Hepatitis C virus testing for case identification in persons born during 1945-1965: Results from three randomized controlled trials.

The Centers for Disease Control and Prevention and US Preventive Services Task Force recommend one-time hepatitis C virus (HCV) testing for persons born during 1945-1965 (birth cohort). However, few studies estimate the effect of birth cohort (BC) testing implementation on HCV diagnoses in primary care settings. We aimed to determine the probability of identifying HCV infections in primary care using targeted BC testing compared with usual care at three academic medical centers. From December 2012 to March 2014, each center compared one of three distinct interventions with usual care using an independently designed randomized controlled trial. Across centers, BC patients with no clinical documentation of previous HCV testing or diagnosis were randomly assigned to receive a one-time offering of HCV antibody (anti-HCV) testing via one of three independent implementation strategies (repeated-mailing outreach, electronic medical record-integrated provider best practice alert [BPA], and direct patient solicitation) or assigned to receive usual care. We estimated model-adjusted risk ratios (aRR) of anti-HCV-positive (anti-HCV+) identification using BC testing versus usual care. In the repeated mailing trial, 8992 patients (intervention, n = 2993; control, n = 5999) were included in the analysis. The intervention was eight times as likely to identify anti-HCV+ patients compared with controls (aRR, 8.0; 95% confidence interval [CI], 2.8-23.0; adjusted probabilities: intervention, 0.27%; control, 0.03%). In the BPA trial, data from 14,475 patients (BC, n = 8928; control, n = 5,547) were analyzed. The intervention was 2.6 times as likely to identify anti-HCV+ patients versus controls (aRR, 2.6; 95% CI, 1.1-6.4; adjusted probabilities: intervention, 0.29%; control, 0.11%). In the patient-solicitation trial, 8873 patients (BC, n = 4307; control, n = 4566) were analyzed. The intervention was five times as likely to identify anti-HCV+ patients compared with controls (aRR, 5.3; 95% CI, 2.3-12.3; adjusted probabilities: intervention, 0.68%; control, 0.11%). Conclusion: BC testing was effective in identifying previously undiagnosed HCV infections in primary care settings. (Hepatology 2018;67:524-533).

Uptake of hepatitis C screening, characteristics of patients tested, and intervention costs in the BEST-C study.

From December 2012 to March 2014, three randomized trials, each implementing a unique intervention in primary care settings (repeated mailing, an electronic health record best practice alert [BPA], and patient solicitation), evaluated hepatitis C virus (HCV) antibody testing, diagnosis, and costs for each of the interventions compared with standard-of-care testing. Multilevel multivariable models were used to estimate the adjusted risk ratio (aRR) for receiving an HCV antibody test, and costs were estimated using activity-based costing. The goal of this study was to estimate the effects of interventions conducted as part of the Birth-Cohort Evaluation to Advance Screening and Testing for Hepatitis C study on HCV testing and costs among persons of the 1945-1965 birth cohort (BC). Intervention resulted in substantially higher HCV testing rates compared with standard-of-care testing (26.9% versus 1.4% for repeated mailing, 30.9% versus 3.6% for BPA, and 63.5% versus 2.0% for patient solicitation) and significantly higher aRR for testing after controlling for sex, birth year, race, insurance type, and median household income (19.2 [95% confidence interval (CI), 9.7-38.2] for repeated mailing, 13.2 [95% CI, 3.6-48.6] for BPA, and 32.9 [95% CI, 19.3-56.1] for patient solicitation). The BPA intervention had the lowest incremental cost per completed test ($24 with fixed startup costs, $3 without) and also the lowest incremental cost per new case identified after omitting fixed startup costs ($1691). CONCLUSION: HCV testing interventions resulted in an increase in BC testing compared with standard-of-care testing but also increased costs. The effect size and incremental costs of BPA intervention (excluding startup costs) support more widespread adoption compared with the other interventions. (Hepatology 2017;65:44-53).

Hepatitis C virus antibody positivity and predictors among previously undiagnosed adult primary care outpatients: cross-sectional analysis of a multisite retrospective cohort study.

