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Background The aim of this analysis was to calculate the incidence of hepatitis C virus (HCV) reinfection and associated factors among 2 clinical trials of HCV direct-acting antiviral treatment in people with recent injecting drug use or currently receiving opioid agonist therapy (OAT). Methods Participants who achieved an end-of-treatment response in 2 clinical trials of people with recent injecting drug use or currently receiving OAT (SIMPLIFY and D3FEAT) enrolled between March 2016 and February 2017 in 8 countries were assessed for HCV reinfection, confirmed by viral sequencing. Incidence was calculated using person-time of observation and associated factors were assessed using Cox proportional hazard models. Results Seventy-three percent of the population at risk of reinfection (n = 177; median age, 48 years; 73% male) reported ongoing injecting drug use. Total follow-up time at risk was 254 person-years (median, 1.8 years; range, 0.2–2.8 years). Eight cases of reinfection were confirmed for an incidence of 3.1/100 person-years (95% confidence interval [CI], 1.6–6.3) overall and 17.9/100 person-years (95% CI, 5.8–55.6) among those who reported sharing needles/syringes. Younger age and needle/syringe sharing were associated with HCV reinfection. Conclusions These data demonstrate the need for ongoing monitoring and improved strategies to prevent HCV reinfection following successful treatment among people with ongoing injecting drug use to achieve HCV elimination. Clinical Trials Registration NCT02336139 and NCT02498015.

Summary: Background: Globally, an estimated 15·6 million people inject drugs. We aimed to investigate global variation in the age profile of people who inject drugs (PWID), identify country-level factors associated with age of PWID, and assess the association between injecting drug use (IDU) in young people and rates of injecting and sexual risk behaviours at the country level. Methods: We derived data from a previously published global systematic review done in April, 2016 (and updated in June, 2017) on the percentage of young PWID, duration of IDU, average age of PWID, average age at IDU initiation, and the percentage of PWID reporting sexual and injecting risk behaviours. We also derived national development indicators from World Bank data. We estimated the percentage of young PWID for each country, using a random-effects meta-analysis (DerSimonian-Laird methodology) and generated pooled regional and global estimates for all indicators of IDU in young people. We used univariable and multivariable generalised linear models to test for associations between the age indicators and country urban population growth, youth unemployment percentage, the percentage of PWID who are female, the percentage of the general population aged 15–24 years, Gini coefficient, opioid substitution therapy coverage (per PWID per year), gross domestic product (GDP) per capita (US$1000), and sexual and injecting risk behaviours. Findings: In the original systematic review, data on age of PWID was reported in 741 studies across 93 countries. Globally, 25·3% (95% uncertainty interval [UI] 19·6–31·8) of PWID were aged 25 years or younger. The highest percentage of young PWID resided in eastern Europe (43·4%, 95% UI 39·4–47·4), and the lowest percentage resided in the Middle East and north Africa (6·9%, 5·1–8·8). At the country level, in multivariable analysis higher GDP was associated with longer median injecting duration (0·11 years per $1000 GDP increase, 95% CI 0·04–0·18; p=0·002), and older median age of PWID (0·13 years per $1000 increase, 0·06–0·20; p

Background Direct-acting antiviral (DAA) treatment for hepatitis C virus (HCV) has been shown to be effective among PWID, but more real-world data on treatment outcomes is needed. The aim of this analysis was to assess the efficacy of DAA therapy, and the rate of reinfection and mortality among people attending an inner-city community health centre in Victoria, Canada. Methods In this retrospective study, patients treated with DAA therapy between November 2014 and Dec 31, 2017 were included. Retrospective chart review was performed to assess recent injecting drug use (IDU, previous six months) or receipt of opioid agonist treatment (OAT). The primary endpoint was Sustained Virologic Response (SVR12). Secondary endpoints included HCV reinfection and mortality. Results Of 270 patients who initiated DAA treatment (31% female), 20% (n=54) had HIV/HCV coinfection, 32% (n=84) had cirrhosis, 67% (n=181) had genotype 1, 6% (n=15) had genotype 2, 26% (n=69) had genotype 3. 46% (n=125) of patients were receiving OAT and 49% (n=132) reported recent IDU. 98% (n=265) completed treatment; two people stopped due to mental health, two people died, and one was non-adherent. 92% (249 of 270) achieved SVR12. 16 patients with End of Treatment (EOT) response did not have a SVR12; 7 were lost to follow-up; 2 people refused bloodwork; 2 people died; 1 had reinfection; and 4 had viral relapse. There was no difference in SVR12 by OAT (OAT, 93% vs. no OAT, 91%, P=0.435), recent injecting drug use (yes, 92% vs. no, 92%, P=0.904), or HIV status (HIV, 92% vs. no HIV, 94%, P=0.498). Eight cases of HCV reinfection were observed over 253 person-years of follow up (3.2 cases per 100 person-years; 95% CI 1.6-6.3). Twenty people died (6.3 per 100 person-years; 95% CI 3.9-10.3), including two during therapy (drug overdose, n=2) and 18 following therapy completion (drug overdose, n=7). Conclusion This study demonstrates that DAA treatment is effective among a marginalized population receiving care in an inner-city community health centre. The high mortality in this study highlights the importance of integrating HCV care within a framework addressing drug-related harms, preventing overdose mortality, addressing social inequalities, and improving the health of PWID.

