Adherence to response-guided pegylated interferon and ribavirin for people who inject drugs with hepatitis C virus genotype 2/3 infection: the ACTIVATE study.

BACKGROUND: The aims of this analysis were to investigate treatment completion and adherence among people with ongoing injecting drug use or receiving opioid substitution therapy (OST) in a study of response-guided therapy for chronic HCV genotypes 2/3 infection. METHODS: ACTIVATE was a multicenter clinical trial recruited between 2012 and 2014. Participants with genotypes 2/3 were treated with directly observed peg-interferon alfa-2b (PEG-IFN) and self-administered ribavirin for 12 (undetectable HCV RNA at week 4) or 24 weeks (detectable HCV RNA at week 4). Outcomes included treatment completion, PEG-IFN adherence, ribavirin adherence, and sustained virological response (SVR, undetectable HCV RNA >12 weeks post-treatment). RESULTS: Among 93 people treated, 59% had recently injected drugs (past month), 77% were receiving OST and 56% injected drugs during therapy. Overall, 76% completed treatment. Mean on-treatment adherence to PEG-IFN and ribavirin were 98.2% and 94.6%. Overall, 6% of participants missed >1 dose of PEG-IFN and 31% took <95% of their prescribed ribavirin., Higher treatment completion was observed among those receiving 12 vs. 24 weeks of treatment (97% vs. 46%, P < 0.001) while the proportion of participants with 95% on-treatment ribavirin adherence was similar between groups (67% vs. 72%, P = 0.664). Receiving 12 weeks of therapy was independently associated with treatment completion. No factors were associated with 95% RBV adherence. Neither recent injecting drug use at baseline nor during therapy was associated with treatment completion or adherence to ribavirin. In adjusted analysis, treatment completion was associated with SVR (aOR 23.9, 95% CI 2.9-193.8). CONCLUSIONS: This study demonstrated a high adherence to directly observed PEG-IFN and self-administered ribavirin among people with ongoing injecting drug use or receiving OST. These data also suggest that shortening therapy from 24 to 12 weeks can lead to improved treatment completion. Treatment completion was associated with improved response to therapy. ACTIVATE trial registration number: NCT01364090 - May 31, 2011.

ITPA genotype protects against anemia during peginterferon and ribavirin therapy but does not influence virological response.

UNLABELLED: On-treatment anemia is associated with higher sustained virological response (SVR) rates during peginterferon plus ribavirin (RBV) therapy. Inosine triphosphatase (ITPA) variants causing ITPase deficiency have been shown to protect against RBV-induced anemia. However, ITPase activity has not been associated with SVR. To study this discrepancy, we examined the relationships between ITPase activity, on-treatment anemia, SVR, and RBV levels in hepatitis C virus genotype 1 (HCV-1) patients from the CHARIOT study. ITPA genotype (rs7270101, rs1127354) was used to define ITPase activity in 546 patients. Plasma RBV levels were measured using high-performance liquid chromatography (HPLC). Relationships between ITPase activity, on-treatment hemoglobin (Hb) levels, RBV levels, and SVR were tested using regression modeling, survival analysis, and locally weighted scatterplot smoothing (LOWESS) plot analysis. Hb decline was independently associated with SVR (P<0.0001). ITPase deficiency was present in 35%. ITPase deficiency strongly protected against Hb decline (P<0.0001), but was not associated with SVR (P=0.28). The probability of SVR increased with lower nadir Hb for both wild-type and deficient ITPase activity, but the association curve shifted to describe a parallel relationship at higher Hb levels in patients with ITPase deficiency. In a subset (n=203), we tested the hypothesis that the association between Hb decline and SVR reflected RBV levels rather than actual Hb level. RBV levels were associated with on-treatment Hb decline and SVR, but not ITPase activity. In regression models, adjustment for RBV levels attenuated the association between Hb decline and SVR. CONCLUSION: ITPase deficiency protects against RBV-induced anemia, but is not associated with SVR. Our data suggest that the relationship between Hb decline and SVR is not mechanistic, but is linked to RBV levels.

