Dual Therapy With Pegylated Interferon Alfa-2a or Alfa-2b Plus Ribavirin

• Seven trials found dual therapy with standard doses of pegylated interferon alfa-2b plus ribavirin associated with lower likelihood of achieving an SVR than pegylated interferon alfa-2a plus ribavirin (pooled RR 0.87, 95% CI 0.80 to 0.95, I²=27.4%), with an absolute difference in SVR rates of 8 percentage points (95% CI 3 to 14) (strength of evidence: moderate).

Dual Therapy With Pegylated Interferon Alfa-2a or Alfa-2b Plus Ribavirin: Duration Effects

• Two trials of patients with genotype 2 or 3 infection found no difference in likelihood of achieving an SVR between 48 versus 24 weeks of dual therapy with pegylated interferon alfa-2a plus ribavirin (pooled RR 0.97, 95% CI 0.84 to 1.11, I²=42.7%) (strength of evidence: moderate).
• Four trials of patients with genotype 2 or 3 infection found 24 weeks of dual therapy with pegylated interferon (alfa-2a or alfa-2b) more effective than 12–16 weeks for achieving an SVR (pooled RR 1.15, 95% CI 1.02 to 1.29, I²=79.5%). Relative risk estimates ranged from 1.0 to 1.3 (strength of evidence: moderate).
• Three trials of patients with genotype 2 or 3 infection with a rapid virologic response (undetectable HCV-RNA by week 4) found no differences between 24 versus 12–16 weeks of dual therapy with pegylated interferon (alfa-2a or alfa-2b) plus ribavirin (pooled RR 0.99, 95% CI 0.86 to 1.14, I²=66.7%). Relative risk estimates ranged from 0.89 to 1.1 (strength of evidence: moderate).

Dual Therapy With Pegylated Interferon Alfa-2a or Alfa-2b Plus Ribavirin: Dose Effects

• Six trials of patients with genotype 2 or 3 infection found lower doses of pegylated interferon alfa-2b (0.75–1.0 mcg/kg or 50 mcg) associated with lower likelihood of achieving an SVR than higher doses (1.5 mcg/kg or 100–150 mcg) (pooled RR 0.90, 95% CI 0.81 to 0.99, I²=20.2%) (strength of evidence: moderate).
• Three trials of patients with genotype 2 or 3 infection who did not specifically have advanced fibrosis or cirrhosis found no clear difference in likelihood of SVR between lower doses of ribavirin (400 or 800 mg flat dose or 600 to 800 mg weight-based dose) versus higher doses (800 or 1200 mg flat dose or 800 to 1400 mg weight-based dose) (strength of evidence: moderate).
• One small trial of patients with genotype 2 or 3 infection (N=60) and advanced fibrosis or cirrhosis (Ishak stage 4–6) found 600 to 800 mg daily of ribavirin associated with lower likelihood of SVR than 1000 to 1200 mg daily (45 vs. 72 percent, RR 0.62, 95% C I 0.40 to 0.98) (strength of evidence: low).

Trials of Triple Therapy With Pegylated Interferon Alfa-2b, Ribavirin, and Boceprevir

• Two trials of patients with HCV genotype 1 infection found dual therapy lead-in with pegylated interferon alfa-2b plus ribavirin for 4 weeks followed by 44 weeks of triple therapy with boceprevir associated with higher likelihood of SVR than dual therapy for 48 weeks (pooled RR 1.81, 95% CI 1.58 to 2.06, I²=0.0%), with an absolute increase in SVR rate of 31 percentage points (95% CI 23 to 39) (strength of evidence: moderate).
• One trial of patients with genotype 1 infection found 48 weeks of triple therapy with boceprevir using low dose of ribavirin (400–1000 mg daily) associated with a non–statistically significant trend towards lower likelihood of SVR than 48 weeks of triple therapy with a standard ribavirin dose (800–1400 mg daily) (36 vs. 50 percent, RR 0.71, 95% CI 0.39 to 1.3) (strength of evidence: low).

Trials of Triple Therapy With Pegylated Interferon Alfa-2a or Alfa-2b, Ribavirin, and Telaprevir

• Three trials of patients with genotype 1 infection found triple therapy with telaprevir for 24 weeks (12 weeks of pegylated interferon alfa-2a or alfa-2b, ribavirin, and telaprevir followed by 12 weeks of pegylated interferon alfa-2a or alfa-2b plus ribavirin) associated with higher likelihood of SVR than dual therapy with pegylated interferon alfa-2a or alfa-2b plus ribavirin for 48 weeks (pooled RR 1.48, 95% CI 1.26 to 1.75, I²=0.0%), with an absolute increase in SVR rate of 22 percentage points (95% CI 13 to 31) (strength of evidence: moderate).
• One trial of patients with genotype 1 infection found no difference in likelihood of SVR between triple therapy with pegylated interferon alfa-2a, ribavirin, and telaprevir for 12 weeks versus dual therapy with pegylated interferon alfa-2a plus ribavirin for 48 weeks (strength of evidence: moderate).
• One trial of patients with genotype 1 infection found response-guided triple therapy with telaprevir (pegylated interferon alfa-2a, ribavirin, and telaprevir for 8 or 12 weeks followed by response-guided dual therapy with pegylated interferon alfa-2a plus ribavirin for an additional 12 or 36 weeks) associated with higher likelihood of SVR than dual therapy with pegylated interferon alfa-2a plus ribavirin for 48 weeks (RR 1.6, 95% CI 1.4 to 1.9), with an absolute increase in SVR rate ranging from 25 to 31 percent. The regimen with 8 weeks of telaprevir was associated with a slightly lower SVR rate than the 12 week telaprevir regimen (69 vs. 75 percent) (strength of evidence: low).
• One trial of patients with genotype 1 infection found no difference in likelihood of SVR between triple therapy with telaprevir for 48 weeks (12 weeks of triple therapy with pegylated interferon alfa-2a, ribavirin, and telaprevir followed by 36 weeks of dual therapy with pegylated interferon alfa-2a plus ribavirin) versus triple therapy with telaprevir for 24 weeks (12 weeks of triple therapy followed by 12 weeks of dual therapy) (strength of evidence: low).
• One trial of response-guided triple therapy with telaprevir (24 or 48 weeks, based on absence or presence of HCV-RNA from weeks 4 through 20) found similar SVR rates (81–85 percent) for regimens that varied on telaprevir dose (750 mg three times daily vs. 1125 mg two times daily) and type of pegylated interferon (alfa-2a or alfa-2b) (strength of evidence: low).
• One trial of patients with an extended rapid virologic response to initial triple therapy with telaprevir reported similar high (92 and 88 percent) SVR rates (92 and 88 percent) in patients randomized to a total of 24 or 48 weeks of therapy (strength of evidence: low).

