Comparative Effectiveness of Antiviral Treatment for Hepatitis C

19 Pages·2012·0.21 MB·English

Review
Annals of Internal Medicine
Comparative Effectiveness of Antiviral Treatment for Hepatitis C Virus
Infection in Adults: A Systematic Review
RogerChou,MD;DanielHartung,PharmD,MPH;BasmahRahman,MPH;NgocWasson,MPH;ErikaBarthCottrell,PhD,MPP;
andRongweiFu,PhD
Background: Multipletreatmentsareavailableforchronichepatitis dard doses (2 to 4 fair-quality trials). For genotype 1 infection,
C virus (HCV) infection. fair-qualitytrialsfoundthattripletherapywithpegylatedinterferon,
ribavirin, and either boceprevir (2 trials) or telaprevir (4 trials) was
Purpose: To compare benefits and harms of antiviral regimens for
associated with a higher likelihood of SVR than was dual therapy
chronic HCV infection in treatment-naive adults.
(absolute difference, 22 to 31 percentage points). Compared with
dual therapy, boceprevir triple therapy increased risk for hemato-
Data Sources: English-languageliteraturefromMEDLINE(1947to
logic adverse events and telaprevir triple therapy increased risk for
August 2012), the Cochrane Library Database, Embase, Scopus,
anemia and rash. A large well-designed cohort study and 18
PsychINFO, and clinical trial registries.
smallercohortstudiesfoundthatanSVRafterantiviraltherapywas
Study Selection: Randomized trials of antiviral treatments and co- associatedwithlowerriskforall-causemortalitythanwasnoSVR.
hort studies examining associations between sustained virologic re-
Limitations: Trials involved highly selected populations. Observa-
sponse (SVR) after therapy and clinical outcomes.
tional studies did not always adequately control for confounders.
Data Extraction: Several investigators abstracted study details and
Conclusion: SVR rates for genotype 1 infection are higher with
quality by using predefined criteria.
triple therapy that includes a protease inhibitor than with standard
Data Synthesis: No trial evaluated effectiveness of treatment on dualtherapy.AnSVRafterantiviraltherapyappearsassociatedwith
long-termclinicaloutcomes.Dualtherapywithpegylatedinterferon improved clinical outcomes.
alfa-2bplusribavirinwasassociatedwithalowerlikelihoodofSVR
Primary Funding Source: Agency for Healthcare Research and
than was pegylated interferon alfa-2a plus ribavirin (absolute dif-
Quality.
ference,8percentagepoints[95%CI,3to14percentagepoints])
on the basis of 7 poor- to fair-quality trials. For genotype 2 or 3
infection, dual therapy for 12 to 16 weeks was associated with a AnnInternMed.2013;158:114-123. www.annals.org
lowerlikelihoodofSVRthanwastherapyfor24weeks,andlower Forauthoraffiliations,seeendoftext.
dosesofpegylatedinterferonalfa-2bwerelesseffectivethanstan- Thisarticlewaspublishedatwww.annals.orgon27November2012.
Chronic hepatitis C virus (HCV) infection is a leading atedwithahighrateofadverseeffects,includinginfluenza-
cause of complications from chronic liver disease, in- like symptoms, fatigue, and neuropsychiatric and hemato-
cluding cirrhosis, liver failure, hepatocellular carcinoma, logic effects (8). In 2011, the U.S. Food and Drug
and death (1, 2). The goal of antiviral treatment is to Administration approved the first direct-acting antiviral
eradicate viremia and prevent long-term complications. agents, boceprevir (9) and telaprevir (10), for chronic ge-
Genotype 1 infection predominates in the United States notype 1 infection.
(about 75% of cases) but is more difficult to treat than Understanding the effectiveness of antiviral regimens
genotype 2 or 3 infection. is critical for making informed treatment decisions for
Intheearly2000s,dualtherapywiththecombination HCV infection. This review focuses on comparative effec-
of pegylated interferon plus ribavirin became the standard tivenessinantiviral-naivepatientsandexamineshoweffec-
HCV treatment (3–6). Pegylation refers to the cross- tiveness varies depending on clinical and demographic
linking of polyethylene glycol molecules to the interferon characteristics.
molecule, which delays renal clearance, permitting once-
weekly dosing (7). Two pegylated interferons are available:
alfa-2a and alfa-2b. Interferon-based treatment is associ- METHODS
Scope
We developed a review protocol and analytic frame-
Seealso: work (Appendix Figure 1, available at www.annals.org)
that included the following key questions:
Print
1. What is the comparative effectiveness of antiviral
Relatedarticles........................101,109
treatment in improving health outcomes in patients with
Web-Only HCV infection, and does it vary according to patient
RelatedCMEquiz subgroup characteristics (including, but not limited to,
Clinician’sandConsumerGuides HCV genotype, age, race, sex, stage of disease, or genetic
markers)?
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TreatmentofHCVInfection
2. What is the comparative effectiveness of antiviral
Figure1.Summaryofevidencesearchandselection.
treatments on the rate of sustained virologic response
(SVR), and does it vary according to patient subgroup
characteristics?
