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EDITORIAL REVIEW

Recently acquired and early chronic hepatitis C in MSM: Recommendations from the European treatment network for HIV, hepatitis and global infectious diseases consensus panel

 European Treatment Network for HIV, Hepatitis and Global Infectious Diseases (NEAT-ID) Consensus Panel∗

Author Information
doi: 10.1097/QAD.0000000000002622

Abstract

Erratum

In this article by European Treatment Network for HIV, Hepatitis and Global Infectious Diseases (NEAT-ID) Consensus Panel , Acknowledgements and Conflicts of interest sections were incorrectly published. These sections should read as follows:

Writing committee: Christoph Boesecke 1 , Anders Boyd 2 , Andri Rauch 3 , Karine Lacombe 4 , Alison Rodger 5 , Anastasia Pharris 6 , Anton Pozniak 7 , Bart Rijnders 8 , Colette Smit 9 , Colette Smith 5 , Elske Hoornenborg 10 , Heiner Wedemeyer 11 , Janke Schinkel 12 , Lina Nerlander 6 , Erika Duffell 6 , Teymur Noori 6 , Juan Berenguer 13 , Lars Peters 14 , Laurent Cotte 15 , Luisa Salazar-Vizcaya 3 , Massimo Puoti 16 , Milosz Parczewski 17 , Natasha Martin 18 , Patrick Ingiliz 19 , Paul Zandkuijl 20 , Stephan Dressler 21 , Susanna Naggie 22 , Thijs van de Laar 23 , Thomas Reiberger 24 , Gail Matthews 25 , Sanjay Bhagani 26 , Maria Prins 2 , Jürgen K. Rockstroh 1 .

Particular thanks to Yvan Hutin from WHO for review.

Authors’ contributions: All authors were responsible for drafting the manuscript. All authors have read and approved the final manuscript submitted for publication.

Funding: The organization and related expenses of the consensus conference were funded through NEAT ID.

Institutional affiliations: 1 Department of Medicine I, Bonn University Hospital, Bonn, Germany; 2 Department of Infectious Diseases, Public Health Service Amsterdam, Amsterdam, The Netherlands; 3 Department of Infectious Diseases, Bern University Hospital, University of Bern, Bern, Switzerland; 4 Sorbonne University, Inserm IPLESP, APHP, Paris, France; 5 Institute for Global Health, University College London, London, UK; 6 European Centre for Disease Prevention and Control, Solna, Sweden; 7 Chelsea and Westminster Hospital NHS Foundation Trust, London, UK; 8 Internal Medicine and Infectious Diseases, Erasmus MC University Medical Center, Rotterdam, Netherlands; 9 Municipal Health Service, Amsterdam, The Netherlands; 10 Public Health Service of Amsterdam, Department of Infectious Diseases, Amsterdam, The Netherlands; 11 Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; 12 Department of Medical Microbiology, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands; 13 Hospital General Universitario Gregorio Marañón, Madrid; 14 CHIP, Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; 15 Service des Maladies Infectieuses et Tropicales, Hôpital de la Croix Rousse, Hospices Civils de Lyon, Lyon, France; 16 Division of Infectious Diseases, ASST Grande Ospedale Metropolitano Niguarda, Milano, Italy; 17 Department of Infectious, Tropical Diseases and Immune Deficiency, Pomeranian Medical University in Szczecin, Szczecin, Poland; 18 Division of Infectious Diseases and Global Public Health, University of California San Diego, La Jolla, California, USA; 19 Department of Hepatology, Charite University Medical Center, Berlin, Germany; 20 aidsfonds, Amsterdam, the Netherlands; 21 National AIDS Centre at the Federal Health Office, Berlin, Germany; 22 Duke University School of Medicine, Durham, NC, United States; 23 Department of Donor Medicine Research, Laboratory of Blood-Borne Infections, Sanquin Research, Amsterdam, the Netherlands; 24 Division of Gastroenterology & Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; 25 Kirby Institute, University of New South Wales Sydney, Sydney, Australia; 26 Department of Infectious Diseases, Royal Free Hospital London NHS Foundation Trust, London, UK

Conflicts of interest: The development of guidelines demanded commercial independence and avoidance of potential conflict of interest which could influence statements and recommendations made. All conference participants were asked to declare any conflict of interest. The NEAT ID consensus panelists who were able to participate at the conference and vote on the statements/recommendations were:

Alison Rodger: No conflict of interest

Anastasia Pharris: No conflict of interest

Anders Boyd (Co-chair Transmission and prevention): No conflict of interest

Andri Rauch (Co-chair case definition and diagnosis): Advisory boards: MSD, Gilead Sciences, Abbvie. Travel grants: Gilead Sciences, Pfizer, Abbvie. Research support: Investigator initiated trial grant from Gilead Sciences. All remuneration went to his home institution and not to AR personally

Anton Pozniak: Research grants from VIIV, Merck, Gilead, and lecture fees and scientific advisory boards VIIV, Merck, Gilead, Janssen and Mylan

Bart Rijnders: Research grants for DAHHS1 and DAHHS2 study from MSD. Research grant from Health-Holland, member of advisory boards for Gilead, MSD, BMS, AbbVie

Christoph Boesecke: Honoraria for lectures and/or consultancies from AbbVie, Gilead, Janssen, MSD and ViiV. Funding from Deutsche Leberstiftung, DZIF, Hector Stiftung and NEAT ID

Colette Smit: No conflict of interest

Colette Smith: Honoraria for preparation and delivery of educational materials from Gilead, Janssen, and ViiV

Elske Hoornenborg: Research grant from Gilead Sciences, paid to institute

Gail Matthews (Co-chair pathogenesis, natural history and treatment): Research funding from Abbvie and Gilead.

Heiner Wedemeyer: Honoraria for speaking/consulting: Abbott, Abbvie, BMS, Bayer, Esei, Gilead, MSD/Merck, Roche. Research grant support: Abbvie, Gilead

Janke Schinkel: Grants from Gilead, Janssen and Abbvie

Juan Berenguer: Research grants from GILEAD sciences, MSD, and ViiV. Honoraria for lectures and/or consultancies from AbbVie, GILEAD, Janssen, MSD, and ViiV

Jürgen K. Rockstroh (Co-chair pathogenesis, natural history and treatment): Honoraria for lectures or consultancies from Abivax, Abbvie, Gilead, Janssen, Merck, Siemens and ViiV

Karine Lacombe (Co-chair Transmission and prevention): Honoraria for lectures and/or consultancies from AbbVie, Gilead, Janssen, MSD and ViiV. Funding from Sidaction and ANRS

Lars Peters: No conflict of interest

Laurent Cotte: Honoraria for lectures and/or consultancies, inscription to conferences and travel expenses from AbbVie, Gilead Sciences, Janssen Cilag, MSD and ViiV

Luisa Salazar-Vizcaya: No conflict of interest

Maria Prins: M.P.'s institution has received speakers fees and independent scientific support from Gilead Sciences, Roche, MSD and Abbvie, outside the submitted work

Massimo Puoti: Honoraria for lectures and or consultancies from MSD, Gilead Science Nordic Pharma and Abbvie

Milosz Parczewski: Honoraria for lectures and or Advisory Boards from AbbVie, Gilead, Janssen, MSD and ViiV. Funding from Polish Minstry of Science and Higher Education.

