A systematic review and meta-analysis of community and primary-care-based hepatitis C testing and treatment services that employ direct acting antiviral drug treatments.

BACKGROUND: Direct Acting Antiviral (DAAs) drugs have a much lower burden of treatment and monitoring requirements than regimens containing interferon and ribavirin, and a much higher efficacy in treating hepatitis C (HCV). These characteristics mean that initiating treatment and obtaining a virological cure (Sustained Viral response, SVR) on completion of treatment, in non-specialist environments should be feasible. We investigated the English-language literature evaluating community and primary care-based pathways using DAAs to treat HCV infection. METHODS: Databases (Cinahl; Embase; Medline; PsycINFO; PubMed) were searched for studies of treatment with DAAs in non-specialist settings to achieve SVR. Relevant studies were identified including those containing a comparison between a community and specialist services where available. A narrative synthesis and linked meta-analysis were performed on suitable studies with a strength of evidence assessment (GRADE). RESULTS: Seventeen studies fulfilled the inclusion criteria: five from Australia; two from Canada; two from UK and eight from USA. Seven studies demonstrated use of DAAs in primary care environments; four studies evaluated integrated systems linking specialists with primary care providers; three studies evaluated services in locations providing care to people who inject drugs; two studies evaluated delivery in pharmacies; and one evaluated delivery through telemedicine. Sixteen studies recorded treatment uptake. Patient numbers varied from around 60 participants with pathway studies to several thousand in two large database studies. Most studies recruited less than 500 patients. Five studies reported reduced SVR rates from an intention-to-treat analysis perspective because of loss to follow-up before the final confirmatory SVR test. GRADE assessments were made for uptake of HCV treatment (medium); completion of HCV treatment (low) and achievement of SVR at 12 weeks (medium). CONCLUSION: Services sited in community settings are feasible and can deliver increased uptake of treatment. Such clinics are able to demonstrate similar SVR rates to published studies and real-world clinics in secondary care. Stronger study designs are needed to confirm the precision of effect size seen in current studies. Prospero: CRD42017069873.

Inpatient hospital burden of hepatitis C-diagnosed patients with decompensated cirrhosis.

BACKGROUND & AIMS: To describe the burden on inpatient hospital resources over time from patients diagnosed with hepatitis C virus (HCV) infection and who have reached the decompensated stage of cirrhosis (DC), as existing estimates of hospital stay in these patients are limited. METHODS: A retrospective longitudinal dataset was formed via record-linkage between the national HCV diagnosis database and inpatient/daycase hospitalisation and death registers in Scotland. The study population consisted of HCV-diagnosed patients with a first DC admission in 1996-2013, with follow-up available until 31 May 2014. We investigated and quantified the mean cumulative length of hospital stay, distributions over discharge diagnosis categories, and trends in admission rates. RESULTS: Among our study population (n = 1543), we identified 10 179 admissions with any diagnosis post-first DC admission. Between 1996 and 2013 there was a 16-fold rise in annual total admissions (from 112 to 1791) and an 11-fold rise in hospital stay (719-8045). When restricting minimum possible follow-up to 2 years, DC patients (n = 1312) had an overall admission rate of 7.3 per person-year, and spent on average 43 days (26 days during first 6 months) in hospital; for all liver-related, liver-related other than HCC/DC, and non-liver related only admissions, this was 39, 14, and 5 days respectively. CONCLUSIONS: HCV-infected DC patients impose a considerable inpatient hospital burden, mostly from DC- and other liver-related admissions, but also from admissions associated with non-liver comorbidities. Estimates will be useful for monitoring the impact of prevention and treatment, and for computing the cost-effectiveness of new therapies.

The contribution of alcohol use disorder to decompensated cirrhosis among people with hepatitis C: An international study.

