# Abstract

 Hepatitis C virus genotype 2 (HCV-2) slow responders poorly respond to 24 weeks of peginterferon (Peg-IFN) plus ribavirin (RBV). We evaluated the efficacy of extended 48-week regimen and the role of interleukin-28B (IL-28B) genotype in this clinical setting. Treatment-naïve HCV-2 patients not achieving rapid virologic response (RVR) by Peg-IFN alfa-2a 180 μg/week plus weight-based RBV (1,000--1,200 mg/day, cutoff body weight of 75 kg) were randomly assigned to receive a total duration of 48 (n = 94) or 24 (n = 93) weeks of therapy. The primary endpoint was sustained virologic response (SVR). Baseline patient characteristics to predict SVR were analyzed. Patients receiving 48 weeks of treatment had a greater SVR rate than those receiving 24 weeks of treatment (70.2% versus 46.2%, *P* = 0.001). Compared to patients treated for 24 weeks, the SVR rate in those treated for 48 weeks increased by 10.9% [95% CI: −5.9% to 27.7%] and 65.6% [95% CI: 44.5% to 86.7%] if they had IL-28B rs8099917 TT genotype, and GT/GG genotype, respectively (interaction *P* = 0.002). In conclusion, 48-week treatment with Peg-IFN plus weight-based RBV provides a greater SVR rate than 24-week treatment in treatment-naïve HCV-2 patients with unfavorable IL-28B genotypes who fail to achieve RVR. # Results 

## Patient Characteristics Among the 190 patients not achieving RVR by Peg-IFN plus weight-based RBV therapy, 187 were allocated to a total duration of 48-week (n = 94) or 24-week (n = 93) therapy. Seventy-four (78.7%) and 80 (86.0%) patients assigned to 48-week and 24-week therapies completed treatment, and 87 (92.6%) and 88 (94.6%) patients completed 24 weeks of post-treatment follow-up to assess the SVR rates ([Fig. 1](#)). The baseline patient characteristics were comparable between the two arms ([Table 1](#)).They were slim with an average BMI of 26.3--26.7 kg/m^2^.Most of the patients had high baseline viral load (62--65%) and favorable IL-28B rs8099917 genotype (71--74%), and were infected with 2a subtype (68--71%). With regard to aspartate aminotransferase (AST)-to-platelet ratio index (APRI) score, 23.7--27.7% patients had a score of >2.00. 

## Efficacy The early virologic response (EVR) (91.5% versus 88.2%, RD: 3.3% [95% CI: −5.3% to 12.0%]; *P* = 0.45) and the end-of-treatment virologic response (ETVR) (88.3% versus 80.6%, RD: 7.7% [95% CI: −2.7% to 18.0%]; *P* = 0.15) rates were comparable between the treatment arms. The SVR rate of 48-week treatment was greater than 24-week treatment (70.2% versus 46.2%, RD: 24.0% [95% CI: 10.3% to 37.7%]; *P* = 0.001) ([Table 2](#)). Patients with RBV cumulative exposure \<60% had lower SVR rates than those with RBV cumulative exposure ≥60% in 48-week arm (77.6% versus 38.9%, \*P \*= 0.003) and 24-week arm (53.8% versus 6.7%, \*P \*= 0.001), respectively. 

## Subgroup Analyses for Prespecified Factors Differences of SVR rates between patients receiving 48 and 24 weeks of treatment did not vary by baseline viral load (interaction *P* = 0.82), subgenotype (interaction *P* = 0.89), age (interaction *P* = 0.73), sex (interaction *P* = 0.94), body mass index (BMI) (interaction *P* = 0.26), APRI score (interaction *P* = 0.83) or RBV cumulative exposure (interaction \*P \*= 0.48) ([Table 3](#)). Compared to patients with favorable IL-28B rs8099917 genotype (69.2% versus 58.3%, risk difference (RD): 10.9% [95% CI: −5.9% to 27.7%]), patients with unfavorable IL-28B rs8099917 genotypes receiving 48-week therapy achieved a greater SVR rate than 24-week therapy (73.9% versus 8.3%, RD: 65.6% [95% CI: 44.5% to 86.7%]; interaction *P* = 0.002). The SVR rates of 48-week and 24-week treatment were similar when the patients had BMI >30 kg/m^2^ (52.6% versus 50.0%, RD: 2.6% [95% CI: −33.5% to 38.8%]). 