BACKGROUND: Hepatitis C virus (HCV) testing guidance issued by the Centers for Disease Control and Prevention in 1998 recommends HCV antibody (anti-HCV) testing for persons with specified risk factors. The purpose of this study was to determine the prevalence and predictors of anti-HCV positivity among primary care outpatients and estimate the proportion of unidentified anti-HCV-positive (anti-HCV+) persons using risk-based testing. METHODS: We analyzed electronic medical record data from a 4-site retrospective study. Patients were aged ≥18 years, utilized ≥1 outpatient primary care service(s) between 2005 and 2010, and had no documented evidence of prior HCV diagnosis. Among persons tested for anti-HCV, we fit a multilevel logistic regression model to identify patient-level independent predictors of anti-HCV positivity. We estimated the proportion of unidentified anti-HCV+ persons by using multiple imputation to assign anti-HCV results to untested patients. RESULTS: We observed 209 076 patients for a median of 5 months (interquartile range, 1-23 months). Among 17 464 (8.4%) patients who were tested for anti-HCV, 6.4% (n=1115) were positive. We identified history of injection drug use (adjusted odds ratio [95% confidence interval], 6.3 [5.2-7.6]), 1945-1965 birth cohort (4.4 [3.8-5.1]), and elevated alanine aminotransferase levels (4.8 [4.2-5.6]) as independently associated with anti-HCV positivity. We estimated that 81.5% (n=4890/6005) of anti-HCV+ patients were unidentified using risk-based testing. CONCLUSIONS: In these outpatient primary care settings, risk-based testing may have missed 4 of 5 newly enrolled patients who are anti-HCV+. Without knowing their status, unidentified anti-HCV+ persons cannot receive further clinical evaluation or antiviral treatment, and are unlikely to benefit from secondary prevention recommendations to limit disease progression and mortality.

Fibrosis improvement in patients with HCV treated with direct-acting antivirals.

BACKGROUND AND AIM: More prospective studies are needed to characterize fibrosis improvement in patients with hepatitis C virus (HCV) who are treated with direct-acting antivirals (DAAs). The aims of this study were to assess changes in elastography scores from baseline to 1-year follow-up in patients with HCV, to identify factors that were independently associated with improvement in fibrosis staging in patients who receive treatment, and to identify factors that were independently associated with no improvement in fibrosis staging among patients who achieved sustained virologic responses (SVR). METHODS: Ultrasound elastography and laboratory tests were performed and collected at baseline and at 1-year follow-up for patients who received HCV treatment and for those who did not receive treatment (n = 240). Binomial logistic regression was used to examine factors that were independently associated with improvement in fibrosis staging. RESULTS: In patients who achieved SVR, the mean fibrosis score decreased significantly (-1.3) from 7.4 (2.3) before treatment to 6.1 (2.0) after treatment (P = 0.00). In multivariate analysis of patients who received treatment, higher pre-treatment fibrosis stages [odds ratio (OR) = 13.02, P < 0.00] were positively associated with improvement in fibrosis staging at 1-year follow-up. Higher BMI (OR = 0.93, P < 0.05) was negatively associated with improvement in fibrosis staging. DISCUSSION: This study supports the growing body of literature that suggests fibrosis regression is achievable in a significant number of patients who achieve SVR with all-oral DAA regimens. Equally important, fibrosis regression is more likely to occur in patients with advanced stages of fibrosis and less likely in patients who are obese.

Hepatocellular carcinoma surveillance: An evidence-based approach.

Hepatocellular carcinoma (HCC) makes up 75%-85% of all primary liver cancers and is the fourth most common cause of cancer related death worldwide. Chronic liver disease is the most significant risk factor for HCC with 80%-90% of new cases occurring in the background of cirrhosis. Studies have shown that early diagnosis of HCC through surveillance programs improve prognosis and availability of curative therapies. All patients with cirrhosis and high-risk hepatitis B patients are at risk for HCC and should undergo surveillance. The recommended surveillance modality is abdominal ultrasound (US) given that it is cost effective and noninvasive with good sensitivity. However, US is limited in obese patients and those with non-alcoholic fatty liver disease (NAFLD). With the current obesity epidemic and rise in the prevalence of NAFLD, abdominal computed tomography or magnetic resonance imaging may be indicated as the primary screening modality in these patients. The addition of alpha-fetoprotein to a surveillance regimen is thought to improve the sensitivity of HCC detection. Further investigation of serum biomarkers is needed. Semiannual screening is the suggested surveillance interval. Surveillance for HCC is underutilized and low adherence disproportionately affects certain demographics such as non-Caucasian race and low socioeconomic status.

