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Background Finger-stick point-of-care and dried blood spot (DBS) hepatitis C virus (HCV) RNA testing increases testing uptake and linkage to care. This systematic review evaluated the diagnostic accuracy of point-of-care testing and DBS to detect HCV RNA. Methods Bibliographic databases and conference presentations were searched for eligible studies. Meta-analysis was used to pool estimates. Results Of 359 articles identified, 43 studies were eligible and included. When comparing the Xpert HCV Viral Load Fingerstick assay to venous blood samples (7 studies with 987 samples), the sensitivity and specificity for HCV RNA detection was 99% (95% confidence interval [CI], 97%–99%) and 99% (95% CI, 94%–100%) and for HCV RNA quantification was 100% (95% CI, 93%–100%) and 100% (95% CI, 94%–100%). The proportion of invalid results following Xpert HCV Viral Load Fingerstick testing was 6% (95% CI, 3%–11%). When comparing DBS to venous blood samples (28 studies with 3988 samples) the sensitivity and specificity for HCV RNA detection was 97% (95% CI, 95%–98%) and 100% (95% CI, 98%–100%) and for HCV RNA quantification was 98% (95% CI, 96%–99%) and 100% (95% CI, 95%–100%). Conclusions Excellent diagnostic accuracy was observed across assays for detection of HCV RNA from finger-stick and DBS samples. The proportion of invalid results following Xpert HCV Viral Load Fingerstick testing highlights the importance of operator training and quality assurance programs.

Background Hepatitis C virus (HCV) infection disproportionately impacts people experiencing homelessness. Hepatitis C virus can lead to negative health outcomes, including mortality. We evaluated the impact of a permanent supportive housing (PSH) program (ie, “treatment”) on liver-related morbidity and mortality among persons with chronic homelessness and HCV infection. Methods We matched records for persons eligible for a New York City PSH program (2007–2014) with Heath Department HCV and Vital Statistics registries and Medicaid claims. Among persons diagnosed with HCV before or 2 years posteligibility, we added stabilized inverse probability of treatment weights to negative binomial regression models to compare rates for liver disease-related emergency department visits and hospitalizations, and hazard ratios for mortality, by program placement 2 and 5 years posteligibility. Results We identified 1158 of 8783 placed and 1952 of 19 019 unplaced persons with laboratory-confirmed HCV infection. Permanent supportive housing placement was associated with significantly reduced liver-related emergency department visits (adjusted rate ratio [aRR] = 0.76, 95% confidence interval [CI] = .61–.95), hospitalizations (aRR = 0.62, 95% CI = .54–.71), and all-cause (adjusted hazard ratio [aHR] = 0.65, 95% CI = .46–.92) and liver-related mortality (aHR = 0.72, 95% CI = .09–.83) within 2 years. The reduction remained significant for hospitalizations after 5 years. Conclusions Placement into PSH was associated with reduced liver-related morbidity and mortality among persons with HCV infection and chronic homelessness.

The World Health Organization has set a goal to eliminate hepatitis C virus (HCV) infection as public health threat by 2030. Although the advent of highly effective and tolerable direct-acting antiviral therapy has paved the way for HCV elimination, most people with HCV infection remain undiagnosed and untreated globally, with striking disparities between high-income and low- to middle-income countries. Novel decentralized and cost-effective “test-and-treat” strategies are critically needed to identify the millions of people unaware of their status and link them to treatment.

Background People with HIV are disproportionately coinfected with hepatitis C virus (HCV) and experience accelerated liver-related mortality. Direct-acting antivirals (DAAs) yield high sustained virologic response (SVR) rates, but uptake is suboptimal. This study characterizes the DAA-era HCV treatment cascade and barriers among US men and women with or at risk for HIV. Methods We constructed HCV treatment cascades using the Women’s Interagency HIV Study (women, 6 visits, 2015–2018, n = 2447) and Multicenter AIDS Cohort Study (men, 1 visit, 2015–2018, n = 2221). Cascades included treatment-eligible individuals (ie, HCV RNA-positive or reported DAAs). Surveys captured self-reported clinical (eg, CD4), patient (eg, missed visits), system (eg, appointment access), and financial/insurance barriers. Results Of 323/92 (women/men) treatment eligible, most had HIV (77%/70%); 69%/63% were black. HIV-positive women were more likely to attain cascade outcomes than HIV-negative women (39% vs 23% initiated, 21% vs 12% SVR); similar discrepancies were noted for men. Black men and substance users were treated less often. Women initiating treatment (vs not) reported fewer patient barriers (14%/33%). Among men not treated, clinical barriers were prevalent (53%). Conclusions HIV care may facilitate HCV treatment linkage and barrier navigation. HIV-negative individuals, black men, and substance users may need additional support. Clinical trials registration NCT00000797 (Women’s Interagency HIV Study); NCT00046280 (Multicenter AIDS Cohort Study).

