WHO/HIV/2014.31 © World Health Organization 2014
Global Hepatitis Programme Guideline development for Hepatitis C virus Screening, Care and Treatment in low- and middle- income countries
PICO 5: Treatment A systematic review of the effectiveness of antiviral treatment compared with no treatment for chronic HCV infection
Conducted by the Burnet Institute, Melbourne and Health Protection Scotland, Glasgow 23 June 2013 Review Members Dr Sourabh Malandkar Ms Katherine Hall Dr Joseph Doyle Dr Esther Aspinall Professor Margaret Hellard Professor Sharon Hutchinson Review Advisory Group Dr Mark Stoove Professor David Goldberg Professor Stanley Luchters Dr Alexander Thompson Dr Stefan Wiktor Dr Tim Nguyen Dr Bryce Smith Dr Yngve Flack-Ytter Ms Rebecca Morgan
Burnet Institute, Melbourne Burnet Institute, Melbourne Burnet Institute, Melbourne Health Protection Scotland/Strathclyde University, Glasgow Burnet Institute, Melbourne Caledonian University, Glasgow
Burnet Institute, Melbourne Health Protection, Scotland, Glasgow Burnet Institute, Melbourne St Vincent’s Hospital, University of Melbourne WHO Global Hepatitis Program, Geneva WHO Global Hepatitis Program, Geneva CDC, Atlanta Case Western Reserve University, Cleveland CDC, Atlanta
PICO 5 (Treatment): Anti-viral treatment versus no treatment for chronic HCV
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Table of Contents BACKGROUND ..................................................................................................................................... 4 METHODS ............................................................................................................................................ 4 RESULTS .............................................................................................................................................. 7 Figure 1: Flow chart describing selection of included studies ........................................................ 9 CONCLUSIONS ................................................................................................................................... 10 TABLES............................................................................................................................................... 11 Table 1: Characteristics of systematic reviews included for data synthesis ................................. 11 Table 2: Evidence profile: Interferon versus no treatment for chronic HCV ................................ 24 Table 3: Evidence profile: Any IFN alone or with RBV interventions versus no treatment for chronic HCV ................................................................................................................................... 26 Table 4: Evidence profile: Ribavirin versus no treatment ............................................................. 28 REFERENCES ...................................................................................................................................... 29 APPENDICIES ..................................................................................................................................... 31 Appendix 1: Search syntax for electronic databases .................................................................... 31 Appendix 2: Summary of all study data ........................................................................................ 33 Appendix 3: AMSTAR – a measurement tool to assess the methodological quality of systematic reviews .......................................................................................................................................... 37 Appendix 4: GRADE approach to assessing the quality of evidence across studies ..................... 40
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PICO 5 (Treatment): Anti-viral treatment versus no treatment for chronic HCV
BACKGROUND Hepatitis C virus (HCV) infection affects more than 3% of the global population and poses a high economic burden (El Khoury et al., 2012, Georgel et al., 2010). Between 130 and 150 million people are chronically infected with hepatitis C, and it is a major cause of hepatocellular carcinoma and liver cirrhosis (Georgel et al., 2010, Coffin et al., 2012). Approved treatments include interferon-alpha (IFN), ribavirin (RBV), and HCV NS3 protease inhibitors. Other classes of agent including additional interferons and direct-acting antiviral agents (DAAs) have been studied for effectiveness and tolerability. The purpose of this rapid review is to assess the effectiveness of HCV anti-viral treatment (IFN, PEG-IFN, RBV) in terms of treatment response, adverse events, quality of life, morbidity, mortality.
METHODS Narrative review question: What is the effectiveness of hepatitis C (HCV) anti-viral treatment compared with no antiviral treatment?
PICO Question: Population: Adults and children with chronic HCV infection Intervention: Any type of HCV anti-viral therapy Comparison: No HCV anti-viral therapy Outcomes: Rates of sustained virological response (SVR), decompensated liver disease, hepatocellular carcinoma, all-cause mortality, treatment-related adverse events leading to discontinuation, quality of life. Cost effectiveness outcomes will require economic modelling which will be conducted separately from this protocol Study type/limits: Systematic reviews and meta-analyses published from 1994 to the present
Search strategy: A search was carried out for relevant systematic reviews or meta-analyses, using the following databases and information sources: OVID MEDLINE, EMBASE, the Cochrane Library (CENTRAL and DARE) (without language restrictions). Reference lists of all relevant reviews Relevant articles identified during the conduct of the other systematic reviews Page 4
PICO 5 (Treatment): Anti-viral treatment versus no treatment for chronic HCV
Search terms included combinations of free text and medical subject heading terms (MeSH, Emtree), briefly summarized as: HCV AND Antiviral agents/ HCV treatment AND systematic reviews/metaanalyses (see Appendix 1).
Conduct of the review: The review process followed the Cochrane methodology for conducting systematic reviews (Smith et al., 2011) and the PRISMA guidelines on review reporting (Liberati et al., 2009). The review was registered with the systematic reviews registry PROPSPERO (University of York). The review was carried out by two reviewers. A third reviewer was consulted on points of difference between the primary and secondary reviewer. The two reviewers assessed all search results, and included those studies that met population, intervention, comparison, and at least one outcome criteria. The bibliographic records and abstracts were used to filter studies that clearly did not meet the inclusion criteria. Full articles were then obtained and assessed to confirm eligibility of potentially relevant studies.
Quality appraisal: Each review selected for inclusion was assessed for quality by two independent reviewers, using the AMSTAR assessment tool for systematic reviews (Shea et al., 2009).
Data extraction: Data was extracted from each study by the primary reviewer and secondary reviewer acting independently. The third reviewer was consulted on points of disagreement between the primary and secondary reviewer.
Data were extracted to a standardised spread sheet noting: Review characteristics (study designs, study objectives, funding sources); Review populations (adults versus children, people who inject drugs [PWID] versus nonPWID); Review settings (general practitioner [GP], hospital clinic; low-middle income country [LMIC] versus high-income country [HIC] setting); Participant details (age, sex, ethnicity); Inclusion/exclusion criteria for reviews; Number of studies included; Intervention (type of HCV therapy; therapy delivered by specialist versus primary care physician); Page 5
PICO 5 (Treatment): Anti-viral treatment versus no treatment for chronic HCV
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Control (selection and characteristics of control group); Analysis (number offered therapy, number accepted therapy, reason for refusal, time to follow-up, study data collection method, statistical analyses, primary and secondary outcomes of study);
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Results (Rates of SVR, decompensated liver disease, hepatocellular carcinoma, all-cause mortality, treatment-related adverse events leading to discontinuation of therapy, quality of life).
GRADE process: The quality of the body of evidence as a whole was assessed using Grading of Recommendations Assessment, Development and Evaluation methodology (GRADE)(Atkins et al.). GRADE rates the quality of evidence across each outcome of interest (i.e. Rates of SVR, decompensated liver disease, hepatocellular carcinoma, all-cause mortality, and treatment-related adverse events leading to discontinuation of therapy, quality of life, resource use) as high, moderate, low or very low, depending on a number of criteria. These include study design, study quality, study consistency (the similarity of estimates of effect across studies) and study directness (the extent to which the evidence is relevant to the population, intervention, and outcome of interest).
Given this was a ‘Review of reviews’ our analysis was based on data collected from systematic reviews which had multiple studies assessing similar outcomes. To produce a single estimate of effect for the evidence profile, we selected the systematic review that included the most studies with the highest methodological (AMSTAR) score. Data synthesis Where sufficient data relating to any of the outcomes of interest was available, subgroup analyses were considered for the following: o o o o o o Outcomes (as above) of administering treatment in adults vs. children; Outcomes (as above) of administering treatment by genotype (GT 1, 2/3 vs 4); Outcomes (as above) of administering treatment by HIV infection status; Outcomes (as above) of administering treatment by PWID/IDU status; Outcomes (as above) of administering treatment by fibrosis stage; Outcomes (as above) of administering treatment in LMIC vs. HIC settings.
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PICO 5 (Treatment): Anti-viral treatment versus no treatment for chronic HCV
RESULTS Seven hundred and seventy unique citations were found from database searches. Seven hundred and twelve citations were excluded based on title review and study design criteria (Figure 1). Abstracts for the remaining citations were reviewed, and a further 41 articles were excluded for not meeting the population/ intervention/ comparison/ outcome (PICO) criteria, primarily for failing to compare antiviral therapy to no treatment. Separate systematic reviews of the effectiveness of pegylated interferon versus standard interferon, and direct acting antiviral therapy versus pegylated interferon/ribavirin have been undertaken for the WHO guideline development process.
Seventeen citations were obtained for full-text appraisal. Following full text review, two articles did not meet intervention or comparison criteria: Shepherd et al. (2000) compared IFN-alpha + RBV versus IFN monotherapy alone/with placebo; Pellicelli et al. (2008) compared treatment options within injecting drug users and non-injectors. One further article published in 2011 was republished in 2012 with more complete data (Kimer et al., 2011) and the 2011 version was thus excluded from this analysis (in favour of the 2012 publication).
Fourteen systematic reviews were included in the final synthesis. Six reported data comparing interferon to placebo (Malaguarnera et al. (1995), Carithers and Emerson (1997), Myers et al. (2009), Hu et al. (2010), Koretz et al. (2013), Tine et al. (2005)). Six combined and compared different types of interferon (standard or pegylated interferon [PEG]) alone or with ribavirin to placebo (Fabrizi et al. (2008), Xirouchakis et al. (2008), Kimer et al. (2012), Iorio et al. (2010), Hartwell and Shepherd (2009), Vezali et al. (2010)). One review (Brok et al., 2009b)) evaluated ribavirin monotherapy compared to placebo. Characteristics of these reviews are expanded on in Table 1.
The systematic reviews of effectiveness of interferon monotherapy compared with placebo universally showed IFN was superior to placebo in achieving SVR. Individual reviews reported combined relative risk of IFN reducing treatment failure (“failure to achieve SVR”) between 0.11 and 0.96 (6 studies) (Table 2). There were inconsistent or statistically non-significant effects of IFN on hepatocellular carcinoma (OR ranged from 0.50 to 0.81; 2 studies), liver-related morbidity (RR 1.07, 95% confidence interval [CI] 0.70-1.63) and all-cause mortality (RR 1.3, 95% CI 0.95-1.79). No reviews studies were found that reported quality of life changes with IFN versus placebo.
