Barbara Yeung

Potential Role for Interleukin-28B Genotype in Treatment Decision-Making in Recent Hepatitis C Virus Infection

Polymorphisms in the IL28B (interleukin‐28B) gene region are important in predicting outcome following therapy for chronic hepatitis C virus (HCV) infection. We evaluated the role of IL28B in spontaneous and treatment‐induced clearance following recent HCV infection. The Australian Trial in Acute Hepatitis C (ATAHC) was a study of the natural history and treatment of recent HCV, as defined by positive anti‐HCV antibody, preceded by either acute clinical HCV infection within the prior 12 months or seroconversion within the prior 24 months. Factors associated with spontaneous and treatment‐induced HCV clearance, including variations in IL28B, were assessed. Among 163 participants, 132 were untreated (n = 52) or had persistent infection (infection duration ≥26 weeks) at treatment initiation (n = 80). Spontaneous clearance was observed in 23% (30 of 132 participants). In Cox proportional hazards analysis (without IL28B), HCV seroconversion illness with jaundice was the only factor predicting spontaneous clearance (adjusted hazards ratio = 2.86; 95% confidence interval = 1.24, 6.59; P = 0.014). Among participants with IL28B genotyping (n = 102 of 163 overall and 79 of 132 for the spontaneous clearance population), rs8099917 TT homozygosity (versus GT/GG) was the only factor independently predicting time to spontaneous clearance (adjusted hazard ratio = 3.78; 95% confidence interval = 1.04, 13.76; P = 0.044). Participants with seroconversion illness with jaundice were more frequently rs8099917 TT homozygotes than other (GG/GT) genotypes (32% versus 5%, P = 0.047). Among participants adherent to treatment and who had IL28B genotyping (n = 54), sustained virologic response was similar among TT homozygotes (18 of 29 participants, 62%) and those with GG/GT genotype (16 of 25, 64%, P = 0.884). Conclusion: During recent HCV infection, genetic variations in IL28B region were associated with spontaneous but not treatment‐induced clearance. Early therapeutic intervention could be recommended for individuals with unfavorable IL28B genotypes. (HEPATOLOGY 2010;)

Effective Treatment of Injecting Drug Users With Recently Acquired Hepatitis C Virus Infection

BACKGROUND & AIMS Patients with acute hepatitis C virus (HCV) infection who receive treatment achieve high rates of sustained virologic response (SVR), but few studies have examined outcomes among injecting drug users (IDUs). We evaluated the efficacy of treatment of recent HCV infection in IDUs with acute and early chronic HCV. METHODS We analyzed data from the Australian Trial in Acute Hepatitis C-a prospective study of the natural history and treatment outcomes of patients with recent HCV infection. Participants eligible for the study had their first anti-HCV antibody-positive test result within the past 6 months and either acute clinical HCV within the past 12 months or documented anti-HCV seroconversion within 24 months. Participants with HCV received pegylated interferon-alfa-2a (180 microg/wk, n = 74); those with HCV/human immunodeficiency virus (HIV) co-infection received pegylated interferon-alfa-2a (180 microg/wk) with ribavirin (n = 35) for 24 weeks. RESULTS From June 2004 to February 2008, 167 participants were enrolled in the Australian Trial in Acute Hepatitis C; 79% had injected drugs in the previous 6 months. Among 74 with only HCV, the SVRs were 55% and 72% by intention-to-treat and per-protocol analysis, respectively. In multivariate analyses, baseline factors independently associated with lower SVR included decreased social functioning and current opiate pharmacotherapy. Adherent participants had higher SVR rates (63% vs 29%; P = .025). Of the 35 participants with HCV/HIV co-infection, the SVRs were 74% and 75% by intention-to-treat and per-protocol analysis, respectively. CONCLUSIONS Treatment of recent HCV infection among IDUs, including those with HIV co-infection, is effective. Strategies to engage socially marginalized individuals and increase adherence should improve treatment outcomes in this population.

