Publications by authors named "Evan B Cunningham"

30 Publications

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Evaluation of hepatitis C treatment-as-prevention within Australian prisons (SToP-C): a prospective cohort study.

Lancet Gastroenterol Hepatol 2021 Jul 7;6(7):533-546. Epub 2021 May 7.

The Kirby Institute, UNSW Sydney, Sydney, NSW, Australia. Electronic address:

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.
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http://dx.doi.org/10.1016/S2468-1253(21)00077-7DOI Listing
July 2021

Elbasvir and grazoprevir for hepatitis C virus genotype 1 infection in people with recent injecting drug use (DARLO-C): An open-label, single-arm, phase 4, multicentre trial.

Health Sci Rep 2020 Jun 15;3(2):e151. Epub 2020 Mar 15.

Viral Hepatitis Clinical Research Program The Kirby Institute, UNSW Sydney Sydney Australia.

Background And Aims: Direct-acting antiviral therapy for hepatitis C virus (HCV) is effective, but few prospective studies among people with ongoing injecting drug use exist. This study evaluated the efficacy of elbasvir/grazoprevir in people with HCV genotype 1/4 (G1/4) infection and recent injecting drug use. An exploratory aim evaluated the feasibility of fingerstick point-of-care HCV RNA testing prior to and following treatment.

Methods: DARLO-C (http://clinicaltrials.gov: NCT02940691) is an open-label phase 4 trial. Participants were recruited between May 2017 and March 2018 from two drug treatment clinics, two hospital clinics, and one community clinic in Australia. Inclusion criteria included recent injection drug use (previous 6 months) and HCV G1/4 infection. Exclusion criteria included prior HCV treatment and decompensated liver disease. Participants received elbasvir/grazoprevir once-daily for 12 weeks. The primary endpoint was undetectable HCV RNA 12 weeks post-treatment (SVR). Fingerstick whole-blood samples were tested using the Xpert HCV Viral Load Fingerstick (Xpert HCV VL Fingerstick) assay and compared to the Aptima HCV Quant Dx Assay on plasma samples.

Results: Of a planned 150 participants, 32 were enrolled due to slower than anticipated recruitment [median age 46 years, 10 (31%) female, 29 (91%) G1a]. Eighteen (56%) were receiving opioid agonist therapy and 29 (91%) injected in the previous month. Twenty-six (81%) of 32 completed treatment (lost to follow-up, n = 5; incarceration, n = 1). There were no virological failures. Twenty-four (75%, 95% CI 59%-91%) of 32 achieved SVR. Two participants who completed treatment did not have SVR (loss to follow-up, n = 1; refused test, n = 1). Among paired samples (n = 36), sensitivity of the Xpert HCV VL Fingerstick assay for HCV RNA detection was 100.0% (95% CI 75.3%-100.0%) and specificity was 95.7% (95% CI 78.1%-99.9%).

Conclusion: Elbasvir/grazoprevir is effective among people with HCV G1 with recent injecting drug use. Implementation of point-of-care HCV RNA testing was feasible, but the high error rate requires investigation.
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http://dx.doi.org/10.1002/hsr2.151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136479PMC
June 2020

Reinfection Following Successful Direct-acting Antiviral Therapy for Hepatitis C Virus Infection Among People Who Inject Drugs.

Clin Infect Dis 2021 04;72(8):1392-1400

The Kirby Institute, University of New South Wales Sydney, Sydney, Australia.

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.
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http://dx.doi.org/10.1093/cid/ciaa253DOI Listing
April 2021

Global systematic review and ecological analysis of HIV in people who inject drugs: National population sizes and factors associated with HIV prevalence.

Int J Drug Policy 2020 03 14;77:102656. Epub 2020 Jan 14.

National Drug and Alcohol Research Centre, University of New South Wales Sydney, Sydney 2052, NSW Australia.

Background: People 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.

Methods: We 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.

Results: Four 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.

Conclusion: The 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.
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http://dx.doi.org/10.1016/j.drugpo.2019.102656DOI Listing
March 2020

Associations between national development indicators and the age profile of people who inject drugs: results from a global systematic review and meta-analysis.