BACKGROUND & AIMS: The advent of direct-acting antivirals (DAAs) has led to ambitious targets for hepatitis C virus (HCV) elimination. However, in the context of alcohol use disorder the ability of DAAs to achieve these targets may be compromised. The aim of this study was to evaluate the contribution of alcohol use disorder to HCV-related decompensated cirrhosis in three settings. METHODS: HCV notifications from British Columbia, Canada; New South Wales, Australia, and Scotland (1995-2011/2012/2013, respectively) were linked to hospital admissions (2001-2012/2013/2014, respectively). Alcohol use disorder was defined as non-liver-related hospitalisation due to alcohol use. Age-standardised decompensated cirrhosis incidence rates were plotted, associated factors were assessed using Cox regression, and alcohol use disorder-associated population attributable fractions (PAFs) were computed. RESULTS: Among 58,487, 84,529, and 31,924 people with HCV in British Columbia, New South Wales, and Scotland, 2,689 (4.6%), 3,169 (3.7%), and 1,375 (4.3%) had a decompensated cirrhosis diagnosis, and 28%, 32%, and 50% of those with decompensated cirrhosis had an alcohol use disorder, respectively. Age-standardised decompensated cirrhosis incidence rates were considerably higher in people with alcohol use disorder in New South Wales and Scotland. Decompensated cirrhosis was independently associated with alcohol use disorder in British Columbia (aHR 1.92; 95% CI 1.76-2.10), New South Wales (aHR 3.68; 95% CI 3.38-4.00) and Scotland (aHR 3.88; 95% CI 3.42-4.40). The PAFs of decompensated cirrhosis-related to alcohol use disorder were 13%, 25%, and 40% in British Columbia, New South Wales and Scotland, respectively. CONCLUSIONS: Alcohol use disorder was a major contributor to HCV liver disease burden in all settings, more distinctly in Scotland. The extent to which alcohol use would compromise the individual and population-level benefits of DAA therapy needs to be closely monitored. Countries, where appropriate, must develop strategies combining promotion of DAA treatment uptake with management of alcohol use disorders, if World Health Organization 2030 HCV mortality reduction targets are going to be achieved. LAY SUMMARY: The burden of liver disease has been rising among people with hepatitis C globally. The recent introduction of highly effective medicines against hepatitis C (called direct-acting antivirals or DAAs) has brought renewed optimism to the sector. DAA scale-up could eliminate hepatitis C as a public health threat in the coming decades. However, our findings show heavy alcohol use is a major risk factor for liver disease among people with hepatitis C. If continued, heavy alcohol use could compromise the benefits of new antiviral treatments at the individual- and population-level. To tackle hepatitis C as a public health threat, where needed, DAA therapy should be combined with management of heavy alcohol use.

Treatment as Prevention: Should Hepatitis C Learn the Lessons from HIV?

Long-term experience in the treatment of HIV-infected individuals has shown indirect benefits of early initiation of antiretroviral therapy, particularly in preventing HIV transmission. With the advent of direct-acting antivirals for the treatment of hepatitis C, the strategy of treatment-as-prevention has become feasible. However, economic, clinical, ethical, and public health issues arise from the concept of using therapeutic interventions only as prevention strategies.

Hepatitis E virus infection in Europe: surveillance and descriptive epidemiology of confirmed cases, 2005 to 2015.

Hepatitis E virus (HEV) is an under-recognised cause of acute hepatitis in high-income countries. The purpose of this study was to provide an overview of testing, diagnosis, surveillance activities, and data on confirmed cases in the European Union/European Economic Area (EU/EEA). A semi-structured survey was developed and sent to 31 EU/EEA countries in February 2016, 30 responded. Twenty of these countries reported that they have specific surveillance systems for HEV infection. Applied specific case definition for HEV infection varied widely across countries. The number of reported cases has increased from 514 cases per year in 2005 to 5,617 in 2015, with most infections being locally acquired. This increase could not be explained by additional countries implementing surveillance for HEV infections over time. Hospitalisations increased from less than 100 in 2005 to more than 1,100 in 2015 and 28 fatal cases were reported over the study period. EU/EEA countries are at different stages in their surveillance, testing schemes and policy response to the emergence of HEV infection in humans. The available data demonstrated a Europe-wide increase in cases. Standardised case definitions and testing policies would allow a better understanding of the epidemiology of HEV as an emerging cause of liver-related morbidity.

Hepatitis C reinfection following treatment induced viral clearance among people who have injected drugs.