Natasha Martin: Unrestricted research grants from Gilead and Merck

Patrick Ingiliz: Unrestricted grant from Gilead, honoraria for lectures or consultancies from Gilead, AbbVie, ViiV

Paul Zandkuijl: Funding for his contribution to NoMoreC, a project of the MC Free (Amsterdam MSM Hepatitis C Free) consortium. MC Free is funded by Gilead Sciences, AbbVie, Janssen-Cilag, Merck Sharpe & Dohme, and Roche Diagnostics

Sanjay Bhagani (Co-chair case definition and diagnosis): Grant and Research support from Abbvie, Gilead, MSD and ViiV. Honoraria for education programmes and advisory Boards for Gilead and ViiV

Stephan Dressler: Honorarium for consultancy from Janssen

Susanna Naggie: Grant support from AbbVie, Gilead, Tacere, Janssen. Scientific Advisor for Vir Bio and BioMarin. Serves on event adjudication committee for FHI360 and PRA

Thijs van de Laar: No conflict of interest

Thomas Reiberger: Grant support from Abbvie, Gilead, MSD; speaking honoraria from Abbvie, Gilead, Roche, MSD; consulting/advisory board fee from Abbvie, Gilead, MSD; and travel support Gilead and Roche.

AIDS. 34(14):2161-2163, November 15, 2020.

Introduction

In response to growing evidence of an expanding epidemic of sexually acquired hepatitis C virus (HCV) infection in HIV-positive MSM, the European AIDS Treatment Network (NEAT) acute hepatitis C consensus panel developed their first recommendations for HCV prevention and care during a consensus conference in May 2010 in Paris, France [1].

Since then, two major breakthroughs have changed the landscape. First, directly acting antivirals (DAA) with high levels of tolerability and HCV cure rates of over 95% are now widely available and will play a large role in the goal of elimination of HCV by 2030 (WHO sector strategy [2]). Second, landmark studies demonstrated that universal test and treatment (UTT) approach as well as the demonstration that HIV cannot be sexually transmitted from a person living with HIV (PLHIV) with an undetectable viraemia [undetectable = untransmittable (U = U) campaign] and HIV preexposure prophylaxis (PrEP) are very effective HIV biomedical prevention strategies for MSM [3–6]. The scale-up of these interventions has reduced HIV incidence in MSM and also changed patterns of sexual networks and behaviour [7,8], which has contributed to increased HCV incidence among HIV-negative MSM who were eligible for or on PrEP. This could potentially refuel the HCV epidemic in high-risk HIV-positive MSM [9–12].

These recent developments, together with new clinical and scientific insights, underscore the importance of updating the statements and recommendations for acute HCV in both HIV-positive and HIV-negative MSM. In June 2019, experts from different disciplines and organizations including community representatives participated at the second acute HCV consensus conference of NEAT Infectious Diseases (NEAT-ID) in Amsterdam, the Netherlands. Three working groups prepared and presented updated draft statements and recommendations for consideration at the meeting, following careful review of the literature and guidelines. Statements and recommendations on case definitions and diagnosis, transmission and prevention, pathogenesis, natural history and implications for treatment and prevention of HCV were fine-tuned and subsequently graded by the strengths of recommendation and the level of evidence, using the grading procedure of the first consensus conference (see Table 1). A consensus was reached if 90% or more of the participants were in favour of a recommendation.

Table 1
Table 1:
Grading strength of recommendation and level of evidence.

Case-definition and diagnosis

Historically, HCV infection has been classified as either acute or chronic. By convention, acute hepatitis C was defined as the first 6 months of infection, and chronic disease from 6 months onwards. But recent insights into the natural history of HCV infection persistence, emerging trends in transmission patterns, and the evolution in HCV therapy challenge this classification.

The term ‘acute’ is defined as ‘an illness present or experienced to a severe or intense degree but of short duration’ (see https://en.oxforddictionaries.com/definition/acute). Acute hepatitis C is usually neither severe nor symptomatic in the vast majority of individuals [13]. Furthermore, the majority of HCV-infected individuals are diagnosed based on elevated serum aminotransferases, by exposure-based testing or by routine HCV screening [14]. Therefore, precise timing of infection is often difficult to identify and many infections traditionally termed ‘acute’ do not fulfil the standard criteria of ‘intense illness of short duration’. Thus, the current classifications of acute and chronic hepatitis C may not be appropriate.

The terminology of ‘acute’ and ‘chronic’ HCV infections is relevant in routine clinical care. Many guidelines [15–17] and funding authorities have used these terms, based on time from diagnosis, to define eligibility for treatment with DAA. DAA therapies are often not reimbursed in those with ‘acute’ infection as the licensing of DAA is based on studies in chronic HCV infection, using its traditional definition of longer than 6 months duration [18–21]. Furthermore, lack of spontaneous clearance and progression to chronic infection can be predicted reliably by 4 weeks after diagnosis (see below). Given the excellent efficacy and safety of DAA and the evident benefits of eradicating HCV infection, delaying therapy in patients with a very low likelihood of spontaneous clearance may serve as an unnecessary barrier to access HCV cure.

The concept of treatment-as-prevention has gained importance as a key strategy to combat HCV epidemics among HIV-positive MSM with a number of studies reporting a reduction in the incidence of HCV infection in the post-DAA era, particularly in settings with widespread access to HCV therapy [22–25]. Recent data from modelling studies [26,27] add weight to the concept that immediate treatment after HCV diagnosis may be a cost-effective strategy when including prevention benefits. Postponing therapy until reaching the largely arbitrary traditional definition of chronic infection increases the risk of onward HCV transmission unnecessarily.

There have been a number of published studies assessing the strategy of shorter durations of interferon (IFN)-sparing or DAA-based therapy in patients with acute and early HCV infection [28–31]. Many of these studies have defined acute or early HCV infection as within 6 months after diagnosis and an estimated duration of infection of less than 12 months. These strategies and recommendations for treatment are discussed in detail in a separate chapter, and emphasize the benefits of earlier access to DAA therapy.

Taken together, there is a need to adapt the current terminology in order to optimize surveillance and management of HCV infections. We, therefore, propose the use of the term ‘recently acquired HCV infection’ to replace ‘acute’ HCV infection (see below for case-definition), and the term ‘early chronic HCV infection’ whenever both lack of spontaneous clearance can be reliably predicted and the estimated duration of infection is less than 12 months (see below for case definition).

Diagnosis of recently acquired hepatitis C virus infection

No commercially available serological test at a single time-point reliably diagnoses recently acquired HCV infection. HCV antibody responses may be delayed or absent in HIV-positive MSM with two-thirds anti-HCV positive at 3 months and 5% remaining negative up to 1 year after infection [32,33].

The most sensitive and earliest marker of HCV infection is serum or plasma HCV-RNA detected through nucleic acid testing (NAT), which is detectable as early as 1 week postinfection [34]. However, in the early phase of infection the HCV RNA levels are dynamic and can be intermittently undetectable. More recently, data have suggested that HCV core-antigen (HCV-cAg) testing is a cheaper useful proxy for HCV-RNA, and may be useful in the diagnosis of new HCV infections, although it is not yet widely available in many settings [35–37].

