Although 20%-40% of persons with acute hepatitis C virus (HCV) infection demonstrate spontaneous clearance, the time course and factors associated with clearance remain poorly understood. We investigated the time to spontaneous clearance and predictors among participants with acute HCV using Cox proportional hazards analyses. Data for this analysis were drawn from an international collaboration of nine prospective cohorts evaluating outcomes after acute HCV infection. Among 632 participants with acute HCV, 35% were female, 82% were Caucasian, 49% had interleukin-28 (IL28)B CC genotype (rs12979860), 96% had injected drugs ever, 47% were infected with HCV genotype 1, and 7% had human immunodeficiency virus (HIV) coinfection. Twenty-eight percent were HCV antibody negative/RNA positive at the time of acute HCV detection (early acute HCV). During follow-up, spontaneous clearance occurred in 173 of 632, and at 1 year after infection, 25% (95% confidence interval [CI]: 21, 29) had cleared virus. Among those with clearance, the median time to clearance was 16.5 weeks (IQR: 10.5, 33.4), with 34%, 67%, and 83% demonstrating clearance at 3, 6, and 12 months. Adjusting for age, factors independently associated with time to spontaneous clearance included female sex (adjusted hazards ratio [AHR]: 2.16; 95% CI: 1.48, 3.18), IL28B CC genotype (versus CT/TT; AHR, 2.26; 95% CI: 1.52, 3.34), and HCV genotype 1 (versus non-genotype 1; AHR: 1.56; 95% CI: 1.06, 2.30). The effect of IL28B genotype and HCV genotype on spontaneous clearance was greater among females, compared to males. Conclusions : Female sex, favorable IL28B genotype, and HCV genotype 1 are independent predictors of spontaneous clearance. Further research is required to elucidate the observed sex-based differences in HCV control.

Aims: To estimate the effects of needle and syringe programmes (NSP) and opioid substitution therapy (OST), alone or in combination, for preventing acquisition of hepatitis C virus (HCV) in people who inject drugs (PWID).Methods: Systematic review and meta‐analysis. Bibliographic databases were searched for studies measuring concurrent exposure to current OST (within the last 6 months) and/or NSP and HCV incidence among PWID. High NSP coverage was defined as regular NSP attendance or ≥ 100% coverage (receiving sufficient or greater number of needles and syringes per reported injecting frequency). Studies were assessed using the Cochrane risk of bias in non‐randomized studies tool. Random‐effects models were used in meta‐analysis.Results: We identified 28 studies (n = 6279) in North America (13), United Kingdom (five), Europe (four), Australia (five) and China (one). Studies were at moderate (two), serious (17) critical (seven) and non‐assessable risk of bias (two). Current OST is associated with 50% [risk ratio (RR) =0.50, 95% confidence interval (CI) = 0.40–0.63] reduction in HCV acquisition risk, consistent across region and with low heterogeneity (I² = 0, P = 0.889). Weaker evidence was found for high NSP coverage (RR = 0.79, 95% CI = 0.39–1.61) with high heterogeneity (I² = 77%, P = 0.002). After stratifying by region, high NSP coverage in Europe was associated with a 56% reduction in HCV acquisition risk (RR = 0.44, 95% CI = 0.24–0.80) with low heterogeneity (I² = 12.3%, P = 0.337), but not in North America (RR = 1.58, I² = 89.5%, P = < 0.001). Combined OST/NSP is associated with a 74% reduction in HCV acquisition risk (RR = 0.26, 95% CI = 0.07–0.89, I² = 80% P = 0.007). According to Grades of Recommendation Assessment, Development and Evaluation (GRADE) criteria, the evidence on OST and combined OST/NSP is low quality, while NSP is very low.Conclusions: Opioid substitution therapy reduces risk of hepatitis C acquisition and is strengthened in combination with needle and syringe programmes (NSP). There is weaker evidence for the impact of needle syringe programmes alone, although stronger evidence that high coverage is associated with reduced risk in Europe.

