Chou 2013

Review Annals of Internal Medicine
Comparative Effectiveness of Antiviral Treatment for Hepatitis C Virus

Infection in Adults: A Systematic Review
Roger Chou, MD; Daniel Hartung, PharmD, MPH; Basmah Rahman, MPH; Ngoc Wasson, MPH; Erika Barth Cottrell, PhD, MPP;
and Rongwei Fu, PhD
Background: Multiple treatments are available for chronic hepatitis dard doses (2 to 4 fair-quality trials). For genotype 1 infection,
C virus (HCV) infection. fair-quality trials found that triple therapy with pegylated interferon,
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
Data Sources: English-language literature from MEDLINE (1947 to dual therapy, boceprevir triple therapy increased risk for hemato-
August 2012), the Cochrane Library Database, Embase, Scopus, logic adverse events and telaprevir triple therapy increased risk for
PsychINFO, and clinical trial registries. anemia and rash. A large well-designed cohort study and 18
smaller cohort studies found that an SVR after antiviral therapy was
Study Selection: Randomized trials of antiviral treatments and co- associated with lower risk for all-cause mortality than was no SVR.
hort studies examining associations between sustained virologic re-
sponse (SVR) after therapy and clinical outcomes. Limitations: Trials involved highly selected populations. Observa-
tional studies did not always adequately control for confounders.
Data Extraction: Several investigators abstracted study details and
quality by using predefined criteria. Conclusion: SVR rates for genotype 1 infection are higher with
triple therapy that includes a protease inhibitor than with standard
Data Synthesis: No trial evaluated effectiveness of treatment on dual therapy. An SVR after antiviral therapy appears associated with
long-term clinical outcomes. Dual therapy with pegylated interferon improved clinical outcomes.
alfa-2b plus ribavirin was associated with a lower likelihood of SVR
than was pegylated interferon alfa-2a plus ribavirin (absolute dif- Primary Funding Source: Agency for Healthcare Research and
ference, 8 percentage points [95% CI, 3 to 14 percentage points]) Quality.
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 Ann Intern Med. 2013;158:114-123. www.annals.org
lower likelihood of SVR than was therapy for 24 weeks, and lower For author affiliations, see end of text.
doses of pegylated interferon alfa-2b were less effective than stan- This article was published at www.annals.org on 27 November 2012.
C hronic hepatitis C virus (HCV) infection is a leading

cause of complications from chronic liver disease, in-
cluding cirrhosis, liver failure, hepatocellular carcinoma,
ated with a high rate of adverse effects, including influenza-
like symptoms, fatigue, and neuropsychiatric and hemato-
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
In the early 2000s, dual therapy with the combination HCV infection. This review focuses on comparative effec-
of pegylated interferon plus ribavirin became the standard tiveness in antiviral-naive patients and examines how effec-
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-
See also: work (Appendix Figure 1, available at www.annals.org)
that included the following key questions:
Print
1. What is the comparative effectiveness of antiviral
Related articles . . . . . . . . . . . . . . . . . . . . . . . . 101, 109
treatment in improving health outcomes in patients with
Web-Only HCV infection, and does it vary according to patient
Related CME quiz subgroup characteristics (including, but not limited to,
Clinician’s and Consumer Guides HCV genotype, age, race, sex, stage of disease, or genetic
markers)?
114 15 January 2013 Annals of Internal Medicine Volume 158 • Number 2 www.annals.org
Downloaded From: http://annals.org/ on 11/01/2016

Treatment of HCV Infection Review
2. What is the comparative effectiveness of antiviral

Figure 1. Summary of evidence search and selection.
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
(n = 3448) (n = 22)
antiviral treatments, and do they vary according to patient
subgroup characteristics?
4. Have improvements in SVR been shown to reduce
the risk for or rates of adverse health outcomes from HCV 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

Full-text articles assessed
articles
A research librarian searched Ovid MEDLINE from for eligibility
excluded
(n = 379)
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
Key question 2b = 13 studies
for inclusion. For the first 3 questions, we included ran- 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- For key questions, see Appendix Figure 1 (available at www.annals.org).
rin, and either telaprevir or boceprevir versus dual therapy; Reproduced from reference 11.
or different doses or durations of dual or triple therapy. * Some studies applied to more than 1 key question. Studies of induc-
tion versus fixed-dose regimens and outcomes related to quality of life
Dose and duration comparisons of dual therapy focused on and histologic changes are not reported here but can be found in the full
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, One investigator abstracted details about the study de-
hepatocellular carcinoma, and need for transplantation. sign, population, setting, interventions, analysis, follow-up,
Sustained virologic response, the primary intermediate out- and results. A second investigator reviewed data for accu-
come, was defined as the absence of detectable HCV RNA racy. Two investigators independently applied predefined
in the serum 6 months after the end of a course of therapy criteria (13–15) to assess study quality as good, fair, or
(4). Harms included withdrawals due to adverse events, poor. Discrepancies were resolved through consensus.
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
and included studies published as conference abstracts only accordance with the AHRQ “Methods Guide for Effective-
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.
previously treated patients. We excluded regimens with an- 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
www.annals.org 15 January 2013 Annals of Internal Medicine Volume 158 • Number 2 115

Review Treatment of HCV Infection
Figure 2. Sustained virologic response, comparisons of dual-therapy regimens.
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 (I 2 = 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 (I 2 = 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 (I 2 = 20.2%; P = 0.281) 0.90 (0.81–0.99) 304/461 285/404
0.25 0.5 1 2
Relative risks ⬎1 favor dual therapy with pegylated interferon alfa-2b over dual therapy with pegylated interferon alfa-2a, 24 wk over 12 to 16 wk, and
lower-dose versus higher-dose pegylated interferon alfa-2b.
DerSimonian–Laird method in a random-effects model report and manuscript. The investigators are solely respon-
(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 (⬍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- Appendix Table 1 (available at www.annals.org) shows the
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 ⫽ 66 to 3070) compared dual therapy
sions and provided project oversight and reviewed the draft with pegylated interferon alfa-2b plus ribavirin versus dual

therapy with pegylated interferon alfa-2a plus ribavirin (6, was present (I2 ⫽ 80%) (Figure 2) (36, 38, 40, 42). The 1
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-
ranged from less than 5% to 20% (23, 29, 31, 32), and the 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 ⫽ 117 ilar (3 trials; pooled RR, 1.2 [CI, 1.1 to 1.3]; I2 ⫽ 47%)
to 1465) (33– 43) compared different durations of dual (36, 38, 40).
therapy, 6 trials (n ⫽ 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 ⫽ 60 to 1831) (35, 49 –51) compared in the likelihood of SVR between 24 and 12 to 16 weeks of
different doses of ribavirin as part of dual therapy for ge- dual therapy (pooled RR, 0.99 [CI, 0.86 to 1.1]; I2 ⫽
notype 2 or 3 infection (Appendix Table 2). One trial was 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-dose pegylated interferon alfa-2b as part of dual
described blinding (23–25, 27–29, 33–39, 42–52), high or
therapy was associated with a lower likelihood of SVR than
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 notype 2 or 3 infection, although the upper limit of the CI
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 ⫽ 20%), on the basis of 6 trials (4 fair-quality and 2
week) pegylated interferon alfa-2b was associated with a poor-quality) (Figure 2) (38, 44 – 48). Excluding the poor-
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 ⫽ 27%) (Figure 2), with a pooled abso- Two fair-quality trials found no clear difference be-
lute difference of 8 percentage points (CI, 3 to 14 percent- tween induction regimens of pegylated interferon alfa-2b
age points), on the basis of 7 trials (5 fair-quality and 2 (higher initial doses followed by lower doses) plus ribavirin
poor-quality) (21, 23–25, 27, 29, 30). Results were similar 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 ⫽ 492), or between 400 mg and
pegylated interferon alfa-2b (26, 28) or when the analysis 800 mg daily, in likelihood of SVR (n ⫽ 282) (35, 49).
excluded poor-quality trials (24, 30). One fair-quality trial (n ⫽ 1831) of pegylated interferon
The largest trial (n ⫽ 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).
Interferon Therapy (IDEAL) study, found no difference in One fair-quality trial (n ⫽ 60) that primarily enrolled
likelihood of SVR for genotype 1 infection between 2 patients with advanced fibrosis or cirrhosis found pegylated
doses of pegylated interferon alfa-2b (1.0 mcg/kg per week interferon alfa-2a plus ribavirin, 600 to 800 mg/d, to be
or 1.5 mcg/kg per week) plus ribavirin, 800 to 1400 mg/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 ⫽ 1097 and 520) compared
to 0.90]; I2 ⫽ 0%) (23–25, 27, 29, 30). triple therapy with boceprevir, pegylated interferon alfa-2b,
and ribavirin versus dual therapy for antiviral treatment–
Duration Effects naive patients with genotype 1 infection (Appendix Table
Two fair-quality trials found no difference between 48 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 ⫽ 43%) (35, 43). Four trials (1 good-quality and 3 (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
limit of the CI nearly crossed 1 and statistical heterogeneity [CI, 1.6 to 2.1]; I2 ⫽ 0%), with a pooled absolute increase

Figure 3. Sustained virologic response, triple therapy with a protease inhibitor versus dual therapy.
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 (I 2 = 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 (I 2 = 0.0%; P = 0.998) 1.48 (1.26–1.75) 196/286 100/220
0.75 1 2 4
The boceprevir regimen consisted of 4 wk of dual-therapy lead-in with pegylated interferon alfa-2b plus ribavirin, followed by the addition of boceprevir
for 44 more wk. The telaprevir regimen consisted of 12 wk of telaprevir, pegylated interferon alfa-2a or -2b, and ribavirin, followed by 12 wk of dual
therapy (pegylated interferon plus ribavirin without telaprevir). Relative risks ⬎1 favor triple therapy.
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 difference between 12 weeks of triple therapy and 48 weeks
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 ⫽ 75) found that triple therapy with One trial (n ⫽ 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,
with triple therapy with standard-dose (800 to 1400 mg/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
Six randomized trials compared triple therapy with te- 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 laprevir dose (750 mg 3 times daily versus 1125 mg 2 times
(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). Another trial of extended rapid virologic respond-
interferon alfa-2a. The prevalence of baseline cirrhosis ers to initial triple therapy with telaprevir reported similar,
ranged from 0% to 11%. One trial (58) was rated as good- 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 ⫽ 189 to 323) found that a 24-week (response-guided or fixed duration) versus 48 weeks of dual
fixed-duration telaprevir regimen was associated with a therapy (20, 57) found no clear differences in RR estimates
higher likelihood of SVR than was 48 weeks of dual ther- based on race, sex, age, baseline fibrosis, and weight. For
apy (pooled RR, 1.5 [CI, 1.3 to 1.8]; I2 ⫽ 0%) (Figure 3), boceprevir, the RR estimate was higher with a baseline

