ANALISIS DINAMICO

Chung and colleagues:68

data extraction and

critical appraisal

Reference and design Intervention Participants Outcome measures

Chung et al., 200468

Trial design:Multicentre RCT Country:USA Sponsor:National Institutes of Health Intervention 1: n= 66 PEG 2a (s.c.): Dose: 180 µg once weekly Duration: 48 weeks RBV (oral): Dose: 600 mg daily Duration: 4 weeks Dose: 800 mg daily Duration: 4 weeks Dose: 1000 mg daily Duration: 40 weeks Intervention 2: n= 67 IFN 2a (s.c.): Dose: 6 million IU three times per week Duration: 12 weeks Dose: 3 MU three times per week Duration: 36 weeks RBV (oral): Dose: 600mg daily Duration: 4 weeks Dose: 800 mg daily Duration: 4 weeks Dose: 1000 mg daily Duration: 40 weeks

Total numbers involved:133 randomised and analysed

Eligibility:HIV-infected patients, aged

≥18 years, confirmed diagnosis of chronic hepatitis C (>600 IU/ml HCV RNA level), biopsy findings consistent with the presence of chronic hepatitis C, not previously treated with IFN, normal or elevated ALT levels, cirrhosis acceptable provided there was no evidence of hepatic decompensation (i.e. ascites, encephalopathy, jaundice, hypoalbuminaemia or coagulopathy)

Recruitment:21 centres in the USA between December 2000 and June 2001

Exclusion criteria: clinically significant anaemia, neutropenia or thrombocytopenia; renal disease; positive tests for hepatitis B surface antigen; uncontrolled

cardiopulmonary disease; poorly controlled psychiatric disease; active HIV-related opportunistic infection

Baseline measurements:

Viral load, HCV RNA level ×10–6_IU/ml

Mean (± SD):

6.2 (± 0.4) Group 1, 6.2 (± 0.3) Group 2 >1 ×106IU/ml, %:

83% Group 1, 82% Group 2

ALT,abnormal level, %: 66% Group 1, 68% Group 2

Histology:

Classification system used: Ishak Fibrosis score, median: 2.0 Group 1, 2.0 Group 2

Cirrhosis, %: 11% Group 1, 9% Group 2 Hepatitis activity index score, median: 5.0 Group 1, 5.0 Group 2

Timing of liver biopsy: within 48 weeks before study entry

Genotype 1, %: 77% Group 1, 78% Group 1

Gender, no. (%): 109 male (82%), 24 female (18%)

Age, mean:45 years Group 1, 44 years Group 2 Primary outcomes: Virological response at week 24 of treatment Secondary outcomes: ● SVR ● end of treatment virological response ● early virological response ● histological response ● adverse events Length of follow-up: 24 weeks after completion of therapy continued

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Reference and design Intervention Participants Outcome measures

Outcome, no. (%) PEG 2a + RBV IFN 2a + RBV p-Value (between-group comparison)

Viral response:

24 weeks 29/66 (44%) 10/67 (15%) <0.001 End of treatment (48 weeks) 27/66 (41%) 8/67 (12%) <0.001 SVR at follow-up 18/66 (27%) 8/67 (12%) 0.03 SVR by genotype:

1 7/51 (14%) 3/52 (6%)

Non-1 11/15 (73%)a 5/15 (33%)a 0.07 Histology

No virological response at week 24: (n = 37) (n = 57) Histological response 9/26b_{(35%) 16/45}c_(36%)

Virological response at week 24: (n = 39) Histological improvement 14/27d_(52%)

No change 11/27d_(41%)

Worsening disease 2/27d(7%)

Adverse events at weeks 0–24, (n = 66) (n = 67) no. of subjectse: Grade 2/3/4f Grade 2/3/4f

Signs and symptoms 26/15/0 20/19/1 Influenza-like symptoms 19/12/0 20/13/0

Depression 5/2/0 6/2/0

Abnormal laboratory values 18/22/15 26/21/4

Anaemia 0/0/2 1/0/0

Neutropenia 13/18/5 10/7/3 Thrombocytopenia 10/2/1 2/0/0 Glucose high or low 12/3/4 14/2/0

ALT high 18/2/0 12/7/0

Lipase high 5/4/0 6/3/0

Lactate high 0/0/0 0/1/0

Adverse events at weeks 25–72, (n = 35) (n = 26)g no. of subjectse: Grade 2/3/4f Grade 2/3/4f

Signs and symptoms 10/4/0 7/3/0 Influenza-like symptoms 5/3/0 4/1/0

Depression 1/1/0 0/0/0

Abnormal laboratory values 13/10/7 8/4/1

Anaemia 0/0/1 0/0/0

Neutropenia 7/6/4 1/2/0

Thrombocytopenia 3/0/0 0/0/0 Glucose high or low 5/4/1 4/1/0

ALT high 5/2/0 1/0/1

Lipase high 3/1/0 2/1/0

Lactate high 0/0/0 0/0/0

Dose discontinuation 8 8

Ethnic groups, no. (%):

White: 64 (48%) Black: 44 (33%) Hispanic: 18 (14%) Other: 7 (5%)

Mode of infection, no. (%):not reported

Losses to follow up:8 subjects in each group (12%) were prematurely withdrawn from treatment because of abnormalities in laboratory values or adverse events

Compliance:0

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Outcome, no. (%) PEG 2a + RBV IFN 2a + RBV p-Value (between group comparison)

a _{p < 0.001 for comparison with genotype 1.} b _{26 of 37 subjects underwent liver biopsy.} c _{45 of 57 subjects underwent liver biopsy.}

d _{27 of 39 subjects underwent liver biopsy at week 48.} e _{Subjects could have >1 adverse event.}

f _{Grade 2 indicates a moderate adverse event, grade 3 a severe adverse event, grade 4 a potentially life-threatening adverse}

event.

g _{Included 3 subjects who continued treatment beyond week 24 while awaiting liver biopsy.}

Additional results: Virological response:

● In genotype 1 subjects at week 24, the virological response was 33% (17/51) and 8% (4/52) for PEG and IFN, respectively (p= 0.001); in genotype non-1 (predominantly genotypes 2 and 3), the virological response was 80% (12/15) and 40% (6/15) for PEG and IFN, respectively.

