this approach leads to significant bias, because disease duration varies widely across the population. This issue has been addressed, at least in part, by the estimation of fibrosis progression rate (FPR) based on the ratio of fibrosis stage to disease duration, which might better reflect the true fibrosis progression. Recent studies, using the latter method, suggested that some viral genotypes, such as genotype 3, are associated with more rapid fibrosis progression than other genotypes.[5–7] In this study, we systematically reviewed the published literature about the impact of HCV genotypes on the natural history of chronic hepatitis C and conducted a meta-analysis of the studies reporting a FPR per genotype. Our aim was to examine the impact of viral genotype 3 on fibrosis progression compared with other genotypes.
Material and Methods
Search Strategy
This meta-analysis was performed according to the PRISMA statement for reporting systematic reviews and meta-analyses.[8] Three electronic databases (PubMed, Embase and ISI Web of Knoweldge) were searched for published studies evaluating the fibrosis progression per genotype in chronic HCV before October 2009 (Table S1). Additionally, the investigators hand-searched the bibliographies of obtained articles and reviews; they did not contact any study authors for further information.
Eligible Studies
Cohort, cross-sectional and case–control published trials studying the fibrosis progression in HCV-infected patients were eligible. There was no restriction on language or publication date. Participants were chronically infected with HCV genotype 3, and controls were chronically infected with other genotypes.
Study Selection
Two investigators independently selected studies meeting the following criteria (Table S1): (i) chronic HCV infection; (ii) fibrosis scoring; (iii) no HCV treatment before biopsies; (iv) an estimated date of HCV infection; and (v) an estimated FPR per genotype. Studies on participants of <18 years of age, studies on orthotopic liver transplant recipients, studies without full text available and reviews were excluded. When more than one article was available from the same cohort, we included the article containing most complete information. Disagreements between the two investigators were solved by discussion.
Study Quality Assessment and Data Extraction
Quality criteria were reported for each study, including study design, case definition, liver biopsy quality, nonviral factors associated with fibrosis progression and method used to estimate the date of infection (Table S1). The two investigators independently extracted data for each study. The extracted data were then cross-checked by two other investigators for accuracy. FPR values were assessed together for all genotype non-3 patients. Patients with unknown genotype were not included.
Statistical Analysis
Eligible studies were separated in two groups: those calculating FPR as the ratio of the fibrosis score to the interval between an estimated date of infection and one pretreatment liver biopsy (defined as 'single-biopsy studies') and those calculating fibrosis progression between two pretreatment liver biopsies ('paired-biopsies studies'). For single-biopsy studies, an effect size (ES) was calculated for each individual study (detailed in Appendix).[9] ES of both continuous and dichotomous outcomes was pooled in the same meta-analysis using a random effect model.[10] ES was then transformed back to odds ratio (OR). For paired biopsies studies, the OR for comparison of genotype 3 vs others was calculated for each individual study. We performed a meta-analysis by pooling the OR using a random effect model. All statistical analyses were performed with Stata software (StataCorp, College Station, TX, USA), version 10.0.
Results
From the 3133 citations yielded by the electronic database search, 2936 were excluded for nonrelevance after title or abstract screenings (Fig. 1). Among 197 remaining full-text papers, 181 were excluded for nonrelevance, inappropriate review design, use of post-treatment biopsy, lack of estimated HCV infection duration, or lack of data on genotyping (no data on genotype 3) or FPR. The remaining 16 studies (eight single-biopsy and eight paired biopsy studies) were selected for the meta-analysis. For single-biopsy studies in which both continuous and dichotomous outcomes were available,[6,7] the continuous outcome was used.
Figure 1.
Flow diagram for study selection.
The characteristics of the studies are shown in Table 1. In most studies, the primary endpoint was to assess together the role of several risk factors on fibrosis progression in chronically HCV-infected patients (N = 7 [6,7,11–15]). No study focused specifically on the role of viral genotypes, but some addressed specific factors such as steatosis (N = 5 [16–20]), cannabis use (N = 1 [5]), host genetic variants (N = 1 [21]), immunosuppression level in HIV-infected patients (N = 1 [22]) or transforming growth factor β (N = 1 [23]).
