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Globally, 130–170 million people have HCV infection; however, distribution patterns are highly variable. This Review outlines the latest information on the epidemiology and natural history of HCV infection. The disease burden and mortality of HCV-related diseases, and the potential effect of HCV treatment on disease burden, are also outlined. Worldwide, an estimated 130–170 million people have HCV infection. HCV prevalence is highest in Egypt at >10% of the general population and China has the most people with HCV (29.8 million). Differences in past HCV incidence and current HCV prevalence, together with the generally protracted nature of HCV disease progression, has led to considerable diversity in the burden of advanced liver disease in different countries. Countries with a high incidence of HCV or peak incidence in the recent past will have further escalations in HCV-related cirrhosis and hepatocellular carcinoma (HCC) over the next two decades. Acute HCV infection is difficult to detect because of the generally asymptomatic nature of the disease and the marginalization of at-risk populations. Around 25% of patients with acute HCV infection undergo spontaneous clearance, with increased rates among those with favourable IL28B genotypes, acute symptoms and in women. The remaining 75% of patients progress to chronic HCV infection and are subsequently at risk of progression to hepatic fibrosis, cirrhosis and HCC. Chronic hepatitis C generally progresses slowly in the initial two decades, but can be accelerated during this time as a result of advancing age and co-factors such as heavy alcohol intake and HIV co-infection. Key Points Although many countries in Asia have a low-to-intermediate prevalence of HCV, around half of the global population of patients infected with HCV reside in this region Many countries have 'ageing cohorts' of people with HCV owing to peak HCV incidences in the recent past (2000 in Australia, 1980s in the USA) or distant past (1920–1940s in Japan) Changes in levels of HCV RNA during acute HCV infection might guide early therapeutic intervention, with levels in patients with viral clearance or persistence diverging after 3–4 months of infection The disease progression of chronic HCV infection often accelerates after 20 years of infection, with lifestyle factors key drivers of hepatic fibrosis Direct-acting antiviral therapies should provide a paradigm shift in treatment over the next few years However, unless rates of diagnosis of HCV and access to treatment improve dramatically, direct-acting antivirals will have a limited effect on global disease burden

We summarise the evidence for medicinal uses of opioids, harms related to the extramedical use of, and dependence on, these drugs, and a wide range of interventions used to address these harms. The Global Burden of Diseases, Injuries, and Risk Factors Study estimated that in 2017, 40·5 million people were dependent on opioids (95% uncertainty interval 34·3–47·9 million) and 109 500 people (105 800–113 600) died from opioid overdose. Opioid agonist treatment (OAT) can be highly effective in reducing illicit opioid use and improving multiple health and social outcomes—eg, by reducing overall mortality and key causes of death, including overdose, suicide, HIV, hepatitis C virus, and other injuries. Mathematical modelling suggests that scaling up the use of OAT and retaining people in treatment, including in prison, could avert a median of 7·7% of deaths in Kentucky, 10·7% in Kiev, and 25·9% in Tehran over 20 years (compared with no OAT), with the greater effects in Tehran and Kiev being due to reductions in HIV mortality, given the higher prevalence of HIV among people who inject drugs in those settings. Other interventions have varied evidence for effectiveness and patient acceptability, and typically affect a narrower set of outcomes than OAT does. Other effective interventions focus on preventing harm related to opioids. Despite strong evidence for the effectiveness of a range of interventions to improve the health and wellbeing of people who are dependent on opioids, coverage is low, even in high-income countries. Treatment quality might be less than desirable, and considerable harm might be caused to individuals, society, and the economy by the criminalisation of extramedical opioid use and dependence. Alternative policy frameworks are recommended that adopt an approach based on human rights and public health, do not make drug use a criminal behaviour, and seek to reduce drug-related harm at the population level.

Key Points HCV prevalence and incidence among people who inject drugs (PWID) remains high Direct-acting antiviral agents (DAA) for HCV with cure in >95% provide a tool for addressing HCV-related liver-disease burden among PWID Adherence and response to DAA therapy among people receiving opioid substitution therapy (OST), including those with ongoing drug use, are comparable to other HCV-infected populations, although more data are required among current PWID who are not on OST HCV reinfection can occur, so strategies to maximize prevention of reinfection (including OST and needle and syringe programmes) and access to DAA retreatment are crucial Improved health services for PWID are needed to enhance HCV prevention, testing, access to care and treatment Continued global leadership and advocacy is required to ensure that HCV prevention, care and treatment for PWID are accessible to all Direct-acting antiviral agents (DAAs) are highly effective treatments for HCV, but are not always accessible to people who inject drugs (PWID). Here, Grebely and colleagues outline the epidemiology of HCV in PWID, discuss current data on DAA outcomes in this population and highlight steps required to broaden access to HCV therapy with the eventual goal of HCV elimination. Globally, 12 million people are estimated to have injected drugs in the past year, 50% of whom have chronic HCV infection, with people who have previously injected drugs presenting an additional large reservoir of infection. The availability of simple and tolerable interferon-free direct-acting antiviral agents (DAAs) for HCV infection, which have a cure rate of >95% represents one of the most exciting advances in clinical medicine in the past few decades. Adherence and response to DAA therapy among people who inject drugs (PWID) receiving opioid substitution therapy (OST) in clinical trials are comparable to populations without a history of injecting drugs. Further data are required among current PWID not receiving OST. Given the potential prevention benefits of treatment, DAAs have enhanced cost-effectiveness among PWID. As HCV therapy is expanded to populations of PWID with high-risk behaviours for re-exposure, acknowledgement that HCV reinfection will occur is crucial, and appropriate strategies must be in place to maximize prevention of reinfection and offer retreatment for reinfection. This Review will also discuss essential components for broadening access to HCV care for PWID as we strive for the global elimination of HCV infection.