Randomized controlled trial of danoprevir plus peginterferon alfa-2a and ribavirin in treatment-naïve patients with hepatitis C virus genotype 1 infection.

BACKGROUND & AIMS: The combination of a hepatitis C virus (HCV) protease inhibitor, peginterferon, and ribavirin is the standard of care for patients with HCV genotype 1 infection. We report the efficacy and safety of response-guided therapy with danoprevir (a potent second-generation protease inhibitor), peginterferon alfa-2a (40 KD), and ribavirin in these patients. METHODS: Treatment-naïve patients (N = 237) were randomly assigned to groups given 12 weeks of danoprevir (300 mg every 8 hours; 600 mg every 12 hours, and 900 mg every 12 hours) or placebo plus peginterferon alfa-2a and ribavirin, followed by peginterferon alfa-2a and ribavirin. Patients given danoprevir who had an extended rapid virologic response (eRVR4-20: HCV RNA <15 IU/mL during weeks 4-20) stopped therapy at week 24; those without an eRVR4-20 continued therapy to 48 weeks. Patients who were given placebo received 48 weeks of peginterferon alfa-2a and ribavirin. The primary efficacy end point was sustained virologic response (SVR: HCV RNA <15 IU/mL after 24 weeks without treatment). RESULTS: Rates of SVR were higher among patients given danoprevir 300 mg (68%), 600 mg (85%), and 900 mg (76%) than placebo (42%) (95% confidence interval: 26%-59%). Seventy-nine percent of patients given danoprevir 600 mg had an eRVR4-20; among these, 96% had an SVR. Serious adverse events were reported in 7% to 8% of patients given danoprevir and 19% given placebo. Four patients given danoprevir (1 patient in the 600-mg group and 3 in the 900-mg group) had reversible, grade 4 increases in alanine aminotransferase, which led to early discontinuation of the 900-mg arm of the study. CONCLUSIONS: The combination of danoprevir, peginterferon alfa-2a, and ribavirin leads to high rates of SVR in patients with HCV genotype 1 infection, but high doses of danoprevir can lead to grade 4 increases in alanine aminotransferase. Studies of lower doses of danoprevir with ritonavir, to reduce overall danoprevir exposure while maintaining potent antiviral activity, are underway; Clinicaltrials.gov number, NCT00963885.

Vitamin D status does not predict sustained virologic response or fibrosis stage in chronic hepatitis C genotype 1 infection.

BACKGROUND & AIMS: The relationship between vitamin D status and response to antiviral therapy and liver histology in hepatitis C virus genotype 1 (HCV-1) infection remains unclear, with studies to date yielding inconsistent results and failing to use reference assay methodology. We therefore analyzed pre-treatment 25-hydroxyvitamin D [25(OH)D] level, using reference liquid chromatography-tandem mass spectrometry methodology, in a cohort of treatment-naïve patients with HCV-1 to evaluate the association between vitamin D status, virologic response, and liver histology. METHODS: 274 patients, with pre-treatment liver biopsy and up to 48 weeks of pegylated interferon alfa-2a plus ribavirin therapy, were tested for serum 25(OH)D level. Predictors of sustained virologic response (SVR), and variables associated with fibrosis stage, activity grade and 25(OH)D status were identified using multivariate analysis. RESULTS: Mean 25(OH)D level was 79.6 nmol/L, with a prevalence of 25(OH)D <75 nmol/L and <50 nmol/L of 48% and 16%, respectively. Season, race and geographic latitude were independent predictors of 25(OH)D status, while vitamin D deficiency was more prevalent in those with high activity grade (21% vs. 11%; p=0.03). Mean 25(OH)D level was lower (76.6 vs. 84.7 nmol/L; p=0.03) and 25(OH)D <75 nmol/L more prevalent (53% vs. 40%; p=0.03) in patients with an SVR, but no association between 25(OH)D status and SVR was found in multivariate analysis. Mean 25(OH)D level did not vary between fibrosis stage or activity grade. CONCLUSIONS: Baseline 25(OH)D level is not independently associated with SVR or fibrosis stage in HCV-1, but vitamin D deficiency is associated with high activity grade.