Background Spontaneous clearance of acute hepatitis C virus (HCV) infection is more common in women than in men, independent of known risk factors. Methods To identify sex-specific genetic loci, we studied 4423 HCV-infected individuals (2903 male, 1520 female) of European, African, and Hispanic ancestry. We performed autosomal, and X chromosome sex-stratified and combined association analyses in each ancestry group. Results A male-specific region near the adenosine diphosphate–ribosylation factor–like 5B (ARL5B) gene was identified. Individuals with the C allele of rs76398191 were about 30% more likely to have chronic HCV infection than individuals with the T allele (OR, 0.69; P = 1.98 × 10−07), and this was not seen in females. The ARL5B gene encodes an interferon-stimulated gene that inhibits immune response to double-stranded RNA viruses. We also identified suggestive associations near septin 6 and ribosomal protein L39 genes on the X chromosome. In box sexes, allele G of rs12852885 was associated with a 40% increase in HCV clearance compared with the A allele (OR, 1.4; P = 2.46 × 10−06). Septin 6 facilitates HCV replication via interaction with the HCV NS5b protein, and ribosomal protein L39 acts as an HCV core interactor. Conclusions These novel gene associations support differential mechanisms of HCV clearance between the sexes and provide biological targets for treatment or vaccine development.

Background Direct-acting antiviral (DAA) therapy for hepatitis C virus (HCV) is highly effective. However, people who inject drugs face significant barriers to DAA access. Methods We describe a program that colocates HCV management within a syringe service program in New York City. We performed a retrospective chart review of all patients with confirmed HCV viremia. Results From 2015 to 2018, 102 patients with viremia completed intake. Fifty-eight patients started DAAs. Nine patients discontinued treatment or were lost to follow-up before completion; 1 is continuing DAA treatment. Of 48 patients who completed therapy, sustained virologic response (SVR) was achieved in 43 (89.6%). Age and established mental health treatment at intake were associated with SVR. Regular cocaine use was negatively associated with SVR in univariate analysis, but this association was not significant after adjustment for age. Of 30 patients completing DAA therapy with active illicit opioid use at intake, 14 (46.4%) engaged in opioid use disorder (OUD) treatment during therapy, and 9 remained in OUD treatment after completion of DAA treatment. Conclusions Loss to follow-up is a challenge for people who inject drugs, but among those who completed treatment, SVR was achieved at a high rate. Mental health treatment may facilitate HCV cure. Conversely, HCV therapy may facilitate engagement in OUD treatment and other services.

Background In the United States, many opioid treatment programs (OTPs) do not offer viral hepatitis (VH) or human immunodeficiency virus (HIV) testing despite high prevalence among OTP clients. We initiated an opt-out VH and HIV testing and linkage-to-care program within our OTP. Methods All OTP intakes are screened for VH and HIV and evaluated for rescreening annually. A patient navigator reviews laboratory results and provides counseling in the OTP clinic. The medical record is queried to identify individuals with previously diagnosed, untreated VH or HIV. Navigation support is provided for linkage or relinkage to VH or HIV care. Results Between March 2018 and Februrary 2019, 532 individuals were screened for hepatitis C virus (HCV), 180 tested HCV antibody positive (34%), and 108 were HCV-ribonucleic acid (RNA) positive (20%). Sixty individuals were identified with previously diagnosed, untreated HCV. Of all HCV RNA+, 49% reported current injection drug use (82 of 168). Ninety-five individuals were seen by an HCV specialist (57% of HCV RNA+), 72 started treatment (43%), and 69 (41%) completed treatment. Individuals with primary care providers were most likely to start treatment. Four individuals were diagnosed with hepatitis B; 0 were diagnosed with HIV. Conclusions The implementation of an OTP-based screening and navigation protocol has enabled significant gains in the identification and treatment of VH in this high prevalence setting.

Background Hepatitis C virus (HCV) remains endemic among people who use drugs (PWUD). Measures of HCV community viral load (CVL) and HCV care continuum outcomes may be valuable for ascertaining unmet treatment need and for HCV surveillance and control. Methods Data from patients in an opioid treatment program during 2013–2016 were used to (1) identify proportions of antibody and viral load (VL) tested, linked-to-care, and treated, in 2013–2014 and 2015–2016, and pre- and postimplementation of qualitative reflex VL testing; (2) calculate engaged-in-care HCV CVL and “documented” and “estimated” unmet treatment need; and (3) examine factors associated with linkage-to-HCV-care. Results Among 11 267 patients, proportions of HCV antibody tested (52.5% in 2013–2014 vs 73.3% in 2015–2016), linked-to-HCV-care (15.7% vs 51.8%), and treated (12.0% vs 44.7%) all increased significantly. Hispanic ethnicity was associated with less linkage-to-care, and Manhattan residence was associated with improved linkage-to-care. The overall engaged-in-care HCV CVL was 4 351 079 copies/mL (standard deviation = 7 149 888); local HCV CVLs varied by subgroup and geography. Documented and estimated unmet treatment need decreased but remained high. Conclusions After qualitative reflex VL testing was implemented, care continuum outcomes improved, but gaps remained. High rates of unmet treatment need suggest that control of the HCV epidemic among PWUD will require expansion of HCV treatment coverage.

BackgroundThe effectiveness of hepatitis C testing and linkage-to-care (LTC) is poorly characterized in low-resource jurisdictions facing gaps in harm reduction, including illegality of syringe exchange services. Effectiveness of a community-based test/LTC program was evaluated in Alabama.MethodsIn 2016–2018, shelters, drug treatment centers (DTCs), AIDS organizations, and Federally Qualified Health Centers (FQHCs) engaged in screening/LTC. A coordinator navigated individuals to confirm viremia and link to substance use treatment or primary care with hepatitis C prescribers.ResultsPoint-of-care (POC) tested 4293 individuals (10% [427] antibody-positive, 71% [299/419] RNA performed, 80% [241/299] viremia confirmed) and 93% linked to care (225/241). Electronic medical record (EMR)-based reflex strategy screened 4654 (15% [679] antibody positive, 99% [670/679] RNA performed, 64% [433/679] viremia confirmed) and 85% linked to care (368/433). We observed higher odds of RNA confirmation in EMR-based reflex versus POC (OR, 2.07; P ConclusionsIn Alabama, screening at high-risk settings identified significant hepatitis C burden and reflex testing outperformed point-of-care linkage indicators. Colocating testing in DTCs and treatment in FQHCs provided key LTC venues to at-risk younger groups.