A community-based public health facility in Sydney, Australia, the Kirketon Road Centre (KRC), provides health care to people who inject drugs (PWID), homeless and other marginalized people. Since March 2016, KRC has provided treatment for chronic hepatitis C virus (HCV) with direct-acting antivirals (DAAs). We aimed to evaluate treatment adherence amongst clients taking DAAs in a highly marginalized population. All clients who commenced DAA therapy prior to March 2018 at KRC were included in this observational cohort with a subset of clients attending daily or weekly for enhanced adherence support and dosing. Demographic, behavioural, clinical measures and medication dosing were recorded, and adherence was calculated as the proportion of doses taken during the expected treatment duration. Factors associated with adherence were examined using logistic regression. A total of 242 individuals commenced DAA therapy, of whom 79 (32%) received enhanced adherence support. Enhanced support was associated with homelessness, daily injecting, Aboriginality, mental health co-morbidity and poly-drug use (all P < .001). Overall adherence was 86%, and 92% of patients missed one or more doses (median 10, IQR 4-24). At least 90% adherence during planned duration was seen in 38%, but increased to 66% by continuing therapy beyond planned duration. Intention-to-treat SVR12 was 68% and 66% in the enhanced adherence support sub-population, with 29% lost to follow-up by SVR12 testing. There were only 2 (0.8%) documented virological failures. Per-protocol SVR12 was 99% and 96% in the enhanced adherence support sub-population. In conclusion, adherence support may benefit those with multiple markers of marginalization. Extension of therapy beyond planned duration is a pragmatic strategy to enhance completion. Strategies to improve follow-up, particularly post-treatment are required.

Background Women-specific factors exist that increases vulnerability to drug-related harms from injection drug use, including blood-borne viruses (BBVs), but gender-based differences in BBV prevalence have not been systematically examined. Methods We conducted meta-analyses to estimate country, regional, and global prevalence of serologically confirmed human immunodeficiency virus (HIV), hepatitis C virus (HCV; based on detection of anti-HCV antibody), and hepatitis B virus (HBV; based on detection of HBV surface antigen) in people who inject drugs (PWID), by gender. Gender-based differences in the BBV prevalence (calculated as the risk among women relative to the risk among men) were regressed on country-level prevalence and inequality measures (Gender inequality index, Human development index, Gini coefficient, and high, low or middle income of the country). Results Gender-based differences varied by countries and regions. HIV prevalence was higher among women than men in sub-Saharan Africa (relative risk [RR], 2.8; 95% confidence interval [CI], 1.8–4.4) and South Asia (RR, 1.7; 95% CI, 1.1–2.7); anti-HCV was lower among women in the Middle East and North Africa (RR, 0.6; 95% CI, .5–.7) and East and Southeast Asia (RR, 0.8; 95% CI, .7–.9). Gender-based differences varied with country-levels of the BBV prevalence in the general population, human development, and income distribution. Conclusion HIV was more prevalent in women who inject drugs as compared to their male counterparts in some countries, but there is variation between and within regions. In countries where women are at higher risks, there is a need to develop gender-sensitive harm-reduction services for the particularly marginalized population of women who inject drugs.

Summary Background Limited empirical evidence exists for the effectiveness of hepatitis C virus (HCV) treatment-as-prevention. The Surveillance and Treatment of Prisoners with hepatitis C (SToP-C) study aimed to assess the effect of HCV treatment-as-prevention in the prison setting. Methods SToP-C was a prospective study, including a before-and-after analysis, within a cohort of people incarcerated in two maximum-security prisons (male) and two medium-security prisons (one male, one female) in New South Wales, Australia. All prison inmates aged at least 18 years were eligible for enrolment. After HCV testing, participants were monitored for risk behaviours and HCV infection, among three sub-populations: uninfected (HCV antibody-negative); previously infected (HCV antibody-positive, HCV RNA-negative); and infected (HCV antibody and HCV RNA-positive). Uninfected participants were followed up every 3–6 months to detect HCV primary infection and previously infected participants were followed up every 3–6 months to detect re-infection. Participants with HCV infection were assessed for treatment, initially standard-of-care treatment (administered by prison health services) from 2014 to mid-2017, then direct-acting antiviral (DAA) treatment scale-up from mid-2017 onwards (12 weeks of sofosbuvir plus velpatasvir, administered through SToP-C). Participants were followed up until study closure in November, 2019. The primary study outcome was HCV incidence before and after DAA treatment scale-up among participants at risk of HCV primary infection or re-infection. This study is registered with ClinicalTrials.gov, NCT02064049. Findings Between Oct 30, 2014, and Sept 30, 2019, 3691 participants were enrolled in the SToP-C study. 719 (19%) participants had detectable HCV RNA, 2240 (61%) were at risk of primary HCV infection, and 725 (20%) were at risk of re-infection at baseline. DAA treatment was initiated in 349 (70%) of 499 eligible participants during the treatment scale-up period. The HCV incidence analysis comprised 1643 participants at risk of HCV infection or re-infection during longitudinal follow-up (median age 33 years [IQR 27–42]; 1350 [82%] male). 487 (30%) of 1643 participants reported injecting drugs in prison. HCV incidence decreased from 8·31 per 100 person-years in the pre-treatment scale-up period to 4·35 per 100 person-years in the post-treatment scale-up period (incidence rate ratio [IRR] 0·52 [95% CI 0·36–0·78]; p=0·0007). The incidence of primary infection decreased from 6·64 per 100 person-years in the pre-treatment scale-up period to 2·85 per 100 person-years in the post-treatment scale-up period (IRR 0·43 [95% CI 0·25–0·74]; p=0·0019), whereas the incidence of re-infection decreased from 12·36 per 100 person-years to 7·27 per 100 person-years (0·59 [0·35–1·00]; p=0·050). Among participants reporting injecting drugs during their current imprisonment, the incidence of primary infection decreased from 39·08 per 100 person-years in the pre-treatment scale-up period to 14·03 per 100 person-years in the post-treatment scale-up period (IRR 0·36 [95% CI 0·16–0·80]; p=0·0091), and the incidence of re-infection decreased from 15·26 per 100 person-years to 9·34 per 100 person-years (0·61 [0·34–1·09]; p=0·093). The adjusted analysis (adjusted for age, Indigenous Australian ethnicity, duration of stay in prison, previous imprisonment, injecting drug use status, and prison site) indicated a significant reduction in the risk of HCV infection between the pre-DAA treatment scale-up and post-DAA treatment scale-up periods (adjusted hazard ratio 0·50 [95% CI 0·33–0·76]; p=0·0014). Interpretation DAA treatment scale-up was associated with reduced HCV incidence in prison, indicative of a beneficial effect of HCV treatment-as-prevention in this setting. These findings support broad DAA treatment scale-up within incarcerated populations. Funding Australian National Health and Medical Research Council Partnership Project Grant and Gilead Sciences.