Dual Therapy With Pegylated Interferon Alfa-2a Plus Ribavirin Compared With Dual Therapy With Pegylated Interferon Alfa-2b Plus Ribavirin

Ten trials that directly compared dual therapy with pegylated interferon alfa-2a plus ribavirin to dual therapy with pegylated interferon alfa-2b plus ribavirin in patients with genotypes 1, 2, or 3 infection met inclusion criteria (Table 2, Appendix H: Evidence Table 1).^{20–23, 53–58} Two of these trials were published only as abstracts and were included only in sensitivity analyses; we could not adequately assess their quality due to limited information in the abstracts.^{54, 56} One other trial compared pegylated interferon alfa-2a versus pegylated interferon alfa-2b as part of response-guided triple therapy with telaprevir and was also only included in sensitivity analysis.⁵⁹ One trial enrolled a mix of treatment naïve and treatment experienced patients but reported SVR in the treatment-naïve subgroup.⁵⁷ Of the eight trials that could be quality rated, two^{21, 58} were rated poor quality and six were rated fair quality (Appendix H: Evidence Table 2). Frequent methodologic shortcomings were open-label design,^{20, 21, 23, 53, 55, 57} high or unclear loss to followup,^20–23 and unclear or inadequate methods of allocation concealment.^{21, 23, 53, 55, 57, 58} Sample sizes ranged from 66 to 3,070. Five trials, including the trial that compared triple therapy regimens, only enrolled patients with genotype 1 HCV infection;^{22, 55, 57–59} the others enrolled either a mix of genotypes or a specific genotype other than genotype 1. The proportion of patients with cirrhosis at baseline ranged from <5–20 percent,^{20, 23, 59, 60} and the proportion of patients with elevated transaminases ranged from 60–100 percent^{20, 21, 23, 53, 58, 60} in trials that reported this information. All but two trials^{54, 57} included a comparison of a standard dose of pegylated interferon alfa-2a (180 mcg/week) with a standard dose of pegylated interferon alfa-2b (1.5 mcg/kg/week). One trial evaluated multiple pegylated interferon alfa-2b doses.²² Ribavirin dosing varied across studies. All trials used weight-based dosing of ribavirin except for one, which used an 800 mg daily flat dose (it also enrolled only genotype 3 patients).⁵⁴ Three trials used different ribavirin doses with pegylated interferon alfa-2a and alfa-2b.^{22, 23, 59} Nine trials evaluated fixed-duration regimens, with 48 weeks of treatment for genotypes 1 or 4 and 24 weeks for genotypes 2 or 3.^{20, 21, 23, 53–58}

Table 2

Trials of dual therapy with pegylated interferon alfa-2a plus ribavirin versus dual therapy with pegylated interferon alfa-2b plus ribavirin.

Dual therapy with a standard dose of pegylated interferon alfa-2b (1.5 mcg/kg/week) plus ribavirin was associated with slightly lower likelihood of achieving an SVR than a standard dose of pegylated interferon alfa-2a (180 mcg/week) plus ribavirin (seven trials, pooled RR 0.87, 95% CI 0.80 to 0.95, I²=27.4%) (Figure 3).^{20–23, 53, 55, 58} The pooled absolute reduction in likelihood of SVR was 8 percentage points (95% CI 3 to 14). Results were similar when the meta-analysis included the trial⁵⁹ that evaluated pegylated interferon alfa-2b versus pegylated interferon alfa-2a as part of a triple therapy regimen with telaprevir and ribavirin (eight trials, pooled RR 0.89, 95% CI 0.82 to 0.96, I²=26%) and a trial⁵⁶ only available as a conference abstract (nine trials, pooled RR 0.90, 95% CI 0.83 to 0.97, I²=25%), or excluded two poor-quality trials (five trials, pooled RR 0.86, 95% CI 0.78 to 0.95, I²=47%).^{21, 58} Two trials, one published only as an abstract, compared only a standard dose of pegylated interferon alfa-2a (180 mcg weekly) versus nonstandard doses of pegylated interferon alfa-2b (1.0 mcg/kg/week or 60–150 mcg/week).^{54, 57} Pooled estimates were similar when these trials were included in the analysis (nine trials, pooled RR 0.88, 95% CI 0.82 to 0.95, I²=22%).

Figure 3

Sustained virologic response: Dual therapy with pegylated interferon alfa-2b plus ribavirin versus dual therapy with pegylated interferon alfa-2a plus ribavirin (standard doses of pegylated interferon only).

The largest head-to-head trial was the Individualized Dosing Efficacy vs. Flat Dosing to Assess Optimal Pegylated Interferon Therapy (IDEAL) study (n=3070, compared with 66 to 477 in the other trials).²² It was rated fair quality because loss to followup exceeded 20 percent. A three-armed trial, IDEAL randomized patients with HCV genotype 1 infection to one of two doses of pegylated interferon alfa-2b (1.0 mcg/kg/week or 1.5 mcg/kg/week) plus ribavirin 800 to1400 mg daily (800 mg 40 to 65 kg; 1000 mg >65 to 85 kg; 1200 mg >85 to 105 kg; 1400 >105 to 125 kg) or pegylated interferon alfa-2a 180 mcg/week plus ribavirin 1000 to 1200 mg/day (1000 mg <75 kg; 1200 mg ≥75 kg). Overall, SVR rates were similar at 38–41 percent in the three arms. However, differences in ribavirin dosing could have affected treatment comparability. Excluding IDEAL²² had little effect on the pooled estimate and eliminated statistical heterogeneity (six trials, pooled RR 0.83, 95% CI 0.76 to 0.90, I²= 0%) (Figure 4).^{20, 21, 23, 53, 55, 58}

Figure 4

Sustained virologic response: Dual therapy with pegylated interferon alfa-2b plus ribavirin versus dual therapy with pegylated interferon alfa-2a plus ribavirin (excluding trials with differential ribavirin dosing or that evaluated triple therapy regimens). (more...)

Dual Therapy With Pegylated Interferon Alfa-2a or Alfa-2b Plus Ribavirin: Duration Effects

Eleven trials compared effects of different treatment durations of dual therapy with pegylated interferon (alfa-2a or alfa-2b) plus ribavirin on SVR rates in patients with HCV genotype 2 or 3 infection (Table 3, Appendix H: Evidence Table 5).^61–71 Nine trials^{61, 62, 64–70} only enrolled patients with genotype 2 or 3 infection and the other two^{63, 71} reported results in the subgroup of patients with genotype 2 or 3 infection. Sample sizes ranged from 117 to 1,465 subjects. One trial⁶⁸ was rated good quality, one trial poor quality,⁶⁶ and the remainder fair quality (Appendix H: Evidence Table 6). Common methodological shortcomings included open-label design^{61, 62, 64, 65, 67, 70–72} and inadequately described randomization or treatment allocation procedures^{62, 64–67, 69–71} One trial also reported high attrition.⁶⁶ Most trials evaluated standard dosing of pegylated interferon alfa-2a (180 mcg/week) and pegylated interferon alfa-2b (1.5 mcg/kg/week), although ribavirin dosing varied across the trials.

Table 3

Trials on effects of duration with dual therapy with pegylated interferon (alfa-2a or alfa-2b) plus ribavirin.