Records identified through Records identified
3. What are the comparative harms associated with database searching through other sources
antiviral treatments, and do they vary according to patient (n = 3448) (n = 22)
subgroup characteristics?
4. Have improvements in SVR been shown to reduce
theriskfororratesofadversehealthoutcomesfromHCV
Records after duplicates removed
infection? (n = 3091)
The protocol was developed by using a standardized
process with input from experts and the public. Details,
including full search strategies, inclusion criteria, and evi-
Records screened
dence tables and quality ratings, are provided in the full (n = 3091)
report, as are results of studies comparing induction versus
fixed-dose regimens and study outcomes related to quality Records excluded
of life and histologic changes (11). (n = 2712)
Data Sources and Searches Full-text articles assessed Full-text
articles
A research librarian searched Ovid MEDLINE from for eligibility
(n = 379) excluded
1947 to August 2012, the Cochrane Library Database (n = 289)
(through the first quarter of 2012), Embase (1976 to Au-
gust 2012), Scopus (1960 to August 2012), PsychINFO
(1806 to August 2012), clinical trials registries, and grants
databases.
Studies included in synthesis (n = 90)*
Key question 1a = 5 studies
Study Selection
Key question 1b = 0 studies
At least 2 reviewers independently evaluated studies key question 2a = 38 studies
for inclusion. For the first 3 questions, we included ran- Key question 2b = 13 studies
Key question 3a = 13 studies
domized trials of antiviral-naive patients that compared Key question 3b = 3 studies
dual therapy with pegylated interferon alfa-2b plus ribavi- Key question 4 = 28 studies
rin versus pegylated interferon alfa-2a plus ribavirin; triple
therapy with pegylated interferon (alfa-2a or -2b), ribavi-
Forkeyquestions,seeAppendixFigure1(availableatwww.annals.org).
rin,andeithertelaprevirorboceprevirversusdualtherapy; Reproducedfromreference11.
or different doses or durations of dual or triple therapy. *Somestudiesappliedtomorethan1keyquestion.Studiesofinduc-
tion versus fixed-dose regimens and outcomes related to quality of life
Doseanddurationcomparisonsofdualtherapyfocusedon
andhistologicchangesarenotreportedherebutcanbefoundinthefull
genotype 2 or 3 infection. For the last question, we in- report(11).
cluded cohort studies that reported adjusted risk estimates
for the association between an SVR after antiviral treat-
ment versus no SVR and clinical outcomes. Clinical out- Data Extraction and Quality Assessment
comes were mortality, cirrhosis, hepatic decompensation, Oneinvestigatorabstracteddetailsaboutthestudyde-
hepatocellular carcinoma, and need for transplantation. sign,population,setting,interventions,analysis,follow-up,
and results. A second investigator reviewed data for accu-
Sustainedvirologicresponse,theprimaryintermediateout-
racy. Two investigators independently applied predefined
come,wasdefinedastheabsenceofdetectableHCVRNA
criteria (13–15) to assess study quality as good, fair, or
intheserum6monthsaftertheendofacourseoftherapy
poor. Discrepancies were resolved through consensus.
(4). Harms included withdrawals due to adverse events,
serious adverse events, neutropenia, anemia, psychological Data Synthesis and Analysis
adverse events, influenza-like symptoms, and rash. We assessed the overall strength of each body of evi-
We restricted inclusion to English-language articles dence as “high,” “moderate,” “low,” or “insufficient” in
andincludedstudiespublishedasconferenceabstractsonly accordancewiththeAHRQ“MethodsGuideforEffective-
in sensitivity analyses. We excluded studies of pregnant ness and Comparative Effectiveness Reviews” (16) on the
women (12), patients who received a transplant, HIV- basis of the quality of studies, consistency between studies,
infected patients, patients undergoing hemodialysis, and precision of estimates, and directness of evidence.
previouslytreatedpatients.Weexcludedregimenswithan- We performed meta-analyses of trials that evaluated
tiviral drugs not approved in the United States for HCV similar populations, interventions, comparisons, and out-
infection. comes to estimate pooled relative risks (RRs) using the
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Figure2.Sustainedvirologicresponse,comparisonsofdual-therapyregimens.
Study, Year (Reference) Relative Risk Events Events
(95% CI) Treatment, n/N Control, n/N
Dual therapy with pegylated interferon alfa-2b plus ribavirin vs.