Characteristics and Treatment Outcomes among HIV-Infected Individuals in the Australian Trial in Acute Hepatitis C

BACKGROUND The Australian Trial in Acute Hepatitis C (ATAHC) is a National Institutes of Health-funded prospective cohort study of the natural history and efficacy of treatment in individuals with recently acquired hepatitis C. Enrollment is open to both human immunodeficiency virus (HIV)-infected and -uninfected individuals. The aim of this article was to evaluate characteristics and virological outcomes among HIV-infected individuals enrolled in ATAHC. METHODS Eligibility criteria included the first positive result of testing for anti-hepatitis C virus (HCV) antibody within 6 months and either clinical hepatitis diagnosed within the past 12 months or documented anti-HCV seroconversion within the past 24 months. RESULTS Of the initial 103 patients enrolled, 27 (26%) were HIV infected. HIV-infected patients were more likely to be older, to have HCV genotype 1 infection and high levels of HCV RNA at baseline than were HCV-monoinfected patients. Sexual acquisition accounted for the majority (56%) of HCV infections among HIV-infected patients, compared with only 8% of HCV-monoinfected patients. The median duration from estimated HCV infection to treatment was 30 weeks. Treatment with 24 weeks of pegylated interferon and ribavirin resulted in rates of undetectability of HCV RNA of 95%, 90%, and 80% at weeks 12, 24, and 48, respectively. Undetectability at week 4 was achieved in 44% of patients and yielded positive and negative predictive values for sustained virological response of 100% and 33%, respectively. CONCLUSIONS Significant differences were demonstrated between HIV-infected and HIV-uninfected individuals enrolled in ATAHC. Treatment responses among HIV-infected individuals with both acute and early chronic infection are encouraging and support regular HCV screening of high-risk individuals and early treatment for recently acquired HCV infection.

Hepatitis C virus reinfection and superinfection among treated and untreated participants with recent infection

The purpose of the study was to evaluate reinfection and superinfection during treatment for recent hepatitis C virus (HCV). The Australian Trial in Acute Hepatitis C (ATAHC) was a prospective study of the natural history and treatment of recent HCV. Reinfection and superinfection were defined by detection of infection with an HCV strain distinct from the primary strain (using reverse‐transcription polymerase chain reaction [RT‐PCR] and subtype‐specific nested RT‐PCR assays) in the setting of spontaneous or treatment‐induced viral suppression (one HCV RNA <10 IU/mL) or persistence (HCV RNA >10 IU/mL from enrollment to week 12). Among 163 patients, 111 were treated, 79% (88 of 111) had treatment‐induced viral suppression, and 60% (67 of 111) achieved sustained virological response. Following treatment‐induced viral suppression, recurrence was observed in 19% (17 of 88), including 12 with relapse and five with reinfection (4.7 cases per 100 person‐years [PY], 95% confidence interval [CI]: 1.9, 11.2). Among 52 untreated patients, 58% (30 of 52) had spontaneous viral suppression and recurrence was observed in 10% (3 of 30), including two with reinfection. Following reinfection, alanine aminotransferase (ALT) levels >1.5× the upper limit of normal were observed in 71% (5 of 7). Among 37 with persistence, superinfection was observed in 16% (3 of 19) of those treated and 17% (3 of 18) of those untreated. In adjusted analysis, reinfection/superinfection occurred more often in participants with poorer social functioning at enrollment and more often in those with ongoing injecting drug use (IDU). Conclusion: Reinfection and superinfection can occur during treatment of recent HCV and are associated with poor social functioning and ongoing IDU. ALT levels may be a useful clinical marker of reexposure. (HEPATOLOGY 2012)

Early IL-10 predominant responses are associated with progression to chronic hepatitis C virus infection in injecting drug users

Summary.  The critical events in clearance or persistence of hepatitis C virus (HCV) infection are unknown but likely to be determined early in acute infection. Type 1 and type 2 cytokine production was assessed by HCV peptide ELISpot and multiplex in vitro cytokine production assays in longitudinally collected samples from 20 untreated participants enrolled in the Australian Trial in Acute Hepatitis C (ATAHC); a prospective cohort of acute HCV infection (77% injecting drug users, IDU). Significantly higher interleukin‐10 (IL‐10) production (P = 0.048), in the relative absence of interferon‐gamma (IFN‐γ) and IL‐2 production, was present early in HCV infection in those who progressed to chronic infection. In contrast, viral clearance was associated with a greater magnitude and broader specificity of IFN‐γ (magnitude P < 0.001, breadth P = 0.004) and IL‐2 responses, in the relative absence of IL‐10. Early IL‐10 production was correlated with higher HCV RNA level at baseline (P = 0.046) and week 12 (P = 0.018), while IFN‐γ and IL‐2 production was inversely correlated with HCV RNA level at baseline (IFN‐γP = 0.020, IL‐2 P = 0.050) and week 48 (IFN‐γP = 0.045, IL‐2 P = 0.026). Intracellular staining (ICS) indicated the HCV‐specific IFN‐γ response was primarily from CD8+ T cells and NK cells, whereas IL‐10 production was predominantly from monocytes, with a subset of IL‐10 producing CD8+ T cells present only in those who progressed to chronic infection. IL‐10, an immunoregulatory cytokine, appears to play a key role in progression to chronic HCV infection.