A rise in serum aminotransferases is common following initial HCV infection by about 6--12 weeks. In a retrospective study in HIV-positive MSM, 88% experienced elevated alanine aminotransferases (ALTs) within 3 months of HCV infection [38]. However, the rise in serum aminotransferases may be modest, and using a cut-off of 10 times upper limit of normal used in previous studies, will miss the majority of patients with recently acquired HCV when no previous anti-HCV or HCV RNA test results are available to document seroconversion. Furthermore, the elevation in serum aminotransferases is transient and can be easily missed if testing frequency is not sufficient.

Spontaneous clearance after HCV infection will occur in up to 15% of HIV-positive MSM [34,38,39]. In a recent modelling study, spontaneous clearance was estimated to occur at a median of 184 days after infection, with a median delay of diagnosis from the time of infection of 115 days or 170 days, depending on whether the frequency of testing interval is 3 months or 6 months [40]. Lack of spontaneous clearance in PLWH may be reliably predicted as early as 4 weeks after initial presentation by serial HCV RNA quantitation measurements: In the PROBE-C study, only two out of 401 HIV-positive MSM with a less than 2 log10 HCV RNA reduction after 4 weeks cleared HCV infection spontaneously [41]. This is also discussed in more detail below in the chapter ‘Pathogenesis, natural history and treatment’.

HCV re-infection either after spontaneous clearance or treatment-induced sustained viral response (SVR12, defined as an undetectable HCV RNA 12 weeks after the end of treatment) is a well recognized phenomenon, especially in HIV-positive MSM with ongoing risk behaviour [42]. However, late relapse post DAA-induced SVR12, although very infrequent, has been observed [43–46], as have rare cases of prolonged spontaneous remission with relapse of viraemia [47]. It is, therefore, important to recognize re-infection, not only in terms of tracking the epidemiology but also for the purposes of addressing risk-behaviour and re-treatment. The distinction between relapse and reinfection is important with regard to treatment, as the recommended regimens may differ between those with previous treatment failure and those with a re-infection, which is treated as a new infection [15–17].

Consensus recommendations: case definition of recently acquired hepatitis C virus infection

Preferred criteria

Positive anti-HCV IgG and a documented negative anti-HCV IgG in the previous 12 months (AII)

OR

Positive HCV-RNA (AII) or HCV-cAg (BII) with a documented negative HCV-RNA or HCV-cAg or negative anti-HCV IgG in the previous 12 months

Alternative criteria

If historical data with regards to serological or HCV-RNA tests are unavailable, recently acquired hepatitis C may be diagnosed if the following criteria are met:

Positive HCV-RNA or HCV-cAg with a concomitant negative anti-HCV IgG (AII)

OR

Positive HCV-RNA or HCV-Ag with a positive anti-HCV IgG and a three-fold or greater rise in ALT above baseline, associated with risk-behaviour (as defined below) in the last 6 months

And

Exclusion of other acute viral hepatitis and more likely causes of acute liver injury (BII)

Consensus recommendations: case-definition of recently acquired HCV re-infection

This may be defined as recently acquired HCV reinfection (using the case-definitions above), with

a positive HCV-RNA or HCV-cAg following spontaneous clearance (i.e. confirmed undetectable HCV RNA after the first positive HCV test) or treatment-induced sustained virological response (i.e. undetectable HCV RNA at least 12 weeks after completion of DAA therapy) (AII)

OR

HCV genotype switch or infection with a different HCV strain of the same genotype (confirmed by sequencing), following documented spontaneous clearance or after end-of-treatment response (AII)

Consensus recommendations: estimating the duration of HCV infection

The time of exposure/infection may be inferred as

the mid-point between last negative anti-HCV IgG and first positive HCV-RNA, HCV-cAg or anti-HCV IgG (whichever is first), in the absence of an ALT rise or clinical symptoms (BII)

OR

in the presence of clinical symptoms or an ALT rise, 6 weeks prior to the highest documented ALT, HCV-RNA or HCV-cAg, whichever comes first (BII).

Consensus recommendations: case-definition of early chronic HCV

This may be defined as

an estimated duration of infection less than 12 months and a low likelihood of spontaneous clearance (AII)

A lack of a 2 log10 reduction on repeat HCV RNA testing 4 weeks after initial presentation with recently acquired HCV may be used to predict low-likelihood (<1%) of spontaneous clearance.

Hepatitis C virus transmission and prevention

Sharing equipment for injecting drug use has long been recognized as a mode of percutaneous transmission of HCV. From the early 2000s, transmission of HCV through sexual contact in MSM has become increasingly recognized, although the specific activities leading to transmission remain unclear [48]. A large body of epidemiological research has emerged from 2010 onwards examining the sexual routes of mucosal HCV transmission in MSM [49–54]. Nevertheless, the combination of activities and small samples across studies have made it difficult to consistently identify the types of risk-factors involved in transmission of HCV through sexual contact. It is clear that contact with infected bodily fluids or blood is necessary for HCV to spread from one individual to the other [55]. Certain risk-factors increase the probability that blood--blood contact occurs (i.e. fisting, sharing sex toys), while there are certain settings whereby at-risk activities are more likely to take place (i.e. group sex, ‘chemsex’ including ‘slamming’).

Consensus recommendations: hepatitis C virus transmission pathways

A known effective mode of percutaneous HCV transmission is sharing equipment for injecting drug use (AII)

Recognized risk-factors associated with mucosal HCV transmission include fisting, receptive condomless anal intercourse, sharing equipment during nasally administered drug use, sharing sex toys, sharing anal douching equipment, and engaging in anal intercourse causing rectal trauma with bleeding. The presence of ulcerative sexually transmitted infections (STIs) increases the risk of HCV transmission (BII).

Recently acquired HCV infection and HCV re-infection have been mostly observed in persons who inject drugs (PWID) [56], HIV-positive MSM [57–60], and HIV-negative MSM using preexposure prophylaxis for HIV [10,37]. Some studies in HIV-negative MSM have failed to identify widespread HCV infection [61–62]. Nevertheless, HCV transmission between these ‘key’ populations has increased over the past years [9,12]. Identifying new HCV infections solely based on belonging to a key population is not sufficient and the assessment of risk of HCV infection should be based on whether the individual is engaging in risk activities associated with HCV transmission. We do note, however, that data on at-risk activity and HCV incidence are lacking for specific key populations, particularly transgender persons.

Consensus recommendations: hepatitis C virus key populations

Key populations for HCV primary infection and reinfection are as follows:

PWID and MSM engaging in activities associated with increased risk of HCV transmission (see above in ‘HCV transmission’) (AII)

Hepatitis C virus testing

Treatment-induced clearance is necessary in order to stop onward transmission from individuals infected with HCV who do not spontaneously clear infection, and who remain untreated and continue to engage in at-risk activity [57]. Early identification of HCV-infected individuals is, therefore, necessary to immediately treat and prevent onwards HCV transmission.