Lancet Glob Health 2020 01;8(1):e76-e91

National Addiction Centre, King's College London, London, UK.

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<0·0001). Urban population growth was associated with higher age at IDU initiation (1·40 years per annual percentage change, 0·41-2·40). No associations were identified between indicators of IDU in young people and youth unemployment, Gini coefficient, or opioid substitution therapy coverage provision at the country level. No associations were identified between injecting and sexual risk behaviours and age of PWID.

Interpretation: Variation in the age profile of PWID was associated with GDP and urbanisation. Regions with the highest prevalence of young PWID (aged ≤25 years) had low coverage of interventions to prevent the spread of blood-borne viruses. Data quality highlights the need for improvements in monitoring of PWID populations.

Funding: Australian National Drug and Alcohol Research Centre, Australian National Health and Medical Research Council, Open Society Foundation, WHO, the Global Fund, UNAIDS, National Institute for Health Research Health Protection Research Unit for Evaluation of Interventions, Wellcome Trust.
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http://dx.doi.org/10.1016/S2214-109X(19)30462-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7024964PMC
January 2020

Hepatitis C reinfection after successful antiviral treatment among people who inject drugs: A meta-analysis.

J Hepatol 2020 04 27;72(4):643-657. Epub 2019 Nov 27.

The Kirby Institute, UNSW Sydney, Sydney, NSW, Australia.

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.
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http://dx.doi.org/10.1016/j.jhep.2019.11.012DOI Listing
April 2020

Adherence to Once-daily and Twice-daily Direct-acting Antiviral Therapy for Hepatitis C Infection Among People With Recent Injection Drug Use or Current Opioid Agonist Therapy.

Clin Infect Dis 2020 10;71(7):e115-e124

The Kirby Institute, University of New South Wales, Sydney, Australia.

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 (<90% adherent) between dosing patterns.

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 (<90% adherent). Recent stimulant injecting (odds ratio [OR], 2.48 [95% confidence interval {CI}, 1.28-4.82]), unstable housing (OR, 2.18 [95% CI, 1.01-4.70]), and twice-daily dosing (OR, 2.81 [95% CI, 1.47-5.36]) were associated with nonadherence. Adherence decreased during therapy. Sustained virologic response was high in nonadherent (89%) and adherent populations (95%, P = .174), with no difference in SVR between those who did and did not miss 7 consecutive doses (92% vs 93%, P = .897).

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.
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http://dx.doi.org/10.1093/cid/ciz1089DOI Listing
October 2020

Combined treatment and prevention strategies for hepatitis C virus elimination in the prisons in New South Wales: a modelling study.

Addiction 2020 05 12;115(5):901-913. Epub 2019 Nov 12.

Viral Immunology Systems Program, Kirby Institute, University of New South Wales, Sydney, NSW, Australia.

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.
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http://dx.doi.org/10.1111/add.14830DOI Listing
May 2020

Patterns of Drug and Alcohol Use and Injection Equipment Sharing Among People With Recent Injecting Drug Use or Receiving Opioid Agonist Treatment During and Following Hepatitis C Virus Treatment With Direct-acting Antiviral Therapies: An International Study.

Clin Infect Dis 2020 05;70(11):2369-2376

Kirby Institute, University of New South Wales, Australia.

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.
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http://dx.doi.org/10.1093/cid/ciz633DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7245153PMC
May 2020

Treatment adherence and support for people who inject drugs taking direct-acting antiviral therapy for hepatitis C infection.

J Viral Hepat 2019 11 13;26(11):1301-1310. Epub 2019 Aug 13.

Kirby Institute, UNSW Sydney, Sydney, NSW, Australia.

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.
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http://dx.doi.org/10.1111/jvh.13175DOI Listing
November 2019

Direct-acting antiviral treatment for hepatitis C, reinfection and mortality among people attending an inner-city community health centre in Victoria, Canada.

Int J Drug Policy 2019 10 6;72:106-113. Epub 2019 Jun 6.

Cool Aid Community Health Centre, Victoria, Canada.