The World Health Organization’s targets for eliminating hepatitis C virus by 2030 have been deemed ambitious by many. However, we believe they are achievable, provided they are supported by global commitment.

The management of acute HCV infection has not been standardized following the availability of direct-acting antiviral agents (DAAs) for chronic HCV infection, and substantial uncertainty exists regarding the optimal treatment regimen and duration. Despite the lack of direct evidence, the 2016 American Association for the Study of Liver Diseases (AASLD)–Infectious Diseases Society of America (IDSA) guidelines supported “the same regimens for acute HCV as recommended for chronic HCV infection … owing to high efficacy and safety”, whereas the 2016 European Association for the Study of the Liver (EASL) guidelines recommended sofosbuvir–ledipasvir, sofosbuvir–velpatasvir or sofosbuvir plus daclatasvir for 8 weeks in acute HCV infection, with a longer duration of 12 weeks recommended for those infected with HIV and/or baseline HCV RNA levels >1,000,000 IU/ml. This Review outlines the epidemiology, natural history and diagnosis of acute HCV infection and provides contemporary information on DAAs for acute and recent HCV infection. The Review also discusses the 2016 AASLD–IDSA and EASL recommendations for acute HCV infection management in light of available evidence and highlights key differences in study populations and design that influence interpretation. We focus on populations at high risk of HCV transmission and acquisition, including people who inject drugs and HIV-positive men who have sex with men, and highlight the potential effects of diagnosis and treatment of acute HCV infection in contributing to HCV elimination.

Australia was one of the first countries to introduce government-funded unrestricted access to direct-acting antiviral (DAA) therapy, with 88,790 treated since March 2016. However, treatment uptake is declining which could potentially undermine Australia’s progress towards the WHO HCV elimination targets. Using mathematical modelling, we updated estimates for those living with chronic HCV in Australia, new cases of decompensated cirrhosis (DC), hepatocellular carcinoma (HCC), and liver-related mortality among the HCV-cured and viraemic populations from 2015 to 2030. We considered various DAA treatment scenarios incorporating annual treatment numbers to 2020, and subsequent uptake per year of 6,790 (pessimistic), 8,100 (intermediate), and 11,310 (optimistic). We incorporated the effects of excess alcohol consumption and reduction in progression to DC and HCC among cirrhosis-cured versus viraemic individuals. At the end of 2020, we estimated 117,810 Australians were living with chronic HCV. New cases per year of DC, HCC, and liver-related mortality among the HCV viraemic population decreased rapidly from 2015 (almost eliminated by 2030). In contrast, the growing population size of those cured with advanced liver disease meant DC, HCC, and liver-related mortality declined slowly. The estimated reduction in liver-related mortality from 2015 to 2030 in the combined HCV viraemic and cured population is 25% in the intermediate scenario. With declining HCV treatment uptake and ongoing individual-level risk of advanced liver disease complications, including among cirrhosis-cured individuals, Australia is unlikely to achieve all WHO HCV elimination targets by 2030.

Key Points As a result of ongoing high-risk behaviours, people who inject drugs (PWID) might commonly harbour mixed HCV infections and are at risk of reinfection following spontaneous or treatment-induced clearance The sensitivity of assays used to screen for mixed infection in individual samples varies widely, particularly in their capacity to detect minor variants Mixed HCV infection among populations of PWID ranges from 14% to 39% when sensitive methods are used for detection and characterization Mixed infection has been shown to compromise interferon-based HCV therapy, but few studies are available to adequately assess how often this occurs HCV reinfection rates after successful interferon-based treatment among PWID are 0–5 cases per 100 person-years, but studies are limited by small sample sizes and heterogeneity in injecting risk after treatment Future studies are needed to evaluate the impact of mixed HCV infection and reinfection following treatment with direct acting antiviral HCV therapies among PWID HCV mixed infection and reinfection occur commonly in people who inject drugs (PWID). The authors review the epidemiology, natural history and methods used to detect mixed HCV infection in PWID. The potential effect of mixed infection and reinfection on treatment outcomes is discussed, as well as how future studies should be designed in the era of direct acting antiviral treatment of HCV. The majority of new and existing cases of HCV infection in high-income countries occur among people who inject drugs (PWID). Ongoing high-risk behaviours can lead to HCV re-exposure, resulting in mixed HCV infection and reinfection. Assays used to screen for mixed infection vary widely in sensitivity, particularly with respect to their capacity for detecting minor variants (<20% of the viral population). The prevalence of mixed infection among PWID ranges from 14% to 39% when sensitive assays are used. Mixed infection compromises HCV treatment outcomes with interferon-based regimens. HCV reinfection can also occur after successful interferon-based treatment among PWID, but the rate of reinfection is low (0–5 cases per 100 person-years). A revolution in HCV therapeutic development has occurred in the past few years, with the advent of interferon-free, but still genotype-specific regiments based on direct acting antiviral agents. However, little is known about whether mixed infection and reinfection has an effect on HCV treatment outcomes in the setting of new direct-acting antiviral agents. This Review characterizes the epidemiology and natural history of mixed infection and reinfection among PWID, methodologies for detection, the potential implications for HCV treatment and considerations for the design of future studies.

