Alcohol-Related Liver Disease Is Rarely Detected at Early Stages Compared With Liver Diseases of Other Etiologies Worldwide.

BACKGROUND & AIMS: Despite recent advances in treatment of viral hepatitis, liver-related mortality is high, possibly owing to the large burden of advanced alcohol-related liver disease (ALD). We investigated whether patients with ALD are initially seen at later stages of disease development than patients with hepatitis C virus (HCV) infection or other etiologies. METHODS: We performed a cross-sectional study of 3453 consecutive patients with either early or advanced liver disease (1699 patients with early and 1754 with advanced liver disease) seen at 17 tertiary care liver or gastrointestinal units worldwide, from August 2015 through March 2017. We collected anthropometric, etiology, and clinical information, as well as and model for end-stage liver disease scores. We used unconditional logistic regression to estimate the odds ratios for evaluation at late stages of the disease progression. RESULTS: Of the patients analyzed, 81% had 1 etiology of liver disease and 17% had 2 etiologies of liver disease. Of patients seen at early stages for a single etiology, 31% had HCV infection, 21% had hepatitis B virus infection, and 17% had nonalcoholic fatty liver disease, whereas only 3.8% had ALD. In contrast, 29% of patients seen for advanced disease had ALD. Patients with ALD were more likely to be seen at specialized centers, with advanced-stage disease, compared with patients with HCV-associated liver disease (odds ratio, 14.1; 95% CI, 10.5-18.9; P < .001). Of patients with 2 etiologies of liver disease, excess alcohol use was associated with 50% of cases. These patients had significantly more visits to health care providers, with more advanced disease, compared with patients without excess alcohol use. The mean model for end-stage liver disease score for patients with advanced ALD (score, 16) was higher than for patients with advanced liver disease not associated with excess alcohol use (score, 13) (P < .01). CONCLUSIONS: In a cross-sectional analysis of patients with liver disease worldwide, we found that patients with ALD are seen with more advanced-stage disease than patients with HCV-associated liver disease. Of patients with 2 etiologies of liver disease, excess alcohol use was associated with 50% of cases. Early detection and referral programs are needed for patients with ALD worldwide.

Loss of virus-specific T-cell responses in HCV exposed uninfected injection drug users with drug rehabilitation.

INTRODUCTION: Hepatitis C virus (HCV)-specific T lymphocyte responses have been demonstrated in peripheral blood from injection drug users (IDUs) persistently HCV antibody and RNA negative despite high-risk behavior. We have termed these apparently HCV resistant cases "Exposed Uninfecteds" (EUs), and have studied the evolution of T-cell responses to determine if they are protective in nature. METHODS: Twenty-one EU cases were studied using a questionnaire to ascertain injecting behavior details. Peripheral blood mononuclear cells were isolated from whole blood and an interferon-gamma (IFN-γ) enzyme-linked immunosorbent spot (ELISPOT) assay used to detect T-cell responses to a panel of HCV proteins. EU cases were subdivided by injecting drug patterns into (1) cases in rehabilitation who stopped injecting, (2) prisoners (infrequent/noninjectors), and (3) cases who continued to inject. RESULTS: EUs continuing to inject had significantly stronger (P < .01) and more frequent (P < .05) HCV-specific IFN-γ ELISPOT responses than controls or noninjecting EUs. EUs in rehabilitation lost their T-cell responses during follow-up, while those continuing to inject maintained them. CONCLUSIONS: HCV-specific T-cell responses in EU cases wane within months of cessation of injection drug use. Maintenance of these T-cell responses appears to be dependent on continuing HCV exposure through injection drug use.

Hepatitis C elimination among people incarcerated in prisons: challenges and recommendations for action within a health systems framework.

Hepatitis C virus (HCV) is a global public health problem in correctional settings. The International Network on Health and Hepatitis in Substance Users-Prisons Network is a special interest group committed to advancing scientific knowledge exchange and advocacy for HCV prevention and care in correctional settings. In this Review, we highlight seven priority areas and best practices for improving HCV care in correctional settings: changing political will, ensuring access to HCV diagnosis and testing, promoting optimal models of HCV care and treatment, improving surveillance and monitoring of the HCV care cascade, reducing stigma and tackling the social determinants of health inequalities, implementing HCV prevention and harm reduction programmes, and advancing prison-based research.

Economic evaluation of direct-acting antivirals for the treatment of genotype 3 hepatitis C infection in Singapore.