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 ⫽ 0%) than with a Table 4). About 25% of patients receiving triple therapy
lower viral load (pooled RR, 1.3 [CI, 1.0 to 1.5]; I2 ⫽ 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, phil count ⬍500 cells/L). There were no differences in risk
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
difference in RR estimates according to genotype, although RR, 1.3 [CI, 1.1 to 1.5]; I2 ⫽ 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 ⫽ 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
interferon alfa-2b versus alfa-2a found no difference in risk (56 –58) (Appendix Table 4). Triple therapy was also as-
for withdrawal due to adverse events (6 trials; pooled RR, sociated with increased risk for thrombocytopenia in 1 trial
1.1 [CI, 0.73 to 1.7]; I2 ⫽ 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
eliminated statistical heterogeneity, but the pooled estimate rash in 7% to 10%) and about half had anemia (severe
was similar (5 trials; pooled RR, 0.88 [CI, 0.7 to 1.1]; I2 ⫽ 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
feron alfa-2b to be associated with lower risk for serious for withdrawal due to adverse events (RR, 3.8 [CI, 2.6 to
adverse events than was dual therapy with pegylated inter- 5.7]), anemia (RR, 2.0 [CI, 1.6 to 2.5]), rash (RR, 1.5 [CI,
feron alfa-2a (pooled RR, 0.76 [CI, 0.61 to 0.95]; I2 ⫽ 1.2 to 1.8]), and severe rash (5% versus 1%; RR, 4.6 [CI,
0%) (21, 29). There were no differences between dual- 1.6 to 13]) than dual therapy for 48 weeks (20).
therapy regimens in risk for anemia, thrombocytopenia, No trial reported harms in patient subgroups. Three
depression, fatigue, myalgia, or influenza-like symptoms trials of dual therapy with pegylated interferon alfa-2b ver-
(Appendix Table 4, available at www.annals.org). Dual sus alfa-2a for genotype 1 infection reported pooled esti-
therapy with pegylated interferon alfa-2b was associated mates for harms similar to the estimates based on all trials
with higher risk for headache (3 trials; pooled RR, 1.1 [CI, (21, 30, 31).
1.1 to 1.2]; I2 ⫽ 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 ⫽ 0%) Nineteen cohort studies (n ⫽ 105 to 16 864) evalu-
(21, 28) and neutropenia (5 trials; pooled RR, 0.61 [CI, ated the association between an SVR after antiviral therapy
0.46 to 0.83]; I2 ⫽ 38%). In the largest study (the IDEAL and mortality or complications of chronic HCV infection
trial), dual therapy with either pegylated interferon was (Appendix Table 5, available at www.annals.org) (60 –78).
associated with serious adverse events in about 4% of pa- Duration of follow-up ranged from 3 to 9 years. Ten stud-
tients, fatigue in 65%, headache in 45%, nausea in 40%, ies were conducted in Asia (60, 67–72, 75, 77, 78). Eight
myalgia in 25%, neutrophil count less than 500 cells/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 uated 5 key confounders (age, sex, genotype, viral load, 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 ⫽ 0%) (21, 23, 28). The largest study (n ⫽ 16 864) had the fewest meth-
Excluding 2 poor-quality trials had little effect on pooled odologic shortcomings (61). It adjusted for multiple poten-
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, and others. It also stratified results by genotype. In a
neutropenia (pooled RR, 1.8 [CI, 1.5 to 2.3]; I2 ⫽ 0%), predominantly male, Veterans Affairs population, SVR af-
dysgeusia (pooled RR, 2.5 [CI, 2.0 to 3.2]; I2 ⫽ 0%), ter antiviral therapy was associated with lower risk for all-
anemia (pooled RR, 2.0 [CI, 1.4 to 2.8]; I2 ⫽ 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 ⫽ years (adjusted hazard ratio, 0.71 [CI, 0.60 to 0.86], 0.62

[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 ated with shorter duration of treatment, an important con-
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-
justed hazard ratios, 0.07 to 0.39) (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;
than in the Veterans Affairs study. The subgroup of studies black patients; and patients with higher baseline viral load,
that focused on patients with advanced fibrosis or cirrhosis genotype 1 infection, or more advanced fibrosis.
at baseline (62, 63, 65– 68, 74 –76) or that were conducted 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
curves in this study suggests possible residual confounding,
DISCUSSION given the typically protracted course of HCV infection.
Antiviral therapy for chronic HCV infection continues 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-
which to evaluate comparative effectiveness. For treatment- language articles. We did not perform formal analyses for
naive patients, dual therapy with pegylated interferon publication bias because of the small numbers of trials, but
alfa-2b is associated with a lower likelihood of SVR than is 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 with 95% CIs close to 1.0 should be interpreted cautiously
events, suggesting potential tradeoffs between benefits and (82). Estimates and conclusions based on small numbers of
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-
about 1%, and antiviral-related adverse events are generally ticularly when statistical heterogeneity is present. The trials
self-limited. generally met criteria for efficacy studies, which could limit
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 Additional research would help clarify the comparative
limited, although differences were small in most studies. effectiveness of antiviral treatments. Studies are needed to
The relative ineffectiveness of dual therapy for geno- understand the long-term clinical outcomes associated with
type 1 infection has led to ongoing efforts to identify more different antiviral treatments, the long-term harms of tel-
effective treatments. Recent trials found triple therapy with aprevir and boceprevir, the comparative effectiveness of tri-
boceprevir or telaprevir superior to dual therapy, with SVR 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).

From Oregon Health & Science University, Portland, Oregon. 12. Pembrey L, Newell ML, Tovo PA; EPHN Collaborators. The management
of HCV infected pregnant women and their children European paediatric HCV
Disclaimer: The findings and conclusions in this document are those of network. J Hepatol. 2005;43:515-25. [PMID: 16144064]
the authors, who are responsible for its content, and do not necessarily 13. Downs SH, Black N. The feasibility of creating a checklist for the assessment
represent the views of AHRQ. No statement in this report should be of the methodological quality both of randomised and non-randomised studies of
construed as an official position of AHRQ or of the U.S. Department of health care interventions. J Epidemiol Community Health. 1998;52:377-84.
Health and Human Services. [PMID: 9764259]
14. Harris RP, Helfand M, Woolf SH, Lohr KN, Mulrow CD, Teutsch SM,
Acknowledgment: The authors thank Robin Paynter, MLIS; Rose et al; Methods Work Group, Third US Preventive Services Task Force. Current
methods of the US Preventive Services Task Force: a review of the process.
Campbell, MLIS; AHRQ Task Order Officer Christine Chang, MD,
Am J Prev Med. 2001;20:21-35. [PMID: 11306229]
MPH; and USPSTF Medical Officer Iris Mabry-Hernandez, MD,
15. Whiting PF, Rutjes AW, Westwood ME, Mallett S, Deeks JJ, Reitsma JB,
MPH. They also thank Tracy Dana, MLS; Christina Bougatsos, MPH; et al; QUADAS-2 Group. QUADAS-2: a revised tool for the quality assessment
and Ian Blazina, MPH, from Oregon Health & Science University, who of diagnostic accuracy studies. Ann Intern Med. 2011;155:529-36. [PMID:
assisted in data extraction and quality checking. 22007046]
16. Agency for Healthcare Research and Quality. Methods guide for effective-
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 June 2012.
.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum 17. Fu R, Gartlehner G, Grant M, Shamliyan T, Sedrakyan A, Wilt TJ, et al.
⫽M12-1658. Conducting quantitative synthesis when comparing medical interventions:
AHRQ and the Effective Health Care Program. J Clin Epidemiol. 2011;64:
1187-97. [PMID: 21477993]
Requests for Single Reprints: Roger Chou, MD, 3181 SW Sam Jack- 18. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis.
son Park Road, Mail Code BICC, Portland, OR 97239; e-mail, chour Stat Med. 2002;21:1539-58. [PMID: 12111919]
@ohsu.edu. 19. Sterne JA, Sutton AJ, Ioannidis JP, Terrin N, Jones DR, Lau J, et al.
Recommendations for examining and interpreting funnel plot asymmetry in
Current author addresses and author contributions are available at www meta-analyses of randomised controlled trials. BMJ. 2011;343:d4002. [PMID:
.annals.org. 21784880]
20. Jacobson IM, McHutchison JG, Dusheiko G, Di Bisceglie AM, Reddy KR,
Bzowej NH, et al; ADVANCE Study Team. Telaprevir for previously untreated
chronic hepatitis C virus infection. N Engl J Med. 2011;364:2405-16. [PMID:
References 21696307]
1. Kim WR. The burden of hepatitis C in the United States. Hepatology. 2002; 21. McHutchison JG, Lawitz EJ, Shiffman ML, Muir AJ, Galler GW, McCone
36:S30-4. [PMID: 12407574] J, et al; IDEAL Study Team. Peginterferon alfa-2b or alfa-2a with ribavirin for
2. Ly KN, Xing J, Klevens RM, Jiles RB, Ward JW, Holmberg SD. The treatment of hepatitis C infection. N Engl J Med. 2009;361:580-93. [PMID:
increasing burden of mortality from viral hepatitis in the United States between 19625712]
1999 and 2007. Ann Intern Med. 2012;156:271-8. [PMID: 22351712] 22. Poordad F, McCone J Jr, Bacon BR, Bruno S, Manns MP, Sulkowski MS,
3. National Institutes of Health. National Institutes of Health Consensus De- et al; SPRINT-2 Investigators. Boceprevir for untreated chronic HCV genotype
velopment Conference Statement: Management of hepatitis C: 2002—June 10- 1 infection. N Engl J Med. 2011;364:1195-206. [PMID: 21449783]
12, 2002. Hepatology. 2002;36:S3-20. [PMID: 12407572] 23. Ascione A, De Luca M, Tartaglione MT, Lampasi F, Di Costanzo GG,
4. Ghany MG, Strader DB, Thomas DL, Seeff LB; American Association for Lanza AG, et al. Peginterferon alfa-2a plus ribavirin is more effective than pegin-
the Study of Liver Diseases. Diagnosis, management, and treatment of hepatitis terferon alfa-2b plus ribavirin for treating chronic hepatitis C virus infection.
C: an update. Hepatology. 2009;49:1335-74. [PMID: 19330875] Gastroenterology. 2010;138:116-22. [PMID: 19852964]
5. Strader DB, Wright T, Thomas DL, Seeff LB; American Association for the
24. Escudero A, Rodrı́guez F, Serra MA, Del Olmo JA, Montes F, Rodrigo JM.
Study of Liver Diseases. Diagnosis, management, and treatment of hepatitis C.
Pegylated alpha-interferon-2a plus ribavirin compared with pegylated alpha-
Hepatology. 2004;39:1147-71. [PMID: 15057920]
interferon-2b plus ribavirin for initial treatment of chronic hepatitis C virus:
6. Magni C, Niero F, Argenteri B, Giorgi R, Mainini A, Pastecchia C, et al.
prospective, non-randomized study. J Gastroenterol Hepatol. 2008;23:861-6.
Antiviral activity and tolerability between pegylated interferon alpha 2a and alpha
[PMID: 18422960]
2b in naive patients with chronic hepatitis C: results of a prospective monocentric
25. Kamal SM, Ahmed A, Mahmoud S, Nabegh L, El Gohary I, Obadan I,
randomized trial [Abstract]. Hepatology. 2009;50:720A.
7. Foster GR. Review article: pegylated interferons: chemical and clinical differ- et al. Enhanced efficacy of pegylated interferon alpha-2a over pegylated interferon
ences. Aliment Pharmacol Ther. 2004;20:825-30. [PMID: 15479353] and ribavirin in chronic hepatitis C genotype 4A randomized trial and quality of
8. Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Gonçales FL Jr, life analysis. Liver Int. 2011;31:401-11. [PMID: 21281434]
et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. 26. Khan A, Awan A, Shahbuddin S, Iqbal Q. Peginterferon alfa 2a/ribavirin
N Engl J Med. 2002;347:975-82. [PMID: 12324553] versus peginterferon alfa 2b/ribavirin combination therapy in chronic hepatitis C
9. U.S. Food and Drug Administration. Approval of Victrelis (boceprevir) a genotype 3 [Abstract]. Gastroenterology. 2007;132:A200.
direct acting antiviral drug (DAA) to treat hepatitis C virus (HCV). 2011. Ac- 27. Mach TH, Cieśla A, Warunek W, Janas-Skulina U, Cibor D, Owczarek D,
cessed at www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/ucm et al. Efficacy of pegylated interferon alfa-2a or alfa-2b in combination with
255413.htm on 12 September 2012. ribavirin in the treatment of chronic hepatitis caused by hepatitis C virus geno-
10. U.S. Food and Drug Administration. Approval of Incivek (telaprevir), a type 1b. Pol Arch Med Wewn. 2011;121:434-9. [PMID: 22157768]
direct acting antiviral drug (DAA) to treat hepatitis C (HCV). 2011.Accessed at 28. Miyase S, Haraoka K, Ouchida Y, Morishita Y, Fujiyama S. Randomized
www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/ucm256328.htm trial of peginterferon ␣-2a plus ribavirin versus peginterferon ␣-2b plus ribavirin
on 12 September 2012. for chronic hepatitis C in Japanese patients. J Gastroenterol. 2012;47:1014-21.
11. Chou R, Hartung D, Rahman B, Cottrell EB, Wasson N, Fu R. Compar- [PMID: 22382633]]
ative Effectiveness of Antiviral Treatment for Hepatitis C Virus Infection 29. Rumi MG, Aghemo A, Prati GM, D’Ambrosio R, Donato MF, Soffredini
in Adults. A Systematic Review. (Prepared by Oregon Evidence-based Practice R, et al. Randomized study of peginterferon-alpha2a plus ribavirin vs
Center under contract no. 290-2007-10057-I.) 2012. Accessed at www.effective peginterferon-alpha2b plus ribavirin in chronic hepatitis C. Gastroenterology.
healthcare.ahrq.gov on 28 November 2012. 2010;138:108-15. [PMID: 19766645]

