Leveraging opportunities for treatment/user simplicity (LOTUS): Navigating the current treatment landscape for achieving hepatitis C virus elimination among persons who inject drugs.

All-oral, direct-acting antivirals can cure hepatitis C virus (HCV) in almost all infected individuals; yet, many individuals with chronic HCV are not treated, and the incidence of acute HCV is increasing in some countries, including the United States. Strains on healthcare resources during the COVID-19 pandemic negatively impacted the progress toward the World Health Organization goal to eliminate HCV by 2030, especially among persons who inject drugs (PWID). Here, we present a holistic conceptual framework termed LOTUS (Leveraging Opportunities for Treatment/User Simplicity), designed to integrate the current HCV practice landscape and invigorate HCV treatment programs in the setting of endemic COVID-19: (A) treatment as prevention (especially among PWID), (B) recognition that HCV cure may be achieved with variable adherence with evidence supporting some forgiveness for missed doses, (C) treatment of all persons with active HCV infection (viremic), regardless of acuity, (D) minimal monitoring (MinMon) during treatment, and (E) rapid test and treat (TnT). The objective of this article is to review the current literature supporting each LOTUS petal; identify remaining gaps in knowledge or data; define the remaining barriers facing healthcare providers; and review evidence-based strategies for overcoming key barriers.

Hepatitis C Virus Elimination Programs in Louisiana and Washington: Importance of Screening and Surveillance Systems.

The US government has established a national goal of hepatitis C virus (HCV) elimination by 2030. To date, most HCV elimination planning and activity have been at the state level. Fifteen states presently have publicly available HCV elimination plans. In 2019, Louisiana and Washington were the first states to initiate 5-year funded HCV elimination programs. These states differ on motivation for pursuing HCV elimination and ranking on several indicators. Simultaneously, however, they have emphasized several similar elimination components including HCV screening promotion through public awareness, screening expansion, surveillance enhancement (including electronic reporting and task force development), and harm reduction. The 13 other states with published elimination plans have proposed the majority of the elements identified by Louisiana and Washington, but several have notable gaps. Louisiana's and Washington's comprehensive plans, funding approaches, and programs provide a useful framework that can move states and the nation toward HCV elimination.

Secular trends in the incidence of cholangiocarcinoma in the USA and the impact of misclassification.

BACKGROUND AND AIMS: It has been reported that the incidence of intrahepatic cholangiocarcinoma (ICC) has increased in the USA, while extrahepatic cholangiocarcinoma (ECC) has decreased or remained stable. However, neither the recent trends nor the effects of the misclassification of Klatskin tumors are known. METHODS: Using the Surveillance, Epidemiology, and End Results program databases, we calculated the average annual age-adjusted incidence rates (AA-IRs) of ICC and ECC in 4-year time periods (1992-1995, 1996-1999, 2000-2003, 2004-2007). These AA-IRs were calculated with misclassified as well as correctly classified Klatskin tumors. AA-IRs were also calculated based on age, sex, and race. Multivariable Poisson regression models were used to evaluate the secular trends of ICC and ECC. RESULTS: The AA-IR of ICC was 0.92 in 1992-1995 and 0.93 in 2004-2007, while the AA-IR of ECC increased from 0.70 in 1992-1995 to 0.95 in 2004-2007. There was no significant trend in AA-IR of ICC (p = 0.07), while there was a significant increase in ECC across the 4-year time periods (p < 0.001). Klatskin tumors comprised 6.7% of CCs with approximately 90 and 45% misclassified as ICC during 1992-2000 and 2001-2007, respectively. Adjusted Poisson models showed no significant differences in the temporal trend of ICC or ECC due to misclassification of Klatskin tumors. CONCLUSIONS: The incidence of ICC has remained stable between 1992 and 2007 with only slight fluctuations, while the incidence of ECC has been increasing. Misclassification of Klatskin tumors does not appear to play a significant role in the trends of CCs.

Clinical outcomes of hepatitis B virus coinfection in a United States cohort of hepatitis C virus-infected patients.