dual therapy with pegylated interferon alfa-2a plus ribavirin
Yenice et al, 2006 (30) 0.72 (0.42–1.25) 13/37 18/37
Escudero et al, 2008 (24) 0.94 (0.76–1.17) 57/92 60/91
Kamal et al, 2011 (25) 0.77 (0.63–0.95) 59/108 77/109
Mach et al, 2011 (27) 0.90 (0.69–1.17) 54/122 68/138
Ascione et al, 2010 (23) 0.79 (0.66–0.94) 87/160 110/160
Rumi et al, 2010 (29) 0.82 (0.70–0.96) 119/219 140/212
McHutchison et al, 2009 (21) 0.97 (0.88–1.08) 406/1019 423/1035
Subtotal (I2 = 27.4%; P = 0.220) 0.87 (0.80–0.95) 795/1757 896/1782
24 wk vs. 12 to 16 wk of dual therapy with pegylated
interferon plus ribavirin
Yu et al, 2007 (42) 1.01 (0.93–1.10) 95/100 47/50
Lagging et al, 2008 (36) 1.33 (1.16–1.53) 147/188 114/194
Manns et al, 2011 (duration) (38) 1.18 (1.02–1.36) 153/230 129/228
Shiffman et al, 2007 (40) 1.13 (1.05–1.22) 515/732 455/733
Subtotal (I2 = 79.5%; P = 0.002) 1.15 (1.02–1.29) 910/1250 745/1205
Lower vs. higher dose of pegylated interferon alfa-2b
as part of dual therapy with ribavirin
Kawaoka et al, 2009 (45) 0.52 (0.30–0.89) 10/26 20/27
Sood et al, 2008 (48) 0.85 (0.73–1.00) 60/76 25/27
Abergel et al, 2006 (44) 1.00 (0.76–1.31) 27/37 30/41
Meyer-Wyss et al, 2006 (47) 0.88 (0.70–1.11) 39/55 29/36
Krawitt et al, 2006 (46) 0.86 (0.61–1.21) 24/43 28/43
Manns et al, 2011 (38) 0.97 (0.85–1.10) 144/224 153/230
Subtotal (I2 = 20.2%; P = 0.281) 0.90 (0.81–0.99) 304/461 285/404
0.25 0.5 1 2
Relativerisks(cid:3)1favordualtherapywithpegylatedinterferonalfa-2boverdualtherapywithpegylatedinterferonalfa-2a,24wkover12to16wk,and
lower-doseversushigher-dosepegylatedinterferonalfa-2b.
DerSimonian–Laird method in a random-effects model reportandmanuscript.Theinvestigatorsaresolelyrespon-
(17). Heterogeneity was assessed with the I2 statistic (18). sible for the manuscript’s content and the decision to sub-
Statistical heterogeneity was explored through sensitivity mit it for publication.
and subgroup analyses based on study quality, differences
in dosing or drugs, and outlier trials. We did not produce
funnel plots because of small numbers ((cid:1)10) of studies RESULTS
(19), but we performed sensitivity analyses that included Figure 1 shows the search and selection results and
studies published only as abstracts. Analyses were per- AppendixTable1(availableatwww.annals.org)showsthe
formed with Stata software, version 11.0 (StataCorp, Col- strength of evidence ratings. No study evaluated the com-
lege Station, Texas). parative effectiveness of current antiviral treatments on
long-term clinical outcomes. Three trials found no differ-
Role of the Funding Source
ences between various dual- or triple-therapy regimens in
The AHRQ’s Effective Health Care Program funded
short-term (6 months after regimen completion) mortality
this work. Investigators worked with AHRQ staff to de-
but reported few deaths (20 total) (20–22).
velop and refine the scope, analytic framework, and key
questions. The AHRQ staff had no role in study selection, Virologic Outcomes
quality assessment, synthesis, or development of conclu- Ten trials (n(cid:2) 66 to 3070) compared dual therapy
sionsandprovidedprojectoversightandreviewedthedraft with pegylated interferon alfa-2b plus ribavirin versus dual
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therapy with pegylated interferon alfa-2a plus ribavirin (6, waspresent(I2(cid:2)80%)(Figure2)(36,38,40,42).The1
21, 23–30) (Appendix Table 2, available at www.annals trial that found no difference (RR, 1.0 [CI, 0.93 to 1.1])
.org). Four trials were restricted to genotype 1 infection reported high overall SVR rates (94% to 95%), was re-
(21, 27, 28, 30). The prevalence of baseline cirrhosis stricted to genotype 2 infection, and used a somewhat dif-
rangedfromlessthan5%to20%(23,29,31,32),andthe ferent ribavirin dosing regimen (42). Excluding this trial
prevalence of elevated aminotransferase levels ranged from reduced statistical heterogeneity, but the estimate was sim-
60% to 100% (23–25, 29, 30, 32). Eleven trials (n(cid:2) 117 ilar (3 trials; pooled RR, 1.2 [CI, 1.1 to 1.3]; I2(cid:2) 47%)
to 1465) (33–43) compared different durations of dual (36, 38, 40).
therapy, 6 trials (n(cid:2) 53 to 454) (38, 44–48) compared Three fair-quality trials of rapid virologic responders
different doses of pegylated interferon as part of dual ther- (undetectable HCV RNA by week 4) found no difference
apy, and 4 trials (n(cid:2) 60 to 1831) (35, 49–51) compared inthelikelihoodofSVRbetween24and12to16weeksof
different doses of ribavirin as part of dual therapy for ge- dual therapy (pooled RR, 0.99 [CI, 0.86 to 1.1]; I2(cid:2)
notype2or3infection(AppendixTable2).Onetrialwas 66%) (34, 39, 41). Absolute differences ranged up to 10
rated as good quality (40), 4 trials as poor quality (24, 30, percentage points in either direction.