Six trials compared fixed-duration regimens of dual therapy with pegylated interferon (alfa-2a or alfa-2b) plus ribavirin in patients with genotype 2 or 3 infection.^{63, 64, 66, 68, 70, 71} Two trials found no difference between 48 versus 24 weeks of dual therapy in likelihood of achieving an SVR (pooled RR 0.97, 95% CI 0.84 to 1.1, I²=43%) (Figure 5).^{63, 71} Four other trials found 24 weeks of dual therapy associated with a higher likelihood of achieving an SVR than 12 to 16 weeks of dual therapy (pooled RR 1.2, 95% CI 1.0 to 1.3; I²=80%),^{64, 66, 68, 70} but substantial statistical heterogeneity was present (I²=80%) (Figure 6). Of the four trials, three found 12 to 16 weeks of dual therapy associated with lower likelihood of SVR compared with 24 weeks.^{64, 66, 68} The fourth trial,⁷⁰ which found no difference between 16 versus 24 weeks of dual therapy (RR 1.0, 95% CI 0.93 to 1.1), used weight-based dosing of ribavirin starting at 1,000 mg (1,000–1,200 mg), compared with a flat dose of 800 mg or weight-based dosing starting at 800 mg (800–1,400 mg) in the other three trials. This trial also enrolled only patients with a genotype 2 infection, whereas the others enrolled genotype 2 or 3. It reported substantially higher overall SVR rates (94 vs. 95 percent) than the other trials (57–62 percent vs. 67–78 percent). Excluding this trial from the meta-analysis reduced statistical heterogeneity, with no appreciable impact on the pooled estimate of effect (three trials, pooled RR 1.2, 95% CI 1.1 to 1.3, I²=47%).^{64, 66, 68} Another potential source of heterogeneity was the evaluation of pegylated interferon alfa-2b and high attrition in one of the trials.⁶⁶ However, excluding this trial did not affect the pooled estimate or reduce statistical heterogeneity (three trials, pooled RR 1.1, 95% CI 0.99 to 1.3, I²=86%).^{64, 68, 70}

Figure 5

Sustained virologic response: Dual therapy with pegylated interferon (alfa-2a or alfa-2b) plus ribavirin for 48 versus 24 weeks in patients with genotype 2 or 3 infection.

Figure 6

Sustained virologic response: Dual therapy with pegylated interferon (alfa-2a or alfa-2b) plus ribavirin for 24 weeks versus 12 to 16 weeks in patients with genotype 2 or 3 infection.

Three trials of patients with genotype 2 or 3 infection who achieved a rapid virologic response (defined as undetectable HCV-RNA by week 4) found no difference between patients randomized to a total of 24 versus 12 to 16 weeks of dual therapy with pegylated interferon alfa-2a (two trials) or alfa-2b (one trial) plus ribavirin (pooled RR 0.99, 95% CI 0.86 to 1.1, I²=66%) (Figure 7).^{62, 67, 69} Although statistical heterogeneity was present, absolute differences were relatively small, ranging from 10 percentage points favoring 24 over 16 weeks of therapy⁶² to 9 percentage points favoring 12 over 24 weeks of therapy.⁶⁷ One trial used the alfa-2b form of pegylated interferon and a somewhat different weight-based ribavirin dosing algorithm, which might account for some of the heterogeneity.⁶²

Figure 7

Sustained virologic response: Dual therapy with pegylated interferon (alfa-2a or alfa-2b) plus ribavirin for a total of 24 versus 12 to 16 weeks in patients with genotype 2 or 3 infection with a rapid virologic response.

Two other trials evaluated other comparisons related to duration of dual therapy with pegylated interferon plus ribavirin in patients with HCV genotype 2 or 3 infection.^{61, 65} One trial found fixed duration therapy with low dose (1.0 mcg/kg/week) pegylated interferon alfa-2b plus ribavirin for 24 weeks associated with nearly identical likelihood of achieving an SVR versus response-guided therapy for 12 or 24 weeks, based on absence or presence of a rapid virologic response (76 vs. 77 percent).⁶⁵ A trial of patients who experienced a rapid virologic response found 12 weeks of pegylated interferon alfa-2a with early discontinuation of ribavirin after 6 weeks associated with lower likelihood of SVR than dual therapy for 12 weeks (54 vs. 82 percent; RR 0.66, 95% CI 0.51 to 0.86).⁶¹

Dual Therapy With Pegylated Interferon Alfa-2a or Alfa-2b Plus Ribavirin: Dose Effects of Pegylated Interferon (Alfa-2a or Alfa-2b)

Six trials of dual therapy with pegylated interferon plus ribavirin compared lower versus higher doses of pegylated interferon alfa-2b in patients with genotype 2 or 3 infection (Table 4, Appendix H: Evidence Table 7).^{66, 73–77} Three trials^{66, 74, 77} restricted enrollment to patients with genotype 2 or 3 infection and three trials^{73, 75, 76} enrolled other genotypes but reported results in the subgroup of patients with genotype 2 or 3 infection. Sample sizes ranged from 53 to 454 people with genotype 2 or 3 infection. Two trials^{66, 76} were rated poor quality and the remainder fair quality (Appendix H: Evidence Table 8). Methodologic shortcomings included open-label or inadequately described blinding procedures^{66, 73–77} and unclear randomization methods.^{66, 73–77} Five trials compared standard dose pegylated interferon alfa-2b (1.5 mcg/kg/week) compared with lower doses (1.0 or 0.75 mcg/kg/week).^{66, 73, 74, 76, 77} The sixth trial evaluated an atypical pegylated interferon alfa-2b dosing regimen of 100–150 mcg weekly (100 mcg if <75 kg or 150 mcg if ≥75 kg) compared with 50 mcg weekly.⁷⁵

Table 4

Dose effects of pegylated interferon, trials of with dual therapy with pegylated interferon (alfa-2a or alfa-2b) plus ribavirin.

Lower dose pegylated interferon alfa-2b as part of dual therapy with ribavirin was associated with lower likelihood of SVR than standard dose (six trials, pooled RR 0.90, 95% CI 0.81 to 0.99, I²=20%) (Figure 8).^{66, 73–77} Excluding two poor quality trials^{66, 76} (four trials, pooled RR 0.85, 95% CI 0.71 to 1.0, I²=38%) or the trial that compared atypical dosing regimens⁷⁵ (five trials, pooled RR 0.89, 95% CI 0.79 to 1.0, I²=35%) had little effect on the pooled estimates.

Figure 8

Sustained virologic response: Dual therapy with lower dose pegylated interferon alfa-2b plus ribavirin versus higher dose pegylated interferon alfa-2b plus ribavirin in patients with genotype 2 or 3 infection.

Two other trials evaluated induction regimens of pegylated interferon alfa-2b (higher initial doses followed by lower doses until completion of therapy) plus ribavirin compared with standard fixed-dose regimens of pegylated interferon alfa-2b plus ribavirin.^{78, 79} One good quality trial found dual therapy with pegylated interferon alfa-2b (3.0 mcg/kg/week) plus ribavirin for 12 weeks followed by 36 weeks of standard dose pegylated interferon alfa-2b plus ribavirin associated with a nonstatistically significant trend towards decreased likelihood of SVR versus standard fixed dose dual therapy for 48 weeks (48 vs. 59 percent, p>0.05).⁷⁹ Another trial found no clear difference in likelihood of achieving an SVR between dual therapy with standard dose pegylated interferon alfa-2b plus ribavirin for 4 weeks followed by 0.5 mcg/kg/week for 44 weeks versus fixed dose dual therapy with standard doses of pegylated interferon alfa-2b for 48 weeks (82 vs. 80 percent), but results are difficult to interpret because ribavirin dosing was higher (1000 to 1200 mg daily) in the induction compared with the standard therapy arm (800 mg daily).⁷⁸

Ribavirin

Four trials compared effects of dual therapy with pegylated interferon plus ribavirin with different doses of ribavirin in patients with genotype 2 or 3 infection (Table 5, Appendix H: Evidence Table 5).^{63, 80–82} One trial⁸⁰ restricted enrollment to patients with genotype 2 or 3 infection and three trials^{63, 81, 82} enrolled other genotypes but reported results in the subgroup of patients with genotype 2 or 3 infection. Sample sizes ranged from 60 to 1831 with genotype 2 or 3 infection. All four trials were rated fair quality (Appendix H: Evidence Table 6). Methodological shortcomings included open-label design or inadequately described blinding^{63, 80–82} and high loss to followup.^{63, 82} Three trials^{63, 80, 81} evaluated ribavirin in combination with pegylated interferon alfa-2a and one trial in combination with pegylated interferon alfa-2b.⁸²

Table 5

Dose effects of ribavirin: Trials of with dual therapy with pegylated interferon (alfa-2a or alfa-2b) plus ribavirin.

