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Unlabelled: Hepatitis C virus reinfection and spontaneous clearance of reinfection were examined in a highly characterised cohort of 188 people who inject drugs over a five-year period. Nine confirmed reinfections and 17 possible reinfections were identified (confirmed reinfections were those genetically distinct from the previous infection and possible reinfections were used to define instances where genetic differences between infections could not be assessed due to lack of availability of hepatitis C virus sequence data). The incidence of confirmed reinfection was 28.8 per 100 person-years (PY), 95%CI: 15.0-55.4; the combined incidence of confirmed and possible reinfection was 24.6 per 100 PY (95%CI: 16.8-36.1). The hazard of hepatitis C reinfection was approximately double that of primary hepatitis C infection; it did not reach statistical significance in confirmed reinfections alone (hazard ratio [HR]: 2.45, 95%CI: 0.87-6.86, p=0.089), but did in confirmed and possible hepatitis C reinfections combined (HR: 1.93, 95%CI: 1.01-3.69, p=0.047) and after adjustment for the number of recent injecting partners and duration of injecting. In multivariable analysis, shorter duration of injection (HR: 0.91; 95%CI: 0.83-0.98; p=0.019) and multiple recent injecting partners (HR: 3.12; 95%CI: 1.08-9.00, p=0.035) were independent predictors of possible and confirmed reinfection. Time to spontaneous clearance was shorter in confirmed reinfection (HR: 5.34, 95%CI: 1.67-17.03, p=0.005) and confirmed and possible reinfection (HR: 3.10, 95%CI: 1.10-8.76, p-value=0.033) than primary infection. Nonetheless, 50% of confirmed reinfections and 41% of confirmed or possible reinfections did not spontaneously clear., Conclusions: Hepatitis C reinfection and spontaneous clearance of hepatitis C reinfection were observed at high rates, suggesting partial acquired natural immunity to hepatitis C virus. Public health campaigns about the risks of hepatitis C reinfection are required.

Introduction: Studies have explored whether spontaneous clearance of hepatitis C virus (HCV) infection decreases the likelihood of reinfection or increases the probability of clearance. This analysis investigates whether the conflicting findings from these studies could be due to differences in frequency of HCV RNA testing., Methods: A model simulated the dynamics of HCV reinfection and clearance among a cohort of injection drug users. For different reinfection incidence and clearance rates, the model evaluated the accuracy of epidemiological studies that used different HCV testing frequencies., Results: Experimental estimates for the reinfection incidence and clearance probability will be accurate (<20% error) if the testing interval is less than the reinfection clearance duration. Otherwise, experimental estimates can greatly underestimate the real values (≤66% error if reinfection duration is 1 month and the testing interval is 3 months). Uncertainty in experimental estimates also increases at lower reinfection incidences, whereas for lower clearance probabilities the uncertainty in the estimated clearance probability increases but estimated reinfection incidence decreases., Discussion: Differences in HCV testing interval could account for most between-study variability in the estimated probability of clearing reinfections and is likely to have biased reinfection incidence estimates. Our findings suggest that a high reinfection clearance probability (>75%) is consistent with data.

Hepatitis C virus (HCV) infection causes significant morbidity and mortality worldwide. T cells play a central role in HCV clearance; however, there is currently little understanding of whether the disease outcome in HCV infection is influenced by the choice of TCR repertoire. TCR repertoires used against two immunodominant HCV determinants--the highly polymorphic, HLA-B*0801 restricted (1395)HSKKKCDEL(1403) (HSK) and the comparatively conserved, HLA-A*0101-restricted, (1435)ATDALMTGY(1443) (ATD)--were analyzed in clearly defined cohorts of HLA-matched, HCV-infected individuals with persistent infection and HCV clearance. In comparison with ATD, TCR repertoire selected against HSK was more narrowly focused, supporting reports of mutational escape in this epitope, in persistent HCV infection. Notwithstanding the Ag-driven divergence, T cell repertoire selection against either Ag was comparable in subjects with diverse disease outcomes. Biased T cell repertoires were observed early in infection and were evident not only in persistently infected individuals but also in subjects with HCV clearance, suggesting that these are not exclusively characteristic of viral persistence. Comprehensive clonal analysis of Ag-specific T cells revealed widespread use of public TCRs displaying a high degree of predictability in TRBV/TRBJ gene usage, CDR3 length, and amino acid composition. These public TCRs were observed against both ATD and HSK and were shared across diverse disease outcomes. Collectively, these observations indicate that repertoire diversity rather than particular Vβ segments are better associated with HCV persistence/clearance in humans. Notably, many of the anti-HCV TCRs switched TRBV and TRBJ genes around a conserved, N nucleotide-encoded CDR3 core, revealing TCR sequence mosaicism as a potential host mechanism to combat this highly variant virus.