Virological response is associated with decline in hemoglobin concentration during pegylated interferon and ribavirin therapy in hepatitis C virus genotype 1.

UNLABELLED: Anemia may increase the likelihood of achieving a sustained virological response (SVR) during pegylated interferon and ribavirin treatment of hepatitis C virus (HCV) infection. To determine whether hemoglobin decline is associated with SVR, we retrospectively evaluated the CHARIOT study of 871 treatment-naïve HCV genotype 1 patients. Anemia (serum hemoglobin <100 g/L) occurred in 137 (16%) patients, of whom only 14 (10%) received erythropoietin. Hemoglobin decline >30g/L from baseline occurred in 76% of patients overall, including 526 patients who did not become anemic. Virological responses were higher in anemic patients compared with those who did not develop anemia (end of treatment, 80% versus 65%, P = 0.003; SVR, 61% versus 50%, P = 0.02); these differences remained significant when patients receiving erythropoietin were excluded from analysis. SVR was also higher in patients with hemoglobin decline >30 g/L compared with patients without a similar decline. In multiple logistic regression analyses with treatment group and baseline characteristics, the odds ratio for SVR was 1.97 (95% confidence interval, 1.08-3.62) for anemia and 2.17 (95% confidence interval, 1.31-3.62) for hemoglobin decline >30 g/L. Patients who first developed a hemoglobin decline >30 g/L during weeks 5-12 and 13-48 were more likely to achieve SVR than those who first developed such changes in weeks 0-4 or who never experienced them. CONCLUSION: Patients with HCV genotype 1 infection who develop anemia or experience a hemoglobin decline >30 g/L during weeks 5-48 of therapy achieve higher virological responses to pegylated interferon and ribavirin therapy that are unrelated to erythropoietin use.

Hepatitis C treatment outcomes in Australian clinics.

OBJECTIVE: To determine hepatitis C (HCV) treatment effectiveness and predictors of response in the "real-world" Australian clinic setting. DESIGN, SETTING AND PARTICIPANTS: Patients with chronic HCV, who were HCV-treatment-naive at enrolment, and were then treated with standard therapy (pegylated interferon-α plus ribavirin), were recruited prospectively through a national network of 24 HCV clinics between April 2008 and December 2009. Patients were interviewed and a medical record review was conducted at enrolment and at routine follow-up clinic visits. MAIN OUTCOME MEASURES: Proportion of patients achieving a sustained virological response (SVR), predictors of SVR, and impact of treatment on biochemical markers of liver disease (alanine aminotransferase levels and aspartate aminotransferase-to-platelet ratio index scores). RESULTS: The SVR by intention to treat was 60% (327/550). Infection with HCV genotype 2 or 3 (compared with genotype 1) was an independent predictor of SVR (odds ratio [OR], 2.45; 95% CI, 1.70-3.52), while HIV coinfection (OR, 0.28; 95% CI, 0.10-0.82), cirrhosis (OR, 0.38; 95% CI, 0.18-0.81), and increased body mass index for ≥ 30 kg/m(2) v ≤ 25 kg/m(2) (OR, 0.58; 95% CI, 0.35-0.96) were independently associated with lower SVR. There was a significant improvement in biochemical markers of liver disease following SVR (P< 0.001). CONCLUSIONS: Our findings are similar to those seen in clinical trials, despite the inclusion of patients with a broad range of comorbid conditions such as injecting drug and alcohol use and psychiatric illness. They suggest that, with appropriate patient and infrastructure support, expansion of treatment services to the broader HCV-infected community is warranted.

Low virological response and high relapse rates in hepatitis C genotype 1 patients with advanced fibrosis despite adequate therapeutic dosing.