Resolution of ascites and hepatic encephalopathy and absence of variceal bleeding in decompensated hepatitis C virus cirrhosis patients.

BACKGROUND AND AIMS: The aims of this study were to examine changes in the proportion of decompensated hepatitis C virus (HCV) cirrhosis patients with ascites, hepatic encephalopathy, and variceal bleeding at pretreatment compared to 3 and 12 months post-sustained virological response (SVR) and to compare pretreatment and post-SVR model of end-stage liver disease and Child-Pugh scores and alpha-fetoprotein levels. METHODS: Electronic medical records of 64 decompensated HCV cirrhosis patients who received direct-acting antivirals were reviewed. The McNemar-Bowker test and the Wilcoxon-Signed Rank test were used to compare patient outcomes. RESULTS: Ascites was resolved in 29% of patients 3 months post-SVR (65% vs 36%, P < 0.01) and in 35% of patients 12 months post-SVR (65% vs 30%, P = 0.07). Hepatic encephalopathy was resolved in 54% of patients 3 months post-SVR (70% vs 16%, P < 0.01) and in 48% of patients 12 months post-SVR (70% vs 22% P = 0.03). Variceal bleeding was absent in 32% of patients 3 months post-SVR (35% vs 3%, P < 0.01) and in 27% of patients 12 months post-SVR (35% vs 8%, P < 0.01). Alpha-fetoprotein levels were significantly reduced post-SVR, but model of end-stage liver disease and Child-Pugh scores were not. CONCLUSIONS: Decompensated HCV cirrhosis patients who achieved SVR with direct-acting antiviral treatment had significant reductions in manifestations of hepatic decompensation sustainable up to 1 year post-SVR.

Effect of Hepatitis C Treatment on Renal Function in Liver Transplant Patients.

Background and Aims: Hepatitis C Virus (HCV) is uniformly recurrent after liver transplant (LT) and recurrence is associated with an increased risk of mortality. Immunosuppressive medications increase the risk of chronic kidney disease, and the presence of chronic kidney disease presents a challenge for HCV treatment in LT recipients. The aim of this study was to assess changes in glomerular filtration rates (GFRs) of LT recipients receiving HCV treatment. Methods: This is a retrospective study of LT patients who received HCV treatment between 2015 and 2016 (n = 60). The outcomes of interest were differences in serum creatinine levels and in GFR, measured at treatment initiation and at 24 weeks after treatment. The average age of the patients was 59 years-old, and 17% were cirrhotic and 67% were treatment-experienced. All patients received sofosbuvir/ledipasvir without ribavirin. Results: All patients achieved sustained virologic response at 12 weeks after treatment (SVR12). At baseline, 55% of patients had GFR <60 mL/min per 1.73 m2. Among those patients, GFR did not change in 18%, 33% had improved GFR, and 48% had worsened GFR. Up to 45% of the patients had a GFR >60 mL/min per 1.73 m2. Among those patients, GFR did not change in 81%, and 19% had worsened GFR. In the entire cohort, 65% of patients had improved or stable GFR and 35% had worsened GFR. The average change in serum creatinine between baseline and 24 weeks was 0.10 (p = 0.18). Conclusions: This study showed improved or unchanged GFR in 65% and worsened GFR in 35% of LT recipients who achieved SVR12. Worsening of GFR was more frequently encountered in those with impaired renal function at baseline. Caution should be used when treating HCV in LT recipients, especially those with baseline status of renal impairment.

Hepatitis C care cascade among persons born 1945-1965: 3 medical centers.

