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Widespread screening for hepatitis C virus (HCV) is necessary for Canada to meet its HCV elimination goals by 2030. People who currently or previously injected drugs are at high risk for HCV. Opioid agonist therapy (OAT, such as methadone and buprenorphine) has been shown to help stabilize the lives of people who are opioid‐dependent. The distribution of OAT in North America typically requires daily, weekly, or monthly clinic visits and presents an opportunity for engagement, screening and treatment for those at high‐risk of HCV. In this study, HCV screening was conducted by staff at OAT clinics in Ontario from 2016 to 2020 and those with chronic infections were treated on‐site with direct‐acting antivirals. Point‐of‐care or dried blood spot (DBS) testing was used for antibodies, DBS or serum for HCV RNA and serum for HCV RNA at SVR12 (sustained virological response). Clinics screened 1954 people (mean age 40 years ±12, 63% male). Forty‐five percent were antibody positive, of whom 64% were HCV RNA+. Eighty percent of those RNA+ set an appointment in which 99% attended. Ninety‐six percent started treatment with 87% completing treatment. Sixty‐eight percent of people who completed treatment submitted a sample for SVR12 testing of which 97% achieved a virological cure. Results suggest that HCV screening and treatment at OAT clinics is feasible, effective and warrants expansion. Data suggest strong treatment adherence due to high rates of SVR12 comparable with other OAT‐based HCV treatment programs. The lack of SVR12 sampling could be addressed by either on‐site phlebotomy or incentivizing SVR12 sampling. [ABSTRACT FROM AUTHOR]

Natural killer ( NK) cells have long been thought of as a purely innate immune cell population, but increasing reports have described developmental and functional qualities of NK cells that are commonly associated with cells of the adaptive immune system. Of these features, the ability of NK cells to acquire functional qualities associated with immunological memory and continuous differentiation resulting in the formation of specific NK cell repertoires has recently been highlighted in viral infection settings. By making use of a unique cohort of monitored, at-risk intravenous drug users in this study, we were able to dissect the phenotypic and functional parameters associated with NK cell differentiation and NK cell memory in patients 3 years after acute HCV infection and either the subsequent self-clearance or progression to chronicity. We observed increased expression of cytolytic mediators and markers CD56bright and NKp46+ of NK cells in patients with chronic, but not self-limited HCV infection. Patients with a self-limited infection expressed higher levels of differentiation-associated markers CD57 and KIRs, and lower levels of NKG2A. A more extensively differentiated NK cell phenotype is associated with self-clearance in HCV patients, while the NK cells of chronic patients exhibited more naïve and effector NK cell phenotypic and functional characteristics. The identification of these distinct NK cell repertoires may shed light on the role NK cells play in determining the outcome of acute HCV infections, and the underlying immunological defects that lead to chronicity. [ABSTRACT FROM AUTHOR]

The aim of this study was to assess the validity of categorization of chronic hepatitis B viral infection into stages or phases based upon measures of disease activity and viral load, assuming these phenotypes will be useful for prognostication and determining the need for antiviral therapy. We assessed the phenotype of hepatitis B of 1,390 adult participants enrolled in the Hepatitis B Research Network Cohort Study, using a computer algorithm. Only 4% were immune tolerant, while 35% had chronic hepatitis B (18% e antigen positive and 17% e antigen negative) while 23% were inactive carriers. Strikingly, 38% of participants did not fit clearly into any one of these groups and were considered indeterminant. The largest subset of indeterminants had elevated serum aminotransferases with low levels of HBV DNA (less than 10,000 iu/mL). Subsequent determination of hepatitis B phenotype on the next available laboratory tests showed that 64% remained indeterminant. These findings call into question the validity of conventional staging of hepatitis B, in large part because of the substantial proportion of patients who do not fit readily into one of the usual stages or phases. Further studies are needed of the indeterminant category of chronic hepatitis B viral infection, including assessments of whether patients in this group are perhaps in transition to another phase or if they are a distinct phenotype with a need to assess liver disease severity and need for antiviral therapy. (ClinicalTrials.gov identifier NCT01263587). [ABSTRACT FROM AUTHOR]