38, 47), and the remainder as fair quality. Methodologic
Dose Effects
shortcomings included open-label design or inadequately
Lower-dosepegylatedinterferonalfa-2baspartofdual
describedblinding(23–25,27–29,33–39,42–52),highor
therapywasassociatedwithalowerlikelihoodofSVRthan
unclear attrition (21, 23, 24, 29, 35, 38, 51), and unclear
was a higher dose (typically 1.5 mcg/kg per week) in ge-
or inadequate randomization or methods for allocation
notype2or3infection,althoughtheupperlimitoftheCI
concealment (24, 25, 27–30, 34, 36–39, 41–48).
nearly crossed 1.0 (pooled RR, 0.90 [CI, 0.81 to 0.99];
Dual therapy with standard-dose (1.5 mcg/kg per I2(cid:2) 20%), on the basis of 6 trials (4 fair-quality and 2
week) pegylated interferon alfa-2b was associated with a
poor-quality)(Figure2)(38,44–48).Excludingthepoor-
slightly lower likelihood of SVR than was dual therapy
quality trials (38, 47) or 1 trial that evaluated an atypical
with standard-dose (180 mcg per week) pegylated inter-
dosing regimen (46) had little effect on the pooled
feron alfa-2a (pooled relative risk [RR], 0.87 [95% CI,
estimate.
0.80 to 0.95]; I2(cid:2) 27%) (Figure 2), with a pooled abso-
Two fair-quality trials found no clear difference be-
lutedifferenceof8percentagepoints(CI,3to14percent-
tween induction regimens of pegylated interferon alfa-2b
age points), on the basis of 7 trials (5 fair-quality and 2
(higherinitialdosesfollowedbylowerdoses)plusribavirin
poor-quality)(21,23–25,27,29,30).Resultsweresimilar
versus standard fixed-dose dual therapy (53, 54).
when the meta-analysis included a trial (31) that evaluated
Two fair-quality trials of pegylated interferon alfa-2a
triple-therapy regimens, a trial (6) published only as an
found no difference between 1000 to 1200 mg and 800
abstract, and 2 trials that evaluated nonstandard doses of mg of ribavirin daily (n(cid:2) 492), or between 400 mg and
pegylated interferon alfa-2b (26, 28) or when the analysis 800 mg daily, in likelihood of SVR (n(cid:2) 282) (35, 49).
excluded poor-quality trials (24, 30). One fair-quality trial (n(cid:2) 1831) of pegylated interferon
The largest trial (n(cid:2) 3070), the Individualized Dos-
alfa-2b found no difference between ribavirin, 800 mg/d
ing Efficacy vs. Flat Dosing to Assess Optimal Pegylated
(flat dose), and 800 to 1400 mg/d (weight-dosed) (51).
InterferonTherapy(IDEAL)study,foundnodifferencein One fair-quality trial (n(cid:2) 60) that primarily enrolled
likelihood of SVR for genotype 1 infection between 2
patientswithadvancedfibrosisorcirrhosisfoundpegylated
dosesofpegylatedinterferonalfa-2b(1.0mcg/kgperweek
interferon alfa-2a plus ribavirin, 600 to 800 mg/d, to be
or1.5mcg/kgperweek)plusribavirin,800to1400mg/d,
associated with a lower likelihood of SVR than was ribavi-
or pegylated interferon alfa-2a, 180 mcg per week, plus
rin, 1000 to 1200 mg/d (45% versus 72%; RR, 0.62 [CI,
ribavirin, 1000 to 1200 mg/d (range, 38% to 41%) (21).
0.40 to 0.98]) (50).
Excluding IDEAL because of differential ribavirin dosing
had little effect on the pooled estimate but eliminated sta- Triple Therapy
tistical heterogeneity (6 trials; pooled RR, 0.83 [CI, 0.76 Two fair-quality trials (n(cid:2) 1097 and 520) compared
to 0.90]; I2(cid:2) 0%) (23–25, 27, 29, 30). tripletherapywithboceprevir,pegylatedinterferonalfa-2b,
and ribavirin versus dual therapy for antiviral treatment–
Duration Effects naive patients with genotype 1 infection (Appendix Table
Twofair-qualitytrialsfoundnodifferencebetween48 3, available at www.annals.org) (22, 55). Seven percent to
and 24 weeks of dual therapy in the likelihood of SVR in 10% of patients had cirrhosis or severe fibrosis at baseline.
genotype 2 or 3 infection (pooled RR, 0.97 [CI, 0.84 to Methodological shortcomings included open-label design
1.1];I2(cid:2)43%)(35,43).Fourtrials(1good-qualityand3 (55) or high attrition (22). A 48-week boceprevir regimen
fair-quality) found that 24 weeks of dual therapy was asso- (4 weeks of dual-therapy lead-in followed by 44 weeks of
ciated with a higher likelihood of SVR than was 12 to 16 triple therapy) was associated with a higher likelihood of
weeks (pooled RR, 1.2 [CI, 1.0 to 1.3]), but the lower SVR than was 48 weeks of dual therapy (pooled RR, 1.8
limitoftheCInearlycrossed1andstatisticalheterogeneity [CI,1.6to2.1];I2(cid:2)0%),withapooledabsoluteincrease
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Figure3.Sustainedvirologicresponse,tripletherapywithaproteaseinhibitorversusdualtherapy.