● In genotype 1 subjects at the end of treatment, the virological response was 29% (15/51) and 6% (3/52) for PEG and IFN, respectively; in genotype non-1, the virological response was 80% (12/15) and 33% (5/15) for PEG and IFN, respectively (p< 0.001 for genotype non-1 vs genotype 1 for the PEG group).

● Receipt of PEG + RBV, genotype non-1, absence of prior injection drug use, a detectable level of HIV-1 RNA at entry, and a Karnofsky score of 100 were predictive of an SVR in univariate analysis. In multivariate analysis, all these variables except the Karnofsky score independently predicted an SVR.

● Of the 106 subjects in whom HCV RNA levels were measured at week 12, 43 (41%) had an early virological response; 22 of these 43 subjects (51%) had an SVR. In contrast, none of the 63 subjects who did not have an early virological response had an SVR (negative predictive value, 100%).

Safety:

● The rate of premature withdrawal (12%) was similar to that in similar studies of subjects with HCV monoinfection. Also, see

Attrition/drop-outbelow.

● 2 subjects in the PEG group discontinued therapy because of grade 4 neutropenia (<500 neutrophils/mm3_{). In 6 others (3}

PEG, 3 IFN), grade 4 neutropenia was successfully managed with a dose reduction, with or without haematopoietic growth factor.

● There was one hospitalisation due to clinically significant pancreatitis, and treatment was discontinued at week 16. The subject was also receiving didanosine. Of 18 subjects with lipase elevations of grade 2 or higher, 4 were taking didanosine.

Methodological comments:

Allocation to treatment groups:randomisation was stratified according to HCV genotype (1 vs non-1) and antiretroviral therapy

status (current vs none). No details reported on actual randomisation method.

Allocation concealment:not reported.

Blinding of outcome assessors:a central pathologist assessed histologic response; no further details reported.

Analysis by ITT:reports that data were assessed using ITT analysis. Results were reported for all 133 randomised patients.

Comparability of treatment groups at pretreatment:there were no statistically significant differences between groups at baseline

for demographics, histology, biochemical or HIV-related characteristics.

Method of data analysis:Associations between dichotomous variables were evaluated with Fisher’s exact test. Associations

involving ordered categorical data or continuous data were evaluated with a Wilcoxon test adjusted for ties. Univariate- and multicovariate-adjusted p-values for the association of the virological response at week 24 with covariates were evaluated with logistic regression stratified according to the HCV genotype and HIV treatment history. All p-values were two-sided. Univariate analyses of SVR were performed with log-rank tests and multicovariate analyses with proportional hazards regression. Because of the limited sample size and because SVR was not a primary outcome, these tests were not stratified according to the group or the HCV genotype. The proportion of subjects who continued to have SVR was estimated with the use of the life-table method.

Power analysis: the study was designed to have a statistical power of 80% (with a two-sided ␣value of 0.05) to detect an

absolute difference in the rate of virological response between groups of 30%. The target sample size of 132 was adjusted for a group-sequential design.

Attrition/drop-out:8 subjects in each group (12%) were prematurely withdrawn from treatment because of abnormalities in

laboratory values or other adverse events. Of the 16 subjects, 3 declined further participation and 1 died of unrelated causes. The remaining 12 were withdrawn because of neuropsychiatric issues (primarily depression) or the need to manage multiple signs and symptoms and abnormal lab values.

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General comments

Generalisability:subjects were co-infected with HIV.

Conflict of interests: six authors reported having received consulting fees or grant support from a range of pharmaceutical

companies; 3 of these authors received fees/support from Roche and Schering-Plough.

Other:study design – treatment duration was 48 weeks. However, an efficacy and safety assessment was performed at week 24

to determine whether subjects could continue. Subjects who had a virological response continued treatment until week 48, at which time they had a liver biopsy. Subjects with no virological response at week 24 underwent a liver biopsy at that time. Those with a histological response continued treatment until week 48; those with no histological response or who did not undergo biopsy stopped taking the study drug.

Definitions:SVR, HCV RNA level <60 IU/ml 24 weeks after completion of therapy, allowing a 6-week window for the sample;

end of treatment response, HCV RNA level <60 IU/ml at the completion of therapy; early virological response, the clearance of HCV RNA or a reduction in HCV RNA levels by more than 2 log (on a base-10 scale) IU/ml at 12 weeks of treatment;

histological response, an improvement in the total hepatic activity index of at least two points as judged by a pathologist.

Quality criteria (NHS CRD Report 4)

1. Was the assignment to the treatment groups really random? Unknown 2. Was the treatment allocation concealed? Unknown 3. Were the groups similar at baseline in terms of prognostic factors? Reported 4. Were the eligibility criteria specified? Adequate 5. Were outcome assessors blinded to the treatment allocation? Unknown 6. Was the patient blinded? Not applicable as

trial was open-label 7. Were the point estimates and measure of variability presented for the primary outcome measure? Inadequate 8. Did the analysis include an ITT analysis? Adequate 9. Were losses to follow-up completely described? Adequate

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