Annual hepatitis C testing and positive tests among gay and bisexual men in Australia from 2016 to 2022: a serial cross-sectional analysis of sentinel surveillance data.

OBJECTIVE: Guidelines recommend annual hepatitis C virus (HCV) testing for gay and bisexual men (GBM) with HIV and GBM prescribed HIV pre-exposure prophylaxis (PrEP). However, there is a limited understanding of HCV testing among GBM. We aimed to examine trends in HCV testing and positivity from 2016 to 2022. METHODS: Using sentinel surveillance data, we examined the proportion of GBM with at least one test and the proportion with a positive test in each year for HCV antibody testing among GBM with no previous HCV positive test, HCV RNA testing among GBM with a positive antibody test but no previous positive RNA test (naïve RNA testing), and HCV RNA testing among people who had a previous RNA positive test and a subsequent negative test (RNA follow-up testing). Trends were examined using logistic regression from 2016 to 2019 and 2020 to 2022. RESULTS: Among GBM with HIV, from 2016 to 2019 antibody testing was stable averaging 55% tested annually. Declines were observed for both naïve HCV RNA testing (75.4%-41.4%: p<0.001) and follow-up HCV RNA testing (70.1%-44.5%: p<0.001). Test positivity declined for HCV antibody tests (2.0%-1.3%: p=0.001), HCV RNA naïve tests (75.4%-41.4%: p<0.001) and HCV RNA follow-up tests (11.3%-3.3%: p=0.001). There were minimal or no significant trends from 2020 to 2022.Among GBM prescribed PrEP, antibody testing declined from 2016 to 2019 (79.4%-69.4%: p<0.001) and was stable from 2020 to 2022. Naïve and follow-up HCV RNA testing was stable with an average of 55% and 60% tested each year, respectively. From 2016-2019, the proportion positive from HCV RNA naïve tests declined (44.1%-27.5%: p<0.046) with no significant change thereafter. Positive follow-up HCV RNA tests fluctuated with no or one new positive test among this group in most years. CONCLUSION: The proportion of GBM with positive HCV tests has declined, however a substantial proportion are not tested annually. A renewed focus on HCV testing, and treatment where required, is warranted to achieve HCV elimination among GBM in Australia.

Hepatitis C virus reinfection incidence among gay and bisexual men with HIV in Australia from 2016 to 2020.

BACKGROUND: There is some concern that hepatitis C virus (HCV) reinfection might impact HCV micro-elimination efforts among gay and bisexual men (GBM) with HIV. However, there is a limited understanding of reinfection incidence in the context of unrestricted government-funded HCV treatment. We aimed to estimate HCV reinfection incidence among GBM with HIV in Australia from 2016 to 2020. METHODS: Data were from 39 clinics participating in ACCESS, a sentinel surveillance network for blood borne viruses and sexually transmissible infections across Australia. GBM with HIV who had evidence of treatment or spontaneous clearance with at least one positive HCV RNA test, a subsequent negative HCV RNA test, and at least one additional HCV RNA test between 1st January 2016 and 31st December 2020 were eligible for inclusion. A new HCV RNA positive test and/or detectable viral load was defined as a reinfection. Generalised linear modelling was used to examine trends in reinfection. RESULTS: Among 12 213 GBM with HIV who had at least one HCV test, 540 were included in the reinfection incidence analysis, of whom 38 (7%) had evidence of reinfection during the observation period. Over 1124 person-years of follow-up, the overall rate of reinfection was 3.4/100PY (95% CI 2.5-4.6). HCV reinfection incidence declined on average 30% per calendar year (Incidence Rate Ratio 0.70, 95% CI 0.54-0.91). CONCLUSION: HCV reinfection incidence has declined among GBM with HIV in Australia since government-funded unrestricted DAAs were made available. Ongoing HCV RNA testing following cure and prompt treatment for anyone newly diagnosed is warranted to sustain this.

The Incidence of Hepatitis C Among Gay, Bisexual, and Other Men Who Have Sex With Men in Australia, 2009-2019.

BACKGROUND: Hepatitis C virus (HCV) infection has been reported among gay, bisexual, and other men who have sex with men (GBM) globally including GBM with human immunodeficiency virus (HIV) and HIV-negative GBM, particularly those using HIV preexposure prophylaxis (PrEP). In Australia, HCV direct-acting antiviral treatment (DAA) was government-funded from 2016. Large implementation studies of PrEP also began in 2016. We examined HCV incidence among GBM to assess whether HCV incidence has changed since 2015. METHODS: Data were drawn from the Australian Collaboration for Coordinated Enhanced Sentinel Surveillance. We included GBM who tested HCV antibody negative at their first test and had ≥1 subsequent test. Generalized linear modeling (Poisson distribution) was used to examine HCV incidence from 2009 to 2019 stratified by HIV status, and among HIV-negative GBM prescribed PrEP from 2016 to 2019. RESULTS: Among 6744 GBM with HIV, HCV incidence was 1.03 per 100 person-years (PY). Incidence declined by 78% in 2019 compared to 2015 (incidence rate ratio [IRR], 0.22 [95% confidence interval {CI}: .09-.55]). Among 20 590 HIV-negative GBM, HCV incidence was 0.20/100 PY, with no significant change over time. Among 11 661 HIV-negative GBM prescribed PrEP, HCV incidence was 0.29/100 PY. Compared to 2016, incidence among GBM prescribed PrEP declined by 80% in 2019 (IRR, 0.20 [95% CI: .06-.64]). CONCLUSIONS: HCV incidence among GBM living with HIV declined following DAA availability. There was no observed change in HCV incidence among HIV-negative GBM overall. Among GBM prescribed PrEP, incidence declined since the early years of PrEP implementation in Australia. Australia is on track to eliminate HCV among GBM before global 2030 targets.