Adherence to treatment for recently acquired hepatitis C virus (HCV) infection among injecting drug users

BACKGROUND & AIMS Adherence to HCV therapy impacts sustained virological response (SVR) but there are limited data on adherence, particularly among injecting drug users (IDUs). We assessed 80/80 adherence (≥80% of PEG-IFN doses, ≥80% treatment), on-treatment adherence, and treatment completion in a study of treatment of recent HCV infection (ATAHC). METHODS Participants with HCV received pegylated interferon (PEG-IFN) alfa-2a (180μg/week, n=74) and those with HCV/HIV received PEG-IFN alfa-2a with ribavirin (n=35), for a planned 24 weeks. Logistic regression analyses were used to identify predictors of PEG-IFN 80/80 adherence. RESULTS A total of 109 out of 163 patients received treatment (HCV, n=74; HCV/HIV, n=35), with 75% ever reporting IDU. The proportion with 80/80 PEG-IFN adherence was 82% (n=89). During treatment, 14% missed ≥1 dose (on-treatment adherence=99%). Completion of 0-4, 5-19, 20-23, and all 24 weeks of PEG-IFN therapy occurred in 10% (n=11), 14% (n=15), 6% (n=7) and 70% (n=76) of cases, respectively. Participants with no tertiary education were less likely to have 80/80 PEG-IFN adherence (AOR 0.29, p=0.045). IDU prior to or during treatment did not impact 80/80 PEG-IFN adherence. SVR was higher among those patients with ≥80/80 PEG-IFN adherence (67% vs. 35%, p=0.007), but similar among those with and without missed doses during therapy (73% vs. 60%, p=0.309). SVR in those patients discontinuing therapy between 0-4, 5-19, 20-23, and 24 weeks was 9%, 33%, 43%, and 76%, respectively (p<0.001). CONCLUSIONS High adherence to treatment for recent HCV was observed, irrespective of IDU prior to, or during, therapy. Sub-optimal PEG-IFN exposure was mainly driven by early treatment discontinuation rather than missed doses during therapy.

Plasma interferon‐gamma‐inducible protein‐10 (IP‐10) levels during acute hepatitis C virus infection

Systemic levels of interferon‐gamma‐inducible protein‐10 (IP‐10) are predictive of treatment‐induced clearance in chronic hepatitis C virus (HCV). In the present study, factors associated with plasma IP‐10 levels at the time of acute HCV detection and the association between IP‐10 levels and spontaneous clearance were assessed in three cohorts of acute HCV infection. Among 299 individuals, 245 (181 male, 47 human immunodeficiency virus‐positive [HIV+]) were HCV RNA+ at acute HCV detection. In adjusted analysis, factors independently associated with IP‐10 levels ≥150 pg/mL (median level) included HCV RNA levels >6 log IU/mL, HIV coinfection and non‐Aboriginal ethnicity. Among 245 HCV RNA+ at acute HCV detection, 214 were untreated (n = 137) or had persistent infection (infection duration ≥26 weeks) at treatment initiation (n = 77). Spontaneous clearance occurred in 14% (29 of 214). Individuals without spontaneous clearance had significantly higher mean plasma IP‐10 levels at the time of acute HCV detection than those with clearance (248 ± 32 versus 142 ± 22 pg/mL, P = 0.008). The proportion of individuals with spontaneous clearance was 0% (0 of 22, P = 0.048) and 16% (27 of 165) and in those with and without plasma IP‐10 levels ≥380 pg/mL. In adjusted analyses, favorable IL28B genotype was associated with spontaneous clearance, while higher HCV RNA level was independently associated with lower odds of spontaneous clearance. Conclusion: High IP‐10 levels at acute HCV detection were associated with failure to spontaneously clear HCV. Patients with acute HCV and high baseline IP‐10 levels, particularly >380 pg/mL, should be considered for early therapeutic intervention, and those with low levels should defer therapy for potential spontaneous clearance. (HEPATOLOGY 2013;)

Effect of pegylated interferon‐α‐2a treatment on mental health during recent hepatitis C virus infection

Background and Aim:  Pegylated interferon (PEG‐IFN) treatment for hepatitis C virus (HCV) infection has neuropsychiatric side effects. Data on the effect of HCV treatment on mental health among injecting drug users (IDUs) are limited. We assessed mental health during treatment of recently acquired HCV, within a predominantly IDU population.