A study reported in 2019 showed that hepatitis C virus (HCV) could help disseminate hepatitis D virus (HDV). To test this finding, 2123 plasma samples positive for anti-HCV antibody were screened for anti-HDV antibodies, and HDV-RNA was searched for in samples positive for anti-HDV antibody. Of 41 samples (1.9%) that tested positive for anti-HDV antibody, 27 (65.9%) were positive and 14 (34.1%) negative for antibody to hepatitis B core antigen (anti-HBc). Anti-HDV antibodies were significantly more present in samples positive for anti-HBc (6.21% vs 0.8% in negative samples; P < .001) and in samples negative for HCV RNA (2.9% vs 1.5% for positive samples; P = .03). Serological ratios were significantly higher in samples positive for anti-HBc (P < .01). No anti-HDV–positive sample was HDV RNA positive. In conclusion, this study found no evidence suggesting a role for HCV in HDV dissemination in humans.

Direct acting antiviral therapies rapidly clear chronic hepatitis C virus (HCV) infection and restore natural killer (NK) cell function. We investigated NK-cell memory formation following HCV clearance by examining NK-cell phenotype and responses from control and chronic HCV patients before and after therapy following sustained virologic response at 12 weeks post therapy (SVR12). NK-cell phenotype at SVR12 differed significantly from paired pretreatment samples, with an increase in maturation markers CD16, CD57, and KLRG1. HCV patients possessed stronger cytotoxic responses against HCV-infected cells as compared to healthy controls; a response that further increased following SVR12. The antigen-specific response was mediated by KLRG1+ NK cells, as demonstrated by increased degranulation and proliferation in response to HCV antigen only. Our data suggest that KLRG1+ HCV-specific memory NK cells develop following viral infection, providing insight into their role in HCV clearance and relevance with regard to vaccine design.

Background Hepatitis C virus (HCV) screening is critical to HCV elimination efforts. Simplified diagnostics are required for low-resource settings and difficult-to-reach populations. This retrospective study assessed performance of rapid diagnostic tests (RDTs) for detection of HCV antibodies. Methods Two lots of 13 RDTs were evaluated at 3 laboratories using archived plasma samples from 4 countries (Nigeria, Georgia, Cambodia, and Belgium). HCV status was determined using 3 reference tests according to a composite algorithm. Sensitivity and specificity were evaluated in HIV-infected and HIV-uninfected populations. Operational characteristics were also assessed. Results In total, 1710 samples met inclusion criteria. In HIV-uninfected samples (n = 384), the majority of RDTs had sensitivity ≥98% in 1 or both lots and most RDTs had specificity ≥99%. In HIV-infected samples (n = 264), specificity remained high but sensitivity was markedly lower than in HIV-uninfected samples; only 1 RDT reached >95%. The majority of HIV-infected samples for which sensitivity was low did not have detectable HCV viral load/core antigen. Interreader variability, lot-to-lot variability, and rate of invalid runs were low for all RDTs ( Conclusions HCV RDTs should be evaluated in the intended target population, as sensitivity can be impacted by population factors such as HIV status. Clinical Trials Registration NCT04033887

Background Direct-acting antiviral (DAA) treatment has revolutionized hepatitis C virus (HCV) care. We aimed to evaluate the risk for the development of hepatocellular carcinoma (HCC) in patients aged 75–84 years with chronic hepatitis C after HCV elimination. Methods This multicenter cohort study included 2405 consecutive patients with chronic hepatitis C without a history of HCC who achieved HCV elimination by DAAs. Patients in whom HCC developed within 1 year of DAA initiation were excluded. Propensity score matching analysis was used to evaluate differences in HCC risk between patients aged 75–84 versus 60–74 years. Results The median observational period was 3.5 years. Among patients aged 75–84 years with a high Fibrosis-4 (FIB-4) index (≥3.25 at baseline), there was no significant difference in the annual incidence of HCCs between groups with an FIB-4 index ≥3.25 (2.75 per 100 person-years [PY]) versus Conclusions Older patients aged 75–84 years remained at high risk for the development of HCC, even after HCV elimination and the improvement of the FIB-4 index to

Background Many long noncoding RNAs (lncRNAs) have important roles in biological processes. The lncRNA HULC was found to be upregulated in human hepatoma tissues. HULC is thought to be involved in multiple steps of hepatoma development and progression; however, the relationship between HULC and hepatitis C virus (HCV) infection, which is a leading cause of hepatoma, remains unclear. Methods We examined the effect of HCV replication on HULC expression and the underlying mechanism using cell culture systems. Subsequently, we tested the effect of HULC suppression and overexpression on HCV replication. Finally, we examined the impact of HCV eradication on HULC expression using human liver tissue and blood samples. Results HCV replication increased HULC expression in cell cultures. A promoter assay showed that an HCV nonstructural protein, NS5A, increased HULC transcription. HULC suppression inhibited HCV replication; conversely, its overexpression enhanced HCV replication. These effects on HCV replication seemed to occur by the modification of HCV translation. Measurements from human liver and blood samples showed that HCV eradication significantly reduced HULC levels in the liver and blood. Conclusions HCV infection increases HULC expression in vitro and in vivo. HULC modulates HCV replication through an HCV internal ribosome entry site–directed translation step.