UNLABELLED: The effect of hepatitis B virus (HBV) coinfection in patients with hepatitis C virus (HCV) remains unclear. We used the National Veterans Affairs HCV Clinical Case Registry to identify patients with confirmed HCV viremia during 1997-2005. We defined HBV coinfection as a positive test for hepatitis B surface antigen, HBV DNA, or hepatitis B e antigen. We defined cirrhosis and hepatocellular carcinoma (HCC) based on the validated ICD-9 codes and determined mortality through the end of 2009. We performed Cox proportional hazard regression analyses to examine the effect of HBV coinfection stratified by HBV DNA status (positive or negative) on the risk of cirrhosis, HCC, and death adjusting for patients' age, gender, race, human immunodeficiency virus (HIV) infection, alcohol or drug use, Deyo Score, and antiviral treatment. Among 99,548 patients with HCV infection, 1,370 patients (1.4%) had HBV coinfection. Of the coinfected patients, 677 (49.4%) patients had at least one HBV DNA test done and 303 patients (44.7%) tested positive for HBV DNA. The incidence rates of cirrhosis, HCC, and death were significantly higher in patients with HBV coinfection and detectable HBV DNA compared to HCV monoinfection (36.8, 6.9, and 41.7 versus 17.4, 3.6, and 31.4 per 1,000 person-years, respectively; P < 0.05 for all comparisons). After adjustment for demographic, clinical, and treatment factors, patients with detectable HBV DNA had a significantly higher risk for cirrhosis (hazard ratio [HR] = 1.89 95% confidence interval [CI] = 1.46-2.45), HCC (HR = 2.12, 95% CI = 1.26-3.60), and death (HR = 1.62, 95% CI = 1.33-1.99) compared to HCV monoinfected patients. There were no differences in the risk of cirrhosis, HCC, or overall mortality between coinfected patients with undetectable HBV DNA and those with HCV monoinfection (HR = 1.18, 95% CI = 0.90-1.55; 1.54, 95% CI = 0.93-2.56; 1.08, 95% CI = 0.88-1.33, respectively). CONCLUSION: We found that while only a small number of HCV patients were coinfected with HBV, patients with documented HBV viremia were at a significantly higher risk for cirrhosis, HCC, and overall death than HCV monoinfected patients. Absence of HBV replication was associated with a clinical course similar to that of HCV monoinfected patients.

Prevalence and predictors of hepatitis B virus coinfection in a United States cohort of hepatitis C virus-infected patients.

UNLABELLED: There are sparse epidemiologic data on coinfection of hepatitis B (HBV) and hepatitis C (HCV) in the United States. Therefore, the aim of this study was to determine the prevalence and predictors of HBV coinfection in a large U.S. population of HCV patients. We used the National Veterans Affairs HCV Clinical Case Registry to identify patients tested for HCV during 1997-2005. Patients were categorized based on HCV exposure (any two +HCV tests or one test with a diagnostic code), HCV infection (+RNA or genotype), HBV exposure (any +HBV test, excluding +HBsAb only), and HBV infection (+HBsAg, HBV DNA, or HBeAg). The prevalence of HBV exposure among patients with HCV exposure and that of HBV infection among patients with HCV infection were determined. Multivariate logistic regression evaluated potential demographic and clinical predictors of HBV coinfection. Among 168,239 patients with HCV exposure, 58,415 patients had HBV exposure for a prevalence of 34.7% (95% confidence interval [CI] 34.5-35.0). Among 102,971 patients with HCV infection, 1,431 patients had HBV coinfection for a prevalence of 1.4% (95% CI 1.3-1.5). Independent associations with HBV coinfection compared with HCV monoinfection were age ≤ 50 years, male sex, positive HIV status, history of hemophilia, sickle cell anemia or thalassemia, history of blood transfusion, cocaine and other drug use; there was decreased risk in patients of Hispanic ethnicity. CONCLUSION: This is the largest cohort study in the U.S. on the prevalence of HBV coinfection in HCV patients. Among veterans with HCV, exposure to HBV is common (~35%), but HBV coinfection is relatively low (1.4%). Several possible risk factors were identified.

Dietary fructose intake and severity of liver disease in hepatitis C virus-infected patients.

