Persistent Transmission of HCV among Men Who Have Sex with Men despite Widespread Screening and Treatment with Direct-Acting Antivirals.

BACKGROUND: In the Netherlands, unrestricted access to direct-acting antivirals (DAAs) halved the incidence of acute hepatitis C virus (HCV) infections among HIV-infected men who have sex with men (MSM). To develop strategies that can further reduce the spread of HCV, it is important to understand the transmission dynamics of HCV. We used phylogenetic analysis of a dense sample of MSM to provide insight into the impact of unrestricted access to DAAs on HCV transmission in the Netherlands and in Belgium. METHODS: We included 89 MSM that were recently infected with HCV genotype 1a in ten Dutch and one Belgian HIV treatment centers. Sequences were generated using next gene sequencing and Sanger sequencing. Maximum likelihood phylogenetic analysis (general time reversible model) was performed on concatenated NS5A and NS5B sequences and a reference set of 389 highly similar control sequences selected from GenBank. A cluster was based on a minimum bootstrap support of 90% and a 3% genetic distance threshold. RESULTS: We found that 78 (88%) of individuals were part of seven major clusters. All clusters included individuals from across the study region, however, different cities were part of different clusters. In three clusters, HIV-negative MSM clustered with sequences from HIV-positive MSM. All clusters that were observed before the introduction of DAAs persisted after unrestricted access to DAAs became available. CONCLUSION: Recently acquired HCV infections among MSM in the Netherlands and Belgium are strongly clustered and therefore highly suitable for targeted prevention strategies, such as contact tracing and partner notification. Importantly, despite an HCV incidence reduction after high DAA uptake and continuously monitoring, HCV transmission persisted in the same clusters.

HCV micro-elimination in individuals with HIV in the Netherlands 4 years after universal access to direct-acting antivirals: a retrospective cohort study.

BACKGROUND: In the Netherlands, access to direct-acting antivirals (DAAs) against hepatitis C virus (HCV) has been unrestricted for chronic infection since 2015. We evaluated whether the nationwide incidence of HCV infections in individuals with HIV has changed since 2015. METHODS: In this retrospective cohort study, data from the ATHENA cohort of people with HIV aged 18 years or older attending any of the 24 HIV treatment centres in the Netherlands between 2000 and 2019 were assessed. We used parametric proportional hazards models with a piecewise exponential survival function to model HCV primary infection and reinfection incidence per 1000 person-years. FINDINGS: Of the 23 590 individuals without previous HCV infection, 1269 cases of HCV primary infection were documented (incidence 5·2 per 1000 person-years [95% CI 5·0-5·5]). The highest incidence was observed in men who have sex with men (MSM; 7·7 per 1000 person-years [7·3-8·2]) and was lower in people who inject drugs (PWID; 1·7 per 1000 person-years [0·7-4·1]) and other key populations (1·0 per 1000 person-years [0·8-1·2]). In MSM, incidence increased in 2007 to 14·3 per 1000 person-years and fluctuated between 8·7 and 13·0 per 1000 person-years from 2008 to 2015. In 2016, incidence declined to 6·1 cases per 1000 person-years and remained steady between 4·1 and 4·9 per 1000 person-years from 2017 to 2019. Of the 1866 individuals with a previous HCV infection, 274 reinfections were documented (incidence 26·9 per 1000 person-years [95% CI 23·9-30·3]). The highest incidence rate was observed in MSM (38·5 per 1000 person-years [33·9-43·7]) and was lower in PWID (10·9 per 1000 person-years [3·5-33·8]) and other key populations (8·9 per 1000 person-years [6·3-12·5]). In MSM, reinfection incidence fluctuated between 38·0 and 88·9 per 1000 person-years from 2006 to 2015, reaching 55·6 per 1000 person-years in 2015. In 2016, reinfection incidence declined to 41·4 per 1000 person-years, followed by further decreases to 24·4 per 1000 person-years in 2017 and 11·4 per 1000 person-years in 2019. INTERPRETATION: The sharp decline in HCV incidence in MSM with HIV shortly after restrictions on DAAs were lifted suggests a treatment-as-prevention effect. HCV incidence was already low in PWID and other groups before unrestricted access. Ongoing HCV transmission is occurring in MSM, as illustrated by a declining but high rate of reinfection, stressing the need for additional preventive measures. FUNDING: Dutch Ministry of Health, Welfare, and Sport.