Background This study investigated adherence and associated factors among people with recent injection drug use (IDU) or current opioid agonist therapy (OAT) and compared once-daily to twice-daily hepatitis C virus (HCV) direct-acting antiviral (DAA) therapy. Methods SIMPLIFY and D3FEAT are international, multicenter studies that recruited participants with recent IDU (previous 6 months; SIMPLIFY, D3FEAT) or current OAT (D3FEAT) between March 2016 and February 2017 in 8 countries. Participants received sofosbuvir/velpatasvir (once daily; SIMPLIFY) or paritaprevir/ritonavir/ombitasvir, dasabuvir (twice daily) ± ribavirin (D3FEAT) for 12 weeks administered in electronic blister packs. We evaluated overall adherence (proportion of prescribed doses taken) and nonadherence ( Results Of 190 participants, 184 (97%) completed treatment. Median adherence was 92%, with higher adherence among those receiving once-daily vs twice-daily therapy (94% vs 87%, P = .005). Overall, 40% of participants (n = 76) were nonadherent ( Conclusions This study demonstrated high adherence to once- and twice-daily DAA therapy among people with recent IDU or currently receiving OAT. Nonadherence described did not impact treatment outcomes, suggesting forgiveness to nonadherence.

Background: Direct-acting antiviral therapy for hepatitis C virus (HCV) infection is safe and effective, but there are little data among people who have recently injected drugs. This study evaluated the efficacy, and safety of paritaprevir/ritonavir, ombitasvir, dasabuvir with or without ribavirin for chronic HCV genotype (G) 1 among people with recent injecting drug use and/or receiving OST. Methods: D3FEAT is an international open-label study that recruited treatment-naive participants with recent injecting drug use (previous 6 months) and/or receiving OST with chronic HCV G1 infection between June 2016 and February 2017 in seven countries. Participants received paritaprevir/ritonavir, ombitasvir, dasabuvir with (G1a) or without ribavirin (G1b) administered twice daily in a one-week electronic blister pack (records timing of each dose) for 12 weeks. The primary endpoint was undetectable HCV RNA 12 weeks post-treatment (SVR12). Results: Among 87 participants (median age 48 years), 23% were female, 8% had cirrhosis, and 90% had G1a. Overall, 71% were receiving OST, 61% injected in the previous six months, 45% injected in the previous month, and 15% injected > daily. Treatment completion was 97% (84 of 87). There were no virological breakthroughs, but three discontinuations (loss to follow-up, n = 1; non-adherence, n = 1; incarceration, n = 1). SVR was 91% (79 of 87, 95% CI, 83%–96%). Five participants who completed treatment did not have SVR (loss to follow-up, n = 1; death, n = 1; virologic relapse, n = 3). Drug use prior to and during treatment did not impact SVR12. Treatment-related adverse events were observed in 46 (53%) patients (six grade 3, no grade 4). Five (6%) patients had at least one serious adverse event (two possibly/probably related to therapy; nausea and myoclonus). Two cases of reinfection were observed. Conclusion: Paritaprevir/ritonavir, ombitasvir, and dasabuvir with or without ribavirin for 12 weeks is effective among people with HCV genotype 1 with recent injecting drug use and/or receiving OST.

BACKGROUND This study investigated treatment adherence among people with recent injecting drug use in a study of sofosbuvir/velpatasvir therapy for HCV infection. METHODS SIMPLIFY is an international open-label, single-arm multicentre study that recruited participants with recent injecting drug use (previous six months) and chronic HCV genotype (G) 1-6 infection between March and October 2016 in seven countries (19 sites). Participants received sofosbuvir/velpatasvir once-daily for 12 weeks administered in a one-week electronic blister pack (records the time and date of each dose) for 12 weeks. We evaluated non-adherence (

Background Uptake of hepatitis C virus (HCV) testing remains inadequate globally. Simplified point-of-care tests should enhance HCV diagnosis and elimination. We aimed to assess the acceptability of finger-stick and venepuncture HCV RNA testing among people who inject drugs (PWID). Methods Participants were enrolled in an observational cohort study with recruitment at 13 sites between June 2016 and February 2018. Capillary whole-blood collected by finger-stick and plasma collected by venepuncture were performed for Xpert® HCV viral load testing. Participants completed a questionnaire on acceptability of, and preferences for, blood collection methods. Results Among 565 participants (mean age, 44 years; 69% male), 64% reported injecting drugs in the last month, and 63% were receiving opioid substitution treatment. Eighty three percent reported that finger-stick testing was very acceptable. Overall, 65% of participants preferred finger-stick over venepuncture testing, with 61% of these preferring to receive results in 60 min. The most common reason for preferring finger-stick over venepuncture testing was it was quick (62%) followed by venous access difficulties (21%). The main reasons for preferring venepuncture over finger-stick testing were that it was quick (61%) and accurate (29%). Females were more likely to prefer finger-stick testing than males (adjusted OR 1.96; 95% CI 1.30, 2.99; p = 0.002). Among people with recent (previous month) injecting drug use, Aboriginal and/or Torres Strait Islander people were less likely than non-Aboriginal people to prefer finger-stick testing (adjusted OR 0.57; 95% CI 0.34, 0.9; p = 0.033). Conclusions Finger-stick whole-blood collection is acceptable to people who inject drugs, with males and Aboriginal and/or Torres Strait Islander people with recent injecting drug use less likely to prefer finger-stick testing. Further research is needed to evaluate interventions integrating simplified point-of-care HCV testing to engage people in care in a single-visit, thereby facilitating HCV treatment scale-up.