30. Yenice N, Mehtap O, Gümrah M, Arican N. The efficacy of pegylated PEG-interferon alpha-2b doses (1.0 or 1.5 microg/kg) combined with ribavirin in
interferon alpha 2a or 2b plus ribavirin in chronic hepatitis C patients. Turk interferon-naı̈ve patients with chronic hepatitis C and up to moderate fibrosis.
J Gastroenterol. 2006;17:94-8. [PMID: 16830289] J Viral Hepat. 2006;13:457-65. [PMID: 16792539]
31. Marcellin P, Forns X, Goeser T, Ferenci P, Nevens F, Carosi G, et al. 48. Sood A, Midha V, Hissar S, Kumar M, Suneetha PV, Bansal M, et al.
Telaprevir is effective given every 8 or 12 hours with ribavirin and peginterferon Comparison of low-dose pegylated interferon versus standard high-dose pegylated
alfa-2a or -2b to patients with chronic hepatitis C. Gastroenterology. 2011;140: interferon in combination with ribavirin in patients with chronic hepatitis C with
459-468.e1; quiz e14. [PMID: 21034744] genotype 3: an Indian experience. J Gastroenterol Hepatol. 2008;23:203-7.
32. McHutchison J, Sulkowski M. Scientific rationale and study design of the [PMID: 17645472]
individualized dosing efficacy vs flat dosing to assess optimal pegylated interferon 49. Ferenci P, Brunner H, Laferl H, Scherzer TM, Maieron A, Strasser M,
therapy (IDEAL) trial: determining optimal dosing in patients with genotype 1 et al; Austrian Hepatitis Study Group. A randomized, prospective trial of riba-
chronic hepatitis C. J Viral Hepat. 2008;15:475-81. [PMID: 18363672] virin 400 mg/day versus 800 mg/day in combination with peginterferon alfa-2a
33. Andriulli A, Cursaro C, Cozzolongo R, Iacobellis A, Valvano MR, Mangia in hepatitis C virus genotypes 2 and 3. Hepatology. 2008;47:1816-23. [PMID:
A, et al. Early discontinuation of ribavirin in HCV-2 and HCV-3 patients re- 18454510]
sponding to Peg-interferon alpha-2a and ribavirin. J Viral Hepat. 2009;16:28-35. 50. Helbling B, Jochum W, Stamenic I, Knöpfli M, Cerny A, Borovicka J, et al;
[PMID: 18761603] Swiss Association for the Study of the Liver (SASL). HCV-related advanced
34. Dalgard O, Bjøro K, Ring-Larsen H, Bjornsson E, Holberg-Petersen M, fibrosis/cirrhosis: randomized controlled trial of pegylated interferon alpha-2a and
Skovlund E, et al; North-C Group. Pegylated interferon alfa and ribavirin for 14 ribavirin. J Viral Hepat. 2006;13:762-9. [PMID: 17052276]
versus 24 weeks in patients with hepatitis C virus genotype 2 or 3 and rapid 51. Jacobson IM, Brown RS Jr, Freilich B, Afdhal N, Kwo PY, Santoro J, et al;
virological response. Hepatology. 2008;47:35-42. [PMID: 17975791] WIN-R Study Group. Peginterferon alfa-2b and weight-based or flat-dose riba-
35. Hadziyannis SJ, Sette H Jr, Morgan TR, Balan V, Diago M, Marcellin P, virin in chronic hepatitis C patients: a randomized trial. Hepatology. 2007;46:
et al; PEGASYS International Study Group. Peginterferon-alpha2a and ribavirin 971-81. [PMID: 17894303]
combination therapy in chronic hepatitis C: a randomized study of treatment 52. Lam KD, Trinh HN, Do ST, Nguyen TT, Garcia RT, Nguyen T, et al.
duration and ribavirin dose. Ann Intern Med. 2004;140:346-55. [PMID: Randomized controlled trial of pegylated interferon-alfa 2a and ribavirin in
14996676] treatment-naive chronic hepatitis C genotype 6. Hepatology. 2010;52:1573-80.
36. Lagging M, Langeland N, Pedersen C, Färkkilä M, Buhl MR, Mørch K, [PMID: 21038410]
et al; NORDynamIC Study Group. Randomized comparison of 12 or 24 weeks 53. Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Re-
of peginterferon alpha-2a and ribavirin in chronic hepatitis C virus genotype 2/3 indollar R, et al. Peginterferon alfa-2b plus ribavirin compared with interferon
infection. Hepatology. 2008;47:1837-45. [PMID: 18454508] alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised
37. Mangia A, Santoro R, Minerva N, Ricci GL, Carretta V, Persico M, et al. trial. Lancet. 2001;358:958-65. [PMID: 11583749]
Peginterferon alfa-2b and ribavirin for 12 vs. 24 weeks in HCV genotype 2 or 3. 54. Mimidis K, Papadopoulos VP, Elefsiniotis I, Koliouskas D, Ketikoglou I,
N Engl J Med. 2005;352:2609-17. [PMID: 15972867] Paraskevas E, et al. Hepatitis C virus survival curve analysis in naı̈ve patients
38. Manns M, Zeuzem S, Sood A, Lurie Y, Cornberg M, Klinker H, et al. treated with peginterferon alpha-2b plus ribavirin. A randomized controlled trial
Reduced dose and duration of peginterferon alfa-2b and weight-based ribavirin in for induction with high doses of peginterferon and predictability of sustained viral
patients with genotype 2 and 3 chronic hepatitis C. J Hepatol. 2011;55:554-63. response from early virologic data. J Gastrointestin Liver Dis. 2006;15:213-9.
[PMID: 21237227] [PMID: 17013444]
39. Mecenate F, Pellicelli AM, Barbaro G, Romano M, Barlattani A, Mazzoni 55. Kwo PY, Lawitz EJ, McCone J, Schiff ER, Vierling JM, Pound D, et al;
E, et al; Club Epatologi Ospedalieri (CLEO) Group. Short versus standard SPRINT-1 investigators. Efficacy of boceprevir, an NS3 protease inhibitor, in
treatment with pegylated interferon alfa-2A plus ribavirin in patients with hepa- combination with peginterferon alfa-2b and ribavirin in treatment-naive patients
titis C virus genotype 2 or 3: the cleo trial. BMC Gastroenterol. 2010;10:21. with genotype 1 hepatitis C infection (SPRINT-1): an open-label, randomised,
[PMID: 20170514] multicentre phase 2 trial. Lancet. 2010;376:705-16. [PMID: 20692693]
40. Shiffman ML, Suter F, Bacon BR, Nelson D, Harley H, Solá R, et al; 56. Hézode C, Forestier N, Dusheiko G, Ferenci P, Pol S, Goeser T, et al;
ACCELERATE Investigators. Peginterferon alfa-2a and ribavirin for 16 or 24 PROVE2 Study Team. Telaprevir and peginterferon with or without ribavirin
weeks in HCV genotype 2 or 3. N Engl J Med. 2007;357:124-34. [PMID: for chronic HCV infection. N Engl J Med. 2009;360:1839-50. [PMID:
17625124] 19403903]
41. von Wagner M, Huber M, Berg T, Hinrichsen H, Rasenack J, Heintges T, 57. Kumada H, Toyota J, Okanoue T, Chayama K, Tsubouchi H, Hayashi N.
et al. Peginterferon-alpha-2a (40KD) and ribavirin for 16 or 24 weeks in patients Telaprevir with peginterferon and ribavirin for treatment-naive patients chroni-
with genotype 2 or 3 chronic hepatitis C. Gastroenterology. 2005;129:522-7. cally infected with HCV of genotype 1 in Japan. J Hepatol. 2012;56:78-84.
[PMID: 16083709] [PMID: 21827730]
42. Yu ML, Dai CY, Huang JF, Hou NJ, Lee LP, Hsieh MY, et al. A ran- 58. McHutchison JG, Everson GT, Gordon SC, Jacobson IM, Sulkowski M,
domised study of peginterferon and ribavirin for 16 versus 24 weeks in patients Kauffman R, et al; PROVE1 Study Team. Telaprevir with peginterferon and
with genotype 2 chronic hepatitis C. Gut. 2007;56:553-9. [PMID: 16956917] ribavirin for chronic HCV genotype 1 infection. N Engl J Med. 2009;360:1827-
43. Zeuzem S, Diago M, Gane E, Reddy KR, Pockros P, Prati D, et al; 38. [PMID: 19403902]
PEGASYS Study NR16071 Investigator Group. Peginterferon alfa-2a (40 kilo- 59. Sherman KE, Flamm SL, Afdhal NH, Nelson DR, Sulkowski MS, Everson
daltons) and ribavirin in patients with chronic hepatitis C and normal amino- GT, et al; ILLUMINATE Study Team. Response-guided telaprevir combina-
transferase levels. Gastroenterology. 2004;127:1724-32. [PMID: 15578510] tion treatment for hepatitis C virus infection. N Engl J Med. 2011;365:1014-24.
44. Abergel A, Hezode C, Leroy V, Barange K, Bronowicki JP, Tran A, et al; [PMID: 21916639]
French multicenter study group. Peginterferon alpha-2b plus ribavirin for treat- 60. Arase Y, Ikeda K, Suzuki F, Suzuki Y, Saitoh S, Kobayashi M, et al.
ment of chronic hepatitis C with severe fibrosis: a multicentre randomized con- Long-term outcome after interferon therapy in elderly patients with chronic hep-
trolled trial comparing two doses of peginterferon alpha-2b. J Viral Hepat. 2006; atitis C. Intervirology. 2007;50:16-23. [PMID: 17164553]
13:811-20. [PMID: 17109680] 61. Backus LI, Boothroyd DB, Phillips BR, Belperio P, Halloran J, Mole LA.
45. Kawaoka T, Kawakami Y, Tsuji K, Ito H, Kitamoto M, Aimitsu S, et al. A sustained virologic response reduces risk of all-cause mortality in patients
Dose comparison study of pegylated interferon-alpha-2b plus ribavirin in naı̈ve with hepatitis C. Clin Gastroenterol Hepatol. 2011;9:509-516.e1. [PMID:
Japanese patients with hepatitis C virus genotype 2: a randomized clinical trial. 21397729]
J Gastroenterol Hepatol. 2009;24:366-71. [PMID: 19032459] 62. Bruno S, Stroffolini T, Colombo M, Bollani S, Benvegnù L, Mazzella G,
46. Krawitt EL, Gordon SR, Grace ND, Ashikaga T, Ray MA, Palmer M, et al; et al; Italian Association of the Study of the Liver Disease (AISF). Sustained
for the New York New England Study Team. A study of low dose peginterferon virological response to interferon-alpha is associated with improved outcome
alpha-2b with ribavirin for the initial treatment of chronic hepatitis C. Am J Gas- in HCV-related cirrhosis: a retrospective study. Hepatology. 2007;45:579-87.
troenterol. 2006;101:1268-73. [PMID: 16771948] [PMID: 17326216]
47. Meyer-Wyss B, Rich P, Egger H, Helbling B, Müllhaupt B, Rammert C, 63. Cardoso AC, Moucari R, Figueiredo-Mendes C, Ripault MP, Giuily N,
et al; Swiss Association for the Study of the Liver (SASL). Comparison of two Castelnau C, et al. Impact of peginterferon and ribavirin therapy on hepatocel-