BackgroundHepatitis C virus (HCV) direct-acting antivirals are highly effective. Less is known about changes in markers of immune activation in persons with human immunodeficiency virus (HIV) in whom a sustained virologic response (SVR) is achieved.MethodsWe conducted a nonrandomized clinical trial of 12 or 24 weeks of paritaprevir-ritonavir-ombitasvir plus dasabuvir (PrOD) with or without ribavirin in persons with HCV-1/HIV coinfection suppressed with antiretroviral therapy. Plasma HCV, soluble CD14 (sCD14), interferon-inducible protein 10, soluble CD163 (sCD163), interleukin 6 (IL-6), interleukin 18, monocyte chemoattractant protein (MCP-1), autotaxin (ATX), and Mac2-binding protein (Mac2BP) were measured over 48 weeks.ResultsParticipants were treated with PrOD for 12 (n = 9) or 24 (n = 36) weeks; the SVR rate at 12 weeks was 93%. At baseline, cirrhosis was associated with higher ATX and MCP-1, female sex with higher ATX and IL-6, older age with higher Mac2BP, higher body mass index with higher ATX, and HIV-1 protease inhibitor use with higher sCD14 levels. In those with SVR, interferon-inducible protein 10, ATX, and Mac2BP levels declined by week 2, interleukin 18 levels declined by the end of treatment, sCD14 levels did not change, and sCD163, MCP-1, and IL-6 levels changed at a single time point.ConclusionsDuring HIV/HCV coinfection, plasma immune activation marker heterogeneity is in part attributable to age, sex, cirrhosis, body mass index, and/or type of antiretroviral therapy. HCV treatment with paritaprevir-ritonavir-ombitasvir plus dasabuvir is highly effective and is associated with variable rate and magnitude of decline in markers of immune activation.Clinical Trials RegistrationNCT02194998.

Background Understanding hepatitis C virus (HCV) transmission among people who inject drugs (PWID) is essential for HCV elimination. We aimed to differentiate reinfections from treatment failures and to identify transmission linkages and associated factors in a cohort of PWID receiving opioid agonist therapy (OAT). Methods We analyzed baseline and follow-up specimens from 150 PWID from 3 OAT clinics in the Bronx, New York. Next-generation sequencing data from the hypervariable region 1 of HCV were analyzed using Global Hepatitis Outbreak and Surveillance Technology. Results There were 3 transmission linkages between study participants. Sustained virologic response (SVR) was not achieved in 9 participants: 7 had follow-up specimens with similar sequences to baseline, and 2 died. In 4 additional participants, SVR was achieved but the participants were viremic at later follow-up: 2 were reinfected with different strains, 1 had a late treatment failure, and 1 was transiently viremic 17 months after treatment. All transmission linkages were from the same OAT clinic and involved spousal or common-law partnerships. Conclusion This study highlights the use of next-generation sequencing as an important tool for identifying viral transmission and to help distinguish relapse and reinfection among PWID. Results reinforce the need for harm reduction interventions among couples and those who report ongoing risk factors after SVR.

Background Xpert HCV Viral Load Fingerstick assay (Xpert HCV VL FS) is a point-of-care test quantifying HCV RNA in Methods This study evaluated time to HCV RNA detection using the Xpert HCV VL FS assay. Fingerstick whole-blood samples were collected from participants in an observational cohort in Australia. Results In May 2018–2019, 1468 participants were enrolled, 1426 had Xpert HCV VL FS testing performed, and 1386 had a valid result. HCV RNA was detected in 23% (325/1386). Among people with undetectable HCV RNA (n = 1061), median time to result was 57 minutes. Among people with detectable HCV RNA (n = 325), median time to HCV RNA detection was 32 minutes and 80% (261/325) had a detectable HCV RNA result in ≤40 minutes. Median time to HCV RNA detection was dependent on HCV RNA level. Conclusions A quicker HCV diagnosis could be achieved by monitoring the time when HCV RNA is first detected with the Xpert HCV VL FS test, rather than HCV RNA quantification, although the current platform does not allow for this. These findings could facilitate new strategies to reduce waiting times for an HCV diagnosis and improve linkage to treatment.

Background Direct-acting antiviral (DAA) agents can successfully treat chronic hepatitis C virus (HCV) infection. However, the ex vivo HCV-specific T-cell function following viral clearance remains unknown. Methods We investigated functional alterations and phenotypic changes in ex vivo HCV-specific CD8+ T cells with a longitudinal analysis of 41 patients with chronic HCV infection who were undergoing DAA treatment. Results A patient subset exhibited a significantly increased T-cell response (mainly CD8+ T cells) at week 4 of treatment. However, this increased T-cell response diminished in later weeks. Relative to pretreatment levels, the ex vivo HCV-specific CD8+ T-cell frequency decreased at 12 weeks after the end of treatment, along with a decreased antigen-experienced CD8+ T-cell population. DAA treatment increased the proliferative capacity of HCV-specific CD8+ T cells, but this change was not correlated with ex vivo function. Patients experiencing viral breakthrough or relapse exhibited defective restoration of T-cell function. Conclusion Our present results indicated that DAA-mediated viral clearance only transiently restored ex vivo T-cell function, suggesting a need to enhance T-cell function in DAA-treated patients.

