best practices and interventions for the diagnosis and ... · ing at a rapid pace. the two new...

Best Practice/Intervention: Konerman MA. et al. (2014) Systematic review: identifying patients with chronic hepatitis C in need of early treatment and intensive monitoring‐‐predictors and predictive models of disease progression. Alimentary Pharmacology & Therapeutics, 40(8):863‐879.

Date of Review: February 16, 2015Reviewer(s): Christine Hu

Part A

Category: Basic Science Clinical Science Public Health/Epidemiology

Social Science Programmatic Review

Best Practice/Intervention: Focus: Hepatitis C Hepatitis C/HIV Other:

Level: Group Individual Other:

Target Population: patients with HCV

Setting: Health care setting/Clinic Home Other:

Country of Origin: USA

Language: English French Other:

Part B

YES NO N/A COMMENTS

Is the best practice/intervention a meta‐analysis or primary research?

meta‐analysis; systematic review to identify and evaluate factors predictive of disease progression (fibrosis progression and clinical outcomes) in patients with HCV

The best practice/intervention has utilized an evidence‐based approach to assess: Efficacy

Effectiveness

The best practice/intervention has been evaluated in more than one patient setting to assess:

Criteria Grid Best Practices and Interventions for the Diagnosis and Treatment of Hepatitis C

Efficacy

Effectiveness

YES NO N/A COMMENTSThe best practice/intervention has been operationalized at a multi‐country level:

The studies included population from Europe, Asia, and North and South America

There is evidence of capacity building to engage individuals to accept treatment/diagnosis

There is evidence of outreach models and case studies to improve access and availability

Do the methodology/results described allow the reviewer(s) to assess the generalizability of the results?

Methodology described clearly

Are the best practices/methodology/results described applicable in developed countries?

Are the best practices/methodology/results described applicable in developing countries?

Similar analysis can be made when using the same inclusion criteria

Evidence of manpower requirements is indicated in the best practice/intervention

Juried journal reports of this treatment, intervention, or diagnostic test have occurred

Alimentary Pharmacology & Therapeutics

International guideline or protocol has been established

The systematic review was conducted by following the recommendations of the PRISMA guidelines.

The best practice/intervention is easily accessed/available electronically

Free to download from http://onlinelibrary.wiley.com/

Is there evidence of a cost effective analysis? If so, what does the evidence say? Please go to Comments section

How is the best practice/intervention funded?Please got to Comments section

The study was funded in part by the National Institutes of Health T32DK062708 training grant (MAK), the Turkish

http://onlinelibrary.wiley.com/

Association for the Study of the Liver and the Tuktawa Foundation

Other relevant information:

‐ Patients with more advance

disease are at higher risk for adverse outcomes

‐ Steatosis as a predictor of outcomes can be a potential modifiable risk factor associated with disease progression

‐ Liver biopsies provide information regarding current staging of liver disease and prognostic information

Systematic review: identifying patients with chronic hepatitis Cin need of early treatment and intensive monitoring –predictors and predictive models of disease progressionM. A. Konerman, S. Yapali & A. S. Lok

Division of Gastroenterology,Department of Internal Medicine,University of Michigan Health System,Ann Arbor, MI, USA.

Correspondence to:Dr M. A. Konerman, Division ofGastroenterology, University ofMichigan Health System, 3912Taubman Center, 1500 E. MedicalCenter Dr., SPC 5362, Ann Arbor, MI48109, USA.E-mail: [email protected]

Publication dataSubmitted 14 June 2014First decision 7 July 2014Resubmitted 11 July 2014Accepted 26 July 2014EV Pub Online 28 August 2014

This uncommissioned review article wassubject to full peer-review.

SUMMARY

BackgroundAdvances in hepatitis C therapies have led to increasing numbers of patientsseeking treatment. As a result, logistical and financial concerns regarding howtreatment can be provided to all patients with chronic hepatitis C (CHC) haveemerged.

AimTo evaluate predictors and predictive models of histological progression andclinical outcomes for patients with CHC.

MethodsMEDLINE via PubMed, EMBASE, Web of Science and Scopus were searchedfor studies published between January 2003 and June 2014. Two authors inde-pendently reviewed articles to select eligible studies and performed data abstrac-tion.

ResultsTwenty-nine studies representing 5817 patients from 20 unique cohorts wereincluded. The outcome incidence rates were widely variable: 16–61% duringmedian follow-up of 2.5–10 years for fibrosis progression; 13–40% over 2.3–14.4 years for hepatic decompensation and 8–47% over 3.9–14.4 years for overallmortality. Multivariate analyses showed that baseline steatosis and baseline fibro-sis score were the most consistent predictors of fibrosis progression (significantin 6/21 and 5/21, studies, respectively) while baseline platelet count (significantin 6/13 studies), aspartate and alanine aminotransferase (AST/ALT) ratio, albu-min, bilirubin and age (each significant in 4/13 studies) were the most consistentpredictors of clinical outcomes. Five studies developed predictive models butnone were externally validated.

ConclusionsOur review identified the variables that most consistently predict outcomes ofpatients with chronic hepatitis C allowing the application of risk basedapproaches to identify patients in need of early treatment and intensive moni-toring. This approach maximises effective use of resources and costly newdirect-acting anti-viral agents.

Aliment Pharmacol Ther 2014; 40: 863–879

ª 2014 John Wiley & Sons Ltd 863

doi:10.1111/apt.12921

Alimentary Pharmacology and Therapeutics

INTRODUCTIONWith the introduction of more efficacious and less toxicdrugs, treatment of chronic hepatitis C (CHC) is evolv-ing at a rapid pace. The two new direct-acting anti-viralagents (DAA), simeprevir and sofosbuvir, increase ratesof sustained virological response (SVR) with shortertreatment durations compared to prior therapies.1, 2

Along with advances in therapy, there has been a focuson the public health impact of CHC. The Centers forDisease Control and Prevention, the Institute of Medi-cine, and the United States Preventive Services TaskForce, have prioritised hepatitis C awareness, screeningand diagnosis.3–5 Treatment is also being advocated as ameans to prevent hepatitis C virus (HCV) infection. Asa result of these processes, the pool of potential treat-ment candidates is expected to balloon. This has causedthe conundrum in HCV treatment to shift from ‘Can weimprove the efficacy and tolerability of HCV treatment?’to ‘Can we afford to treat all patients with CHC?’