lular carcinoma: incidence and survival in hepatitis C patients with advanced 74. Morgan TR, Ghany MG, Kim HY, Snow KK, Shiffman ML, De Santo JL,
fibrosis. J Hepatol. 2010;52:652-7. [PMID: 20346533] et al; HALT-C Trial Group. Outcome of sustained virological responders with
64. Coverdale SA, Khan MH, Byth K, Lin R, Weltman M, George J, et al. histologically advanced chronic hepatitis C. Hepatology. 2010;52:833-44.
Effects of interferon treatment response on liver complications of chronic hepa- [PMID: 20564351]
titis C: 9-year follow-up study. Am J Gastroenterol. 2004;99:636-44. [PMID: 75. Shiratori Y, Ito Y, Yokosuka O, Imazeki F, Nakata R, Tanaka N, et al;
15089895] Tokyo-Chiba Hepatitis Research Group. Antiviral therapy for cirrhotic hepatitis
65. Braks RE, Ganne-Carrie N, Fontaine H, Paries J, Grando-Lemaire V, C: association with reduced hepatocellular carcinoma development and improved
Beaugrand M, et al. Effect of sustained virological response on long-term clinical survival. Ann Intern Med. 2005;142:105-14. [PMID: 15657158]
outcome in 113 patients with compensated hepatitis C-related cirrhosis treated by 76. Veldt BJ, Heathcote EJ, Wedemeyer H, Reichen J, Hofmann WP, Zeuzem
interferon alpha and ribavirin. World J Gastroenterol. 2007;13:5648-53. [PMID: S, et al. Sustained virologic response and clinical outcomes in patients with
17948941] chronic hepatitis C and advanced fibrosis. Ann Intern Med. 2007;147:677-84.
66. Fernández-Rodrı́guez CM, Alonso S, Martinez SM, Forns X, Sanchez- [PMID: 18025443]
Tapias JM, Rincón D, et al; Group for the Assessment of Prevention of Cir- 77. Yoshida H, Arakawa Y, Sata M, Nishiguchi S, Yano M, Fujiyama S, et al.
rhosis Complications and Virological Response (APREVIR). Peginterferon plus Interferon therapy prolonged life expectancy among chronic hepatitis C patients.
ribavirin and sustained virological response in HCV-related cirrhosis: outcomes Gastroenterology. 2002;123:483-91. [PMID: 12145802]
and factors predicting response. Am J Gastroenterol. 2010;105:2164-72. [PMID: 78. Yu ML, Lin SM, Chuang WL, Dai CY, Wang JH, Lu SN, et al. A sustained
20700116] virological response to interferon or interferon/ribavirin reduces hepatocellular
67. Hasegawa E, Kobayashi M, Kawamura Y, Yatsuji H, Sezaki H, Hosaka T, carcinoma and improves survival in chronic hepatitis C: a nationwide, multicen-
et al. Efficacy and anticarcinogenic activity of interferon for hepatitis C virus-
tre study in Taiwan. Antivir Ther. 2006;11:985-94. [PMID: 17302368]
related compensated cirrhosis in patients with genotype 1b low viral load or
79. PEGASYS [package insert]. Nutley, NJ: Hoffmann-La Roche; 2002.
genotype 2. Hepatol Res. 2007;37:793-800. [PMID: 17593231]
80. PEG-Intron [package insert]. Kenilworth, NJ: Schering; 2005.
68. Hung CH, Lee CM, Lu SN, Wang JH, Hu TH, Tung HD, et al. Long-
81. Chou R, Cottrell EB, Wasson N, Rahman B, Guise JM. Screening for
term effect of interferon alpha-2b plus ribavirin therapy on incidence of hepato-
Hepatitis C Virus Infection in Adults: A Comparative Effectiveness Review (Pre-
cellular carcinoma in patients with hepatitis C virus-related cirrhosis. J Viral
pared by Oregon Evidence-based Practice Center under contract no. 290-2007-
Hepat. 2006;13:409-14. [PMID: 16842444]
10057-I.) 2012. Accessed at www.effectivehealthcare.ahrq.gov on 28 November
69. Imazeki F, Yokosuka O, Fukai K, Saisho H. Favorable prognosis of chronic
hepatitis C after interferon therapy by long-term cohort study. Hepatology. 2003; 2012.
38:493-502. [PMID: 12883494] 82. Brockwell SE, Gordon IR. A comparison of statistical methods for meta-
70. Innes HA, Hutchinson SJ, Allen S, Bhattacharyya D, Bramley P, Dela- analysis. Stat Med. 2001;20:825-40. [PMID: 11252006]
hooke TE, et al; Hepatitis C Clinical Database Monitoring Committee. Excess 83. Bhandari M, Busse JW, Jackowski D, Montori VM, Schünemann H,
liver-related morbidity of chronic hepatitis C patients, who achieve a sustained Sprague S, et al. Association between industry funding and statistically significant
viral response, and are discharged from care. Hepatology. 2011;54:1547-58. pro-industry findings in medical and surgical randomized trials. CMAJ. 2004;
[PMID: 22045672] 170:477-80. [PMID: 14970094]
71. Izumi N, Yasuhiro A, Kurosaki M, Onuki Y, Nishimura Y, Inoue K, et al. 84. Lexchin J, Bero LA, Djulbegovic B, Clark O. Pharmaceutical industry spon-
Development of hepatocellular carcinoma after interferon therapy in chronic hep- sorship and research outcome and quality: systematic review. BMJ. 2003;326:
atitis C. Is it possible to reduce the incidence by ribanirin and IFN combination 1167-70. [PMID: 12775614]
therapy? Intervirology. 2005;48:59-63. [PMID: 15785091] 85. Sun XPC, Williams C, Senger CA, Kapka TJ, Whitlock EP. Interventions
72. Kasahara A, Tanaka H, Okanoue T, Imai Y, Tsubouchi H, Yoshioka K, to Improve Patient Adherence to Hepatitis C Treatment: A Comparative Effec-
et al. Interferon treatment improves survival in chronic hepatitis C patients show- tiveness Review. Comparative Effectiveness Review. (Prepared by the Oregon
ing biochemical as well as virological responses by preventing liver-related death. Evidence-based Practice Center under contract no. HHS-290-2007-10057-I.)
J Viral Hepat. 2004;11:148-56. [PMID: 14996350] 2012. Accessed at www.effectivehealthcare.ahrq.gov.
73. Maruoka D, Imazeki F, Arai M, Kanda T, Fujiwara K, Yokosuka O. 86. Lok AS, Gardiner DF, Lawitz E, Martorell C, Everson GT, Ghalib R, et al.
Long-term cohort study of chronic hepatitis C according to interferon efficacy. Preliminary study of two antiviral agents for hepatitis C genotype 1. N Engl
J Gastroenterol Hepatol. 2012;27:291-9. [PMID: 21793911] J Med. 2012;366:216-24. [PMID: 22256805]

Annals of Internal Medicine
Current Author Addresses: Drs. Chou, Hartung, Rahman, Wasson, Critical revision of the article for important intellectual content:
Cottrell, and Fu: 3181 SW Sam Jackson Park Road, Mail Code BICC, R. Chou, D. Hartung, N. Wasson, R. Fu.
Portland, OR 97239. Final approval of the article: R. Chou, D. Hartung, R. Fu.
Statistical expertise: R. Chou, D. Hartung, R. Fu.
Author Contributions: Conception and design: R. Chou, D. Hartung. Obtaining of funding: R. Chou.
Analysis and interpretation of the data: R. Chou, D. Hartung, N. Was- Administrative, technical, or logistic support: B. Rahman, N. Wasson.
son, E.B. Cottrell, R. Fu. Collection and assembly of data: R. Chou, D. Hartung, B. Rahman,
Drafting of the article: R. Chou, D. Hartung. N. Wasson.
Appendix Figure 1. Analytic framework for treatment of HCV in adults.
KQ 1
Final Clinical
Outcomes*
Intermediate
Antiviral Outcomes*
Treatment
Patients with Mortality
chronic KQ 2 Sustained KQ 4
Morbidity
HCV virologic
Transmission
infection response
of HCV
KQ 3
Harms
Key Questions:
1a. What is the comparative effectiveness of antiviral treatment in improving health outcomes in patients
with HCV infection?
1b. How does the comparative effectiveness of antiviral treatment for health outcomes vary according to
patient subgroup characteristics?†
2a. What is the comparative effectiveness of antiviral treatments on intermediate outcomes on the rate of
SVR?
2b. How does the comparative effectiveness of antiviral treatment for intermediate outcomes vary according
to patient subgroup characteristics?†
3a. What are the comparative harms associated with antiviral treatments?
3b. Do these harms differ according to patient subgroup characteristics?†
4. Have improvements in SVR been shown to reduce the risk or rates of adverse health outcomes from HCV
infection?
This analytic framework outlines the population, interventions, and outcomes considered in the review. It is a modified version of a larger framework
depicting the effect of both screening for and treatment of hepatitis C in adults. This figure focuses on the treatment portion of the framework. The
population includes adults with chronic HCV infection. The interventions include pegylated interferon alfa-2a with ribavirin or pegylated interferon
alfa-2b with ribavirin, with or without the protease inhibitors telaprevir or boceprevir. Intermediate outcomes include liver function, sustained virologic
remission, and histologic changes. Final outcomes include morbidity and mortality from HCV (including hepatic cirrhosis, hepatocellular carcinoma,
liver transplantation rates, and quality of life) and harms of antiviral therapies (including influenza-like symptoms, hematologic effects, and psychiatric
effects). HCV ⫽ hepatitis C virus; KQ ⫽ key question.
* Including but not limited to HCV genotype, age, race, sex, stage of disease, or genetic markers.
W-72 15 January 2013 Annals of Internal Medicine Volume 158 • Number 2 www.annals.org