To analyse the immune correlates in a setting of recurrent exposure to hepatitis C virus (HCV), we studied T(CD8) responses in injecting drug users (IDUs) with different disease outcomes. Ex vivo HCV-specific T(CD8) responses assessed by interferon-gamma (IFNgamma) enzyme-linked immunospot (ELISPOT) were comparable in human lymphocyte antigen (HLA)-matched IDUs with spontaneous HCV clearance or persistent infection. A detailed characterization of these T(CD8) cells in age and HLA-matched IDUs demonstrated that HCV clearance and protection from reinfection correlated with HCV-specific T(CD8) cells that could proliferate in vitro, possessed cytotoxic potential and produced IFNgamma and tumour-necrosis factor-alpha, rather than with the circulating frequency of responding T(CD8) cells determined ex vivo. While validating the importance of multifunctional T(CD8) in mediating protection in IDUs with recurrent exposure to HCV our findings highlight that the magnitude and/or breadth of HCV-specific T(CD8) determined in ex vivo ELISPOT may not be the sole determinant of protection especially in a setting of recurrent exposure.

Background: The hepatitis C virus (HCV) causes significant morbidity and mortality worldwide, and is highly prevalent among injecting drug users (IDUs). Whether initial HCV infection and clearance provides protection from reinfection has not been established, but is an important question for vaccine development., Objective: To elucidate an unusual history of HCV infection and clearance in an IDU., Study Design: The subject was interviewed and gave blood samples at approximately three-month intervals; all samples were tested for anti-HCV and HCV RNA, genotyped if RNA detected, and checked for mixed genotypes; phylogenetic analysis performed on the subject's and injecting partners' core HCV sequences., Results: We observed consecutive infections with HCV genotypes 3a, 1a and 6l, and intervening clearances, in a young IDU over 449 days. Genotypes 1a and 6l were probably acquired from the subject's injecting partners, who had genetically related infections., Conclusion: This case illustrates (1) the ease with which IDUs can acquire HCV, (2) that prior HCV infection does not protect against reinfection with heterologous strains, and (3) that IDUs can clear consecutive HCV infections. Our subject's history of HCV infection and clearance offers hope for vaccine development, yet demonstrates that HCV vaccines must have cross-genotypic effectiveness.

The social networks of 49 ethnic Vietnamese injecting drug users (IDUs) and 150 IDUs of other ethnicities recruited in Melbourne, Australia, were examined for ethnic differences in distribution of hepatitis C virus infection risk using social network analysis and molecular epidemiology. Vietnamese IDUs were more highly connected than non-Vietnamese IDUs, and more likely to be members of dense injecting sub-networks. More related infections were detected in IDUs with discordant ethnicities than were captured in the social network data; nonetheless, most dyads and most IDU pairs with related infections had matching ethnicity, confirming that mixing was assortative on that criterion. Mixing was not obviously dissortative by risk; low-risk Vietnamese IDUs injected more frequently than did correspondingly low-risk non-Vietnamese IDUs, but results for other measures were reversed or equivocal. Network measurements suggest that ethnic Vietnamese IDUs are at elevated risk of blood-borne infection, a conclusion supported by their relatively high HIV prevalence.

Multiple genotypes of the hepatitis C virus (HCV) were detected in five of 138 HCV RNA positive injecting drug users (IDUs) recruited in Melbourne, Australia. Two were detected by combined LiPA and core and NS5a region sequencing, and three more (selected for testing due to their high-risk behaviour) by heteroduplex mobility analysis. We conclude that the true prevalence of mixed infection in IDUs is undoubtedly higher than the 3.6% (five of 138) we observed, and is underestimated by LiPA, the most common method of genotyping. As responsiveness to HCV treatment varies significantly with genotype, a high prevalence of mixed HCV infections in IDUs must diminish overall treatment efficacy and lessen our ability to reduce the burden of HCV-related disease.

Background: We aimed to measure the overlap between the social networks of injection drug users (IDUs) and the patterns of related hepatitis C virus (HCV) infections among IDUs., Methods: A cohort of 199 IDUs (138 of whom were HCV RNA positive) was recruited from a local drug scene in Melbourne, Australia, and was studied using social network analysis and molecular phylogenetic analysis of 2 regions of the HCV genome., Results: Eighteen clusters of related infections involving 51 IDUs (37.0% of HCV RNA-positive IDUs) were detected; these clusters could be separated into 66 discrete pairs. Twelve (18.2%) of the 66 IDU pairs with related infections reported having previously injected drugs together; conversely, only 12 (3.8%) of the 313 pairs of HCV RNA-positive IDUs who were injection partners had strong molecular evidence of related infections. The social and genetic distances that separated IDUs with identical genotypes were weakly associated. Significant clusters of phylogenetically related sequences identified from core region analysis persisted in the analysis of the nonstructural 5a protein region. Genotyping and sequence analysis revealed 2 mixed-genotype infections., Conclusions: Static social network methods are likely to gather information about a minority of patterns of HCV transmission, because of the difficulty of determining historical infection pathways in an established social network of IDUs. Nevertheless, molecular epidemiological methods identified clusters of IDUs with related viruses and provided information about mixed-genotype infection status.

Hepatitis C affects many millions of people worldwide and is at very high prevalence among people who inject drugs. In our study of hepatitis C virus (HCV) in the social networks of injecting drug users (IDUs), five IDUs with injecting careers of 9 years or more were HCV antibody and RNA negative. All injected frequently with HCV RNA-positive IDUs, and two had recently injected with the syringe of an RNA-positive IDU. Our data suggest the existence of immune protection from HCV infection.