Impact of COVID-19 lockdown restrictions on hepatitis C testing in Australian primary care services providing care for people who inject drugs.

In 2020, the Australian state of Victoria experienced the longest COVID-19 lockdowns of any jurisdiction, with two lockdowns starting in March and July, respectively. Lockdowns may impact progress towards eliminating hepatitis C through reductions in hepatitis C testing. To examine the impact of lockdowns on hepatitis C testing in Victoria, de-identified data were extracted from a network of 11 services that specialize in the care of people who inject drugs (PWID). Interrupted time-series analyses estimated weekly changes in hepatitis C antibody and RNA testing from 1 January 2019 to 14 May 2021 and described temporal changes in testing associated with lockdowns. Interruptions were defined at the weeks corresponding to the start of the first lockdown (week 14) and the start (week 80) and end (week 95) of the second lockdown. Pre-COVID, an average of 80.6 antibody and 25.7 RNA tests were performed each week. Following the first lockdown in Victoria, there was an immediate drop of 23.2 antibody tests and 8.6 RNA tests per week (equivalent to a 31% and 46% drop, respectively). Following the second lockdown, there was an immediate drop of 17.2 antibody tests and 4.6 RNA tests per week (equivalent to a 26% and 33% drop, respectively). With testing and case finding identified as a key challenge to Australia achieving hepatitis C elimination targets, the cumulative number of testing opportunities missed during lockdowns may prolong efforts to find, diagnose and engage or reengage in care of the remaining population of PWID living with hepatitis C.

Microelimination of Hepatitis C Among People With Human Immunodeficiency Virus Coinfection: Declining Incidence and Prevalence Accompanying a Multicenter Treatment Scale-up Trial.

BACKGROUND: Gay and bisexual men (GBM) are a key population affected by human immunodeficiency virus (HIV) and hepatitis C virus (HCV) coinfection. We aimed to measure HCV treatment effectiveness and to determine the population impact of treatment scale-up on HCV prevalence and incidence longitudinally among GBM. METHODS: The co-EC Study (Enhancing Care and Treatment Among HCV/HIV Coinfected Individuals to Eliminate Hepatitis C Transmission) was an implementation trial providing HCV direct-acting antiviral treatment in Melbourne, Australia, during 2016-2018. Individuals with HCV/HIV coinfection were prospectively enrolled from primary and tertiary care services. HCV viremic prevalence and HCV antibody/viremic incidence were measured using a statewide, linked, surveillance system. RESULTS: Among 200 participants recruited, 186 initiated treatment during the study period. Sustained virological response in primary care (98% [95% confidence interval {CI}, 93%-100%]) was not different to tertiary care (98% [95% CI, 86%-100%]). From 2012 to 2019, between 2434 and 3476 GBM with HIV infection attended our primary care sites annually, providing 13 801 person-years of follow-up; 50%-60% received an HCV test annually, and 10%-14% were anti-HCV positive. Among those anti-HCV positive, viremic prevalence declined 83% during the study (54% in 2016 to 9% in 2019). HCV incidence decreased 25% annually from 1.7/100 person-years in 2012 to 0.5/100 person-years in 2019 (incidence rate ratio, 0.75 [95% CI, .68-.83]; P < .001). CONCLUSIONS: High treatment effectiveness by nonspecialists demonstrates the feasibility of treatment scale-up in this population. Substantial declines in HCV incidence and prevalence among GBM provides proof-of-concept for HCV microelimination. CLINICAL TRIALS REGISTRATION: NCT02786758.

Lessons learned from the Amsterdam Cohort Studies among people who use drugs: a historical perspective.

