Primary Hepatitis C Virus Infection Research Articles

Coordinated expansion of memory T follicular helper and B cells mediates spontaneous clearance of HCV reinfection.

Follicular helper T cells are essential for helping in the maturation of B cells and the production of neutralizing antibodies (NAbs) during primary viral infections. However, their role during recall responses is unclear. Here, we used hepatitis C virus (HCV) reinfection in humans as a model to study the recall collaborative interaction between circulating CD4 T follicular helper cells (cTfh) and memory B cells (MBCs) leading to the generation of NAbs. We evaluated this interaction longitudinally in subjects who have spontaneously resolved primary HCV infection during a subsequent reinfection episode that resulted in either another spontaneous resolution (SR/SR, n = 14) or chronic infection (SR/CI, n = 8). Both groups exhibited virus-specific memory T cells that expanded upon reinfection. However, early expansion of activated cTfh (CD4+CXCR5+PD-1+ICOS+FoxP3-) occurred in SR/SR only. The frequency of activated cTfh negatively correlated with time post-infection. Concomitantly, NAbs and HCV-specific MBCs (CD19+CD27+IgM-E2-Tet+) peaked during the early acute phase in SR/SR but not in SR/CI. Finally, the frequency of the activated cTfh1 (CXCR3+CCR6-) subset correlated with the neutralization breadth and potency of NAbs. These results underscore a key role for early activation of cTfh1 cells in helping antigen-specific B cells to produce NAbs that mediate the clearance of HCV reinfection.

Risk of Primary Incident Hepatitis C Infection Following Bacterial Sexually Transmissible Infections Among Gay and Bisexual Men in Australia From 2016 to 2020.

In Australia, the incidence of hepatitis C virus (HCV) has declined among gay and bisexual men (GBM) with human immunodeficiency virus (HIV) since 2015 and is low among GBM using HIV preexposure prophylaxis (PrEP). However, ongoing HCV testing and treatment remains necessary to sustain this. To assess the potential utility of sexually transmissible infections (STIs) to inform HCV testing among GBM with HIV and GBM using PrEP, we examined the association between bacterial STI diagnoses and subsequent primary HCV infection. Data were from a national network of 46 clinics participating in the Australian Collaboration for Coordinated Enhanced Sentinel Surveillance. GBM included had ≥1 HCV antibody negative test result and ≥1 subsequent HCV antibody and/or RNA test. Discrete time survival analysis was used to estimate the association between a positive syphilis, rectal chlamydia, and rectal gonorrhea diagnosis in the previous 2 years and a primary HCV diagnosis, defined as a positive HCV antibody or RNA test result. Among 6529 GBM with HIV, 92 (1.4%) had an incident HCV infection. A prior positive syphilis diagnosis was associated with an incident HCV diagnosis (adjusted hazard ratio, 1.99 [95% confidence interval, 1.11-3.58]). Among 13 061 GBM prescribed PrEP, 48 (0.4%) had an incident HCV diagnosis. Prior rectal chlamydia (adjusted hazard ratio, 2.75 [95% confidence interval, 1.42-5.32]) and rectal gonorrhea (2.54 [1.28-5.05]) diagnoses were associated with incident HCV. Diagnoses of bacterial STIs in the past 2 years was associated with HCV incidence. These findings suggest that STIs might be useful for informing HCV testing decisions and guidelines for GBM with HIV and GBM using PrEP.

The rate of hepatitis C reinfection in Canadians coinfected with HIV and its implications for national elimination.

The World Health Organisation (WHO) has set targets for the rate of new infections as a way to measure progress towards the elimination of hepatitis C virus (HCV) as a public health threat. As more people are successfully treated for HCV, a higher proportion of new infections will be reinfections. We consider whether the reinfection rate has changed since the interferon era and what we can infer about national elimination efforts from the current reinfection rate. The Canadian Coinfection Cohort is representative of HIV HCV coinfected people in clinical care. We selected cohort participants successfully treated for a primary HCV infection either in the interferon era or in the era of direct acting antivirals (DAAs). Selected participants were followed from 12 weeks after completing a successful treatment until the end of 2019 or until their last measured HCV RNA. We estimated the reinfection rate in each treatment era, overall and in participant subgroups, using proportional hazard models appropriate for interval censored data. Among 814 successfully treated participants with additional HCV RNA measurements, there were 62 reinfections. The overall reinfection rate was 2.6 (95% confidence interval, CI, 1.2-4.1) /100 person years (PY) in the interferon era and 3.4 (95% CI 2.5-4.4) /100 PY in the DAA era. The rate in those reporting injection drug use (IDU) was much higher: 4.7 (95% CI 1.4-7.9) /100 PY and 7.6 (95% CI 5.3-10) /100 PY in the interferon and DAA eras respectively. The overall reinfection rate in our cohort is now above the WHO target set for new infections in people who inject drugs. The reinfection rate in those reporting IDU has increased since the interferon era. This suggests Canada is not on track to achieve HCV elimination by 2030.