There are several existing recommendations available for HCV testing [15,63–65]. The overarching theme of these recommendations is that individuals engaging in at-risk activity should be frequently and repeatedly tested for HCV as long as they are still at-risk of infection. Increasing testing frequency may be required for HCV elimination depending on the population prevalence and incidence of HCV infection and patterns of ongoing at-risk activity (herein defined as the ‘local epidemiology’) [65]. Here, we emphasize the need to regularly test for HCV in light of at-risk behaviour.

Consensus recommendations: hepatitis c virus testing intervals

MSM engaging in activities associated with increased risk of HCV transmission (defined in ‘HCV transmission’) should be tested for HCV infection every 3--6 months (AIII)

Recommendations have also provided guidance on the most sensitive viral markers to be used in order to identify recently acquired HCV infection. Individuals known to have never had an HCV infection, who are thus susceptible to primary infection, can be screened for HCV using a quality assured anti-HCV antibody assay. Some HIV positive persons suspected of recently acquired primary HCV infection might not have seroconverted to become anti-HCV positive (preseroconversion) for up to 1 year after infection and will require testing for HCV RNA replication [32,33]. Those who have previously spontaneously cleared infection are very likely to maintain anti-HCV antibody-positive status for extended periods of time, often for life [66]. Patients who received DAA therapy within 6 months after infection quite often do not develop HCV IgG antibodies or serorevert from anti-HCV positive to negative. Individuals, who are susceptible to reinfection, need to be screened using HCV RNA unless seroreversion was documented after which HCV IgG screening can be used instead. Alternatively, active infection can be screened using HCV-core antigen (Ag) as a proxy for active replication [35].

Consensus recommendations: HCV testing methods

HCV testing includes anti-HCV antibodies for primary infection and HCV-RNA or HCV-core Ag detection for reinfection or suspected recently acquired primary HCV infection (preseroconversion) (AII)

Given the strong association between sexually transmitted infections (STI) and HCV infection [49,50,53,54,67,68] as well as the shared routes of transmission with HIV [63], these infections should be tested in persons newly diagnosed with HCV. Partners (i.e. those who have engaged in risk behaviour with the person infected with HCV, be it through sexual contact and/or injecting drug use) should be notified of a potential HCV infection and should be referred for testing.

Consensus recommendations: additional testing

The management of those diagnosed with recently acquired HCV infection should include screening for HIV/STIs and partner notification for HCV testing (AII)

HIV testing for HIV-negative individuals.

Efforts needed to reduce hepatitis C virus transmission

HCV prevention must entail a comprehensive strategy, which includes risk assessment, strategies for test and treat, and education about HCV transmission risk behaviours, how to reduce these behaviours and psychological support to achieve behaviour change [69]. Tools are available for risk-factor assessment [16,70] and physicians need to ask their patients in a nonstigmatizing/nonjudgmental manner about possible risk behaviours associated with HCV transmission. As the steps involved in HCV care might be unclear for many individuals in key populations [71], information should be provided on how those at-risk of infection can be tested and how those recently diagnosed can access care and receive prompt treatment. As many patients are unaware of how HCV is acquired [72,73], any individual receiving a diagnosis of HCV infection should be educated about risk factors and risk-reduction strategies. For MSM, these include promoting safe practices and/or discouraging unsafe practices including: Not sharing injection equipment, safe disposal of syringes/needles, not sharing straws for nasally administered drug use, condom use for anal sex, using (and importantly not reusing) gloves for fisting, not sharing anal douches or sex toys. Single-use injection equipment, straws, gloves, anal douches, and so forth, help ensure that these materials are not shared. Naturally, prevention strategies might differ between individuals who have never had an HCV infection, are currently infected, or have been previously infected.

Consensus recommendations: risk assessment

For those belonging to a key population who never had an HCV infection, assessment of risk for HCV infection should be performed. Information on testing opportunities and risk reduction should be provided where indicated.

For those with viremic HCV infection, advice regarding HCV treatment and risk factors for transmission to others should be given.

For those with previous HCV infection, assessment of risk for HCV reinfection should be performed. Information on testing opportunities and support to achieve risk reduction should be provided (AIII)

Successful anti-HCV therapies have given hope that elimination of HCV is possible. One of the elimination targets set by the WHO is an 80% reduction in the incidence of HCV infection, from 2015 levels, by 2030 [74]. The intensity of intervention scale-up required to achieve this target depends in part on the local epidemiology. Modelling indicates that DAA treatment scale-up, particularly in combination with harm reduction, can achieve the WHO incidence target globally, as well as among MSM [75–77]. Already, several settings, specifically after widespread uptake of DAA therapy, have seen large declines in incidence rates of recently acquired HCV among MSM, whereas others have observed steady or even increased rates [22,23,58,78]. The explanation for these latter situations could be insufficient changes in risk behaviour and/or insufficient testing practices needed to curb HCV incidence, as illustrated in modelling studies [79,80]. Consequently, other measures involving more frequent testing, scale-up of screening, and risk behaviour reduction alongside treatment and retreatment of reinfection might be required. We stress that local epidemiology and key populations affected should guide the needs for these public health measures.

Consensus recommendations: HCV transmission reduction

Providing HCV treatment immediately after diagnosis to those with ongoing risk behaviour can act as a public health measure by reducing HCV transmission.

To further reduce HCV transmission, other public health measures include a combination of screening, treatment (including treatment of re-infection), and interventions to reduce HCV risk behaviour (AII)

Natural history and implications for treatment of recently acquired hepatitis C

Rates and predictors of spontaneous hepatitis C virus RNA clearance

A recently acquired hepatitis C infection induces a range of innate and adaptive immune responses potentially leading to spontaneous clearance of HCV infection.

The rate of and factors associated with spontaneous viral clearance in HIV-positive MSM with recently acquired acute hepatitis C have been studied in prospective cohorts. Rates of spontaneous viral clearance in HIV-positive MSM with recently acquired hepatitis C in the large PROBE-C cohort have been reported to be low with 11.8% [41]. In this observational European cohort, 465 acute hepatitis C episodes between 2007 and 2016 were documented in HIV-positive patients with at least 12 months of follow-up. The only significant factor associated with spontaneous clearance was a greater than 2 log10 drop in HCV RNA 4 weeks after initial HCV determination. There was, however, no statistically significant association between spontaneous clearance and HCV transmission risk, HCV genotype, HCV RNA levels nor baseline ALT or HIV parameters [41]. Further data come from a single centre of the St Mary's Acute HCV Cohort, which again found spontaneous clearance to be strongly associated with not only an approximate 2 log10 viral load drop within 100 days of infection but also elevated bilirubin (≥ 40 μmol/l), elevated alanine aminotransferase (ALT; ≥ 1000 IU/ml) and higher baseline CD4+ cell count at least 650/μl [38]. Moreover, spontaneous clearance was noted only in patients with genotype 1 infection. Higher spontaneous clearance rates of 24% were reported by Grebely et al.[81] for PLWH with recently acquired HCV infection, which was only slightly lower than the 28% clearance rates observed in HIV-negative individuals with recently acquired HCV infection. In this large cohort female sex, favourable IL28B genotype, and HCV genotype 1 were identified as independent predictors of spontaneous clearance [81]. More recently, a meta-analysis estimated that spontaneous viral clearance occurs in 15.4% of HIV-positive MSM [82]. In multivariate analysis among HIV-positive MSM, no variables were found to affect spontaneous viral clearance [82].