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PICO 5 (Treatment): Anti-viral treatment versus no treatment for chronic HCV
The systematic reviews of effectiveness of different interferon types (IFN or PEG), in combination with ribavirin or alone compared with placebo showed clear benefit of HCV treatment in achieving SVR (Table 3). The presentation of pooled effect estimates of effect in these systematic reviews prevented assessment of individual antiviral agents effectiveness versus no treatment, and it was not possible to disaggregate the data. There were inconsistent or statistically non-significant effects of Pegylated IFN with ribavirin on hepatocellular carcinoma, liver-related morbidity and all-cause mortality during treatment and the follow up period in the short-medium term afterwards. No IFN versus placebo reviews reported comparative data on quality of life to make any statistical comparisons. Two reviews presented data among individuals with cirrhosis on treatment showing a marked improvement in SVR for those receiving treatment (OR 8.84, 95%CI 3.29 to 23.77).
The systematic review comparing ribavirin with placebo showed no significant beneficial effect of ribavirin in achieving SVR (Risk difference 0.0%, 95% CI -0.03 to 0.02), reducing all-cause mortality (RD 0.0%, 95% CI -0.02 to 0.03) or quality of life (RD -0.11 QALY, 95% CI -0.27 to 0.06). Treatment discontinuation was observed as an adverse event in 5% of the intervention group and there was no improvement in quality of life with ribavirin intervention (Table 4).
One study reported on the virological outcomes and adverse effects of treatment among children (SVR IFN 45% v. no treatment 9%, p=0.06; RR 0.45 (0.28 to 0.72) (Hu, Doucette et al., 2010). None of the interventions reported differential SVR findings among PWID or HIV-infected individuals as these were most often exclusion criteria for the studies themselves. However, one review among HIV coinfected patients did make other comparisons of different treatment regimens (eg PEG versus IFN) which is addressed in a separate systematic review as part of the WHO HCV evidence review process (Refer to PICO 6 Treatment: PEG vs IFN).
All reviews of IFN, PEG or RBV versus placebo synthesised randomised controlled trials using appropriate meta-analytical methods and received moderate to high quality scores using the AMSTAR rating. Overall outcome ranking according to GRADE criteria saw outcomes rated down for imprecision where small events occurred (mortality and morbidity during the study period, SVR among children, and serious adverse events), or short duration of follow up (mortality and HCC detection during the study period). Inconsistency within previous meta-analyses reduced outcome ratings for liver-related and all-cause mortality. Finally, at least moderate risk of bias identified in primary RCTs downgraded effect estimated for SVR among treatment experienced individuals and treatment discontinuation due to adverse events.
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PICO 5 (Treatment): Anti-viral treatment versus no treatment for chronic HCV
Records identified through database searches (Embase, Medline, Cochrane) (N=1109)
Duplicates removed (n=339)
Records assessed for eligibility by article type & title (n=770) A Records excluded from further review with reasons (n=712) o Not a systematic review o Not relevant to PICO Records included for title & abstract review (n=58)
Records excluded by reviewing abstract (n=42)
Records included for full text reviews (n=16)
Records excluded following full text review (n=3) o (Shepherd et al., 2000) Compared IFN-alpha + RBV v/s IFN monotherapy alone/with placebo; o (Pellicelli et al., 2008) Compared treatment options within injecting drug users and non-injectors; o (Kimer et al., 2011) Updated data in 2012 publication
Reviews included for data extraction (n=13)
Figure 1: Flow chart describing selection of included studies
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PICO 5 (Treatment): Anti-viral treatment versus no treatment for chronic HCV
CONCLUSIONS Overall, IFN or PEG used alone or with RBV, is effective in achieving sustained virological response. With evolving research, numerous regimens have become available for the treatment of chronic HCV. The only anti-viral regimens that have been reported in systematic reviews in comparison to either no therapy or placebo are IFN, PEG and RBV.
Treatment with interferon (alfa-2a, alpha-2b) significantly improves the likelihood of achieving SVR and reducing liver related mortality but is associated with adverse events.
Treatment with ribavirin mono-therapy has no significant effect on SVR, end of treatment virological response, liver-related morbidity and mortality during treatment but significantly increases the risk of adverse reactions, including anaemia.
Implications for clinical practice There is evidence demonstrating the efficacy of antiviral therapy in achieving SVR but less conclusive evidence supporting improvements in mortality, morbidity and quality of life.
Implications for research Translational and implementation research into developing cost-effective treatment regimens, improving side-effects profiles and delivering medications in low and middle income countries especially are now needed to see successful therapies implemented.
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PICO 5 (Treatment): Anti-viral treatment versus no treatment for chronic HCV
TABLES Table 1: Characteristics of systematic reviews included for data synthesis Review 1: Malaguarnera, Restucciaet al.1995 Study Objectives Methods The aim of this study was to assess the long term efficacy of Interferon-alpha treatment in chronic HCV 27 Randomized clinical trials; Meta-analysis performed Inclusion Criteria: o o Abstracts that had at least 5 studies for statistical analysis Abstracts presented at international congresses
Exclusion Criteria: o Studies by the same author containing a different number of patients and if it was not clear whether the same patients had been included in both studies. Study characteristics Country: Not stated Study Setting: Unclear Study size: 1579 Funding source: Not stated Study Population: Adults with chronic HCV Age (Mean): Not stated Sex (% male): Not stated Ethnicity: Not stated Follow up: 33.9 weeks (Median 25 weeks, Range =2 to 74 weeks) Intervention (N) Control (n) Outcomes IFN- alfa2a or IFN-alfa2b or Lyphoblastoidalfa or IFN-alpha (918) No treatment (661) SVR o Overall (Complete long term remission): Intervention= 30.0% v. Control= 10.1% ; OR 4.44 (3.42-5.75) o Recombinant IFN-alpha2a: Intervention= 31.5% v. Control= 1.6%; o Recombinant IFN-alpha2b : Intervention= 18.5% v. Control= 4.0%; o Lymphoblastoid IFN- alpha: Intervention= 40.4% v. Control= 1.9%; OR 8.66(4.66-15.79) o 3 million units [MU] IFN- alpha: Intervention= 44.5% v. Control=22.3%; o 3 or 1 MU IFN-alpha: Intervention= 17.4% v. Control=3.4%; Results OR 3.83 (2.11-6.88) OR 3.25(2.27-4.66) OR 4.58 (2.8-7.46) OR 8.44 (4.48-15.8)
IFN capable of modifying the natural history of HCV. Marked improvement in the histological picture and long term remission seems to occur with doses of 3MU/week. Elevated long term efficacy seen in studies adopting lymphoblastoid IFN alpha (OR8.66). Inferior results obtained in studies utilising IFN-alpha2b and it is less efficacious than lymphoblastoid IFNalpha and IFN-alpha2a.
Comments
Amstar rating: 7
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PICO 5 (Treatment): Anti-viral treatment versus no treatment for chronic HCV
Review 2: Carithers and Emerson (1997) Study Objectives To systematically examine the bio-chemical, virological and histological outcomes of patients with chronic HCV enrolled in well-designed RCT's of IFN alfa-2b therapy Methods 20 Randomized clinical trials; Meta-analysis performed Inclusion Criteria: o Adult patients (>18 years) with chronic hepatitis and no previous history of treatment with IFN.
Exclusion Criteria: o Studies with inadequate information, lack of randomization, inclusion of previously treated patients, inadequate treatment duration, studies of acute HCV Study characteristics Country: Not stated Study Setting: Unclear Study size: 552 Funding source: Not stated Study Population: Adults with chronic HCV ; 25% of patients were cirrhotic Age (Mean): 54 years Sex (% male): 68 Ethnicity: Not stated Intervention (N) Control (n) Outcomes IFN-alfa2b 2MU three times daily for a minimum of 24wks (Not stated) Placebo or No treatment (Not stated) SVR: Absence of circulating RNA(maintained for 6months after discontinuation of therapy) o Intervention=8% v. control=1%; OR 8.6 (1.0-74.8)
Normalisation of ALT levels 6months post treatment (not based on HCV RNA) assessed in 18 studies: o Intervention=23% v. Control=2%; OR 17.8 (8.5-37.3)
End-of treatment virological response: o Intervention=29% v. Control=5%: OR 9.4 (3.4-25.7)
Results Comments
IFN alfa-2b is effective as therapy for chronic Hep C Amstar rating: 8
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PICO 5 (Treatment): Anti-viral treatment versus no treatment for chronic HCV
Review 3: Myers et al. (2009) (initially published 2002, updated 2009) Study Objectives To evaluate the response to IFN (at a standard dose) in IFN naïve patients with chronic HCV. The effect of treatment dose and duration and the response in patients with cirrhosis and those with normal aminotransferases was also investigated Methods 24 Randomized clinical trials; Meta-analysis performed Inclusion Criteria: o RCTs comparing IFN with placebo, no treatment or different regimens of IFN in treatment naive patients were selected, studies with at least one of the following: biochemical ETR, biochemical SR, virological ETR, virological SR Exclusion Criteria: o Abstracts, patients post liver transplantation or infected with HBV and or HIV, trials involving previously treated patients, interim reports and studies employing an initial run-in period of IFN treatment were excluded Study characteristics Country: Not stated Study Setting: Not stated Study size: 1213 meeting PICO (total review n=6545) Funding source: o Dr. V. Feinman Hepatology Fellowship from the Canadian Association for the Study of the Liver o Detweiler Travelling Fellowship from the Royal College of Physicians o Surgeons of Canada, Recherche et Partage o Association Francaise pour l'Etude du Foie o Club Francophone de l'HypertensionPortale Study Population: Adults with chronic HCV; Treatment naive patients Age (Mean): Not stated Sex (% male): Not stated Ethnicity: Not stated IFN 3MU thrice/weekfor 6 months (619) No intervention or control (594) SVR o IFN v. Control Intervention = 32% v. Control=2%; OR 8.30 (4.65 – 14.80) o IFN 3MU thrice weekly for 6 months: Intervention= 23% v. control= 1%; OR 8.05 (3.82-16.96) o IFN 3MU thrice weekly for 12 months: Intervention= 17% v. Control= 3%; OR 4.60 (1.53-13.85) o Two RCT’s in patients with normal aminotransferases: Intervention= 8% v. Control= 0%; OR 7.48 (0.43-130.05) o Two RCT’s in cirrhotic patients: Intervention=17% v. Control=0%; OR 8.84 (3.29-23.77) HCC IFN v. Control (Results from two studies): Intervention= 13% v. Control= 24%; OR 0.50 (0.21-1.21) o Cirrhotic patients (Results from three RCT’s): Intervention= 43% v. Control= 46%; OR 0.74 (0.38-1.47) IFN is effective in achieving viral clearance and improving liver bio-chemistry and histology in IFN naïve patients with chronic HCV. It is also associated with benefits in cirrhotic patients. The most effective regimen of IFN monotherapy for this outcome appears to be at least 6MU thrice/weekly for 12 months treatment duration but at a cost of more adverse events. Comments Amstar rating: 11 Only one of the included RCTs had adequate allocation concealment and was double blinded. o
Intervention (N) Control (n) Outcomes
Results
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PICO 5 (Treatment): Anti-viral treatment versus no treatment for chronic HCV
Review 4: Tine et al. (2005) Study Objectives To review HCV trials before the introduction of interferon and Ribavirin as standard treatment of chronic HCV and give insight into the complexity of the data and to explain the heterogeneity of interferon effects Methods 36 randomized clinical trials; Meta-analysis performed
Inclusion Criteria: o Published RCTs assessing IFN-alpha for their activity in patients with chronic HCV and aminotransferase elevation which had never been treated before. Exclusion Criteria: o Letters, Non English papers ,Clinical series, Trials in patients with acute Hep-C, Trials in patients with normal ALT , Trials in non-responders or relapsers after interferon, pPatients with coinfections (HBV,HIV) or in OLT carriers, patients with commonly associated HCV diseases (haemophilia, thalassemia orcyoglobulinemia), trials in haemodialysis patients. Study characteristics Country: Not stated Study Setting: Not stated Study size: 2454 Funding source: o MIUR ex 60%, 1998, Massimo AttanasioMIUR ex60%,2002, Massimo Attanasio
Study Population: 64% genotype 1 ; 31%cirrhotic/fibrosis Age (Mean): 49years Sex (% male): 61% Ethnicity: not stated Intervention (N) 9MU or 18MU of IFN/week for 6-12months o o o Control (n) Outcomes IFN alpha-2b (58.3%) IFN alpha-2a(22.2%) Other types of IFN(19.5%)
Placebo (albumin or sterile water) or untreated (80) Sustained ALT normalization: o IFN v. placebo/no treatment (Pooled result): OR 9.5 (6.3-14.2) AE: o o Patients who stopped IFN: 83.3% Patients who had reason to stop: 77.8%
Results
This meta-analysis included RCT’s conducted in naïve, relapsers and non-responders and analysed HCV-RNA as end point.Sustained response was most likely in experimental arms of IFN+ribavirin or other drugs, arms using yearly schedule, trial principle from Asia, trial sample size >200, and arms enrolling less than 50% cirrhotics.