Incidence of primary hepatitis C virus infection among people who inject drugs in Australia pre- and post-unrestricted availability of direct acting antiviral therapies.

The 2016 Global Health Sector Strategy (GHSS) on viral hepatitis aims to reduce new hepatitis C virus (HCV) infections by 80% by 2030, including a 30% reduction by 2020. This study aimed to estimate primary HCV incident infection among a national sample of people who inject drugs (PWID) before and after the introduction of unrestricted access to HCV direct-acting antiviral (DAA) therapy via Australia's Pharmaceutical Benefits Scheme in 2016. A simple deterministic linkage method identified repeat respondents in serial cross-sectional surveys conducted among PWID. Two separate retrospective cohorts of HCV antibody-negative respondents were created, corresponding to the pre- (2010-15) and post- (2016-21) DAA time-periods. This study took place in Australia. Among 757 PWID retained (376 pre-DAA, 381 post-DAA), more than half were male (60%), the majority were heterosexual (80%), the median age was 40 years (interquartile range = 33-46 years) and the predominant drugs last injected were heroin (24%), pharmaceutical opioids (27%) and methamphetamine (41%). The primary outcome was HCV seroconversion, defined as a negative HCV antibody test result followed by a positive HCV antibody result. Time to primary incident HCV infection was estimated using the person-years (PY) method. A total 97 of 376 (2010-15) and 41 of 381 (2016-21) HCV seroconversions were identified. Primary HCV incidence more than halved, from 13.6 per 100 PY [95% confidence intervals (CI) = 11.2, 16.6] in 2010-15 to 5.4 per 100 PY (95% CI =3.9, 7.3) in 2016-21. The decline was independent of observed differences in demographic and drug use characteristics over the two time-periods (adjusted hazard ratio =0.47, 95% CI =0.31-0.69, P<0.001). Australia has had a 53% reduction in primary hepatitis C virus (HCV) incidence among people who inject drugs following unrestricted availability of HCV direct acting antiviral therapy in March 2016. Given that PWID are the predominant population at risk of HCV infection in Australia, findings add to the evidence that Australia has probably met its 2020 Global Health Sector Strategy subtarget of a 30% decline in new infections.

The functional and molecular determinants of HCV-specific CD8 T cell responses during early infection

Abstract T-cell exhaustion is a hallmark of hepatitis C virus (HCV) infection and limits protective immunity in chronic viral infections and cancer. However, limited knowledge exists of the initial dynamics that establish exhaustion in humans. We studied longitudinal blood samples from a unique cohort of primary HCV infection subjects using single cell multi-omics and viral dynamics to identify the functions and phenotypes of HCV-specific CD8+ T cells. The magnitude of IFN-γ production against the transmitted virus was associated with the rate of immune escape, larger clonal expansion, and a molecular profile consistent with a progenitor of early-exhaustion. Lineage tracing within clones revealed fate plasticity through the course of the infection and differentiation fates of progenitor exhausted subsets. This study provides new insights on the contribution of CD8+ T cells to HCV disease outcome and exhaustion, and supports future studies on early T-cell differentiation in human infections. Supported by grants from the NHMCR and scholarships from the Australian Government Research Training Program.

Hepatitis C virus (HCV) incidence among men who have sex with men (MSM) living with HIV: results from the French Hospital Database on HIV (ANRS CO4-FHDH) cohort study, 2014 to 2017.

