Evan B. Cunningham

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

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 9·0% (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.

Mixed HCV infection and reinfection in people who inject drugs[mdash]impact on therapy

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.

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

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.

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

Summary 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.

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

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.

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

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.

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

[Marshall, A. D.; Cunningham, E. B.; Dore, G. J.; Grebely, J.] UNSW Sydney, Kirby Inst, Sydney, NSW, Australia. [Nielsen, S.] Freelance Epidemiologist, Madrid, Spain. [Aghemo, A.] Univ Milan, Fdn IRCCS CA Granda Osped Maggiore Policlin, Div Gastroenterol & Hepatol, Milan, Italy. [Alho, H.] Helsinki Univ Hosp, Abdominal Ctr, Helsinki, Finland. [Alho, H.] Univ Helsinki, Helsinki, Finland. [Backmund, M.] Univ Hosp Munich, Dept Med 2, Munich, Germany. [Bruggmann, P.] Arud Ctr Addict Med, Zurich, Switzerland. [Dalgard, O.] Univ Oslo, Akershus Univ Hosp, Dept Infect Dis, Oslo, Norway. [Dalgard, O.] Univ Oslo, Fac Med, Oslo, Norway. [Flisiak, R.] Med Univ Bialystok, Dept Infect Dis & Hepatol, Bialystok, Poland. [Foster, G.] Queen Mary Univ London, London, England. [Gheorghe, L.] Fundeni Clin Inst, Gastroenterol & Hepatol, Bucharest, Romania. [Goldberg, D.] Hlth Protect Scotland, Glasgow, Lanark, Scotland. [Goulis, I.] Dept Internal Med, Thessaloniki, Greece. [Hickman, M.] Univ Bristol, Social Med, Bristol, Avon, England. [Hoffmann, P.] Minist Hlth Luxembourg, Luxembourg, Luxembourg. [Jancoriene, L.] Vilnius Univ Hosp, Santariskiu Klin, Ctr Infect Dis, Vilnius, Lithuania. [Jarcuska, P.] Univ Hosp, Dept Internal Med 1, Kosice, Slovakia. [Jarcuska, P.] Univ Pavol Jozef Safarik, Kosice, Slovakia. [Kaberg, M.] Karolinska Univ Hosp, Dept Infect Dis, Stockholm, Sweden. [Makara, M.] St Istvan & St Laszlo Hosp, Hepatol Ctr, Budapest, Hungary. [Maimets, M.] Univ Tartu, Dept Internal Med, Tartu, Estonia. [Marinho, R.] Hosp Santa Maria, Med Sch Lisbon, Dept Gastroenterol & Hepatol, Lisbon, Portugal. [Maticic, M.] Univ Med Ctr, Clin Infect Dis & Febrile Illnesses, Ljubljana, Slovenia. [Norris, S.; Tait, M.] Dr Steevens Hosp, Natl Hepatitis Treatment Programme C, Hlth Serv Execut, Dublin, Ireland. [Olafsson, S.] Landspitali Univ Hosp, Dept Med, Div Gastroenterol, Reykjavik, Iceland. [Ovrehus, A.] Univ Southern Denmark, Odense Univ Hosp, Dept Infect Dis, Odense, Denmark. [Pawlotsky, J. -M.] Univ Paris Est, Hop Henri Mondor, Creteil, France. [Pocock, J.] Mater Hosp, Gastroenterol Dept, Msida, Malta. [Robaeys, G.] Ziekenhuis Oost Limburg, Dept Gastroenterol & Hepatol, Genk, Belgium. [Robaeys, G.] UHasselt, Dept Med & Life Sci, Hasselt, Belgium. [Robaeys, G.] UZLeuven, Dept Hepatol, Leuven, Belgium. [Roncero, C.] Univ Autonoma Barcelona, Hosp Univ Vall dHebron, Psychiat Serv, Addict & Dual Diag Unit, Barcelona, Spain. [Simonova, M.] Mil Med Acad, Dept Gastroenterol HPB Surg & Transplantol, Sofia, Bulgaria. [Sperl, J.] Inst Clin & Expt Med, Dept Hepatogastroenterol, Prague, Czech Republic. [Tolmane, I.] Infectol Ctr Latvia, Dept Hepatol, Riga, Latvia. [Tomaselli, S.] Off Publ Hlth, Vaduz, Liechtenstein. [van der Valk, M.] Acad Med Ctr, Dept Infect Dis, Amsterdam, Netherlands. [Vince, A.] Univ Zagreb, Sch Med, Univ Hosp Infect Dis, Zagreb, Croatia. [Lazarus, J. V.] Univ Copenhagen, Rigshosp, CHIP, Copenhagen, Denmark. [Lazarus, J. V.] Hosp Clin Barcelona, Barcelona Inst Global Hlth ISGlobal, Barcelona, Spain.

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

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.

Efficacy and safety of sofosbuvir/velpatasvir in people with chronic hepatitis C virus infection and recent injecting drug use: the SIMPLIFY study

Jason Grebely1, Olav Dalgard2, Brian Conway3, Evan Cunningham1, Philip Bruggmann4, Behzad Hajarizadeh1, Janaki Amin5, Philippa Marks1, Sophie Quiene1, Tanya L Applegate1, Julie Bruneau5, Margaret Hellard6, Alain Litwin7, Tracy Swan8, Jude Byrne9, Melanie Lacalamita10, Adrian Dunlop11, Gail V. Matthews1,12, Jeff Powis13, David Shaw14, Maria Christine Thurnheer10, Martin Weltman15, Ian Kronborg I16, Curtis Cooper C17, Jordan J Feld18, Chris Fraser19, John Dillon20, Phillip Read21, Ed Gane22 and Gregory J Dore1,12 on behalf of the SIMPLIFY Study Group

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

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.