BACKGROUND: Although people who inject drugs (PWID) are an important group to receive Hepatitis C Virus (HCV) antiviral therapy, initiation onto treatment remains low. Concerns over reinfection may make clinicians reluctant to treat this group. We examined the risk of HCV reinfection among a cohort of PWID (encompassing all those reporting a history of injecting drug use) from Scotland who achieved a sustained virological response (SVR). METHODS: Clinical and laboratory data were used to monitor RNA testing among PWID who attained SVR following therapy between 2000 and 2009. Data were linked to morbidity and mortality records. Follow-up began one year after completion of therapy, ending on 31st December, 2012. Frequency of RNA testing during follow-up was calculated and the incidence of HCV reinfection estimated. Cox proportional hazards regression was used to examine factors associated with HCV reinfection. RESULTS: Among 448 PWID with a SVR, 277 (61.8%) were tested during follow-up, median 4.5 years; 191 (69%) received one RNA test and 86 (31%) received at least two RNA tests. There were seven reinfections over 410 person years generating a reinfection rate of 1.7/100py (95% CI 0.7-3.5). For PWID who have been hospitalised for an opiate or injection related cause post SVR (11%), the risk of HCV reinfection was greater [AHR=12.9, 95% CI 2.2-76.0, p=0.002] and the reinfection rate was 5.7/100py (95% CI 1.8-13.3). CONCLUSION: PWID who have been tested, following SVR, for HCV in Scotland appear to be at a low risk of reinfection. Follow-up and monitoring of this population are warranted as treatment is offered more widely.

Liver mortality attributable to chronic hepatitis C virus infection in Denmark and Scotland--using spontaneous resolvers as the benchmark comparator.

UNLABELLED: Liver mortality among individuals with chronic hepatitis C (CHC) infection is common, but the relative contribution of CHC per se versus adverse health behaviors is uncertain. We explored data on spontaneous resolvers of hepatitis C virus (HCV) as a benchmark group to uncover the independent contribution of CHC on liver mortality. Using national HCV diagnosis and mortality registers from Denmark and Scotland, we calculated the liver mortality rate (LMR) for persons diagnosed with CHC infection (LMRchronic ) and spontaneously resolved infection (LMRresolved ), according to subgroups defined by age, sex, and drug use. Through these mortality rates, we determined subgroup-specific attributable fractions (AFs), defined as (LMRchronic - LMRresolved )/LMRchronic , and then calculated the total attributable fraction (TAF) as a weighted average of these AFs. Thus, the TAF represents the overall fraction (where 0.00 = not attributable at all; and 1.00 = entirely attributable) of liver mortality attributable to CHC in the diagnosed population. Our cohort comprised 7,005 and 21,729 persons diagnosed with HCV antibodies in Denmark and Scotland, respectively. Mean follow-up duration was 6.3-6.9 years. The TAF increased stepwise with age. It was lowest for death occurring at <45 years of age (0.21 in Denmark; 0.26 in Scotland), higher for death occurring at 45-59 years (0.69 in Denmark; 0.69 in Scotland), and highest for death at 60+years (0.92 in Denmark; 0.75 in Scotland). Overall, the TAF was 0.66 (95% confidence interval [CI]: 0.55-0.78) in Denmark and 0.55 (95% CI: 0.44-0.66) in Scotland. CONCLUSIONS: In Denmark and Scotland, the majority of liver death in the CHC-diagnosed population can be attributed to CHC-nevertheless, an appreciable fraction cannot, cautioning that liver mortality in this population is a compound problem that can be reduced, but not solved, through antiviral therapy alone.

Expansion of HCV treatment access to people who have injected drugs through effective translation of research into public health policy: Scotland's experience.

