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Franco et al. Hepatoma Res 2018;4:74 I http://dx.doi.org/10.20517/2394-5079.2018.94 Page 5 of 18

[99]
treatment) and social isolation . People living with HCV are frequently blamed for the disease, putting
themselves at risk to acquire HIV infection, and viewed as irresponsible, not accountable, “unworthy” [100,101] .
Perceived and real stigma towards HCV, within families and workplaces, affect self-esteem and quality of
life, causes delay or impediment to timely diagnosis and treatment, and leads to continuing risk of disease
transmission [102] . The response to stigma requires broad-based, societal educational efforts in order to in-
crease the understanding of this disease, still connected to several pejorative stereotypes [103,104] . These efforts
are expected to bring greater compassion, patient-centered healthcare, and improved coping skills to people
[105]
living with HCV .

Among the 71 million people infected globally, there is a large burden of HCV infection among PWID, with
a 50% prevalence of chronic infection, representing an estimated 5.6 million individuals - 8% of all infections
globally [106] . There is also a large and unquantified number of chronic infections among PWID who have
ceased injecting, and HCV morbidity and mortality continues to rise among recent and former PWID [107] .
In 2015, there were 1.7 million new HCV infections globally - this is a greater number than patients who
were started on treatment in the same year - with 23% of these new infections attributable to current inject-
ing drug use in many settings [9,108-111] . Along with unsafe healthcare practices and injections, intravenous
drug use is a leading contributor to HCV incidence, especially in the European and Eastern Mediterranean
[9]
Regions . Even in areas of the world where the incidence was low in 2015, an increase in transmission may
occur at any time, due to epidemic spread associated with injection drug use. Despite years of HCV decline
in the US, the incidence of HCV infection doubled between 2010 and 2014, due to an intensifying opioid
epidemic and rise in injecting drug use behavior [112] . The number of reported cases of acute HCV among
persons reporting injection drug use has increased, particularly in rural areas [113,114] . In the US, injection
drug use among PWID has resulted in rapid dissemination of HIV and HCV, as well as some transmission
of hepatitis B virus (HBV) [115,116] . There have been few studies evaluating the HCV cascade of care among
PWID, and contemporary studies from Australia and Kentucky has similarly shown high prevalence of anti-
body positivity, poor rates of viral load confirmation and minimal rates of treatment uptake, both during the
interferon era and in the first few years of the DAA era [117,118] . In the Netherlands, access and reimbursement
for DAA therapy occurred earlier (since 2014) than many other countries, and cohorts of PWID have been
well-characterized. Despite rates of viral load testing as high as 95% among seropositive individuals, DAA
uptake has remained low, largely limited by fibrosis staging restrictions that were in effect until October 2015
and subsequently lifted [119] .

Transmission of HCV among men who have sex with men (MSM) infected with HIV has also been reported
in Europe, Australia and the US as well as reinfection among HIV-infected MSM who were successfully
cured with treatment for hepatitis [120,121] . No estimates are available to quantify how much this emerging is-
sue contributes to the overall transmission of HCV [122,123] . The observed risk of reinfection in HIV-infected
MSM during the interferon era ranged from 5.3 to 13.2/100 persons years [121,124,125] , including subgroups with
multiple HCV reinfections and at risk of transmission of HCV virus with resistant variants [121,126] . These re-
infection rates are higher than the rates observed in retrospective and prospective studies of PWID treated
for chronic HCV infection, ranging from 1.21 to 4.9/100 persons years [127-130] . The role of HIV infection in
increasing the risk of HCV reinfection is likely associated with an approximately threefold reduction in
rates of spontaneous clearance following acute HCV infection, as well as high-risk sexual practices among
predominantly male cohorts representing HIV-infected MSM [131,132] . Traditionally, individuals at risk of rein-
fection have been grouped as either HIV-infected MSM or PWID; however, there is clearly a subset of HIV-
infected men who both use injection drugs and have sex with men. As such, interventions targeted at both
safer sexual practices and safer drug use practices are indicated among HIV-infected MSM.

HCV is highly prevalent among incarcerated populations, with global prevalence over 10%, and considerably
higher among incarcerated PWID [133-135] . Globally, more than 10 million people are incarcerated on a daily
basis, with many more annually, making prisons a key setting for implementation of HCV elimination strat-