Study, Year (Reference) Relative Risk Events Events
(95% CI) Treatment, n/N Control, n/N
Boceprevir triple therapy for 48 wk vs.
dual therapy for 48 wk
Kwo et al, 2010 (55)
1.99 (1.52–2.62) 77/103 39/104
Poordad et al, 2011 (22)
1.75 (1.51–2.04) 242/366 137/363
Subtotal (I2 = 0.0%; P = 0.416)
1.81 (1.58–2.06) 319/469 176/467
Telaprevir triple therapy for 24 wk vs.
dual therapy for 48 wk
Kumada et al, 2012 (57) 1.48 (1.13–1.95) 92/126 31/63
McHutchison et al, 2009 (58) 1.47 (1.06–2.03) 48/79 31/75
Hézode et al, 2009 (56) 1.49 (1.13–1.96) 56/81 38/82
Subtotal (I2 = 0.0%; P = 0.998) 1.48 (1.26–1.75) 196/286 100/220
0.75 1 2 4
Theboceprevirregimenconsistedof4wkofdual-therapylead-inwithpegylatedinterferonalfa-2bplusribavirin,followedbytheadditionofboceprevir
for44morewk.Thetelaprevirregimenconsistedof12wkoftelaprevir,pegylatedinterferonalfa-2aor-2b,andribavirin,followedby12wkofdual
therapy(pegylatedinterferonplusribavirinwithouttelaprevir).Relativerisks(cid:3)1favortripletherapy.
of 31 percentage points (CI, 23 to 39 percentage points) with an absolute increase of 22 percentage points (CI, 13
(22, 55) (Figure 2). Other triple-therapy regimens evalu- to 31 percentage points) (56–58). Excluding a trial that
ated in the trials (28 weeks with or without dual-therapy evaluated pegylated interferon alfa-2b instead of alfa-2a
lead-in, 48 weeks without dual-therapy lead-in, or had no effect on the estimate (57). Two trials found no
response-guided triple therapy for 28 or 48 weeks) were differencebetween12weeksoftripletherapyand48weeks
associated with lower or similar SVR rates compared with of dual therapy (56, 58), and 1 trial found no difference
the 48-week regimen with lead-in. between 48 and 24 weeks of telaprevir triple therapy (58).
One trial (n(cid:2) 75) found that triple therapy with One trial (n(cid:2) 1088) found response-guided triple
weight-based ribavirin, 400 to 1000 mg/d, was associated therapy with telaprevir (triple therapy for 8 or 12 weeks
with a trend toward lower likelihood of SVR compared followed by dual therapy for a total of 24 or 48 weeks,
withtripletherapywithstandard-dose(800to1400mg/d) depending on extended rapid virologic response) to be as-
ribavirin (36% versus 50%; RR, 0.71 [CI, 0.39 to 1.3]) sociated with a higher likelihood of SVR than was dual
(55). therapy for 48 weeks (RR, 1.6 [CI, 1.4 to 1.9]), with an
Sixrandomizedtrialscomparedtripletherapywithte- absolute increase of 25 to 31 percentage points (20).
laprevir, pegylated interferon, and ribavirin versus dual One trial found similar SVR rates (81% to 85%) for
therapy for genotype 1 infection (Appendix Table 3) (20, response-guided triple-therapy regimens that varied on te-
31, 56–59). One trial used pegylated interferon alfa-2b laprevirdose(750mg3timesdailyversus1125mg2times
(57), 1 evaluated regimens with pegylated interferon daily) and type of pegylated interferon (alfa-2a versus alfa-
alfa-2a or alfa-2b (31), and the remainder used pegylated 2b)(31).Anothertrialofextendedrapidvirologicrespond-
interferon alfa-2a. The prevalence of baseline cirrhosis ers to initial triple therapy with telaprevir reported similar,
rangedfrom0%to11%.Onetrial(58)wasratedasgood- high SVR rates with 24- and 48-week regimens (92% and
quality and the remainder as fair-quality. Methodological 88%, respectively) (59).