At the core of the dilemma is the high cost of thesenew drugs. The estimated wholesale price of a 12-weekcourse of sofosbuvir in the United States (US) is $84 000and of simeprevir $66 000.6, 7 These staggering costsexclude retail markup, and associated cost of pegylatedinterferon (IFN), ribavirin, physician visits and labora-tory tests. While these new treatment regimens haveSVR rates of 80–90%, and SVR has been shown todecrease cirrhosis complications, hepatocellular carci-noma (HCC) and liver-related mortality, even resour-ce-replete countries like the US cannot afford to treat allthose who are infected.1, 2, 8 The logistical and financialbarriers are much higher in resource-limited countries,many of which have higher prevalence of HCV infectionthan western countries. Clinicians and health policymakers will need to determine an optimal yet practicalapproach to provide these highly efficacious, but extre-mely costly therapies to this burgeoning patient popula-tion.

One solution is to adopt a risk-stratified approach thattargets therapy to those at the greatest risk of diseaseprogression. There have been many studies investigatingrisk factors for disease progression in patients with CHCbut few have employed a longitudinal study design ingeneralisable patient populations using data that are rou-tinely available in clinical practice. Results of the existingstudies have also not been systematically summarised ina single document. Therefore, we performed a systematicreview of the literature to (i) identify factors predictiveof disease progression (fibrosis progression and clinical

outcomes) in patients with CHC and (ii) assess existingpredictive models.

METHODS

Data sources and search strategyWe followed the Preferred Reporting Items for System-atic Reviews and Meta-Analyses (PRISMA) recommen-dations in conducting this systematic review.9 With theassistance of a medical research librarian, we performedserial literature searches for English and non-Englisharticles. MEDLINE (via PubMed), EMBASE, Web of Sci-ence and Scopus were searched using the following key-words: ‘cirrhosis’ or ‘liver cirrhosis’ or ‘fibrosis’, ‘hepatitisC’ or ‘hepatitis C, chronic’ or ‘chronic hepatitis C’, ‘dis-ease progression’ or ‘progression’ or ‘decompensation’.Boolean operators and medical subject heading terms aswell as other controlled vocabulary were used to enhanceelectronic searches. An example of specific search strat-egy details is shown in Table S1.

All human subject studies published in full-text orabstract were eligible for inclusion. The search was lim-ited to publications from 2003 to 2014 as this 10-yearperiod contained the most contemporary and relevantdata with respect to treatment and current practice.Additional studies of interest were identified by handsearches of bibliographies and cited reference trackingand consultation with clinical experts on the topic. Theinitial search was performed in October 2013 and thesearch was last updated on 2 June 2014.

Study eligibility and selection criteriaTwo authors (M.A.K. and A.S.L.) sequentially deter-mined study eligibility. Studies were initially screened bythe first author; decisions about study inclusion weremade independently by both authors (M.A.K and A.S.L).Differences in opinion regarding study inclusion wereresolved through consensus. Studies were included ifthey: (i) included human studies with participants18 years of age or older; (ii) systematically evaluated pre-dictors of fibrosis progression and/or clinical outcomesfor patients with CHC; and (iii) used a longitudinalcohort study design. We focused on studies of untreatedpatients but also included studies with a mix of treatedand untreated patients provided that <20% of the studypopulation achieved SVR and results were stratified bytreatment outcomes. For studies evaluating predictors offibrosis progression, we selected studies only when pairedbiopsy was used to assess progression.

864 Aliment Pharmacol Ther 2014; 40: 863-879

ª 2014 John Wiley & Sons Ltd

M. A. Konerman et al.

We excluded studies that enrolled (i) patients co-in-fected with hepatitis B (HBV) or human immunodefi-ciency virus (HIV); (ii) patients with additional causes ofchronic liver disease; (iii) patients with prior liver trans-plantation and (iv) specific groups of patients (e.g. thal-assaemia patients) only. These patient populations wereexcluded because they likely have different rates and riskfactors for disease progression compared to the generalpopulation of patients with CHC. In addition, studiesthat evaluated HCC as the only outcome of interest wereexcluded as we were interested in broad clinical out-comes for patients with CHC, and predictors of HCCdevelopment alone may not be the same as predictors ofdisease progression in CHC in general. Lastly, studiesthat focused on predictors that are not readily availableclinically (e.g. genetic or other serum markers for whichcommercial assays are not available, and experimentalimaging techniques) were excluded given that they wouldnot be relevant to current clinical practice.

Definition of variables and outcomesPatients with CHC were defined as those with detectableHCV ribonucleic acid (RNA). We were interested in twooutcomes: histological progression and clinical progres-sion. The definition of histological progression was anincrease of ≥1 METAVIR (range 0–4) or Ishak (range 0–6) fibrosis stage on follow-up liver biopsy. The definitionof clinical progression encompassed the progression fromcompensated to decompensated cirrhosis, and liver-re-lated or overall mortality. The definition of compensatedcirrhosis was based on histology when available (Ishakfibrosis score ≥5 or METAVIR 4) or on the combinedresults of other noninvasive testing including laboratorytests and imaging. Decompensated cirrhosis was definedby the presence of any of the following: ascites, sponta-neous bacterial peritonitis (SBP), variceal bleeding orhepatic encephalopathy (HE). The presence of HCC asdefined by histology or American Association for Studyof Liver Diseases radiological criteria was variablyincluded as a clinical outcome.10

Data abstraction and validity assessmentData from eligible studies were abstracted by two authors(M.A.K. and S.Y.) using a standardised template adaptedfrom the Cochrane Collaboration.11 For all studies, werecorded: study design, sample size, patient populationcharacteristics, duration of follow-up, predictor variablesstudied, outcomes measured, criteria used to define theseoutcomes and measures of association/predictiveness ofrisk for these outcomes. We accepted the outcome defi-

nitions as stated by each study without independentlyvalidating or reviewing their data. Study authors weredirectly contacted for additional, unpublished data.

Assessment of risk of bias and study qualityTwo authors (M.A.K and S.Y.) independently assessed therisk of study bias and study quality. Since all the includedstudies were nonrandomised cohort studies, the Newcas-tle-Ottawa scale was used to judge study quality as recom-mended by the Cochrane Collaboration.12 This scale usesa star system to assess the quality of a study based on threedomains: selection of the study population, comparabilityof the study groups and method of outcomes assessment.For our review, given that no study had a comparisongroup, we excluded comparability components of the scaleacross all studies. Studies which received stars in everydomain were assessed as being of high quality.