Seven years have elapsed since the Scottish Government launched its Hepatitis C Action Plan - a Plan to improve services to prevent transmission of infection, particularly among people who inject drugs (PWID), identify those infected and ensure those infected receive optimal treatment. The Plan was underpinned by industrial scale funding (around £100 million, in addition to the general NHS funding, will have been invested by 2015), and a web of accountable national and local multi-disciplinary multi-agency networks responsible for the planning, development and delivery of services. Initiatives ranged from the introduction of testing in specialist drug services through finger-prick blood sampling by non-clinical staff, to the setting of government targets to ensure rapid scale-up of antiviral therapy. The Plan was informed by comprehensive national monitoring systems, indicating the extent of the problem not just in terms of numbers infected, diagnosed and treated but also the more penetrative data on the number advancing to end-stage liver disease and death, and also through compelling modelling work demonstrating the potential beneficial impact of scaling-up therapy and the mounting cost of not acting. Achievements include around 50% increase in the proportion of the infected population diagnosed (38% to 55%); a sustained near two-and-a-half fold increase in the annual number of people initiated onto therapy (470 to 1050) with more pronounced increases among PWID (300 to 840) and prisoners (20 to 140); and reversing of an upward trend in the overall number of people living with chronic infection. The Action Plan has demonstrated that a Government-backed, coordinated and invested approach can transform services and rapidly improve the lives of thousands. Cited as "an impressive example of a national strategy" by the Global Commission on Drug Policy, the Scottish Plan has also provided fundamental insights of international relevance into the management of HCV among PWID.

Evidence of continued injecting drug use after attaining sustained treatment-induced clearance of the hepatitis C virus: Implications for reinfection.

BACKGROUND: People who inject drugs (PWID) are at the greatest risk of hepatitis C virus (HCV) infection, yet are often denied immediate treatment due to fears of on-going risk behaviour. Our principal objective was to examine evidence of continued injecting drug use among PWID following successful treatment for HCV and attainment of a sustained viral response (SVR). METHODS: PWID who attained SVR between 1992 and June 2012 were selected from the National Scottish Hepatitis C Clinical Database. Hospitalisation and mortality records were sourced for these patients using record linkage techniques. Our primary outcome variable was any hospitalisation or death, which was indicative of injecting drugs post-SVR. RESULTS: The cohort comprised 1170 PWID (mean age at SVR 39.6y; 76% male). The Kaplan Meier estimate of incurring the primary outcome after three years of SVR was 10.59% (95% CI, 8.75-12.79) After adjusting for confounding, the risk of an injection related hospital episode or death post-SVR was significantly increased with advancing year of SVR: AHR:1.07 per year (95% CI, 1.01-1.14), having a pre-SVR acute alcohol intoxication-related hospital episode: AHR:1.83 (95% CI, 1.29-2.60), and having a pre-SVR opiate or injection-related hospital episode: AHR:2.59 (95% CI, 1.84-3.64). CONCLUSION: Despite attaining the optimal treatment outcome, these data indicate that an increasing significant minority of PWID continue to inject post-SVR at an intensity which leads to either hospitalisation or death and increased risk of reinfection.

Global policy and access to new hepatitis C therapies for people who inject drugs.

People who inject drugs (PWID) are disproportionately affected by hepatitis C virus (HCV). This review outlines policy recommendations made in the 2014 World Health Organisation (WHO) Guidelines on Screening, Care and Treatment of HCV and their relevance to PWID. It also canvasses issues that will affect translation of these global guidelines into practice. The first global HCV guidelines released by WHO have recently advocated targeted HCV testing for PWID, assessment of liver disease and support for alcohol reduction during care. They also strongly advocate treatment using currently licensed direct-acting antiviral agents for all individuals, in particular PWID as a key affected population. New HCV treatment regimens have the potential to cure more than 90% of treated individuals. Scaling-up treatment among PWID has the potential to improve individual and population health by reducing HCV transmission, improving quality of life and supporting behaviour modifications that lead to less risk-taking over time. PWID face several barriers to accessing HCV care and treatment that need to be overcome. Testing services need re-orientation toward PWID, individuals need to be informed of their results and provided with direct linkage to ongoing care. Health services need to provide care in the community using simpler, cheaper and more accessible modes of delivery. Healthcare costs and pharmaceutical costs need to be minimised so PWID, who are highly marginalised, can access HCV treatment. Sustained scale-up of treatment for PWID could simultaneously improve individual health and achieve the goal of eliminating HCV transmission among this high-risk and vulnerable group.