shortcomings included open-label design or unclear blind-
ing procedures (31, 56, 59), unclear randomization meth- Effectiveness in Subgroups
ods (56, 58), and unclear attrition (57, 58). In all triple- In patients with genotype 1 infection, 1 trial of dual
therapy regimens, telaprevir was administered with therapy with pegylated interferon alfa-2b versus alfa-2a
pegylated interferon plus ribavirin for the first 8 to 12 (21), 2 trials of 48 weeks of triple therapy with boceprevir
weeks. For regimens longer than 12 weeks, dual therapy and dual-therapy lead-in versus 48 weeks of dual therapy
was continued to the end of treatment. (22, 55), and 2 trials of triple therapy with telaprevir
Three trials (n(cid:2) 189 to 323) found that a 24-week (response-guidedorfixedduration)versus48weeksofdual
fixed-duration telaprevir regimen was associated with a therapy(20,57)foundnocleardifferencesinRRestimates
higher likelihood of SVR than was 48 weeks of dual ther- based on race, sex, age, baseline fibrosis, and weight. For
apy(pooledRR,1.5[CI,1.3to1.8];I2(cid:2)0%)(Figure3), boceprevir, the RR estimate was higher with a baseline
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HCV RNA viral load greater than 600 to 800,000 IU/mL 0%) than dual therapy for 48 weeks (22, 55) (Appendix
(pooled RR, 2.0 [CI, 1.7 to 2.3]; I2(cid:2) 0%) than with a Table 4). About 25% of patients receiving triple therapy
lowerviralload(pooledRR,1.3[CI,1.0to1.5];I2(cid:2)0%) experienced anemia (4% to 5% severe, defined as hemo-
(22, 55), but there was no clear difference in RR estimates globin level less than 80 or less than 85 g/L) and about
for telaprevir triple therapy versus dual therapy according 33% neutropenia (8% to 15% severe, defined as neutro-
to baseline viral load in 2 trials (20, 57). Across regimens, philcount(cid:1)500cells/L).Therewerenodifferencesinrisk
absolute SVR rates were lower in older patients, black pa- for withdrawal due to adverse events, serious adverse
tients, patients with more advanced fibrosis, and patients events, or other adverse events.
with higher viral load. Four trials of dual therapy with A 24-week regimen of triple therapy with telaprevir
pegylated interferon alfa-2b versus alfa-2a found no clear was associated with higher risk for anemia (3 trials; pooled
differenceinRRestimatesaccordingtogenotype,although RR, 1.3 [CI, 1.1 to 1.5]; I2(cid:2) 0%) and rash (3 trials;
absolute SVR rates were lower by 24% to 42% with geno- pooled RR, 1.4 [CI, 1.1 to 1.7]; I2(cid:2) 0%) than was dual
type 1 (6, 23, 24, 29). therapy for 48 weeks, but there were no statistically signif-
icant differences in risk for serious adverse events, with-
Harms of Antiviral Treatments drawal due to adverse events, neutropenia, depression, fa-
Six head-to-head trials of dual therapy with pegylated tigue, headache, chills/rigors, or influenza-like symptoms
interferonalfa-2bversusalfa-2afoundnodifferenceinrisk (56–58) (Appendix Table 4). Triple therapy was also as-
for withdrawal due to adverse events (6 trials; pooled RR, sociatedwithincreasedriskforthrombocytopeniain1trial
1.1 [CI, 0.73 to 1.7]; I2(cid:2) 42%) (21, 23, 24, 28–30). (RR, 1.8 [CI, 1.2 to 2.5]) (57). About half of the patients
Excluding 1 outlier trial (RR, 4.2 [CI, 1.5 to 12]) (23) randomly assigned to telaprevir experienced rash (severe
eliminatedstatisticalheterogeneity,butthepooledestimate rash in 7% to 10%) and about half had anemia (severe
wassimilar(5trials;pooledRR,0.88[CI,0.7to1.1];I2(cid:2) anemia in 4% to 11%) (56–58).
0%). One trial found that response-guided therapy with te-
Two trials found dual therapy with pegylated inter- laprevir for 24 to 48 weeks was associated with higher risk
for withdrawal due to adverse events (RR, 3.8 [CI, 2.6 to
feron alfa-2b to be associated with lower risk for serious
5.7]),anemia(RR,2.0[CI,1.6to2.5]),rash(RR,1.5[CI,
adverse events than was dual therapy with pegylated inter-
feron alfa-2a (pooled RR, 0.76 [CI, 0.61 to 0.95]; I2(cid:2) 1.2 to 1.8]), and severe rash (5% versus 1%; RR, 4.6 [CI,
1.6 to 13]) than dual therapy for 48 weeks (20).
0%) (21, 29). There were no differences between dual-
No trial reported harms in patient subgroups. Three
therapy regimens in risk for anemia, thrombocytopenia,
trialsofdualtherapywithpegylatedinterferonalfa-2bver-
depression, fatigue, myalgia, or influenza-like symptoms
sus alfa-2a for genotype 1 infection reported pooled esti-
(Appendix Table 4, available at www.annals.org). Dual
mates for harms similar to the estimates based on all trials
therapy with pegylated interferon alfa-2b was associated
(21, 30, 31).
withhigherriskforheadache(3trials;pooledRR,1.1[CI,
1.1 to 1.2]; I2(cid:2) 0%) (21, 23, 28) and lower risk for rash
Association Between SVR and Clinical Outcomes
(2 trials; pooled RR, 0.79 [CI, 0.71 to 0.88]; I2(cid:2) 0%) Nineteen cohort studies (n(cid:2) 105 to 16864) evalu-
(21, 28) and neutropenia (5 trials; pooled RR, 0.61 [CI,
atedtheassociationbetweenanSVRafterantiviraltherapy
0.46to0.83];I2(cid:2)38%).Inthelargeststudy(theIDEAL
and mortality or complications of chronic HCV infection
trial), dual therapy with either pegylated interferon was
(AppendixTable5,availableatwww.annals.org)(60–78).