Data synthesis and analysisGiven the substantial variation in the design, methods andinclusion/exclusion criteria within our included studies,meta-analysis was not performed. Two authors (M.A.K.and S.Y.) qualitatively synthesised the results of theincluded studies, focusing on the risk factors evaluatedand their independent predictiveness in terms of the out-comes measured and patient populations studied. Studieswere categorised according to the outcome of interest:predictors of histological progression, predictors of clini-cal outcomes or studies investigating both clinical and his-tological outcomes. All authors had access to the studydata and had reviewed and approved the final manuscript.

RESULTS

Studies included in the systematic reviewAfter removal of duplicate entries, 2257 unique articleswere identified by our systematic literature search(Figure 1). On the basis of abstract review, 69 wereselected for full-text review. Two study authors classified29 articles as meeting the predefined criteria for analysis.In total, these 29 studies included 5817 unique patientsfrom 20 separate patient cohorts. Sixteen of these studiesinvestigated predictors of histological progression, eightstudies evaluated predictors of clinical outcomes, and theremaining five studies investigated both histological andclinical outcomes.13–41 Fourteen studies included treat-ment-na€ıve patients only, five included both treat-ment-na€ıve and treatment-experienced patients, eightincluded treatment-experienced patients only, and twostudies did not describe the treatment status of the

Aliment Pharmacol Ther 2014; 40: 863-879 865


Systematic review: predictors of hepatitis C progression

patients. We contacted four authors to obtain additionalunpublished data.

Characteristics of studies on histological progressionA total of 21 studies evaluated predictors of histologicalprogression. The studies included populations from

Europe (n = 10), Asia (n = 2), and North (n = 8) andSouth America (n = 1). Only one study was prospectivewith the remaining 20 being retrospective analyses ofpreviously collected data. The sample size for includedstudies varied (range 36–622 patients) with the majorityhaving <200 patients (n = 14). A number of studies

Figure 1 | Flow diagram of studies included in the systematic review. aMany studies met multiple exclusion criteria.Each study was coded under a single criterion only. bIncludes animal models, paediatric populations, patients who hadpreviously undergone liver transplant, patients with chronic liver disease other than HCV monoinfection, evaluation ofonly specific subsets of populations with CHC. cIncludes studies that were descriptive papers only, studies that didnot specifically evaluate for predictors of histological or clinical progression, and studies that evaluated predictors thatare not readily clinically available. dIncludes studies that focused on risk factors for the development of HCC only, andstudies where some patients achieved SVR and the results were not stratified based on response to treatment.




had overlapping cohorts. Four studies were derivedfrom the Hepatitis C Anti-viral Long-term TreatmentAgainst Cirrhosis (HALT-C) cohort, a US multi-centrerandomised controlled trial to evaluate the safety andefficacy of low dose pegylated IFN in CHC patientswith advanced fibrosis who failed to respond to priorIFN therapy. Four other pairs of studies drew from thesame cohort of patients.17, 21, 25, 29, 33, 35, 38, 41 Thesestudies were included in the review despite overlappingcohorts given differences in predictors examined, out-comes evaluated and criteria for selection of subsets ofpatients analysed within the overall larger cohort. Theaverage duration of follow-up ranged from a median of2.5–10 years.

The studies had varied inclusion and exclusion criteriaas detailed in Table 1. Among the non-HALT-C studies,11 studies had explicit requirements for baseline Ishak/METAVIR fibrosis stage. Five studies required minimalor no fibrosis at baseline and the remaining six studiesrequired lack of cirrhosis on initial biopsy. Only 14 stud-ies described criteria used to determine adequacy ofbiopsy specimens. The majority of the studies had a sin-gle pathologist blinded to clinical data score the biopsieswhile the HALT-C study had a panel of pathologistsreview the biopsies and consensus staging was recorded.Exclusionary alcohol intake was described in nine studiesthough the cut-off amounts and methods for ascertainingalcohol intake varied across the studies. The studies werepredominately comprised of male patients in their late30s to early 50s.

Characteristics of studies of clinical outcomesA total of 13 studies evaluated predictors of clinicaloutcomes. Six studies were conducted in the US(including 5 HALT-C studies), five in Europe and twoin Asia. Only two studies were prospective with theremaining 11 being retrospective analyses. Sample sizein each study varied from 52 to 1457 patients. Apartfrom the HALT-C studies, there was only one addi-tional overlapping cohort.36, 37 The average duration offollow-up ranged from a median of 2.3 to a maximumof 14.4 years. Compared to studies on histological pro-gression, the studies on clinical outcomes consisted ofpatients who were older, had more advanced fibrosisat baseline, and were more likely to be treatmentexperienced.

Incidence of histological progressionA summary of the specific outcomes evaluated and inci-dence of these outcomes in each study is displayed in

Tables 2–4. For studies where the outcome was definedas ≥1 fibrosis stage increase on follow-up biopsy(n = 13), the incidence of that outcome ranged from 21–61% over a range of follow-up of 2.5–10 years.14, 16, 18, 21, 25, 28–33, 35, 41 Studies applying astricter definition of fibrosis progression (≥2 stageincrease on follow-up biopsy, n = 3) had less variabilityin range of incidence of outcome, reporting 22–34% overa range of follow-up of 3.5–5.8 years.13, 23, 26 Studieswith higher rates of fibrosis progression tended to havelonger follow-up durations (>6 years), though there wereseveral studies with follow-up of ≥6 years that had lowrates of fibrosis progression. No identifiable differencesin patient characteristics between studies with high vs.low incidence of fibrosis progression were noted.

