County-Level Variation in Hepatitis C Virus Mortality and Trends in the United States, 2005-2017.

BACKGROUND AND AIMS: Since 2013, the national hepatitis C virus (HCV) death rate has steadily declined, but this decline has not been quantified or described on a local level. APPROACH AND RESULTS: We estimated county-level HCV death rates and assessed trends in HCV mortality from 2005 to 2013 and from 2013 to 2017. We used mortality data from the National Vital Statistics System and used a Bayesian multivariate space-time conditional autoregressive model to estimate age-standardized HCV death rates from 2005 through 2017 for 3,115 U.S. counties. Additionally, we estimated county-level, age-standardized rates for persons <40 and 40+ years of age. We used log-linear regression models to estimate the average annual percent change in HCV mortality during periods of interest and compared county-level trends with national trends. Nationally, the age-adjusted HCV death rate peaked in 2013 at 5.20 HCV deaths per 100,000 persons (95% credible interval [CI], 5.12, 5.26) before decreasing to 4.34 per 100,000 persons (95% CI, 4.28, 4.41) in 2017 (average annual percent change = -4.69; 95% CI, -5.01, -4.33). County-level rates revealed heterogeneity in HCV mortality (2017 median rate = 3.6; interdecile range, 2.19, 6.77), with the highest rates being concentrated in the West, Southwest, Appalachia, and northern Florida. Between 2013 and 2017, HCV mortality decreased in 80.0% (n = 2,274) of all U.S. counties with a reliable trend estimate, with 25.8% (n = 803) of all counties experiencing a decrease larger than the national decline. CONCLUSIONS: Although many counties have experienced a shift in HCV mortality trends since 2013, the magnitude and composition of that shift have varied by place. These data provide a better understanding of geographic differences in HCV mortality and can be used by local jurisdictions to evaluate HCV mortality in their areas relative to surrounding areas and the nation.

Human Immunodeficiency Virus and Hepatitis C Virus Infection Testing Among Commercially Insured Persons Who Inject Drugs, United States, 2010-2017.

BACKGROUND: We assessed prevalence of testing for human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infection among persons who inject drugs (PWID). METHODS: Using a nationwide health insurance database for claims paid during 2010-2017, we identified PWID by using codes from the International Classification of Diseases, Current Procedural Terminology, and National Drug Codes directory. We then estimated the percentage of PWIDs tested for HIV or HCV within 1 year of an index encounter, and we used multivariate logistic regression models to assess demographic and clinical factors associated with testing. RESULTS: Of 844 242 PWIDs, 71 938 (8.5%) were tested for HIV and 65 188 (7.7%) were tested for HCV infections. Missed opportunities were independently associated with being male (odds ratios [ORs]: HIV, 0.50 [95% confidence interval {CI}, 0.49-0.50], P < .001; HCV, 0.66 [95% CI, 0.65-0.72], P < .001), rural residence (ORs: HIV, 0.67 [95% CI, 0.65-0.69], P < .001; HCV, 0.75 [95% CI, 0.73-0.77], P < .001), and receiving services for skin infections or endocarditis (adjusted ORs: HIV, 0.91 [95% CI, 0.87-0.95], P < .001; HCV, 0.90 [95% CI, 0.86-0.95], P < .001). CONCLUSIONS: Approximately 90% of presumed PWIDs missed opportunities for HIV or HCV testing, especially male rural residents with claims for skin infections or endocarditis, commonly associated with injection drug use.

Risk behaviours of homeless people who inject drugs during an outbreak of hepatitis C, Northern Ireland, 2016-2017.