BackgroundDespite the availability of highly effective direct-acting antivirals (DAAs) and the expected treatment as prevention (TasP) effect, transmission of hepatitis C virus (HCV) persists in men who have sex with men (MSM) who engage in high-risk sexual behaviours.AimWe aimed to estimate the incidence of primary HCV infection among MSM living with HIV in France when DAA was readily available.MethodsWe used data from a large French hospital cohort of persons living with HIV (ANRS CO4-FHDH) prospectively collected between 2014 and 2017. HCV incidence rates were calculated using person-time methods for HCV-negative MSM at inclusion who had serological follow-up from 1 January 2014 to 31 December 2017. Sensitivity analyses were performed by varying the main assumptions to assess their impact on the results.ResultsOf 14,273 MSM living with HIV who were initially HCV-seronegative, 330 acquired HCV during follow-up over 45,866 person-years (py), resulting in an overall estimated incidence rate of 0.72/100 py (95% CI: 0.65–0.80). HCV incidence significantly decreased from 0.98/100 py (95% CI: 0.81–1.19) in 2014 to 0.45/100 py (95% CI: 0.35–0.59) in 2017 (54% decrease; 95% CI: 36–67). This trend was confirmed by most of the sensitivity analyses.ConclusionThe primary incidence of HCV was halved for MSM living with HIV between 2014 and 2017. This decrease may be related to unrestricted DAA availability in France for individuals living with HIV. Further interventions, including risk reduction, are needed to reach HCV micro-elimination in MSM living with HIV.

Evaluation of hepatitis C treatment-as-prevention within Australian prisons (SToP-C): a prospective cohort study

Limited empirical evidence exists for the effectiveness of hepatitis C virus (HCV) treatment-as-prevention. The Surveillance and Treatment of Prisoners with hepatitis C (SToP-C) study aimed to assess the effect of HCV treatment-as-prevention in the prison setting. SToP-C was a prospective study, including a before-and-after analysis, within a cohort of people incarcerated in two maximum-security prisons (male) and two medium-security prisons (one male, one female) in New South Wales, Australia. All prison inmates aged at least 18 years were eligible for enrolment. After HCV testing, participants were monitored for risk behaviours and HCV infection, among three sub-populations: uninfected (HCV antibody-negative); previously infected (HCV antibody-positive, HCV RNA-negative); and infected (HCV antibody and HCV RNA-positive). Uninfected participants were followed up every 3-6 months to detect HCV primary infection and previously infected participants were followed up every 3-6 months to detect re-infection. Participants with HCV infection were assessed for treatment, initially standard-of-care treatment (administered by prison health services) from 2014 to mid-2017, then direct-acting antiviral (DAA) treatment scale-up from mid-2017 onwards (12 weeks of sofosbuvir plus velpatasvir, administered through SToP-C). Participants were followed up until study closure in November, 2019. The primary study outcome was HCV incidence before and after DAA treatment scale-up among participants at risk of HCV primary infection or re-infection. This study is registered with ClinicalTrials.gov, NCT02064049. Between Oct 30, 2014, and Sept 30, 2019, 3691 participants were enrolled in the SToP-C study. 719 (19%) participants had detectable HCV RNA, 2240 (61%) were at risk of primary HCV infection, and 725 (20%) were at risk of re-infection at baseline. DAA treatment was initiated in 349 (70%) of 499 eligible participants during the treatment scale-up period. The HCV incidence analysis comprised 1643 participants at risk of HCV infection or re-infection during longitudinal follow-up (median age 33 years [IQR 27-42]; 1350 [82%] male). 487 (30%) of 1643 participants reported injecting drugs in prison. HCV incidence decreased from 8·31 per 100 person-years in the pre-treatment scale-up period to 4·35 per 100 person-years in the post-treatment scale-up period (incidence rate ratio [IRR] 0·52 [95% CI 0·36-0·78]; p=0·0007). The incidence of primary infection decreased from 6·64 per 100 person-years in the pre-treatment scale-up period to 2·85 per 100 person-years in the post-treatment scale-up period (IRR 0·43 [95% CI 0·25-0·74]; p=0·0019), whereas the incidence of re-infection decreased from 12·36 per 100 person-years to 7·27 per 100 person-years (0·59 [0·35-1·00]; p=0·050). Among participants reporting injecting drugs during their current imprisonment, the incidence of primary infection decreased from 39·08 per 100 person-years in the pre-treatment scale-up period to 14·03 per 100 person-years in the post-treatment scale-up period (IRR 0·36 [95% CI 0·16-0·80]; p=0·0091), and the incidence of re-infection decreased from 15·26 per 100 person-years to 9·34 per 100 person-years (0·61 [0·34-1·09]; p=0·093). The adjusted analysis (adjusted for age, Indigenous Australian ethnicity, duration of stay in prison, previous imprisonment, injecting drug use status, and prison site) indicated a significant reduction in the risk of HCV infection between the pre-DAA treatment scale-up and post-DAA treatment scale-up periods (adjusted hazard ratio 0·50 [95% CI 0·33-0·76]; p=0·0014). DAA treatment scale-up was associated with reduced HCV incidence in prison, indicative of a beneficial effect of HCV treatment-as-prevention in this setting. These findings support broad DAA treatment scale-up within incarcerated populations. Australian National Health and Medical Research Council Partnership Project Grant and Gilead Sciences.