The Netherlands is well known for its early adoption of harm reduction (HR) programs at the height of its heroin crisis in the 1970s/1980s, including the implementation of the first needle and syringe program worldwide. In this manuscript, we describe how the Amsterdam Cohort Studies (ACS) among people who use drugs (PWUD) was conceived within the context of the Dutch HR approach, including the challenges scientists faced while establishing this cohort. This required striking a balance between public health and individual benefit, solving research dilemmas in the face of uncertainty, developing controversial innovative and cutting-edge interventions, which changed the prevention landscape for PWUD, and using longitudinal cohort data to provide unique insights. Studies from the ACS covering follow-up between 1985 and 2016 revealed that participation in both opioid agonist therapy and needle and syringe programs led to a major decrease in the risk of HIV and hepatitis B and C infection acquisition. ACS data have shown that the observed decrease in incidence also likely included shifts in drug markets and drug culture over time, selective mortality among those with the highest levels of risk behaviour, demographic changes of the PWUD population, and progression of the HIV and HCV epidemics. Moreover, HR programs in the Netherlands provided services beyond care for drug use, such as social support and welfare services, likely contributing to its success in curbing the HIV and viral hepatitis epidemics, increasing access and retention to HIV and HCV care and ultimately decreases in overdose mortality over time. Given the low coverage of HR programs in certain regions, it is unsurprising that continued HIV and HCV outbreaks occur and that transmission is ongoing in many countries worldwide. If we aim to reach the World Health Organization viral hepatitis and HIV elimination targets in 2030, as well as to improve the life of PWUD beyond infection risk, comprehensive HR programs need to be integrated as a part of prevention services, as in the Netherlands. We should use the evidence generated by longstanding cohorts, including the ACS, as a basis for which implementation and improved coverage of integrated HR services can be achieved for PWUD worldwide.

Measuring hepatitis C virus elimination as a public health threat: Beyond global targets.

An increasing number of countries are committing to meet the World Health Organization (WHO) targets to eliminate hepatitis C virus (HCV) as a public health threat by 2030. These include service coverage targets (90% diagnosed and 80% of diagnosed patients treated) and impact targets (80% and 65% reductions in incidence and mortality, respectively, compared to 2015 levels). Currently, a dozen countries are on track to reach 2030 WHO HCV targets. However, while striving for the WHO targets is important, it should be recognized that progress on impact targets is derived from mathematical models projecting decreases in incidence and mortality on a global scale. Despite HCV treatment access in many counties for a number of years, limited empirical data are available to evaluate progress towards elimination. In some countries, substantial incidence and mortality reductions based on reaching the WHO service coverage targets may be unachievable. For example, in countries with ageing hepatitis C-infected populations, even if they have a quality hepatitis C response, high hepatitis C-related morbidity at baseline may not be reversible even with increased HCV treatment uptake and diagnosis. Finally, WHO targets are not necessarily easily or reliably measurable. Measuring relative impact targets requires high-quality data at baseline (ie 2015) and longitudinal data to assess temporal trends. In this commentary, we propose alternative additional measures to track progress on reducing the HCV burden, offer examples where the WHO targets may not be informative or achievable, and potential practical solutions.

Frequent delayed spontaneous seroclearance of hepatitis B virus after incident HBV infection among adult high-risk groups.

High rates (~25%) of developing chronic hepatitis B virus (HBV) infection (hepatitis B surface antigen (HBsAg)-positive for > 6 months following infection) have been observed in people who use drugs (PWUD) and men who have sex with men (MSM). We aimed to estimate the frequency of delayed HBsAg seroclearance, along with its determinants, and time to delayed HBsAg seroclearance. Data were used from MSM and PWUD enrolled in the Amsterdam Cohort Studies (1985-2002) who had anti-hepatitis B core antibody seroconversion. Potential determinants for standard HBsAg seroclearance, delayed HBsAg seroclearance and chronic HBV were examined using multinominal logistic regression. Time to HBsAg seroclearance was estimated using Kaplan-Meier curves. A total of 147 incident HBV infections occurred during follow-up. On initial HBsAg testing after infection (6-12 months), 42 (29%) were HBsAg-positive and 105 (71%) were HBsAg-negative ('standard HBsAg seroclearance'). Of the 42 initially HBsAg-positive individuals, 22 subsequently tested HBsAg-negative (of whom 7 (31.8%) were HBV DNA positive at last visit, suggesting occult HBV). Overall, 15 became HBsAg-negative and HBV DNA-negative ('delayed HBsAg seroclearance'), while 27 remained HBsAg and/or HBV DNA-positive ('chronic HBV'). The 5-year cumulative probability of delayed HBsAg seroclearance was 41.6% for initially HBsAg-positive individuals. Delayed HBsAg seroclearance and remaining chronically infected were associated with younger age and HIV/hepatitis C virus (HCV)-co-infection. In conclusion, delayed HBsAg seroclearance is common in these key adult populations at-risk for HBV, while proportion developing HBV chronicity (18%) is still higher compared to the general population (~5%). Given the proportion of individuals with occult HBV infection and that HCV direct-acting antivirals can lead to HBV reactivation, HBV DNA testing in HCV co-infected MSM/PWUD are warranted prior to treatment initiation.

Model projections on the impact of HCV treatment in the prevention of HCV transmission among people who inject drugs in Europe.