From July to August 2016, 4 homeless people who injected drugs (PWID) with acute or recent hepatitis C virus (HCV) infection were reported in Belfast. A multidisciplinary team including public health, homeless and addiction services undertook an investigation to identify risk behaviours and interrupt transmission chains. Recent HCV cases were defined as negative test within the previous year, or reported injecting for less than 1 year; acute cases had tested negative within the previous 6 months. Contacts in the injecting networks of cases were identified for testing. We undertook a cross-sectional survey using structured questionnaires to elicit risk behaviours for PWID and compare behaviours between self-reported hepatitis C positive and negative subjects. During the outbreak investigation until December 2017, 156 PWID were tested and 45 (29%) cases identified, including 7 (16%) recent and 13 (29%) acute infections. 68 PWID, including 12 cases, were interviewed. All respondents reported using heroin, with 76% injecting once or more daily. Sharing was reported for spoons (58%) and filters (53%), but also needles (27%) and syringes (29%). Hepatitis C positive individuals had higher odds to be injecting in public toilets (AOR 17, 95% CI 0.71-400, P < .05) when compared with hepatitis C negative individuals. Hepatitis C positive individuals were more likely to inject in public spaces, but all respondents indicated concerning risk behaviours. We recommend active surveillance with ongoing testing, expanding existing harm reduction programmes and access to bespoke services.

Hepatitis C treatment ­ yesterday, tomorrow and / Therapie der Hepatitis C ­ gestern, heute und

During the last years, treatment of chronic hepatitis C virus infection (HCV) was characterized by the development of new therapeutic agents and their combined use. By now the problem of treating HCV seems to be largely solved. The broad range of available therapeutics has the potential to enable a complete cure of this liver disease, which is associated with many complications, thus providing also economic benefits.

Transmission of Hepatitis C Virus among Prisoners, Australia, 2005-2012.

Hepatitis C virus (HCV) is predominantly transmitted between persons who inject drugs. For this population, global prevalence of HCV infection is high and incarceration is common and an independent risk factor for HCV acquisition. To explore HCV transmission dynamics in incarcerated populations, we integrated virus sequences with risk behavior and spatiotemporal data and analyzed transmission clusters among prisoners in Australia. We detected 3 clusters of recent HCV transmission consisting of 4 likely in-custody transmission events involving source/recipient pairs located in the same prison at the same time. Of these 4 events, 3 were associated with drug injecting and equipment sharing. Despite a large population of prisoners with chronic HCV, recent transmission events were identified in the prison setting. This ongoing HCV transmission among high-risk prisoners argues for expansion of prevention programs to reduce HCV transmission in prisons.

[The specific enzyme inhibitors for potential therapeutic use]. / Specyficzne inhibitory enzymów o potencjalnym zastosowaniu terapeutycznym.

Therapy for hepatitis C virus (HCV) initially consisted on administering ribavirin - having a broad spectrum of action - and pegylated interferon, and was only effective in 40-50% of patients. Appropriate was to find effective inhibitors of viral replication e.g. by inhibition of a viral enzyme, NTPase/helicase required in the process of translation and RNA replication of the HCV. We developed methods of synthesis of many compounds belonging to different groups - derivatives of nucleosides, benzotriazole, benzimidazole, tropolone and epirubicine. Some of the derivatives inhibit HCV helicase activity at low concentrations and reduces replication of the viral RNA in subgenomic replicon system. In the process of HCV replication casein kinase CK2 plays an important role. It regulates the level of phosphorylation of HCV protein NS5A, which affects the production of infectious virions of HCV. Effective and selective inhibitors of kinase CK2 could be of use in the treatment of HCV in combination with other drugs. CK2 kinase phosphorylates approximately 300 proteins that affect the growth, differentiation, proliferation or apoptosis. Elevated CK2 kinase activity has been observed in several types of cancer and other diseases, therefore, inhibitors of this enzyme are potential therapeutic importance, particularly for anti-cancer treatment. Research carried out in collaboration with prof. Shugar led to the synthesis of one of the most selective inhibitors of this enzyme which is 4,5,6,7-tetrabromo-1H-benzotriazole, used for the study of the role of kinase CK2 in a number of metabolic processes in tumor cells.

National estimates of healthcare utilization by individuals with hepatitis C virus infection in the United States.