Transmission of NS5A-Inhibitor Resistance-Associated Substitutions Among Men Who Have Sex With Men Recently Infected with Hepatitis C Virus Genotype 1a.

The transmission of direct-acting antiviral resistance-associated substitutions (RAS) could hamper hepatitis C virus (HCV) cure rates and elimination efforts. A phylogenetic analysis of 87 men who have sex with men recently infected with HCV genotype 1a placed one-third (28/87) in a large cluster, in which 96% harbored NS5A M28V RAS.

Early treatment of acute hepatitis C infection is cost-effective in HIV-infected men-who-have-sex-with-men.

BACKGROUND: Treatment of hepatitis C virus infections (HCV) with direct acting antivirals (DAA) can prevent new infections since cured individuals cannot transmit HCV. However, as DAAs are expensive, many countries defer treatment to advances stages of fibrosis, which results in ongoing transmission. We assessed the epidemiological impact and cost-effectiveness of treatment initiation in different stages of infection in the Netherlands where the epidemic is mainly concentrated among HIV-infected MSMs. METHODS: We calibrated a deterministic mathematical model to the Dutch HCV epidemic among HIV-infected MSM to compare three different DAA treatment scenarios: 1) immediate treatment, 2) treatment delayed to chronic infection allowing spontaneous clearance to occur, 3) treatment delayed until F2 fibrosis stage. All scenarios are simulated from 2015 onwards. Total costs, quality adjusted life years (QALY), incremental cost-effectiveness ratios (ICERs), and epidemiological impact were calculated from a providers perspective over a lifetime horizon. We used a DAA price of €35,000 and 3% discounting rates for cost and QALYs. RESULTS: Immediate DAA treatment lowers the incidence from 1.2/100 person-years to 0.2/100 person-years (interquartile range 0.1-0.2) and the prevalence from 5.0/100 person-years to 0.5/100 person-years (0.4-0.6) after 20 years. Delayed treatment awaiting spontaneous clearance will result in a similar reduction. However, further delayed treatment to F2 will increases the incidence and prevalence. Earlier treatment will cost society €68.3 and €75.1 million over a lifetime for immediate and awaiting until the chronic stage, respectively. The cost will increase if treatment is further delayed until F2 to €98.4 million. Immediate treatment will prevent 7070 new infections and gains 3419 (3019-3854) QALYs compared to F2 treatment resulting in a cost saving ICER. Treatment in the chronic stage is however dominated. CONCLUSIONS: Early DAA treatment for HIV-infected MSM is an excellent and sustainable tool to meet the WHO goal of eliminating HCV in 2030.

Treatment of acute hepatitis C genotypes 1 and 4 with 8 weeks of grazoprevir plus elbasvir (DAHHS2): an open-label, multicentre, single-arm, phase 3b trial.