associated with serious adverse events in about 4% of pa-
Durationoffollow-uprangedfrom3to9years.Tenstud-
tients, fatigue in 65%, headache in 45%, nausea in 40%,
ies were conducted in Asia (60, 67–72, 75, 77, 78). Eight
myalgiain25%,neutrophilcountlessthan500cells/mm3
(64–66, 72, 75–78) were rated as poor-quality and the
in 5%, and hemoglobin level less than 85 g/L in 3% (21). remainder as fair-quality. Although all studies reported ad-
Excluding the low-dose pegylated interferon alfa-2b justed risk estimates, only 8 (60, 61, 63, 67–70, 73) eval-
group from the IDEAL trial had little effect on pooled uated5keyconfounders(age,sex,genotype,viralload,and
estimates, except that pegylated interferon alfa-2b became fibrosis stage). No study clearly described assessment of
associated with increased risk for depression (3 trials; outcomes blinded to SVR status.
pooled RR, 1.2 [CI, 1.0 to 1.4]; I2(cid:2) 0%) (21, 23, 28). The largest study (n(cid:2) 16864) had the fewest meth-
Excluding 2 poor-quality trials had little effect on pooled odologicshortcomings(61).Itadjustedformultiplepoten-
estimates (24, 30). tial confounders, including age, sex, viral load, presence of
Two trials found a 48-week boceprevir regimen with cirrhosis, multiple comorbid conditions, aminotransferase
dual-therapy lead-in was associated with higher risk for levels,andothers.Italsostratifiedresultsbygenotype.Ina
neutropenia (pooled RR, 1.8 [CI, 1.5 to 2.3]; I2(cid:2) 0%), predominantly male, Veterans Affairs population, SVR af-
dysgeusia (pooled RR, 2.5 [CI, 2.0 to 3.2]; I2(cid:2) 0%), ter antiviral therapy was associated with lower risk for all-
anemia (pooled RR, 2.0 [CI, 1.4 to 2.8]; I2(cid:2) 0%), and cause mortality than was no SVR, after a median of 3.8
thrombocytopenia (pooled RR, 3.2 [CI, 1.2 to 8.2]; I2(cid:2) years (adjusted hazard ratio, 0.71 [CI, 0.60 to 0.86], 0.62
www.annals.org 15January2013 AnnalsofInternalMedicine Volume158•Number2 119
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TreatmentofHCVInfection
[CI, 0.44 to 0.87], and 0.51 [CI, 0.35 to 0.75] for geno- Triple therapy for genotype 1 infection is also associ-
types 1, 2, and 3, respectively). Mortality curves began to atedwithshorterdurationoftreatment,animportantcon-
separate as soon as 3 to 6 months after SVR assessment. sideration given the high frequency of adverse effects asso-
Eighteen other cohort studies also found SVR to be ciated with interferon-based therapy. However, triple
associated with decreased risk for all-cause mortality (ad- therapy is also associated with increased risk for hemato-
justedhazardratios,0.07to0.39)(60,69,72,73,75–78), logic adverse events with boceprevir (neutropenia, anemia,
liver-related mortality (adjusted hazard ratios, 0.04 to and thrombocytopenia) and anemia and rash with telapre-
0.27) (60, 62, 63, 69, 70, 72, 74, 76, 77), hepatocellular vir (including severe rash in less than 10% of patients),
carcinoma (adjusted hazard ratios, 0.12 to 0.46) (60, 62, although there was no clear increase in risk for serious
63, 67, 68, 71, 73–76, 78), and other complications of adverse events overall. Across all antiviral regimens, abso-
end-stage liver disease versus no SVR, with effects larger lute treatment response rates are lower in older patients;
thanintheVeteransAffairsstudy.Thesubgroupofstudies blackpatients;andpatientswithhigherbaselineviralload,
thatfocusedonpatientswithadvancedfibrosisorcirrhosis genotype 1 infection, or more advanced fibrosis.
atbaseline(62,63,65–68,74–76)orthatwereconducted The strongest evidence on the association between vi-
in Asia (60, 67–72, 75, 77, 78) reported similar ranges of rologic and clinical outcomes is a large Veterans Affairs
risk estimates. cohort study that found SVR to be associated with a 30%
to 50% reduction in mortality risk, after adjustment for
many confounders (61). The rapid separation of mortality
curvesinthisstudysuggestspossibleresidualconfounding,
DISCUSSION
given the typically protracted course of HCV infection.
AntiviraltherapyforchronicHCVinfectioncontinues
Therefore, estimates of benefit may be exaggerated, al-
to evolve. No study evaluated comparative effectiveness of
though it is not possible to determine to what degree.
current antiviral regimens on long-term clinical outcomes. Eighteen other cohort studies also found that SVR was
Such trials are a challenge to carry out because of the long associated with decreased risk for serious complications of
time course over which complications of HCV infection chronic HCV infection, but these studies had more
develop. methodological shortcomings than did the Veterans Af-
In lieu of direct evidence on long-term clinical out- fairs study.