BACKGROUND AND AIM: The prohibitively high cost of direct-acting antivirals (DAA) for hepatitis C virus (HCV) infection remains a barrier to treatment access in Singapore. We aimed to evaluate whether DAA as first-line therapy would be cost-effective for genotype 3 (GT3) HCV patients compared with pegylated interferon and ribavirin (PR). METHODS: A decision tree analysis was used to compare the costs and outcomes of DAA and PR as first-line therapy. Treatment effectiveness, defined as sustained virological response, was assessed using a retrospective cohort of treated GT3 HCV patients. Direct medical costs were estimated from the payer's perspective using billing information. We obtained health utilities from published literature. We performed extensive one-way sensitivity analyses and probabilistic sensitivity analyses to account for uncertainties regarding the model parameters. RESULTS: In base case analysis, first-line therapy with DAA and PR yielded quality-adjusted life years (QALYs) of 0.69 and 0.62 at a cost of USD 54 634 and USD 23 857, respectively. The resultant incremental cost-effectiveness ratio (ICER) (USD 449 232/QALY) exceeded the willingness-to-pay threshold (USD 53 302/QALY). The ICER was robust for uncertainties regarding the model parameters. The cost of DAA is the key factor influencing the cost-effectiveness of HCV treatment. At current price, DAA as first-line therapy is not cost-effective compared with PR, with or without consideration of retreatment. Threshold analysis suggested that DAA can be cost-effective if it costs less than USD 17 002 for a 12-week treatment course. CONCLUSION: At current price, DAA as first-line therapy is not cost-effective compared with PR in GT3 HCV patients in Singapore.

Late acute liver allograft rejection; a study of its natural history and graft survival in the current era.

BACKGROUND: Late acute rejection (LAR) after liver transplantation is often associated with poor clinical outcomes. We reviewed our experience of managing LAR in the current era to determine its natural history. METHODS: A database of 970 consecutive adult liver transplants was reviewed retrospectively. LAR was defined as histologically proven acute cellular rejection occurring more than 90 days after transplantation. RESULTS: The incidence of LAR was 11%, with a mean time of 565 days (median, 311 days; range, 90-2922 days) after transplantation. The highest rates for LAR were in seronegative hepatitis (17%), primary biliary cirrhosis (16%), and primary sclerosing cholangitis (13%) with an odds ratio of 2.3, 2.1, and 1.8, respectively. Logistic regression showed that younger recipients, primary biliary cirrhosis, and previous graft loss were independent predictors of LAR (P<0.001). Mean trough whole blood tacrolimus levels were at their lowest levels 1 week before the diagnosis of rejection (5.5 ng/mL; SD, 2.6) compared with levels of 7.7 ng/mL 4 weeks before rejection, showing a clear temporal relation. Graft survival was worse in those with LAR (P<0.01), whereas the best graft survival was among early acute rejection cases (85% 10-year survival; P<0.01). Poor response to treatment correlated with the development of ductopenic rejection (r=0.3; P<0.01). Approximately half with early ductopenic rejection eventually died (n=15). CONCLUSION: LAR continues to provide a risk to patient and graft survival: understanding risk factors may allow an improvement in monitoring and early intervention and so prevent early graft loss.

Hepatitis C virus (HCV)--specific T cell responses in injection drug users with apparent resistance to HCV infection.

BACKGROUND: Injection drug users (IDUs) are at risk of acquiring hepatitis C virus (HCV) infection. We have identified a cohort of long-term IDUs who remain uninfected by HCV despite high-risk behavior. We have categorized these subjects as "exposed uninfected" and have sought immunological correlates with this apparent resistance. METHODS: We studied 40 exposed uninfected subjects testing negative for both HCV antibody and HCV RNA. Details of injection behavior were ascertained by questionnaire. In vitro interferon (IFN)-gamma production by T cells in response to HCV proteins (core, E1, NS3, NS4, and NS5) was quantified by enzyme-linked immunospot assay, and findings were compared with those in 21 healthy control subjects. RESULTS: All exposed uninfected subjects reported sharing needles or other injection paraphernalia on multiple occasions. The mean duration of injecting was 9.3 years (range, 0.5-26 years), with a median estimated number of injection episodes of 8760. IFN-gamma production in response to HCV proteins was found in 23 (58%) of 40 exposed uninfected subjects versus 4 (19%) of 21 control subjects (P = .004), with 14 exposed uninfected subjects responding to multiple antigens, compared with none of the control subjects (P = .001). CONCLUSIONS: The majority of long-term IDUs who remain uninfected by HCV despite their high-risk behavior have HCV-specific T cell responses. These responses were frequently found for multiple HCV proteins, making cross-reactivity to other homologous antigens unlikely. These responses may represent an immunological footprint of HCV exposure that has not resulted in viremia or HCV antibody seroconversion. The potential role played by these responses in protection from HCV infection is of clinical importance.