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.
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http://dx.doi.org/10.1016/j.drugpo.2019.03.001DOI Listing
October 2019

A Global Meta-analysis of the Prevalence of HIV, Hepatitis C Virus, and Hepatitis B Virus Among People Who Inject Drugs-Do Gender-Based Differences Vary by Country-Level Indicators?

J Infect Dis 2019 06;220(1):78-90

National Drug and Alcohol Research Centre, Australia.

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.
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http://dx.doi.org/10.1093/infdis/jiz058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6775227PMC
June 2019

Acceptability and preferences of point-of-care finger-stick whole-blood and venepuncture hepatitis C virus testing among people who inject drugs in Australia.

Int J Drug Policy 2018 11 25;61:23-30. Epub 2018 Oct 25.

The Kirby Institute, UNSW Sydney, Sydney, New South Wales, Australia.

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.
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http://dx.doi.org/10.1016/j.drugpo.2018.08.011DOI Listing
November 2018

Paritaprevir, ritonavir, ombitasvir, and dasabuvir with and without ribavirin in people with HCV genotype 1 and recent injecting drug use or receiving opioid substitution therapy.

Int J Drug Policy 2018 12 29;62:94-103. Epub 2018 Oct 29.

The Kirby Institute, UNSW Sydney, Wallace Wurth Building, UNSW NSW 2052, Australia.

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-naïve 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.
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http://dx.doi.org/10.1016/j.drugpo.2018.10.004DOI Listing
December 2018

Adherence to sofosbuvir and velpatasvir among people with chronic HCV infection and recent injection drug use: The SIMPLIFY study.

Int J Drug Policy 2018 12 22;62:14-23. Epub 2018 Oct 22.

The Kirby Institute, UNSW Sydney, Sydney, Australia.

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 (<90% adherent) as measured by electronic blister-pack assessed using logistic regression and generalised estimating equations (continuous) with detailed analyses of dosing dynamics.

Results: Among 103 participants, 97% (n = 100) completed treatment. Median adherence to therapy was 94%. Overall, 32% (n = 33) were considered non-adherent (<90% adherence). Adherence significantly decreased over the course of therapy. Recent stimulant injecting (cocaine and/or amphetamines) at treatment initiation and during treatment was independently associated with non-adherence. Inconsistent dose timing (standard deviation of daily dose timing of ≥240 min) was also independently associated with non-adherence to therapy. Factors associated with inconsistent dose timing included lower levels of education and recent stimulant injecting. SVR was similar among adherent and non-adherent populations (94% vs. 94%, P = 0.944).

Conclusion: This study demonstrated high adherence to once-daily sofosbuvir/velpatasvir therapy among a population of people with recent injecting drug use. Recent stimulant injecting prior to and during DAA therapy and inconsistent dose-timing during treatment was associated with non-adherence. However, there was no impact of non-adherence on response to therapy, suggesting that adherence is not a significant barrier to successful DAA therapy in people with recent injecting drug use.
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http://dx.doi.org/10.1016/j.drugpo.2018.08.013DOI Listing
December 2018

Australia on track to achieve WHO HCV elimination targets following rapid initial DAA treatment uptake: A modelling study.

J Viral Hepat 2019 01 14;26(1):83-92. Epub 2018 Nov 14.

Kirby Institute, UNSW Sydney, Sydney, NSW, Australia.

Subsidized direct-acting antiviral (DAA) treatment recently became available to all adults living with chronic hepatitis C virus (HCV) in Australia. Based on rapid uptake (32 600 people initiated DAA in 2016), we estimated the impact on HCV epidemiology and mortality in Australia and determined if Australia can meet the WHO HCV elimination targets by 2030. Using a mathematical model, we simulated pessimistic, intermediate and optimistic DAA treatment scenarios in Australia over 2016-2030. We assumed treatment and testing rates were initially higher for advanced fibrosis and the same across HCV transmission risk level sub-populations. We also assumed constant testing rates after 2016. We compared the results to the 2015 level and a counterfactual (IFN-based) scenario. During 2016-2030, we estimated an intermediate DAA treatment scenario (2016, 32 600 treated; 2017, 21 370 treated; 2018 17 100 treated; 2019 and beyond, 13 680 treated each year) would avert 40 420 new HCV infections, 13 260 liver-related deaths (15 320 in viraemic; -2060 in cured) and 10 730 HCC cases, equating to a 53%, 63% and 75% reduction, respectively, compared to the IFN-based scenario. The model also estimated that Australia will meet the WHO targets of incidence and treatment by 2028. Time to a 65% reduction in liver-related mortality varied considerably between HCV viraemic only cases (2026) and all cases (2047). Based on a feasible DAA treatment scenario incorporating declining uptake, Australia should meet key WHO HCV elimination targets in 10 to15 years. The pre-DAA escalation in those with advanced liver disease makes the achievement of the liver-related mortality target difficult.
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http://dx.doi.org/10.1111/jvh.13013DOI Listing
January 2019