Incidence of clinical progressionStudies assessing risk factors for clinical progression(n = 13) included several distinct outcomes. Four studiesevaluating progression from compensated to decompen-sated cirrhosis reported an incidence between 13%and 40% over a range of follow-up of 2.3–14.4 years.15, 24, 31, 34 No clear pattern was identifiedbetween length of follow-up or patient characteristics andrate of outcomes. Notably, the definition of decompensa-tion varied across studies. Four studies evaluating the inci-dence of overall mortality reported incidences between 8%and 47%. The range of follow-up for these studies was3.9–14.4 years, with a higher rate of outcomes reported instudies with longer duration of follow-up.15, 27, 39, 40 Theremaining studies used an aggregate outcome encompass-ing a broad range of clinical end points including decom-pensation, increase in Child–Turcotte–Pugh score,development of HCC, liver transplant and liver related aswell as overall mortality. The reported incidence of thisaggregate outcome was 13–31% over a range of follow-upof 3.5–6.3 years.19, 20, 23, 26, 36, 37

Predictors of histological progressionA detailed list of the predictors evaluated and theresults of univariate analysis is provided in Tables S3–S5. For each study, the predictor variables were categor-ised as follows: (i) baseline clinical characteristicsincluding demographics and relevant co-morbidities; (ii)baseline laboratory results; (iii) baseline histological fea-tures or (iv) longitudinal laboratory and histologyresults.

All studies investigating predictors of histological pro-gression evaluated baseline clinical characteristics, base-line laboratory results and baseline histology results




Table 1 | General characteristics of included studies*

Study andCountry

Samplesize (n)

%Genotype1 Age

%Male

Study population

Inclusion criteria/patientcharacteristics Exclusion criteria

Predictors of histological progressionBaran, 2014Turkey

125 95 Mean45

38 Ishak <4 on initial biopsy>9 portal tracts on liverbiopsy

Treatment na€ıve ornon-SVR with priortreatment

HIV co-infectedOther chronic liverdisease

HCCHistory ofimmunosuppressivetherapy

Boccato, 2006Italy

106 62 Mean41.6

56 METAVIR F0 or F1 oninitial biopsy

Biopsy length >15 mmand ≥7 portal tracts

Minimum 4 yearfollow-up

Treatment na€ıveCastera, 2003France

96 62 Mean41

61 No cirrhosis on initialbiopsy

Treatment na€ıve

HBV or HIV co-infected

Colletta, 2005Italy

40 30 Median43.5

55 Ishak ≤2 on initial biopsySerial ALT values < 1.2times ULN

Treatment na€ıveCross, 2009United Kingdom

112 58 Median44

66 Biopsy length >10 mmTreatment na€ıve

HBV or HIV co-infectedOther chronic liverdisease

Prior liver transplantETOH intake ≥80g/day (male), ≥60g/day (female)

Fabris, 2012Italy

93 52 Median38

46 Ishak ≤1 on initial biopsyPersistently normal or nearnormal ALT

Treatment na€ıveFartoux, 2005France

135 60 Mean38.5

59 METAVIR ≤1 on initialbiopsy

Biopsy length >10 mmOnly one known riskfactor for HCVinfection

Treatment na€ıve


Prothrombin time >80%Platelets >150 000/mLHyaluronic acid<85 lg/L

Ghany, 2003United States

123 70 Mean41

63 Treatment na€ıve

Khouri, 2003Brazil

55 NR Mean38

58 Biopsy length >15 mmMinimum of 1 yearinterval betweenbiopsies

18–75 years oldTreatment na€ıve

HBV or HIV co-infectedImmunosuppressedpatients

Chronic renal failureUsing ‘potentiallyhepatotoxic drugs’

Kurosaki, 2008Japan

97 88 Median52


Treatment with IFNbetween biopsieswithout SVR


ETOH consumption>20 g/d




Table 1 | (Continued)

Study andCountry

Samplesize (n)

%Genotype1 Age

%Male

Study population


Levine, 2006Ireland

167 100 Mean53

0 Women infected fromcontaminatedimmunoglobulin

Biopsy length >15 mmand ≥5 portal tracts

Treatment na€ıveMummadi, 2010United States

36 NR Median47


Minimum of 1 yearinterval betweenbiopsies


Prior organ transplantETOH intake >30 g/dayHCC

Perumalswami, 2006United States

136 76 Mean44

58 >10 portal tracts on liverbiopsy

Treatment na€ıve

Decompensated cirrhosisHBV or HIV co-infectedOther chronic liverdisease

ETOH ≥60 g/day (male),≥40 g/day (female)

MalignancySteroid therapy

Ryder, 2004United Kingdom

214 34 Median36


>5 portal tractson liver biopsy

Treatment na€ıve

HIV co-infectedCoagulation disorderHaemodialysis

Tamaki, 2013Japan

314 NR Mean53.7

47 Minimum of 1.5 yearinterval betweenbiopsies

Biopsy length >15 mmIFN between biopsies,without SVR

HBV or HIV co-infectedETOH ≥40 g/dayHCCNASH

Williams, 2011United Kingdom

282 44 Mean37

61 Ishak 0 or 1 on initialbiopsy

>5 portal tracts on liverbiopsy

Minimum of 2 yearinterval betweenbiopsies

No treatment duringstudy

HIV co-infectedCoagulation disorderHaemodialysis

Predictors of clinical outcomesBruno, 2009Italy

324 63 Median59

51.1 Compensated cirrhosis(Child A)

≤70 years oldIFN based treatment(55%) without SVR


HCC‘unable to attend regularfollow-up visits’





Study andCountry

Samplesize (n)

%Genotype1 Age

%Male

Study population



470 94 Mean49.8

71.3 HALT-C cohort:Ishak ≥3 on initialbiopsy

Prior treatment withIFN based therapywithout SVR

Evaluated controlpatients withoutfurther treatment

HIV co-infectedOther chronic liverdisease

ETOH abuse withinpast year

CTP score ≥7History of hepaticdecompensation

Platelets <75 000Neutrophil count<1500

Haematocrit <33%HCC or AFP>300 ng/mLBilirubin >2.5 mg/dLCreatinine >1.5 mg/dL‘Serious medicaldisorder’