There is a lack of knowledge regarding the effect of peginterferon ( PEG- IFN) on the expression of intrahepatic hepatitis B core and surface antigen ( HBc Ag and HBs Ag) in chronic hepatitis B ( CHB) and its relation with response to therapy. Fifty-two HBe Ag-positive and 67 HBe Ag-negative CHB patients with paired liver biopsies taken at baseline and after 1 year of PEG- IFN therapy were studied. After PEG- IFN therapy, HBe Ag-negative patients showed a significant reduction in both intrahepatic HBc Ag ( P = 0.04) and HBs Ag expression ( P < 0.001). In contrast, a reduction in intrahepatic HBc Ag expression was not observed in HBe Ag-positive patients, while a trend in reduction of intrahepatic HBs Ag staining was found ( P = 0.09). Post-treatment, 7 (13%) HBe Ag-positive and 9 (14%) HBe Ag-negative patients had no expression of intrahepatic HBs Ag. Patients without any intrahepatic HBs Ag expression post-treatment were more likely to achieve a combined response ( HBe Ag loss with hepatitis B virus ( HBV) DNA <2000 IU/mL for HBe Ag -positive and HBV DNA <2000 IU/mL and normal alanine aminotransferase for HBe Ag-negative CHB): 71% vs 5% for HBe Ag-positive ( P < 0.001) and 60% vs 16% for HBe Ag-negative patients ( P = 0.004), respectively. Moreover, a more profound decline of serum HBs Ag was observed in patients with absence of intrahepatic HBs Ag staining (3.1 vs 0.4 log IU/mL, P < 0.001 and 1.7 vs 0.4 log IU/mL, P = 0.005 for HBe Ag-positive and HBe Ag-negative CHB, respectively). In conclusion, PEG- IFN reduces expression of intrahepatic HBs Ag. Loss of HBs Ag as assessed by immunohistochemistry from the liver predicts a sustained response and is reflected in a pronounced serum HBs Ag decline. [ABSTRACT FROM AUTHOR]

Cirrhotic patients with chronic hepatitis C virus ( HCV) infection remain at risk for complications following sustained virological response ( SVR). Therefore, we aimed to evaluate treatment efficacy with the number needed to treat ( NNT) to prevent clinical endpoints. Mortality and cirrhosis-related morbidity were assessed in an international multicentre cohort of consecutively treated patients with HCV genotype 1 infection and cirrhosis. The NNT to prevent death or clinical disease progression (any cirrhosis-related event or death) in one patient was determined with the adjusted (event-free) survival among patients without SVR and adjusted hazard ratio of SVR. Overall, 248 patients were followed for a median of 8.3 ( IQR 6.2-11.1) years. Fifty-nine (24%) patients attained SVR. Among patients without SVR, the adjusted 5-year survival and event-free survival were 94.4% and 80.0%, respectively. SVR was associated with reduced all-cause mortality ( HR 0.15, 95% CI 0.05-0.48, P = 0.002) and clinical disease progression ( HR 0.16, 95% CI 0.07-0.36, P < 0.001). The NNT to prevent one death in 5 years declined from 1052 (95% CI 937-1755) at 2% SVR (interferon monotherapy) to 61 (95% CI 54-101) at 35% SVR (peginterferon and ribavirin). At 50% SVR, which might be expected with triple therapy, the estimated NNT was 43 (95% CI 38-71). The NNT to prevent clinical disease progression in one patient in 5 years was 302 (95% CI 271-407), 18 (95% CI 16-24) and 13 (95% CI 11-17) at 2%, 35% and 50% SVR, respectively. In conclusion, the NNT to prevent clinical endpoints among cirrhotic patients with HCV genotype 1 has declined enormously with the improvement of antiviral therapy. [ABSTRACT FROM AUTHOR]

Narlaprevir, a hepatitis C virus (HCV) NS3/4A serine protease inhibitor, has demonstrated robust antiviral activity in a placebo-controlled phase 1 study. To study evolutionary dynamics of resistant variants, the NS3 protease sequence was clonally analysed in thirty-two HCV genotype 1-infected patients following treatment with narlaprevir. Narlaprevir monotherapy was administered for one week (period 1) followed by narlaprevir/pegylated interferon-alpha-2b combination therapy with or without ritonavir (period 2) during two weeks, interrupted by a washout period of one month. Thereafter, all patients initiated pegylated interferon-alpha-2b/ribavirin combination therapy. Longitudinal clonal analysis was performed in those patients with NS3 mutations. After narlaprevir re-exposure, resistance-associated mutations at position V36, T54, R155 and A156 were detected in five patients in >95% of the clones. Narlaprevir retreatment resulted in a 2.58 and 5.06 log10 IU/mL viral load decline in patients with and without mutations, respectively ( P = <0.01). After treatment, resistant variants were replaced with wild-type virus within 2-24 weeks in three patients. However, the R155K mutation was still observed 3.1 years after narlaprevir dosing in two patients in 5% and 45% of the viral population. Resistant variants could be detected early during treatment with narlaprevir. A slower viral load decline was observed in those patients with resistance-associated mutations detectable by direct population sequencing. These mutations disappeared within six months following treatment with the exception of R155K mutation, which persisted in two patients. [ABSTRACT FROM AUTHOR]

