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Patients and Methods
Patients
Male and female patients aged 18–70 years with HCV genotypes 1, 3 and 6 infection who had not received antiviral therapy were eligible for enrolment and had to fulfil the following entry criteria: HCV RNA level more than 10 000 IU/mL; increased serum alanine aminotransferase (ALT) levels at screening and liver biopsy performed within 12 months preceding study enrolment confirming chronic hepatitis. Exclusion criteria were as follows: decompensated liver disease; hepatitis B virus (HBV) or human immunodeficiency virus (HIV) co-infection; other causes of liver disease; active injection drug use or alcohol dependence (self-reported intake, ≥40 g/day in women and ≥60 g/day in men); pregnancy or breast-feeding; serum creatinine level ≥1.5 mg/dL; haemoglobin concentration, <11 g/dL in women or <12 g/dL in men; neutrophil count, <1500 cells/mm; platelet count, <80 000 platelets/mm; a major psychiatric illness; seizure disorder; serious co-morbid conditions and evidence of malignant neoplastic diseases.
Study Design
This pilot prospective study was conducted in a single tertiary hospital (King Chulalongkorn Memorial Hospital) in Bangkok, Thailand from May 2009 to April 2011. The protocol of the study had been approved by the Institutional Review Board, and all participants had provided written informed consent. The study followed the Helsinki Declaration and Good Clinical Practice guidelines. To compare the response rate of HCV genotype 6 with those of genotypes 1 and 3, patients infected with genotypes 1, 3 and 6 were enrolled on a 1:1:2 basis. All patients received PEG-IFN-α2a (Pegasys; Roche Pharmaceuticals, Bangkok, Thailand) 180 μg/week plus weight-based RBV (Copegus; Roche Pharmaceuticals) according to the following body weights: ≤75 kg, 1000 mg/day; and >75 kg, 1200 mg/day. Regarding treatment duration, patients infected with HCV genotype 1 (group 1) and HCV genotype 3 (group 3) were treated for a fixed duration of 48 and 24 weeks, respectively. Patients infected with HCV genotype 6 (group 6) who achieved RVR were assigned to treatment for 24 weeks [response-guided therapy (RGT)-group 6] and the remaining patients were treated for 48 weeks [standard therapy (ST)-group 6].
Patients with undetectable HCV RNA at week 12 were defined as having a complete early virological response (cEVR), whereas those with a minimum 2-log10 decrease from the baseline in HCV RNA at week 12 were defined as having a partial early virological response (pEVR). Patients with no or minimal change in HCV RNA levels (<2-log10 decrease from the baseline at week 12) were defined as nonresponders and therapy was discontinued. All patients who completed the treatment were followed up for an additional 24 weeks after the end of therapy to assess SVR.
Laboratory Tests
HCV genotype was determined by nucleotide sequencing of the core and NS5B regions followed by phylogenetic analysis as described previously. The levels of serum HCV RNA were assessed at baseline; at weeks 4, 12, 24, end-of-treatment and at 24 weeks of follow-up by real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR) (COBAS TaqMan HCV assay; Roche Diagnostics, Basel, Switzerland), in accordance with the manufacturer's instructions.
Assessment of Efficacy
The primary efficacy end point was to achieve SVR, defined as undetectable HCV RNA 24 weeks after the end-of-treatment. Treatment failures were defined as follows: breakthrough (reappearance of HCV RNA during antiviral treatment period), relapse (reappearance of HCV RNA during follow-up period in patients with an end-of-treatment virological response), and nonresponse (a decrease in the HCV RNA level <2 log10 after 12 weeks of treatment or detectable viral load at week 24), or discontinuation (treatment withdrawal for any reason). Secondary end points were to study the variables associated with SVR and to investigate the efficacy of week 4 virological response to predict treatment outcome.
Assessment of Safety
Safety was assessed through the monitoring of adverse events and laboratory tests at weeks 2, 4, 6 and 8 then monthly thereafter during treatment and at weeks 12 and 24 after therapy discontinuation. Any life-threatening adverse event prompted treatment withdrawal. Stepwise reduction of RBV dosage of 200 mg/day and reductions of PEG-IFN-α2a dose to 135 and 90 μg/week were permitted to manage adverse events or laboratory abnormalities. Hematopoietic growth factors for the management of significant haematological toxicity were not used in this study.
Statistical Analysis
The rates of SVR in each group of patients were calculated on an intention-to-treat basis. The Mann–Whitney's U test or Student's test were used to compare continuous variables, and the χ test or Fisher's exact test were used to compare categorical variables. Univariate and multivariate logistic regression analysis was used to assess odd ratios relating pretreatment variables and viral kinetics associated with SVR. P < 0.05 for a two-tailed test was considered statistically significant. All statistical analyses were performed using the SPSS software for Windows version 17.0 (SPSS, Chicago, IL, USA).
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