The trials each evaluated a different ribavirin dose comparison, precluding pooled analyses. The two largest trials found no clear differences between lower flat doses of ribavirin versus higher or weight-based doses.^{63, 82} One trial (n=492 with genotype 2 or 3 infection) randomized patients to dual therapy with pegylated interferon alfa-2a 180 mcg/week plus flat-dose ribavirin, in one of four regimens: 24 weeks with ribavirin 800 mg/day, 24 weeks with ribavirin 1000–1200 mg/day, 48 weeks with ribavirin 800 mg/day, and 48 weeks with ribavirin 1000–1200 mg/day.⁶³ Rates of SVR were very similar in the combined 800 mg versus the combined 1200 mg arms (82 vs. 80 percent, RR 1.1, 95% CI 0.99 to 1.2). Another trial (n=1831 with genotype 2 or 3 infection) found no difference between dual therapy for 24 weeks with pegylated interferon alfa-2b 1.5 mcg/kg week and flat-dose ribavirin 800 mg versus weight-dosed ribavirin 800 to 1400 mg (60 vs. 62 percent, RR 0.96, 95% CI 0.89 to 1.0).⁸² One other smaller trial (n=282) found no difference between dual therapy with pegylated interferon alfa-2a with flat doses of ribavirin 400 mg versus ribavirin 800 mg in likelihood of an SVR (64 vs. 69 percent, RR 0.92, 95% C I 0.78 to 1.1). ⁸⁰

One trial (n=60 with genotype 2 or 3 infection) of pegylated interferon alfa-2a found 600–800 mg daily of ribavirin associated with lower likelihood of SVR than 1000–1200 mg daily (45 vs. 72 percent, RR 0.62, 95% CI 0.40 to 0.98), but differed from the others in that it enrolled subjects primarily with advanced fibrosis or cirrhosis (Ishak stage F4–F6).⁸¹

Trials of Triple Therapy With Pegylated Interferon Alfa-2b, Ribavirin, and Boceprevir

Two randomized trials compared triple therapy with boceprevir, pegylated interferon alfa-2b and weight-based ribavirin with dual therapy with pegylated interferon alfa-2b plus ribavirin in antiviral treatment-naïve patients with chronic HCV genotype 1 infection (Table 6, Appendix H: Evidence Table 3).^{30, 32} The Serine Protease Inhibitor Therapy (SPRINT-1)³⁰ and SPRINT-2³² trials (n=1088 and 520, respectively) were conducted in the U.S., Canada, and Europe. In SPRINT-1,³⁰ 7 percent of enrolled patients had cirrhosis at baseline and in SPRINT-2³² about 10 percent had either severe fibrosis or cirrhosis. Both trials were rated fair quality (Appendix H: Evidence Table 4). SPRINT-1 was an open label trial, and in SPRINT-2, 24 percent of patients did not complete followup. Neither trial evaluated the FDA-recommended dosing regimen for boceprevir in antiviral-naïve patients without cirrhosis at baseline (4 weeks of dual therapy lead-in with pegylated interferon alfa-2a or alfa-2b plus ribavirin, followed by triple therapy with the addition of boceprevir for either 24 or 32 weeks, based on virologic response at weeks 8 and 24),⁸⁴ although both trials evaluated the FDA-recommended dosing regimen for boceprevir in antiviral treatment-naïve patients with cirrhosis at baseline (4 weeks of dual therapy lead-in, followed by triple therapy for the final 44 weeks).

Table 6

Trials of triple therapy with pegylated interferon alfa-2b, ribavirin, and boceprevir versus dual therapy with pegylated interferon alfa-2b plus ribavirin.

SPRINT-1 randomized patients to five different antiviral regimens: (1) 4-week dual therapy lead-in with pegylated interferon alfa-2b plus ribavirin followed by the addition of boceprevir for 24 weeks (total 28 weeks); (2) 28 weeks of triple therapy with pegylated interferon alfa-2b, ribavirin, and boceprevir with no lead-in; (3) 4-week dual therapy lead-in followed by triple therapy for 44 weeks (total 48 weeks); (4) 48 weeks of triple therapy with no lead-in; or (5) dual therapy for 48 weeks.³⁰ SVR rates were 56 percent and 54 percent in the 28-week boceprevir treatment arms and 75 percent and 67 percent in the 48-week boceprevir treatment arms (with and without dual therapy lead- in, respectively), versus 38 percent with dual therapy (p<0.01 for each triple therapy arm vs. dual therapy), for an absolute risk difference for triple compared with dual therapy that ranged from 19–37 percent. Versus dual therapy, the relative risk for achieving an SVR for the two 48-week triple therapy arms combined was 1.9 (95% CI 1.5 to 2.5), and for the two 28-week triple therapy arms combined was 1.5 (95% CI 1.1 to 1.9). Four-week dual therapy lead-in was associated with an increased absolute rate of achieving an SVR versus no lead-in of 2 percent for the 28-week regimens and 8 percent for the 48-week regimens.

SPRINT-2 compared a fixed duration triple therapy regimen, a response-guided triple therapy regimen, and dual therapy.³² The fixed duration regimen consisted of four weeks of dual therapy lead-in with pegylated interferon alfa-2b plus ribavirin followed by the addition of boceprevir for 44 weeks (48 weeks total). The response-guided approach consisted of a four-week dual therapy lead-in, followed by triple therapy for 24 weeks. Patients with undetectable serum HCV-RNA from weeks 8 through 24 completed their antiviral treatment at week 28. Patients with detectable HCV-RNA at any time between weeks 8 and 24 continued dual therapy for another 20 weeks (48 weeks total). The third (control) arm consisted of dual therapy for 48 weeks. SVR rates for the three regimens were 66, 63, and 38 percent, respectively, (p<0.001 for either boceprevir regimen vs. dual therapy), with an absolute risk difference of 25–28 percent for triple compared with dual therapy. Compared with dual therapy, the relative risk for achieving an SVR for the two regimens with boceprevir combined was 1.7 (95% CI 1.5 to 2.0).

The only treatment regimen evaluated in both SPRINT trials was the 48-week regimen with dual therapy lead-in for the first 4 weeks and boceprevir added for the final 44 weeks. Based on data from both trials, triple therapy was associated with a higher likelihood of SVR than dual therapy (pooled RR 1.8, 95% CI 1.6 to 2.1, I²=0%), with a pooled absolute increase in SVR of 31 percentage points (95% CI 23 to 39) (Figure 9).^{30, 32}

Figure 9

Sustained virologic response: 48 weeks of triple therapy with boceprevir (4 weeks of dual therapy lead-in with pegylated interferon alfa-2b followed by the addition of 44 weeks boceprevir) versus 48 weeks of dual therapy in patients with genotype 1 infection. (more...)