## Safety The constitutional and laboratory adverse events (AEs) were similar between the two arms ([Table 4](#)). Four and 3 patients in 48-week and 24-week arms had serious AEs during treatment (4.3% versus 3.2%, RD: 1.1% [95% CI: −4.4% to 6.5%]. The AE-related withdrawal rates were 11.7% in 48-week treatment arm and 6.5% in 24-week treatment arm (RD: 5.2% [95% CI: 2.9% to 13.5%]). The rates of anemia beyond week 6 of treatment were 44.7% and 34.4% (RD: 10.3% [95% CI: −3.7% to 24.2%]. <figure> <p><img src="" /></p> <figcaption>Study Flow Diagram. Peg-IFN: peginterferon, RBV: ribavirin; RVR: rapid virologic response, AE: adverse event.</figcaption> </figure> <figure> <p><img src="" /></p> <figcaption>Study Design. Peg-IFN: peginterferon, RBV: ribavirin; RVR: rapid virologic response, ETV: early virologic response, ETVR: end-of-treatment virologic response, SVR: sustained virologic response, SD: weight-based dosing, W: week.</figcaption> </figure> ::::table-wrap

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##

##

## Baseline Patient Characteristics[\*](#).

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Characteristics SD48W, N = 94 SD24W, N = 93

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Mean age (SD), y 56 (12) 56 (13)
Age >50 y 64 (68) 59 (63)
Male sex 51 (54) 52 (56)
Mean weight (SD), kg 69 (13) 69 (11)
Mean BMI (SD), kg/m^2^ 26.7 (4.5) 26.3 (3.5)
BMI (SD), kg/m^2^\
≤27.0 54 (57.4) 52 (55.9)
27.1--30.0 21 (22.3) 29 (31.2)
\>30.0 19 (20.2) 12 (12.9)
Mean hemoglobin level (SD), g/dL 14.4 (1.5) 14.7 (1.4)
Mean white cell count (SD), 10^9^cells/L 5.6 (1.4) 5.8 (1.5)
Mean neutrophil count (SD), 10^9^cells/L 3.0 (1.1) 3.2 (1.2)
Mean platelet count (SD), 10^9^cells/L 175 (61) 182 (64)
Mean albumin level (SD), g/dL 4.3 (0.4) 4.3 (0.3)
Mean total bilirubin level (SD), mg/dL 1.0 (0.4) 1.0 (0.5)
Mean AST quotient (SD), ULN 2.2 (1.2) 2.3 (1.1)
Mean ALT quotient (SD), ULN 3.4 (2.1) 3.8 (2.3)
Mean APRI score (SD) 1.5 (1.0) 1.5 (1.1)
APRI score\
≤1.50 56 (59.6) 50 (53.8)
1.51--2.0 12 (12.7) 21 (22.5)
\>2.00 26 (27.7) 22 (23.7)
Mean HCV RNA level (SD), log~10~ IU/mL 6.0 (0.9) 6.0 (0.6)
HCV RNA level, IU/mL\
≤800,000 33 (35) 35 (38)
\>800,000 61 (65) 58 (62)
Subgenotype\
2a 64 (68) 66 (71)
2b 24 (26) 20 (22)
2a + 2b 6 (6) 7 (8)
IL-28B rs8099917 genotype[†](#)\
TT 65 (74) 60 (71)
GT and GG 23 (26) 24 (29)

SD: standard deviation, BMI: body mass index, AST: aspartate
aminotransferase, ALT: alanine aminotransferase, ULN: upper limit of
normal, APRI: aspartate aminotransferase to platelet ratio index, HCV:
hepatitis C virus, IU: international unit, IL: interleukin, SD48W: 48
weeks of peginterferon alfa-2a plus weight-based ribavirin, SD24W: 24
weeks of peginterferon alfa-2a plus weight-based ribavirin.

^\*^Values are numbers (percentages) unless otherwise indicated.

^†^Available number of patients (%) for analysis: 88 (94%) and 84 (90%)
in SD48W and SD24W arms, respectively.:::: ::::table-wrap
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##

##

## On-treatment and Off-treatment Virologic Responses.

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Variable SD48W, n/N (%) SD24W, n/N (%) RD (95% CI) *P* value[\*](#)

______________________________________________________________________

On-treatment virologic response\
EVR 86/94 (91.5) 82/93 (88.2) 3.3 (−5.3 to 12.0) 0.45
ETVR 83/94 (88.3) 75/93 (80.6) 7.7 (−2.7 to 18.0) 0.15
Virologic outcome\
SVR[†](#) 66/94 (70.2) 43/93 (46.2) 24.0 (10.3 to 37.7) 0.001
Non-SVR 28/94 (29.8) 50/93 (53.8)
Relapse 12/94 (12.8) 28/93 (30.1)
Null-response[‡](#) 9/94 (9.6) 12/93 (12.9)
Viral breakthrough[§](#) 2/94 (2.1) 5/93 (5.4)
Undetermined[||](#) 5/94 (5.3) 5/93 (5.4)

RD; risk reduction, EVR: early virologic response, ETVR:
end-of-treatment virologic response, SVR: sustained virologic response,
CI: confidence interval.