Incidence of Hepatitis C Virus Infections Among Users of Human Immunodeficiency Virus Pre-exposure Prophylaxis

Sexual transmission of hepatitis C virus (HCV) is well documented among human immunodeficiency virus (HIV)-uninfected individuals. The use of HIV pre-exposure prophylaxis (PrEP) may be associated with engagement in activities that facilitate the transmission of sexually transmitted infections (STIs) and possibly HCV among PrEP users. Between 2012 and 2019, the incidence of HCV and bacterial STIs were calculated among HIV-negative indviduals receiving PrEP at the University Health Network HIV Prevention Clinic.Mucosal, anal, and blood samples were taken to test for HIV, syphilis, and anti-HCV antibodies. Among 344 HIV-uninfected patients receiving PrEP, 86% were men having sex with men (MSM). Five individuals were HCV-antibody positive at the time of PrEP initiation. Serologic and virologic follow-up data were available for 109 HCV-negative individuals over 282 patient-years (PY). Two new infections were recorded, yielding an incidence of primary HCV infection of 0.7 per 100 PY. In contrast with HCV, the incidence rates of chlamydia, gonorrhea, and syphilis were 49.2 per 100 PY, 36.3 per 100 PY, and 5.2 per 100 PY, respectively. Both individuals with new HCV diagnoses reported being MSM with a history of unprotected intercourse and 1 individual also reported recreational drug use. Both individuals were asymptomatic at the time of diagnosis and the infections were detected by routine laboratory monitoring. The low incidence of HCV infections despite significantly higher rates of other STIs suggests that sexual transmission of HCV is uncommon in HIV-negative MSM PrEP users in this community. Performing routine risk-based HCV surveillance among PrEP users should be evaluated. The high incidence of STIs in this population indicates a vital role for periodic STI monitoring in those receiving PrEP.

A212 INCIDENCE OF HEPATITIS C VIRUS INFECTIONS AMONG USERS OF HUMAN IMMUNODEFICIENCY VIRUS PRE-EXPOSURE PROPHYLAXIS

Abstract Background Sexual transmission of hepatitis C virus (HCV) is well-documented among HIV-uninfected individuals. The use of HIV pre-exposure prophylaxis (PrEP) may lead to increased engagement in activities that facilitate the transmission of sexually transmitted infections (STI) and possibly HCV among PrEP users. Aims To assess the incidence of Hepatitis C Virus Infections among HIV negative pre-exposure prophylaxis (PrEP) users Methods Between 2012 and 2019, the incidence of HCV and bacterial STIs were calculated among HIV-negative patients receiving PrEP at the University Health Network HIV Prevention Clinic. Mucosal, anal and blood samples were taken to test for HIV, syphilis, and anti-HCV antibodies. Results Among 344 HIV-uninfected patients receiving PrEP, 86% were men having sex with men (MSM). Five individuals were HCV-antibody positive at the time of PrEP initiation. Serological and virological follow-up was available for 109 HCV-negative individuals over 282 patient-years (PY). Two new infections were recorded, yielding an incidence of primary HCV infection of 0.7/100 PY. In contrast with HCV, the incidence rates of chlamydia, gonorrhea, and syphilis were 49.2/100 PY, 36.3/100 PY, and 5.2/100 PY, respectively. Both individuals with new HCV diagnoses reported being MSM with a history of unprotected intercourse and one also reported recreational drug use. Both individuals were asymptomatic at the time of diagnosis and were detected by routine laboratory monitoring. Conclusions The low incidence of HCV infections despite significantly higher rates of other STIs suggests that sexual transmission of HCV is uncommon in HIV-negative MSM PrEP users. Performing routine risk-based HCV surveillance among PrEP users should be evaluated. The high incidence of STIs in this population indicates a vital role for periodic STI monitoring in those receiving PrEP. Funding Agencies vircan

Hepatitis C Virus Transmission Among Men Who Have Sex With Men in Amsterdam: External Introductions May Complicate Microelimination Efforts.