Hepatitis C is a pandemic human RNA virus, which commonly causes chronic infection and liver disease. The characterization of viral populations that successfully initiate infection, and also those that drive progression to chronicity is instrumental for understanding pathogenesis and vaccine design. A comprehensive and longitudinal analysis of the viral population was conducted in four subjects followed from very early acute infection to resolution of disease outcome. By means of next generation sequencing (NGS) and standard cloning/Sanger sequencing, genetic diversity and viral variants were quantified over the course of the infection at frequencies as low as 0.1%. Phylogenetic analysis of reassembled viral variants revealed acute infection was dominated by two sequential bottleneck events, irrespective of subsequent chronicity or clearance. The first bottleneck was associated with transmission, with one to two viral variants successfully establishing infection. The second occurred approximately 100 days post-infection, and was characterized by a decline in viral diversity. In the two subjects who developed chronic infection, this second bottleneck was followed by the emergence of a new viral population, which evolved from the founder variants via a selective sweep with fixation in a small number of mutated sites. The diversity at sites with non-synonymous mutation was higher in predicted cytotoxic T cell epitopes, suggesting immune-driven evolution. These results provide the first detailed analysis of early within-host evolution of HCV, indicating strong selective forces limit viral evolution in the acute phase of infection. Primary hepatitis C (HCV) infection is typically asymptomatic and commonly results in persistent infection. The characteristics of early infection remain undefined. Four subjects were studied longitudinally from within a few weeks of transmission until resolution of outcome, via a full genome analysis of viral evolution. In the acute phase (<100 days post-infection) there were two periods with a major reduction in genetic diversity (i.e. a bottleneck) irrespective of subsequent clearance (n = 2) or chronic infection (n = 2). The first bottleneck was associated with transmission, with generally only one ‘founder’ virus successfully establishing infection. The second occurred following the primary peak in viraemia, concomitant with seroconversion, approximately 100 days post-infection. In the subjects who became chronically infected, the second bottleneck was followed by emergence of a new cluster of variants, which evolved from the founder(s), and carried only a small number of mutated residues that reached fixation. Some fixations occurred in known targets of CD8 cytotoxic T cell and neutralizing antibody responses. These results indicate a common evolutionary pattern, independent of disease outcome in the acute phase of HCV infection, with strong signatures of selective pressures driving the transition into chronic infection. These novel data will inform preventative vaccine strategies.

Background Needle syringe programmes and opioid substitution therapy for preventing hepatitis C transmission in people who inject drugs Needle syringe programmes (NSP) and opioid substitution therapy (OST) are the primary interventions to reduce hepatitis C (HCV) transmission in people who inject drugs. There is good evidence for the effectiveness of NSP and OST in reducing injecting risk behaviour and increasing evidence for the effectiveness of OST and NSP in reducing HIV acquisition risk, but the evidence on the effectiveness of NSP and OST for preventing HCV acquisition is weak. Objectives To assess the effects of needle syringe programmes and opioid substitution therapy, alone or in combination, for preventing acquisition of HCV in people who inject drugs. Search methods We searched the Cochrane Drug and Alcohol Register, CENTRAL, the Cochrane Database of Systematic Reviews (CDSR), the Database of Abstracts of Reviews of Effects (DARE), the Health Technology Assessment Database (HTA), the NHS Economic Evaluation Database (NHSEED), MEDLINE, Embase, PsycINFO, Global Health, CINAHL, and the Web of Science up to 16 November 2015. We updated this search in March 2017, but we have not incorporated these results into the review yet. Where observational studies did not report any outcome measure, we asked authors to provide unpublished data. We searched publications of key international agencies and conference abstracts. We reviewed reference lists of all included articles and topic‐related systematic reviews for eligible papers. Selection criteria We included prospective and retrospective cohort studies, cross‐sectional surveys, case‐control studies and randomised controlled trials that measured exposure to NSP and/or OST against no intervention or a reduced exposure and reported HCV incidence as an outcome in people who inject drugs. We defined interventions as current OST (within previous 6 months), lifetime use of OST and high NSP coverage (regular attendance at an NSP or all injections covered by a new needle/syringe) or low NSP coverage (irregular attendance at an NSP or less than 100% of injections covered by a new needle/syringe) compared with no intervention or reduced exposure. Data collection and