SPRINT-1 also included a separate trial of 75 patients randomized to weight-based low dose (400–1000 mg) or standard dose (800–1400 mg) ribavirin as part of 48 weeks of triple therapy with boceprevir without dual therapy lead in³⁰ Low dose ribavirin was associated with a non–statistically significant trend towards lower likelihood of SVR (36 vs. 50%, RR 0.71, 95% CI 0.39 to 1.3).

Trials of Triple Therapy With Pegylated Interferon (Alfa-2a or Alfa-2b), Ribavirin, and Telaprevir

Six randomized trials compared triple therapy with telaprevir, pegylated interferon alfa-2a or alfa-2b and weight-based ribavirin compared with dual therapy with pegylated interferon alfa-2a or alfa-2b and ribavirin for antiviral treatment-naïve patients with chronic HCV genotype 1 infection (Table 7, Appendix H: Evidence Table 3).^{31, 51, 59, 85–87} A seventh, small trial was excluded because it evaluated patients with HCV genotype 2 or 3 (telaprevir is only approved for use in genotype 1 infection).⁸⁸ One trial³¹ was rated good quality and the remainder fair quality (Appendix H: Evidence Table 4). The proportion of patients with cirrhosis at baseline in the trials ranged from 0–10 percent. Methodological shortcomings included open-label design or unclear blinding procedures,^{59, 85, 87} unclear randomization methods,^{31, 85} and unclear reporting of attrition.^{31, 86} Three trials (n=189 to 323) evaluated fixed duration triple compared with dual therapy regimens (12, 24, or 48 weeks).^{31, 85, 86} Two other trials^{51, 59} (n=161 and 1088) evaluated response-guided duration triple therapy regimens, including one trial⁵¹ that compared the FDA-recommended telaprevir dosing regimen (12 weeks of triple therapy followed by 12 or 36 weeks of dual therapy, depending on early virologic response) with dual therapy.⁸⁴ The sixth trial (n=322) compared different durations of antiviral therapy in patients who experienced an extended rapid virologic response.⁸⁷ In all evaluated triple therapy regimens, telaprevir was administered with pegylated interferon (alfa-2a or alfa-2b) plus ribavirin for the first 8 to 12 weeks. For regimens longer than 12 weeks, dual therapy with pegylated interferon alfa-2a or alfa-2b plus ribavirin without telaprevir was continued for the remainder of the regimen.

Table 7

Trials of triple therapy with pegylated interferon alfa-2b, ribavirin, and telaprevir.

Three trials found the 24-week fixed duration triple therapy with pegylated interferon alfa-2a or alfa-2b, ribavirin, and telaprevir associated with higher likelihood of achieving an SVR than 48 weeks of dual therapy (pooled RR 1.5, 95% CI 1.3 to 1.8, I²=0%) (Figure 10).^{31, 85, 86} The pooled absolute increase in SVR rates was 22 percentage points (95% CI 13 to 31). Two of the trials found no difference between the 12-week fixed duration triple therapy regimen versus 48 weeks of dual therapy (pooled RR 1.2, 95% CI 0.86 to 1.6, I²=14%) (Figure 11).^{31, 85} One of the trials also found a 48-week triple therapy regimen with telaprevir associated with similar likelihood of SVR versus a 24-week triple therapy regimen (RR 1.1, 95% CI 0.87 to 1.4).³¹ The other trial also found a 12-week triple therapy regimen of telaprevir plus pegylated interferon without ribavirin associated with a non–statistically significant trend towards lower likelihood of achieving an SVR than pegylated interferon alfa-2a plus ribavirin for 48 weeks (RR 0.77, 95% CI 0.53 to 1.1).⁸⁵ One trial of 24-week fixed duration triple therapy with telaprevir was conducted in Japan,⁸⁶ while the other two were conducted in the United States and Europe. Additionally, the Japanese trial studied telaprevir with pegylated interferon alfa-2b, compared with pegylated interferon alfa-2a in the other fixed duration trials. Excluding this trial did not change the pooled result for SVR (two trials, pooled RR 1.5, 95% CI 1.20 to 1.8, I²=0%).^{31, 85}

Figure 10

Sustained virologic response: Triple therapy with pegylated interferon alfa-2a, ribavirin, and telaprevir for 12 weeks followed by dual therapy for 12 weeks versus dual therapy with pegylated interferon alfa-2a plus ribavirin for 48 weeks in patients (more...)

Figure 11

Sustained virologic response: Triple therapy with pegylated interferon alfa-2a, ribavirin, and telaprevir for 12 weeks versus dual therapy with pegylated interferon alfa-2a plus ribavirin for 48 weeks in patients with genotype 1 infection.

One trial compared response-guided duration triple therapy with telaprevir compared with dual therapy.⁵¹ Patients were randomized to 8 weeks of initial triple therapy with pegylated interferon alfa-2a, ribavirin, and telaprevir, 12 weeks of initial triple therapy, or dual therapy with pegylated interferon alfa-2a plus ribavirin. In the telaprevir arms, patients with an extended rapid viral response (HCV-RNA undetectable between weeks 4 and 12) continued pegylated interferon plus ribavirin for a total of 24 weeks, while those without an extended rapid viral response continued dual therapy for a total of 48 weeks. Patients randomized to dual therapy received pegylated interferon alfa-2a plus ribavirin for a fixed duration of 48 weeks. Both telaprevir treatment-guided response regimens were associated with higher SVR rates than dual therapy (69, 75, and 44 percent for 8 weeks of telaprevir, 12 weeks of telaprevir, and dual therapy, respectively; p<0.001 for either telaprevir regimen vs. dual therapy), with an absolute increase in SVR ranging from 25–31 percent for triple therapy compared with dual therapy. The relative risk for achieving an SVR in the combined telaprevir arms versus dual therapy was 1.6 (95% CI 1.4 to 1.9).

One trial of response-guided triple therapy with telaprevir (24 or 48 weeks, based on absence or presence of HCV-RNA from weeks 4 through 20) found similar SVR rates (81–85 percent) for regimens that varied on telaprevir dose (750 mg three times daily vs. 1,125 mg two times daily) and type of pegylated interferon (alfa-2a or alfa-2b).⁵⁹ Another trial of patients with an extended rapid virologic response to initial triple therapy with telaprevir reported similar, high (92 and 88 percent) SVR rates in patients randomized to a total of 24 or 48 weeks of therapy, meeting the study’s predefined noninferiority threshold.⁸⁷

Dual Therapy With Pegylated Interferon Alfa-2a Plus Ribavirin Compared With Pegylated Interferon Alfa-2b Plus Ribavirin