It is unclear whether unrestricted access and high uptake of direct-acting antivirals (DAAs) is sufficient to eliminate hepatitis C virus (HCV) in high-risk populations such as men who have sex with men (MSM). This study presents historic trends and current dynamics of HCV transmission among MSM in Amsterdam based on sequence data collected between 1994 and 2019. Hypervariable region 1 sequences of 232 primary HCV infections and 56 reinfections were obtained from 244 MSM in care in Amsterdam. Maximum-likelihood phylogenies were constructed for HCV genotypes separately, and time-scaled phylogenies were constructed using a Bayesian coalescent approach. Transmission clusters were determined by Phydelity and trends in the proportion of unclustered sequences over time were evaluated using logistic regression. Seventy-six percent (218/288) of sequences were part of 21 transmission clusters and 13 transmission pairs. Transmission cluster sizes ranged from 3 to 44 sequences. Most clusters were introduced between the late 1990s and early 2010s and no new clusters were introduced after 2012. The proportion of unclustered sequences of subtype 1a, the most prevalent subtype in this population, fluctuated between 0% and 20% in 2009-2012, after which an increase occurred from 0% in 2012 to 50% in 2018. The proportion of external introductions of HCV infections among MSM in Amsterdam has recently increased, coinciding with high DAA uptake. Frequent international transmission events will likely complicate local microelimination efforts. Therefore, international collaboration combined with international scale-up of prevention, testing, and treatment of HCV infections (including reinfections) is warranted, in particular for local microelimination efforts.

Envelope-Specific IgG3 and IgG1 Responses Are Associated with Clearance of Acute Hepatitis C Virus Infection.

Hepatitis C virus (HCV) can be cleared naturally in a subset of individuals. However, the asymptomatic nature of acute HCV infection makes the study of the early immune response and defining the correlates of protection challenging. Despite this, there is now strong evidence implicating the humoral immune response, specifically neutralising antibodies, in determining the clearance or chronicity outcomes of primary HCV infection. In general, immunoglobulin G (IgG) plays the major role in viral neutralisation. However, there are limited investigations of anti-HCV envelope protein 2 (E2) isotypes (IgM, IgG, IgA) and IgG subclasses (IgG1–4) in early HCV infection. In this study, using a rare cohort of 14 very recently HCV-infected individuals (4–45 days) with varying disease outcome (n = 7 clearers), the timing and potency of anti-HCV E2 isotypes and IgG subclasses were examined longitudinally, in relation to neutralising antibody activity. Clearance was associated with anti-E2 IgG, specifically IgG1 and IgG3, and appeared essential to prevent the emergence of new HCV variants and the chronic infection outcome. Interestingly, these IgG responses were accompanied by IgM antibodies and were associated with neutralising antibody activity in the subjects who cleared infection. These findings provide novel insights into the early humoral immune response characteristics associated with HCV disease outcome.

Single-Dose Vaccination with a Hepatotropic Adeno-associated Virus Efficiently Localizes T Cell Immunity in the Liver with the Potential To Confer Rapid Protection against Hepatitis C Virus.

Hepatitis C virus (HCV) is a significant contributor to the global disease burden, and development of an effective vaccine is required to eliminate HCV infections worldwide. CD4+ and CD8+ T cell immunity correlates with viral clearance in primary HCV infection, and intrahepatic CD8+ tissue-resident memory T (TRM) cells provide lifelong and rapid protection against hepatotropic pathogens. Consequently, we aimed to develop a vaccine to elicit HCV-specific CD4+ and CD8+ T cells, including CD8+ TRM cells, in the liver, given that HCV primarily infects hepatocytes. To achieve this, we vaccinated wild-type BALB/c mice with a highly immunogenic cytolytic DNA vaccine encoding a model HCV (genotype 3a) nonstructural protein (NS5B) and a mutant perforin (pVAX-NS5B-PRF), as well as a recombinant adeno-associated virus (AAV) encoding NS5B (rAAV-NS5B). A novel fluorescent target array (FTA) was used to map immunodominant CD4+ T helper (TH) cell and cytotoxic CD8+ T cell epitopes of NS5B in vivo, which were subsequently used to design a KdNS5B451-459 tetramer and analyze NS5B-specific T cell responses in vaccinated mice in vivo The data showed that intradermal prime/boost vaccination with pVAX-NS5B-PRF was effective in eliciting TH and cytotoxic CD8+ T cell responses and intrahepatic CD8+ TRM cells, but a single intravenous dose of hepatotropic rAAV-NS5B was significantly more effective. As a T-cell-based vaccine against HCV should ideally result in localized T cell responses in the liver, this study describes primary observations in the context of HCV vaccination that can be used to achieve this goal.IMPORTANCE There are currently at least 71 million individuals with chronic HCV worldwide and almost two million new infections annually. Although the advent of direct-acting antivirals (DAAs) offers highly effective therapy, considerable remaining challenges argue against reliance on DAAs for HCV elimination, including high drug cost, poorly developed health infrastructure, low screening rates, and significant reinfection rates. Accordingly, development of an effective vaccine is crucial to HCV elimination. An HCV vaccine that elicits T cell immunity in the liver will be highly protective for the following reasons: (i) T cell responses against nonstructural proteins of the virus are associated with clearance of primary infection, and (ii) long-lived liver-resident T cells alone can protect against malaria infection of hepatocytes. Thus, in this study we exploit promising vaccination platforms to highlight strategies that can be used to evoke highly functional and long-lived T cell responses in the liver for protection against HCV.