Comments
Amstar rating: 9
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PICO 5 (Treatment): Anti-viral treatment versus no treatment for chronic HCV
Review 5:Fabrizi et al. (2008) Study Objectives Methods To evaluate efficacy and safety of antiretroviral therapy for HCV in patients with chronic kidney disease 13 Prospective CCT’s and Randomized clinical trials; Meta-analysis performed
Inclusion Criteria: o Full articles published in peer-reviewed journals, CCT's on chronic kidney disease patients receiving antiviral therapy versus controls not receiving therapy, studies on patients with long term dialysis or renal transplant patients were eligible Exclusion Criteria: o Studies enrolling HBsAg and HIV positive patients, abstracts, interim reports, letters and review articles, and clinical studies with combined transplant (kidney/pancreas or other organs) Study characteristics Country: 8 studies in Europe (61.5%) and 3 Saudi Arabia, 3 France, Argentina, 2 Spain, 2Turkey, Egypt, Italy. Study Setting: Not stated Study size: 539 Funding source: Project glomerulonephritis Study Population: 10 studies enrolled patients on maintenance dialysis, 3 studies on replacement therapy, 2 studies with acute hep c patients, 76.9% of the studies enrolled patients on maintenance dialysis or were replacement therapy recipients Age (Mean): 35.9(+- 10.6) to 49.4 (+-8.0) Sex (% male): 41.6-76% Ethnicity: Not stated Intervention (N) IFN alpha or alpha2b or Ribavirin or PEG IFN or Lymphoblastoid-IFN or alpha2a+ ribavirin or Ribavirin+Amantadine (244) Control (n) Outcomes Placebo or No intervention (295) “Failure to achieve SVR”: Treatment v. Control o Pooled relative results (Pooled proportion in each treatment arm not available): OR 0.081 (0.029 - 0.230) o Subset using dialysis (n=6): OR 0.054 (0.019-0.150) AE: Treatment v. Control o Overall dropout rate: OR 0.385 (0.155- 0.957) ; o In dialysis patients dropout rate: OR 0.920 (0.367-2.311) Results Viral response greater in patients with chronic kidney disease who received ARV therapy than controls, Immune compromise conferred from chronic uraemia does not affect viral response to ARV Rx for HCV Comments Amstar rating: 9 Information on drop-outs unclear, significant heterogeneity between studies in the primary analysis
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PICO 5 (Treatment): Anti-viral treatment versus no treatment for chronic HCV
Review 6: Xirouchakis et al. (2008) Study Objectives Methods To assess efficacy, tolerability and safety of Peg/ribavirin in liver transplant candidates and recipients 3 CCT (NRT) + one randomized clinical trials; Meta-analysis performed
Inclusion Criteria: o Published abstract of full paper; CCT or RCT, Cirrhotic candidates for liver transplantation or transplanted patients with Hep-C; SVR was stated, therapy with PEG-IFN alpha-2a or alpha-2b and ribavirin; Combination therapy used for at least 24 weeks Exclusion Criteria: o Mixed sequential regimens containing Peg IFN only in part; Patients co-infected with HIV or HBV; Patients with cirrhosis not considered for transplantation Study characteristics Country: Not stated Study Setting: Not stated Study size: 244 Funding source: The Hellenic Foundation for Gastroenterology and Nutrition (ELIGAST) Study Population: Liver transplant candidates and recipients with HCV cirrhosis; Studies included 69% - 100% of patients with genotype 1 Age (Mean): Not stated Sex (% male): Not stated Ethnicity: Not stated Intervention 1: PEG-IFN 1.0µg + rb 0.8 to 1.0g for 24 weeks (129) Intervention 2: PEG-IFN 1.5mcg + RBV 600 to 800 mg for 24+24 weeks if RNA negative (48) Intervention 3: PEG-IFN 1.5mcg + RBV 800-1000mg for 48 weeks (48) Intervention 4: PEG-IFN 1.5mg + RBV 800mg 48 weeks (54) Control (n) Outcomes No treatment (not stated) SVR: Overall Treatment v. no treatment or low dose treatment o Intervention=41% v. Control=9.2%; Risk Difference 0.316 (0.18- 0.44) Outcomes for liver transplant candidates with HCV related cirrhosis: o Intervention1= 19.6% v. No treatment=0% Outcomes in patients transplanted for HCV related cirrhosis with recurrent disease: o Intervention 2=33.3% v. No treatment= 0% o Intervention 3= 29.6% v. No treatment= 0% o Intervention 4= 48% v. No treatment= 0% AE: Overall Treatment v. No treatment: RD -0.010 (0.044- -0.064) o Intervention=5% v. Control= 6.4%; Treatment discontinuation in liver transplant candidates with HCV related cirrhosis (Intervention 1): o Intervention = 19.6% v. No treatment= 0% Mortality: Overall Treatment v. no treatment or low dose treatment o Intervention= 7% v. Control=5%; Risk Difference 0.042 (0.027 to -1.55)) Outcomes for liver transplant candidates with HCV related cirrhosis (End of follow up) o Intervention= 7.5% v. No treatment= 6.3% ; Risk difference between study groups= 1.2% (CI ; OR 1.2 (95%CI 0.25-6.4) Results PEG-IFN with Ribavirin in optimal standard doses is efficacious, in both liver transplant candidates, and in recipients, to treat recurrent HCV disease. However it is associated with low median SVR of19.6% (19.6-50%) in liver transplant candidates and 41% (29.6-77.7%) in those with recurrent disease after liver transplantation. Comments Amstar rating: 10 No of studies and patients included in each study was small and the comparison groups were not Homogenous
Intervention (N)
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Review 7: Brok et al. (2009a) Study Objectives Methods To assess the beneficial and harmful effects of ribavirin mono-therapy for patients with chronic HCV 11 Randomized clinical trials; Meta-analysis performed
Inclusion Criteria: o o o Patients with chronic HCV for more than 6 months Patients with chronic HCV documented on liver biopsy Patients diagnosed with non-A, non-B chronic hepatitis.
Exclusion Criteria: o o Study characteristics Excluded patients with HIV co-infection or who had undergone liver transplantation Quasi-randomized trials and observational studies
Intervention (N)
Country: Not stated Study Setting: Not stated Study size: 523 (657) Funding source: The Hellenic Foundation for Gastroenterology and Nutrition (ELIGAST) Study Population: Adults with Chronic HCV (treatment naive patients, non-responders, relapsers): Genotype-1: 73% (Median) (Range- 40-97% ) Cirrhotic/Fibrosis: 15% (Median) (Range- 0-35%) Age (Median): 45 years (Range 38-50 years) Sex (% male): 74% ( median): range 63-100% Ethnicity: Not stated Ribavirin administered in clinical trial setting between 8-52 weeks (283) Five trials -1200mg/day, Four trials - 1000-1200mg/day, One trial- 800-1000mg/day, One trial- 15mg/kg/day, One trial- dose not reported
Control (n) Outcomes (RD= Risk Difference)
Placebo or no intervention (240) SVR: In 5 studies with 353 participants o Intervention=0% v. Control= 0%; RD 0.00 (-0.02 - 0.03) Adverse events: o Depression- RD 0.17 (0.01-0.33) o Anaemia- 16%; RD 0.16(0.11-0.22) o Fatigue- RD 0.05(-0.01- 0.11) o Irritability- RD 0.03(-0.03-0.08) o Anxiety- RD 0.03(-0.06- 0.12) o Pruritus-RD 0.06(-0.00- 0.12) o Infections- RD 0.17(0.03-0.32) o Cough- RD 0.21(0.04-0.38) o Chest Pain- RD 0.07(0.00-0.14) o Skin disorders- RD 0.14 (0.06-0.23) o Nervous systemic disorders- RD 0.14(0.06-0.23) o Gastro-intestinal- RD 0.03 (-0.04-0.09) o Headache- RD 0.03(-0.04-0.09) o Vasculitis- RD 0.02 (-0.04-0.09) ; o Dose reductions- 11%; RD 0.11 (0.06-0.16) o Treatment discontinuations- 5%; RD0.05 (0.01-0.10) Mortality and morbidity o 3%; RD 0.00(-0.02 - 0.03) in 11 studies with 521 patients QOL: o Intervention=0.828 v. Control=0.933; RD -0.11(-0.27- 0.06) Ribavirin had no significant effect on SVR, end of treatment virological response, liver-related morbidity and mortality but significantly increased the risk of adverse reactions, including anaemia.
Results
Comments
Amstar rating: 11 Majority of trials had inadequate or unclear control of bias.