Summary Background There are concerns around poorer response to direct-acting antiviral (DAA) therapy for hepatitis C virus infection among people who use drugs. This systematic review assessed DAA treatment outcomes among people with recent drug use and those receiving opioid substitution therapy. Methods Bibliographic databases and conference presentations were searched for observational studies and clinical trials assessing DAA treatment completion, sustained virological response (SVR), and loss to follow-up among people with recent drug use (injecting or non-injecting) and those receiving opioid substitution therapy. Meta-analysis was used to pool estimates and meta-regression to explore heterogeneity. Findings 38 eligible studies, with 3634 participants, were included. The definition of recent drug use varied across studies, with drug use in the past 6 months and at the initiation of or during DAA therapy most commonly used. Among individuals with recent injecting or non-injecting drug use (21 studies; 1408 participants), treatment completion was 97·5% (95% CI 96·6–98·3) and SVR was 87·7% (95% CI 84·2–91·3). Among individuals receiving opioid substitution therapy (36 studies; 2987 participants), treatment completion was 97·4% (95% CI 96·5–98·3) and SVR was 90·7% (95% CI 88·5–93·0). Among individuals with recent injecting drug use (eight studies; 670 participants), treatment completion was 96·9% (95% CI 95·6–98·2) and SVR was 87·4% (95% CI 82·0–92·8). In meta-regression analysis, clinical trials (vs observational studies; adjusted odd ratio 2·18, 95% CI 1·27–3·75; p=0·006) and higher mean or median age (1·07, 1·02–1·12; p=0·008) were significantly associated with higher SVR. Clinical trials (0·45, 0·22–0·94; p=0·033) and older age (0·94, 0·88–0·99; p=0·034) were also significantly associated with a lower proportion of participants lost to follow-up. Interpretation Response to DAA therapy was favourable among people with recent drug use (including those who inject) and those receiving opioid substitution therapy, supporting broadening access in these populations. Funding The Kirby Institute, UNSW Sydney, and National Health and Medical Research Council of Australia.

usc Background: HCV transmission remains high in prisons globally. Understanding injecting risk behaviours in prisons is crucial to effectively develop and implement HCV prevention programs in this setting including treatment as prevention. Methods: HITS-p is a cohort study which enrolled people with a history of injecting drug use in prisons in NSW, Australia from 2005 to 2013. Participants completed an interview at enrolment and follow-up visits to determine injecting behaviours. Generalized estimating equation (GEE) and logistic regression methods were used to assess injecting risk behaviours prior to and following prison entry and to investigate injecting risk behaviours in prison. Results: Overall, 499 participants with a history of injecting drug use were included (median age, 26 years; 65% male). Participants were significantly less likely to inject drugs following incarceration. Among injectors, participants were less likely to inject ≥weekly but more likely to share a needle/syringe. At enrolment, the proportion reporting any injecting, ≥weekly injecting, and needle/syringe sharing in prison was highest among younger individuals. Younger age was associated with both re-initiation and continuation of injecting drug use following prison entry. Among those continuously imprisoned, younger age was associated with increased odds of any injecting, ≥weekly injecting, and sharing a needle/syringe. Conclusions: Upon entry to prison, injecting drug use decreased but syringe sharing increased among injectors. Younger individuals are most likely to exhibit high-risk injecting behaviours in prison. These data highlight the need for improved HCV prevention strategies (including improved needle/syringe access and scale up of HCV therapy) for those at increased risk of HCV transmission in prison, including younger individuals. Refereed/Peer-reviewed

BACKGROUND Despite revised guidelines that no longer exclude people who inject drugs (PWID) from treatment for hepatitis C virus (HCV) infection, many clinicians are reluctant to treat recent PWID. This study aimed to evaluate the efficacy of sofosbuvir and velpatasvir therapy in people with chronic HCV infection and recent injection drug use. METHODS In this open-label, single-arm phase 4 trial (SIMPLIFY), we recruited participants with recent injection drug use (past 6 months) and chronic HCV genotype 1-6 infection from seven countries (19 sites). Participants received oral sofosbuvir (400 mg) and velpatasvir (100 mg) once daily for 12 weeks. Therapy was given in 1-week electronic blister packs to record the time and date of each dose. The primary endpoint was the proportion of patients with sustained virological response 12 weeks after completion of treatment (SVR12; defined as HCV RNA

BACKGROUND: People who inject drugs (PWID) are a key population affected by the global HIV and hepatitis C virus (HCV) epidemics. HIV and HCV prevention interventions for PWID include needle and syringe programmes (NSP), opioid substitution therapy (OST), HIV counselling and testing, HIV antiretroviral therapy (ART), and condom distribution programmes. We aimed to produce country-level, regional, and global estimates of coverage of NSP, OST, HIV testing, ART, and condom programmes for PWID. METHODS: We completed searches of peer-reviewed (MEDLINE, Embase, and PsycINFO), internet, and grey literature databases, and disseminated data requests via social media and targeted emails to international experts. Programme and survey data on each of the named interventions were collected. Programme data were used to derive country-level estimates of the coverage of interventions in accordance with indicators defined by WHO, UNAIDS, and the UN Office on Drugs and Crime. Regional and global estimates of NSP, OST, and HIV testing coverage were also calculated. The protocol was registered on PROSPERO, number CRD42017056558. FINDINGS: In 2017, of 179 countries with evidence of injecting drug use, some level of NSP services were available in 93 countries, and there were 86 countries with evidence of OST implementation. Data to estimate NSP coverage were available for 57 countries, and for 60 countries to estimate OST coverage. Coverage varied widely between countries, but was most often low according to WHO indicators (200 needle-syringes distributed per PWID and >40 OST recipients per 100 PWID). INTERPRETATION: Coverage of HIV and HCV prevention interventions for PWID remains poor and is likely to be insufficient to effectively prevent HIV and HCV transmission. Scaling up of interventions for PWID remains a crucial priority for halting the HIV and HCV epidemics. FUNDING: Open Society Foundations, The Global Fund, WHO, UNAIDS, United Nations Office on Drugs and Crime, Australian National Drug and Alcohol Research Centre, University of New South Wales Sydney