Injecting risk behaviours following treatment for hepatitis C virus infection among people who inject drugs: The Australian Trial in Acute Hepatitis C

BACKGROUND A barrier to hepatitis C virus (HCV) treatment among people who inject drugs (PWID) has been a concern that interferon-based HCV treatment may increase injecting risk behaviours. This study evaluated recent (past month) injecting risk behaviours during follow-up among PWID that did and did not receive HCV treatment. METHODS The Australian Trial in Acute Hepatitis C (ATAHC) was a prospective study of natural history and treatment of recent HCV infection. Analyses were performed using generalized estimating equations. RESULTS Among 124 participants with a history of injecting drug use (median age 32 years), 69% were male, and 68% were treated for HCV infection. HCV treatment was not associated with an increase in recent injecting drug use (adjusted odds ratio (aOR) 1.06, 95% CI 0.93, 1.21) or recent used needle and syringe borrowing during follow-up (aOR 0.99, 95% CI 0.89, 1.08). HCV treatment was associated with a decrease in recent ancillary injecting equipment sharing during follow-up (aOR 0.85, 95% CI 0.74, 0.99). Further, among treated participants who remained in follow-up (n=24), ancillary injecting equipment sharing significantly decreased from 54% at enrolment to 17% during follow-up (P=0.012). CONCLUSIONS HCV treatment was not associated with drug use or used needle and syringe borrowing during follow-up, but was associated with decreased ancillary injecting equipment sharing during follow-up. Programs to enhance HCV assessment and treatment among PWID should be expanded, given that HCV treatment does not lead to increases in injecting risk behaviours and has previously been demonstrated to be safe and effective among PWID.

Virological responses during treatment for recent hepatitis C virus: potential benefit for ribavirin use in HCV/HIV co-infection.

Objective:The role of ribavirin (RBV) in the treatment of recent hepatitis C virus (HCV) (acute/early chronic) is unclear, particularly in HIV-infected individuals. This study evaluated early virological decline during recent HCV therapy in HIV-uninfected individuals receiving pegylated interferon (PEG-IFN) monotherapy and HIV-infected individuals receiving PEG-IFN/RBV. Design:The Australian Trial in Acute Hepatitis C was a nonrandomized prospective study of patients with recent HCV. Methods:All participants received PEG-IFN (24 weeks); HCV/HIV participants also received RBV. Early HCV RNA decline was assessed among adherent participants (≥80% PEG-IFN, ≥80% treatment). Logistic regression identified predictors of rapid virological response (RVR) (<10 IU/ml). Results:Of 109 treated, 82% were adherent (HCV, n = 57; HCV/HIV, n = 32). Overall, RVR was 51% (HCV: 55% vs. HCV/HIV: 43%; P = 0.323). Factors independently associated with RVR included duration of infection less than 26 weeks, HCV RNA below 5.6 log10 IU/ml at baseline and HCV genotype 2/3 infection. Between baseline and week 12, mean decline in HCV RNA was greater in HCV/HIV participants (PEG-IFN/RBV) compared to HCV participants (PEG-IFN) (4.19 vs. 3.32 log10 IU/ml; P = 0.029). Greater HCV RNA decline was observed in those treated with RBV, particularly amongst those with an estimated duration of infection at least 26 weeks and those with unfavourable IL28B genotypes. Adherent HIV-uninfected and infected participants had similar early virological response (76 vs. 90%; P = 0.102) and sustained virological response (63 vs. 75%; P = 0.253), respectively. RVR was highly predictive of sustained virological response (adjusted odds ratio 4.09; 1.49, 11.25). Conclusion:The results of this study suggest a potential benefit for PEG-IFN and RBV combination therapy in maximizing virological responses in HCV/HIV participants with recent HCV, particularly those with a longer duration of HCV infection and unfavourable IL28B genotypes.