BACKGROUND: Hepatitis C virus (HCV) infection is a major public health problem in the United States. Although prior studies have evaluated the HCV-related healthcare burden, these studies examined a single treatment setting and did not account for the growing "baby boomer" population (individuals born during 1945-1965). METHODS: Data from the National Ambulatory Medical Care Survey, the National Hospital Ambulatory Medical Care Survey, and the Nationwide Inpatient Sample were analyzed. We sought to characterize healthcare utilization by individuals infected with HCV in the United States, examining adult (≥18 years) outpatient, emergency department (ED), and inpatient visits among individuals with HCV diagnosis for the period 2001-2010. Key subgroups included persons born before 1945 (older), between 1945 and 1965 (baby boomer), and after 1965 (younger). RESULTS: Individuals with HCV infection were responsible for >2.3 million outpatient, 73 000 ED, and 475 000 inpatient visits annually. Persons in the baby boomer cohort accounted for 72.5%, 67.6%, and 70.7% of care episodes in these settings, respectively. Whereas the number of outpatient visits remained stable during the study period, inpatient admissions among HCV-infected baby boomers increased by >60%. Inpatient stays totaled 2.8 million days and cost >$15 billion annually. Nonwhites, uninsured individuals, and individuals receiving publicly funded health insurance were disproportionately affected in all healthcare settings. CONCLUSIONS: Individuals with HCV infection are large users of outpatient, ED, and inpatient health services. Resource use is highest and increasing in the baby boomer generation. These observations illuminate the public health burden of HCV infection in the United States.

Emerging epidemic of hepatitis C virus infections among young nonurban persons who inject drugs in the United States, 2006-2012.

BACKGROUND: Reports of acute hepatitis C in young persons in the United States have increased. We examined data from national surveillance and supplemental case follow-up at selected jurisdictions to describe the US epidemiology of hepatitis C virus (HCV) infection among young persons (aged ≤30 years). METHODS: We examined trends in incidence of acute hepatitis C among young persons reported to the Centers for Disease Control and Prevention (CDC) during 2006-2012 by state, county, and urbanicity. Sociodemographic and behavioral characteristics of HCV-infected young persons newly reported from 2011 to 2012 were analyzed from case interviews and provider follow-up at 6 jurisdictions. RESULTS: From 2006 to 2012, reported incidence of acute hepatitis C increased significantly in young persons-13% annually in nonurban counties (P = .003) vs 5% annually in urban counties (P = .028). Thirty (88%) of 34 reporting states observed higher incidence in 2012 than 2006, most noticeably in nonurban counties east of the Mississippi River. Of 1202 newly reported HCV-infected young persons, 52% were female and 85% were white. In 635 interviews, 75% of respondents reported injection drug use. Of respondents reporting drug use, 75% had abused prescription opioids, with first use on average 2.0 years before heroin. CONCLUSIONS: These data indicate an emerging US epidemic of HCV infection among young nonurban persons of predominantly white race. Reported incidence was higher in 2012 than 2006 in at least 30 states, with largest increases in nonurban counties east of the Mississippi River. Prescription opioid abuse at an early age was commonly reported and should be a focus for medical and public health intervention.

Prevalence and risk factors of Hepatitis C virus infection in Brazil, 2005 through 2009: a cross-sectional study.