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PICO 5 (Treatment): Anti-viral treatment versus no treatment for chronic HCV
Review 8: Hartwell and Shepherd (2009) Study Objectives To assess the clinical effectiveness of pegylated and non -pegylated IFN-alfa and ribavirin for treatment of adults with histologically mild HCV. Methods Three randomized clinical trial of treatment versus no treatment; Meta-analysis performed to compare IFN monotherapy with three trials of IFN +Placebo and one trial of IFN + RBV Inclusion Criteria: o o RCT's or systematic reviews of RCT's Studies evaluating PEG-2a or Peg-2b as dual therapy with RBV or mono-therapy for those unable to tolerate RBV o o Studies of IFN-2a or IFN-2b with RBV Studies reporting ≥ 70% of adult patients at baseline with histologically mild HCV
Exclusion Criteria: o Study characteristics Studies where it was not possible to determine the severity of HCV
Country: Not stated Study Setting: Not stated Study size: 687 Funding source: Not stated Study Population: Studies reporting >70% of adult patients at baseline with histologically mild HCV Age (Mean): 36-49 Sex (% male): Not stated Ethnicity: Not stated
Intervention (N)
Different durations of treatment. no treatment: o PEG-alpha2a 180µg + RBV 800mg for 24 weeks (212) o PEG-alpha2a 180µg + RBV 800mg for 48 weeks (210) o IFN-alpha2b3MU + RBV 1000-1200mg for 48 weeks (98)
Control (n) Outcomes
No treatment (167) SVR: Relative Risk = 1.7 o PEG-alpha2a 180µg + RBV 800mg for 24 weeks: Intervention=30% v. Control= 0% o PEG-alpha2a 180µg + RBV 800mg for 48 weeks: Intervention=52% v. Control=0% o IFN-alpha2b 3MU + RBV 1000-1200mg for 48 weeks (98): Intervention=33%v. Control=0% Adverse events: o o o QOL: o PEG trial- At 24 weeks after end of treatment-HRQoL scores were significantly better in patients with an SVR compared with untreated patients (PEG trial) o IFN trial- Body pain Influenza symptoms (Headache, fatigue, fever, myalgia); Depression; Dose modifications in HIV co-infected patients treated with PEG
Results
SVR was higher in IFN+ RBV compared with no treatment; SVR was higher for patients with genotype non-1 compared with genotype 1 for Peg+RBV and IFN+RBV Treatment
Comments
Amstar rating: 10 RCTs had poor reporting of randomization methods and blinding of assessors
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PICO 5 (Treatment): Anti-viral treatment versus no treatment for chronic HCV
Review 9: Iorio et al. (2010) Study Objectives To evaluate the benefits and harms of antiviral treatment for chronic HCV in patients with Human immunodeficiency virus (HIV) co-infection Methods One randomized clinical trial; Meta-analysis performed Inclusion Criteria: o Patients with chronic HCV and stable HIV co-infection; Included irrespective of previous antiviral therapy, level of plasma HIV RNA and CD4 positive cell counts Exclusion Criteria: o Study characteristics Excluded quasi-randomised trials and observational studies
Country: USA or Europe Study Setting: Not stated Study size: 30 Funding source: Not stated Study Population (mean): Studies included 44-78% of genotype-1 participants Age (Mean): 36-45 Years (all trials) Sex (% male): 60%-90% ( all trials) Ethnicity: Not stated
Intervention (N) Control (n) Outcomes (RR= Risk Ratio)
IFN 3MU 3 times weekly + RBV (18) No treatment (12) SVR: o Not reported
End of treatment virological response: o AE o Drop-out rate Intervention= 0.11% v. Control=0% o Flu-like symptoms: Intervention= 0.83% v. Control= 0%; Results (Fishers exact P <0.01) Intervention= 0.39% v. Control= 0%; (Fishers exact P=0.02)
No SVR data was available for the treatment v no treatment comparison. Treatment increased the risk of adverse events including anaemia and flu-like symptoms and serious adverse events including fatal lactic acidosis, liver failure and suicide due to depression.
Comments
Amstar rating: 11
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PICO 5 (Treatment): Anti-viral treatment versus no treatment for chronic HCV
Review 10: Hu et al. (2010) Study Objectives Methods To assess the efficacy and safety of HCV therapy in children Two of four Randomized clinical trials; 31 non-randomized studies; Meta-analysis not performed Inclusion Criteria: o o o Studies including children (≤ 18 years of age) Provided details of treatment regimen Provided data for SVR (as negative HCV RNA at least 24 weeks after therapy cessation)
Exclusion Criteria: o Study characteristics No criteria
Country: Italy Study Setting: Not stated Study size: 48 Funding source: Not stated Study Population: Children (<18) with HCV Age (Mean): Not stated Sex (% male): Study 1: Group A= 63% males; Group B = 40% males Study 2: Group A= 50% males; Group B = 38% males Genotype: Study1 Group A= 58% ; Group B= 70% Study 2 Group A= 50%; Group B = 46% Ethnicity: Not stated Study 1 intervention - IFN-alpha 3MU/m23 times weekly for 12 months (11) Study 2 intervention - IFN-alpha-2b 5MU/m2 3 times weekly for 12 months (14)
Intervention (N)
Control (n) Outcomes
No intervention (23) SVR o Study 1: At 30 months: Intervention= 45% v. No treatment=9%; OR 8.3 (0.6-432.5) o Study 2: At 24 months: Intervention= 69% v. No treatment= 0%, OR indeterminate but 95%CI OR>7.4 AE: No comparative data presented for treatment v. no treatment. All treatment patients showed transient influenza flu-like symptoms (other effects: anorexia, asthenia, irritability, headache, abdominal pain, leukopenia, pruritus, weight loss).
Results Comments
SVR rates are significantly higher in children with genotype 2 or 3 compared to genotype 1 Amstar rating: 7
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PICO 5 (Treatment): Anti-viral treatment versus no treatment for chronic HCV
Review 11: Vezali, Aghemo et al. (2010) Study Objectives This review highlights the efficacy and safety of HCV infection in cirrhotic patients with respect to the clinical stage of the disease Methods 5 of 45 Randomized, prospective, observational , retrospective clinical trials; Meta-analysis not performed Inclusion Criteria: o Adults> 18 years with chronic Hep-C infection treated with IFN or RBV; studies with baseline characteristics and involving cirrhotic and non-cirrhotic patients.. Exclusion Criteria: o Study characteristics Review articles were not used, except to identify papers
Country: Not stated Study Setting: Not stated Study size: 1676 Funding source: Helenic Association for the study of Liver Diseases ; Schering-Plough, Roche, Bristol-Myers Squibb, Gilead sciences Inc, Bayer healthcare AG Study Population: Combine data not available Age (Mean): 55-63 years of age Sex (% male): combined data not available Ethnicity: Not stated
Intervention (N)
Intervention in study 1: IFN (193) – retrospective cohort Intervention in study 2: : IFN-alpha2b for 48 weeks (47) - RCT Intervention in study 3: PEG IFN-alpha2b 1.0µg/kg/wk and RBV 800-1000mg/d for 24 weeks in decompensated cirrhotics (66) – non-randomised prospective trial
Control (n)
Study 1: Untreated (136) Study 2: Untreated (52) Study 3: Patients who refused treatment (63)
Outcomes
Study 1: HCC (annual incidence) : Untreated 2.3%v. Treated1% (p=0.09) Hepatic decompenstation: Untreated 1.5% v. Treated 5.7% (p=0.07)
Study 2: HCC(annual incidence) : Untreated-17%v.Treated-11% Hepatic decompenstation: Untretaed-10% v. Treated – 15% 3- year mortality: Treated 21% v untreated 10%; OR 2.5 (0.7-10.2)
Study 3: SVR: 19.5% (13/66) treated, 0% (0/63) untreated; OR N/A (cannot calculate) AE : Risk of infections with PEGIFN=0.95/1000 v. Controls= 0.38/1000 patients months
[IRR 2.43 (1.02-5.77)]
Hepatic decompensation at 30 months: 88.1% untreated, 59.0% treated, OR 0.19 (0.06-0.53) Mortality (all cause) at 30 months: 32.2% untreated, 16.4% treated, OR 0.41 (0.15-1.06) Results Anti HCV treatment in cirrhotic patients is less effective than in non-cirrhotic patients. Viral eradication reduces the risk of liver complications and improved survival in non-cirrhotic. Therapy has a significant effect on patients with compensated cirrhosis while decompensated patients need to weigh the risks versus benefits of treatment Comments Amstar rating: 11
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PICO 5 (Treatment): Anti-viral treatment versus no treatment for chronic HCV
Review 12: Kimer et al. (2012) Study Objectives To determine whether antiviral therapy reduces the risk of developing hepatocellular carcinoma in patients with chronic HCV Methods Eight Randomized clinical trials and five prospective studies; Meta-analysis was performed with primary analysis using RCTs Inclusion Criteria: o o All trials on IFN or PEG-IFN alone or with RBV were included; Trials on patients with HCV related cirrhosis or fibrosis treated with antiviral therapy were included.