The risk of hepatitis C virus (HCV) reinfection due to continued injecting risk behaviours might remain a barrier to HCV treatment among people who inject drugs. We aimed to evaluate changes in risk behaviours during and following HCV treatment among people with ongoing injecting drug use or receiving opioid substitution treatment (OST).ACTIVATE was an international multicentre clinical trial conducted between 2012 and 2014. Participants with HCV genotypes 2/3 infection were treated with peg-interferon/ribavirin for 12 or 24 weeks and completed a self-administered behavioural questionnaire at each study visit. The impact of time in treatment and follow-up on longitudinally measured recent (past month) behavioural outcomes was evaluated using generalized estimating equations.Among 93 enrolled participants (83% male, median age 41 years), 55 (59%) had injected in the past month. Any injecting drug use decreased during HCV treatment and follow-up (OR 0.89 per incremental study visit; 95% CI 0.83-0.95). No significant changes were found in ≥daily injecting (OR 0.98; 95% CI 0.89-1.07), use of non-sterile needles (OR 0.94; 95% CI 0.79-1.12), sharing of injecting paraphernalia (OR 0.87; 95% CI 0.70-1.07) or non-injecting drug use (OR 1.01; 95% CI 0.92-1.10). Hazardous alcohol use decreased throughout (OR 0.56; 95% CI 0.40-0.77) and OST increased between enrolment and end of treatment (OR 1.48; 95% CI 1.07-2.04).Recent injecting drug use and hazardous alcohol use decreased, while OST increased during and following HCV treatment among participants with ongoing injecting drug use. These findings support further expansion of HCV care among PWID.

Background The burden of hepatitis C virus (HCV) infection is escalating among people who inject drugs (PWID), yet testing and treatment remains suboptimal. The aim of this systematic review was to evaluate the effectiveness of interventions to enhance HCV testing, linkage to care, and treatment uptake among PWID. Methods A systematic literature search of Medline (Ovid 1946 – present), Embase, Global Health, Cochrane Central Register of Controlled Trials, PsycINFO, Clinical Trials Registry, and Web of Science was conducted covering interventional studies published before 20 July 2016. Studies evaluating interventions to enhance HCV testing, linkage to care or treatment among PWID were included. Data from included studies was extracted by one reviewer and checked by a second reviewer with disagreements discussed until consensus was reached. Relative risk ratios and corresponding confidence intervals were generated for studies included in analysis. Results After adjusting for duplicates, 10,116 records were identified. A total of 14 studies were included for analysis, of which 57% were randomised controlled trials. Interventions to enhance HCV testing included on-site testing with pre-test counselling and education; and dried blood spot testing. Interventions to enhance linkage to care included facilitated referral for HCV assessment and scheduling of specialist appointments for clients. Interventions to enhance HCV treatment uptake included integrated HCV care, drug use and psychiatric services delivered by a multidisciplinary team with case management services, with or without non-invasive liver disease assessment. All studies were conducted in the interferon treatment era and there were no studies conducted in low- and middle-income countries. Conclusions In the direct acting antiviral treatment era, well-designed studies evaluating interventions to enhance a simplified care cascade are crucial in facilitating treatment scale-up.

Background There are few data on treatment for hepatitis C virus (HCV) infection among people with ongoing injecting drug use. This study evaluated the efficacy of response-guided therapy for chronic HCV genotypes 2/3 infection among people with ongoing injecting drug use or receiving opioid substitution therapy (OST). A secondary aim was to identify predictors of HCV treatment response. Methods ACTIVATE was a multicentre clinical trial recruited between 2012 and 2014. Participants with genotypes 2/3 were treated with directly observed peg-interferon alfa-2b and self-administered ribavirin for 12 (undetectable HCV RNA at week 4) or 24 weeks (detectable HCV RNA at week 4). Participants were recruited from drug treatment clinics, private practices, hospital clinics and community clinics in Australia, Canada, and five countries in Europe. The primary study outcome was sustained virological response (SVR, undetectable HCV RNA >12 weeks post-treatment). Results Among 93 people with ongoing injecting drug use or receiving OST treated for HCV genotype 2/3, 59% had recently (past month) injected drugs, 77% were receiving OST and 56% injected drugs during therapy. Overall SVR was 66% (61/93). SVR was 84% in those with undetectable HCV RNA at week 4 (12 weeks) compared to 38% in those without (24 weeks). In adjusted analysis, cirrhosis vs. no/mild fibrosis [adjusted OR (aOR) 0.33, 95% CI 0.13, 0.86] predicted reduced SVR, while response at week 4 was associated with increased SVR [aOR 8.11, 95% CI 2.73, 24.10]. Recent injecting drug use at baseline or during therapy was not associated with SVR. Conclusion This study demonstrates that people with recent injecting drug use or OST with chronic HCV can achieve responses to interferon-based therapy similar to other populations, despite injecting drugs prior to or during therapy. Cirrhosis was predictive of reduced response to HCV therapy, while response at week 4 (despite shortened therapy) was predictive of improved response.

usc Hepatitis C virus (HCV) transmission is high in prisons. This study investigated trends in HCV incidence and associated factors among a cohort of prisoners with a history of injecting drug use in New South Wales, Australia. Data were available from the Hepatitis C Incidence and Transmission Study—prisons (HITS-p) from 2005 to 2014. Temporal trends in HCV incidence were evaluated. Factors associated with time to HCV seroconversion among people with ongoing injecting was assessed using Cox proportional hazards. Among 320 antibody-negative participants with a history of injecting drug use (mean age 26; 72% male), 62% (n=197) reported injecting drug use during follow-up. Overall, 93 infections were observed. HCV incidence was 11.4/100 person-years in the overall population and 6.3/100 person-years among the continually imprisoned population. A stable trend in HCV incidence was observed. Among the overall population with ongoing injecting during follow-up, ≥weekly injecting drug use frequency was independently associated with time to HCV seroconversion. Among continuously imprisoned injectors with ongoing injecting during follow-up, needle/syringe sharing was independently associated with time to HCV seroconversion. This study demonstrates that prison is a high-risk environment for acquisition of HCV infection. Needle and syringe sharing was associated with HCV infection among continually imprisoned participants, irrespective of frequency of injecting or the type of drug injected. These findings highlight the need for the evaluation of improved HCV prevention strategies in prison, including needle/syringe programmes and HCV treatment. Refereed/Peer-reviewed