BACKGROUND: Hepatitis C chronic liver disease is a major cause of liver transplant in developed countries. This article reports the first nationwide population-based survey conducted to estimate the seroprevalence of HCV antibodies and associated risk factors in the urban population of Brazil. METHODS: The cross sectional study was conducted in all Brazilian macro-regions from 2005 to 2009, as a stratified multistage cluster sample of 19,503 inhabitants aged between 10 and 69 years, representing individuals living in all 26 State capitals and the Federal District. Hepatitis C antibodies were detected by a third-generation enzyme immunoassay. Seropositive individuals were retested by Polymerase Chain Reaction and genotyped. Adjusted prevalence was estimated by macro-regions. Potential risk factors associated with HCV infection were assessed by calculating the crude and adjusted odds ratios, 95% confidence intervals (95% CI) and p values. Population attributable risk was estimated for multiple factors using a case-control approach. RESULTS: The overall weighted prevalence of hepatitis C antibodies was 1.38% (95% CI: 1.12%-1.64%). Prevalence of infection increased in older groups but was similar for both sexes. The multivariate model showed the following to be predictors of HCV infection: age, injected drug use (OR = 6.65), sniffed drug use (OR = 2.59), hospitalization (OR = 1.90), groups socially deprived by the lack of sewage disposal (OR = 2.53), and injection with glass syringe (OR = 1.52, with a borderline p value). The genotypes 1 (subtypes 1a, 1b), 2b and 3a were identified. The estimated population attributable risk for the ensemble of risk factors was 40%. Approximately 1.3 million individuals would be expected to be anti-HCV-positive in the country. CONCLUSIONS: The large estimated absolute numbers of infected individuals reveals the burden of the disease in the near future, giving rise to costs for the health care system and society at large. The known risk factors explain less than 50% of the infected cases, limiting the prevention strategies. Our findings regarding risk behaviors associated with HCV infection showed that there is still room for improving strategies for reducing transmission among drug users and nosocomial infection, as well as a need for specific prevention and control strategies targeting individuals living in poverty.

Epidemic history of hepatitis C virus infection in two remote communities in Nigeria, West Africa.

We investigated the molecular epidemiology and population dynamics of HCV infection among indigenes of two semi-isolated communities in North-Central Nigeria. Despite remoteness and isolation, ~15% of the population had serological or molecular markers of hepatitis C virus (HCV) infection. Phylogenetic analysis of the NS5b sequences obtained from 60 HCV-infected residents showed that HCV variants belonged to genotype 1 (n=51; 85%) and genotype 2 (n=9; 15%). All sequences were unique and intermixed in the phylogenetic tree with HCV sequences from people infected from other West African countries. The high-throughput 454 pyrosequencing of the HCV hypervariable region 1 and an empirical threshold error correction algorithm were used to evaluate intra-host heterogeneity of HCV strains of genotype 1 (n=43) and genotype 2 (n=6) from residents of the communities. Analysis revealed a rare detectable intermixing of HCV intra-host variants among residents. Identification of genetically close HCV variants among all known groups of relatives suggests a common intra-familial HCV transmission in the communities. Applying Bayesian coalescent analysis to the NS5b sequences, the most recent common ancestors for genotype 1 and 2 variants were estimated to have existed 675 and 286 years ago, respectively. Bayesian skyline plots suggest that HCV lineages of both genotypes identified in the Nigerian communities experienced epidemic growth for 200-300 years until the mid-20th century. The data suggest a massive introduction of numerous HCV variants to the communities during the 20th century in the background of a dynamic evolutionary history of the hepatitis C epidemic in Nigeria over the past three centuries.

HCV routes of transmission: what goes around comes around.

The widespread availability of injectable therapies and increase in illicit injection drug use were responsible for the rapid emergence of hepatitis C virus (HCV) infection in the latter half of the 20th century. Iatrogenic exposures and illicit injection drug use have been the predominant risk factors for HCV transmission worldwide. In developing countries, unsafe therapeutic injection practices appear to be responsible for most infections. In developed countries, donor testing has virtually eliminated transfusion-related infections, but infections transmitted to patients by unsafe injections practices is an emerging problem. Injection drug use is the major risk factor for HCV; incidence remains high among new injectors, and this behavior likely contributes to and/or confounds reported associations between HCV-positive persons and histories of noninjection drug use, tattooing, and incarceration. Increased use of illegal drugs also may play a role in the emergence of sexually transmitted HCV infections among HIV-positive men who have sex with men. Ongoing monitoring of the epidemiology of HCV infection is crucial for preventing future infections.