BACKGROUND & AIMS: Prevention of hepatitis C virus (HCV) transmission among people who inject drugs (PWID) is critical for eliminating HCV in Europe. We estimated the impact of current and scaled-up HCV treatment with and without scaling up opioid substitution therapy (OST) and needle and syringe programmes (NSPs) across Europe over the next 10 years. METHODS: We collected data on PWID HCV treatment rates, PWID prevalence, HCV prevalence, OST, and NSP coverage from 11 European settings. We parameterised an HCV transmission model to setting-specific data that project chronic HCV prevalence and incidence among PWID. RESULTS: At baseline, chronic HCV prevalence varied from <25% (Slovenia/Czech Republic) to >55% (Finland/Sweden), and <2% (Amsterdam/Hamburg/Norway/Denmark/Sweden) to 5% (Slovenia/Czech Republic) of chronically infected PWID were treated annually. The current treatment rates using new direct-acting antivirals (DAAs) may achieve observable reductions in chronic prevalence (38-63%) in 10 years in Czech Republic, Slovenia, and Amsterdam. Doubling the HCV treatment rates will reduce prevalence in other sites (12-24%; Belgium/Denmark/Hamburg/Norway/Scotland), but is unlikely to reduce prevalence in Sweden and Finland. Scaling-up OST and NSP to 80% coverage with current treatment rates using DAAs could achieve observable reductions in HCV prevalence (18-79%) in all sites. Using DAAs, Slovenia and Amsterdam are projected to reduce incidence to 2 per 100 person years or less in 10 years. Moderate to substantial increases in the current treatment rates are required to achieve the same impact elsewhere, from 1.4 to 3 times (Czech Republic and France), 5-17 times (France, Scotland, Hamburg, Norway, Denmark, Belgium, and Sweden), to 200 times (Finland). Scaling-up OST and NSP coverage to 80% in all sites reduces treatment scale-up needed by 20-80%. CONCLUSIONS: The scale-up of HCV treatment and other interventions is needed in most settings to minimise HCV transmission among PWID in Europe. LAY SUMMARY: Measuring the amount of HCV in the population of PWID is uncertain. To reduce HCV infection to minimal levels in Europe will require scale-up of both HCV treatment and other interventions that reduce injecting risk (especially OST and provision of sterile injecting equipment).

Risk of Primary Incident Hepatitis C Infection Following Bacterial Sexually Transmissible Infections Among Gay and Bisexual Men in Australia From 2016 to 2020.

Background: In Australia, the incidence of hepatitis C virus (HCV) has declined among gay and bisexual men (GBM) with human immunodeficiency virus (HIV) since 2015 and is low among GBM using HIV preexposure prophylaxis (PrEP). However, ongoing HCV testing and treatment remains necessary to sustain this. To assess the potential utility of sexually transmissible infections (STIs) to inform HCV testing among GBM with HIV and GBM using PrEP, we examined the association between bacterial STI diagnoses and subsequent primary HCV infection. Methods: Data were from a national network of 46 clinics participating in the Australian Collaboration for Coordinated Enhanced Sentinel Surveillance. GBM included had ≥1 HCV antibody negative test result and ≥1 subsequent HCV antibody and/or RNA test. Discrete time survival analysis was used to estimate the association between a positive syphilis, rectal chlamydia, and rectal gonorrhea diagnosis in the previous 2 years and a primary HCV diagnosis, defined as a positive HCV antibody or RNA test result. Results: Among 6529 GBM with HIV, 92 (1.4%) had an incident HCV infection. A prior positive syphilis diagnosis was associated with an incident HCV diagnosis (adjusted hazard ratio, 1.99 [95% confidence interval, 1.11-3.58]). Among 13 061 GBM prescribed PrEP, 48 (0.4%) had an incident HCV diagnosis. Prior rectal chlamydia (adjusted hazard ratio, 2.75 [95% confidence interval, 1.42-5.32]) and rectal gonorrhea (2.54 [1.28-5.05]) diagnoses were associated with incident HCV. Conclusions: Diagnoses of bacterial STIs in the past 2 years was associated with HCV incidence. These findings suggest that STIs might be useful for informing HCV testing decisions and guidelines for GBM with HIV and GBM using PrEP.

All-cause mortality before and after DAA availability among people living with HIV and HCV: An international comparison between 2010 and 2019.

BACKGROUND: Among people living with HIV and hepatitis C virus (HCV), people who inject drugs (PWID) have historically experienced higher mortality rates. Direct-acting antivirals (DAA), which have led to a 90 % HCV cure rate independently of HIV co-infection, have improved mortality rates. However, DAA era mortality trends among PWID with HIV/HCV remain unknown. Using data from the International Collaboration on Hepatitis C Elimination in HIV Cohorts (InCHEHC), we compared pre/post-DAA availability mortality changes in three groups: PWID, men who have sex with men (MSM), and all other participants. METHODS: We included InCHEHC participants with HIV/HCV followed between 2010 and 2019 in Canada, France, the Netherlands, Spain, and Switzerland. All-cause mortality hazard was compared in the three groups, using Cox proportional hazards regression models adjusted for sex, age, advanced fibrosis/cirrhosis, and pre/post DAA availability. RESULTS: Of the 11,029 participants, 76 % were men, 46 % were PWID, baseline median age was 46 years (interquartile range [IQR] = 40;51), and median CD4 T-cell count was 490 cells/mm3 (IQR = 327;689). Over the study period (median follow-up = 7.2 years (IQR = 3.7;10.0)), 6143 (56 %) participants received HCV treatment, 4880 (44 %) were cured, and 1322 participants died (mortality rate = 1.81/100 person-years (PY) [95 % confidence interval (CI)=1.72-1.91]). Overall, PWID had higher mortality rates than MSM (2.5/100 PY [95 % CI = 2.3-2.6] vs. 0.8/100 PY [95 % CI = 0.7-0.9], respectively). Unlike women with other transmission modes, those who injected drugs had a higher mortality hazard than men who did not inject drugs and men who were not MSM (adjusted Hazard-Ratio (aHR) [95 % CI] = 1.3[1.0-1.6]). Post-DAA availability, mortality decreased among MSM in the Netherlands, Spain, and Switzerland and increased among PWID in Canada (aHR [95 % CI] = 1.73 [1.15-2.61]). CONCLUSION: Post-DAA availability, all-cause mortality did not decrease in PWID. Determinants of cause-specific deaths (drug-related, HIV-related, or HCV-related) need to be identified to explain persistently high mortality among PWID in the DAA era.