BACKGROUND & AIMS: The impact of fibrosis stage on chronic hepatitis C virus (HCV) treatment response was explored in CHARIOT, a study of high dose peginterferon alfa-2a (PEG-IFNalpha-2a) induction therapy in treatment naïve genotype 1 infection. METHODS: Eight hundred and ninety-six patients were randomised 1:1 to 360 microg (n=448) or 180 microg (n=448) PEG-IFNalpha-2a weekly with RBV 1000-1200 mg/day for 12 weeks followed by 36 weeks of 180 microg PEG-IFNalpha-2a weekly plus RBV 1000-1200 mg/day. Virological responses were assessed at week 4, 8, 12, 24, 48 (end of therapy), and 24 weeks following therapy (sustained virological response, SVR). As previously reported, there was no significant difference in SVR in the induction (53%) and standard (50%) arms, therefore the pooled study population was used for analysis of SVR and relapse. RESULTS: A marked step-wise decline in SVR was evident by fibrosis stage: F0 (70%); F1 (60%); F2 (51%); F3 (31%); F4 (10%) (p<0.0001). Early virological responses were lower among F3/4 patients, including rapid virological response (RVR) (21% vs. 34% for F3/4 and F0-2, respectively) (p=0.0072), and the RVR positive predictive value was also lower (63% vs. 80%). Virological relapse rates were similar in early disease stages (F0, 16%; F1, 23%; F2, 26%), but increased markedly in advanced fibrosis (F3, 50%; F4, 80%) (p<0.0001). Cumulative PEG-IFNalpha-2a and ribavirin doses were similar among patients with F3/4 and F0-2 within treatment arms through week 4, 8, 12, and week 24. CONCLUSIONS: Low virological response in hepatitis C genotype 1 patients with advanced fibrosis is not explained by inadequate cumulative PEG-IFN and ribavirin doses.

Impact of high-dose peginterferon alfa-2A on virological response rates in patients with hepatitis C genotype 1: a randomized controlled trial.

UNLABELLED: This study tested the hypothesis that high-dose peginterferon alfa-2a (PEG-IFNalpha-2a) for the first 12 weeks would increase early and sustained virological response (SVR) rates in patients with chronic hepatitis C genotype 1. Eight hundred ninety-six patients were randomized 1:1 to 360 microg (n = 448) or 180 microg (n = 448) PEG-IFNalpha-2a weekly plus ribavirin at 1000-1200 mg/day for 12 weeks, followed by 36 weeks of 180 microg PEG-IFNalpha-2a weekly plus ribavirin at 1000-1200 mg/day with 871 patients evaluable for the intention-to-treat analysis. Virological responses were assessed by TaqMan (limit of detection 15 IU/mL) at week 4, 8, 12, 24, 48 (end of therapy), and 24 weeks following therapy (SVR). Undetectable hepatitis C virus RNA rates were significantly higher among patients receiving high-dose induction therapy at week 4 (36% versus 26%, P < 0.005), week 8 (61% versus 50%, P < 0.005), and week 12 (74% versus 62%, P < 0.005). However, SVR was not significantly different between patients receiving high-dose (53%) and standard (50%) therapy. Significant baseline prognostic factors for SVR included age, sex, race, histological stage, and viral load. SVR was considerably higher among patients with no or minimal fibrosis (64% and 60%, respectively) compared to those with severe fibrosis/cirrhosis (28% and 24%, respectively). The frequency of serious adverse events and drug discontinuations were similar in both groups, whereas PEG-IFN dose modification, weight and appetite reduction, and grade IV neutropenia were significantly higher in the induction arm. CONCLUSION: Induction dosing with 360 microg/week PEG-IFNalpha-2a for 12 weeks was well tolerated and enhanced early virological response but not SVR rates. The high SVR rates in patients with minimal fibrosis highlight the benefit of early treatment in patients with hepatitis C virus genotype 1.

Changes in risk behaviours during and following treatment for hepatitis C virus infection among people who inject drugs: The ACTIVATE study.