comes, SVR rates are the primary outcome measure with Our study has limitations. We excluded non–English-
whichtoevaluatecomparativeeffectiveness.Fortreatment- language articles. We did not perform formal analyses for
naive patients, dual therapy with pegylated interferon publicationbiasbecauseofthesmallnumbersoftrials,but
alfa-2bisassociatedwithalowerlikelihoodofSVRthanis analyses of abstracts and searches of clinical trials registries
dual therapy with pegylated interferon alfa-2a (absolute did not suggest publication bias. Meta-analyses were per-
difference, about 8 percentage points). Although there was formed by using the DerSimonian–Laird random-effects
no difference between dual-therapy regimens in risk for model, which results in CIs that are slightly too narrow
withdrawals due to adverse events, pegylated interferon when heterogeneity is present, so that pooled estimates
alfa-2b was associated with a lower risk for serious adverse with95%CIscloseto1.0shouldbeinterpretedcautiously
events, suggesting potential tradeoffs between benefits and (82).Estimatesandconclusionsbasedonsmallnumbersof
harms. However, serious adverse events were reported in trials should also be interpreted cautiously. For example,
only 2 trials (21, 29), the absolute difference was only pooled estimates based on 2 trials can be unreliable, par-
about1%,andantiviral-relatedadverseeventsaregenerally ticularlywhenstatisticalheterogeneityispresent.Thetrials
self-limited. generallymetcriteriaforefficacystudies,whichcouldlimit
For genotype 2 or 3 infection, standard doses and du- their applicability because of exclusion of patients with co-
rations (24 weeks) of pegylated interferon as part of dual morbid conditions, and greater adherence than typically
therapy are more effective than shorter regimens or lower observed in clinical practice. Almost all of the randomized
doses, lending support to current dosing guidance (4, 79, trials were funded by pharmaceutical companies (83, 84).
80). Evidence on differential effects of ribavirin dose is Additionalresearchwouldhelpclarifythecomparative
limited, although differences were small in most studies. effectiveness of antiviral treatments. Studies are needed to
The relative ineffectiveness of dual therapy for geno- understandthelong-termclinicaloutcomesassociatedwith
type1infectionhasledtoongoingeffortstoidentifymore different antiviral treatments, the long-term harms of tel-
effectivetreatments.Recenttrialsfoundtripletherapywith aprevirandboceprevir,thecomparativeeffectivenessoftri-
boceprevirortelaprevirsuperiortodualtherapy,withSVR ple therapy with telaprevir versus boceprevir, and effective
approaching the 70% to 80% rates observed in trials of strategies to improve adherence (85). Other direct-acting
dual therapy for genotype 2 or 3 infection (20, 22, 31, antiviral agents, including second-generation protease in-
55–59). This has important implications for treatment, as hibitors, polymerase inhibitors, NS5A inhibitors, and oth-
well as for screening, because screening benefits depend in ers, are in active development, with all-oral, interferon-
part on the effectiveness of available treatments (81). sparing regimens expected within the next few years (86).
120 15January2013 AnnalsofInternalMedicine Volume158•Number2 www.annals.org
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Review
TreatmentofHCVInfection
FromOregonHealth&ScienceUniversity,Portland,Oregon. 12.PembreyL,NewellML,TovoPA;EPHNCollaborators.Themanagement
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represent the views of AHRQ. No statement in this report should be ofthemethodologicalqualitybothofrandomisedandnon-randomisedstudiesof
construedasanofficialpositionofAHRQoroftheU.S.Departmentof health care interventions. J Epidemiol Community Health. 1998;52:377-84.
[PMID:9764259]
HealthandHumanServices.
14.HarrisRP,HelfandM,WoolfSH,LohrKN,MulrowCD,TeutschSM,
etal;MethodsWorkGroup,ThirdUSPreventiveServicesTaskForce.Current
Acknowledgment: The authors thank Robin Paynter, MLIS; Rose
methods of the US Preventive Services Task Force: a review of the process.
Campbell, MLIS; AHRQ Task Order Officer Christine Chang, MD,
AmJPrevMed.2001;20:21-35.[PMID:11306229]
MPH; and USPSTF Medical Officer Iris Mabry-Hernandez, MD,
15.WhitingPF,RutjesAW,WestwoodME,MallettS,DeeksJJ,ReitsmaJB,
MPH.TheyalsothankTracyDana,MLS;ChristinaBougatsos,MPH;
etal;QUADAS-2Group.QUADAS-2:arevisedtoolforthequalityassessment
andIanBlazina,MPH,fromOregonHealth&ScienceUniversity,who
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assistedindataextractionandqualitychecking. 22007046]
16.AgencyforHealthcareResearchandQuality.Methodsguideforeffective-
Grant Support: By AHRQ (contract 290-2007-10057-I, task order 8), ness and comparative effectiveness reviews. AHRQ publication no. 10(12)-
Rockville,Maryland. EHC063-EF. April 2012. Accessed at www.effectivehealthcare.ahrq.gov/ehc
/products/60/318/MethodsGuide_Prepublication-Draft_20120523.pdf on 19
Potential Conflicts of Interest: Disclosures can be found at www June2012.
17.FuR,GartlehnerG,GrantM,ShamliyanT,SedrakyanA,WiltTJ,etal.
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18.HigginsJP,ThompsonSG.Quantifyingheterogeneityinameta-analysis.
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