Consensus recommendation: natural history of hepatitis C infection

Following recently acquired HCV infection, transition to chronic hepatitis C is by far the most common outcome in individuals with or without HIV infection (AII)

Monitoring and timing of early antiviral therapy

Ideally, only those MSM without spontaneous HCV clearance would be considered candidates for early antiviral treatment. However, delays in treatment may lead to onward HCV transmission in the setting of ongoing risk behaviour. The high rate of HCV reinfection in HIV-positive as well as HIV-negative MSM underlines the difficulties in changing or modifying ongoing risk behaviour [42,10]. Indeed, in almost all treatment trials of recently acquired HCV infection in MSM, reinfections before the SVR12 time-point have been observed, and was determined by appearance of a different HCV genotype or reinfection with a new HCV infection from the same genotype demonstrated by phylogenetic analysis (see Table 2). Moreover, early treatment of recently acquired hepatitis C was followed by a dramatic decrease in new HCV infections of around 50% during continued follow-up in recent study reports from Netherlands, Switzerland and the United Kingdom [16,22,88]. Importantly this suggests that early treatment of recently acquired HCV infection from a public health point of view will contribute to HCV elimination. Further, treating early is likely to over-treat only a small proportion of MSM who otherwise may have cleared infection spontaneously as the large majority of MSM (>80%) with recent HCV infection will eventually require DAA therapy anyway. DAA therapy is also highly tolerable with an excellent side effect profile so there is no contraindication for use in recently acquired HCV infection even in those who may have gone onto spontaneously clearing HCV infection. On the basis of these findings, we consider a newly detected HCV RNA as an indication for antiviral therapy in all MSM with ongoing risk behaviour in order to prevent any further HCV transmission.

Table 2
Table 2:
Interferon-free direct-acting antivirals in clinical trials of acute and recent hepatitis C virus infection.

Therefore, in all MSM without a 2 log10 drop in HCV-RNA after 4 weeks after initial HCV RNA positivity, early chronic HCV infection can be assumed and immediate antiviral therapy is recommended. For those MSM, who do exhibit a more than 2 log10 drop at week 4, repeat HCV RNA measurements are recommended as fluctuations in HCV viral load and subsequent reappearance of HCV vermeil has been described [89,90]. All patients with confirmed spontaneous clearance [2 HCV RNA levels below the limit of detection (TND) at least 4 weeks apart], should have a further HCV RNA 6–12 months subsequently for final confirmation and repeated HCV RNA testing every 3–6 months in the ones at risk of HCV reinfection.

Consensus recommendation: monitoring and initiation of treatment in the course of hepatitis C infection

Detection of HCV-RNA is an indication for the consideration of DAA therapy (AII)

In MSM with ongoing risk behaviour, immediate HCV treatment after diagnosis is recommended to prevent transmission (AII)

In MSM without ongoing risk behaviours, deferral of therapy may be considered; HCV RNA should then be re-quantified after another 4 weeks (AII)

In those without a 2 log10 drop (i.e. 100-fold) of HCV RNA 4 weeks after diagnosis or meeting other criteria for early chronic infection, HCV treatment is recommended (AII)

MSM spontaneously achieving undetectable HCV RNA should undergo repeated HCV-RNA testing to confirm spontaneous clearance; this should be done at least 4 weeks from first undetectable result and confirmed after another 6 and 12 months (AII)

Treatment of recently acquired hepatitis C in the era of directly acting antiviral therapies

Prior to the availability of DAA therapy, management of acute or recently acquired HCV infection involved the use of IFN-based treatment in short and/or response-guided durations [29,91–94]. Even in the setting of HIV infection, SVR rates were relatively high compared with those in chronic HCV infection [95–97]. Over the last decade, the advent of highly effective, well tolerated all oral DAA therapies has dramatically altered the paradigm of treatment in chronic hepatitis C with increases in rates of cure to more than 95% [98–100]. During the same period, various research studies have evaluated the use of these new agents in shortened durations in acute/recent infection.

The first IFN-free and RBV-free regimens in recently acquired infection were explored in two separate German studies using a 6-week treatment course of SOF/ledipasvir (LDV) for genotype 1/4 infection [28,85]. The HEP-NET Acute HCV 4 study included 20 HCV mono-infected individuals, whilst SOL included 26 individuals with HIV/HCV co-infection. Although the SVR12 rate reached 100% in the HEP-NET study, the HCV RNA load at the start of therapy was atypically low at 4 log10 and no PLWH were included. The 6-week SOF/LDV regimen was less successful in the subsequent SOL study at 77% [95% confidence interval (CI) 56–91%] in intention-to-treat (ITT) analysis. In the per-protocol analysis the results were better but still suboptimal at 86% with three patients relapsing. Baseline HCV RNA in these three patients was high (>6.7 log10). Other studies in the GT1/4 HIV-positive population have included Cohort 2 of the SWIFT-C study (n = 27; 8 weeks SOF/LDV: SVR 100%) [30], TARGETED Cohort 1 (n = 30; 8 weeks paritaprevir/ritonavir/ombitasvir + dasabuvir +/- RBV; SVR ITT 97%, PP 100%) [29] and DAHHS2 (n = 80; 8 weeks elbasvir/grazoprevir; SVR ITT 94%, PP 99%) [31]. Although these data generally support the use of 8 weeks of DAA therapy with GT1/4 regimens, all studies except the DAHHS2 study are small studies with diverse populations and entry criteria. To avoid the potential for relapse, particularly in patients with very high baseline viral loads, noncirrhotic HIV-positive or HIV-negative MSM with acute or recently acquired HCV infection may more safely be treated with the same duration regimens as recommended for treatment-naïve noncirrhotics with chronic HCV infection.

Current treatment guidelines for chronic HCV infection generally recommend the use of pan-genotypic regimens wherever possible because of their very high efficacy and the ability to avoid genotyping. Data on the two pan-genotypic regimens of SOF/velpatasvir (VEL) and glecaprevir/pibrentasvir (G-P) in the setting of acute or recent infection are currently limited. One study (TARGETED Cohort 2) has been reported to date using 6 weeks of G-P in 30 individuals with recent HCV (77% with HIV) [86]. The SVR rate in this small study was 90% by ITT and 96% by per-protocol analysis. The one patient with virological relapse (confirmed by sequencing) had very high baseline viral load at 7.7 log10. A number of other pan-genotypic studies are currently ongoing: REACT study (NCT02625909, 6 versus 12 weeks SOF/VEL), TARGETED Cohort 3 (NCT02634008, 4 weeks of G/P) and ACTG PURGE-C (NCT04042740, 4 weeks G/P) and final results are expected in 2020. Following a higher number of relapsers in the 6 weeks arm the data and safety monitoring board (DSMB) of the REACT Study stopped enrollment into the trial and interim results showing inferiority of a shortened treatment duration of 6 versus 12 weeks of SOF/VEL were recently presented [101]. Unfortunately, except for the REACT study all these pan-genotypic regimen studies are set-up as pilot studies. Therefore, adequately powered studies with a sufficient number of each of the three most frequent genotypes typically diagnosed in patients with a recently acquired HCV infection (genotype 1, 3 and 4) are urgently needed to get to the registration of DAA regimens for the treatment of recently acquired HCV. Pending further data, the Consensus Conference Panel recommends the following in relation to the treatment of recently acquired HCV infection:

Consensus recommendations: treatment of recently acquired HCV infection

All oral DAA combination therapy is recommended for the treatment of recently acquired hepatitis C infection (AI)

In case of immediate treatment or unavailable HCV genotype result, a pan-genotypic DAA regimen is recommended (AII)

Dosing and duration of DAA regimens for recently acquired HCV infection should follow current HCV treatment guidelines (AII)

Immediate treatment of HCV reinfection with DAAs is recommended (AII)

Acknowledgements

Particular thanks to Lina Nerlander, Erika Duffell and Teymur Noori from ECDC and Yvan Hutin from WHO for review.