BACKGROUND: The risk of hepatitis C virus (HCV) reinfection due to continued injecting risk behaviours might remain a barrier to HCV treatment among people who inject drugs. We aimed to evaluate changes in risk behaviours during and following HCV treatment among people with ongoing injecting drug use or receiving opioid substitution treatment (OST). METHODS: ACTIVATE was an international multicentre clinical trial conducted between 2012 and 2014. Participants with HCV genotypes 2/3 infection were treated with peg-interferon/ribavirin for 12 or 24 weeks and completed a self-administered behavioural questionnaire at each study visit. The impact of time in treatment and follow-up on longitudinally measured recent (past month) behavioural outcomes was evaluated using generalized estimating equations. RESULTS: Among 93 enrolled participants (83% male, median age 41 years), 55 (59%) had injected in the past month. Any injecting drug use decreased during HCV treatment and follow-up (OR 0.89 per incremental study visit; 95% CI 0.83-0.95). No significant changes were found in ≥daily injecting (OR 0.98; 95% CI 0.89-1.07), use of non-sterile needles (OR 0.94; 95% CI 0.79-1.12), sharing of injecting paraphernalia (OR 0.87; 95% CI 0.70-1.07) or non-injecting drug use (OR 1.01; 95% CI 0.92-1.10). Hazardous alcohol use decreased throughout (OR 0.56; 95% CI 0.40-0.77) and OST increased between enrolment and end of treatment (OR 1.48; 95% CI 1.07-2.04). CONCLUSIONS: Recent injecting drug use and hazardous alcohol use decreased, while OST increased during and following HCV treatment among participants with ongoing injecting drug use. These findings support further expansion of HCV care among PWID.

Efficacy of response-guided directly observed pegylated interferon and self-administered ribavirin for people who inject drugs with hepatitis C virus genotype 2/3 infection: The ACTIVATE study.

BACKGROUND: There are few data on treatment for hepatitis C virus (HCV) infection among people with ongoing injecting drug use. This study evaluated the efficacy of response-guided therapy for chronic HCV genotypes 2/3 infection among people with ongoing injecting drug use or receiving opioid substitution therapy (OST). A secondary aim was to identify predictors of HCV treatment response. METHODS: ACTIVATE was a multicentre clinical trial recruited between 2012 and 2014. Participants with genotypes 2/3 were treated with directly observed peg-interferon alfa-2b and self-administered ribavirin for 12 (undetectable HCV RNA at week 4) or 24 weeks (detectable HCV RNA at week 4). Participants were recruited from drug treatment clinics, private practices, hospital clinics and community clinics in Australia, Canada, and five countries in Europe. The primary study outcome was sustained virological response (SVR, undetectable HCV RNA >12 weeks post-treatment). RESULTS: Among 93 people with ongoing injecting drug use or receiving OST treated for HCV genotype 2/3, 59% had recently (past month) injected drugs, 77% were receiving OST and 56% injected drugs during therapy. Overall SVR was 66% (61/93). SVR was 84% in those with undetectable HCV RNA at week 4 (12 weeks) compared to 38% in those without (24 weeks). In adjusted analysis, cirrhosis vs. no/mild fibrosis [adjusted OR (aOR) 0.33, 95% CI 0.13, 0.86] predicted reduced SVR, while response at week 4 was associated with increased SVR [aOR 8.11, 95% CI 2.73, 24.10]. Recent injecting drug use at baseline or during therapy was not associated with SVR. CONCLUSION: This study demonstrates that people with recent injecting drug use or OST with chronic HCV can achieve responses to interferon-based therapy similar to other populations, despite injecting drugs prior to or during therapy. Cirrhosis was predictive of reduced response to HCV therapy, while response at week 4 (despite shortened therapy) was predictive of improved response.

Treatment for hepatitis C virus infection among people who inject drugs attending opioid substitution treatment and community health clinics: the ETHOS Study.