Use of illicit drugswithin past 2 years

Giannini, 2003Italy

63 NR Mean52

73 HBV or HIV co-infectedOther chronic liverdisease

ETOH >40 g/dayRincon, 2013Spain

145 NR Median51

77 Compensated cirrhosisTreatment na€ıve or non-SVR

Other chronic liverdisease

Prior liver transplantHCC >3 cm ormultilobular or vascularinvasion

Sinn, 2008South Korea

647 71 Mean58.2

49 Compensated cirrhosisMinimum of 1 yearfollow-up

Treatment na€ıve

HBV or HIV co-infectedCTP score >5HCC

Sinn, 2013South Korea

232 62 Mean57.2

38 Compensated cirrhosisMinimum of 1 yearfollow-up

ALT< 40 IU/l atbaseline

Treatment na€ıve

HBV or HIV co-infectedCTP score >5HCC

VanDerMeer, 2012Europe and Canada

405 76 Median48

68 Ishak ≥4 at baselinePrior treatment withIFN based therapywithout SVR


Vergniol, 2011France

1457 58 Mean51.2

53.4 52% patients with priortreatment; 38%without SVR

14% SVR with resultsadjusted for treatmentresponse

HBV co-infectedOther chronic liverdisease




except for Tamaki et al. who did not evaluate baselinehistological features.38 Only half of the studies evaluatedlongitudinal variables which were predominantly serialaminotransferase levels. Longitudinal biopsy results suchas changes in steatosis score or histological activity index(HAI) were assessed in only five studies.16, 22, 28–30 Thepredictors that were most consistently evaluated arelisted in Figure 2a. The most common clinical character-istics assessed were age, gender, HCV genotype, alcoholintake, body mass index (BMI) and biopsy interval, andthe most common laboratory values evaluated wereplatelet count and ALT levels. Baseline histological fea-tures were also frequently investigated predictors andwere included in >70% of studies.

Multivariable analysis was performed in all but twostudies.19, 31 Variables found to be independently predic-tive of histological progression are listed in Tables 2 and

4. Among all the variables assessed, baseline steatosiswas most consistently reported as independently predic-tive of subsequent fibrosis progression (significant onmultivariate analysis in 6 of 21 studies) with an oddsratio (OR) [(95% confidence interval (CI)] of 4.8 (1.3–18.3) to 14.3 (2.1–111.1).12, 16, 18, 20, 24, 27 Notably, onestudy found that effect of baseline steatosis on fibrosisprogression was dependent on baseline fibrosis stage.20

Baseline Ishak/METAVIR fibrosis stage was the nextmost consistently identified independent predictor of his-tological progression (significant on multivariable analy-ses in five of 21 studies).20, 25, 30, 33, 35 Only one of thesestudies reported the effect size, with adjusted relative riskof 1.93 (95% CI 1.3–9.0).35 Figure 2a depicts the numberof studies in which individual variables were significantlyor not significantly predictive of histological progressionon multivariate analyses.


Study andCountry

Samplesize (n)

%Genotype1 Age

%Male

Study population


Predictors of histological progression and clinical outcomesDienstag, 2011United States

1050clinical

622histological

94 Mean51

71 HALT-C cohort (SeeGhany 2011 above)

517 patients in IFN armand 533 control arm

HALT-C cohort (SeeGhany 2011 above)

Everhart, 2009United States

985clinical

557histological

94 Mean50.2


488 patients from IFNarm and 497 controlarm


Fontana, 2010United States

462clinical

209histological

94 Mean49.5

70.3 HALT-C cohort (SeeGhany 2011 above)

49.4% patients inIFN arm



1050clinical

547histological

94 Mean50


517 in IFN arm and533 in control arm


Livingston, 2010United States

52 67 Median41

51 Alaska Native andAmerican Indianpersons

Ishak ≤4 on initial biopsyTreatment na€ıve


AFP, alpha-fetoprotein; ALT, alanine aminotransferase; CTP, Child–Turcotte–Pugh; ETOH, alcohol; HALT-C, hepatitis c anti-virallong-term treatment against cirrhosis; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HIV, humanimmunodeficiency virus; IFN, interferon; NASH, nonalcoholic steatohepatitis; SVR, sustained virological response; ULN, upper limitof normal.

* For select studies, reported data here reflect only a subset of the total study population based on the patient population andoutcome of interest for this systematic review.




Predictors of clinical outcomesAll 13 studies examining predictors of clinical outcomesincluded baseline clinical characteristics and laboratoryresults (Tables S4 and S5). Baseline histology was

assessed in only eight studies though biopsies were per-formed in every study. Only three studies incorporated lon-gitudinal data which consisted of serial laboratory valuesonly.23, 24, 36 The predictors that were most consistently

Table 2 | Outcomes and predictors evaluated and summary of results: histological progression

StudyOutcomesevaluated

%withoutcome

Years follow-up(s.d.; range)

Predictors significant onmultivariate analysis OR (95% CI)

Only patients with minimal fibrosis at baselineBoccato, 2006 ≥1 METAVIR

stage increase60 Mean 7.8 (1.51; 5–10) ETOH intake (>40 g/day)

Baseline steatosisNR

Colletta, 2005 METAVIR ≥2on follow-upbiopsy

35 Median 6.5 (NR; 2.25–5.5) HCV RNA >8.0 9 106

copies/mLETOH intake >20 g/day

NR

Fabris, 2012 ≥1 Ishak stageincrease

61 Median 10 (NR; 5.1–10) HCV RNA >400 000 IU/mLETOH intake >30 g/dayIL28B T/* 9 chol ≤175 mg/dLFollow-up >8 year

4.3 (1.4–13)100 (8–1300)4.1 (1.5–11)4.9 (1.8–13)

Fartoux, 2005 METAVIR 3 or4 onfollow-upbiopsy

16 Mean 5.2 (2.3; 1.5–13.1) Baseline steatosis 4.8 (1.3–18.3)

Williams, 2011 ≥1 Ishak stageincrease

42 Median 4.4 (NR; 2–16) Age (older)Median ALT per 10 IU/L

1.34 (1.03–1.74)1.07 (1.01–1.13)

Includes patients with more advanced fibrosis at baselineBaran, 2014 ≥2 Ishak stage

increase22 Mean 5.8 (NR; 1.25–18) Baseline GGT

Follow-up ALT (<40 IU/L)Treatment experience (failed)

1.03 (1.01–1.5)0.16 (0.03–0.93)5.97 (1.81–19.7)

Castera, 2003 ≥1 METAVIRstage increase

31 Mean 4 (2.6; 0.8–14.6) Worsening steatosis 4.7 (1.3-10.8)

Cross, 2009 ≥1 Ishak stageincrease

21 Median 4.2 (NR; 2.8–6.1) Baseline steatosis 14.3 (2.1-111.1)

Ghany, 2003 ≥1 Ishak stageincrease

39 Mean 3.7 (NR; 0.25–17.6) Baseline Ishak (low)Baseline HAIBaseline ALT (elevated)

NR

Khouri, 2003 ≥1 Ludwigstage increase

27 Mean 3.25 (1.1;1-6.8) None NR

Kurosaki, 2008 ≥1 METAVIRstage increase

23 Mean 5.9 (NR; 1.2–11.6) Baseline steatosisAverage ALT ≥100 IU/l

5.14 (1.6–15.7)5.21 (1.4–18.2)