^\*^P values were obtained by Wald asymptotic test.

^†^Patients who were lost to 24-week follow-up, were null-responsive to
treatment, or had viral breakthrough or relapsed after treatment were
considered failure to achieve SVR.

^‡^SD48W arm: 5 patients failed to achieve EVR; 4 patients achieved EVR
but remained viremic at week 24 of treatment. SD24W arm: 7 patients
failed to achieve ETR; 5 patients achieved EVR but remained viremic at
week 24 of treatment.

^§^SD48W arm: 2 patients had viral breakthrough at week 48 of treatment.
SD24W arm: 5 patients had viral breakthrough at week 24 of treatment.

^||^All patients lost to 24-week post-treatment follow-up, and all had
undetectable HCV RNA level at the time of treatment discontinuation.
SD48W arm: 3 completed 48 weeks of treatment, and 2 prematurely
discontinued treatment at weeks 36 and 40 due to serious adverse events.
SD24W arm: 2 completed 24 weeks of treatment, 2 prematurely discontinued
treatment at weeks 12 and 16 due to serious adverse events and 1
prematurely discontinued treatment at week 12 due to constitutional
adverse event.:::: ::::table-wrap
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##

##

## Subgroup Analyses of Prespecified Factors for SVR.

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Variable SD48W, n/N (%) SD24W, n/N (%) RD (95% CI) *P*value for interaction[\*](#)

______________________________________________________________________

Baseline viral load       0.82
≤800,000 IU/mL 27/33 (81.8) 21/35 (60.0) 21.8 (0.9 to 42.7)
\>800,000 IU/mL 39/61 (63.9) 22/58 (37.9) 26.0 (8.7 to 43.3)
Subgenotype       0.89
2a 44/64 (68.8) 31/66 (45.5) 21.8 (5.2 to 38.3)
2b 18/24 (75.0) 10/20 (50.0) 25.0 (−2.9 to 52.9)
2a+2b 4/6 (67.7) 3/7 (42.9) 23.8 (−28.8 to 76.4)
IL-28B rs8099917 genotype[†](#)       0.002
TT 45/65 (69.2) 35/60 (58.3) 10.9 (−5.9 to 27.7)
GT and GG 17/23 (73.9) 2/24 (8.3) 65.6 (44.5 to 86.7)
Age       0.73
≤50 y 23/30 (76.7) 17/34 (50.0) 26.7 (4.1 to 49.3)
\>50 y 43/64 (67.2) 26/59 (44.1) 23.1 (6.1 to 40.2)
Sex       0.94
Female 30/43 (69.8) 19/41 (46.3) 23.4 (2.9 to 44.0)
Male 36/51 (70.6) 24/52 (46.2) 24.4 (6.0 to 43.0)
BMI       0.26
≤27.0 kg/m^2^ 41/54 (75.9) 25/52 (48.1) 27.9 (10.1 to 45.6)
27.1--30.0 kg/m^2^ 15/21 (71.4) 12/29 (41.4) 30.1 (3.7 to 56.4)
\>30.0 kg/m^2^ 10/19 (52.6) 6/12 (50.0) 2.6 (−33.5 to 38.8)
APRI score       0.83
≤1.50 38/56 (67.9) 23/50 (46.0) 21.9 (3.4 to 40.3)
1.51--2.00 9/12 (75.0) 9/21 (42.9) 32.1 (−0.2 to 64.5)
\>2.00 19/26 (73.1) 11/22 (50.0) 23.1 (−3.9 to 50.0)
RBV cumulative exposure       0.48
\<60% 7/18 (38.9) 1/15 (6.7) 32.2 (6.4 to 58.4)
60%--80% 15/19 (77.8) 9/20 (45.0) 34.0 (5.5 to 62.4)
≥80% 44/57 (77.2) 33/58 (56.9) 20.3 (3.5 to 37.1)

RD: risk reduction, CI: confidence interval, IL: interleukin, BMI: body
mass index, APRI: aspartate aminotransferase to platelet ratio index

^\*^The interaction for the prespecified factors was compared by
stratified Mantel-Haenszel test.