Mortality and cause of death in a cohort of people who had ever injected drugs in Glasgow: 1982-2012.

BACKGROUND: To describe all-cause and cause-specific mortality in a cohort of people who had ever injected drugs (PWID) with a low prevalence of HIV over 20-30 years. METHODS: Using a retrospective study design, identifying data from a cohort of PWID recruited between 1982 and 1993 through in-patient drug treatment services were linked to National Records for Scotland deaths data using probabilistic record linkage. We report all-cause and cause-specific mortality rates; standardized mortality ratios (SMR) across time, gender and age were estimated. RESULTS: Among 456 PWID, 139 (30.5%) died over 9024 person-years (PY) of follow-up. Mortality within the cohort was almost nine times higher than the general population, and remained elevated across all age groups. The greatest excess mortality rate was in the youngest age group, who were 15-24 years of age (SMR 31.6, 95% CI 21.2-47.1). Drug-related deaths declined over time and mortality was significantly higher among HIV positive participants. Although SMRs declined with follow-up, the SMR of the oldest age group (45-60) was 4.5 (95% CI 3.0-6.9). There were no significant differences in all-cause mortality rates between participants who were 25 years and older at cohort entry compared to younger participants. CONCLUSION: Mortality rates remained higher than the general population across all age groups. Screening services that identify a history of injecting drug use may be an opportunity to address risk factors faced by an ageing population of PWID and potentially have implications for future health care planning.

Trends in mortality after diagnosis of hepatitis C virus infection: an international comparison and implications for monitoring the population impact of treatment.

BACKGROUND & AIMS: People living with hepatitis C virus (HCV) are at increased risk of all-cause and liver-related mortality, although successful treatment has been shown to reduce this risk. The aim of this study was to provide baseline data on trends in cause-specific mortality and to establish an international surveillance system for evaluating the population level impact of HCV treatments. METHODS: Population level HCV diagnosis databases from Scotland (1997-2010), Australia (New South Wales [NSW]) (1997-2006), and Canada (British Columbia [BC]) (1997-2003) were linked to corresponding death registries using record linkage. For each region, age-adjusted cause-specific mortality rates were calculated, and trends in annual age-adjusted liver-related mortality were plotted. RESULTS: Of 105,138 individuals diagnosed with HCV (21,810 in Scotland, 58,484 in NSW, and 24,844 in BC), there were 7275 deaths (2572 in Scotland, 2655 in NSW, and 2048 in BC). Liver-related deaths accounted for 26% of deaths in Scotland, 21% in NSW, and 22% in BC. Temporal trends in age-adjusted liver related mortality were stable in Scotland (males p=0.4; females p=0.2) and NSW (males p=0.9; females p=0.9), while there was an increase in BC (males p=0.002; females p=0.04). CONCLUSIONS: The risk of liver-related mortality after a diagnosis of HCV has remained stable or increased over time across three regions with well-established diagnosis databases, highlighting that HCV treatment programmes to-date have had minimal impact on population level HCV-related liver disease. With more effective therapies on the horizon, and greater uptake of treatment anticipated, the potential of future therapeutic strategies to reduce HCV-related mortality is considerable.

Are needle and syringe programmes associated with a reduction in HIV transmission among people who inject drugs: a systematic review and meta-analysis.

BACKGROUND: Needle and syringe programmes (NSP) aim to reduce the risk of HIV by providing people who inject drugs (PWID) with sterile injecting equipment. A recent review of reviews (ROR) concluded that there was only tentative evidence to support the effectiveness of NSP in reducing HIV. We carried out a systematic review and meta-analysis to assess the association between NSP and HIV transmission. METHODS: Relevant primary articles presenting data on the risk of HIV transmission associated with NSP were identified in two stages: (i) from reviews identified in two published RORs (covering the period 1980-2008); and (ii) a literature search of CINAHL, Cochrane Library, EMBASE, MEDLINE and PsychINFO for primary articles published since the most recent high quality review (covering the period 2008-12). Study results were synthesized using random-effects meta-analysis. RESULTS: There were 12 studies comprising at least 12 000 person-years of follow-up. Exposure to NSP was associated with a reduction in HIV transmission: pooled effect size 0·66 [95% confidence interval (CI) 0·43, 1·01] across all studies, and 0·42 (95% CI 0·22, 0·81) across six higher quality studies (according to the Newcastle-Ottawa tool). CONCLUSIONS: There is evidence to support the effectiveness of NSP in reducing the transmission of HIV among PWID, although it is likely that other harm reduction interventions have also contributed to the observed reduction in HIV risk. NSP should be considered as just one component of a programme of interventions to reduce both injecting risk and other types of HIV risk behaviour.