Levine, 2006 ≥1 Ishak stageincrease

27 Mean 5 (NR; NR) Baseline IshakBaseline ALT (elevated)

NR

Mummadi,2010

≥1 stageincrease on0–4 scale

53 Median 4 (NR; 2–9) DAPRIDFIB-4

NR

Perumalswami,2006

≥1 Ishak stageincrease

40 Mean 3.6 (NR; 0.5–17) Age (older)Baseline ALT (elevated)Baseline Ishak (low)Baseline HAI (higher severity)

NR

Ryder, 2004 ≥1 Ishak stageincrease

33 Median 2.5 (NR; 1.9–9.4) Age (older)Baseline Ishak (+fibrosis)

1.08* (1.03–1.11)1.93* (1.3–9.0)

Tamaki, 2013 Not defined 23 Mean 4.9 (2.9; NR) DFIB-4 index/year 3.7 (1.07–12.5)

ALT, alanine aminotransferase; APRI, aspartate aminotransferase to platelet ratio index; ETOH, alcohol; GGT, gamma-glutamyltranspeptidase; HAI, histological activity index; HCV, hepatitis C virus; NR, not reported; RNA, ribonucleic acid.

* Represents adjusted relative risk (RR) instead of OR.




Table 3 | Outcomes and predictors evaluated and summary of results: clinical outcomes

Study Outcomes evaluated% withoutcome


Predictors significanton multivariate analysis HR (95% CI)

Cohorts with patients with a broader range of fibrosisGhany, 2011 1. Decompensation:

(i) ascites; (ii) varicealbleeding; (iii) HE or;(iv) SBP

2. Hepatic mortality/livertransplant

1. 13

2. 17

Median 6.3(NR; 1.4–8.7)

1. DecompensationBaseline platelets ≤150Baseline bilirubin ≤0.8 mg/dLBaseline AST/ALT ≤0.8>15% decrease in platelets>15% increase in bilirubin>15% decrease in albumin

2. Hepatic mortality/transplantBaseline platelets ≤150Baseline albumin ≤3.9>15% increase in albumin5–15% increase in AST/ALT

2.76 ( 1.47–5.19)0.37 (0.18–0.75)0.50 (0.27–0.92)2.29 (1.26–4.14)2.62 (1.37–5.00)3.85 (1.81–8.18)

4.14 (2.29–7.47)2.32 (1.33–4.06)3.56 (1.82–6.97)2.14 (1.16–3.96)

Giannini, 2003 1 year overall mortality 25 ≥1(NR; NR)

Baseline AST/ALT >1.16Baseline MELD >9Baseline CTP score >7

NR

VanDerMeer,2012

Overall mortality 25 Median 8.1(NR; NR)

Age (per year)Gender (male)Baseline Platelets per 10 9 109/LLog Baseline AST/ALT (per 0.1)

1.06 (1.03–1.09)1.90 (1.10–3.29)0.90 (0.86–0.95)1.29 (1.11–1.50)

Vergniol, 2011 Overall 5 year mortality 8 Median 3.9(NR; NR)

Age (older)TreatmentLiver stiffnessFibroTestActiTest

1.03 (1.01–1.04)0.28 (0.19–0.42)2.9 (2.0–4.3)60 (14–255)0.19 (0.07–0.53)

Cohorts restricted to patients with cirrhosisBruno, 2009 1. Decompensation:

(i) ascites; (ii) varicealbleeding or; (iii) HE

2. Hepatic mortality

3. Overall mortality

1. 40

2. 33

3. 47

Median 14.4(NR; 0.9–19.5)

1. DecompensationHCV genotype (1b vs. 2a/c)Oesophageal varicesBaseline platelets <80Baseline bilirubin ≥1.2 mL/dLAFP ≥10 ng/mLHCC development

2. Hepatic mortalityAge (10 year increase)Gender (male)HCV genotype(1b vs. 2a/c)Oesophageal varicesCreatinine (≥1.2 mg/dl)MELD >10DecompensationHCC development

3. Overall mortalityAge (10 year increase)Gender (male)HCV genotype(1b vs. 2a/c)Oesophageal varicesMELD >10AFP ≥1 ng/mL

2.17 (1.31–3.59)2.09 (1.33–3.30)1.95 (1.08–3.51)1.79 (1.16–2.76)1.59 (1.09–2.32)5.52 (3.77–8.09)

1.61 (1.21–2.13)1.87 (1.23–2.84)2.37 (1.33–4.22)2.27 (1.41–3.66)3.07 (1.65–5.73)2.43 (1.57–3.76)16.9 (9.97-28.6)8.62 (5.57–13.3)

1.63 (1.28–2.06)1.88 (1.33–2.66)1.83 (1.18–2.86)2.19 (1.47–3.27)2.15 (1.50–3.09)1.62 (1.15–2.29)




evaluated are listed in Figure 2B. The most common clini-cal characteristics assessed were age, gender and BMI; themost common laboratory values evaluated were plateletcount and ALT level.

Multivariable analysis was performed in all but twostudies.19, 31 The variables found to be independentlypredictive of clinical progression are listed in Tables 3and 4. Among the variables assessed, baseline plateletcount was the most consistent independent predictor ofclinical outcomes (significant on multivariate analysis insix of 13 studies) followed by age, baseline AST/ALTratio, albumin and bilirubin (each significant in fourstudies).15, 24, 26, 36, 37, 39 Figure 2B depicts the numberof studies in which individual variables were significantlyor not significantly predictive of clinical outcomes inmultivariate analyses.

Mathematical prediction modelsFive studies provided prediction models, three for fibro-sis progression and four for clinical outcomes (TableS6).23, 26, 32, 39, 40 Four of the models were derived fromthe HALT-C study. All the prediction models are pri-marily comprised of baseline laboratory results. Onlyone of the models incorporated longitudinal data. Noneof the models had been validated in external CHCcohorts and only two models reported the associatedarea under the receiver operating characteristiccurve.23, 40

Quality assessment and risk of biasStudies evaluating predictors of histological progres-sion were of varying quality, whereas studies investi-gating predictors of clinical outcomes or studiesinvestigating combined outcomes were all of highquality except for one study.31 Six studies on histologi-cal progression included a small number of patientswith advanced fibrosis or cirrhosis on initial biopsywho were not able to progress according to theauthor’s definition.17, 18, 25, 28, 33, 38 Two studies eval-uated select cohorts (Levine et al. evaluated untreatedIrish women who acquired HCV infection duringpregnancy only, and Livingston et al. evaluated onlytreatment na€ıve Alaska Native and American Indianpersons) and were scored as having limited representa-tiveness.30, 31 The remaining studies were scored asbeing at least somewhat representative of the averagepatient with CHC in the community (Table S2).