Background Scale-up of direct-acting antiviral therapy is expected to abate hepatitis C virus (HCV) incidence among human immunodeficiency virus (HIV)-positive men who have sex with men (MSM). International transmission could influence this process. We classified HCV infections in HIV-positive MSM as either domestically or internationally acquired, and estimated how this classification changed over time. Methods HCV subtype 1a (the most frequent subtype among MSM) genomes from 99 persons enrolled in the Swiss HIV Cohort Study and diagnosed with replicating HCV infections, were sequenced. Sixty-six of these sequences were from MSM. We inferred maximum-likelihood phylogenetic trees and time trees containing a fragment of the NS5B region of these and 374 circulating strains. We inferred transmission clusters from these trees and used the country composition of such clusters to attribute infections to domestic or international transmission. Results Of HCV transmissions, 50% to 80% were classified as domestic depending on the classification criterion. Between 2000 and 2007, the fraction attributable to domestic transmission was 54% (range 0–75%). It increased to 85% (range 67%–100%) between 2008 and 2016. Conclusions International and domestic transmission have played major roles in this epidemic. While international transmission persists, local transmission has established as the main source of infections., We used phylogenetics and phylodynamics to classify over time HCV infections in HIV-positive MSM as either domestically or internationally acquired. We found that while international transmission dominated initially and persists, local transmission has established as the main source of infections.

Background Women-specific factors exist that increases vulnerability to drug-related harms from injection drug use, including blood-borne viruses (BBVs), but gender-based differences in BBV prevalence have not been systematically examined. Methods We conducted meta-analyses to estimate country, regional, and global prevalence of serologically confirmed human immunodeficiency virus (HIV), hepatitis C virus (HCV; based on detection of anti-HCV antibody), and hepatitis B virus (HBV; based on detection of HBV surface antigen) in people who inject drugs (PWID), by gender. Gender-based differences in the BBV prevalence (calculated as the risk among women relative to the risk among men) were regressed on country-level prevalence and inequality measures (Gender inequality index, Human development index, Gini coefficient, and high, low or middle income of the country). Results Gender-based differences varied by countries and regions. HIV prevalence was higher among women than men in sub-Saharan Africa (relative risk [RR], 2.8; 95% confidence interval [CI], 1.8–4.4) and South Asia (RR, 1.7; 95% CI, 1.1–2.7); anti-HCV was lower among women in the Middle East and North Africa (RR, 0.6; 95% CI, .5–.7) and East and Southeast Asia (RR, 0.8; 95% CI, .7–.9). Gender-based differences varied with country-levels of the BBV prevalence in the general population, human development, and income distribution. Conclusion HIV was more prevalent in women who inject drugs as compared to their male counterparts in some countries, but there is variation between and within regions. In countries where women are at higher risks, there is a need to develop gender-sensitive harm-reduction services for the particularly marginalized population of women who inject drugs.

Since 2002, a global epidemic of acute hepatitis C virus (HCV) infection has been noted in men who have sex with men (MSM). Transmission of HCV, particularly in the context of traumatic sex practices that increase the risk of blood-blood contacts (eg, anal sex and fisting), was initially found in human immunodeficiency virus (HIV)–coinfected and more recently in HIV-uninfected MSM, especially those receiving pre-exposure prophylaxis (PrEP). Early HCV treatment with all-oral direct-acting antiviral combination therapy has been associated with very high HCV cure rates of up to 100%. Indeed, immediate treatment of recently acquired HCV directly after new HCV diagnosis, or after 4 weeks if no 2-log10 drop in HCV RNA level occurs, promises rapid HCV elimination. Reports from the Netherlands, Switzerland, and the United Kingdom all show that with increased treatment uptake in this particular patient group, dramatic reductions in new HCV infections can be achieved. A general consensus on how to best screen for and manage acute HCV infections, along with broad access to rapid HCV therapy initiation, is crucial to attaining HCV elimination, a goal that is challenged by high HCV reinfection rates among MSM.

Background Chronic hepatitis C virus (HCV) infection affects 71 million individuals, mostly residing in low- and middle-income countries (LMICs). Direct-acting antivirals (DAAs) give high rates of sustained virological response (SVR) in high-income countries where a restricted range of HCV genotypes/subtypes circulate. Methods We studied United Kingdom–resident patients born in Africa to examine DAA effectiveness in LMICs where there is far greater breadth of HCV genotypes/subtypes. Viral genome sequences were determined from 233 patients. Results Full-length viral genomic sequences for 26 known subtypes and 5 previously unidentified isolates covering 5 HCV genotypes were determined. From 149 patients who received DAA treatment/retreatment, the overall SVR was 93%. Treatment failure was associated primarily with 2 subtypes, gt1l and gt4r, using sofosbuvir/ledipasvir. These subtypes contain natural resistance-associated variants that likely contribute to poor efficacy with this drug combination. Treatment failure was also significantly associated with hepatocellular carcinoma. Conclusions DAA combinations give high SVR rates despite the high HCV diversity across the African continent except for subtypes gt1l and gt4r, which respond poorly to sofosbuvir/ledipasvir. These subtypes are widely distributed across Western, Central, and Eastern Africa. Thus, in circumstances where accurate genotyping is absent, ledipasvir and its generic compounds should not be considered as a recommended treatment option.