Primary Incidence of Hepatitis C Virus Infection Among HIV-Infected Men Who Have Sex With Men in San Diego, 2000-2015.

BackgroundLittle is known about the hepatitis C virus (HCV) epidemic among HIV-infected men who have sex with men (HIV+ MSM) in the United States. In this study, we aimed to determine the incidence of primary HCV infection among HIV+ MSM in San Diego, California.MethodsWe performed a retrospective cohort analysis of HCV infection among HIV+ MSM attending 2 of the largest HIV clinics in San Diego. Incident HCV infection was assessed among HIV+ MSM with a negative anti-HCV test and subsequent HCV test between 2000 and 2017, with data censored to 2015. HCV reinfection was assessed among HIV+ MSM successfully treated for HCV between 2008 and 2015. Infection/reinfection rates were calculated using person-time methods.ResultsAmong 3068 initially HCV-seronegative HIV+ MSM, 178 new infections occurred over 15 796 person-years, giving an incidence of 1.13 per 100 person-years (/100py; 95% confidence interval [CI], 0.97–1.31). Incidence was stable from 2000 to 2014 (0.83/100py; 95% CI, 0.41–1.48), with an increase to 3.01/100py (95% CI, 1.97–4.42) in 2015 (P = .02). Among 43 successfully treated patients, 3 were reinfected.ConclusionsHCV incidence is high among HIV+ MSM in San Diego, with evidence suggesting a recent increase in 2015. Strong HCV testing guidelines and active prevention efforts among HIV+ MSM are urgently needed that include rapid diagnosis, treatment, and risk reduction.

Hepatitis C virus prevalence and associated risk factors among Indigenous Australians who inject drugs

Objective:To examine factors associated with hepatitis C virus (HCV) infection among a national sample of Indigenous and non‐Indigenous people who inject drugs (PWID) in Australia. Methods:Respondents were recruited from Australia’s Needle Syringe Program Survey; an annual bio‐behavioural surveillance project that monitors HCV antibody prevalence among PWID. Data from 2006–2015 were de‐duplicated to retain only one record where individuals participated in >1 survey round. Univariate and multivariable logistic regression examined demographic characteristics and injection‐related behaviours associated with exposure to HCV. Results:Among 17,413 respondents, 2,215 (13%) were Indigenous Australians. Compared to their non‐Indigenous counterparts, Indigenous respondents were significantly more likely to be exposed to HCV infection (53% vs. 60% respectively, p<0.001). Among Indigenous respondents, HCV antibody positivity was independently associated with a history of imprisonment (Adjusted Odd Ratio [AOR] 2.13, 95%CI 1.73–2.64), opioid injection (AOR 1.53, 95%CI 11.43–2.16), recruitment in a metropolitan location (AOR 1.27, 95%CI 1.02–1.59), engagement in opioid substitution therapy (AOR 2.83, 95%CI 2.23–3.59) and length of time since first injection (p<0.001). Conclusion:Indigenous PWID are more likely to be exposed to HCV infection than their non‐Indigenous counterparts. Implications for public health:Increased access to culturally sensitive harm reduction programs is required to prevent primary HCV infection and reinfection among Indigenous PWID. Given recent advances in HCV treatment, promotion of treatment uptake among Indigenous PWID may reduce future HCV‐related morbidity and mortality.