Five trials of dual therapy with pegylated interferon alfa-2a plus ribavirin versus pegylated interferon alfa-2b evaluated SVR rates in patients subgroups defined by demographic and clinical characteristics (Appendix H: Evidence Table 1 and Evidence Table 2).^{20–23, 56} The largest study (n=3070), the IDEAL trial, which only enrolled patients with genotype 1 infection, reported no clear differences in relative risk estimates for SVR dual therapy with pegylated interferon alfa-2b plus ribavirin versus dual therapy with pegylated interferon alfa-2a plus ribavirin in patients stratified by race (RR 0.88, 95% CI 0.59 to 1.3 for Black patients and RR 0.98, 95% CI 0.84 to 1.2 for white patients), sex (RR 0.92, 95% CI 0.77 to 1.1 for males and RR 1.1, 95% CI 0.86 to 1.3 for females), age (RR 0.95, 95% CI 0.77 to 1.2 for <40 years and RR 0.99, 95% CI 0.88 to 1.1 for age >40 years), baseline fibrosis (RR 0.88, 95% CI 0.53 to 1.4 for METAVIR F3 or F4 and RR 0.97, 95% CI 0.87 to 1.1 for METAVIR F0 to F2), and baseline viral load (RR 0.99, 95% CI 0.87 to 1.1 for HCV-RNA >600,000 IU/mL and RR 0.93, 95% CI 0.79 to 1.1 for HCV-RNA ≤600,000 IU/mL).²² However, overall absolute SVR rates across dual therapy regimens were lower in older (38 percent) versus younger (53–56 percent) patients, Black patients (23–26 percent) versus white patients (53–55 percent), patients with F3 or F4 (21–24 percent) versus F0 to F2 fibrosis (42–44 percent), and patients with high (35–36 percent) versus low viral load (61–66 percent). The relative risk estimate was somewhat lower for patients 75 to 85 kg (RR 0.80, 95% CI 0.65 to 0.98) than other weight groups (RR ranged from 0.89 to 1.1) but the confidence intervals for the estimates overlapped, and results were potentially confounded by differential ribavirin dosing according to weight.

Four smaller (n=183 to 431) trials found no clear differences in relative risk estimates in patients stratified by genotype, although rates of SVR were lower by 24–42 percent for genotype 1 infection than genotypes 2 and 3 infection.^{20, 21, 23, 56} One of these trials also found no clear differences in relative risk estimates in patient groups stratified by presence or absence of cirrhosis, or high or low viral load.²⁰

Two trials that compared different durations of therapy in patients with genotype 2 or 3 infection reported risk estimates for SVR stratified by patient characteristics.^{68, 70} They found no differences in relative risk estimates for 16 weeks of therapy compared with 24 weeks of therapy when patients were stratified according to fibrosis stage, body mass index, sex, or age (all RR estimates close to 1). Although the pooled estimates suggested lower likelihood of SVR with 16 compared with 24 weeks of therapy in patients with HCV-RNA >800,000 IU/mL (pooled RR 0.84, 95% CI 0.77 to 0.93, I²=0%) and no difference in those with a viral load less than 800,000 IU/mL (pooled RR 0.99, 95% CI 0.93 to 1.06, I²=0%), the estimates were imprecise and the confidence intervals overlapped.^{68, 70}

Another large trial that compared 48 weeks with 24 weeks of dual therapy with pegylated interferon alfa-2a plus ribavirin found similar rates of SVR in patients with genotype 2 or 3 infection regardless of baseline viral load.⁶³

Triple Therapy With Pegylated Interferon (Alfa-2a or Alfa-2b), Ribavirin, and Boceprevir or Telaprevir

Dual Therapy With Pegylated Interferon Alfa-2b Plus Ribavirin Compared With Dual Therapy With Pegylated Interferon Alfa-2a Plus Ribavirin

Seven head-to-head randomized trials of dual therapy with pegylated interferon alfa-2b plus ribavirin versus dual therapy with pegylated interferon alfa-2a plus ribavirin reported adverse events (Table 8, Appendix H: Evidence Table 1 and Evidence Table 2).^{20–23, 53, 57, 58} Characteristics of the trials were described earlier (see Key Question 2a).

Table 8

Harms: Dual therapy with pegylated interferon alfa-2b plus ribavirin versus dual therapy with pegylated interferon alfa-2a plus ribavirin.

There was no difference between dual therapy with pegylated interferon alfa-2b and dual therapy with pegylated interferon alfa-2a in risk of withdrawal due to adverse events (six trials, pooled RR 1.1, 95% CI 0.73 to 1.7, I²=42%) (Figure 12).^{20, 22, 23, 53, 57, 58} In the largest study, the IDEAL trial, about 13 percent of patients randomized to dual therapy with standard doses of pegylated interferon alfa-2b or pegylated interferon alfa-2a plus ribavirin withdrew due to adverse events, versus about 10 percent in those randomized to low-dose pegylated interferon alfa-2b plus ribavirin.²² Excluding the low-dose pegylated interferon alfa-2b arm of IDEAL from the pooled analysis resulted in a similar pooled estimate (six trials, RR 1.2, 95% CI 0.8 to 1.7, I²=30%).^{20, 22, 23, 53, 57, 58} One outlier trial found dual therapy with pegylated interferon alfa-2b associated with substantially higher risk of withdrawal due to adverse events than dual therapy with pegylated interferon alfa-2a (RR 4.2, 95% CI 1.5 to 12).²⁰ Excluding it eliminated statistical heterogeneity, but the association remained non–statistically significant (five trials, pooled RR 0.88, 95% CI 0.7 to 1.1, I²=0%).^{22, 23, 53, 57, 58}

Figure 12

Withdrawal due to adverse events: Dual therapy with pegylated interferon alfa-2b plus ribavirin versus dual therapy with pegylated interferon alfa-2a plus ribavirin.

Two trials found dual therapy with pegylated interferon alfa-2b plus ribavirin associated with lower risk of serious adverse events than dual therapy with pegylated interferon alfa-2a plus ribavirin (pooled RR 0. 76, 95% CI 0. 61 to 0.95, I²=0%).^{22, 23} In the IDEAL trial, serious treatment-related adverse events occurred in about 4 percent of patients.²² There were no statistically significant differences between regimens in risk of anemia, thrombocytopenia, depression, fatigue, myalgia, or flulike symptoms (Table 8). Dual therapy with pegylated interferon alfa-2b plus ribavirin was associated with slightly greater risk of headache (three trials, pooled RR 1. 1, 95% CI 1.1 to 1. 2, I²=0%)^{20, 22, 57} and slightly lower risk of rash (two trials, pooled RR 0.79, 95% CI 0.71 to 0.88, I²=0%)^{22, 57} and neutropenia (five trials, pooled RR 0.61, 95% CI 0.46 to 0.83, I²=38%)^{20–23, 57} than dual therapy with pegylated interferon alfa-2a plus ribavirin. In the IDEAL trial, dual therapy with either pegylated interferon (alfa-2a or alfa-2b) was associated with fatigue in about 65 percent of patients, headache in about 45 percent, nausea in about 40 percent, and myalgia in about 25 percent, neutrophil count <500/mm³ in about 5 percent, and hemoglobin <8.5 g/dL in about 3 percent.²²

Excluding data from the IDEAL trial²² for patients who received pegylated interferon alfa-2b at a lower dose of 1.0 mcg/kg/week had little effect on pooled results, except the pooled estimate for depression became greater and statistically significant in favor of dual therapy with pegylated interferon alfa-2a (three trials, pooled RR 1.2, 95% CI 1.0 to 1.4, I²=0%)^{20, 22, 57} There was also reduced statistical heterogeneity in the analysis of neutropenia, but the risk estimate was unchanged (five trials, pooled RR 0.64, 95% CI 0.51 to 0.80, I²=0%).^{20–23, 57} Excluding two poor-quality trials^{21, 58} from the pooled analysis also had little effect on estimates.

Trials of Triple Therapy With Pegylated Interferon (Alfa-2a or Alfa-2b), Ribavirin, and Boceprevir or Telaprevir

Five trials of triple therapy with pegylated interferon (alfa-2a or alfa-2b), ribavirin, and either boceprevir or telaprevir versus dual therapy with pegylated interferon (alfa-2a or alfa-2b) plus ribavirin without a protease inhibitor in patients with genotype 1 infection reported adverse events (Appendix H: Evidence Table 3 and Evidence Table 4).^{30–32, 85, 86} Characteristics of the trials were described earlier (see Key Question 2a).