Panel members and conflicts of interest: The development of guidelines demanded commercial independence and avoidance of potential conflicts of interest, which could influence statements and recommendations made. The organization and related expenses of the consensus conference were, therefore, solely funded through NEAT ID.

All conference participants were asked to declare any conflicts of interest.

The NEAT ID consensus panelists who were able to participate at the conference and vote on the statements/recommendations were:

Alison Rodger: no conflicts of interest.

Anastasia Pharris: no conflicts of interest.

Anders Boyd (Co-chair Transmission and Prevention): no conflicts of interest.

Andri Rauch (Co-chair Case Definition and Diagnosis): Advisory boards: MSD, Gilead Sciences, Abbvie. Travel grants: Gilead Sciences, Pfizer, Abbvie. Research support: Investigator initiated trial grant from Gilead Sciences. All remuneration went to his home institution and not to AR personally.

Anton Pozniak: research grants from VIIV, Merck, Gilead, and lecture fees and scientific advisory boards VIIV, Merck, Gilead, Janssen and Mylan.

Bart Rijnders: research grants for DAHHS1 and DAHHS2 study from MSD. Research grant from Health-Holland, member of advisory boards for Gilead, MSD, BMS, AbbVie.

Christoph Boesecke: honoraria for lectures and/or consultancies from AbbVie, Gilead, Janssen, MSD and ViiV. Funding from Deutsche Leberstiftung, DZIF, Hector Stiftung and NEAT ID.

Colette Smit: no conflicts of interest.

Colette Smith: honoraria for preparation and delivery of educational materials from Gilead, Janssen, and ViiV.

Elske Hoornenborg: research grant from Gilead Sciences, paid to institute.

Gail Matthews (Co-chair Pathogenesis, Natural History and Treatment): research funding from Abbvie and Gilead.

Heiner Wedemeyer: honoraria for speaking/consulting: Abbott, Abbvie, BMS, Bayer, Esei, Gilead, MSD/Merck, Roche. Research grant support: Abbvie, Gilead

Janke Schinkel: grants from Gilead, Janssen and Abbvie.

Juan Berenguer: research grants from GILEAD sciences, MSD, and ViiV. Honoraria for lectures and/or consultancies from AbbVie, GILEAD, Janssen, MSD and ViiV.

Jürgen K. Rockstroh (Co-chair Pathogenesis, Natural History and Treatment): honoraria for lectures or consultancies from Abivax, Abbvie, Gilead, Janssen, Merck, Siemens and ViiV.

Karine Lacombe (Co-chair Transmission and Prevention): honoraria for lectures and/or consultancies from AbbVie, Gilead, Janssen, MSD and ViiV. Funding from Sidaction and ANRS.

Lars Peters: no conflicts of interest.

Laurent Cotte: honoraria for lectures and/or consultancies, inscription to conferences and travel expenses from AbbVie, Gilead Sciences, Janssen Cilag, MSD, and ViiV.

Luisa Salazar-Vizcaya: no conflicts of interest.

Maria Prins: M.P.'s institution has received speakers fees and independent scientific support from Gilead Sciences, Roche, MSD and Abbvie, outside the submitted work.

Massimo Puoti: honoraria for lectures and or consultancies from MSD, Gilead Science Nordic Pharma and Abbvie.

Milosz Parczewski: honoraria for lectures and or Advisory Boards from AbbVie, Gilead, Janssen, MSD and ViiV. Funding from Polish Minstry of Science and Higher Education.

Natasha Martin: unrestricted research grants from Gilead and Merck.

Patrick Ingiliz: unrestricted grant from Gilead, honoraria for lectures or consultancies from Gilead, AbbVie, Viiv.

Paul Zandkuijl: funding for his contribution to NoMoreC, a project of the MC Free (Amsterdam MSM Hepatitis C Free) consortium. MC Free is funded by Gilead Sciences, AbbVie, Janssen-Cilag, Merck Sharpe & Dohme, and Roche Diagnostics.

Sanjay Bhagani (Co-chair Case Definition and Diagnosis): grant and research support from Abbvie, Gilead, MSD and ViiV. Honoraria for education programmes and advisory Boards for Gilead and ViiV.

Stephan Dressler: honorarium for consultancy from Janssen.

Susanna Naggie: grant support from AbbVie, Gilead, Tacere, Janssen. Scientific Advisor for Vir Bio and BioMarin. Serves on event adjudication committee for FHI360 and PRA.

Thijs van de Laar: no conflicts of interest.

Thomas Reiberger: grant support from Abbvie, Gilead, MSD; speaking honoraria from Abbvie, Gilead, Roche, MSD; consulting/advisory board fee from Abbvie, Gilead, MSD; and travel support Gilead and Roche.

Conflicts of interest

Conflicts are individually declared. No other conflicts of interest.