Hepatitis B, hepatitis C and HIV transfusion-transmitted infections in the 21st century.

In the past, transfusion-transmitted virus (TTV) infections were not uncommon. In recent years with advanced technologies and improved donor screening, the risk of viral transfusion transmission has been markedly reduced. Hepatitis B virus (HBV), hepatitis C virus (HCV) and human immunodeficiency virus (HIV) have all shown marked reduction in transmission rates. However, the newer technologies, including nucleic acid technology (NAT) testing, have affected the residual rates differently for these virally transmitted diseases. Zero risk, which has been the goal, has yet to be achieved. False negatives still persist, and transmissions of these viruses still occur, although rarely. It is known that HBV serological testing misses some infected units; likewise, HBV NAT-negative units have also been known to transmit the virus. Similarly, HIV minipool NAT-negative units have transmitted HIV, as recently as 2007; likely, these transmissions would have been prevented with single-unit NAT testing. Newer technologies, such as pathogen inactivation (PI), will (ideally) eliminate these falsely test negative components, regardless of the original testing method used for detecting the viruses.

The long and winding road leading to the identification of the hepatitis C virus.

This review describes work conducted largely in my laboratory at the Chiron Corporation between 1982 and 1989 that led to the identification of the hepatitis C virus (HCV). Key colleagues included Dr. Qui-Lim Choo in my laboratory and Dr. George Kuo also of Chiron as well as my collaborator Dr. Daniel Bradley at the CDC who provided many biological samples from the NANBH chimpanzee model. Numerous molecular approaches were explored including the screening of tens of millions of bacterial cDNA clones derived from these materials. While this early genomics approach resulted in the identification of many host gene activities associated with NANBH, no genes of proven infectious etiology could be identified. A separate avenue of our research led to the molecular characterization of the complete hepatitis delta viral genome but unfortunately, this could not be used as a molecular handle for HCV. Largely following input from Dr. Kuo, I initiated a blind cDNA immunoscreening approach involving the large-scale screening of bacterial proteomic cDNA libraries derived from NANBH-infectious chimpanzee materials (prior to the development of PCR technology) using sera from NANBH patients as a presumptive source of viral antibodies. Eventually, this novel approach to identifying agents of infectious etiology led to the isolation of a single small cDNA clone that was proven to be derived from the HCV genome using various molecular and serological criteria. This discovery has facilitated the development of effective diagnostics, blood screening tests and the elucidation of promising drug and vaccine targets to control this global pathogen.

The history of the "natural history" of hepatitis C (1968-2009).

In the late 1960's, only types A and B hepatitis were believed to exist, distinguished by circumstances of exposure and incubation periods. In the early 1970's, studies of transfusion recipients were begun with the belief that hepatitis B would be responsible should transfusion-associated hepatitis develop. After discovery of the viruses of hepatitis A and B, neither agent was found responsible, hence non-A, non-B (NANB) hepatitis. Initial follow-up of these cases showed that approximately 50% developed chronic hepatitis based on persistence of serum enzymes for at least 6 months. Approximately 15 years later, after the hepatitis C virus had been identified as the cause for NANB hepatitis, chronic hepatitis was found to develop more frequently as indicated by persistent viral infection in over 80% of infected adults but in only about 50% of infected children or young women. Follow-up over 2 to 4 decades indicated that many infected persons developed progressive hepatic fibrosis, sometimes culminating in cirrhosis and/or liver cancer. Long-term natural history studies have proved to be challenging because disease onset is often silent and progression extremely slow. Differing strategies have been used to determine the natural history, the descriptions and results of which are presented in this review.

Advances in viral hepatitis: 50 years of Australian gastroenterology.

Viral hepatitis classification, treatments and pathogenesis has been increasingly defined over the past 50 years. Australian researchers have made significant contributions in the areas of viral hepatitis A vaccine development, treatment outcomes for chronic hepatitis B and C, the role of liver transplantation and the pathogenesis of injury and disease progression. This review outlines some of these contributions.