DISCUSSIONAlthough there is abundant literature on the topic ofpredictors of histological and clinical outcomes forpatients with CHC, only 29 studies met our inclusioncriteria which captured studies with a longitudinal studydesign in broad patient populations. Within the 29 stud-ies included, the incidence of outcomes varied widely:16–61% during a median follow-up of 2.5–10 years forfibrosis progression; 13–40% over 2.3–14.4 years for


Study Outcomes evaluated% withoutcome


Predictors significanton multivariate analysis HR (95% CI)

DecompensationHCC development

7.08 (4.88–10.2)3.80 (2.67–5.42)

Rincon, 2013 Decompensation:(i) ascites; (ii) varicealbleeding or; (iii) HE

29 Median 2.3(NR; 0.2–9.2)

HVPGBaseline albumin

1.11 (1.05–1.17)0.42 (0.22–0.82)

Sinn, 2008 First occurrence of:(i) ≥2 increase CTPscore; (ii) HCC;(iii) SBP; (iv) varicealbleed; (v) HE or;(vi) hepatic mortality

22 Median 4.6(NR; 1–12.6)

Age > 55Gender (Male)DiabetesBaseline platelets <140Baseline APRI >1

2.2 (1.4–3.6)1.7 (1.2–2.3)1.8 (1.3–2.7)4.9 (3.4–7.2)5.4 (3.5–8.3)

Sinn, 2013 Disease progressionusing same 2008definition

14 Median 4.5(NR; 1–12.6)

Baseline ALT >26 (male)Baseline ALT> 23 (female)Baseline platelets (low, male)Baseline platelets (low, female)

5.35 (1.05–27.3)4.40 (1.12–15.8)0.98 (0.96–0.99)0.97 (0.96–0.98)

AFP, alpha-fetoprotein; ALT, alanine aminotransferase; APRI, aspartate aminotransferase to platelet ratio index; AST, aspartateaminotransferase; CTP, Child–Turcotte–Pugh; CI, confidence interval; HE, hepatic encephalopathy; HCC, hepatocellular carcinoma;HCV, hepatitis C virus; HVPG, hepatic vein pressure gradient; HR, hazard ratio; MELD, model for end-stage liver disease; NR, notreported; SBP, spontaneous bacterial peritonitis




hepatic decompensation; and 8–47% over 3.9–14.4 yearsfollow-up for overall mortality. The wide range in inci-dence of outcomes highlights the heterogeneity in patient

population evaluated, stage of liver disease at enrollment,duration of follow-up, and definition of outcomes.Interestingly, higher rates of outcomes did not clearly

Table 4 | Outcomes and predictors evaluated and summary of results: histological progression and clinical outcomes

Study Outcomes evaluated % with OutcomeYears Follow-up(s.d.; range)

Predictors significanton multivariateanalysis HR (95% CI)

Dienstag,2011

1. Progression to cirrhosis

2. Any clinical outcome:(i) hepatic decompensation:ascites/variceal bleeding/HE/SBP; (ii) transplant; (iii) HCC;(iv) ≥7 CTP score; (v) hepaticmortality; (vi) overall mortality

1. 29

2. 31

Median 6(NR; 0.8–7)

Not performed

Everhart,2009

Combined outcome: ≥2Increase in Ishak, hepaticmortality or hepaticdecompensation (≥7 CTPscore, ascites, varicealbleed, HE)

28 Mean 3.5(NR; NR)

Baseline Ishak(cirrhosis)

HOMA2-IR(quartiles)

Baseline steatosis(if cirrhosis)

Mallory bodies

1.92 (1.12–3.28)

1.25 (1.08–1.45)

0.49 (0.35–0.70)

1.59 (1.10–2.31)Fontana,2010

1. ≥2 Increase in Ishak

2. Clinical outcomes:(i) Hepatic decompensation:ascites/variceal bleeding/HE/SBP; (ii) HCC; (iii) ≥7 CTPscore or; (iv) overall mortality

1. 34

2. 15

Mean 4.25(NR; NR)

1. Histological progressionBaseline platelet(per 50 K, low)

Baseline log HA

2. Any clinicaloutcome

Baseline bilirubin(elevated)

Baseline INR (>1.0)Baseline albumin (low)Baseline logYKL-40

0.72 (0.57–0.91)

2.42 (0.27–4.47)

2.42 (1.42–4.13)

2.25 (1.30–3.89)0.20 (0.10–0.38)2.44 (1.28–4.63)

Ghany,2010

1. ≥2 Increase in Ishak

2. Clinical outcomes:(i) Hepatic decompensation:ascites/variceal bleeding/HE/SBP; (ii) ≥7 CTP score or;(iii) hepatic mortality

1. 28

2. 13

Mean 3.5(NR; NR)

1. Histological progressionBaseline BMI (high)Baseline platelets (low)Baseline steatosis

2. Any clinical outcomeBaseline LogAST/ALT (high)

Baseline bilirubin(elevated)

Baseline albumin(low)

Baseline platelets/50 K (low)

NR

3.34 (1.84–6.06)

1.82 (1.37–2.42)

0.20 (0.13–0.32)

0.59 (0.49–0.72)

Livingston,2010

1. ≥1 increase in Ishak

2. Hepatic decompensation:ascites/oesophagealvarices/HE/coagulopathy

1. 60

2. 17

Mean 6.2(NR; 2.3–13.3)

Not performed

ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; CTP, Child-Turcotte-Pugh; CI, confidenceinterval; HA, hyaluronic acid; HE, hepatic encephalopathy; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HR, hazardratio; INR, international normalised ratio; NR, not reported; RNA, ribonucleic acid; SBP, spontaneous bacterial peritonitis.




correlate with longer durations of follow-up or moreadvanced disease at baseline across studies, pointing tomore complex underlying interactions driving outcomes.Although the incidence data were not conducive to pro-viding consensus outcome rates, we were able to identifyrisk factors that have most consistently been associatedwith outcomes of interest. Baseline steatosis and fibrosisscore were the most consistent predictors of fibrosis pro-gression and baseline platelet count, AST/ALT ratio,albumin, bilirubin and patient age were the most consis-tent predictors of clinical outcomes.