BACKGROUND: Direct-acting antivirals effectively treat chronic hepatitis C virus (HCV) infection but there is a paucity of data on their efficacy for acute HCV, when immediate treatment could prevent onward transmission. We assessed the efficacy of grazoprevir plus elbasvir treatment in acute HCV infection and investigated whether treatment can be shortened during the acute phase of HCV infection. METHODS: The Dutch Acute HCV in HIV study number 2 (DAHHS2) study was a single-arm, open-label, multicentre, phase 3b trial. Adult patients (≥18 years) with acute HCV genotype 1 or 4 infection (duration of infection 26 weeks or less, according to presumed day of infection) were recruited at 15 HIV outpatient clinics in the Netherlands and Belgium. All patients were treated with 8 weeks of grazoprevir 100 mg plus elbasvir 50 mg administered as one oral fixed drug combination tablet once daily. The primary efficacy endpoint was sustained virological response at 12 weeks after the end of treatment (SVR12; HCV RNA <15 IU/mL) in all patients who started treatment. Reinfection with a different HCV virus was not considered treatment failure in the primary analysis. This trial is registered with ClinicalTrials.gov, number NCT02600325. FINDINGS: Between Feb 15, 2016, and March 2, 2018, we assessed 146 patients with a recently acquired HCV infection for eligibility, of whom 86 were enrolled and 80 initiated therapy, all within 6 months after infection. All patients who initiated treatment completed treatment and no patients were lost to follow-up. 79 (99%, 95% CI 93-100) of 80 patients achieved SVR12. All 14 patients who were infected with a virus carrying a clinically significant polymorphism in NS5A were cured. If reinfections were considered treatment failures, 75 (94%, 86-98) of 80 patients achieved SVR12. Two serious adverse events not considered related to the treatment were reported (traumatic rectal bleeding and low back surgery). The most common adverse event was a new sexually transmitted infection (19 [24%] of 80 patients). The most common reported possibly drug-related adverse events were fatigue (11 [14%] patients), headache (seven [9%] patients), insomnia (seven [9%] patients), mood changes (five [6%] patients), dyspepsia (five [6%] patients), concentration impairment (four [5%] patients), and dizziness (4 [5%] patients), all of which were regarded as mild by the treating physician. No adverse events led to study drug discontinuation. INTERPRETATION: 8 weeks of grazoprevir plus elbasvir was highly effective for the treatment of acute HCV genotype 1 or 4 infection. The ability to treat acute HCV immediately after diagnosis might help physicians to reach the WHO goal of HCV elimination by 2030. FUNDING: Merck Sharp and Dohme and Health-Holland.

Is hepatitis C virus elimination possible among people living with HIV and what will it take to achieve it?

INTRODUCTION: The World Health Organization targets for hepatitis C virus (HCV) elimination include a 90% reduction in new infections by 2030. Our objective is to review the modelling evidence and cost data surrounding feasibility of HCV elimination among people living with HIV (PLWH), and identify likely components for elimination. We also discuss the real-world experience of HCV direct acting antiviral (DAA) scale-up and elimination efforts in the Netherlands. METHODS: We review modelling evidence of what intervention scale-up is required to achieve WHO HCV elimination targets among HIV-infected (HIV+) people who inject drugs (PWID) and men who have sex with men (MSM), review cost-effectiveness of HCV therapy among PLWH and discuss economic implications of elimination. We additionally use the real-world experience of DAA scale-up in the Netherlands to illustrate the promise and potential challenges of HCV elimination strategies in MSM. Finally, we summarize key components of the HCV elimination response among PWLH. RESULTS AND DISCUSSION: Modelling indicates HCV elimination among HIV+ MSM and PWID is potentially achievable but requires combination treatment and either harm reduction or behavioural risk reductions. Preliminary modelling indicates elimination among HIV+ PWID will require elimination efforts among PWID more broadly. Treatment for PLWH and high-risk populations (PWID and MSM) is cost-effective in high-income countries, but costs of DAAs remain a barrier to scale-up worldwide despite the potential low production price ($50 per 12 week course). In the Netherlands, universal DAA availability led to rapid uptake among HIV+ MSM in 2015/16, and a 50% reduction in acute HCV incidence among HIV+ MSM from 2014 to 2016 was observed. In addition to HCV treatment, elimination among PLWH globally also likely requires regular HCV testing, development of low-cost accurate HCV diagnostics, reduced costs of DAA therapy, broad treatment access without restrictions, close monitoring for HCV reinfection and retreatment, and harm reduction and/or behavioural interventions. CONCLUSIONS: Achieving WHO HCV Elimination targets is potentially achievable among HIV-infected populations. Among HIV+ PWID, it likely requires HCV treatment scale-up combined with harm reduction for both HIV+ and HIV- populations. Among HIV+ MSM, elimination likely requires both HCV treatment and behaviour risk reduction among the HIV+ MSM population, the latter of which to date has not been observed. Lower HCV diagnostic and treatment costs will be key to ensuring scale-up of HCV testing and treatment without restriction, enabling elimination.