AIMS: To estimate adherence and response to therapy for chronic hepatitis C virus (HCV) infection among people with a history of injecting drug use. A secondary aim was to identify predictors of HCV treatment response. DESIGN: Prospective cohort recruited between 2009 and 2012. Participants were treated with peg-interferon alfa-2a/ribavirin for 24 (genotypes 2/3, G2/3) or 48 weeks (genotype 1, G1). SETTING: Six opioid substitution treatment (OST) clinics, two community health centres and one Aboriginal community-controlled health organization providing drug treatment services in New South Wales, Australia. PARTICIPANTS: Among 415 people with a history of injecting drug use and chronic HCV assessed by a nurse, 101 were assessed for treatment outcomes (21% female). MEASUREMENTS: Study outcomes were treatment adherence and sustained virological response (SVR, undetectable HCV RNA >24 weeks post-treatment). FINDINGS: Among 101 treated, 37% (n = 37) had recently injected drugs (past 6 months) and 62% (n = 63) were receiving OST. Adherence ≥ 80% was 86% (n = 87). SVR was 74% (75 of 101), with no difference observed by sex (males: 76%, females: 67%, P = 0.662). In adjusted analysis, age < 35 (versus ≥ 45 years) [adjusted odds ratio (aOR) = 5.06, 95% confidence interval (CI) = 1.47, 17.40] and on-treatment adherence ≥ 80% independently predicted SVR (aOR = 19.41, 95% CI = 3.61, 104.26]. Recent injecting drug use at baseline was not associated with SVR. CONCLUSIONS: People with a history of injecting drug use and chronic hepatitis C virus attending opioid substitution treatment and community health clinics can achieve adherence and responses to interferon-based therapy similar to other populations, despite injecting drugs at baseline. Younger age and adherence are predictive of improved response to hepatitis C virus therapy.

Safety profile of standard- vs. high-dose peginterferon alfa-2a plus standard-dose ribavirin in HCV genotype 1/4 patients: pooled analysis from 5 randomized studies.

OBJECTIVE: This analysis examines the safety profile of standard- versus high-dose peginterferon alfa-2a. METHODS: Data were pooled from five trials including HCV genotype 1- or 4-infected naive and treatment-experienced patients (n = 2,940). Patients were randomized to receive peginterferon alfa-2a at 180 µg/week (standard-dose; n = 1,672) or 360 µg/week (high-dose; n = 1,268) plus ribavirin 1,000/1,200 mg/day for 12 weeks; after 12 weeks, all received standard dose. This safety analysis was restricted to the first 12 weeks. RESULTS: In standard and high-dose groups, similar frequencies of serious adverse events (SAEs, 3.2 and 4.2%, respectively) and treatment discontinuations for safety reasons (2.8 and 2.9%) were reported. More patients reported weight decrease as an adverse event (AE) in the 360 µg/week group (7.7 vs. 3.3%). Significant (p < 0.05) independent predictors for discontinuation due to safety were older age, male gender, lower albumin and low neutrophil count, but not the starting dose of peginterferon alfa-2a. Although more laboratory abnormalities were reported in patients receiving high-dose peginterferon alfa-2a, this was not reflected in AEs or discontinuations, suggesting these are adequately managed by dose modification. CONCLUSIONS: High-dose peginterferon alfa-2a for 12 weeks does not significantly increase the incidence of SAEs or discontinuations for safety reasons, beyond that of a standard dose regimen.

Clinical experience with the treatment of hepatitis C infection in patients on opioid pharmacotherapy.