Background Hepatitis C virus (HCV) incidence has increased in the worsening opioid epidemic. We examined the HCV preventive efficacy of medication-assisted treatment (MAT), and geographic variation in HCV community viral load (CVL) and its association with HCV incidence. Methods HCV incidence was directly measured in an open cohort of patients in a MAT program in New York City between 1 January 2013 and 31 December 2016. Area-level HCV CVL was calculated. Associations of individual-level factors, and of HCV CVL, with HCV incidence were examined in separate analyses. Results Among 8352 patients, HCV prevalence was 48.7%. Among 2535 patients seronegative at first antibody test, HCV incidence was 2.25/100 person-years of observation (PYO). Incidence was 6.70/100 PYO among those reporting main drug use by injection. Female gender, drug injection, and lower MAT retention were significantly associated with higher incidence rate ratios. Female gender, drug injection, and methadone doses Conclusions HCV incidence was higher among those with lower MAT retention and was lower among those receiving higher methadone doses, suggesting the need to ensure high MAT retention, adequate doses, and increased HCV prevention and treatment engagement. HCV CVLs vary geographically and merit further study as predictors of HCV incidence.

Background The influence of direct-acting antivirals (DAAs) on the composition of gut microbiota in hepatitis C virus (HCV)–infected patients with or without human immunodeficiency virus (HIV) is unclear. Methods We enrolled 62 patients with HCV monoinfection and 24 patients with HCV/HIV coinfection receiving elbasvir-grazoprevir from a clinical trial. Fecal specimens collected before treatment and 12 weeks after treatment were analyzed using amplicon-based 16S ribosomal RNA sequencing. Results Sustained virological response rates in the monoinfection and coinfection groups were similar (98.4% vs 95.8%). Pretreatment bacterial communities in the patient groups were less diverse and distinct from those of healthy controls. Compared with HCV-monoinfected patients, HCV/HIV-coinfected individuals showed comparable microbial alpha diversity but decreased Firmicutes-Bacteroidetes ratios. The improvement of microbial dysbiosis was observed in responders achieving sustained virological response across fibrosis stages but was not found in nonresponders. Responders with a low degree of fibrosis exhibited a recovery in alpha diversity to levels comparable to those in healthy controls. Reciprocal alterations of increased beneficial bacteria and reduced pathogenic bacteria were also observed in responders. Conclusions This study indicates a short-term effect of direct-acting antivirals in restoration of microbial dysbiosis. The favorable changes in gut microbiota profiles after viral eradication might contribute toward the reduction of HCV-related complications among infected individuals.

Background Simplified diagnostic strategies are needed increase hepatitis C virus (HCV) testing to determine active infection and link people into treatment. Collection methods such as dried blood spots (DBS) have advantages over standard phlebotomy, especially within marginalized populations. Methods We evaluated the diagnostic performance of the Aptima HCV Quant assay for the quantification and detection of HCV RNA from paired DBS and venepuncture samples. Specimens were collected from participants enrolled in an Australian observational study. We compared HCV RNA detection from DBS against venepuncture samples (gold standard). Results One hundred sixty-four participants had paired samples and HCV RNA was detected in 45 (27% [95% confidence interval, 21%–35%]) by the Aptima assay in venepuncture samples. Sensitivity of the Aptima assay for HCV RNA quantification from DBS (≥10 IU/mL in plasma) was 100% and specificity was 100%. Sensitivity for HCV RNA detection from DBS was 95.6% and specificity was 94.1%. A small bias in plasma over DBS was observed with good agreement (R2 = 0.96). Conclusions The Aptima HCV Quant assay detects active infection from DBS samples with acceptable diagnostic performance and is clinically comparable to plasma. These data will strengthen the case for the registration of a DBS kit insert claim, enabling future clinical utility.

Sexually acquired hepatitis C virus (HCV) infections among human immunodeficiency virus (HIV)-uninfected men who have sex with men (MSM) have been rare. With the introduction of preexposure prophylaxis (PrEP) against HIV, we hypothesized that these infections would increase. Between 2013 and 2018, we diagnosed 15 likely sexually acquired HCV infections among 14 MSM using PrEP. Most (87%) were asymptomatic, detected by routine alanine transaminase (ALT) or HCV monitoring. Half reported increasing sex partners and drug use after starting PrEP; 5 reported injection of methamphetamine. Interventions are needed to prevent sexually acquired HCV infections by MSM using PrEP. Centers for Disease Control and Prevention guidelines for monitoring during PrEP should include regular ALT and HCV testing.

Background We aimed to investigate the long-term outcomes in hepatitis B (HBV)/hepatitis C virus (HCV) dual-infected patients after anti-HCV therapy. Methods A total of 192 HBV/HCV dual-infected patients who had received pegylated interferon treatment were recruited. The investigation outcomes included HBV DNA ≥2000 IU/mL, with or without alanine aminotransferase (ALT) ≥2-fold the upper limit of normal, and hepatitis B surface antigen (HBsAg) seroclearance. Results Four (2.1%) patients developed early HBV reactivation before the end of treatment. Fifty (26.6%) of the remaining patients had an episode of HBV DNA ≥2000 IU/mL in a mean follow-up of 68.8 months. The risk was 4.6 per 100 person years. Only 19 (10.1%) patients developed concomitant ALT flare with oral HBV antiviral therapy; the risk was 1.7 per 100 person years. Despite HBV flare, 67 (34.9%) patients had a favorable outcome of HBsAg seroclearance. The probability was 5.7 per 100 person years. A pretreatment HBV DNA level of 300 IU/mL served as an independent predictor for all the outcomes. The combined pretreatment HBV DNA level and HCV response further enhanced the prediction of HBV flare and HBsAg seroclearance. Conclusions A pretreatment HBV DNA level of 300 IU/mL predicts HBV flare and HBsAg seroclearance after anti-HCV therapy.