Exclusion Criteria: o Study characteristics Trials on HIV and hepatitis-B patients were excluded
Country: France, Italy, Spain, Japan and USA Study Setting: Not stated Study size: 2230 Funding source: Not stated Study Population: Patients with cirrhosis (8 RCTs); Cirrhotic patients (41%); All patients in intervention group underwent ultrasound, serological testing and liver biopsy at baseline Age (Mean): Not stated Sex (% male): Not stated Ethnicity: Not stated
Intervention (N)
Intervention :IFN monotherapy (Five RCTs); Peg-IFN (Two RCTs); IFN +RBV (One RCT) (1156) Therapy ranges from 1 to 5 years, and follow up from 2 to 8.7 years
Control (n) Outcomes (RR= Risk Ratio)
No intervention (1074)
Hepatocellular carcinoma: o Intervention =7.01% v. control=12.01%: RR 0.53 (0.34 - 0.81)
Morbidity: Liver related: o Intervention= 8.5% v. control=10.8% ; RR 0.73 (0.48 - 1.11)
Mortality:(Recorded from 4 trials) All cause: Intervention= 10.1%v. Control=9.7% ; RR 0.81 (0.33-2.03) Liver related: RR 0.71(0.2 -2.51), no proportion available Results Antiretroviral therapy may reduce the risk of hepatocellular carcinoma in HCV related cirrhosis and fibrosis. Effects of ARV therapy are seen irrespective of virological response, but are more pronounced in responders compared to non-responders. Hepatocellular carcinoma incidence is diminished in both virological responders and non-responders. Comments Amstar rating: 11
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PICO 5 (Treatment): Anti-viral treatment versus no treatment for chronic HCV
Review 13: Kortez et al (2013) Study Objectives Methods To assess the benefits and harms of interferon mono-therapy retreatment in chronic HCV patients who are non-responders to and relapsers of previous interferon therapy. 7 Randomized clinical trials; Meta-analysis performed Inclusion Criteria: o Trials comparing interferon mono-therapy with no treatment in non-responding and relapsing patients with chronic HCV. Exclusion Criteria: o Patients who had undergone liver transplantation, were co-infected with HBV and/or HIV, and/or had evidence of hepatic decompensation. Country: Not stated Study Setting: Unclear Study size: 1676 Funding source: National institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Study Population: Patients with chronic HCV who are non-responders to and relapsers ofprevious IFN therapy Age (Mean): Not stated Sex (% male): Not stated Ethnicity: Not stated IFN monotherapy ranging from 24 weeks (3 studies), 48 weeks (1), 96 weeks (1) and 3-5 years treatment (2 studies) Placebo or no treatment (Not stated) SVR: o Intervention=3.6% v. Control=0.2%: OR 0.046 (0.0 – 0.29) Hepatocellular carcinoma: o RR 0.81(0.55-1.19), baseline proportion unavailable Mortality ( o All cause: Intervention= 9.3% v. Control= 7.2% ; RR 1.30 (0.95-1.79) o Liver related: Intervention=7.7% v. Control =7.2%; RR 1.07 (0.70-1.63) Morbidity comparing maintenance IFN monotherapy for 3-5 years with no therapy among patients with severe histologic disease (grade 3 or 4 fibrosis) who have failed previous antiviral therapy):: o Hepatic encephalopathy: RR 0.92 (0.38-2.26) o Variceal bleeding: Intervention= 0.5% v. Control= 2.1%; RR 0.26(0.09-0.71) o Ascites: RR 1.12 (0.62-2.00) o Spontaneous bacterial peritonitis: RR 0.38(0.04-3.54) AE: o Any adverse event- RR 1.02 (0.99-1.05) o Serious adverse event- RR 1.18(0.99-1.41) o Hematologic- RR 2.41(1.71-3.39) o Psychiatric events – RR 1.44(0.94-2.19) o Infections- RR 1.51(1.05-2.16) o Gastrointestinal- RR 0.99(0.87-1.14) o Systemic symptoms – RR 1.82(1.61-2.05) o Cardiopulmonary – RR 0.96(0.74-1.25) o Musculoskeletal – RR 1.13(0.82-1.56) o Dermatologic- RR - 2.78(1.95-3.97) o Metabolic – RR 0.84(0.35-2.03) o Neoplasms – RR 0.74(0.33-1.65) o Other systems- RR 0.82(0.47-1.41) o Hospital Admission – RR 0.0 (0.0-0.0) Interferon mono- therapy is not effective when used to retreat patients, especially those with severe fibrosis. Amstar rating: 11 Number of trials used for systematic review is small(n=7) and only some provided clinical data
Study characteristics
Intervention (N) Control (n) Outcomes (RR= Risk Ratio)
Results Comments
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PICO 5 (Treatment): Anti-viral treatment versus no treatment for chronic HCV
EVIDENCE PROFILES Table 2: Evidence profile: Interferon versus no treatment for chronic HCV Question: Should Interferon vs Placebo be used for chronic HCV treatment? Quality assessment Participants Risk of bias Inconsistency (studies) Follow up Indirectness Imprecision Publication bias Overall quality of evidence Study event rates (%) With Placebo With Interferon
Summary of Findings Relative effect (95% CI) Anticipated absolute effects Risk with Placebo Risk difference with Interferon (95% CI)
Failure to achieve SVR (Treatment naive) (CRITICAL OUTCOME; assessed with: HCV RNA test 6 months post treatment; Myers 2009) 409 (8 studies) 72 weeks no serious risk of bias no serious inconsistency no serious indirectness no serious imprecision undetected ⊕⊕⊕⊕ HIGH 198/200 (99%) 176/209 (84.2%) OR 0.15 (0.076 to 0.30) 990 virological failures per 1000 53 fewer virological failures per 1000 (from 23 fewer to 107 fewer)
Failure to achieve SVR (Treatment experienced) (CRITICAL OUTCOME; assessed with: HCV RNA test 6 months post treatment; Kortez 2013) 1136 (4 studies) 72 weeks serious1 no serious inconsistency no serious indirectness no serious imprecision undetected ⊕⊕⊕⊝ MODERATE1 due to risk of bias 578/579 (99.8%) 537/557 (96.4%) RR 0.96 (0.95 to 0.98) 998 virological failures per 1000 40 fewer virological failures per 1000 (from 20 fewer to 50 fewer)
Failure to achieve SVR (Children only) (CRITICAL OUTCOME; assessed with: HCV RNA test 6 months post treatment; Hu 2010) 48 (2 studies) 24-30 months no serious risk of bias no serious inconsistency no serious indirectness serious2 undetected ⊕⊕⊕⊝ MODERATE2 due to imprecision 23/24 (95.8%) 10/24 (41.7%) RR 0.45 (0.28 to 0.72) 958 virological failures per 1000 527 fewer virological failures per 1000 (from 268 fewer to 690 fewer)
Failure to achieve SVR (Cirrhotic patients) (CRITICAL OUTCOME; assessed with: HCV RNA test 6 months post treatment; Myers 2009) 201 (3 studies) 72 weeks no serious risk of bias no serious inconsistency no serious indirectness no serious imprecision undetected ⊕⊕⊕⊕ HIGH 101/101 (100%) 83/100 (83%) OR 0.11 (0.03 to 0.39) 1000 virological failures per 1000 170 fewer virological failures per 1000 (from 30 more to 390 more)3
Serious adverse events during treatment (CRITICAL OUTCOME; assessed with: unspecified serious AEs; Kortez 2013) 1103 (2 studies) 3-5 years no serious risk of bias no serious inconsistency no serious indirectness serious4 undetected ⊕⊕⊕⊝ MODERATE4 due to imprecision 157/560 (28%) 180/543 (33.1%) RR 1.18 (0.99 to 1.41) 0 events per 1000** 50 more events per 1000 (from 3 fewer to 115
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PICO 5 (Treatment): Anti-viral treatment versus no treatment for chronic HCV
more)
All-cause mortality during or after treatment (CRITICAL OUTCOME; assessed with: Kortez 2013) 1710 (3 studies) 1-5 years no serious risk of bias serious5 no serious indirectness serious6 undetected 62/867 ⊕⊕⊝⊝ LOW5,6 (7.2%) due to inconsistency, imprecision 78/843 (9.3%) RR 1.30 (0.95 to 1.79) 72 deaths per 1000 21 more deaths per 1000 (from 4 fewer to 56 more)
Liver-related mortality during or after treatment (CRITICAL OUTCOME; assessed with: Kortez 2013) 1084 (2 studies) 3-5 years no serious risk of bias serious5 no serious indirectness serious6 undetected 40/552 ⊕⊕⊝⊝ (7.2%) LOW5,6 due to inconsistency, imprecision 41/532 (7.7%) RR 1.07 (0.70 to 1.63) 72 deaths per 1000 5 more deaths per 1000 (from 22 fewer to 46 more)
Hepatocellular carcinoma detected during study (IMPORTANT OUTCOME; assessed with: HCC detected by any method; Myer 2009) 128 (2 studies) 72 weeks 1 2
no serious risk of bias
no serious inconsistency
no serious indirectness
very serious7
undetected
⊕⊕⊝⊝ LOW7 due to imprecision
16/67 (23.9%)
8/61 (13.1%)
OR 0.50 (0.21 to 1.21)
239 diagnoses per 103 fewer diagnoses 1000 per 1000 (from 177 fewer to 36 more)
High-risk bias identified by Kortez review for some of primary studies used in the pooled result Imprecision given small number of events 3 Estimated absolute difference assumed baseline risk of 100% failure to achieve SVR among untreated cirrhotic individuals 4 Imprecision due to inconsistent definition of serious adverse events 5 Inconsistency due to heterogeneity between studies 6 Imprecision given small event numbers and short duration of follow up for mortality 7 Imprecision in short duration of follow up, and inadequate ascertainment of HCC disease free at study outset **Absolute risk of serious adverse events estimated to be 0 per 1000 among patients not on treatment
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PICO 5 (Treatment): Anti-viral treatment versus no treatment for chronic HCV
Table 3: Evidence profile: Any IFN alone or with RBV interventions versus no treatment for chronic HCV Question: Should Any interferon alone or with ribavirin vs Placebo be used for chronic HCV? Quality assessment Participants Risk of (studies) bias Follow up Inconsistency Indirectness Imprecision Publication bias Overall quality of Study event rates (%) evidence With With Any Placebo interferon alone or with ribavirin
Summary of Findings Relative effect (95% CI) Anticipated absolute effects Risk with Placebo Risk difference with Any interferon alone or with ribavirin (95% CI)
Failure to achieve SVR (Treatment naive) (CRITICAL OUTCOME; assessed with: HCV RNA test 6 months post treatment; Myers 20091) 409 (8 studies) 72 weeks no serious no serious risk of bias inconsistency no serious indirectness no serious imprecision undetected ⊕⊕⊕⊕ HIGH 198/200 (99%) 176/209 (84.2%) OR 0.15 (0.076 to 0.30) 990 virological failures per 1000 53 fewer virological failures per 1000 (from 23 fewer to 107 fewer)
Failure to achieve SVR (cirrhotics pre or post transplant) (CRITICAL OUTCOME; assessed with: HCV RNA test 6 months post treatment; Xirouchakis 2008) 279 (4 studies) 72 weeks no serious no serious risk of bias inconsistency no serious indirectness no serious imprecision undetected ⊕⊕⊕⊕ HIGH 125/135 (92.6%) 102/144 (70.8%) RR 0.71 (0.64 to 0.79) 926 virological failures per 1000 269 fewer virological failures per 1000 (from 194 fewer to 333 fewer)
Treatment discontinuation due to adverse events (CRITICAL OUTCOME; assessed with: treatment stopped; Xirouchakis 2008) 129 (1 study) 72 weeks serious2 no serious inconsistency no serious indirectness no serious imprecision undetected 0/63 ⊕⊕⊕⊝ MODERATE2 (0%) due to risk of bias 13/66 (19.7%) RD 0.20 (0.09 to 0.30) 0 discontinuation per 1000 197 more discontinuation per 1000 (from 90 more to 300 more)