Boceprevir

For boceprevir, two trials evaluated a 48-week fixed duration regimen consisting of dual therapy lead-in for 4 weeks with pegylated interferon alfa-2b plus ribavirin, with the addition of boceprevir from weeks 5 through 48.^{30, 32} Triple therapy was associated with increased risk of neutropenia (two trials, pooled RR 1.8, 95% CI 1.5 to 2.3, I²=0%), dysgeusia (two trials, pooled RR 2.5, 95% CI 2.0 to 3.2, I²=0%), anemia (two trials, pooled RR 2.0, 95% CI 1.4 to 2.8, I²=0%), and thrombocytopenia (two trials, pooled RR 3.2, 95% CI 1.2 to 8.2, I²=0%) versus dual therapy with pegylated interferon alfa-2b plus ribavirin (Table 9). About 25 percent of patients on triple therapy experienced anemia and about 33 percent neutropenia, with an incidence of severe neutropenia (neutrophil count <500 cells per mL) that ranged from 8–15 percent and an incidence of severe anemia (hemoglobin <80 or <85 g/L) of 4–5 percent. In addition, more patients randomized to boceprevir triple therapy used erythropoietin (43 and 87 percent) than those randomized to dual therapy (24 and 33 percent). One of the trials reported similar use of granulocyte stimulating agents with boceprevir triple therapy and dual therapy (8 vs. 6 percent).³² There were no statistically significant differences between triple therapy and dual therapy in risk of withdrawal due to adverse events, serious adverse events, depression, fatigue, headache, myalgia, chills/rigors, rash, or flulike symptoms (Table 9).

Table 9

Harms: Triple therapy with boceprevir, pegylated interferon alfa-2b, and ribavirin versus dual therapy with pegylated interferon alfa-2b plus ribavirin.

Telaprevir

For fixed duration triple therapy with telaprevir (administered during the first 12 weeks in combination with pegylated interferon and ribavirin), we focused on 12- or 24-week regimens, as 48 week triple therapy regimens have not been shown to be more effective than 24 weeks.^{31, 87} There were no differences between a 12-week regimen of triple therapy with telaprevir versus dual therapy with pegylated interferon alfa-2a plus ribavirin for 48 weeks in risk of serious adverse events, neutropenia, anemia, depression, fatigue, headache, myalgia, chills/rigors, rash, or flulike symptoms (Table 10). Rash was reported in 44–77 percent of patients randomized to 12 weeks of triple therapy with telaprevir, with 6 percent of patients reporting severe rash.^{31, 85}

Table 10

Harms: Triple therapy with telaprevir, pegylated interferon (alfa-2a or alfa-2b), and ribavirin versus dual therapy with pegylated interferon (alfa-2a or alfa-2b) plus ribavirin.

A 24-week regimen of triple therapy with telaprevir was associated with increased risk of anemia (three trials, pooled RR 1.3, 95% CI 1.1 to 1.5, I²=0%) and increased risk of rash (three trials, pooled RR 1.4, 95% CI 1.1 to 1.7, I²=0%) versus dual therapy for 48 weeks, but there were no statistically significant differences in risk of serious adverse events, neutropenia, depression, fatigue, headache, chills/rigors, or flulike symptoms (Table 10).^{31, 85, 86} Triple therapy was also associated with increased risk of thrombocytopenia, but this outcome was only evaluated in one trial (RR 1.8, 95% CI 1.2 to 2.5).⁸⁶ One-third to two-thirds of patients randomized to the 24-week regimen with telaprevir experienced a rash, with the incidence of severe rash ranging from 7–10 percent.^{31, 85, 86} The incidence of anemia with telaprevir was 27–91 percent,^{31, 85, 86} with two trials^{31, 85} reporting severe anemia in 4–9 percent of patients and another trial⁸⁶ reporting grade 3 anemia (hemoglobin <8 g/dl) in 11 percent of patients. Two trials found no difference in risk of withdrawal due to adverse events (RR 1.1, 95% CI 0.45 to 2.6, I²=60%).^{85, 86} The third trial did not report withdrawal due to adverse events separately for the 24 week telaprevir regimen, but reported a similar trend towards higher risk of withdrawal due to adverse events for all telaprevir regimens combined (12, 24, or 48 weeks) versus dual therapy (21 vs. 11 percent, RR 2.0, 95% CI 0.97 to 4.1).³¹

One trial evaluated triple therapy with telaprevir for 8 or 12 weeks followed by response-guided dual therapy for 12 or 36 weeks versus dual therapy for 48 weeks.⁵¹ Since the two telaprevir regimens were associated with similar rates of harms, results were combined. The trial found response-guided therapy with telaprevir associated with increased risk of withdrawal due to adverse events (27 vs. 7.2 percent, RR 3.8, 95% CI 2.6 to 5.7), anemia (38 vs. 19 percent, RR 2.0, 95% CI 1.6 to 2.5), any rash (36 vs. 24 percent, RR 1.5, 95% CI 1.2 to 1.8), and severe rash (5 vs. 1 percent, RR 4.6, 95% CI 1.6 to 13).

A trial of extended early virologic responders (undetectable HCV-RNA levels at weeks 4 and 12) to telaprevir triple therapy reported very similar rates of adverse events in patients randomized after 20 weeks of therapy to 4 weeks versus 28 more weeks of dual therapy.⁸⁷ The overall incidence of rash was 38 percent (severe rash 5 percent) and the incidence of anemia 42 percent (severe anemia 6 percent).

All-Cause Mortality, Liver-Related Mortality, and Complications Related to Chronic Hepatitis C Virus Infection

Nineteen cohort studies evaluated the association between achieving an SVR following interferon-based antiviral therapy and mortality (all-cause or liver-related) or complications related to chronic HCV infection, such as HCC, ascites, hepatic encephalopathy, or gastrointestinal bleeding, and these 19 studies reported risk estimates adjusted for potential confounders (Table 11, Appendix F, Appendix H: Evidence Table 9).^{8, 9, 89–105} Sample sizes ranged from 105 to 16,864 subjects and duration of followup ranged from 3 to 9 years. Ten studies were conducted in Asia.^{89, 95–100, 102, 104, 105} Four studies focused on patients who received pegylated interferon (alfa-2a or alfa-2b) plus ribavirin.^{8, 9, 91, 94} The others evaluated patients who received nonpegylated interferon plus ribavirin, or either pegylated or nonpegylated interferon monotherapy. Ten studies^{8, 89, 92, 97–101, 104, 105} evaluated general populations of HCV patients treated with antiviral therapy (baseline rate of cirrhosis ranged from 3–20 percent) and nine studies^{9, 90, 91, 93–96, 102, 103} focused on patients with advanced fibrosis or cirrhosis at the time of antiviral treatment. Six studies^{90, 93–96, 102} enrolled patients with cirrhosis only, and the baseline rate of cirrhosis ranged from 21–77 percent in three others.^{9, 91, 103}

Table 11

Sustained virologic response and clinical outcomes.