Direct-acting antiviral treatment for hepatitis C among people who use or inject drugs: a systematic review and meta-analysis.

Lancet Gastroenterol Hepatol 2018 11 21;3(11):754-767. Epub 2018 Sep 21.

The Kirby Institute, UNSW Sydney, Sydney, New South Wales, Australia.

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.
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http://dx.doi.org/10.1016/S2468-1253(18)30304-2DOI Listing
November 2018

Global, regional, and country-level estimates of hepatitis C infection among people who have recently injected drugs.

Addiction 2019 01 28;114(1):150-166. Epub 2018 Aug 28.

National Drug and Alcohol Research Centre, UNSW Sydney, Sydney, NSW, Australia.

Background And Aims: 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.

Methods: 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.

Results: 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).

Conclusions: Although, globally, 39.2% of people with recent injecting drug use are living with hepatitis C virus (HCV) and 8.5% of all HCV infections occur globally among people with recent injecting drug use, there is wide variation among countries and regions.
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http://dx.doi.org/10.1111/add.14393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6657799PMC
January 2019

Longitudinal injecting risk behaviours among people with a history of injecting drug use in an Australian prison setting: The HITS-p study.

Int J Drug Policy 2018 04 24;54:18-25. Epub 2018 Jan 24.

The Kirby Institute, UNSW Sydney, Sydney, Australia.

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.
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http://dx.doi.org/10.1016/j.drugpo.2017.12.013DOI Listing
April 2018

Sofosbuvir and velpatasvir for hepatitis C virus infection in people with recent injection drug use (SIMPLIFY): an open-label, single-arm, phase 4, multicentre trial.

Lancet Gastroenterol Hepatol 2018 03 6;3(3):153-161. Epub 2018 Jan 6.

Auckland City Hospital, Auckland, New Zealand.

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 <12 IU/mL), analysed in all patients who received at least one dose. This study is registered with ClinicalTrials.gov, number NCT02336139, and follow-up is ongoing to evaluate the secondary endpoint of HCV reinfection.

Findings: Between March 29, and Oct 31, 2016, we enrolled 103 participants; 29 (28%) of whom were female, nine (9%) had cirrhosis, 36 (35%) had HCV genotype 1, five (5%) had genotype 2, 60 (58%) had genotype 3, and two (2%) had genotype 4. 61 (59%) participants were receiving opioid substitution therapy during the study, 76 (74%) injected in the past month, and 27 (26%) injected at least daily in the past month. 100 (97%) of 103 participants completed treatment; two people were lost to follow-up and one person died from an overdose. There were no virological failures. 97 (94%, 95% CI 88-98) of 103 people achieved SVR12. Three participants with an end-of-treatment response did not have a SVR; two were lost to follow-up and one had reinfection. Drug use before and during treatment did not affect SVR12. Treatment-related adverse events were seen in 48 (47%) patients (one grade 3, no grade 4). Seven (7%) patients had at least one serious adverse event; only one such event (rhabdomyolysis, resolved) was possibly related to the therapy. One case of HCV reinfection was observed.

Interpretation: HCV treatment should be offered to PWID, irrespective of ongoing drug use. Recent injection drug use should not be used as a reason to withhold reimbursement of HCV therapy.