Liver-related morbidity during or after treatment (CRITICAL OUTCOME; assessed with: Composite definition; 789 (4 studies) 5-9 years no serious no serious risk of bias inconsistency no serious indirectness serious 4
Kimer 2012 3) RR 0.73 (0.48 to 1.11) 108 deaths per 1000 29 fewer deaths per 1000 (from 56 fewer to 12 more)
undetected
42/389 ⊕⊕⊕⊝ (10.8%) MODERATE4 due to imprecision
34/400 (8.5%)
Hepatic decompensation during or after treatment (Cirrhotic patients) (IMPORTANT OUTCOME; assessed with: composite definition; Vezali 2012) 99 (1 study) 30 months no serious no serious risk of bias inconsistency no serious indirectness serious5 undetected 5/52 ⊕⊕⊕⊝ MODERATE5 (9.6%) due to imprecision 7/47 (14.9%) RR 1.55 (0.59 to 3.45) 96 decompensation 53 more decompensation per 1000 per 1000 (from 39 fewer to 236 more)
All-cause mortality during or after treatment (Cirrhotic patients) (CRITICAL OUTCOME; assessed with: deaths; Vezali 2012) 99 no serious no serious no serious serious5 undetected ⊕⊕⊕⊝ 5/52 10/47 RR 2.21 96 deaths per 1000 116 more deaths per
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PICO 5 (Treatment): Anti-viral treatment versus no treatment for chronic HCV
(1 study) 30 months
risk of bias inconsistency
indirectness
MODERATE5 (9.6%) due to imprecision
(21.3%)
(0.69 to 8.25)
1000 (from 30 fewer to 697 more)
All-cause mortality during or after treatment (CRITICAL OUTCOME; assessed with: deaths; Kimer 2012) 1850 (4 studies) 5-9 years no serious serious6 risk of bias no serious indirectness no serious imprecision undetected ⊕⊕⊕⊝ MODERATE6 due to inconsistency 90/932 (9.7%) 93/918 (10.1%) RR 0.81 (0.33 to 2.03) 97 deaths per 1000 18 fewer deaths per 1000 (from 65 fewer to 99 more)
Hepatocellular carcinoma during or after treatment, patients with compensated advanced fibrosis (IMPORTANT OUTCOME; assessed with: HCC detection not specified; Kimer 2012) 2230 (8 studies) 2-9 years no serious serious7 risk of bias no serious indirectness serious8 undetected ⊕⊕⊝⊝ LOW7,8 due to inconsistency, imprecision 129/1074 81/1156 (12%) (7%) RR 0.53 (0.34 to 0.81) 120 diagnoses per 1000 56 fewer diagnoses per 1000 (from 23 fewer to 79 fewer)
1 2
Myers et al 2009 examined IFN v placebo. Used as a reference point for benefits of treatment compared with no treatment to compare with other outcomes Review rated primary studies as having significant risk of bias 3 Liver morbidity defined as variceal bleeding, hepatorenal syndrome, liver failure, spontaneous bacterial peritonitis 4 Imprecision given composite outcome and short-medium term follow up post treatment 5 Imprecision given short duration of follow-up for mortality 6 Inconsistency due to heterogeneity between studies with high I-square 7 Significant heterogeneity in results 8 Imprecision in inadequate ascertainment of HCC disease free at study outset
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PICO 5 (Treatment): Anti-viral treatment versus no treatment for chronic HCV
Table 4: Evidence profile: Ribavirin versus no treatment Question: Should Ribavirin monotherapy vs Placebo be used for chronic HCV? Quality assessment Participants Risk of (studies) bias Follow up Inconsistency Indirectness Imprecision Publication bias Overall quality of evidence Study event rates (%) With Placebo With Ribavirin monotherapy
Summary of Findings Relative effect (95% CI) Anticipated absolute effects Risk with Placebo Risk difference with Ribavirin monotherapy (95% CI)
Failure to achieve SVR (CRITICAL OUTCOME; assessed with: HCV RNA test 6 months post treatment; Brok 2009) 353 (5 studies) 72 weeks no serious no serious risk of bias inconsistency no serious indirectness no serious imprecision undetected ⊕⊕⊕⊕ HIGH 153/154 198/199 (99.4%) (99.5%) RD 0.00 (-0.02 to 0.03) 994 virological failures per 1000 0 fewer virological failures per 1000 (from 20 fewer to 30 more)
All-cause mortality during AND liver-related mortality (CRITICAL OUTCOME; assessed with: Combined end-point; Brok 2009) 521 (11 studies) 72 weeks no serious no serious risk of bias inconsistency no serious indirectness very serious1 undetected ⊕⊕⊝⊝ LOW1 due to imprecision 1/239 (0.42%) 2/282 (0.71%) RD 0.00 (-0.02 to 0.03) 4 deaths per 1000 0 fewer deaths per 1000 (from 20 fewer to 30 more)
Treatment discontinuations due to adverse events (IMPORTANT OUTCOME; assessed with: treatment stopped; Brok 2009) 428 (6 studies) 72 weeks no serious no serious risk of bias inconsistency no serious indirectness no serious imprecision undetected ⊕⊕⊕⊕ HIGH 8/192 (4.2%) 21/236 (8.9%) RD 0.05 (0.01 to 0.10) 42 discontinuations per 1000 50 more discontinuations per 1000 (from 10 fewer to 100 more)
Quality of life (IMPORTANT OUTCOME; assessed with: Fatigue at end of treatment; Brok 2009) 59 (1 study) 48 weeks 1 2
no serious no serious risk of bias inconsistency
serious2
no serious imprecision
undetected
⊕⊕⊕⊝ MODERATE2 due to indirectness
28/30 (93.3%)
24/29 (82.8%)
RD -0.11 (-0.27 to 0.06)
933 quality of life per 110 fewer quality of life 1000 per 1000 (from 270 fewer to 60 more)
Significant imprecision given 2 events in RBV arm and 1 event in control arm and short duration of follow-up Fatigue used as indirect measure of quality of life
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PICO 5 (Treatment): Anti-viral treatment versus no treatment for chronic HCV
REFERENCES ATKINS, D., BEST, D., BRISS, P. A., ECCLES, M., FALCK-YTTER, Y., FLOTTORP, S., GUYATT, G. H., HARBOUR, R. T., HAUGH, M. C., HENRY, D., HILL, S., JAESCHKE, R., LENG, G., LIBERATI, A., MAGRINI, N., MASON, J., MIDDLETON, P., MRUKOWICZ, J., O'CONNELL, D., OXMAN, A. D., PHILLIPS, B., SCHUNEMANN, H. J., EDEJER, T., VARONEN, H., VIST, G. E., WILLIAMS, J. W., JR., ZAZA, S. & GROUP, G. W. Grading quality of evidence and strength of recommendations. BMJ, 328, 1490. BROK, J., GLUUD LISE, L. & GLUUD, C. 2009a. Ribavirin monotherapy for chronic hepatitis C. Cochrane Database of Systematic Reviews [Online]. Available: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD005527.pub2/abstract. BROK, J., GLUUD, L. L. & GLUUD, C. 2009b. Ribavirin monotherapy for chronic hepatitis C. Cochrane Database of Systematic Reviews, CD005527. CARITHERS, R. L., JR. & EMERSON, S. S. 1997. Therapy of hepatitis C: Meta-analysis of interferon alfa-2b trials. Hepatology, 26, 83S-885. COFFIN, P. O., SCOTT, J. D., GOLDEN, M. R. & SULLIVAN, S. D. 2012. Cost-effectiveness and population outcomes of general population screening for hepatitis C. Clinical Infectious Diseases, 54, 1259-71. EL KHOURY, A. C., WALLACE, C., KLIMACK, W. K. & RAZAVI, H. 2012. Economic burden of hepatitis C-associated diseases: Europe, Asia Pacific, and the Americas. Journal of Medical Economics, 15, 887-96. FABRIZI, F., GANESHAN, S. V., LUNGHI, G., MESSA, P. & MARTIN, P. 2008. Antiviral therapy of hepatitis C in chronic kidney diseases: meta-analysis of controlled clinical trials. Journal of Viral Hepatitis, 15, 600-6. GEORGEL, P., SCHUSTER, C., ZEISEL, M. B., STOLL-KELLER, F., BERG, T., BAHRAM, S. & BAUMERT, T. F. 2010. Virus-host interactions in hepatitis C virus infection: implications for molecular pathogenesis and antiviral strategies. Trends in Molecular Medicine, 16, 27786. HARTWELL, D. & SHEPHERD, J. 2009. Pegylated and non-pegylated interferon-alfa and ribavirin for the treatment of mild chronic hepatitis C: A systematic review and meta-analysis. International Journal of Technology Assessment in Health Care, 25, 56-62. HU, J., DOUCETTE, K., HARTLING, L., TJOSVOLD, L. & ROBINSON, J. 2010. Treatment of hepatitis C in children: A systematic review. PLoS ONE, 5. IORIO, A., MARCHESINI, E., AWAD, T. & GLUUD, L. L. 2010. Antiviral treatment for chronic hepatitis C in patients with human immunodeficiency virus. Cochrane database of systematic reviews (Online), CD004888. KIMER, N., DAHL, E. K., GLUUD, L. L. & KRAG, A. 2012. Antiviral therapy for prevention of hepatocellular carcinoma in chronic hepatitis C: Systematic review and meta-analysis of randomised controlled trials. BMJ Open, 2. KIMER, N., GLUUD, L. L., DAHL, E. K. & KRAG, A. 2011. Interferon and risk of hepatocellular carcinoma in hepatitis C related cirrhosis. Hepatology, 54, 1272A. KORETZ, R. L., PLEGUEZUELO, M., ARVANITI, V., BARRERA BAENA, P., CIRIA, R., GURUSAMY, K. S., DAVIDSON, B. R. & BURROUGHS, A. K. 2013. Interferon for interferon nonresponding and relapsing patients with chronic hepatitis C. Cochrane Database of Systematic Reviews, 1, CD003617. LIBERATI, A., ALTMAN, D. G., TETZLAFF, J., MULROW, C., GOTZSCHE, P. C., IOANNIDIS, J. P., CLARKE, M., DEVEREAUX, P. J., KLEIJNEN, J. & MOHER, D. 2009. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ, 339, b2700. Page 29
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MALAGUARNERA, M., RESTUCCIA, S., TROVATO, G., SICILIANO, R., MOTTA, M. & TROVATO, B. A. 1995. Interferon-alpha treatment in patients with chronic hepatitis C: A meta-analytic evaluation. Clinical Drug Investigation, 9, 141-149. MYERS, R. P., REGIMBEAU, C., THEVENOT, T., LEROY, V., MATHURIN, P., OPOLON, P., ZARSKI, J. P. & POYNARD, T. 2009. Interferon for interferon naive patients with chronic hepatitis C. Cochrane database of systematic reviews (Online), CD000370. PELLICELLI, A. M., BARBARO, G., BARBARINI, G., SOCCORSI, F. & GROUP, C. 2008. Management of chronic hepatitis in drug addicts: a systematic review. Clinica Terapeutica, 159, 41-9. SHEA, B. J., HAMEL, C., WELLS, G. A., BOUTER, L. M., KRISTJANSSON, E., GRIMSHAW, J., HENRY, D. A. & BOERS, M. 2009. AMSTAR is a reliable and valid measurement tool to assess the methodological quality of systematic reviews. Journal of Clinical Epidemiology, 62, 101320. SHEPHERD, J., WAUGH, N. & HEWITSON, P. 2000. Combination therapy (interferon alfa and ribavirin) in the treatment of chronic hepatitis C: a rapid and systematic review. Health Technology Assessment (Winchester, England), 4, 1-67. SMITH, V., DEVANE, D., BEGLEY, C. M. & CLARKE, M. 2011. Methodology in conducting a systematic review of systematic reviews of healthcare interventions. BMC Medical Research Methodology, 11, 15. TINE, F., ATTANASIO, M., RUSSO, F. & PAGLIARO, L. 2005. A decade of trials of interferon-alpha for chronic hepatitis C. A meta-regression analysis. Contemporary Clinical Trials, 26, 179210. VEZALI, E., AGHEMO, A. & COLOMBO, M. 2010. A review of the treatment of chronic hepatitis C virus infection in cirrhosis. Clinical Therapeutics, 32, 2117-2138. XIROUCHAKIS, E., TRIANTOS, C., MANOUSOU, P., SIGALAS, A., CALVARUSO, V., CORBANI, A., LEANDRO, G., PATCH, D. & BURROUGHS, A. 2008. Pegylated-interferon and ribavirin in liver transplant candidates and recipients with HCV cirrhosis: systematic review and meta-analysis of prospective controlled studies. Journal of Viral Hepatitis, 15, 699-709.