analysis We followed the standard Cochrane methodological procedures incorporating new methods for classifying risk of bias for observational studies. We described study methods against the following 'Risk of bias' domains: confounding, selection bias, measurement of interventions, departures from intervention, missing data, measurement of outcomes, selection of reported results; and we assigned a judgment (low, moderate, serious, critical, unclear) for each criterion. Main results We identified 28 studies (21 published, 7 unpublished): 13 from North America, 5 from the UK, 4 from continental Europe, 5 from Australia and 1 from China, comprising 1817 incident HCV infections and 8806.95 person‐years of follow‐up. HCV incidence ranged from 0.09 cases to 42 cases per 100 person‐years across the studies. We judged only two studies to be at moderate overall risk of bias, while 17 were at serious risk and 7 were at critical risk; for two unpublished datasets there was insufficient information to assess bias. As none of the intervention effects were generated from RCT evidence, we typically categorised quality as low. We found evidence that current OST reduces the risk of HCV acquisition by 50% (risk ratio (RR) 0.50, 95% confidence interval (CI) 0.40 to 0.63, I² = 0%, 12 studies across all regions, N = 6361), but the quality of the evidence was low. The intervention effect remained significant in sensitivity analyses that excluded unpublished datasets and papers judged to be at critical risk of bias. We found evidence of differential impact by proportion of female participants in the sample, but not geographical region of study, the main drug used, or history of homelessness or imprisonment among study samples. Overall, we found very low‐quality evidence that high NSP coverage did not reduce risk of HCV acquisition (RR 0.79, 95% CI 0.39 to 1.61) with high heterogeneity (I² = 77%) based on five studies from North America and Europe involving 3530 participants. After stratification by region, high NSP coverage in Europe was associated with a 76% reduction in HCV acquisition risk (RR 0.24, 95% CI 0.09 to 0.62) with less heterogeneity (I² =0%). We found low‐quality evidence of the impact of combined high coverage of NSP and OST, from three studies involving 3241 participants, resulting in a 74% reduction in the risk of HCV acquisition (RR 0.26 95% CI 0.07 to 0.89). Authors' conclusions OST is associated with a reduction in the risk of HCV acquisition, which is strengthened in studies that assess the combination of OST and NSP. There was greater heterogeneity between studies and weaker evidence for the impact of NSP on HCV acquisition. High NSP coverage was associated with a reduction in the risk of HCV acquisition in studies in Europe.

People who inject drugs (PWID) experience a high prevalence of incarceration and might be at high risk of HIV and hepatitis C virus (HCV) infection during or after incarceration. We aimed to assess whether incarceration history elevates HIV or HCV acquisition risk among PWID. In this systematic review and meta-analysis, we searched MEDLINE, Embase, and PsycINFO databases for studies in any language published from Jan 1, 2000 until June 13, 2017 assessing HIV or HCV incidence among PWID. We included studies that measured HIV or HCV incidence among community-recruited PWID. We included only studies reporting original results and excluded studies that evaluated incident infections by self-report. We contacted authors of cohort studies that met the inclusion or exclusion criteria, but that did not report on the outcomes of interest, to request data. We extracted and pooled data from the included studies using random-effects meta-analyses to quantify the associations between recent (past 3, 6, or 12 months or since last follow-up) or past incarceration and HIV or HCV acquisition (primary infection or reinfection) risk among PWID. We assessed the risk of bias of included studies using the Newcastle-Ottawa Scale. Between-study heterogeneity was evaluated using the I² statistic and the P-value for heterogeneity. We included published results from 20 studies and unpublished results from 21 studies. These studies originated from Australasia, western and eastern Europe, North and Latin America, and east and southeast Asia. Recent incarceration was associated with an 81% (relative risk [RR] 1·81, 95% CI 1·40-2·34) increase in HIV acquisition risk, with moderate heterogeneity between studies (I²=63·5%; p=0·001), and a 62% (RR 1·62, 95% CI 1·28-2·05) increase in HCV acquisition risk, also with moderate heterogeneity between studies (I²=57·3%; p=0·002). Past incarceration was associated with a 25% increase in HIV (RR 1·25, 95% CI 0·94-1·65) and a 21% increase in HCV (1·21, 1·02-1·43) acquisition risk. Incarceration is associated with substantial short-term increases in HIV and HCV acquisition risk among PWID and could be a significant driver of HCV and HIV transmission among PWID. These findings support the need for developing novel interventions to minimise the risk of HCV and HIV acquisition, including addressing structural risks associated with drug laws and excessive incarceration of PWID. Engineering and Physical Sciences Research Council, National Institute for Health Research, National Institutes of Health.