Serum IFN-λ3 Levels Correlate with Serum Hepatitis C Virus RNA Levels in Symptomatic Patients with Acute Hepatitis C

Background: Recent genome-wide association studies demonstrated that 2 single nucleotide polymorphisms (SNPs), upstream of the interferon-λ (IFNL) 3 gene, are associated with the spontaneous clearance of hepatitis C virus (HCV) in symptomatic patients with acute hepatitis C (AHC). Although these 2 SNPs, rs8099917 and rs12979860, have established their significant roles in the innate immunity response to spontaneously clear HCV in patients with AHC, the detailed mechanisms of their roles remain largely unknown. Aim: This study is aimed at clarifying the factors affecting IFNL3 production and assessing the roles of IFNL3 in AHC. Materials and Methods: A total of 21 AHC patients who visited the hospital within 10 days after symptom onset were assessed. As controls, 23 healthy volunteers (HVs) were examined. Serum IFNL3 levels were quantified using an in-house, IFNL3-specific chemiluminescence enzyme immunoassay (CLEIA) kit. Serum IFNL1, IFN-α, IFN-β, and IFN-γ induced protein-10 (IP-10) levels were assayed using commercial enzyme-linked immunosorbent assay (ELISA) kits. Results: At baseline, serum IFNL3 levels were higher in AHC patients than in HVs (p < 0.0001). The higher levels in AHC patients did not differ between patients with the rs8099917 TT genotype and those with the non-TT (TG/GG) genotype (p = 0.546). Serial measurement of serum IFNL3 levels did not predict the outcome of conventional AHC. However, serum IFNL3 levels at baseline correlated positively with the HCV RNA levels (p = 0.005). Following HCV eradication, serum IFNL3 levels reduced to within the range obtained for HVs. Baseline serum IFNL1 levels did not differ significantly between AHC patients and HVs (p = 0.284). Serum levels of IFNL1 and IFNL3 at baseline also showed no correlative power (p = 0.288). Serum IFN-α and IFN-β were detected together with remarkably high serum IFNL3 levels in only one patient who progressed to acute liver failure (ALF). Conclusion: These findings indicate that serum IFNL3 levels at baseline are higher in AHC patients regardless of the rs8099917 polymorphism, and primary HCV infection triggers the production of IFNL3. As a first line of defense in the innate immune system against invading HCV, increased IFNL3 levels play an important role, but serum IFNL3 levels are not the principal determinant of the clinical course of conventional AHC.

Decreased pro-inflammatory immune responses during recurrent acute HCV infections in HIV co-infected patients.

Patients in high-risk groups continue to transmit the hepatitis C virus (HCV) and frequently experience reinfections. Since little is known regarding the immune response to HCV during reinfection, we compared primary and consecutive acute HCV infections in patients with an HIV infection, and focused on the cytokine bridging innate to adaptive immunity. We observed that the serum levels of IL-12p40, MIP-1β, MIG and IP-10 increased during primary acute HCV infection, but not during subsequent secondary acute reinfections. The weaker pro-inflammatory cytokine responses observed during HCV reinfections suggest more limited secondary acute immune responses, which may prevent damage to the infected liver.

Hepatitis C Virus Reinfection and Spontaneous Clearance of Reinfection—the InC3Study

We aimed to characterize the natural history of hepatitis C virus (HCV) reinfection and spontaneous clearance following reinfection (reclearance), including predictors of HCV reclearance. Data were synthesized from the 9 prospective cohorts of the International Collaboration of Incident Human Immunodeficiency Virus and HCV in Injecting Cohorts study, which evaluated HCV infection outcomes among people who inject drugs. Participants with primary HCV infection were classified as having achieved viral suppression if they had negative results of at least 1 subsequent HCV RNA test. Those with positive results of an HCV RNA test following viral suppression were investigated for reinfection. Viral sequence analysis was used to identify reinfection (defined as detection of heterologous virus with no subsequent detection of the original viral strain). Among 591 participants with acute primary HCV infection, 118 were investigated for reinfection. Twenty-eight participants were reinfected (12.3 cases/100 person-years; 95% confidence interval [CI], 8.5-17.8). Peak HCV RNA level was lower during reinfection than primary infection (P = .011). The proportion of individuals with reclearance 6 months after reinfection was 52% (95% CI, 33%-73%). After adjustment for study site, females with the IFNL4 (formerly IFNL3 and IL28B) rs12979860 CC genotype detected were more likely to have reclearance (hazard ratio, 4.16; 95% CI, 1.24-13.94; P = .021). Sex and IFNL4 genotype are associated with spontaneous clearance after reinfection.

Hepatitis C virus (HCV) antibody dynamics following acute HCV infection and reinfection among HIV-infected men who have sex with men.