Appendix Table 1. Summary of Evidence on Comparative Effectiveness of Treatment for Hepatitis C
www.annals.org
Therapy Strength of Evidence Studies Identified, n Overall Consistency Directness Precision Summary of Findings
of Findings* Participants, n Quality (High, Moderate, (Direct or (High,
Low) Indirect) Moderate,
Low)
Comparative effectiveness of antiviral
treatments for SVR
Dual therapy with pegylated interferon ␣-2a Moderate 7 randomized trials Fair High Direct High Dual therapy with standard-dose pegylated interferon ␣-2b
plus ribavirin vs. pegylated interferon ␣-2b 4660 associated with lower likelihood of achieving SVR than
plus ribavirin standard-dose pegylated interferon ␣-2a (pooled RR, 0.87
[95% CI, 0.80–0.95]; I2 ⫽ 27%), with an absolute difference
of 8 percentage points (95% CI, 3–14 percentage points)

Duration effects, dual therapy with pegylated
interferon plus ribavirin (genotype 2 or 3)
SVR: 48 vs. 24 wk Moderate 2 randomized trials Fair High Direct Moderate No difference in likelihood of achieving SVR (pooled RR, 0.97
609 [95% CI, 0.84–1.1]; I2 ⫽ 43%)
SVR: 24 vs. 12–16 wk Moderate 4 randomized trials Fair High Direct Moderate 24 wk of dual therapy more effective than 12–16 wk for
2599 achieving SVR (pooled RR, 1.2 [95% CI, 1.0–1.3; I2 ⫽
80%); RR estimates ranged from 1.0 to 1.3
SVR: 24 vs. 12–16 wk in patients with rapid Moderate 3 randomized trials Fair High Direct Moderate No difference between 24 vs. 12–16 wk of dual therapy
virologic response 583 (pooled RR, 0.99 [95% CI, 0.86–1.1]; I2 ⫽ 66%); RR
estimates ranged from 0.89 to 1.1
Dose effects, dual therapy with pegylated

interferon plus ribavirin (genotype 2 or 3)
SVR: Lower- vs. higher-dose pegylated Moderate 6 randomized trials Fair High Direct Moderate Lower doses of pegylated interferon ␣-2b associated with
interferon 865 lower likelihood of achieving SVR than higher doses
(pooled RR, 0.90 [95% CI, 0.81–0.99]; I2 ⫽ 20%)
SVR: Lower- vs. higher-dose ribavirin Moderate 3 randomized trials Fair Moderate Direct Moderate No clear difference in likelihood of SVR between lower versus
2605 higher doses of ribavirin
SVR: Lower- vs. higher-dose ribavirin, Low 1 randomized trial Fair Unknown Direct Low 600–800 mg of ribavirin daily associated with lower likelihood
patients with advanced fibrosis or cirrhosis 60 (1 study) of SVR than 1000–1200 mg daily (45% vs. 72%; RR, 0.62
[95% CI, 0.40–0.98])
Triple therapy with boceprevir for genotype 1

infection
SVR: Triple therapy with boceprevir vs. dual Moderate 2 randomized trials Fair High Direct Moderate Triple therapy with boceprevir for 48 wk associated with
therapy 1608 higher likelihood of SVR than dual therapy for 48 wk
(pooled RR, 1.8 [95% CI, 1.6–2.1]; I2 ⫽ 0%), with an
absolute increase in SVR rate of 31 percentage points
(95% CI, 23–39 percentage points)
Triple therapy with telaprevir for genotype 1

infection
SVR: 24 wk of fixed-duration triple therapy Moderate 3 randomized trials Fair High Direct Moderate Triple therapy with telaprevir for 24 wk associated with
with telaprevir vs. 48 wk of dual therapy 506 higher likelihood of SVR than dual therapy for 48 wk
(pooled RR, 1.5 [95% CI, 1.3–1.8]; I2 ⫽ 0%), with an
absolute increase in SVR rate of 22 (95% CI, 13–31)
percentage points
SVR: response-guided triple therapy with Low 1 randomized trial Fair Unknown Direct Low Response-guided triple therapy with telaprevir associated with
telaprevir vs. dual therapy 1088 (1 study) higher likelihood of SVR than dual therapy for 48 wk (RR,
1.6 [95% CI, 1.4–1.9]), with an absolute increase in SVR
rate ranging from 25 to 31 percentage points
Continued on following page
15 January 2013 Annals of Internal Medicine Volume 158 • Number 2 W-73

Appendix Table 1—Continued
Therapy Strength of Evidence Studies Identified, n Overall Consistency Directness Precision Summary of Findings
of Findings* Participants, n Quality (High, Moderate, (Direct or (High,
Low) Indirect) Moderate,
Low)
Effectiveness in patient subgroups
SVR: Effects of race, sex, age, baseline Low to moderate† 9 randomized trials Fair High (low for viral Direct Moderate Across regimens, absolute SVR rates were lower in older
fibrosis stage, or baseline viral load 7116 load and to high patients, black patients, patients with more advanced
telaprevir) fibrosis, and patients with higher viral load

Harms of antiviral treatments
Dual therapy with pegylated interferon ␣-2b Moderate 5 randomized trials, Fair High Direct Moderate Dual therapy with pegylated interferon ␣-2b was associated
plus ribavirin vs. pegylated interferon ␣-2a depending on with slightly higher risk for headache (3 trials; pooled RR,
plus ribavirin specific harm 1.1 [95% CI, 1.1–1.2]; I2 ⫽ 0%), and lower risk for
4047 serious adverse events (2 trials; pooled RR, 0.74 [95% CI,
0.57–0.95]; I2 ⫽ 0%), neutropenia (5 trials; pooled RR,
0.61 [95% CI, 0.46–0.83]), rash (2 trials; pooled RR, 0.79
[95% CI, 0.71–0.88]; I2 ⫽ 0%) than dual therapy with
pegylated interferon ␣-2a
W-74 15 January 2013 Annals of Internal Medicine Volume 158 • Number 2

Triple therapy with boceprevir for 48 wk Moderate 2 randomized trials Fair High Direct Moderate Triple therapy with boceprevir for 48 wk was associated with
(4-wk lead-in plus 44 wk dual therapy) vs. 3501 higher risk for neutropenia (2 trials; pooled RR, 1.8 [95%
dual therapy for 48 wk CI, 1.5– 2.3]; I2 ⫽ 0%), dysgeusia (2 trials; pooled RR, 2.5
[95% CI, 2.0–3.2]; I2 ⫽ 0%), anemia (2 trials; pooled RR,
2.0 [95% CI, 1.4–2.8]; I2 ⫽ 0%), and thrombocytopenia
(2 trials; pooled RR, 3.2 [95% CI, 1.2–8.2]) than dual
therapy for 48 wk
24 wk of fixed duration triple therapy with Moderate 3 randomized trials Fair High Direct Moderate Triple therapy with telaprevir for 24 wk was associated with
telaprevir vs. 48 wk of dual therapy 3591 increased risk for anemia (3 trials; pooled RR, 1.3 [95 CI,
1.1–1.5]; I2 ⫽ 0%) and rash (3 trials; pooled RR, 1.4 [95%
CI, 1.1–1.7]) versus dual therapy for 48 wk
Response-guided triple therapy with Low 1 randomized trial Fair Unknown Direct Low Response-guided triple therapy with telaprevir was associated
telaprevir vs. dual therapy 189 (1 study) with increased risk for withdrawal due to adverse events
(RR, 3.8 [95% CI, 2.6–5.7]), anemia (RR, 2.0 [95% CI,
1.6–2.5]), any rash (RR, 1.5 [95% CI, 1.2–1.8]), and severe
rash (RR, 4.6 [95% CI, 1.6–13]) vs. dual therapy for 48 wk
Association between SVR and clinical

outcomes
Mortality and long-term hepatic Moderate 19 cohort studies Fair High Direct High One large study that controlled well for potential
complications 27 992 confounders found SVR after antiviral therapy associated
with lower risk for all-cause mortality vs. no SVR (adjusted
HR, 0.71 [95% CI, 0.60–0.86], 0.62 [95% CI, 0.44–0.87],
and 0.51 [95% CI, 0.35–0.75] for genotypes 1, 2, and 3,
respectively); 18 other cohort studies found SVR associated
with decreased mortality and liver complications than no
SVR but did not control as well for confounders
HR ⫽ hazard ratio; RR ⫽ relative risk; SVR ⫽ sustained virologic response.