Overall, 3860 patients were included in the meta-analyses, 3182 (range 71–1157) from single-biopsy studies and 678 (range 20–136) from paired biopsies studies (Table S2). Most patients included in the studies were men (62%), the most frequent ethnicity was Caucasian (95%, data available in five studies) and the mean age was 42 years. The most frequent routes of infection were intravenous drug use (41%) and blood transfusion (31%). Eight studies included only HCV mono-infected patients (N = 8), two included both HCV mono-infected and HCV/HIV co-infected patients (percentage of co-infection 7% and 22%), two included only co-infected patients, while four other studies did not give any information on co-infection. The mean duration of HCV infection in single-biopsy studies was 13 years (range 10–17, six studies; median 9 and 21 years in two other studies). The mean interval time between paired biopsies was 5.3 years (range 2.3–12, 5 studies; median 4.1, 4.2 and 6 years in three other studies).
Study Quality
The studies showed a relative homogeneity in terms of design and settings: 11 were retrospective cohort studies (Table 1), four were prospective cohort studies and one was a retrospective case–control study. All studies performed in tertiary hospitals or liver centres, and all published between 1997 and 2009 (Table 1). Seven studies gave a fibrosis score according to the METAVIR system,[24] while four used Ishak's modified histology activity index (HAI),[25] three used the Knodell's HAI,[26] one used Desmet's system[27] and one study gave Scheuer's grades[28] (scores summarized in Table S3). In most single-biopsy studies (N = 6), the date of infection was considered to be the first reported event at risk (blood transfusion, IV drug or nosocomial infection). In most studies, the association of viral genotype 3 with FPR was solely assessed in univariate models, with multivariate analyses performed in only three single-biopsy studies (Fig. S1).
Meta-analyses
The meta-analysis of single-biopsy studies showed a faster FPR in patients infected by genotype 3 compared with the others (overall pooled ES = 0.23, [95% CI 0.06–0.40], P = 0.007, OR = 1.52 [95% CI 1.12–2.07], Fig. 2). The I2 test result was 62.2% (P = 0.010). Similar results were obtained when studies including HIV-infected patients were removed, but the number of patients was smaller (N = 455) and the association was at the limit of significance (OR = 1.67, [95% CI 0.99–2.85], P = 0.056). The cumulative meta-analysis showed that the effect of genotype 3 on fibrosis progression became significant only in 2009 (Fig. 3). The meta-analysis of paired biopsies studies showed a trend towards faster progression for genotype 3 patients compared with the others (OR = 1.37, 95% CI 0.87–2.17, P = 0.17, Fig. 4). The I2 test was 0.0% (P = 0.455). The dichotomization process differed widely across studies, with a progression definition ranging from a worsening of fibrosis unit between two biopsies to a fixed higher fibrosis score value at the second biopsy (Table 2).
Figure 2.
Forest plot of fibrosis progression rates estimated from one biopsy, genotype 3 vs other genotypes. ES, effect size; OR, odds ratio; 95% CI, 95% confidence interval.
Figure 3.
Meta-cumulative analysis of studies estimating fibrosis progression rate based on an estimated date of infection, genotypes 3 vs non-3. ES, effect size; OR, odds ratio; 95% CI, 95% confidence interval.
Figure 4.
Forest plot of odds ratio of fibrosis progression between two liver biopsies, genotype 3 vs non-3. OR, odds ratio; 95% CI, 95% confidence interval.
Discussion
Viral factors have usually been considered to have limited influence on liver FPR in chronically infected HCV patients.[29] However, recent studies highlighted a possible association between viral genotypes and rapid fibrosis progression. By pooling results from several, often small-sized studies, this meta-analysis provides a comprehensive summary of the published literature on the topic as well as new insights into the natural history of chronic HCV infection. The pooled analyses of eight single-biopsy studies clearly confirmed a significantly faster progression for genotype 3 patients compared with the other genotypes. Among them, five showed a significantly faster fibrosis progression or a clear trend towards faster progression for genotype 3-infected patients compared with others.[5–7,16,22] The failure of some studies to detect a significant effect for viral genotype 3 probably results from their insufficient sample size (i.e. 342 cases and 684 controls are necessary for 80% power to detect an OR of 1.5 for viral genotype 3 on fibrosis progression, considering a 30% prevalence of this genotype). Despite a much smaller observation time, the pooled analysis of eight paired biopsies studies showed a trend towards faster progression for genotype 3-infected compared with genotype non-3-infected patients.
A previous study assessing stage-specific FPR using a Markov model suggested that viral genotype 1 (compared with other genotypes) may influence fibrosis progression, but the estimation was performed using a meta-regression.[30] It is known that such ecological associations may lead to incorrect estimates of the relation for individual patients.