Changes in incidence of hepatitis C virus reinfection and access to direct-acting antiviral therapies in people with HIV from six countries, 2010-19: an analysis of data from a consortium of prospective cohort studies.

BACKGROUND: Reinfection after successful treatment with direct-acting antivirals is hypothesised to undermine efforts to eliminate hepatitis C virus (HCV) infection among people with HIV. We aimed to assess changes in incidence of HCV reinfection among people with HIV following the introduction of direct-acting antivirals, and the proportion of all incident cases attributable to reinfection. METHODS: We pooled individual-level data on HCV reinfection in people with HIV after spontaneous or treatment-induced clearance of HCV from six cohorts contributing data to the International Collaboration on Hepatitis C Elimination in HIV Cohorts (InCHEHC) in Australia, Canada, France, the Netherlands, Spain, and Switzerland between Jan 1, 2010, and Dec 31, 2019. Participants were eligible if they had evidence of an HCV infection (HCV antibody or RNA positive test) followed by spontaneous clearance or treatment-induced clearance, with at least one HCV RNA test after clearance enabling measurement of reinfection. We assessed differences in first reinfection incidence between direct-acting antiviral access periods (pre-direct-acting antiviral, limited access [access restricted to people with moderate or severe liver disease and other priority groups], and broad access [access for all patients with chronic HCV]) using Poisson regression. We estimated changes in combined HCV incidence (primary and reinfection) and the relative contribution of infection type by calendar year. FINDINGS: Overall, 6144 people with HIV who were at risk of HCV reinfection (median age 49 years [IQR 42-54]; 4989 [81%] male; 2836 [46%] men who have sex with men; 2360 [38%] people who inject drugs) were followed up for 17 303 person-years and were included in this analysis. The incidence of first HCV reinfection was stable during the period before the introduction of direct-acting antivirals (pre-introduction period; 4·1 cases per 100 person-years, 95% CI 2·8-6·0). Compared with the pre-introduction period, the average incidence of reinfection was 4% lower during the period of limited access (incidence rate ratio [IRR] 0·96, 95% CI 0·78-1·19), and 28% lower during the period of broad access (0·72, 0·60-0·86). Between 2015 and 2019, the proportion of incident HCV infections due to reinfection increased, but combined incidence declined by 34%, from 1·02 cases per 100 person-years (95% CI 0·96-1·07) in 2015 to 0·67 cases per 100 person-years (95% CI 0·59-0·75) in 2019. INTERPRETATION: HCV reinfection incidence and combined incidence declined in people with HIV following direct-acting antiviral introduction, suggesting reinfection has not affected elimination efforts among people with HIV in InCHEHC countries. The proportion of incident HCV cases due to reinfection was highest during periods of broad access to direct-acting antivirals, highlighting the importance of reducing ongoing risks and continuing testing in people at risk. FUNDING: Australian National Health and Medical Research Council.

Comprehensive needle and syringe program and opioid agonist therapy reduce HIV and hepatitis c virus acquisition among people who inject drugs in different settings: A pooled analysis of emulated trials.

BACKGROUND AND AIMS: Although the Netherlands, Canada and Australia were early adopters of harm reduction for people who inject drugs (PWID), their respective HIV and hepatitis C (HCV) epidemics differ. We measured the pooled effect of needle and syringe program (NSP) and opioid agonist therapy (OAT) participation on HIV and HCV incidence in these settings. DESIGN: For each cohort, we emulated the design and statistical analysis of a target trial using observational data. SETTING AND PARTICIPANTS: We included PWID at risk of HIV or HCV infection from the Amsterdam Cohort Studies (1985-2013), Vancouver Injection Drug Users Study (1997-2009) and Melbourne Injecting Drug User Cohort Study (SuperMIX) (2010-2021). MEASUREMENTS: Separately for each infection and cohort (only HCV in SuperMIX), marginal structural models were used to compare the effect of comprehensive (on OAT and 100% NSP coverage or on OAT only if no recent injection drug use) versus no/partial NSP/OAT (no OAT and/or <100% NSP coverage) participation. Pooled hazard ratios (HR) and 95% CI were calculated using random-effects meta-analysis. FINDINGS: We observed 94 HIV seroconversions and 81 HCV seroconversions among 2023 and 430 participants, respectively. Comprehensive NSP/OAT led to a 41% lower risk of HIV acquisition (pooled HR = 0.59, 95% CI = 0.36-0.96) and a 76% lower risk of HCV acquisition (pooled HR = 0.24, 95% CI = 0.11-0.51), compared with no/partial NSP/OAT, with little heterogeneity between studies for both infections (I2  = 0%). CONCLUSIONS: In the Netherlands, Canada and Australia, comprehensive needle and syringe program and opioid agonist therapy participation appears to substantially reduce HIV and hepatitis C acquisition compared with no or partial needle and syringe program/opioid agonist therapy participation. These findings from an emulated trial design reinforce the critical role of comprehensive access to harm reduction in optimizing infection prevention for people who inject drugs.