The variables identified as being most predictive ofoutcomes were not unexpectedly markers of moreadvanced liver disease. Though the overall finding thatpatients with more advanced disease are at higher riskfor adverse outcomes is not novel, our study is the firstto systematically identify the specific risk factors fromamong the many markers of advanced liver disease thatportends worse prognosis. For example, among the labo-ratory markers of more advanced liver disease, plateletcount, bilirubin, albumin and AST/ALT ratio conveyedmeaningful risk information whereas INR, AST, ALTand MELD score did not. Differences in study designmade it difficult to identify clear cut-off values for eachpredictor apart from platelet count with values ≤150 000/uL consistently associated with worse prognosis. Further-more, individual laboratory markers may be less reliablein predicting outcomes than panels of markers such asaspartate aminotransferase to platelet ratio index (APRI),FIB-4, Fibrotest and/or measurements of liver stiffness.The finding that patients with more advanced diseasehave greater risk of disease progression suggests theremay be subsets of patients who are rapid progressors.Understanding whether some patients are destined to berapid progressors and being able to identify these patientsat an early stage will help target limited resources to treatthose patients who will derive the most benefit. Thoughnone of the existing predictive models have been exter-nally validated, the model developed by Ghany and col-leagues is most readily applicable in clinical practice as itis based on routinely available data and evaluates impor-tant liver-related clinical outcomes.26

Examining the results in more detail yielded severaluseful insights. First, the finding of steatosis as a predictorof outcomes highlights a potential modifiable risk factorassociated with disease progression. This is particularlyrelevant given the evolving obesity epidemic. Our datasuggest that patients may benefit from aggressive lifestyleinterventions in addition to other standard of care treat-ment for patients with CHC. The prognostic information

gained from baseline liver biopsy results suggests thatliver biopsies not only provide information regarding cur-rent staging of liver disease but also useful prognosticinformation. As performance of liver biopsies continue todecline, evaluating whether noninvasive assessment offibrosis and steatosis will provide the same prognosticinformation would be important. Though only one studyincluded in our review used an additional modality toassess liver fibrosis in conjunction with biopsy, this studyshowed that liver stiffness measurements were associatedwith overall mortality.40

Our review also highlights several areas for improve-ment for future studies on predictors of disease progres-sion in CHC. Analysis of the individual predictive valueof each risk factor found that there was a notable lack ofincorporation of longitudinal variables. In the few studiesthat did assess longitudinal data, these variables wereusually restricted to laboratory values, predominantlyAST and ALT levels. These models do not mirror clinicalpractice where assessments of risk of disease progressionare based on the pattern of a patient’s test results overtime. Models restricted to only baseline data also cannotdistinguish between patients with similar initial data butwho go on to have distinct disease courses and outcomes.Future studies can also benefit from implementing stan-dardised definitions and criteria for outcomes andemploying a panel of investigators to adjudicate out-comes as the variability in definition of predictor andoutcome variables was one of the biggest challenges.

There are other limitations to our review such as sam-ple selection bias, sampling error and misclassificationbias in studies requiring paired biopsies. In the majorityof studies, biopsies were assessed by a single pathologistand criteria for adequacy of biopsies was described inonly 14 of 21 studies. Finally, the variability in durationof follow-up impacts not only incidence rates of out-comes but also predictiveness of variables examined.

In summary, this systematic review demonstrated thatwhile there is an abundance of literature on factors asso-ciated with histological and/or clinical progression inCHC, there is a lack of longitudinal studies of representa-tive, untreated, well characterised patients followed for asufficiently long duration to allow the development ofsimple prediction models. Despite the limitations inher-ent to the existing literature, we were able to identify spe-cific risk factors that have been consistently identified asbeing independently predictive of disease progression. Byselecting studies consisting of broad patient populationsand those that evaluated routinely obtained clinical data,our findings can be generalised to and applied in many




clinical settings. From a policy standpoint, we have high-lighted that it is possible to identify patients at higher riskfor adverse outcomes. Policies that target costly newHCV therapies to these patients who would derive themost benefit will maximise their cost effectiveness. Theavailability of risk prediction tools that can be applied inthe clinic will help both physicians and patients decidewhether to embark on HCV treatment now or to wait formore affordable treatment. These types of tools will beparticularly important in resource-limited countries andmust therefore be validated in broad patient populations.

AUTHORSHIPGuarantor of the article: Monica A. Konerman.Author Contributions: Monica A. Konerman: study con-cept and design; acquisition of data; analysis and inter-pretation of data; drafting and revision of themanuscript. Suna Yapali: data abstraction; analysis andinterpretation of data; revision of the manuscript. AnnaS. Lok: study concept and design; analysis and interpre-tation of data; critical revision of the manuscript. Allauthors approved the final version of the article, includ-ing the authorship list.

ACKNOWLEDGEMENTSThe authors acknowledge Marisa Conte (University ofMichigan Health System) for assistance with serialliterature searches. We acknowledge Dr. Michael Volkand Dr. Robert Fontana for their input and expertiseregarding the existing literature; and Dr. Vineet Chopra,Dr. Michael Volk and Dr. Robert Fontana for critiqueand editing of the manuscript. We thank Dr. Vander-Meer for providing additional unpublished data for thisreview.Declaration of personal interests: No personal interestedrelevant to this study.Declaration of funding interests: This study was fundedin part by the National Institutes of HealthT32DK062708 training grant (MAK), the Turkish Asso-ciation for the Study of the Liver (SY) and the TuktawaFoundation (ASL and SY).

SUPPORTING INFORMATIONAdditional Supporting Information may be found in theonline version of this article:Table S1. Medline via PubMed search strategy.Table S2. Risk of bias within the included studies.

Figure 2 | List of variables identified to have significant predictive value for (a) histological and (b) clinicalprogression.




Table S3. Outcomes and predictors evaluated withsummary of results: histological progression.Table S4. Outcomes and predictors evaluated with

summary of results: clinical outcomes.

Table S5. Outcomes and predictors evaluated withsummary of results: histological progression and clinicaloutcomes.Table S6. Mathematical prediction models.

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