Background & Aims HCV reinfection following successful treatment can compromise treatment outcomes. This systematic review assessed the rate of HCV reinfection following treatment among people with recent drug use and those receiving opioid agonist therapy (OAT). Methods We searched bibliographic databases and conference abstracts for studies assessing post-treatment HCV reinfection rates among people with recent drug use (injecting or non-injecting) or those receiving OAT. Meta-analysis was used to cumulate reinfection rates and meta-regression was used to explore heterogeneity across studies. Results Thirty-six studies were included (6,311 person-years of follow-up). The overall rate of HCV reinfection was 5.9/100 person-years (95% CI 4.1–8.5) among people with recent drug use (injecting or non-injecting), 6.2/100 person-years (95% CI 4.3–9.0) among people recently injecting drugs, and 3.8/100 person-years (95% CI 2.5–5.8) among those receiving OAT. Reinfection rates were comparable following interferon-based (5.4/100 person-years; 95% CI 3.1–9.5) and direct-acting antiviral (3.9/100 person-years; 95% CI 2.5–5.9) therapy. In stratified analysis, reinfection rates were 1.4/100 person-years (95% CI 0.8–2.6) among people receiving OAT with no recent drug use, 5.9/100 person-years (95% CI 4.0–8.6) among people receiving OAT with recent drug use, and 6.6/100 person-years (95% CI 3.4–12.7) among people with recent drug use not receiving OAT. In meta-regression analysis, longer follow-up was associated with lower reinfection rate (adjusted rate ratio [aRR] per year increase in mean/median follow-up 0.77; 95% CI 0.69–0.86). Compared with people receiving OAT with no recent drug use, those with recent drug use receiving OAT (aRR 3.50; 95% CI 1.62–7.53), and those with recent drug use not receiving OAT (aRR 3.96; 95% CI 1.82–8.59) had higher reinfection rates. Conclusion HCV reinfection risk following treatment was higher among people with recent drug use and lower among those receiving OAT. The lower rates of reinfection observed in studies with longer follow-up suggested higher reinfection risk early post-treatment. Lay summary Our findings demonstrate that although reinfection by hepatitis C virus occurs following successful treatment in people with recent drug use, the rate of hepatitis C reinfection is lower than the rates of primary infection reported in the literature for this population – reinfection should not be used as a reason to withhold therapy from people with ongoing injecting drug use. The rate of hepatitis C reinfection was lowest among people receiving opioid agonist therapy with no recent drug use. These data illustrate that harm reduction services are required to reduce the reinfection risk, while regular post-treatment hepatitis C assessment is required for early detection and retreatment.

Background In many settings, recent or prior injection drug use remains a barrier to accessing direct-acting antiviral treatment (DAA) for hepatitis C virus (HCV) infection. We examined patterns of drug and alcohol use and injection equipment sharing among people with recent injecting drug use or receiving opioid agonist treatment (OAT) during and following DAA-based treatment. Methods SIMPLIFY and D3FEAT are phase 4 trials evaluating the efficacy of DAA among people with past 6-month injecting drug use or receiving OAT through a network of 25 international sites. Enrolled in 2016–2017, participants received sofosbuvir/velpatasvir (SIMPLIFY) or paritaprevir/ritonavir/dasabuvir/ombitasvir ± ribavirin (D3FEAT) for 12 weeks and completed behavioral questionnaires before, during, and up to 2 years posttreatment. The impact of time in HCV treatment and follow-up on longitudinally measured longitudinally measured behaviors was estimated using generalized estimating equations. Results At screening, of 190 participants (mean age, 47 years; 74% male), 62% reported any past-month injecting 16% past-month injection equipment sharing, and 61% current OAT. Median alcohol use was 2 (Alcohol Use Disorders Identification Test–Consumption; range, 1–12). During follow-up, opioid injecting (odds ratio [OR], 0.95; 95% confidence interval [CI], 0.92–0.99) and sharing (OR, 0.87; 95% CI, 0.80–0.94) decreased, whereas no significant changes were observed for stimulant injecting (OR, 0.98; 95% CI, 0.94–1.02) or alcohol use (OR, 0.99; 95% CI, 0.95–1.04). Conclusions Injecting drug use and risk behaviors remained stable or decreased following DAA-based HCV treatment. Findings further support expanding HCV treatment to all, irrespective of injection drug use. Clinical Trials Registration SIMPLIFY, NCT02336139; D3FEAT, NCT02498015.

Background People who inject drugs (PWID) do so at varying frequencies. More frequent injecting is associated with skin and soft tissue infection, blood borne viruses, and overdose. The aims of this review are to estimate the prevalence of injecting frequency among PWID and compare these estimates to current needle–syringe distribution coverage estimates, and identify socio-demographic and risk characteristics, and harms associated with daily or more injecting. Methods We conducted a systematic review of the peer-reviewed and grey literature from 2008 to 2018 and extracted needle–syringe distribution coverage data from a recent systematic review. We generated country-, region-, and global-level estimates of daily or more injecting. We also ran meta-regression analyses to determine associations between daily or more injecting and socio-demographic characteristics, injecting risk behaviour, non-fatal overdose, injection site skin infection, and blood borne virus prevalence. Results Our search resulted in 61,077 sources, from which 198 studies were eligible for inclusion in this review. There were 74 countries with estimates for injecting frequency. Globally, we estimated that 68.1% (95%CI 64.5-71.6%) of PWID, equating to approximately 10.5 (95% UI 6.8–15.0) million people, inject daily or more frequently. There was a higher percentage of participants reporting daily or more injecting among samples with shorter injecting careers, more male participants and higher reporting of opioids as their main drug injected. Daily or more injecting was also associated with samples reporting a higher prevalence of HIV and hepatitis C antibody (anti-HCV), non-fatal overdose, and receptive needle sharing in the previous month. Implications WHO recently recommended a needle–syringe distribution target of 300 needles per PWID per year which is unlikely to be sufficient for the majority of PWID injecting daily or more who are out of drug treatment. Funding The Australian National Drug and Alcohol Research Centre, Australian National Health and Medical Research Council, University of New South Wales