^†^Available number of patients (%) for analysis: 88 (94%) and 84 (90%)
in SD48W and SD24W arms, respectively.:::: ::::table-wrap
::: caption



##

##

## Adverse Events, Dose reduction and Treatment Discontinuation in Treated Patients [\*](#).

:::

Parameter SD48W, N = 94 SD24W, N = 93

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Serious AEs\
All[†](#) 4 (4.3) 3 (3.2)
Death 0 (0) 0 (0)
Treatment-related 3 (3.2) 3 (3.2)
Treatment withdrawal due to AEs 11 (11.7) 6 (6.5)
Dose reduction to AEs\
Peginterferon 23 (24.5) 20 (21.5)
Ribavirin 45 (47.9) 35 (37.6)
Constitutional AEs\
Flu-like symptoms 29 (30.9) 27 (29.0)
Fatigue 57 (60.6) 54 (58.1)
Headache 26 (27.7) 28 (30.1)
Insomnia 34 (36.2) 33 (35.5)
Irritability 11 (11.7) 10 (10.8)
Depression 14 (14.9) 12 (12.9)
Anorexia 30 (31.9) 27 (29.0)
Diarrhea 12 (12.8) 12 (12.9)
Constipation 11 (11.7) 8 (8.6)
Cough 14 (14.9) 15 (16.1)
Dermatitis 28 (29.8) 25 (26.9)
Injection site reaction 15 (16.0) 13 (14.0)
Hair loss/alopecia 25 (26.6) 24 (25.8)
Laboratory AEs[‡](#)\
Anemia (week 1--6)[§](#) 7 (7.4) 6 (6.5)
Hemoglobin level: 8.5--9.9 g/dL 6 (6.4) 5 (5.4)
Hemoglobin level: \<8.5 g/dL 1 (1.1) 1 (1.1)
Anemia (week 6 to end-of-treatment)[§](#) 42 (44.7) 32 (34.4)
Hemoglobin level: 8.5--9.9 g/dL 27 (28.7) 22 (23.7)
Hemoglobin level: \<8.5 g/dL 15 (16.0) 10 (10.8)
Neutropenia 17 (18.1) 14 (15.1)
Neutrophil count: 0.500--0.749 × 10^9^ cells/L 13 (13.8) 11 (11.8)
Neutrophil count: \<0.500 × 10^9^ cells/L 4 (4.3) 3 (3.2)
Thrombocytopenia 9 (9.6) 11 (11.8)
Platelet count: 25--49 × 10^9^ cells/L 8 (8.5) 10 (10.8)
Platelet count: \<25 × 10^9^ cells/L 1 (1.1) 1 (1.1)
ALT elevation

> 2 times ULN 16 (17.0) 18 (19.4)
> 5 times ULN 2 (2.1) 3 (3.2)
> Total bilirubin elevation[¶](#)\
> 2 mg/dL 5 (5.3) 4 (4.3)
> 5 mg/dL 0 (0.0) 0 (0.0)

AE: adverse event, ALT: alanine aminotransferase, ULN: upper limit of
normal.

^\*^Values are numbers (percentages).

^†^SD48W arm: spontaneous bacterial peritonitis at week 36 of treatment,
cellulitis at week 20 of treatment, severe anemia with postural
dizziness at week 12 of treatment (hemoglobin level: 7.1 g/dL), and
multiple myeloma at week 40 of treatment. SD24W arm: urinary tract
infection at week 12 of treatment, community-acquired pneumonia at week
16 of treatment, severe anemia with postural dizziness at week 16 of
treatment (hemoglobin level: 7.3 g/dL), respectively. All except the
patients developing multiple myeloma were considered treatment-related.

^‡^The grading of the laboratory AEs was shown for patients with the
on-treatment nadir level.

^§^Anemia was defined as a nadir hemoglobin level \<10.0 g/dL.

^¶^No patient with total bilirubin elevation had concomitant ALT
elevation >5 times ULN.::::


Extracted trial result:
Outcome: The SVR rates when the patients had BMI >30 kg/m2 (binary)
Intervention: peginterferon (Peg-IFN) plus ribavirin (RBV) for 48 weeks
Comparator: peginterferon (Peg-IFN) plus ribavirin (RBV) for 24 weeks
Intervention events: 10
Intervention group size: 19
Comparator events: 6
Comparator group size: 12
Notes: Even though the outcome says rate, the way that the results are reported in the table makes it easier to calculate as binary outcome.