Funding: Gilead Sciences.
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http://dx.doi.org/10.1016/S2468-1253(17)30404-1DOI Listing
March 2018

Global, regional, and country-level coverage of interventions to prevent and manage HIV and hepatitis C among people who inject drugs: a systematic review.

Lancet Glob Health 2017 12 23;5(12):e1208-e1220. Epub 2017 Oct 23.

National Drug and Alcohol Research Centre, UNSW Sydney, Sydney, NSW, Australia.

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 (<100 needle-syringes distributed per PWID per year; <20 OST recipients per PWID per year). Data on HIV testing were sparser than for NSP and OST, and very few data were available to estimate ART access among PWID living with HIV. Globally, we estimate that there are 33 (uncertainty interval [UI] 21-50) needle-syringes distributed via NSP per PWID annually, and 16 (10-24) OST recipients per 100 PWID. Less than 1% of PWID live in countries with high coverage of both NSP and OST (>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.
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http://dx.doi.org/10.1016/S2214-109X(17)30373-XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5683737PMC
December 2017

Global prevalence of injecting drug use and sociodemographic characteristics and prevalence of HIV, HBV, and HCV in people who inject drugs: a multistage systematic review.

Lancet Glob Health 2017 12 23;5(12):e1192-e1207. Epub 2017 Oct 23.

National Drug and Alcohol Research Centre, UNSW Sydney, Sydney, NSW, Australia.

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 9·0% (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.
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http://dx.doi.org/10.1016/S2214-109X(17)30375-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5683738PMC
December 2017

Restrictions for reimbursement of interferon-free direct-acting antiviral drugs for HCV infection in Europe.

Lancet Gastroenterol Hepatol 2018 02 3;3(2):125-133. Epub 2017 Oct 3.

Department of Gastroenterology and Hepatology, Ziekenhuis Oost Limburg, Genk, Belgium; Department of Medicine and Life Sciences, University of Hasselt, Hasselt, Belgium; Department of Hepatology, UZ Leuven, Leuven, Belgium.

All-oral direct-acting antiviral drugs (DAAs) for hepatitis C virus, which have response rates of 95% or more, represent a major clinical advance. However, the high list price of DAAs has led many governments to restrict their reimbursement. We reviewed the availability of, and national criteria for, interferon-free DAA reimbursement among countries in the European Union and European Economic Area, and Switzerland. Reimbursement documentation was reviewed between Nov 18, 2016, and Aug 1, 2017. Primary outcomes were fibrosis stage, drug or alcohol use, prescriber type, and HIV co-infection restrictions. Among the 35 European countries and jurisdictions included, the most commonly reimbursed DAA was ombitasvir, paritaprevir, and ritonavir, with dasabuvir, and with or without ribavirin (33 [94%] countries and jurisdictions). 16 (46%) countries and jurisdictions required patients to have fibrosis at stage F2 or higher, 29 (83%) had no listed restrictions based on drug or alcohol use, 33 (94%) required a specialist prescriber, and 34 (97%) had no additional restrictions for people co-infected with HIV and hepatitis C virus. These findings have implications for meeting WHO targets, with evidence of some countries not following the 2016 hepatitis C virus treatment guidelines by the European Association for the Study of Liver.
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http://dx.doi.org/10.1016/S2468-1253(17)30284-4DOI Listing
February 2018

Interventions to enhance testing, linkage to care and treatment uptake for hepatitis C virus infection among people who inject drugs: A systematic review.

Int J Drug Policy 2017 09 7;47:34-46. Epub 2017 Aug 7.

The Kirby Institute, UNSW Sydney, Sydney, New South Wales, Australia.

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.
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http://dx.doi.org/10.1016/j.drugpo.2017.07.002DOI Listing
September 2017

Changes in risk behaviours during and following treatment for hepatitis C virus infection among people who inject drugs: The ACTIVATE study.

Int J Drug Policy 2017 09 19;47:230-238. Epub 2017 Jun 19.

The Kirby Institute, UNSW Sydney, Australia.

Background: 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).

Methods: 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.

Results: 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).

Conclusions: 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.
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http://dx.doi.org/10.1016/j.drugpo.2017.05.040DOI Listing
September 2017

Efficacy of response-guided directly observed pegylated interferon and self-administered ribavirin for people who inject drugs with hepatitis C virus genotype 2/3 infection: The ACTIVATE study.