BACKGROUND AND GOALS: Dietary fructose intake in the United States has been increasing, and fructose intake has been associated with the metabolic syndrome and hepatic steatosis. This study aimed to determine whether dietary fructose intake is associated with advanced hepatic fibrosis and inflammation in an hepatitis C virus (HCV)-infected male population. STUDY: We conducted a cross-sectional study of HCV-infected male veterans. The main exposure variable was daily dietary fructose calculated from the National Cancer Institute Diet History Questionnaire and the main outcome variables were FibroSURE-ActiTest determined hepatic fibrosis (F0-F3=mild vs. F3/F4-F4=advanced) and inflammation (A0-A2=mild vs. A2/A3-A3=advanced). We examined this association in logistic regression adjusting for demographic, clinical, and other dietary variables. RESULTS: Among 313 HCV* males, 103 (33%) had advanced fibrosis and 89 (28%) had advanced inflammation. Median daily fructose intake was 46.8 g (interquartile range, 30.4 to 81.0). Dietary fructose intake across quartiles among males with advanced versus mild fibrosis was 21.4% versus 25.2%, 32.0% versus 24.8%, 24.3% versus 25.2%, and 22.3% versus 24.8%, respectively, and among males with advanced versus mild inflammation was 20.2% versus 25.5%, 41.6% versus 21.4%, 22.5% versus 25.9%, and 15.7% versus 27.2%, respectively. In multivariate analysis, there were no significant associations between daily fructose intake and advanced fibrosis. There was a significant association only between the second quartile of daily fructose intake (30 to 48 g) and advanced inflammation. CONCLUSIONS: There were no significant associations between dietary fructose intake and hepatic fibrosis risk, as assessed by FibroSURE, in HCV-infected males. Additional research is needed to clarify the potential role of fructose intake and HCV-related hepatic inflammation.

Referral and receipt of treatment for hepatocellular carcinoma in United States veterans: effect of patient and nonpatient factors.

UNLABELLED: The delivery of treatment for hepatocellular carcinoma (HCC) could be influenced by the place of HCC diagnosis (hospitalization versus outpatient), subspecialty referral following diagnosis, as well as physician and facility factors. We conducted a study to examine the effect of patient and nonpatient factors on the place of HCC diagnosis, referral, and treatment in Veterans Administration (VA) hospitals in the United States. Using the VA Hepatitis C Clinical Case Registry, we identified hepatitis C virus (HCV)-infected patients who developed HCC during 1998-2006. All cases were verified and staged according to Barcelona Clinic Liver Cancer (BCLC) criteria. The main outcomes were place of HCC diagnosis, being seen by a surgeon or oncologist, and treatment. We examined factors related to these outcomes using hierarchical logistic regression. These factors included HCC stage, HCC surveillance, physician specialty, and facility factors, in addition to risk factors, comorbidity, and liver disease indicators. Approximately 37.2% of the 1,296 patients with HCC were diagnosed during hospitalization, 31.0% were seen by a surgeon or oncologist, and 34.3% received treatment. Being seen by a surgeon or oncologist was associated with surveillance (adjusted odds ratio [aOR] = 1.47; 95% CI: 1.20-1.80) and varied by geography (1.74;1.09-2.77). Seeing a surgeon or oncologist was predictive of treatment (aOR = 1.43; 95% CI: 1.24-1.66). There was a significant increase in treatment among patients who received surveillance (aOR = 1.37; 95% CI: 1.02-1.71), were seen by gastroenterology (1.65;1.21-2.24), or were diagnosed at a transplant facility (1.48;1.15-1.90). CONCLUSION: Approximately 40% of patients were diagnosed during hospitalization. Most patients were not seen by a surgeon or oncologist for treatment evaluation and only 34% received treatment. Only receipt of HCC surveillance was associated with increased likelihood of outpatient diagnosis, being seen by a surgeon or oncologist, and treatment.

Determinants of serum alpha-fetoprotein levels in hepatitis C-infected patients.