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APPENDICIES Appendix 1: Search syntax for electronic databases MEDLINE 268 citations 1. exp Hepatitis C/ 2. hepacivirus.ti,ab,hw. 3. HCV.ti,ab,hw. 4. Hepatitis C.ti,ab,hw. 5. HepC.ti,ab,hw. 6. hepC.ti,ab,hw. 7. 1 or 2 or 3 or 4 or 5 or 6 8. exp Antiviral Agents/ 9. antiviralagents.ti,ab,hw. 10. (antiviral agent* adj6 (hepC or hepatitis C or HCV or hepacivirus)).ti,ab,hw. 11. ((therapy or treat* or drug*) adj2 (hepC or hepatitis C or HCV or hepacivirus)).ti,ab,hw. 12. exp Ribavirin/ 13. exp Interferon-alpha/ 14. ribavirin.ti,ab,hw. 15. pegylatedinterferon.ti,ab,hw. 16. Interferon-alpha.ti,ab,hw. 17. 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 18. 7 and 17 19. exp Meta-Analysis/ 20. meta-analys?s.ti,ab,hw. 21. systematic adj2 review*).ti,ab,hw. 22. metaanalys?s.ti,ab,hw. 23. 19 or 20 or 21 or 22 24. 18 and 23 25. limit 25 to yr="1994 -Current" EMBASE 750 citations 1 exp Hepatitis C/ 2 hepacivirus.ti,ab,hw. 3 HCV.ti,ab,hw. 4 Hepatitis C.ti,ab,hw. 5 HepC.ti,ab,hw. 6 hepC.ti,ab,hw. 7 1 or 2 or 3 or 4 or 5 or 6 8 exp Antiviral Agents/ 9 antiviralagents.ti,ab,hw. 10 (antiviral agent* adj6 (hepC or hepatitis C or HCV or hepacivirus)).ti,ab,hw. 11 ((therapy or treat* or drug*) adj2 (hepC or hepatitis C or HCV or hepacivirus)).ti,ab,hw. 12 exp Ribavirin/ 13 exp Interferon-alpha/ 14 ribavirin.ti,ab,hw. 15 pegylatedinterferon.ti,ab,hw. 16 Interferon-alpha.ti,ab,hw. Page 31
PICO 5 (Treatment): Anti-viral treatment versus no treatment for chronic HCV
17 18 19 20 21 22 23 24
8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 exp Meta-Analysis/ meta-analys?s.ti,ab,hw. systematic adj2 review*).ti,ab,hw. metaanalys?s.ti,ab,hw. 19 or 20 or 21 or 22 18 and 23 limit 25 to yr="1994 -Current"
COCHRANE 91 Citations 1 MeSH descriptor: [Hepatitis C] explode all trees 2 hepacivirus:ti,ab,kw (Word variations have been searched) 3 HCV:ti,ab,kw (Word variations have been searched) 4 Hepatitis C:ti,ab,kw (Word variations have been searched) 5 HepC:ti,ab,kw (Word variations have been searched) 6 hep C:ti,ab,kw (Word variations have been searched) 7 #1 or #2 or #3 or #4 or #5 or #6 8 MeSH descriptor: [Antiviral Agents] explode all trees 9 antiviral agents:ti,ab,kw (Word variations have been searched) 10 (antiviral agent* near/6 (hepC or hepatitis C or HCV or hepacivirus)):ti,ab,kw (Word variations have been searched) 11 ((therapy or treat* or drug*) near/2 (hepC or hepatitis C or HCV or hepacivirus)):ti,ab,kw (Word variations have been searched) 12 MeSH descriptor: [Ribavirin] explode all trees 13 MeSH descriptor: [Interferon-alpha] explode all trees 14 "ribavirin":ti,ab,kw (Word variations have been searched) 15 "pegylated interferon":ti,ab,kw (Word variations have been searched) 16 "interferon-alpha":ti,ab,kw (Word variations have been searched) 17 #8 or #9 or #10 or #11 or #12 or #13 or #14 or #15 or #16 18 #7 and #17 19 MeSH descriptor: [Meta-Analysis] explode all trees 20 meta-analys?s:ti,ab,kw (Word variations have been searched) 21 (systematic near/2 review*):ti,ab,kw (Word variations have been searched) 22 metaanalys?s:ti,ab,kw (Word variations have been searched) 23 #19 or #20 or #21 or #22 24 #18 and #23
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PICO 5 (Treatment): Anti-viral treatment versus no treatment for chronic HCV
Appendix 2: Summary of all study data Appendix Table 1: Summary of study data - Interferon versus no treatment for chronic HCV Outcome Study (year) No of participants (Studies) 1579 (27) 552 (20) 1136 (4) 409 (8) 201 (3) Hu et al (2010) 48 (2) Relative effect (95% CI) Anticipated absolute effects Risk Risk with difference no treatment with treatment 899 failures per 198 fewer failures per 1000 1000 990 failures per 1000 998 failures per 1000 990 failures per 1000 1000 failures per 1000 70 fewer failures per 1000 40 fewer failures per 1000 53 fewer failures per 1000 170 fewer failures per 1000
Failure to achieve SVR
Malaguarnera et al (1995) Carithers et al (1997) Kortez et al (2013) Myers et al (2009)
OR 0.22 (0.29- 0.17)
OR 0.11 (0.01- 1.0 )
RR 0.96 (0.95 – 0.98)
OR 0.15 (0.076 - 0.30)
SVR among cirrhotic patients: OR 0.11 (0.03 - 0.39) SVR among children: Study 1: RR 0.45 (0.28 to 0.72)
958 failures per 1000
527 fewer failures per 1000
Study 2: OR : NA Intervention= 69% vs. No treatment= 0% Rates of hepatocellular carcinoma Myers et al (2009) 128 (2) OR 0.50 (0.21-1.21)
1000 failures per 1000
690 fewer failures per 1000
239 cases per 1000
103 fewer cases per 1000
SVR among cirrhotic patients: OR 0.74 (0.38-1.47) Kortez et al (2013) Rates of Decompensated liver disease Kortez et al (2013) Kortez et al (2013) Kortez et al (2013) Kortez et al (2013) 1710 (3) 1676 (2) 1710 (3) 1084 (2) 1676 (2) RR 0.81 (0.55-1.19)
460 cases per 1000 30 fewer cases per 1000 62 cases per 1000 12 fewer cases per 1000
Hepatic encephalopathy RR 0.92 (0.38-2.26) Variceal bleeding RR 0.26 (0.09-0.71) Spontaneous bacterial peritonitis RR 0.38 (0.04-3.54) Ascites RR 1.12 (0.62-2.00)
12 case per 1000
1 case fewer per 1000
21 cases per 1000
16 fewer cases per 1000
4 cases per 1000
3 cases fewer per 1000
25 cases per 1000
3 more cases (10 fewer to 25 more) per 1000
All-cause Mortality during or after treatment (3-5 years) Liver-related morality during or after treatment (3-5 years) Serious adverse events
Kortez et al (2013)
1710 (3)
Among cirrhotic patients previous failed treatment: All-cause mortality RR 1.30 (0.95-1.79) Liver related mortality RR 1.07 (0.70-1.63)
72 deaths per 1000
21 more deaths (4 fewer to 56 more) per 1000
Kortez et al (2013)
1084 (2)
72 deaths per 1000
5 more deaths (22 fewer to 46 more) per 1000
Kortez et al (2013)
1103 (2)
RR 1.18 (0.99-1.41)
0 events per 1000
50 more events per 1000
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PICO 5 (Treatment): Anti-viral treatment versus no treatment for chronic HCV
Appendix Table 2: Summary of study data – Any Interferon alone or with RBV interventions versus no treatment for chronic HCV Outcome Study No of participants (Studies) 539 (13) Relative effect (95% CI) Anticipated absolute effects Risk Risk with difference no treatment with treatment Baseline proportion NA not reported Baseline proportion not reported NA
Failure to achieve SVR
Fabrizi et al (2008) (Among patients with renal failure)
Treatment v control OR 0.081 (0.029 - 0.230) Subset using dialysis (n=6): Treatment v control OR 0.054 (0.019-0.150)
Xirouchakis et al (2008) Hartwell et al (2009)
279 (4) 687 (3)
RR 0.71 (0.64-0.79)
926 failures per 1000 1000 failures per 1000
269 fewer failures per 1000 300 fewer failures per 1000
PEG-alpha2a 180µg + RBV 800mg for 24 weeks: Intervention=70% v. Control=100% PEG-alpha2a 180µg + RBV 800mg for 48 weeks: Intervention= 48% v. Control=100% IFN-alpha2b 3MU + RBV 1000-1200mg for 48 weeks: Intervention= 67% v. Control=100%
1000 failures per 1000
520 fewer failures per 1000
1000 failures per 1000
330 fewer failures per 1000
Vezali et al (2010)
188 (1)
SVR among cirrhotics: OR= NA Intervention 19.5 % v. Control 0%, HCC among cirrhotics: Study 1: HCC(annual incidence): RR1.55 (0.59 to 3.45) Untreated-2.3%v. Treated-1% Study 2: HCC(annual incidence): Untreated-17%v.Treated-11% RR= 0.612 RR 0.53 (0.34 – 0.81)
1000 failures per 1000
195 fewer failures per 1000
Rates of hepatocellular carcinoma
Vezali et al (2010)
329 (1)
96 decompensations per 1000 17 cases per 1000
53 more decompensation per 1000 6 fewer cases per 1000
99 (1)
Kimer et al (2012) Morbidity Xirouchakis et al (2008) Vezali et al (2010)
2230 (8) 244 (4) 329 (1)
120 diagnoses per 1000 50 deaths per 1000
56 fewer diagnoses per 1000 20 more deaths per 1000
RD 0.042 (0.027 –-1.55) Intervention= 7% v. Control=5%; Morbidity among cirrhotics: Study 1:Hepatic decompenstation: Untreated-1.5% v. Treated – 5.7% (P=0.07) Study 2:Hepatic decompenstation: Untretaed-10% v. Treated – 15% Study 3:Hepatic decompensation (30th Month) :OR 0.19 (0.06-0.53), Untreated 88.1% v. 59.0% treated Liver related: RR 0.73 (0.48 - 1.11) Intervention= 8.5 % v. control=10.8% Dropout rate-Overall: OR 0.39(0.16- 0.96) Dropout rate-Dialysis patients: OR 0.92 (0.37-2.31)
15 cases per 1000
42 more cases per 1000
99 (1) 129 (1)
100 cases per 1000
50 more cases per 1000
881 cases per 1000
291 fewer per 1000
Kimeret al (2012)
789 (4)
108 cases per 1000
29 fewer cases per 1000
All-cause Mortality
Fabrizi et al (2008)
539 (13)
Baseline proportion not reported Baseline proportion not reported 96 deaths per 1000
NA
NA
Vezali et al
99(1)
Mortality among cirrhotics
116 more deaths per
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PICO 5 (Treatment): Anti-viral treatment versus no treatment for chronic HCV
2010 Kimeret al (2012) 1850 (4)
All-cause mortality at 30 months RR 2.21 (0.68 to 8.25) All cause: RR 0.81 (0.33-2.03) Intervention= 10.1% v.Control=9.7% Liver related: (4 trials) RR 0.71 (0.2- 2.51)
1000 97 deaths per 1000 18 fewer deaths per 1000
Baseline proportion not reported 0 events per 1000
NA 197 more discontinuations per 1000
Adverse events leading to treatment discontinuation
Xirouchakis et al (2008)
129 (1)
RD 0.20 (0.09 to 0.30)
Hartwell et al (2009)
687 (3)