All studies had methodological shortcomings (Appendix H: Evidence Table 10). Eight studies^{92–94, 100, 102–105} were rated poor quality and the remainder fair quality. Although all of the studies reported adjusted risk estimates, only eight^{8, 89, 91, 95–98, 101} of the 19 studies evaluated five key potential confounders (age, sex, genotype, viral load, and fibrosis stage). No study clearly described assessment of outcomes blinded to SVR status and only five studies^{8, 94, 97, 98, 102} reported the number of patients who met inclusion criteria but were excluded due to missing data or loss to followup.

For general populations of HCV patients treated with antiviral therapy, the largest study (n=16,864) had the fewest methodological shortcomings and was also conducted in the United States. (Appendix H: Evidence Table 11).⁸ It adjusted for multiple potential confounders, including age, sex, viral load, presence of cirrhosis, multiple comorbidities, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, and others; and stratified results by genotype. In a predominantly male (>95 percent) population of veterans, the study found SVR after antiviral therapy associated with decreased risk of all-cause mortality versus no SVR, after a median followup of 3.8 years (adjusted HR 0.71 [0.60 to 0.86], 0.62 [0.44 to 0.87] and 0.51 [0.35 to 0.75] for genotypes 1, 2, and 3, respectively). Although point estimates showed somewhat smaller effects for genotype 1 compared with genotypes 2 or 3, the confidence intervals for the three genotypes overlapped. The very rapid (within 3 months after assessing for SVR for genotype 3) separation of mortality curves suggests possible residual confounding, given the expected duration required to observe benefits in long-term clinical outcomes. Clinical outcomes other than mortality were not assessed.

Nine other studies also evaluated the association between achieving an SVR and mortality or hepatic complications in general populations of HCV patients (Appendix H: Evidence Table 11).^{89, 92, 97–101, 104, 105} One fair-quality study from Scotland found an SVR after antiviral therapy associated with decreased risk of liver-related mortality (adjusted HR 0.22, 95% CI 0.09 to 0.58) and liver-related hospital episodes (adjusted HR 0.22, 95% CI 0.15 to 0.34) versus no SVR.⁹⁸ One Australian study (poor quality) found no statistically significant association between virologic response status (SVR, response-relapse, or nonresponse) and all-cause mortality, liver-related mortality, or HCC, although trends favored the SVR group.⁹² The other seven studies (three poor quality), all conducted in Asia, each found an SVR after antiviral therapy associated with substantially lower risk of all-cause mortality, liver-related mortality, or HCC versus no SVR.^{89, 97, 99–101, 104, 105} Six studies reported substantially lower risk for all-cause mortality than the U.S. study described above (adjusted HR range 0.12 to 0.39).^{89, 97, 100, 101, 104, 105} For liver-related mortality, four studies^{89, 97, 100, 104} reported adjusted HRs that ranged from 0.04 to 0.17 and for HCC, four studies reported adjusted HRs that ranged from of 0.12 to 0.36.^{89, 99, 101, 105}

Six studies of European or North American populations (two poor quality) evaluated the association between achieving an SVR after antiviral therapy and clinical outcomes in patients with advanced fibrosis and cirrhosis prior to antiviral treatment (Appendix H: Evidence Table 11).^{9, 90, 91, 93, 94, 103} One study (fair quality) found an SVR after antiviral therapy associated with decreased risk of all-cause mortality or liver transplantation versus no SVR (adjusted HR 0.17, 95% CI 0.06 to 0.46).⁹ Another study (poor quality) found an SVR associated with decreased risk of all-cause mortality (adjusted HR 0.31, 95% CI 0.07 to 1.4).¹⁰³ Four studies found an SVR associated with decreased risk of liver-related mortality and HCC versus no SVR (adjusted HRs ranged from 0.12 to 0.27 and from 0.19 to 0.46, respectively).^{9, 90, 91, 103} For complications of chronic HCV infection (variably defined), six studies reported adjusted HRs that ranged from 0.13 to 0.38.^{9, 90, 91, 93, 94, 103} Results from three Asian studies^{95, 96, 102} (one poor quality) were consistent with the North American and European studies. One study¹⁰² found an SVR associated with lower risk of all-cause mortality versus no SVR (adjusted HR 0.07, 95% CI 0.09 to 0.56) and three studies^{95, 96, 102} found an SVR associated with lower risk of HCC versus no SVR (adjusted HR range 0.18 to 0.40).

One study stratified results according to presence or absence of cirrhosis of baseline. Although effects of an SVR versus no SVR on all-cause mortality appeared more favorable in patients with cirrhosis compared with those without cirrhosis, estimates were imprecise and confidence intervals overlapped substantially, precluding strong conclusions.¹⁰⁴

The only study to evaluate the association between improvement in histological outcomes and clinical outcomes did not meet inclusion criteria because it did not report adjusted risk estimates.¹⁰⁶ In 96 patients with chronic HCV infection and cirrhosis, it found regression of cirrhosis (defined as a decrease in METAVIR fibrosis score from 4 to ≤2) after interferon-based therapy associated with decreased risk of liver-related events (ascites, hepatic encephalopathy, variceal bleeding, spontaneous bacterial peritonitis, HCC, or liver transplantation) or death (0 vs. 4 events/100 patients-years, p=0.002) after a median followup of 10.5 years. Transplantation-free survival was 100 percent in patients with regression of cirrhosis compared with 74 percent in those without regression (p=0.02). In addition to failure to analyze potential confounders, the study only included patients who underwent a post-treatment biopsy, which could have resulted in selection bias, and cirrhosis regression only occurred in 13 patients, resulting in low precision.

Quality of Life

Nine cohort studies evaluated the association between an SVR following interferon-based antiviral therapy and outcomes related to quality of life (Appendix H: Evidence Table 12).^107–115 Sample sizes ranged from 138 to 1121. Only one study¹⁰⁷ reported adjusted risk estimates, thus we included studies that reported unadjusted risk estimates. Eight studies^{107, 108, 110–115} evaluated patients originally enrolled in randomized trials^{27, 41, 116–119} of antiviral treatments. Two studies evaluated the same cohort of patients^{113, 115} and one study¹¹⁴ evaluated a cohort of patients included in a study¹⁰⁸ that reported results for three pooled cohorts. One study included patients randomized to pegylated interferon (alfa-2a or alfa-2b) plus ribavirin, although results were not stratified according to what type of antiviral therapy was received.¹¹¹ The remainder of the studies evaluated nonpegylated interferon plus ribavirin combination therapy, or nonpegylated or pegylated interferon monotherapy.

All studies were rated poor quality (Appendix H: Evidence Table 13). One study adjusted for potential confounders,¹⁰⁷ one study reported low loss to followup,¹¹² and one study reported blinding of patients to virologic outcomes.¹¹⁰ Followup was at 24 weeks after treatment (typically 72 weeks from start of treatment) in all studies. No study evaluated longer term quality of life according to SVR status.

All of the studies found patients with an SVR experienced better improvement from baseline on individual SF-36 domains as well as SF-36 physical and mental component summary scores compared with those with no SVR (Appendix H: Evidence Table 14). In most studies, differences between patients with and without an SVR on various SF-36 domains were less than 5 to 10 points. Patients with an SVR also reported greater improvements from baseline on hepatitis C specific quality of life measures (health distress and limitations) and measures related to fatigue and sleep somnolence. However, results are subject to the methodological limitations of the studies.

One study also found achieving an overall response (defined as SVR plus 2-point improvement in the Histological Activity Index) associated with improved quality of life compared with those without an overall response.¹¹³