BACKGROUND & AIMS: Little information is available about what factors determine serum levels of alpha fetoprotein (AFP) (eg, demographic, virologic, or clinical features) among individuals who do not develop hepatocellular carcinoma (HCC). This information might improve AFP-based algorithms for HCC detection. METHODS: We examined data from patients in the national Veterans' Affairs Hepatitis C Virus (HCV) Clinical Case Registry who received at least 1 AFP test (258,275 AFP tests in 76,357 patients; 1.9% developed HCC). We constructed hierarchical multivariate models of AFP levels. Potential predictors of AFP values included patients' sex, race, cirrhosis status, Model for End-Stage Liver Disease (MELD) score, HCV genotype, level of alanine aminotransferase (ALT) within 30 days before the AFP test, time to diagnosis of HCC, and time elapsed from the HCV index date. RESULTS: Significant determinants for increased levels of AFP included presence of cirrhosis, higher MELD scores, and increased levels of ALT. AFP levels were also affected by the interaction between ALT levels and the presence and time to development of HCC. Among patients who did not have HCC, the AFP level increased with the level of ALT; the AFP values in the presence of ALT 37-56 U/L, ALT 57-92 U/L, or ALT >92 U/L were 16%, 35%, and 68% higher, respectively, than AFP values at ALT 0-36 U/L. However, patients who developed HCC within 30 days of receiving the AFP test had a lower rate of increase in AFP with each higher category of ALT level, with increases of 31%, 39%, and 37% for the same respective ALT categories. CONCLUSIONS: In patients with chronic HCV infection, AFP and ALT values correlate; however, among patients with HCC, levels of AFP increase disproportionately to or unaccompanied by increases in levels of ALT. The prognostic and diagnostic value of AFP levels might be increased by adjusting for ALT values.

Level of α-fetoprotein predicts mortality among patients with hepatitis C-related hepatocellular carcinoma.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) can result from hepatitis C virus (HCV)-related liver disease and is the fastest-growing cause of cancer-related death in the United States. α-fetoprotein (AFP) has been used as a prognostic factor for HCC, but the value of AFP as a prognostic factor for HCV-related HCC in the United States is unknown. We investigated whether higher levels of AFP at the time of diagnosis are associated with increased mortality of patients with HCV-related HCC. METHODS: In a retrospective study, we collected data from a cohort of HCV-infected veterans, identifying incident HCC cases from October 1, 1998, to January 1, 2007 (n = 1480 patients). The mean serum levels of AFP, obtained within 60 days before to 30 days after HCC diagnosis, were determined for 1064 patients and categorized as less than 10 ng/mL (18%), 10 to less than 100 ng/mL (30%), 100 to less than 1000 ng/mL (22%), or 1000 ng/mL or more (29%). Cox proportional hazard models were used to associate serum levels of AFP with mortality, adjusting for demographic features, clinical factors, and treatment. RESULTS: The median survival times were significantly lower among patients with higher levels of AFP: 709 days for patients with less than 10 ng/mL, 422 days for patients with 10 to less than 100 ng/mL, 208 days for patients with 100 to less than 1000 ng/mL, and 68 days for patients with 1000 ng/mL or more. In the multivariate analysis, increased levels of AFP (10 to <100, 100 to <1000, and ≥1000) were associated significantly with increased mortality, compared with a serum AFP level of less than 10; hazard ratios were 1.50, 2.23, and 4.35, respectively. CONCLUSIONS: Serum AFP level at the time of diagnosis with HCV-related HCC is an independent predictor of mortality.

Risk factors for cholangiocarcinoma.

Cholangiocarcinoma (CC) is the second most common primary hepatic malignancy after hepatocellular cancer. CC accounts for approximately 10%-25% of all hepatobiliary malignancies. There are considerable geographic and demographic variations in the incidence of CC. There are several established risk factors for CC, including parasitic infections, primary sclerosing cholangitis, biliary-duct cysts, hepatolithiasis, and toxins. Other less-established potential risk factors include inflammatory bowel disease, hepatitis C virus, hepatitis B virus, cirrhosis, diabetes, obesity, alcohol drinking, tobacco smoking, and host genetic polymorphisms. In studies where the distinction between intra- and extrahepatic CC was used, some potential risk factors seem to have a differential effect on CC, depending on the site. Therefore, the consistent use of a more refined classification would allow a better understanding of risk factors for CC.