Int J Drug Policy 2017 09 16;47:177-186. Epub 2017 Jun 16.

The Kirby Institute, UNSW Sydney, Sydney, New South Wales, Australia.

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.
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http://dx.doi.org/10.1016/j.drugpo.2017.05.020DOI Listing
September 2017

Adherence to response-guided pegylated interferon and ribavirin for people who inject drugs with hepatitis C virus genotype 2/3 infection: the ACTIVATE study.

BMC Infect Dis 2017 06 13;17(1):420. Epub 2017 Jun 13.

The Kirby Institute, UNSW Sydney, Sydney, NSW, Australia.

Background: The aims of this analysis were to investigate treatment completion and adherence among people with ongoing injecting drug use or receiving opioid substitution therapy (OST) in a study of response-guided therapy for chronic HCV genotypes 2/3 infection.

Methods: ACTIVATE was a multicenter clinical trial recruited between 2012 and 2014. Participants with genotypes 2/3 were treated with directly observed peg-interferon alfa-2b (PEG-IFN) and self-administered ribavirin for 12 (undetectable HCV RNA at week 4) or 24 weeks (detectable HCV RNA at week 4). Outcomes included treatment completion, PEG-IFN adherence, ribavirin adherence, and sustained virological response (SVR, undetectable HCV RNA >12 weeks post-treatment).

Results: Among 93 people treated, 59% had recently injected drugs (past month), 77% were receiving OST and 56% injected drugs during therapy. Overall, 76% completed treatment. Mean on-treatment adherence to PEG-IFN and ribavirin were 98.2% and 94.6%. Overall, 6% of participants missed >1 dose of PEG-IFN and 31% took <95% of their prescribed ribavirin., Higher treatment completion was observed among those receiving 12 vs. 24 weeks of treatment (97% vs. 46%, P < 0.001) while the proportion of participants with 95% on-treatment ribavirin adherence was similar between groups (67% vs. 72%, P = 0.664). Receiving 12 weeks of therapy was independently associated with treatment completion. No factors were associated with 95% RBV adherence. Neither recent injecting drug use at baseline nor during therapy was associated with treatment completion or adherence to ribavirin. In adjusted analysis, treatment completion was associated with SVR (aOR 23.9, 95% CI 2.9-193.8).

Conclusions: This study demonstrated a high adherence to directly observed PEG-IFN and self-administered ribavirin among people with ongoing injecting drug use or receiving OST. These data also suggest that shortening therapy from 24 to 12 weeks can lead to improved treatment completion. Treatment completion was associated with improved response to therapy. ACTIVATE trial registration number: NCT01364090 - May 31, 2011.
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http://dx.doi.org/10.1186/s12879-017-2517-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5470219PMC
June 2017

Hepatitis C virus core antigen: A simplified treatment monitoring tool, including for post-treatment relapse.

J Clin Virol 2017 07 11;92:32-38. Epub 2017 May 11.

The Kirby Institute, UNSW Sydney, Sydney, Australia. Electronic address:

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.
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http://dx.doi.org/10.1016/j.jcv.2017.05.007DOI Listing
July 2017

Methamphetamine injecting is associated with phylogenetic clustering of hepatitis C virus infection among street-involved youth in Vancouver, Canada.

Drug Alcohol Depend 2015 Jul 20;152:272-6. Epub 2015 Apr 20.

Viral Hepatitis Clinical Research Program, The Kirby Institute, UNSW Australia, Sydney, NSW, Australia.

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.
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http://dx.doi.org/10.1016/j.drugalcdep.2015.04.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4461061PMC
July 2015

Mixed HCV infection and reinfection in people who inject drugs--impact on therapy.

Nat Rev Gastroenterol Hepatol 2015 Apr 17;12(4):218-30. Epub 2015 Mar 17.

The Kirby Institute, UNSW Australia, Sydney, NSW 2052, Australia.

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.
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http://dx.doi.org/10.1038/nrgastro.2015.36DOI Listing
April 2015