AIMS: To evaluate the efficacy, safety and adherence to hepatitis C (HCV) therapy in patients attending tertiary hepatitis clinics who are receiving opioid replacement therapy. DESIGN: A non-randomized, open-label study. Participants were treated with pegylated interferon alpha-2a and weight-based ribavirin for 24 weeks (genotype non-1, n = 31) or 48 weeks (genotype 1, n = 22). SETTING: Four tertiary hospital hepatitis clinics in Australia. PARTICIPANTS: Fifty-three patients with chronic HCV who were receiving opioid replacement therapy. MEASUREMENTS: Patients were monitored for virological response, adverse events and adherence. They were also screened for psychiatric illness prior to and throughout the study utilizing two validated instruments: the Mini International Neuropsychiatric Interview (MINI) and Beck Depression Interview (BDI)-II. FINDINGS: The overall sustained virological response (SVR) rate was 57% (71% genotype non-1 versus 36% genotype 1), and was similar in active injectors (63%) and non-injectors (53%). The psychological profile of patients based on validated instruments did not change on therapy. The pattern and frequency of adverse effects were comparable to non-opioid replacement patients. Eighty-five per cent of patients were adherent to therapy by 80/80/80 criteria and only two patients who had an end-of-treatment response relapsed, one of whom was not an active injector. CONCLUSIONS: Patients on opioid replacement therapy, even if they continue to inject actively, can achieve comparable sustained virological response rates to other populations with pegylated interferon alpha-2a and ribavirin therapy, suffer no excess rates of adverse effects or psychological complications and have good adherence to therapy.

Effect of low-level HCV viraemia at week 24 on HCV treatment response in genotype 1 patients.

BACKGROUND: We examined the detection of low-level viraemia at week 24 as a predictor of sustained virological response (SVR) and viral relapse/breakthrough, and the agreement between the Roche Cobas TaqMan™ HCV RNA assay (TaqMan) and Roche Cobas(®) Amplicor HCV qualitative assay (Amplicor; both Roche Molecular Diagnostics, Pleasanton, CA, USA) for detection of low-level viraemia. METHODS: A total of 871 treatment-naive HCV genotype 1 patients participating in an induction-dose pegylated interferon therapy study had virological responses assessed using TaqMan. A total of 151 patients with HCV RNA levels ≤500 IU/ml had samples tested in parallel using the Amplicor and TaqMan assays. RESULTS: SVR was significantly lower and relapse/breakthrough significantly higher in patients with low-level residual viraemia at week 24 compared with those who had undetectable viraemia: SVR was 72%, 29% and 14% (P<0.0001) and relapse/breakthrough 28%, 71% and 86% (P<0.0001) in patients with viraemia that was undetectable, detectable <15 IU/ml and detectable 15-<50 IU/ml, respectively, at week 24. The negative predictive value (NPV) for a week-24 virological response for SVR was 86%, 90% and 90% using TaqMan cutoffs of undetectable, <15 IU/ml and <50 IU/ml, respectively. The percentage agreement between Amplicor and TaqMan was similarly high for TaqMan cutoffs of 50 IU/ml and 15 IU/ml, but lower for undetectable viraemia (83%, 83% and 70%, respectively). CONCLUSIONS: These data emphasize the importance of achieving undetectable HCV RNA during pegylated interferon therapy to maximize SVR; however, the current 24-week stopping rule of undetectable HCV RNA appears too stringent when using sensitive PCR assays given the observed lower NPV for SVR using the TaqMan undetectable cutoff. Our data also suggest that a TaqMan <15 IU/ml result is comparable to an Amplicor-negative result (that is, below the assay cutoff value) when monitoring viral response.

IL28B is associated with response to chronic hepatitis C interferon-alpha and ribavirin therapy.

Hepatitis C virus (HCV) infects 3% of the world's population. Treatment of chronic HCV consists of a combination of PEGylated interferon-alpha (PEG-IFN-alpha) and ribavirin (RBV). To identify genetic variants associated with HCV treatment response, we conducted a genome-wide association study of sustained virological response (SVR) to PEG-IFN-alpha/RBV combination therapy in 293 Australian individuals with genotype 1 chronic hepatitis C, with validation in an independent replication cohort consisting of 555 individuals. We report an association to SVR within the gene region encoding interleukin 28B (IL28B, also called IFNlambda3; rs8099917 combined P = 9.25 x 10(-9), OR = 1.98, 95% CI = 1.57-2.52). IL28B contributes to viral resistance and is known to be upregulated by interferons and by RNA virus infection. These data suggest that host genetics may be useful for the prediction of drug response, and they also support the investigation of the role of IL28B in the treatment of HCV and in other diseases treated with IFN-alpha.