As chronic hepatitis C patients with progressive disease can present themselves with normal ALT levels, more sensitive biomarkers are needed. Micro RNAs are newly discovered small noncoding RNAs that are stable and detectable in the circulation. We aimed to investigate the association between hepatocyte-derived micro RNAs in serum and liver injury in patients with chronic hepatitis C. The hepatocyte-derived mi R-122 and mi R-192 were analysed in sera of 102 chronic HCV-infected patients and 24 healthy controls. Serum levels of mi R-122 and mi R-192 correlated strongly with ALT ( R = 0.67 and R = 0.65, respectively, P < 0.001 for both). Median levels of mi R-122 and mi R-192 in HCV-infected patients were 23 times and 8 times higher as in healthy controls ( P < 0.001 for both). Even within the HCV-infected patients with a normal ALT ( n = 38), the levels of mi R-122 and mi R-192 were 12 times and 4 times higher compared with healthy controls ( P < 0.001 for both). Multivariate logistic regression analyses showed that only mi R-122 was a significant predictor of the presence of chronic HCV infection ( P = 0.026). Importantly, mi R-122 was also superior in discriminating chronic HCV-infected patients with a normal ALT from healthy controls compared with the ALT level ( AUC = 0.97 vs AUC = 0.78, P = 0.007). In conclusion, our study confirmed that liver injury is associated with high levels of hepatocyte-derived micro RNAs in circulation and demonstrated that in particular mi R-122 is a sensitive marker to distinguish chronic hepatitis C patients from healthy controls. More sensitive blood markers would benefit especially those patients with minor levels of hepatocellular injury, who are not identified by current screening with ALT testing. [ABSTRACT FROM AUTHOR]

Tenofovir, an antihuman immunodeficiency virus (HIV) drug, has activity against lamivudine-resistant hepatitis B virus (HBV) mutants. To describe the efficacy of tenofovir in patients with lamivudine-resistant hepatitis B we applied two investigative approaches based on mathematical models of viral dynamics: the individual nonlinear fitting and the mixed-effect group fitting approaches. Eleven chronic HBV patients on lamivudine for a median of 176 weeks (range: 72–382) with YMDD mutation-related HBV-DNA breakthrough received ‘add-on’ tenofovir 300 mg once-daily, while maintaining their existing therapy. Sequential sera were taken at day 1 ( t = 0 and t = 8 h), days 2, 4, 7, 10, 14, 21, 28 and every 4 weeks thereafter, and HBV-DNA levels were assessed using a validated quantitative polymerase chain reaction (PCR) assay. Median baseline log HBV-DNA was 8.62 (range: 6.48–9.76 log HBV-DNA). Tenofovir treatment resulted in a mean (±SD) log HBV-DNA decline of 1.37 ± 0.51 in the first phase, 2.54 ± 0.91 after 4 weeks, and 4.95 ± 0.90 log HBV-DNA after 24 weeks. The median effectiveness of blocking viral replication in the individual fit model was 93% (range: 73–99) for η = 0 and 93% (range: 59–99) for η = 1. There was only a small difference between the efficacy parameter ‘ ℇ’ of the individual nonlinear fitting and mixed-effect group fitting on the biphasic exponential model. These data show that tenofovir has good efficacy in blocking viral replication in HBV patients with lamivudine-induced drug-resistant HBV mutants, but effectiveness varies greatly among individuals. Both models can be used to describe viral decay during tenofovir therapy. [ABSTRACT FROM AUTHOR]

Summary. Vertical transmission of hepatitis B virus (HBV) can occur occasionally despite vaccination of the child. This vaccination breakthrough has been associated with high maternal viraemia. We treated eight highly viraemic (HBV-DNA ≥ 1.2 × 109 geq/mL) mothers with 150 mg of lamivudine daily during the last month of pregnancy. HBV-DNA, hepatitis B surface antigen (HBsAg), anti-HBs and anti-HBc of their offspring were measured at birth and at 3, 6 and 12 months, respectively. Twenty-four children, born to untreated HBsAg-positive mothers with HBV-DNA levels ≥1.2 × 109 geq/mL served as historical controls. All children received passive-active immunization at birth and were followed-up for 12 months. In the lamivudine group one of the eight children (12.5%) was still HBsAg and HBV-DNA positive at the age of 12 months. All other children seroconverted to anti-HBs and maintained seroprotection. In three children, HBV-DNA was temporarily detected by polymerase chain reaction. In the untreated historical control group, perinatal transmission occurred in seven of 25 children (28%). In highly viraemic HBsAg-positive mothers, reduction of viraemia by lamivudine therapy in the last month of pregnancy may be an effective and safe measure to reduce the risk of child vaccination breakthrough. This approach should be evaluated in a large controlled trial. [ABSTRACT FROM AUTHOR]