Influenza-like symptoms; Depression; Dose modifications in HIV co-infected patients treated with PEG. 24 weeks after end of treatment: HRQoL scores significantly better in patients with an SVR compared with untreated patients (PEG trial) AEs among HIV co-infection: Drop-out rate Intervention= 11% v. Control=0%, RR na, p=0.50. Flu-like symptoms: Intervention= 83% v. Control= 0%; RR na, p <0.01)
Baseline proportion not reported
NA
Hartwell et al (2009)
687 (3)
Baseline proportion not reported
NA
Iorio et al (2010)
30 (1)
0 cases per 1000
110 more cases per 1000
0 cases per 1000
830 more cases per 1000
Vezali et al (2010)
129 (1)
AEs among cirrhotics: Risk of infections RR 2.43 (1.02-5.77)
Baseline proportion not reported
NA
Quality of life assessment
No data
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Appendix Table 3: Summary of study data – Ribavirin versus placebo Outcome study No of participants (studies) 353 (5) 521 (11) 387 (6) Relative effect (95% CI) Anticipated absolute effects Risk Risk with difference no treatment with treatment 994 treatment 0 fewer virological failures per 1000 failures per 1000 4 deaths per 1000 0 fewer deaths per 1000
Failure to achieve SVR Morbidity and mortality (All-cause) Adverse events leading to dose reduction
Brok et al (2009) Brok et al (2009) Brok et al (2009)
RD 0.00 (-0.02 to 0.03)
RD 0.00(-0.02 to 0.03)
RD 0.11 (0.06-0.16) Dose reductions: 11%
0 events per 1000
110 more events per 1000
Adverse events leading to treatment discontinuation Quality of life assessment (measured as fatigue at end of treatment)
Brok et al (2009)
428 (6)
RD 0.05 (0.01-0.10) Treatment discontinuations: 5%
42 discontinuations per 1000
50 more discontinuation per 1000
Brok et al (2009)
59 (1)
RD -0.11(-0.27 to 0.06) Intervention=82.8%v. Control=93.3%;
933 quality of life per 1000
110 fewer quality of life per 1000
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PICO 5 (Treatment): Anti-viral treatment versus no treatment for chronic HCV
Appendix 3: AMSTAR – a measurement tool to assess the methodological quality of systematic reviews 1. Was an 'a priori' design provided? The research question and inclusion criteria should be established before the conduct of the review. Note: Need to refer to a protocol, ethics approval, or pre-determined/a priori published research objectives to score a “yes.” 2. Was there duplicate study selection and data extraction? There should be at least two independent data extractors and a consensus procedure for disagreements should be in place. Note: 2 people do study selection, 2 people do data extraction, consensus process or one person checks the other’s work. 3. Was a comprehensive literature search performed? At least two electronic sources should be searched. The report must include years and databases used (e.g., Central, EMBASE, and MEDLINE). Key words and/or MESH terms must be stated and where feasible the search strategy should be provided. All searches should be supplemented by consulting current contents, reviews, textbooks, specialized registers, or experts in the particular field of study, and by reviewing the references in the studies found. □ Yes □ No □ Can't answer □ Not applicable □ Yes □ No □ Can't answer □ Not applicable
□ Yes □ No □ Can't answer □ Not applicable
Note: If at least 2 sources + one supplementary strategy used, select “yes” (Cochrane register/Central counts as 2 sources; a grey literature search counts as supplementary). 4. Was the status of publication (i.e. grey literature) used as an inclusion criterion? The authors should state that they searched for reports regardless of their publication type. □ Yes The authors should state whether or not they excluded any reports (from the systematic □ No □ Can't answer review), based on their publication status, language etc. □ Not applicable Note: If review indicates that there was a search for “grey literature” or “unpublished literature,” indicate “yes.” SIGLE database, dissertations, conference proceedings, and trial registries are all considered grey for this purpose. If searching a source that contains both grey and non-grey, must specify that they were searching for grey/unpublished lit. 5. Was a list of studies (included and excluded) provided? A list of included and excluded studies should be provided.
□ Yes □ No Note: Acceptable if the excluded studies are referenced. If there is an electronic link to the list □ Can't answer □ Not applicable but the link is dead, select “no.” 6. Were the characteristics of the included studies provided? In an aggregated form such as a table, data from the original studies should be provided on the □ Yes participants, interventions and outcomes. The ranges of characteristics in all the studies □ No □ Can't answer □ Not applicable Page 37
PICO 5 (Treatment): Anti-viral treatment versus no treatment for chronic HCV
analyzed e.g., age, race, sex, relevant socioeconomic data, disease status, duration, severity, or other diseases should be reported. Note: Acceptable if not in table format as long as they are described as above.
7. Was the scientific quality of the included studies assessed and documented? 'A priori' methods of assessment should be provided (e.g., for effectiveness studies if the author(s) chose to include only randomized, double-blind, placebo controlled studies, or allocation concealment as inclusion criteria); for other types of studies alternative items will be relevant.
□ Yes □ No □ Can't answer □ Not applicable
Note: Can include use of a quality scoring tool or checklist, e.g., Jadad scale, risk of bias, sensitivity analysis, etc., or a description of quality items, with some kind of result for EACH study (“low” or “high” is fine, as long as it is clear which studies scored “low” and which scored “high”; a summary score/range for all studies is not acceptable). 8. Was the scientific quality of the included studies used appropriately in formulating conclusions? The results of the methodological rigor and scientific quality should be considered in the analysis and the conclusions of the review, and explicitly stated in formulating recommendations.
□ Yes □ No □ Can't answer □ Not applicable
Note: Might say something such as “the results should be interpreted with caution due to poor quality of included studies.” Cannot score “yes” for this question if scored “no” for question 7. 9. Were the methods used to combine the findings of studies appropriate? For the pooled results, a test should be done to ensure the studies were combinable, to assess their homogeneity (i.e., Chi-squared test for homogeneity, I2). If heterogeneity exists a random effects model should be used and/or the clinical appropriateness of combining should be taken into consideration (i.e., is it sensible to combine?).
□ Yes □ No □ Can't answer □ Not applicable
Note: Indicate “yes” if they mention or describe heterogeneity, i.e., if they explain that they cannot pool because of heterogeneity/variability between interventions. 10. Was the likelihood of publication bias assessed? An assessment of publication bias should include a combination of graphical aids (e.g., funnel plot, other available tests) and/or statistical tests (e.g., Egger regression test, Hedges-Olken). □ Yes □ No □ Can't answer □ Not applicable Note: If no test values or funnel plot included, score “no”. Score “yes” if mentions that publication bias could not be assessed because there were fewer than 10 included studies. 11. Was the conflict of interest included? Potential sources of support should be clearly acknowledged in both the systematic review and the included studies. Note: To get a “yes,” must indicate source of funding or support for the systematic review AND for each of the included studies. Shea et al. BMC Medical Research Methodology 2007 7:10 doi:10.1186/1471-2288-7-10
□ Yes □ No □ Can't answer □ Not applicable
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PICO 5 (Treatment): Anti-viral treatment versus no treatment for chronic HCV
Additional notes (in italics) made by Michelle Weir, Julia Worswick, and Carolyn Wayne based on conversations with Bev Shea and/or Jeremy Grimshaw in June and October 2008 and July and September 2010.
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PICO 5 (Treatment): Anti-viral treatment versus no treatment for chronic HCV
Appendix 4: GRADE approach to assessing the quality of evidence across studies Upgrading Factors
Quality of Evidence (summary score)
Study Design
Downgrading Factors Study Limitations: -1 Serious -2 Very serious
High (4) =Further research is very unlikely to change our confidence in the estimate of effect.
Randomized trials or valid accuracy studies for diagnostic tests begin with a score of High (4)
Moderate (3) = Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Consistency: -1 Serious -2 Very serious
Large effect +1 Large +2 Very large
Low (2) = Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Observational studies or indirect accuracy studies for diagnostic tests begin with a score of low (2).
Directness: -1 Serious -2 Very serious
Plausible confounding would change the effect +1
Precision: -1 Serious -2 Very serious Very low (1) = Any estimate of effect is very uncertain. Publication Bias: -1 Serious -2 Very serious Dose-response gradient +1 if Present
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