usc Background and aims: Australia is currently on track to meet the World Health Organization (WHO) global hepatitis C virus (HCV) elimination goals by 2030, reflecting universal subsidized access to testing and direct-acting antiviral (DAA) treatment. In New South Wales, DAA treatment in prisons has scaled-up substantially, with 1000 prisoners treated in 2017. However, HCV prevalence and incidence in this setting is high, which could undermine elimination efforts. This study aimed to test the preventative effects of DAA treatment scale-up, opiate substitution treatment (OST) and needle and syringe programme (NSP) strategies for prisons. Design: Modelling study using an individual-based mathematical model of a typical prison setting. The model was calibrated against Australian epidemiological data sets and executed in-prison events for each individual daily, including movements between prisons, changes in risk behaviour and uptake of prevention measures such as OST and NSP, as well as DAA treatment. Scenarios were projected from 2018 to 2030. Setting:New South Wales prisons. Participants: New South Wales prisoners. Measurements: Variables including prison populations, prevalence and incidence rate were calculated. Prisoners were described by demographic characteristics, HCV infection history, risk behaviours and accessing treatment and prevention measures in varied security settings. Findings: Increasing the number of prisoners treated for HCV to 2000 annually was projected to reduce the HCV incidence rate to 8.69 [95% confidence interval (CI) = 8.17, 9.20] per 100 person-years (100 p.y.). Combined treatment and prevention strategies were necessary to reduce the projected incidence rate to 5.22 (95% CI = 5.13, 5.52) per 100 p.y. Considering the expected reductions in the prevalence of chronic HCV in the Australian community, incidence rate was predicted to drop to 0.93 (95% CI = 0.92, 0.98) per 100 p.y. by 2030. Conclusions: This model, which simulates prison scenarios to inform Australia's national hepatitis C virus elimination efforts, suggests that continued direct-acting antiviral (coverage in the community combined with a moderate increase of direct-acting antiviral treatments in prisons, and introduction of improved harm reduction via opiate substitution treatment and/or needle and syringe programmes, makes hepatitis C virus elimination feasible in Australian prisons. Refereed/Peer-reviewed

People who have recently injected drugs are a priority population in efforts to achieve hepatitis C virus (HCV) elimination. This study estimated the prevalence and number of people with recent injecting drug use living with HCV, and the proportion of people with recent injecting drug use among all people living with HCV infection at global, regional, and country-levels. Data from a global systematic review of injecting drug use and HCV antibody prevalence among people with recent (previous year) injecting drug use were used to estimate the prevalence and number of people with recent injecting drug use living with HCV. These data were combined with a systematic review of global HCV prevalence to estimate the proportion of people with recent injecting drug use among all people living with HCV. There are an estimated 6.1 million [95% uncertainty interval (UI) 3.4-9.2] people with recent injecting drug use aged 15-64 years living with HCV globally (39.2% viraemic prevalence; UI 31.6-47.0), with the greatest numbers in East and Southeast Asia (1.5 million, UI 1.0-2.1), Eastern Europe (1.5 million, UI 0.7-2.4), and North America (1.0 million, UI 0.4-1.7). People with recent injecting drug use comprise an estimated 8.5% (UI 4.6-13.1) of all HCV infections globally, with the greatest proportions in North America (30.5%, UI 11.7-56.7), Latin America (22.0%, UI 15.3-30.4), and Eastern Europe (17.9%, UI 8.2-30.9). Although globally about forty percent of people with recent injecting drug use are living with hepatitis C virus (HCV) and almost nine percent of all HCV infections globally occur among people with recent injecting drug use, there is wide variation among countries and regions. National Drug and Alcohol Research Centre, UNSW Sydney; Australian National Health and Medical Research Council; John C Martin Foundation.

BackgroundPeople who inject drugs (PWID) are at elevated risk of HIV infection. Data on population sizes of PWID living with HIV are needed to inform the implementation of prevention, treatment and care programs. We estimated national population sizes of people who recently (past 12 months) injected drugs living with HIV and evaluated ecological associations with HIV prevalence in PWID.MethodsWe used national data on the prevalence of injecting drug use and of HIV among PWID, derived from systematic reviews, to estimate national population sizes of PWID living with HIV. Uncertainty was estimated using Monte Carlo simulation with 100,000 draws. We extracted data on sample characteristics from studies of HIV prevalence among PWID, and identified national indicators that have been observed or hypothesised to be associated with HIV prevalence in PWID. We used linear regression to evaluate associations between these variables and HIV prevalence in PWID.ResultsFour countries comprised 55% of the estimated global population of PWID living with HIV: Russia (572,500; 95% uncertainty interval (UI) 235,500–1,036,500); Brazil (462,000; 95% UI 283,500–674,500); China (316,500; 95% UI 171,500–493,500), and the United States (195,500; 95% UI 80,000–343,000). Greater anti-HCV prevalence and national income inequality were associated with greater HIV prevalence in PWID.ConclusionThe countries with the largest populations of PWID living with HIV will need to dramatically scale up prevention, treatment and care interventions to prevent further increases in population size. The association between anti-HCV prevalence and HIV prevalence among PWID corroborates findings that settings with increasing HCV should implement effective interventions to prevent HIV outbreaks. The association between income inequality and HIV among PWID reinforces the need to implement structural interventions alongside targeted individual-level strategies.

Background Among prospective cohorts of people who inject drugs (PWID), phylogenetic clustering of HCV infection has been observed. However, the majority of studies have included older PWID, representing distant transmission events. The aim of this study was to investigate phylogenetic clustering of HCV infection among a cohort of street-involved youth. Methods Data were derived from a prospective cohort of street-involved youth aged 14–26 recruited between 2005 and 2012 in Vancouver, Canada (At Risk Youth Study, ARYS). HCV RNA testing and sequencing (Core-E2) were performed on HCV positive participants. Phylogenetic trees were inferred using maximum likelihood methods and clusters were identified using ClusterPicker (Core-E2 without HVR1, 90% bootstrap threshold, 0.05 genetic distance threshold). Results Among 945 individuals enrolled in ARYS, 16% ( n = 149, 100% recent injectors) were HCV antibody positive at baseline interview ( n = 86) or seroconverted during follow-up ( n = 63). Among HCV antibody positive participants with available samples ( n = 131), 75% ( n = 98) had detectable HCV RNA and 66% ( n = 65, mean age 23, 58% with recent methamphetamine injection, 31% female, 3% HIV+) had available Core-E2 sequences. Of those with Core-E2 sequence, 14% ( n = 9) were in a cluster (one cluster of three) or pair (two pairs), with all reporting recent methamphetamine injection. Recent methamphetamine injection was associated with membership in a cluster or pair ( P = 0.009). Conclusion In this study of street-involved youth with HCV infection and recent injecting, 14% demonstrated phylogenetic clustering. Phylogenetic clustering was associated with recent methamphetamine injection, suggesting that methamphetamine drug injection may play an important role in networks of HCV transmission.