OBJECTIVES: Effective screening, diagnosis, and treatment are needed to reduce chronic hepatitis C virus (HCV) infection-associated morbidity and mortality. In order to successfully increase HCV treatment, it is necessary to identify and understand gaps in linkage of antibody-positive patients with newly identified HCV to subsequent HCV RNA testing, clinical evaluation, and treatment. STUDY DESIGN: To estimate attainment of HCV care cascade steps among antibody-positive patients with newly identified HCV, we conducted chart reviews of patients with a new positive HCV antibody test at 3 academic medical centers participating in the Birth-Cohort Evaluation to Advance Screening and Testing of Hepatitis C (BEST-C) study. METHODS: We tracked receipt of RNA testing, clinical evaluation, treatment initiation, and treatment completion among individuals born between 1945 and 1965 who were newly diagnosed as HCV antibody-positive between December 2012 and October 2015 at 3 BEST-C centers, predominantly from the participating medical centers' primary care practices and emergency departments. RESULTS: Of the 130 HCV-seropositive individuals identified, 118 (91%) had an RNA or genotype test, 75 (58%) were RNA-positive, 73 (56%) were linked to care, 22 (17% overall; 29% among RNA-positive) started treatment, and 21 (16%; 28% among RNA-positive) completed treatment. CONCLUSIONS: This analysis showed that although linkage to care was largely successful in the target birth cohort, the largest gap in the HCV care cascade was seen in initiating treatment. Greater emphasis on linking patients to clinical evaluation and treatment is necessary in order to achieve the public health benefits promised by birth-cohort testing.

The Effect of Transjugular Intrahepatic Portosystemic Shunt on Platelet Counts in Patients With Liver Cirrhosis.

Thrombocytopenia is a well-known complication of liver cirrhosis. Although the pathogenesis of thrombocytopenia is not well understood, splenic congestion resulting from portal hypertension is considered the most significant underlying mechanism. Therapeutic measures that lower portal hypertension, such as transjugular intrahepatic portosystemic shunt (TIPS), are expected to improve thrombocytopenia associated with liver cirrhosis. At present, there are few studies on the effect of TIPS on platelet counts, and the results are conflicting. This article assesses the effect of TIPS on thrombocytopenia associated with liver cirrhosis. Methods: Seventy-four patients with liver cirrhosis who were referred for TIPS were included in this study. Platelet counts were measured on 3 different occasions over a 3-month period prior to and following placement of TIPS. Thrombocytopenia was defined as a platelet count of 150,000/mm3 or less. Moderate thrombocytopenia was defined as a platelet count of 100,000/mm3 or less. Severe thrombocytopenia was defined as a platelet count of 50,000/mm3 or less. A significant increase in platelet count was defined as a 20% or higher increase from pre-TIPS values. The portosystemic pressure gradient (PSPG) was measured before and after placement of TIPS. The patency of the shunt was checked using Doppler ultrasound 24 hours and 3 months after the procedure. Results: Thirty-four of the 74 patients (46%) who underwent TIPS showed a significant increase in platelet count, with an average increase of 22% (P<.0005). Twenty-five of 40 patients (62%) with moderate thrombocytopenia showed a significant increase in platelet count, with an average increase of 36% (P<.0005). Patients with severe thrombocytopenia showed the greatest response to TIPS; 8 of 11 patients (73%) had a significant increase in platelet count (average increase, 55%; P<.0005). No correlation was found between the response to TIPS and age, sex, etiology of liver disease, pre-TIPS PSPG, or the amount of decrease in PSPG. Conclusion: TIPS may improve thrombocytopenia associated with liver cirrhosis. Patients with severe thrombocytopenia are more likely to benefit from this procedure. No factors other than pre-TIPS platelet count were found to influence the response to TIPS.

Short article: Alcohol and substance use, race, and insurance status predict nontreatment for hepatitis C virus in the era of direct acting antivirals: a retrospective study in a large urban tertiary center.