* Outcomes related to quality of life and histologic changes are not reported in this publication but can be found in the full report (11).
† Details about strength of evidence for subgroup effects for specific drug comparisons are available in the full report (11).
www.annals.org
Appendix Table 2. Trials Comparing Dual-Therapy Regimens
www.annals.org
Study, Year; Country (Reference) Quality Sample Cirrhosis at Baseline, Elevated Genotype Weekly Pegylated Daily Ribavirin Dose, mg Duration, wk Sustained
Sizes, n % Aminotransferase Mix, % Interferon Dose Virologic
Levels at Response
Baseline, % Rate, %
Pegylated interferon ␣-2a plus ribavirin versus

pegylated interferon ␣-2b plus ribavirin
Ascione et al, 2010; Italy (23) Fair A: 160 A: 21 100 ⬃60 genotype A: ␣-2a, 180 mcg 1000–1200 24–48 by A: 69
B: 160 B: 16 1 or 4 B: ␣-2b, 1.5 mcg/kg genotype* B: 54
Escudero et al, 2008; Spain (24) Poor A: 91 Not reported 100 ⬃75 genotype A: ␣-2a, 180 mcg 800–1200 24–48 by A: 66
B: 92 1 or 4 B: ␣-2b, 1.5 mcg/kg genotype* B: 62
Kamal et al, 2011; Egypt (25) Fair A: 109 Not reported 100 100 genotype A: ␣-2a, 180 mcg 1000–1200 48 A: 71
B: 108 4 B: ␣-2b, 1.5 mcg/kg B: 55
Khan et al, 2007; Pakistan (26) Not assessed† A: 33 Not reported Not reported 100 genotype A: ␣-2a, 180 mcg 800 24 A: 79
B: 33 3 B: 82

B: ␣-2b, 1.0 mcg/kg
Mach et al, 2011; Poland (27) Fair A: 138 Not reported Not reported 100 genotype A: ␣-2a, 180 mcg 1000–1200 48 A: 49
B: 122 1b B: ␣-2b, 1.5 mg/kg B: 44
Magni et al, 2009; Italy (6) Not assessed† A: 100 Not reported Not reported ⬃55 genotype A: ␣-2a, 180 mcg 10.5/kg 24–48 by A: 68
B: 118 1 or 4 B: ␣-2b, 1.5 mcg/kg genotype* B: 67
McHutchison and Sulkowski, 2008 (IDEAL); Fair A: 1035 A: 10‡ A: 80 100 genotype A: ␣-2a, 180 mcg A: 1000–1200 48 A: 41
United States (21, 32) B: 1019 B: 11‡ B: 81 1 B: ␣-2b, 1.5 mcg/kg B: 800–1400 B: 40
C: 1016 C: 11‡ C: 81 C: ␣-2b, 1.0 mcg/kg C: 800–1400 C. 38
Miyase et al, 2012; Japan (28) Fair A: 101 A. 20 Not reported 100 genotype A: ␣-2a, 180 mcg 600–1000 48 A: 65
B: 100 B. 17 1 B: ␣-2b, 60-150 mcg/kg B: 51
(weight-based)
Rumi et al, 2010; Italy (29) Fair A: 212 A: 20 A: 59§ ⬃50 genotype A: ␣-2a, 180 mcg A: 1000–1200 (genotypes 1 24–48 by A: 66
B: 219 B: 18 B: 59§ 1 or 4 B: ␣-2b, 1.5 mcg/kg or 4) and 800 mg genotype* B: 54
(genotypes 2 or 3)
B: 800–1200
Yenice et al, 2006; Turkey (30) Poor A: 37 Not reported (all had at A: 70 100 genotype A: ␣-2a, 180 mcg 800–1200 48 A: 49
B: 37 least minimal fibrosis) B: 76 1 B: ␣-2b, 1.5 mcg/kg B: 35
Duration effects㛳
48 wk vs. 24 wk
Hadziyannis et al, 2004 (PEGASYS); worldwide (35) Fair A: 99 A: 7 100 38 genotype 2 ␣-2a, 180 mcg A: 800 A/B: 48 A/B: 75
B: 153 B: 8 or 3 B: 1200 C/D: 24 C/D. 82
C: 96 C: 5 C: 800
D: 144 D: 7 D: 1200
Zeuzem et al, 2004 (PEGASYS); Australia, Europe, Fair A: 59 A: 1 0 28 genotype 2 ␣-2a, 180 mcg 800 A: 48 A: 78
New Zealand, North and South America (43) B: 58 B: 0 or 3 B: 24 B: 72
24 wk vs. 12–16 wk
Lagging et al, 2008; Denmark and Finland (36) Fair A: 188 A: 13 Not reported 100 genotype ␣-2a, 180 mcg 800 A: 24 A: 78
B: 194 B: 13 2 or 3 B: 12 B: 59
Manns et al, 2011; international (38) Poor A: 230 Not reported 100 100 genotype ␣-2b, 1.5 mcg/kg 800–1400 A: 24 A: 67
B: 228 2 or 3 B: 16 B: 57
Shiffman et al, 2007; 132 centers worldwide (40) Good A: 732 A: 23‡ 100 100 genotype ␣-2a, 180 mcg 800 A: 24 A: 70
B: 733 B: 25‡ 2 or 3 B: 16 B: 62
Yu et al, 2007; Taiwan (42) Fair A: 100 A: 20‡ 100 100 genotype ␣-2a, 180 mcg 1000–1200 A: 24 A: 95
B: 50 B: 22‡ 2 or 3 B: 16 B: 94
24 wk vs. 12–16 weeks among those with undetectable
virus by wk 4
Dalgard et al, 2008; Denmark, Sweden, Norway (34) Fair A: 150 Not reported 100 100 genotype ␣-2b, 1.5 mcg/kg 800–1400 A: 24 A: 91
B: 148 2 or 3 B: 14 B: 81
Mecenate et al, 2010 (CLEO); Italy (39) Fair A: 71 10 (overall) 100 100 genotype ␣-2a, 180 mcg 800–1200 A: 24 A: 75
B: 72 2 or 3 B: 12 B: 83
von Wagner et al, 2005; Germany (41) Fair A: 71 Not reported 100 100 genotype ␣-2a, 180 mcg 800–1200 A: 24 A: 80
B: 71 2 or 3 B: 16 B: 82
Other duration comparisons
Andriulli et al, 2009¶; Italy (33) Fair A: 61 Not reported 100 100 genotype ␣-2a, 180 mcg A: 1000–1200 for 12 wk 12 A: 82
B: 59 2 or 3 B: 1000–1200 for 6 wk B: 54

Study, Year; Country (Reference) Quality Sample Cirrhosis at Baseline, Elevated Genotype Weekly Pegylated Daily Ribavirin Dose, mg Duration, wk Sustained
Sizes, n % Aminotransferase Mix, % Interferon Dose Virologic
Levels at Response
Baseline, % Rate, %
Mangia et al, 2005; Italy (37) Fair A: 70 A: 23‡ 100 100 genotype ␣-2b, 1.0 mcg/kg 1000–1200 A. 24 A: 76
B: 213 B: 16‡ 2 or 3 B. 12–24** B: 77

Dose effects: pegylated interferon㥋
Higher vs. lower doses of pegylated
interferon ␣-2b
Abergel et al, 2006; France (44) Fair A: 37 A: 46 100 38 genotype 2 A: ␣-2b, 0.75 mcg/kg 800 48 A: 73
B: 41 B: 57 or 3 B: ␣-2b, 1.5 mcg/kg B: 73
Kawaoka et al, 2009; Japan (45) Fair A: 26 None Not reported 100 genotype A: ␣-2b, 1.0 mcg/kg 600–1000 24 A: 39
B: 27 2 or 3 B: ␣-2b, 1.5 mcg/kg B: 74
Krawitt et al, 2006; United Fair A: 43 A: 17 A: 88†† 29 genotype 2 A: ␣-2b, 50 mcg 1000 48 A: 56
States (46) B: 43 B: 10 B: 88†† or 3 B: ␣-2b, 100-150 mcg B: 65

Meyer-Wyss, 2006; Poor A: 55 None 100 42 genotype 2 A: ␣-2b, 1.0 mcg/kg 800 24–48 by A: 71
Switzerland (47) B: 36 or 3 B: ␣-2b, 1.5 mcg/kg genotype* B: 81
Sood et al, 2008; India (48) Fair A: 76 Not reported 100 100 genotype A: ␣-2b, 1.0 mcg/kg 10–12/kg 24 A: 79
B: 27 2 or 3 B: ␣-2b, 1.5 mcg/kg B: 93
Manns et al, 2011; Poor A: 224 Not reported 100 100 genotype A: ␣-2b, 1.0 mcg/kg 800–1400 24 A: 64
international (38) B: 230 2 or 3 B: ␣-2b, 1.5 mcg/kg B: 67
Dose effects: ribavirin㛳

Ferenci et al, 2008; Austria (49) Poor A: 141 Not reported 100 100 genotype ␣-2a, 180 mcg A: 400 24 A: 64
B: 141 2 or 3 B: 800 B: 69
Hadziyannis et al, 2004 (PEGASYS); Fair A: 96 A: 5 100 38 genotype 2 ␣-2a, 180 mcg A/C. 800 A: 24 A/C: 80
worldwide (35) B: 144 B: 7 or 3 B/D. 1000–1200 B: 24 B/D: 77
C: 99 C: 7 C: 48
D: 153 D: 8 D: 48
Helbling et al, 2006; Fair A: 31 A: 57 100 48 genotype 2 ␣-2a, 180 mcg A: 600–800 24–48 by A: 45
Switzerland (50) B: 29 B: 52 or 3 B: 1000–1200 genotype* B: 72
Jacobson et al, 2007 (WIN-R); Fair A: 911 A: 10 100 37 genotype 2 ␣-2b, 1.5 mcg/kg A: 800 24–48 by A: 60
United States (51) B: 920 B: 10 or 3 B: 800–1400 genotype* B: 62
Cirrhosis ⫽ METAVIR (Meta-analysis of Histologic Data in Viral Hepatitis) F4, Ishak 5– 6, or equivalent; Minimal or no fibrosis ⫽ METAVIR F0 –F1, Ishak 0 –2, or equivalent; CLEO ⴝ Club Epatologi Ospedalieri; HCV ⫽
hepatitis C virus; IDEAL ⫽ Individualized Dosing Efficacy vs. Flat Dosing to Assess Optimal Pegylated Interferon Therapy; WIN-R ⫽ Weight-based dosing of pegINterferon ␣-2b and Ribavirin.
* Treatment duration varied according to genotype: typically 48 wk for genotype 1 or 4 and 24 wk for genotype 2 or 3.
† Published as abstract only; only included in sensitivity analysis.
‡ Severe fibrosis or cirrhosis.
§ More than 2 times the upper limit of normal.
㛳 Sample sizes and results are restricted to patients with genotype 2 or 3 infection.
¶ Patients who had undetectable virus by wk 4 were randomly assigned to 12 or 6 wk of ribavirin.
** Treatment for 12 wk if HCV RNA undetectable at 4 wk and for 24 wk if detectable.
†† Alanine aminotransferase level ⬎40 IU/L.
www.annals.org
www.annals.org
Appendix Table 3. Trials of Triple Therapy With Boceprevir or Telaprevir, Pegylated Interferon, and Ribavirin
Study, Year; Country (Reference) Quality Sample Cirrhosis, % Elevated Boceprevir or Weekly Pegylated Daily Ribavirin Dose, Duration, Sustained
Sizes, n Aminotransferase Telaprevir Interferon Dose mg wk Virologic
Levels, % Dose/Duration Response
Rate, %
Trials of triple therapy with pegylated interferon ␣-2b,

ribavirin, and boceprevir versus dual therapy with
pegylated interferon ␣-2b plus ribavirin
Kwo et al, 2010, SPRINT-1; United States, Canada, Fair A: 103 7 overall Not reported A: 800 mg tid wk 1–48 ␣-2b, 1.5 mcg/kg 800–1400 A: 48 A: 67