References

1. European AIDS Treatment Network (NEAT) Acute Hepatitis C. Infection Consensus PanelAcute hepatitis C in HIV-infected individuals: recommendations from the European AIDS Treatment Network (NEAT) consensus conference. AIDS 2011; 25:399409.
2. World Health OrganizationCombating hepatitis B and C to reach elimination by 2030. Geneva:World Health Organization; 2016.
3. Grant RM, Lama JR, Anderson PL, McMahan V, Liu AY, Vargas L, et al. iPrEx Study TeamPreexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med 2010; 363:25872599.
4. McCormack S, Dunn DT, Desai M, Dolling DI, Gafos M, Gilson R, et al. Preexposure prophylaxis to prevent the acquisition of HIV-1 infection (PROUD): effectiveness results from the pilot phase of a pragmatic open-label randomised trial. Lancet 2016; 387:5360.
5. Molina JM, Capitant C, Spire B, Pialoux G, Cotte L, Charreau I, et al. On-demand preexposure prophylaxis in men at high risk for HIV-1 infectionANRS IPERGAY Study Group. N Engl J Med 2015; 373:22372246.
6. Rodger AJ, Cambiano V, Bruun T, Vernazza P, Collins S, Degen O, et al. PARTNER Study GroupRisk of HIV transmission through condomless sex in serodifferent gay couples with the HIV-positive partner taking suppressive antiretroviral therapy (PARTNER): final results of a multicentre,prospective, observational study. Lancet 2019; 393:24282438.
7. Traeger MW, Schroeder SE, Wright EJ, Hellard ME, Cornelisse VJ, Doyle JS, Stoové MA. Effects of preexposure prophylaxis for the prevention of human immunodeficiency virus infection on sexual risk behavior in men who have sex with men: a systematic review and meta-analysis. Clin Infect Dis 2018; 67:676686.
8. Brown AE, Nash S, Connor N, Kirwan PD, Ogaz D, Croxford S, et al. Towards elimination of HIV transmission, AIDS and HIV-related deaths in the UK. HIV Med. 2018 Jun 20. HIV Med 2019; 20:7476.
9. Hoornenborg E, Achterbergh RCA, Schim van der Loeff MF, Davidovich U, Hogewoning A, de Vries HJC, et al. Amsterdam PrEP Project team in the HIV Transmission Elimination AMsterdam Initiative, MOSAIC study groupMSM starting preexposure prophylaxis are at risk of hepatitis C virus infection. AIDS 2017; 31:16031610.
10. Cotte L, Cua E, Reynes J, Raffi F, Rey D, Delobel P, et al. Dat’AIDS study GroupHepatitis C virus incidence in HIV-infected and in preexposure prophylaxis (PrEP)-using men having sex with men. Liver Int 2018; June 30.
11. Price JC, McKinney JE, Crouch PC, Dillon SM, Radix A, Stivala A, et al. Sexually acquired hepatitis C infection in HIV-uninfected men who have sex with men using preexposure prophylaxis against HIV. J Infect Dis 2018; 219:13731376.
12. Ramière C, Charre C, Miailhes P, Bailly F, Radenne S, Uhres AC, et al. Lyon Acute Hepatitis Study GroupPatterns of HCV transmission in HIV-infected and HIV-negative men having sex with men. Clin Infect Dis 2019; 69:21272135.
13. Orland J, Wright TL, Cooper S. Acute hepatitis C. Hepatology 2001; 33:321327.
14. Hajarizadeh B, Grebely J, Dore G. Case definitions for acute hepatitis C virus infection: a systematic review. J Hepatol 2012; 57:13491360.
15. European Association for the Study of the LiverEASL Recommendations on Treatment of Hepatitis C 2018. J Hepatol 2018; 69:461511.
16. The American Association of the Study of Liver Diseases and the Infectious Diseases Society of America. HCV Guidance: recommendations for Testing, Managing and Treating Hepatitis C. Last updated 24 May 2018. Available at: https://www.hcvguidelines.org/sites/default/files/full-guidance-pdf/HCVGuidance_May_24_2018b.pdf. [Accessed 14 September 2019]
17. European AIDS Clinical Society Guidelines v 10, November 2019. Available at: http://www.eacsociety.org/files/2018_guidelines-10-english.pdf. [Accessed 14 November 2019]
18. Maviret 400 mg/100 mg. Summary of product characteristics. Available at: https://www.ema.europa.eu/en/documents/product-information/maviret-epar-product-information_en.pdf. [Accessed 14 November 2019]
19. Epclusa 400 mg/100 mg. Summary of Product Characteristics. Available at: https://www.ema.europa.eu/en/documents/product-information/epclusa-epar-product-information_en.pdf. [Accessed 14 November 2019]
20. Harvoni 90 mg/400 mg. Summary of Product Characteristics. Available at: https://www.ema.europa.eu/en/documents/product-information/harvoni-epar-product-information_en.pdf. [Accessed 14 November 2019]
21. Zepatier 50 mg/100 mg. Summary of Product Characteristics. Available at: https://www.ema.europa.eu/en/documents/product-information/zepatier-epar-product-information_en.pdf. [Accessed 14 November 2019]
22. Boerekamps A, De Weggheleire A, van den Berk GE, Lauw FN, Claassen MAA, Posthouwer D, et al. Declining hepatitis C virus (HCV) in Dutch human immunodeficiency virus-positive me who have sex with men after unrestricted access to HCV therapy. Clin Infect Dis 2018; 66:13601365.
23. Salazar-Viscaya L, Wandeler G, Fehr J, Braun D, Cavassini M, Stoeckle M, et al. Impact of direct acting antivirals on the burden of hcv infection among persons who inject drugs and men who have sex with men in the Swiss HIV Cohort Study. Open Forum Infect Dis 2018; 5:ofy154.
24. Braun D, Hampel B, Kouyos R, Nguyen H, Shah C, Flepp M, et al. A treatment as prevention trial to eliminate HCV in HIV+ MSM: the Swiss HCVREE trial [abstract]. Clin Infect Dis 2019; 68:569576.
25. Garvey LJ, Cooke GS, Smith C, Stingone C, Ghosh I, Dakshina S, et al.Fall in HCV incidence in HIV+ MSM in London following wider access to DAA therapy [abstract].Conference on Retroviruses and Opportunistic Infections; 4--7 March 2019, Seattle, Washington. CROI; 2019 (Abstract 85).
26. Bethea ED, Chen Q, Hur C, Chung RT, Chhatwal J, et al. Should we treat acute hepatitis C? A decision and cost-effectiveness analysis. Hepatology 2018; 67:837846.
27. Popping S, Hullegie SJ, Boerekamps A, Rijnders BJA, de Knegt RJ, Rockstroh JK, et al. Early treatment of acute hepatitis C infection is cost-effective in HIV-infected men-who-have-sex-with-men. PLoS One 2019; 14:e0210179.
28. Deterding K, Spinner CD, Schotte E, Welzel TM, Gerken G, Klinker H, et al. Ledipasvir plus sofosbuvir fixed-dose combination for six weeks in patients with acute Hepatitis C virus genotype-1 monoinfection (Hepnet Acute HCV IV); an open-label, single-arm, phase 2b study. Lancet Infect Dis 2017; 17:215222.
29. Martinello M, Orkin C, Cooke G, Bhagani S, Gane E, Kulasegaram R, et al. Shortened therapy for eight weeks with paritaprevir/ritonavir/ombitasvir and dasabuvir is highly effective in people with recent HCV genotype 1 infection. J Viral Hepat 2018; 25:11801188.
30. Naggie S, Fierer DS, Hughes MD, Kim AY, Leutkemeyer A, Vu V, et al. for the AIDS Clinical Trials Group (ACTG) 5327 Study TeamLedipasvir-sofosbuvir for 8 weeks to treat acute hepatitis C virus infection in men with HIV-1 infection: SWIFT-C. Clin Infect Dis 2019; 69:514522.