OBJECTIVE: Direct acting antivirals (DAAs) have overcome many long-standing medical barriers to hepatitis C virus (HCV) treatment (i.e. host characteristics and medical contraindications) and treatment outcome disparities that were associated with interferon regimens. The public health and clinical benefit of current and forthcoming DAA discoveries will be limited if efforts are not made to examine racial, psychological, and socioeconomic factors associated with being treated with DAAs. This study examined racial, psychological, and socioeconomic factors that facilitate and inhibit patients receiving DAAs for HCV. PATIENTS AND METHODS: This was a single-center retrospective cohort study at a large urban tertiary center of patients (n=747) who were referred for evaluation and treatment of HCV. RESULTS: Sixty-eight percent of patients were non-Hispanic White, 31% were African American, and 1% were of other ethnicities. The majority of patients received treatment, but 29% (218/747) did not. Patients who were older [odds ratio (OR)=1.02, 95% confidence interval (CI): 1.01-1.04] and insured (OR=2.73, 95% CI: 1.12-6.97) were more likely to receive HCV treatment. Patients who were African American (OR=0.46, 95% CI: 0.46-1.06), used drugs (OR=0.09, 95% CI: 0.04-0.17), smoked (OR=0.55, 95% CI: 0.37-0.81), and used alcohol (OR=0.11, 95% CI: 0.06-0.20) were less likely to receive HCV treatment. CONCLUSION: Though DAAs have eliminated many historically, long-standing medical barriers to HCV treatment, several racial, psychological and socioeconomic barriers, and disparities remain. Consequently, patients who are African American, uninsured, and actively use drugs and alcohol will suffer from increased HCV-related morbidity and mortality in the coming years if deliberate public health and clinical efforts are not made to facilitate access to DAAs.

HIV Infection Status as a Predictor of Hepatitis C Virus RNA Testing in Primary Care.

INTRODUCTION: Receipt of hepatitis C virus (HCV) RNA testing following a positive HCV antibody (anti-HCV+) test result to establish current infection is a quality indicator for HCV-related care. This study examines HIV infection status as a predictor of HCV RNA test receipt after an anti-HCV+ result in the primary care setting. METHODS: Electronic medical records of anti-HCV+ patients from a multisite retrospective study of patients aged ≥18 years who utilized one or more primary care outpatient services during 2005-2010 were analyzed in 2014. A multivariable logistic regression model examined the independent relationships between patient characteristics and receipt of HCV RNA testing. RESULTS: Among 1,115 anti-HCV+ patients, 133 (11.9%) were also HIV-positive. Of these, 77.4% (n=103) underwent HCV RNA testing to determine current infection status. By contrast, 66.7% (n=654/980) of anti-HCV+ patients who were HIV-negative received HCV RNA testing. Following multivariable adjustment, the odds of receiving HCV RNA testing were higher among anti-HCV+ patients who were also HIV-positive (AOR=1.9, 95% CI=1.2, 3.0), compared with their HIV-negative counterparts. Elevated alanine aminotransferase level was also associated with receipt of HCV RNA testing (AOR=1.9, 95% CI=1.4, 2.4). Black race was associated with decreased odds of receiving HCV RNA testing (AOR=0.7, 95% CI=0.5, 1.0). CONCLUSIONS: HIV infection status is independently associated with the likelihood of receiving HCV RNA testing following an anti-HCV+ result. One quarter of anti-HCV+ patients who were also HIV-positive and one third of their HIV-negative counterparts, respectively, did not receive testing to establish active HCV infection, which is imperative for appropriate care and treatment.

Resolution of hereditary hemorrhagic telangiectasia and anemia with prolonged alpha-interferon therapy for chronic hepatitis C.

Hereditary hemorrhagic telangiectasia is a group of autosomal dominant disorders, characterized by telangiectases that develop in the skin, mucous membranes, and visceral organs. Currently, there is no satisfactory treatment of hereditary hemorrhagic telangiectasia. Interferon has never been used for the treatment of hereditary hemorrhagic telangiectasia. In this case, we report disappearance of hereditary hemorrhagic telangiectasia lesions after 12 months of treatment with interferon-alpha for chronic hepatitis C. Further studies are warranted to evaluate its role and potential use in the treatment of hereditary hemorrhagic telangiectasia.

Hemoglobinuria with ribavirin treatment.

Chronic hepatitis C virus is a major worldwide cause of hepatitis, cirrhosis, end-stage liver disease, and hepatocellular carcinomas. Combination therapy of ribavirin with short- or long-acting interferon-alpha is now the standard treatment of chronic hepatitis C. This therapy is associated with a wide range of side effects. Although hemolysis is almost an invariable result of ribavirin, black urine due to hemoglobinuria has never been previously reported. We recently encountered two cases of black urine (hemoglobinuria) in patients treated with combination therapy. Based on reports of dark urine in many of our patients, we suggest that this phenomenon may be more common than is currently appreciated. It indicates a marked degree of hemolysis, which prompts immediate measurement of hemoglobin level.