BACKGROUND Vertical transmission is the major cause of pediatric hepatitis C virus (HCV) infection. The objective of this study was to better understand HCV pathogenesis in pregnant women and provide insights into risk factors and mechanisms involved in vertical transmission. METHODS Evolutionary dynamics of HCV variant spectra and HCV-specific neutralizing antibody responses were examined using high-throughput sequencing and pseudoparticle-based assays in pregnant women monoinfected with HCV (n = 17) or coinfected with HCV and human immunodeficiency virus (HIV)-1 (n = 15). RESULTS Overall, statistically significant associations were found between HCV quasispecies diversity, selective pressure exerted on the HCV E2 envelope protein, and neutralizing activity of maternal immunoglobulins. Women with low quasispecies diversity displayed significantly higher mean aspartate aminotransferase and alanine aminotransferase levels throughout pregnancy, but this difference was restricted to monoinfected participants. Low quasispecies diversity and inefficient neutralizing activity were also significantly associated with vertical transmission, but only in the monoinfected group. CONCLUSIONS These results indicate that maternal neutralizing antibody responses play a role in the prevention of vertical HCV transmission, but not in presence of HIV-1 coinfection, and suggest that the mechanism of vertical transmission may be different between monoinfected and coinfected women. These findings could inform management strategies for the prevention of vertical HCV transmission.

Global control of hepatitis C virus (HCV) depends on development of a prophylactic vaccine. We studied escape for cross-genotype–reactive neutralizing antibody AR4A, providing valuable information for HCV vaccine design. We cultured HCV core-NS2 recombinants H77 (genotype 1a)/JFH1 or the highly antibody-susceptible hypervariable region 1 (HVR1)–deleted variants H77/JFH1(∆HVR1) and J6(genotype 2a)/JFH1(∆HVR1) in Huh7.5 cells with AR4A. Long-term AR4A exposure of H77/JFH1 and H77/JFH1(∆HVR1) did not yield resistance. However, J6/JFH1(∆HVR1) developed the envelope-E2 substitutions I696T or I696N, which reduced AR4A binding (I696N > I696T). I696N conferred greater AR4A resistance than I696T in J6/JFH1(∆HVR1), whereas the reverse was observed in J6/JFH1. This was because I696N but not I696T conferred broadly increased antibody neutralization susceptibility to J6/JFH1. I696N and I696T abrogated infectivity of H77/JFH1 and broadly increased neutralization susceptibility of S52 (genotype 3a)/JFH1. In conclusion, I696 is in the AR4A epitope, which has a high barrier to resistance, thus strengthening the rationale for its inclusion in rational HCV vaccine designs.

Pegylated interferon-alpha (pIFN-α) is suggested to lower human immunodeficiency virus type-1 (HIV-1) DNA load in antiretroviral therapy (ART)-treated patients. We studied kinetics of HIV-1 DNA levels in 40 HIV-1/hepatitis C virus (HCV) coinfected patients, treated with pIFN-α for HCV and categorized into 3 groups according to start of ART: chronic HIV-1 infection (n = 22), acute HIV-1 infection (n = 8), no-ART (n = 10). Total HIV-1 DNA levels in 247 peripheral blood mononuclear cell samples were stable before, during, and after pIFN-α treatment in all groups. Our results question the benefit of pIFN-α as an immunotherapeutic agent for reducing the HIV-1 reservoir.

Background The independent contributions of microbial translocation and liver fibrosis to immune activation in human immunodeficiency virus (HIV) and/or hepatitis C virus (HCV)-infected persons are unclear. Methods Multivariable linear regression was used to evaluate whether intestinal fatty acid binding protein (I-FABP: a marker of gut epithelial integrity) and transient elastography-measured liver fibrosis might mediate the association of HIV and HCV with the soluble CD14 (sCD14) level in 120 individuals with HIV and HCV coinfection, 262 with HIV monoinfection, 72 with HCV monoinfection, and 170 without infection. Results Coinfected individuals, HIV-monoinfected individuals, and HCV-monoinfected individuals had 37%, 21%, and 12% higher sCD14 levels, respectively, than uninfected individuals, after multivariable adjustment. Additional adjustment for I-FABP level modestly attenuated the association of HIV infection, but attenuation occurred to a lesser extent in the HCV-monoinfected group. Adjustment for liver fibrosis substantially attenuated the association of HCV infection, but attenuation occurred to a lesser extent in the HIV-monoinfected group. Relative to the uninfected group, the primary mediator of the sCD14 level was the I-FABP level in the HIV-infected groups and liver fibrosis in the HCV-monoinfected group. Conclusion HIV and HCV are independently and additively associated with higher a sCD14 level. Our findings suggest that microbial translocation contributes to an increased sCD14 level during HIV infection, whereas liver fibrosis plays a stronger role during HCV monoinfection. Coinfected persons may be at greatest risk for progression, because of the independent effects of microbial translocation and liver fibrosis on immune activation.