Treatment of hepatitis C virus infection among people who are actively injecting drugs: a systematic review and meta-analysis.

BACKGROUND: Although guidelines recommend that people who inject drugs (PWID) should not be excluded from hepatitis C (HCV) treatment, some services remain reluctant to treat PWID. The aim of this review was to investigate sustained virologic response (SVR), adherence, discontinuation, and HCV reinfection among PWID. METHODS: A search of Medline, Embase, and Cochrane databases (between 2002 and January 2012) was conducted for primary articles/conference abstracts examining HCV treatment outcomes in PWID. Meta-analysis was used to obtain pooled estimates of SVR, adherence, discontinuation, and HCV reinfection. RESULTS: Ten primary articles and 1 conference abstract met the inclusion criteria. Across 6 studies (comprising 314 drug users, of whom 141 [45%] were PWID), pooled SVR was 56% (95% confidence interval [CI], 50%-61%) for all genotypes, 37% (95% CI, 26%-48%) for genotypes 1/4, and 67% (95% CI, 56%-78%) for genotypes 2/3. Pooled 80/80/80 adherence was 82% (95% CI, 74%-89%) across 2 studies, and pooled treatment discontinuation was 22% (95% CI, 16%-27%) across 4 studies. Across 5 studies (comprising 131 drug users) examining reinfection, pooled risk was 2.4 (95% CI, .9-6.1) per 100 person-years. CONCLUSIONS: HCV treatment outcomes are acceptable in PWID, supporting treatment guidelines. The pooled estimate of HCV reinfection risk was low, but there was considerable uncertainty around this estimate. Further studies on the risk of reinfection are needed to assess the long-term effectiveness of HCV treatment in PWID.

A retrospective study of secondary bacteraemia in hospitalised adults with community acquired non-typhoidal Salmonella gastroenteritis.

BACKGROUND: The clinical significance of bacteraemia secondary to non-typhoidal Salmonella (NTS) gastroenteritis in hospitalised adults is uncertain. METHODS: Adults admitted to a hospital in Liverpool, UK, with NTS gastroenteritis were identified using hospital discharge data and laboratory records. Patients with known HIV infection were excluded. Risk factors for a complicated or fatal course were determined. RESULTS: Between 1982 and 2006 inclusive, 633 adults were identified. Serovars causing infection included Enteritidis (46.6%), Typhimurium (27.6%) and Virchow (4.9%). A blood culture was taken in 364 (57.5%) patients who were generally sicker than those who were not cultured. Bacteraemia was detected in 63 (17.3%) patients who had blood cultures taken (63/633 (10.0%) of all patients). Bacteraemia was more common in those aged ≥ 65 years (p < 0.001) and in those aged < 65 years who had an underlying chronic disease. A complicated course occurred in 91 (25.0%) patients who had had a blood culture taken (148/633 (23.4%) of all patients). Independent factors associated with a complicated or fatal course among the patients investigated with a blood culture were bacteraemia (Adjusted Odds Ratio 5.34, 95% CI 2.86-9.95); new onset confusion or coma (AOR 4.80, 95% CI 1.91-12.07); prolonged symptoms prior to admission (AOR 2.48, 95% CI 1.44-4.27); dehydration (AOR1.90, 95% CI 1.07-3.38); and absence of fever (AOR 0.56, 95% CI 0.32-0.95). The 30 day attributable case fatality for all patients was 1.5%. CONCLUSIONS: In this study secondary bacteraemia, as well as other clinical factors, was independently associated with a complicated or fatal course in non-HIV infected adults admitted to hospital with NTS gastroenteritis.