Summary Background Sharing of equipment used for injecting drug use (IDU) is a substantial cause of disease burden and a contributor to blood-borne virus transmission. We did a global multistage systematic review to identify the prevalence of IDU among people aged 15–64 years; sociodemographic characteristics of and risk factors for people who inject drugs (PWID); and the prevalence of HIV, hepatitis C virus (HCV), and hepatitis B virus (HBV) among PWID. Methods Consistent with the GATHER and PRISMA guidelines and without language restrictions, we systematically searched peer-reviewed databases (MEDLINE, Embase, and PsycINFO; articles published since 2008, latest searches in June, 2017), searched the grey literature (websites and databases, searches between April and August, 2016), and disseminated data requests to international experts and agencies (requests sent in October, 2016). We searched for data on IDU prevalence, characteristics of PWID, including gender, age, and sociodemographic and risk characteristics, and the prevalence of HIV, HCV, and HBV among PWID. Eligible data on prevalence of IDU, HIV antibody, HBsAg, and HCV antibody among PWID were selected and, where multiple estimates were available, pooled for each country via random effects meta-analysis. So too were eligible data on percentage of PWID who were female; younger than 25 years; recently homeless; ever arrested; ever incarcerated; who had recently engaged in sex work, sexual risk, or injecting risk; and whose main drugs injected were opioids or stimulants. We generated regional and global estimates in line with previous global reviews. Findings We reviewed 55 671 papers and reports, and extracted data from 1147 eligible records. Evidence of IDU was recorded in 179 of 206 countries or territories, which cover 99% of the population aged 15–64 years, an increase of 31 countries (mostly in sub-Saharan Africa and the Pacific Islands) since a review in 2008. IDU prevalence estimates were identified in 83 countries. We estimate that there are 15·6 million (95% uncertainty interval [UI] 10·2–23·7 million) PWID aged 15–64 years globally, with 3·2 million (1·6–5·1 million) women and 12·5 million (7·5–18·4 million) men. Gender composition varied by location: women were estimated to comprise 30·0% (95% UI 28·5–31·5) of PWID in North America and 33·4% (31·0–35·6) in Australasia, compared with 3·1% (2·1–4·1) in south Asia. Globally, we estimate that 17·8% (10·8–24·8) of PWID are living with HIV, 52·3% (42·4–62·1) are HCV-antibody positive, and 9·1% (5·1–13·2) are HBV surface antigen positive; there is substantial geographic variation in these levels. Globally, we estimate 82·9% (76·6–88·9) of PWID mainly inject opioids and 33·0% (24·3–42·0) mainly inject stimulants. We estimate that 27·9% (20·9–36·8) of PWID globally are younger than 25 years, 21·7% (15·8–27·9) had recently (within the past year) experienced homelessness or unstable housing, and 57·9% (50·5–65·2) had a history of incarceration. Interpretation We identified evidence of IDU in more countries than in 2008, with the new countries largely consisting of low-income and middle-income countries in Africa. Across all countries, a substantial number of PWID are living with HIV and HCV and are exposed to multiple adverse risk environments that increase health harms. Funding Australian National Drug and Alcohol Research Centre, Australian National Health and Medical Research Council, Open Society Foundation, World Health Organization, the Global Fund, and UNAIDS.

Background: Simple, affordable diagnostic tools are essential to facilitate global hepatitis C virus (HCV) elimination efforts. Objectives: This study evaluated the clinical performance of core antigen (HCVcAg) assay from plasma samples to monitor HCV treatment efficacy and HCV viral recurrence. Study design: Plasma samples from a study of response-guided pegylated-interferon/ribavirin therapy for people who inject drugs with chronic HCV genotype 2/3 infection were assessed for HCV RNA (AmpliPrep/COBAS Taqman assay, Roche) and HCVcAg (ARCHITECT HCV Ag, Abbott Diagnostics) during and after therapy. The sensitivity and specificity of the HCVcAg assay was compared to the HCV RNA assay (gold standard). Results: A total of 335 samples from 92 enrolled participants were assessed (mean 4 time-points per participant). At baseline, end of treatment response (ETR) and sustained virological response (SVR) visits, the sensitivity of the HCVcAg assay with quantifiable HCV RNA threshold was 94% (95% CI: 88%, 98%), 56% (21%, 86%) and 100%, respectively. The specificity was between 98 to 100% for all time-points assessed. HCVcAg accurately detected all six participants with viral recurrence, demonstrating 100% sensitivity and specificity. One participant with detectable (non-quantifiable) HCV RNA and non-reactive HCVcAg at SVR12 subsequently cleared HCV RNA at SVR24. Conclusions: HCVcAg demonstrated high sensitivity and specificity for detection of pre-treatment and post-treatment viraemia. This study indicates that confirmation of active HCV infection, including recurrent viraemia, by HCVcAg is possible. Reduced on-treatment sensitivity of HCVcAg may be a clinical advantage given the moves toward simplification of monitoring schedules. This study was funded by the Australian Government Department of Health and Ageing. The views expressed in this publication do not necessarily represent the position of the Australian Government. The Kirby Institute is affiliated with the Faculty of Medicine, University of New South Wales. The opinions expressed in this paper are those of the authors and do not necessarily represent that of Merck Sharp and Dohme. Support from Abbott Diagnostics for the supply of reagents is gratefully acknowledged. GD is supported by a National Health and Medical Research Council Practitioner Research Fellowships. JG is supported by a National Health and Medical Research Council Career Development Fellowship. BH is supported by a National Health and Medical Research Council Early Career Fellowship. The ARCHITECT HCV Ag kits for this study were kindly provided by Abbott.

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