Background: There is a paucity of patient-reported outcomes (PROs) data for people undergoing hepatitis C virus (HCV) treatment who are treated with opioid substitution therapy (OST) for addiction. Methods: Patients enrolled in phase 3 clinical trials of sofosbuvir completed 4 PRO instruments-SF-36v2, FACIT-F, CLDQ-HCV, and WPAI-HCV-before, during, and after treatment. Results: A total of 8450 HCV-infected subjects were included; 4.8% (407) were receiving OST. At baseline, OST recipients had significantly (P < .0001) lower PRO scores (by -3.5 to -15.6 on a 0-100 scale). By the end of treatment, subjects receiving pegylated interferon, ribavirin, and sofosbuvir (IFN+RBV+SOF) experienced significant decreases in PROs regardless of OST use. Subjects receiving IFN-free RBV-containing regimens had significant but smaller PRO decreases, again similar in the OST and non-OST groups. Finally, subjects treated with regimens free of both IFN and RBV (IFN/RBV-free) showed improvements in nearly all PROs during treatment, with improvements more pronounced in OST recipients. Achieving a sustained virological response for 12 consecutive weeks after treatment cessation (SVR-12) was associated with improvement of PROs in OST recipients treated with IFN/RBV-free regimens. In contrast, OST recipients who achieved SVR-12 with IFN+RBV+SOF did not have consistent PRO gains after the SVR-12. Conclusions: Receiving IFN-free regimens leads to PRO improvement during treatment and after the SVR-12, regardless of OST status. HCV-infected subjects receiving OST did not experience similar PRO improvements with IFN-containing therapy, suggesting that IFN-based therapy may be less suitable for this vulnerable population.

Background It is unknown whether ribavirin (RBV) coadministration modifies the early rate of decline of hepatitis C virus (HCV) RNA in the liver versus plasma compartments, specifically. Methods This partially randomized, open-label, phase 2 study enrolled treatment-naive, noncirrhotic patients with HCV genotype 1a. Patients were randomized 1:1 into Arms A and B, and then enrolled in Arm C. Patients received ombitasvir/paritaprevir/ritonavir plus dasabuvir for 12 weeks with either: no RBV for the first 2 weeks followed by weight-based dosing thereafter (Arm A), weight-based RBV for all 12 weeks (Arm B), or low-dose RBV (600 mg) once daily for all 12 weeks. Fine needle aspiration (FNA) was used to determine HCV RNA decline within liver. Results Baseline HCV RNA was higher and declined more rapidly in plasma than liver; however, RBV dosing did not impact either median plasma or liver HCV RNA decline during the first 2 weeks of treatment. Liver-to-plasma drug concentrations were variable over time. The most common adverse event was pain associated with FNA. Conclusions Coadministration of RBV had minimal visible impact on the plasma or liver kinetics of HCV RNA decline during the first 2 weeks of treatment, regardless of RBV dosing.

Background Ombitasvir/paritaprevir/ritonavir with dasabuvir (OBV/PTV/r + DSV) ± ribavirin (RBV) is approved for hepatitis C virus (HCV) genotype 1 (GT1) treatment in HIV-1 coinfected patients. In healthy controls, coadministration of OBV/PTV/r + DSV + darunavir (DRV) lowered DRV trough concentration (Ctrough) levels. To assess the clinical significance of this change, TURQUOISE-I, Part 1b, evaluated the efficacy and safety of OBV/PTV/r + DSV + RBV in coinfected patients on stable, DRV-containing antiretroviral therapy (ART). Methods Patients were HCV treatment-naive or interferon-experienced, had CD4+ lymphocyte count ≥200 cells/µL or ≥14%, and plasma HIV-1 RNA suppression on once-daily (QD) DRV-containing ART at screening. Patients were randomized to maintain DRV 800 mg QD or switch to twice-daily (BID) DRV 600 mg; all received OBV/PTV/r + DSV + RBV for 12 weeks. Results Twenty-two patients were enrolled and achieved SVR12. No adverse events led to discontinuation. Coadministration had minimal impact on DRV maximum observed plasma concentration and area under the curve; DRV Ctrough levels were slightly lower with DRV QD and BID. No patient experienced plasma HIV-1 RNA >200 copies/mL during treatment. Conclusions HCV GT1/HIV-1 coinfected patients on stable DRV-containing ART achieved 100% SVR12 while maintaining plasma HIV-1 RNA suppression. Despite DRV exposure changes, episodes of intermittent HIV-1 viremia were infrequent.

Background Athough curative therapy is now available for hepatitis C virus (HCV) infection in the United States, it is not clear whether all affected persons have been diagnosed and/or linked to care. Methods This cross-sectional study utilized data from the National Health and Nutrition Examination Survey (1999–2016) and included 46 465 nonincarcerated and noninstitutionalized participants. Results Viremic HCV prevalence decreased from 1.32% in 1999–2004 to 0.80% in 2011–2016, although most of the decrease occurred in US-born whites and blacks but not the foreign-born or those born after 1985. In 2011–2016, approximately 1.90 million US adults remained viremic with HCV, and 0.33 million were at higher risk for advanced fibrosis, but only 49.8% were aware of their HCV infection, with higher disease awareness in those with health insurance coverage and US-born persons. Conclusions The prevalence of viremic HCV has decreased in recent years among US born whites and blacks but not in other race/ethnicities and foreign-born persons and birth cohort born after 1985. Less than half of the viremic population was aware of having HCV infection. Improved HCV screening and linkage to care are needed, especially for the uninsured, foreign-born, birth cohort after 1985 and certain ethnic minorities.