Europe (55) B: 107 B: 800 mg tid wk 1–28 B: 28 B: 54
C: 103 C: 800 mg tid wk C: 48 C: 75*
D: 103 5–48* D: 28 D: 56
E: 104 D: 800 mg tid wk 5–28 E: 48 E: 38
E: placebo
Poordad et al, 2011, SPRINT-2; United States and Fair A: 366 A: 11† A: 74 A: 800 mg tid wk 5–48 ␣-2b, 1.5 mcg/kg A: 600–1400 wk 5–48 A: 48 A: 66*
Europe (22) B: 368 B: 9† B: 80 B: 800 mg tid wk 5–28 B: 600–1400 wk 5–28 B: 28/48‡ B: 63
C: 363 C: 7† C: 77 C: placebo C: 600–1400 C: 48 C: 38
Trials of triple therapy with pegylated interferon ␣-2b,

ribavirin, and telaprevir
Hézode et al, 2009; Europe (56) Fair A: 82 A: 0 Not reported A: 750 mg tid wk 1–12 ␣-2a, 180 mcg A: 1000–1200 A: 12 A: 60
B: 81 B: 0 B: 750 mg tid wk 1–12 B: 1000–1200 B: 24 B: 69
C: 78 C: 1 C: 750 mg tid wk 1–12 C: placebo C: 12 C: 36
D: 82 D: 0 D: placebo D: 1000–1200 D: 48 D: 46
Jacobson et al, 2011; worldwide (20) Good A: 364 6 overall Not reported A: 750 mg tid wk 1–8 ␣-2a, 180 mcg 1000–1200 A: 24/48§ A: 69
B: 363 B: 750 mg tid wk 1–12 B: 24/48§ B: 75
C: 361 C: placebo C: 48 C: 44㛳
Kumada et al, 2012; Japan (57) Fair A: 126 Not reported Not reported A: 750 mg tid wk 1–12 ␣-2b, 1.5 mcg/kg 600–1000 A: 24 A: 73
B: 63 (decompensated B: placebo B: 48 B: 49
cirrhosis
excluded)
Marcellin et al, 2011; Europe (31) Fair A: 40 A: 2.5 Not reported A: 750 mg tid wk 1–12 A: ␣-2a, 180 mcg A: 1000–1200 24/48¶ A: 85
B: 42 B: 2.4 B: 750 mg tid wk 1–12 B: ␣-2b, 1.5 B: 800–1200 B: 81
C: 40 C: 0 C: 1125 mg bid wk mcg/kg C: 1000–1200 C: 83
D: 39 D: 5.1 1–12 C: ␣-2a, 180 mcg D: 800–1200 D: 82
D: 1125 mg bid wk D: ␣-2b, 1.5
1–12 mcg/kg
McHutchison et al, 2009, PROVE1; United Fair A: 17 None Not reported A: 750 mg tid wk 1–12 ␣-2a, 180 mcg 1000–1200 A: 12 A: 35
States (58) B: 79 B: 750 mg tid wk 1–12 B: 24 B: 61
C: 79 C: 750 mg tid wk 1–12 C: 48 C: 67
D: 75 D: placebo D: 48 D: 41
Sherman et al, 2011, ILLUMINATE; United Fair A: 162 A: 11 Not reported A: 750 mg tid wk 1–12 ␣-2a, 180 mcg 1000–1200 A: 24 A: 92
States (59)** B: 160 B: 8 B: 750 mg tid wk 1–12 B: 48 B: 88
bid ⫽ twice daily; HCV ⫽ hepatitis C virus; ILLUMINATE ⫽ Illustrating the Effects of Combination Therapy with Telaprevir; PROVE ⫽ Protease Inhibition for Viral Evaluation; SPRINT ⫽ Serine Protease Inhibitor Therapy;
tid ⫽ thrice daily. Cirrhosis ⫽ METAVIR (Meta-analysis of Histologic Data in Viral Hepatitis) F4, Ishak 5– 6, or equivalent. Minimal or no fibrosis ⫽ METAVIR F0 –F1, Ishak 0 –2, or equivalent.
* Dosing recommended by the U.S. Food and Drug Administration for boceprevir in antiviral-naive patients with cirrhosis at baseline.
† Severe fibrosis or cirrhosis.
‡ Response-guided duration: 28 wk of pegylated interferon/ribavirin if HCV RNA is negative from wk 8 –24. Patients not meeting these criteria continued until wk 48.
§ Response-guided duration: 24 wk of pegylated interferon/ribavirin if HCV RNA negative from week 4 through week 12. Patients not meeting these criteria continued until week 48.
㛳 Dosing regimen recommended by the U.S. Food and Drug Administration for telaprevir.
¶ Response-guided duration: 24 weeks of treatment with pegylated interferon/ribavirin if HCV RNA is negative from wk 4 –20. Patients not meeting these criteria continued until wk 48.
** Patients with undetectable HCV RNA at wk 4 and wk 12 randomly assigned to 24 or 48 wk of dual therapy.

Appendix Table 4. Harms of Triple Therapy With Boceprevir or Telaprevir With Pegylated Interferon, and Ribavirin Versus Dual
Therapy With Pegylated Interferon ␣-2b Plus Ribavirin
Therapy Relative Risk (95 CI); Pooled Event Rates (95 CI), % Risk Difference Trials, n (References)
Harms I2, % (95 CI),
Intervention 1 Intervention 2 percentage points
Dual therapy with pegylated interferon ␣-2b plus
ribavirin versus dual therapy with pegylated
interferon ␣-2a plus ribavirin*
Serious adverse events 0.76 (0.61 to 0.95); 0 4.7 (0 to 1.3) 6.3 (0 to 17) ⫺1.0 (⫺3.8 to 1.8) 2 (21, 29)
Withdrawal due to adverse events 1.1 (0.73 to 1.7); 42 7.7 (2.9 to 13) 6.6 (1.7 to 12) 0.8 (⫺2.0 to 3.6) 6 (21, 23, 25, 28–30)
Neutropenia 0.61 (0.46 to 0.83); 38 9.9 (4.5 to 15) 15 (7.4 to 22) ⫺3.0 (⫺6.1 to 0.0) 5 (21, 23, 24, 28, 29)
Anemia 0.97 (0.72 to 1.3); 64 26 (5.7 to 47) 24 (7.0 to 42) 0.9 (⫺3.9 to 5.7) 4 (21, 23, 28, 29)
Thrombocytopenia 0.87 (0.59 to 1.3); 0 8.8 (1.1 to 16) 10 (1.7 to 19) ⫺0.9 (⫺3.1 to 1.2) 3 (23, 28, 29)
Depression 1.1 (0.92 to 1.2); 0 12 (0 to 25) 12 (2.2 to 23) 0.6 (⫺1.9 to 3.1) 3 (21, 23, 28)
Fatigue 1.0 (0.96 to 1.1); 7 55 (40 to 69) 57 (48 to 66) 0.9 (⫺3.7 to 5.6) 3 (21, 23, 28)
Influenza-like symptoms 0.98 (0.85 to 1.1) 62 (56 to 68) 63 (57 to 70) ⫺1.1 (⫺10 to 8.0) 1 (29)
Headache 1.1 (1.1 to 1.2); 0 30 (7.2 to 53) 29 (10 to 47) 3.7 (⫺1.6 to 9.0) 3 (21, 23, 28)
Myalgia 1.1 (0.86 to 1.5); 33 18 (7.2 to 30) 18 (12 to 24) 1.9 (⫺3.8 to 7.5) 3 (21, 23, 28)
Rash 0.79 (0.71 to 0.88); 0 39 (5.4 to 72) 49 (7.5 to 90) ⫺7.6 (⫺14 to ⫺1.2) 2 (21, 28)
Triple therapy with boceprevir versus dual

therapy for 48 wk†
Serious adverse events 1.4 (0.93 to 2.2) 12 (8.9 to 16) 8.5 (5.7 to 11) 3.8 (⫺0.7 to 8.2) 1 (22)
Withdrawal due to adverse events 1.1 (0.77 to 1.4); 0 13 (5.3 to 20) 12 (4.1 to 20) 0.8 (⫺3.5 to 5.2) 2 (22, 55)
Neutropenia 1.8 (1.5 to 2.3); 0 33 (29 to 38) 18 (14 to 22) 15 (9.8 to 21) 2 (22, 55)
Anemia 2.0 (1.4 to 2.8); 0 25 (0 to 67) 12 (0 to 34) 12 (⫺18 to 41) 2 (22, 55)
Thrombocytopenia 3.2 (1.2 to 8.2); 0) 3.8 (2.1 to 5.6) 1.4 (0.2 to 2.6) 2.8 (0.8 to 4.8) 2 (22, 55)
Depression 0.87 (0.65 to 1.2) 19 (15 to 23) 22 (18 to 26) ⫺2.9 (⫺8.7 to 2.9) 1 (22)
Fatigue 1.1 (0.82 to 1.5); 83 64 (50 to 77) 59 (54 to 63) 5.9 (⫺12 to 2.4) 2 (22, 55)
Influenza-like symptoms 0.80 (0.58 to 1.1); 27 19 (11 to 27) 25 (21 to 29) ⫺4.7 (⫺10 to 1.0) 2 (22, 55)
Headache 1.1 (0.96 to 1.3); 0 48 (42 to 54) 42 (38 to 47) 4.7 (⫺1.6 to 11) 2 (22, 55)
Myalgia 0.97 (0.76 to 1.2) 25 (21 to 30) 26 (21 to 30) ⫺0.8 (⫺7.1 to 5.6) 1 (22)
Rash 1.1 (0.81 to 1.4) 24 (20 to 28) 23 (18 to 27) 1.2 (⫺5.0 to 7.3) 1 (22)
Dysgeusia 2.5 (2.0 to 3.2); 0 35 (20 to 50) 13 (4.6 to 22) 23 (17 to 29) 2 (22, 55)
Triple therapy with telaprevir for 24 weeks

versus dual therapy for 48 wk†
Serious adverse events 1.0 (0.50 to 2.0) 16 (8.1 to 24) 16 (7.9 to 24) 0.2 (⫺11 to 11) 1 (56)
Withdrawal due to adverse events 1.1 (0.45 to 2.6); 60 15 (10 to 20) 14 (0 to 29) 1.0 (⫺11 to 13) 2 (56, 57)
Neutropenia 0.81 (0.51 to 1.3); 53 41 (0 to 94) 48 (0.4 to 96) ⫺7.7 (⫺17 to 1.5) 2 (57, 58)
Anemia 1.3 (1.1 to 1.5); 0 52 (6.4 to 97) 39 (6.5 to 71) 13 (5.8 to 21) 3 (56–58)
Thrombocytopenia 1.8 (1.2 to 2.5) 64 (56 to 73) 36 (25 to 48) 28 (13 to 42) 1 (57)
Depression 1.0 (0.66 to 1.6); 0 21 (14 to 27) 20 (14 to 26) 0.4 (⫺8.4 to 9.3) 2 (56, 58)
Fatigue 0.96 (0.74 to 1.2); 53 51 (26 to 76) 54 (29 to 78) ⫺2.5 (⫺15 to 9.8) 3 (56, 58)
Influenza-like symptoms 0.87(0.63 to 1.2); 50 35 (15 to 55) 40 (24 to 56) ⫺5.1 (⫺16 to 5.7) 3 (56–58)
Headache 0.83 (0.69 to 1.0); 0 42 (36 to 48) 52 (43 to 61) ⫺8.8 (⫺18 to ⫺0.01) 3 (56–58)
Myalgia 0.76 (0.43 to 1.3); 57 18 (7.4 to 28) 23 (17 to 28) ⫺5.4 (⫺15 to 4.4) 3 (56, 58)
Rash 1.4 (1.1 to 1.7); 0 49 (36 to 61) 35 (28 to 42) 14 (5.0 to 22) 3 (56–58)
RR ⫽ relative risk.
* Intervention 1: interferon ␣-2b; intervention 2: interferon ␣-2a.
† Intervention 1: triple therapy with pegylated interferon and ribavirin for 48 wk with boceprevir from weeks 5 to 24; intervention 2: dual therapy for 48 wk.
‡ Intervention 1: triple therapy with telaprevir, pegylated interferon ␣-2, and ribavirin for 12 wk followed by dual therapy for 12 wk; intervention 2: dual therapy for 48 wk.
W-78 15 January 2013 Annals of Internal Medicine Volume 158 • Number 2 www.annals.org