Incidence and Prevalence of Hepatitis C Virus Among HIV-Negative Gay and Bisexual Men Using HIV Pre-exposure Prophylaxis (PrEP): A Systematic Review and Meta-analysis.

Background: Gay and bisexual men using HIV pre-exposure prophylaxis (PrEP) are at increased risk for sexually transmissible infections. Hepatitis C virus (HCV) risk among PrEP users is less clear. We explored HCV prevalence and incidence among cohorts of gay and bisexual men using PrEP and sources of heterogeneity across studies. Methods: This was a systematic review and meta-analysis of open-label PrEP studies to April 2022 reporting HCV prevalence at baseline or incidence during follow-up among gay and bisexual men using PrEP. Pooled prevalence and incidence estimates were calculated using random-effects meta-analysis, and subgroup analyses were performed by study- and country-level characteristics, including availability of HCV direct-acting antiviral (DAA) therapy at time of study. Results: Twenty-four studies from 9 countries were included, with a total sample of 24 733 gay and bisexual men. Pooled HCV antibody baseline prevalence was 0.97% (95% CI, 0.63%-1.31%), and pooled HCV RNA baseline prevalence was 0.38% (95% CI, 0.19%-0.56%). Among 19 studies reporting HCV incidence, incidence ranged from 0.0 to 2.93/100 person-years (py); the pooled estimate was 0.83/100py (95% CI, 0.55-1.11). HCV incidence was higher in 12 studies that began follow-up before broad DAA availability (1.27/100py) than in 8 studies that began follow-up after broad DAA availability (0.34/100py) and higher in studies in Europe compared with North America and Australia. Conclusions: Early reports of high HCV incidence among PrEP-using cohorts likely reflect enrollment of individuals based on specific risk-based eligibility criteria for smaller studies and enrollment before DAA scale-up. In contexts where both DAAs and PrEP have been implemented at scale, studies report lower HCV incidence. PrEP-specific HCV testing guidelines should be guided by local epidemiology.

Reasons for not commencing direct-acting antiviral treatment despite unrestricted access for individuals with HIV and hepatitis C virus: a multinational, prospective cohort study.

BACKGROUND: Individuals with HIV and hepatitis C virus (HCV) who remain untreated with direct-acting antivirals can contribute to HCV transmission and HCV-related mortality. We aimed to compare rates of uptake of direct-acting antivirals following unrestricted access to this treatment in high-income countries and examine factors associated with remaining untreated. METHODS: This multinational, prospective cohort study used data from the International Collaboration on Hepatitis C Elimination in HIV Cohorts (InCHEHC). We analysed data from nine observational cohorts participating in the InCHEHC, including data from six high-income countries (Australia, Canada, France, the Netherlands, Spain, and Switzerland). We included individuals aged 18 years and older, with HIV and HCV (ie, HCV-RNA positive without evidence of spontaneous clearance) during unrestricted access to interferon-free direct-acting antiviral treatment in each country. We calculated the cumulative proportion of participants who remained untreated with direct-acting antivirals, with follow-up starting after the date of unrestricted access or cohort inclusion, whichever occurred most recently. Factors associated with the commencement rate of direct-acting antiviral treatment were assessed using competing-risks regression with the Fine-Gray method. FINDINGS: The date of unrestricted access to direct-acting antiviral treatment for people with HIV ranged from Nov 1, 2014, in France to Nov 1, 2017, in Switzerland. We included 4552 individuals with HIV-HCV, mainly men who have sex with men (MSM; n=2156 [47%]) and people who inject or have injected drugs (n=1453 [32%]). 1365 (30%) of 4552 participants remained untreated with direct-acting antivirals. For individuals treated with direct-acting antivirals, median time from start of follow-up to treatment was 5 months (IQR 2-12). For individuals who were not treated with direct-acting antivirals, median follow-up was 22 months (8-30). Being linked to care in Australia, France, or the Netherlands, on antiretroviral therapy, having undetectable HIV RNA, and shorter duration since first positive HCV test were independently associated with higher commencement rate of direct-acting antiviral treatment. Compared with MSM, male heterosexuals and females with unknown or other routes of HIV transmission (ie, neither injection drug use nor heterosexual transmission) had lower rates of commencement. INTERPRETATION: Despite unrestricted access, almost a third of individuals with HIV-HCV remained untreated with direct-acting antivirals during follow-up, with variation in commencement rate of HCV treatment between countries and key populations. Increased efforts are required to reach the remaining individuals with HIV who are HCV-viraemic to achieve HIV-HCV micro-elimination. FUNDING: None.