A decline of hepatitis C virus (HCV) antibody titers (anti-HCV), ultimately resulting in seroreversion, has been reported following clearance of viremia in both acute and chronic HCV infection. However, frequency of seroreversion remains unknown in human immunodeficiency virus (HIV)/HCV-coinfected patients. We describe anti-HCV dynamics among HIV-infected men who have sex with men (MSM) following acute HCV infection and reinfection. Primary acute HCV infection was assumed when a subject was anti-HCV negative prior to the first positive HCV RNA test. Anti-HCV was measured at least annually in 63 HIV-infected MSM, with a median follow-up of 4.0 years (interquartile range [IQR], 2.5-5.7 years). Time from HCV infection to seroconversion, and from seroconversion to seroreversion, was estimated using the Kaplan-Meier method. Longitudinal anti-HCV patterns were studied using a random-effects model to adjust for repeated measures. Median time from HCV infection to seroconversion was 74 days (IQR, 47-125 days). Subjects who cleared HCV RNA (n = 36) showed a significant decrease in anti-HCV levels (P < .001). Among 31 subjects with sustained virologic response (SVR), anti-HCV became undetectable during follow-up in 8; cumulative incidence of seroreversion within 3 years after seroconversion was 37% (95% confidence interval, 18%-66%). Eighteen subjects became reinfected during follow-up; this coincided with a subsequent increase in anti-HCV reactivity. A decline of anti-HCV reactivity was associated with HCV RNA clearance. Seroreversion was very common following SVR. Upon reinfection, anti-HCV levels increased again. Monitoring anti-HCV levels might therefore be an effective alternative for diagnosis of HCV reinfection.

Assessing the feasibility of hepatitis C virus vaccine trials: Results from the Hepatitis C Incidence and Transmission Study-community (HITS-c) vaccine preparedness study

Efficacy trials of preventive hepatitis C virus (HCV) vaccine candidates raise challenging scientific and ethical issues. Based on data from the first 3years of a community-based prospective observational study – the Hepatitis C Incidence and Transmission Study-community (HITS-c) – this paper examines the feasibility of conducting trials of candidate HCV vaccines with people who inject drugs (PWID) in Sydney, Australia. Of the 166 PWID confirmed HCV antibody negative and eligible for enrolment, 156 (94%) completed baseline procedures. Retention was high, with 89% of participants retained at 48weeks and 76% of participants completing at least 75% of study visits within 2weeks of schedule. The rate of primary HCV infection was 7.9/100py (95% CI 4.9, 12.7). Of the 17 incident cases, 16 completed at least one follow-up assessment and 12 (75%) had evidence of chronic viraemia with progression to chronic HCV infection estimated to be 6/100py. Power calculations suggest a chronic HCV infection rate of at least 12/100py (primary HCV infection rate 16/100py) will be required for stand-alone trials of highly efficacious candidates designed to prevent chronic infection. However, elevated primary HCV infection was observed among participants not receiving opioid substitution therapy who reported heroin as the main drug injected (26.9/100py, 95% CI 14.5, 50.0) and those who reported unstable housing (23.5/100py, 95% CI 7.6, 72.8), daily or more frequent injecting (22.7/100py, 95% CI 12.2, 42.2) and receptive syringe sharing (23.6/100py, 95% CI 9.8, 56.7) in the 6months prior to baseline. These data suggest that it is possible to recruit and retain at-risk PWID who adhere to study protocols and that modification of eligibility criteria may identify populations with sufficiently high HCV incidence. Results support the feasibility of large multi-centre HCV vaccine trials, including in the Australian setting.

A bioinformatics pipeline for the analyses of viral escape dynamics and host immune responses during an infection.

Rapidly mutating viruses, such as hepatitis C virus (HCV) and HIV, have adopted evolutionary strategies that allow escape from the host immune response via genomic mutations. Recent advances in high-throughput sequencing are reshaping the field of immuno-virology of viral infections, as these allow fast and cheap generation of genomic data. However, due to the large volumes of data generated, a thorough understanding of the biological and immunological significance of such information is often difficult. This paper proposes a pipeline that allows visualization and statistical analysis of viral mutations that are associated with immune escape. Taking next generation sequencing data from longitudinal analysis of HCV viral genomes during a single HCV infection, along with antigen specific T-cell responses detected from the same subject, we demonstrate the applicability of these tools in the context of primary HCV infection. We provide a statistical and visual explanation of the relationship between cooccurring mutations on the viral genome and the parallel adaptive immune response against HCV.