The association of viral genotype 3 with FPR may have important practical implications. It has been reported that the uptake of antiviral therapy for hepatitis C has been declining during recent years.[31] Apart from poor rate of diagnosis and lack of referral, two major factors may account for this trend: the widespread perception on the supposedly slow average progression rate of hepatitis C, coupled with the huge expectations surrounding novel, more effective direct antiviral agents (DAA), to be first marketed in 2011–2012. Genotype 3-infected patients should be aware of a potentially faster progression rate and may benefit from individualized counselling, with particular attention given to the controllable factors, such as alcohol consumption and overweight.[32] While therapy with peginterferon alpha and ribavirin usually achieves 70–80% of sustained viral response among patients infected with HCV genotype 3, certain subgroups of patients still have high relapse rates, such as those with elevated baseline viral load (>800 000 copies/mL,[33,34]) and advanced fibrosis.[32] Patients with chronic hepatitis C may be deferred from current treatment regimens just because more potent DAA will be licensed in the near future.[35] However, this 'warehousing' attitude may not be justified in infections with genotype 3, given that the serine protease inhibitors, such as telaprevir, have very limited activity against genotype 3.[36] DAAs with significant activity against genotype 3, such as the nucleoside RNA polymerase inhibitor R7128[37] or the cyclophilin-binding molecule Debio 025,[38] are far from completing clinical development. These considerations argue against the indiscriminate deferral from antiviral therapy in patients infected with genotype 3.
Multiple reasons may explain why paired biopsies studies did not show a significant effect of genotype 3. First, confounding by indication is likely to be a major problem in paired biopsies studies, as only selected patients undergo a second biopsy (e.g. those with multiple comorbidities and potentially rapidly evolving liver disease). Second, paired biopsies studies have a smaller sample size than single-biopsy studies. Out of eight studies, none included more than 30 genotype 3 patients, and four included <7 genotype 3 patients, resulting in low power to detect a given ES. Third, paired biopsies studies have a much smaller observation time than single-biopsy studies (~5 years between 2 biopsies compared with ~13 years from the infection date to the first biopsy, Fig. S3). This short duration may not be sufficient to detect genotype-specific differences in terms of FPRs. Fourth, paired biopsies studies have used arbitrary cut-offs for dichotomizing the outcome into progression vs nonprogression, for instance a worsening of the score by one or several units[13–15,17,18,20,23] or reaching a specific fibrosis stage at the second biopsy.[19] This method results in more information loss if one considers that the process of fibrosis is continuous. Finally, given that FPRs are not constant over time, paired biopsies studies may have included patients when the progression rate is the slowest (e.g. transition from Metavir scores F1–F2[30] or F2–F3[7]), making it even more difficult to detect genotype-specific differences (Fig. S2).
As in many systematic reviews, the limitation of this study results from the limitation of the original studies themselves. Those include the inability to precisely determine the date of infection, the variability in the assessment of fibrosis staging, the nonlinearity of fibrosis progression over time, the failure to account for multiple risk factors. However, several studies addressed these issues. In three studies, the role of viral genotype 3 in fibrosis progression was confirmed in multivariate analyses, accounting for different covariates such as age, alcohol consumption and steatosis.[5–7] In one of them, the authors suggested that cannabis use, which may be more prevalent among genotype 3-infected patient, may have been a confounding factor for the role of genotype 3. However, this study clearly identified cannabis use, genotype 3, age at infection, alcohol intake and steatosis all as independent risk factors for rapid fibrosis progression (>0.74 U/year) in a stepwise logistic regression model of 267 patients.[5] In another study, the association of genotype 3 with faster progression remained significant among patients infected by blood transfusion (for whom the date of infection is certain), among different age groups, or among different periods of infection, and when using different methods to assess the progression rate.[7]
Owing to our stringent selection criteria, the number of studies included in the meta-analysis is relatively small. Therefore, it was not possible to perform a meta-regression analysis and explore the role of potential confounders. We could not include a large confirmatory study (N = 327, N genotype 3 = 80), showing that patients infected with HCV genotype 3 had shorter time to infection than others, because it did not provide FPR rates.[39]
This study provides new insight into the natural history of HCV infection. The evidence for a role of genotype 3 in fibrosis progression may have important implications for the management of patients infected with this genotype.
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