Declining Hepatitis C Virus (HCV) Incidence in Dutch Human Immunodeficiency Virus-Positive Men Who Have Sex With Men After Unrestricted Access to HCV Therapy.

Background: Direct-acting antivirals (DAAa) cure hepatitis C virus (HCV) infections in 95% of infected patients. Modeling studies predict that universal HCV treatment will lead to a decrease in the incidence of new infections but real-life data are lacking. The incidence of HCV among Dutch human immunodeficiency virus (HIV)-positive men who have sex with men (MSM) has been high for >10 years. In 2015 DAAs became available to all Dutch HCV patients and resulted in a rapid treatment uptake in HIV-positive MSM. We assessed whether this uptake was followed by a decrease in the incidence of HCV infections. Methods: Two prospective studies of treatment for acute HCV infection enrolled patients in 17 Dutch HIV centers, having 76% of the total HIV-positive MSM population in care in the Netherlands. Patients were recruited in 2014 and 2016, the years before and after unrestricted DAA availability. We compared the HCV incidence in both years. Results: The incidence of acute HCV infection decreased from 93 infections during 8290 person-years of follow-up (PYFU) in 2014 (11.2/1000 PYFU; 95% confidence interval [CI], 9.1-13.7) to 49 during 8961 PYFU in 2016 (5.5/1000 PYFU; 4.1-7.2). The incidence rate ratio of 2016 compared with 2014 was 0.49 (95% CI, .35-.69). Simultaneously, a significant increase in the percentage positive syphilis (+2.2%) and gonorrhea (+2.8%) tests in HIV-positive MSM was observed at sexual health clinics across the Netherlands and contradicts a decrease in risk behavior as an alternative explanation. Conclusions: Unrestricted DAA availability in the Netherlands was followed by a 51% decrease in acute HCV infections among HIV-positive MSM.

High Treatment Uptake in Human Immunodeficiency Virus/Hepatitis C Virus-Coinfected Patients After Unrestricted Access to Direct-Acting Antivirals in the Netherlands.

Background: The Netherlands has provided unrestricted access to direct-acting antivirals (DAAs) since November 2015. We analyzed the nationwide hepatitis C virus (HCV) treatment uptake among patients coinfected with human immunodeficiency virus (HIV) and HCV. Methods: Data were obtained from the ATHENA HIV observational cohort in which >98% of HIV-infected patients ever registered since 1998 are included. Patients were included if they ever had 1 positive HCV RNA result, did not have spontaneous clearance, and were known to still be in care. Treatment uptake and outcome were assessed. When patients were treated more than once, data were included from only the most recent treatment episode. Data were updated until February 2017. In addition, each treatment center was queried in April 2017 for a data update on DAA treatment and achieved sustained virological response. Results: Of 23574 HIV-infected patients ever linked to care, 1471 HCV-coinfected patients (69% men who have sex with men, 15% persons who [formerly] injected drugs, and 15% with another HIV transmission route) fulfilled the inclusion criteria. Of these, 87% (1284 of 1471) had ever initiated HCV treatment between 2000 and 2017, 76% (1124 of 1471) had their HCV infection cured; DAA treatment results were pending in 6% (92 of 1471). Among men who have sex with men, 83% (844 of 1022) had their HCV infection cured, and DAA treatment results were pending in 6% (66 of 1022). Overall, 187 patients had never initiated treatment, DAAs had failed in 14, and a pegylated interferon-alfa-based regimen had failed in 54. Conclusions: Fifteen months after unrestricted DAA availability the majority of HIV/HCV-coinfected patients in the Netherlands have their HCV infection cured (76%) or are awaiting DAA treatment results (6%). This rapid treatment scale-up may contribute to future HCV elimination among these patients.