Treatment as prevention effect of direct-acting antivirals on primary hepatitis C virus incidence: Findings from a multinational cohort between 2010 and 2019.

Background: Broad direct-acting antiviral (DAA) access may reduce hepatitis C virus (HCV) incidence through a "treatment as prevention" (TasP) effect. We assessed changes in primary HCV incidence following DAA access among people living with HIV (PLHIV). Methods: We used pooled individual-level data from six cohorts from the International Collaboration on Hepatitis C Elimination in HIV Cohorts (InCHEHC). Follow-up started from the first recorded negative HCV antibody test date and ended at last negative antibody test or estimated infection date. Follow-up was restricted to 2010-2019. We used segmented Poisson regression to model trends across pre-, limited- (i.e., restrictions on access) and broad-DAA access periods. Findings: Overall, 45,942 participants had at least one HCV antibody negative result and follow-up between 2010 and 2019. We observed 2042 incident HCV infections over 248,189 person-years (PY). Pooled incidence decreased from 0.91 per 100 PY in 2015 to 0.41 per 100 PY in 2019. Compared to the average pre-DAA period incidence (0.90 per 100 PY), average incidence was similar during the limited-DAA access period (Incidence rate ratio [IRR] = 0.98; 95%CI = 0.87, 1.11), and 52% lower during the broad-DAA access period (IRR = 0.48; 95%CI = 0.42, 0.52). The average annual decline in HCV incidence was 2% in the pre-DAA period; an additional 9% annual decline in incidence was observed during the limited-DAA access period (IRR = 0.91; 95%CI = 0.82, 1.00) and a further 20% decline in the broad-DAA access period (IRR = 0.80, 95%CI = 0.73, 0.89). Interpretation: Our findings suggest that broad DAA access has a TasP effect on primary HCV incidence among PLHIV. Based on the initial years of DAA availability, the countries in the InCHEHC collaboration are on track to meet the World Health Organization's 80% HCV incidence reduction target for PLHIV by 2030. Funding: This study was funded by the Australian Government National Health and Medical Research Council (Grant number GNT1132902).

Incidence of HIV and hepatitis C virus among people who inject drugs, and associations with age and sex or gender: a global systematic review and meta-analysis.

BACKGROUND: Measuring the incidence of HIV and hepatitis C virus (HCV) infection among people who inject drugs (PWID) is key to track progress towards elimination. We aimed to summarise global data on HIV and primary HCV incidence among PWID and associations with age and sex or gender. METHODS: In this systematic review and meta-analysis, we updated an existing database of HIV and HCV incidence studies among PWID by searching MEDLINE, Embase, and PsycINFO, capturing studies published between Jan 1, 2000, and Dec 12, 2022, with no language or study design restrictions. We contacted authors of identified studies for unpublished or updated data. We included studies that estimated incidence by longitudinally re-testing people at risk of infection or by using assays for recent infection. We pooled incidence and relative risk (RR; young [generally defined as ≤25 years] vs older PWID; women vs men) estimates using random-effects meta-analysis and assessed risk of bias with a modified Newcastle-Ottawa scale. This study is registered with PROSPERO, CRD42020220884. FINDINGS: Our updated search identified 9493 publications, of which 211 were eligible for full-text review. An additional 377 full-text records from our existing database and five records identified through cross-referencing were assessed. Including 28 unpublished records, 125 records met the inclusion criteria. We identified 64 estimates of HIV incidence (30 from high-income countries [HICs] and 34 from low-income or middle-income countries [LMICs]) and 66 estimates of HCV incidence (52 from HICs and 14 from LMICs). 41 (64%) of 64 HIV and 42 (64%) of 66 HCV estimates were from single cities rather than being multi-city or nationwide. Estimates were measured over 1987-2021 for HIV and 1992-2021 for HCV. Pooled HIV incidence was 1·7 per 100 person-years (95% CI 1·3-2·3; I2=98·4%) and pooled HCV incidence was 12·1 per 100 person-years (10·0-14·6; I2=97·2%). Young PWID had a greater risk of HIV (RR 1·5, 95% CI 1·2-1·8; I2=66·9%) and HCV (1·5, 1·3-1·8; I2=70·6%) acquisition than older PWID. Women had a greater risk of HIV (RR 1·4, 95% CI 1·1-1·6; I2=55·3%) and HCV (1·2, 1·1-1·3; I2=43·3%) acquisition than men. For both HIV and HCV, the median risk-of-bias score was 6 (IQR 6-7), indicating moderate risk. INTERPRETATION: Although sparse, available HIV and HCV incidence estimates offer insights into global levels of HIV and HCV transmission among PWID. Intensified efforts are needed to keep track of the HIV and HCV epidemics among PWID and to expand access to age-appropriate and gender-appropriate prevention services that serve young PWID and women who inject drugs. FUNDING: Canadian Institutes of Health Research, Fonds de recherche du Québec-Santé, Canadian Network on Hepatitis C, UK National Institute for Health and Care Research, and WHO.

Hepatitis C incidence among patients attending primary care health services that specialise in the care of people who inject drugs, Victoria, Australia, 2009 to 2020.