Appendix Table 5. Sustained Virologic Response and Clinical Outcomes Summary Results*
Study, Year; Country Quality Study Type Adjusted Hazard Ratio (95% CI) Results Adjusted for at Least Age,
www.annals.org
(Reference) Patients Analyzed, n Sex, Viral Load, Genotype, and
Duration of Follow-up Hepatocellular Carcinoma Liver-Related Mortality All-Cause Mortality Other Clinical Outcomes Fibrosis Stage, or No Association
Proportion With Cirrhosis: Found in Univariate Analyses
SVR vs. no SVR, %
Studies of general populations
of treated patients with
HCV infection
Arase et al, 2007; Japan (60) Fair Retrospective cohort SVR vs. no SVR: 0.19 SVR vs. no SVR: 0.13 SVR vs. no SVR: 0.39 NR Yes
500 (0.08–0.45) (0.03⫺0.59) (0.16⫺0.93)
Mean, 7.4 y
Cirrhosis: 9 vs. 16
Backus et al, 2011; United Fair Retrospective cohort NR NR SVR vs. no SVR (genotypes NR Yes
States (61)† 16 864 1, 2, and 3,
Median, 3.8 y respectively):

Cirrhosis: 9⫺12 vs. 12⫺20 0.71 (0.60⫺0.86),
0.62 (0.44⫺0.87), and
0.51 (0.35⫺0.75)
Coverdale et al, 2004; Poor Prospective cohort (some patients SVR vs. response––relapse SVR vs. response–relapse NR SVR vs. response relapse vs. Unclear
Australia (64)‡ originally enrolled in vs. nonresponse vs. nonresponse nonresponse
randomized trials) Adjusted HR not reported Liver transplant or Liver-related complications§:
343 (P ⬎ 0.05) liver-related death: Adjusted HR not reported
Median, 9 y Adjusted HR not (P ⫽ 0.06)
Cirrhosis: Not reported, Median, reported (P ⫽ 0.20)
fibrosis score F2 (Scheuer)
Imazeki et al, 2003; Fair Retrospective cohort NR SVR vs. no SVR: 0.11 SVR vs. no SVR: 0.12 NR Yes
Japan (69) 459 (0.01⫺0.96)㛳 (0.01⫺1.3)㛳
Mean, 8.2 y
Cirrhosis: 13 overall
Innes et al, 2011; United Fair Retrospective cohort NR SVR vs. no SVR: 0.22 NR SVR vs. no SVR Yes
Kingdom (70) 1215 (0.09⫺0.58) Liver-related hospital
Mean, 5.3 y episode: 0.22
Cirrhosis: 10 vs. 18 (0.15⫺0.34)
Izumi et al, 2005; Japan (71) Fair Cohort study, appears SVR vs. no SVR: 0.36 NR NR NR Unclear
retrospective (0.04–0.83)
495
Follow-up NR
Cirrhosis: 5.1 overall
Kasahara et al, 2004; Poor Retrospective cohort NR SVR vs. no SVR: 0.04 SVR vs. no SVR: 0.14 NR No
Japan (72) 2698 (0.005⫺0.30) (0.06⫺0.35)
Mean, 6 y
Cirrhosis: 3.0 vs. 5.4
Maruoka et al, 2012; Fair Retrospective cohort SVR vs. no SVR: 0.12 NR SVR vs. no SVR: 0.20 NR Yes
Japan (73) 577 (0.04–0.40)㛳 (0.08⫺0.54)㛳
Mean, 9.9 y
Yoshida et al, 2002; Poor Retrospective cohort NR SVR vs. no SVR: 0.13 SVR vs. no SVR: 0.32 NR No
Japan (77) 2889 (0.02⫺0.66)㛳 (0.12⫺0.86)㛳
Mean, 5.4 y
Cirrhosis: 6.5 vs. 11
Yu et al, 2006; Taiwan (78) Poor Retrospective cohort SVR vs. no SVR: 0.25 NR SVR vs. no SVR: 0.28 NR No
1057 (0.13–0.50)㛳 (0.08⫺1.0)㛳
Mean, 5.2 y
Studies of populations with

advanced fibrosis and
cirrhosis
Bruno et al, 2007; Italy (62) Fair Retrospective cohort study SVR vs. no SVR: 0.39 SVR vs. no SVR: 0.14 NR SVR vs. no SVR No
883 (0.17–0.88) (0.04⫺0.59) Ascites, encephalopathy, or
Mean, 8 y gastrointestinal bleeding:
Cirrhosis: All Not calculated, 0 events/
1061 person-years vs.
107 events/5703
person-years (1.88
events/100 person-years)

Study, Year; Country Quality Study Type Adjusted Hazard Ratio (95% CI) Results Adjusted for at Least Age,
(Reference) Patients Analyzed, n Sex, Viral Load, Genotype, and
Duration of Follow-up Fibrosis Stage, or No Association
Proportion With Cirrhosis: Hepatocellular Carcinoma Liver-Related Mortality All-Cause Mortality Other Clinical Outcomes Found in Univariate Analyses
SVR vs. no SVR, %
Cardoso et al, 2010; Fair Retrospective cohort study (of SVR vs. no SVR: 0.33 SVR vs. no SVR: 0.27 NR SVR vs. no SVR Yes
France (63) patients originally enrolled in (0.23–0.89) (0.08⫺0.95) Ascites or variceal bleeding:
clinical trials) 0.21 (0.05⫺0.92)
307
Median, 3.5 y

Cirrhosis: 53 vs. 61
Braks et al, 2007; Poor Retrospective cohort study NR NR NR SVR vs. no SVR No
France (65) 113 Clinical events
Mean, 7.7 y (hepatocellular cancer,
Cirrhosis: All ascites, hepatic
encephalopathy, or
death): 0.14 (0.04⫺0.45)
Fernández⫺Rodríguez, Poor Retrospective cohort study NR NR NR SVR vs. no SVR Unclear
2010; Spain (66)† 509 Combined clinical
Median, 35 mo endpoint¶: 0.38
Cirrhosis: All (0.18⫺0.76)

Hasegawa et al, 2007; Fair Retrospective cohort study SVR vs. no SVR: 0.18 NR NR NR Yes
Japan (67)** 105 (0.04–0.81)
Median, 4.6 y
Cirrhosis: All
Hung et al, 2006; Fair Cohort study (unclear if SVR vs. no SVR: 0.28 NR NR NR Yes
Taiwan (68) retrospective or prospective) (0.09–0.92)
132
Median, 37 mo
Cirrhosis: All
Morgan et al, 2010; United Fair Prospective cohort study of SVR vs. no SVR: 0.19 SVR vs. no SVR SVR vs. no SVR SVR vs. no SVR Unclear
States (74)† patient enrolled in a (0.04–0.80) Liver-related mortality or All-cause mortality or liver Any liver-related
randomized trial liver transplantation: transplantation: 0.17 outcome:†† 0.15
526 0.12 (0.03⫺0.48) (0.06⫺0.46) (0.06⫺0.38)
Median, 79 to 86 mo Decompensated liver
Cirrhosis: 21 vs. 43 disease: 0.13 (0.03⫺0.53)
Shiratori et al, 2005; Poor Prospective cohort study of SVR vs. no SVR: 0.40 NR SVR vs. no SVR: 0.07 NR No
Japan (75) patients enrolled in randomized (0.18–0.89)㛳 (0.01⫺0.56)㛳
trials
271
Median, 6.8 y
Cirrhosis: All
Veldt et al, 2007; Europe Fair Retrospective cohort SVR vs. no SVR: 0.46 SVR vs. no SVR: 0.19 SVR vs. no SVR: 0.31 SVR vs. no SVR No
and Canada (76) 479 (0.12–1.7) (0.02⫺1.4) (0.07⫺1.4) Any event (death, liver
Median, 2.1 y failure, and hepatocellular
Cirrhosis: 71 vs. 77 cancer): 0.20 (0.07⫺0.58)
HCV ⫽ hepatitis C virus; HR ⫽ hazard ratio; NR ⫽ not reported; SVR ⫽ sustained virologic response.
* SVR defined in all studies as undetectable HCV RNA in serum 6 mo after the end of antiviral therapy, except as noted.
† Study primarily evaluated patients who received pegylated interferon plus ribavirin.
‡ SVR defined as undetectable HCV RNA on at least 2 occasions at least 2 years after completion of therapy.
§ Hepatic decompensation, complications of portal hypertension, hepatocellular carcinoma, liver transplantation, and liver-related mortality.
㛳 Calculated from estimates for SVR vs. untreated and no SVR vs. untreated.
¶ Hepatic decompensation, upper gastrointestinal bleeding secondary to rupture of esophageal or gastric varices, hepatocellular carcinoma, liver transplantation, and liver-related or liver-unrelated mortality.
** Duration of undetectability to meet criteria for SVR not reported.
†† Decompensated liver disease (ascites, variceal bleeding, hepatic encephalopathy, spontaneous bacterial peritonitis), hepatocellular carcinoma, liver transplantation, and liver-related mortality.
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Review Annals of Internal Medicine

Comparative Effectiveness of Antiviral Treatment for Hepatitis C Virus

C hronic hepatitis C virus (HCV) infection is a leading

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2. What is the comparative effectiveness of antiviral

report, as are results of studies comparing induction versus

Data Sources and Searches Full-text

rin versus pegylated interferon alfa-2a plus ribavirin; triple

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Figure 2. Sustained virologic response, comparisons of dual-therapy regimens.

Study, Year (Reference) Relative Risk Events Events

24 wk vs. 12 to 16 wk of dual therapy with pegylated

Lower vs. higher dose of pegylated interferon alfa-2b

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Study, Year (Reference) Relative Risk Events Events

Telaprevir triple therapy for 24 wk vs.

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Appendix Figure 1. Analytic framework for treatment of HCV in adults.

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Dose effects, dual therapy with pegylated

Triple therapy with boceprevir for genotype 1

Triple therapy with telaprevir for genotype 1

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Association between SVR and clinical

HR ⫽ hazard ratio; RR ⫽ relative risk; SVR ⫽ sustained virologic response.

Pegylated interferon ␣-2a plus ribavirin versus

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Dose effects: ribavirin㛳

Trials of triple therapy with pegylated interferon ␣-2b,

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Trials of triple therapy with pegylated interferon ␣-2b,

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Triple therapy with boceprevir versus dual

Triple therapy with telaprevir for 24 weeks

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Studies of populations with

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