Hepatitis C virus (HCV) was discovered more than two decades ago, but progress towards a vaccine has been slow. HCV infection will spontaneously clear in about 25% of people. Studies of spontaneous HCV clearance in chimpanzees and human beings have identified host and viral factors that could be important in the control of HCV infection and the design of HCV vaccines. Although data from studies of chimpanzees suggest that protection against reinfection is possible after spontaneous clearance, HCV is a human disease. Results from studies of reinfection risk after spontaneous clearance in injecting drug users are conflicting, but some people seem to have protection against HCV persistence. To guide future vaccine development, we assess data from studies of HCV reinfection after spontaneous clearance, discuss flaws in the methods of previous human studies, and suggest essential components for future investigations of control of HCV infection.

Background Deimplementation, the removal or reduction of potentially hazardous approaches to care, is key to progressing social equity in health. While the benefits of opioid agonist treatment (OAT) are well-evidenced, wide variability in the provision of treatment attenuates positive outcomes. During the COVID-19 pandemic, OAT services deimplemented aspects of provision which had long been central to treatment in Australia; supervised dosing, urine drug screening, and frequent in-person attendance for review. This analysis explored how providers considered social inequity in health of patients in the deimplementation of restrictive OAT provision during the COVID-19 pandemic. Methods Between August and December 2020, semi-structured interviews were conducted with 29 OAT providers in Australia. Codes relating to the social determinants of client retention in OAT were clustered according to how providers considered deimplementation in relation to social inequities. Normalisation Process Theory was then used to analyse the clusters in relation to how providers understood their work during the COVID-19 pandemic as responding to systemic issues that condition OAT access. Results We explored four overarching themes based on constructs from Normalisation Process Theory: adaptive execution, cognitive participation, normative restructuring, and sustainment. Accounts of adaptive execution demonstrated tensions between providers’ conceptions of equity and patient autonomy. Cognitive participation and normative restructuring were integral to the workability of rapid and drastic changes within the OAT services. Key transformative actors included communities of practice and “thought leaders” who had long supported deimplementation for more humane care. At this early stage of the pandemic, providers had already begun to consider how this period could inform sustainment of deimplementation. When considering a future, post-pandemic period, several providers expressed discomfort at operating with “evidence-enough” and called for narrowly defined types of data on adverse events (e.g. overdose) and expert consensus on takeaway doses. Conclusions The possibilities for achieving social equity in health are limited by the divergent treatment goals of providers and people receiving OAT. Sustained and equitable deimplementation of obtrusive aspects of OAT provision require co-created treatment goals, patient-centred monitoring and evaluation, and access to a supportive community of practice for providers.

Background Injecting drug use is associated with considerable morbidity and mortality. Estimates of the size of the population of people who inject drugs are critical to inform service planning and estimate disease burden due to injecting drug use. We aimed to estimate the size of the population of people who inject drugs in Australia. Methods We applied a multiplier method which used benchmark data (number of people in opioid substitution therapy (OST) on a snapshot day in 2014) and multiplied it by a factor derived from the prevalence of current OST among people who inject drugs participating in the Australian Needle and Syringe Program Survey in 2014. Estimates of the total population of people who inject drugs were calculated in each state and territory and summed to produce a national estimate. We used the sex and age group distribution seen in datasets relating to people who inject drugs to derive sex- and age-stratified estimates, and calculated prevalence per 1000 population. Results Between 68,000 and 118,000 people aged 15–64 years inject drugs in Australia. The population prevalence of injecting drug use was 6.0 (lower and upper uncertainty intervals of 4.3 and 7.6) per 1000 people aged 15–64 years. Injecting drug use was more common among men than women, and most common among those aged 35–44 years. Comparison of expected drug-related deaths based on these estimates to actual deaths suggest that these figures may be underestimates. Conclusions These are the first indirect prevalence estimates of injecting drug use in Australia in over a decade. This work has identified that there are limited data available to inform estimates of this population. These estimates can be used as a basis for further work estimating injecting drug use in Australia.