BACKGROUND: Monitoring trends in hepatitis C virus (HCV) incidence is critical for evaluating strategies aimed at eliminating HCV as a public health threat. We estimate HCV incidence and assess trends in incidence over time among primary care patients. METHODS: Data were routinely extracted, linked electronic medical records from 12 primary care health services. Patients included were aged ≥16 years, tested HCV antibody negative on their first test recorded and had at least one subsequent HCV antibody or RNA test (January 2009-December 2020). HCV incident infections were defined as a positive HCV antibody or RNA test. A generalised linear model assessed the association between HCV incidence and calendar year. RESULTS: In total, 6711 patients contributed 17,098 HCV test records, 210 incident HCV infections and 19,566 person-years; incidence was 1.1 per 100 person-years (95% confidence interval (CI): 0.9 to 1.2). Among 559 (8.2%) patients ever prescribed opioid-related pharmacotherapy (ORP) during the observation period, 135 infections occurred during 2,082 person-years (incidence rate of 6.5 per 100 person-years (95% CI: 5.4 to 7.7)). HCV incidence declined 2009-2020 overall (incidence rate ratio per calendar year 0.8 (95% CI: 0.8 to 0.9) and among patients ever prescribed ORT (incidence rate ratio per calendar year 0.9, 95% CI: 0.75 to 1.0). CONCLUSION: HCV incidence declined among patients at primary care health services including among patients ever prescribed ORP and during the period following increased access to DAA therapy.

The effect of needle and syringe program and opioid agonist therapy on the risk of HIV, hepatitis B and C virus infection for people who inject drugs in Amsterdam, the Netherlands: findings from an emulated target trial.

BACKGROUND AND AIMS: Major declines in HIV and hepatitis C and B virus (HCV/HBV) incidence among people who inject drugs (PWID) have been attributed to early implementation of harm-reduction programs (HRP) in the Netherlands, but alternative factors such as selective mortality and demographic and drug market shifts over time probably contributed to observed incidence declines. We quantified and tested the effect of HRP participation on risk of these infections among PWID in Amsterdam, the Netherlands. DESIGN: We emulated the design of a hypothetical, ideal randomized trial using observational data from the Amsterdam Cohort Studies (1985-2014). SETTING: Amsterdam, the Netherlands. PARTICIPANTS: We included PWID who ever used opioids, had a recent history of injecting drug use (IDU) and tested negative for HIV, HCV or HBV. Of 983 participants, 640, 137 and 308 were included for the HIV, HCV and HBV analyses and 59, 45 and 49 seroconversions were observed, respectively. INTERVENTIONS: Intervention arms were: complete HRP participation [≥ 60 mg/day methadone and 100% needle and syringe program (NSP) coverage, or any methadone dose if no recent injection drug use] versus no HRP and partial HRP participation combined (< 60 methadone mg/day and/or < 100% NSP coverage). CONCLUSIONS: Complete participation in harm reduction programs appears to have led to substantial decreases in HIV and hepatitis C and B virus acquisition risk among people who inject drugs in the Netherlands. MEASUREMENTS: Separately for each infection, we estimated the hazard ratios (HR) comparing HRP arms using marginal structural models. FINDINGS: Compared with no/partial HRP participation, complete HRP participation led to lower risk of HIV [HR = 0.54, 95% confidence interval (CI) = 0.27-1.08], HCV (HR = 0.16, 95% CI = 0.06-0.40) and HBV (HR = 0.28, 95% CI = 0.13-0.61) acquisition.

A Feasibility Study to Increase Chronic Hepatitis C Virus RNA Testing and Linkage to Care among Clients Attending Homeless Services in Amsterdam, The Netherlands.

People who inject drugs (PWID) are disproportionately affected by hepatitis C virus (HCV) infections and are frequently homeless. To improve HCV case finding in these individuals, we examined the feasibility of rapid HCV RNA testing in homeless services in Amsterdam. In 2020, we provided a comprehensive service to homeless facilities, which included workshops on HCV for personnel, a "hepatitis ambassador" at each facility, a rapid, onsite HCV RNA fingerstick test service, and assistance with linkage to care. Risk factors for HCV RNA-positive status were examined using Bayesian logistic regression. Of the 152 participants enrolled, 150 (87% men; median age: 47 years) accepted rapid HCV testing. Seven tested HCV RNA positive (4.7%, 95%CrI = 1.31-8.09; 7/150). Of these, five (71%) were linked to care, of whom four (57%, 4/7) initiated treatment and one (14%, 1/7) delayed treatment due to a drug-drug interaction. Of these four people, two completed treatment (50%), of whom one (25%) achieved sustained virologic response after 12 weeks. HCV RNA-positive individuals were more likely to originate from Eastern Europe (posterior-odds ratio (OR) = 3.59 (95% credible interval (CrI) = 1.27-10.04)) and to inject drugs (ever: posterior-OR = 3.89 (95% CrI = 1.37-11.09); recent: posterior-OR = 3.94 (95% CrI = 1.29-11.71)). We identified HCV RNA-positive individuals and linkage to care was relatively high. Screening in homeless services with rapid testing is feasible and could improve HCV case finding for PWID who do not regularly attend primary care or other harm reduction services for people who use drugs.