31. Boerekamps A, De Weggheleire A, van den Berk GE, Lauw FN, Claassen MAA, Posthouwer D, et al. 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. Lancet Gastroenterol Hepatol 2019; 4:269277.
32. Thomson E, Nastoul E, Main J, Karayiannis P, Eliahoo J, Muir D, McClure MO. Delayed anti-HCV antibody response in HIV-positive men acutely infected with HCV. AIDS 2009; 23:8993.
33. Vanhommerig JW, Thomas XV, van der Meer JT, Geskus RB, Bruisten SM, Molenkamp R, et al. MOSAIC (MSM Observational Study for Acute Infection with hepatitis C) Study GroupHepatitis C virus (HCV) antibody dynamics following acute HCV infection and reinfection among HIV-infected men who have sex with men. Clin Infect Dis 2014; 59:16781685.
34. Martinello M, Hajarizadeh B, Grebely J, Dore GJ, Matthews GV. Management of acute HCV infection in the era of direct-acting antiviral therapy. Nat Rev Gastroeneterol Hepatol 2018; 15:413424.
35. Cresswell F, Fisher M, Hughes D, et al. Hepatitis C core antigen testing: a reliable, quick and potentially cost-effective alternative to hepatitis C polymerase chain reaction in diagnosing acute hepatitis C virus infection. Clin Infect Dis 2015; 60:263266.
36. Hullegie SJ, Geurtsvankessel L, van der Eljk A, Ramakers C, Rijnders BJA. HCV antigen instead of RNA testing to diagnose acute HCV in patients treated in the Dutch Acute HCV in HIV Study. J Int AIDS Soc 2017; 20:21621.
37. Gras J, Mahjoub N, Charreau I, et al. Early diagnosis and risk factors of acute hepatitis C in high-risk men who have sex with men on preexposure prophylaxis. AIDS 2020; 34:4752.
38. Thomson E, Flemming V, Main J, et al. Predicting spontaneous clearance of acute hepatitis C in a large cohort of HIV-1 infected men. Gut 2011; 60:837845.
39. Aisyah DN, Shallcross L, Hully AJ, O’Brien A, Hayward A. Assessing hepatitis C spontaneous clearance and understanding associated factors-a systematic review and meta-analysis. J Viral Hepat 2018; 25:680698.
40. Ragonnet R, Deuffic-Burban S, Boesecke C, Guiguet M, Lacombe K, Guedj J, et al. Estimating the time to diagnosis and the chance of spontaneous clearance during acute hepatitis C in human immunodeficiency virus infected individuals. Open Forum Infect Dis 2017; 4:ofw235.
41. Boesecke C, Nelson M, Ingiliz P, Lutz T, Scholten S, Cordes C, et al.Can’t buy me love? Obstacles to micro-elimination of acute HCV in Europe [abstract].Conference on Retroviruses and Opportunistic Infections; 2019, March 4-7, Seattle, Washington (WA). CROI; 2019. Abstract [576].
42. Ingiliz P, Martin TC, Rodger A, Stellbrink HJ, Mauss S, Boesecke C, et al. NEAT study groupHCV reinfection incidence and spontaneous clearance rates in HIV-positive men who have sex with men in Western Europe. J Hepatol 2017; 66:282287.
43. Hayashi K, Ishigami M, Ishizu Y, Kuzuya T, Honda T, Hirooka Y, et al. Late relapse of hepatitis C virus in patients with sustained virological response after daclatasvir and asunaprevir therapy. J Viral Hepat 2018; 25:14461451.
44. Wei L, Huang YH. Long-term outcomes in patients with chronic hepatitis C in the current era of direct-acting antiviral agents. Expert Rev Anti Infect Ther 2019; 17:311325.
45. Pisaturo M, Minichini C, Starace M, Caroprese M, Macera M, Brancaccio G, et al. Hepatitis C late relapse in patients with directly acting antiviral-related sustained virological response at week 12. Liver Int 2019; 39:844853.
46. Sarrazin C, Isakov V, Svarovskaia ES, Hedskog C, Martin R, Chodavarapu K, et al. Late relapse versus hepatitis C virus reinfection in patients with sustained virologic response after sofosbuvir-based therapies. Clin Infect Dis 2017; 64:4452.
47. Westbrook RH, Dusheiko G. Natural history of hepatitis C. J Hepatol 2014; 61:S58S68.
48. Nijmeijer BM, Koopsen J, Schinkel J, Prins M, Geijtenbeek TB. Sexually transmitted hepatitis C virus infections: current trends, and recent advances in understanding the spread in men who have sex with men. J Int AIDS Soc 2019; 22: (Suppl 6): e25348.
49. Apers L, Vanden Berghe W, De Wit S, Kabeya K, Callens S, Buyze J, et al. Risk factors for HCV acquisition among HIV-positive MSM in Belgium. J Acquir Immune Defic Syndr 2015; 68:585593.
50. Medland NA, Chow EP, Bradshaw CS, Read TH, Sasadeusz JJ, Fairley CK. Predictors and incidence of sexually transmitted hepatitis C virus infection in HIV positive men who have sex with men. BMC Infect Dis 2017; 17:185.
51. Newsum AM, Stolte IG, van der Meer JT, Schinkel J, van der Valk M, Vanhommerig JW, et al. MOSAIC collaboratorsDevelopment and validation of the HCV-MOSAIC risk score to assist testing for acute hepatitis C virus (HCV) infection in HIV-infected men who have sex with men (MSM). Euro Surveill 2017; 22:30540.
52. Schmidt AJ, Rockstroh JK, Vogel M, An der Heiden M, Baillot A, Krznaric I, et al. Trouble with bleeding: risk factors for acute hepatitis C among HIV-positive gay men from Germany--a case-control study. PLoS One 2011; 6:e17781.
53. Vanhommerig JW, Lambers FA, Schinkel J, Geskus RB, Arends JE, van de Laar TJ, et al. Risk factors for sexual transmission of hepatitis C virus among human immunodeficiency virus-infected men who have sex with men: a case-control study. Open Forum Infect Dis 2015; 2:ofv115.
54. Witt MD, Seaberg EC, Darilay A, Young S, Badri S, Rinaldo CR, et al. Incident hepatitis C virus infection in men who have sex with men: a prospective cohort analysis, 1984–2011. Clin Infect Dis 2013; 57:7784.
55. Delage G, Infante-Rivard C, Chiavetta JA, Willems B, Pi D, Fast M. Risk factors for acquisition of hepatitis C virus infection in blood donors: results of a case-control study. Gastroenterology 1999; 116:893899.
56. Morris MD, Shiboski S, Bruneau J, Hahn JA, Hellard M, Prins M, et al. Geographic differences in temporal incidence trends of hepatitis C virus infection among people who inject drugs: the InC3 collaboration. Clin Infect Dis 2017; 64:860869.
57. Braun DL, Hampel B, Martin E, Kouyos R, Kusejko K, Grube C, et al. Swiss HIV Cohort StudyHigh number of potential transmitters revealed in a population-based systematic hepatitis C virus RNA screening among human immunodeficiency virus-infected men who have sex with men. Clin Infect Dis 2019; 68:561568.
58. Chaillon A, Sun X, Cachay ER, Looney D, Wyles D, Garfein RS, et al. Primary incidence of hepatitis C virus infection among HIV-infected men who have sex with men in San Diego, 2000–2015. Open Forum Infect Dis 2019; 6:ofz160.
59. van Santen DK, van der Helm JJ, Del Amo J, Meyer L, D’Arminio Monforte A, Price M, et al. CASCADE Collaboration in EuroCoordLack of decline in hepatitis C virus incidence among HIV-positive men who have sex with men during 1990–2014. J Hepatol 2017; 67:255262.
60. Hagan H, Jordan AE, Neurer J, Cleland CM. Incidence of sexually transmitted hepatitis C virus infection in HIV-positive men who have sex with men. AIDS 2015; 29:23352345.
61. Newsum AM, van Rooijen MS, Kroone M, Bruisten SM, Matser A, Hogewoning A, et al. Stable low hepatitis c virus antibody prevalence among HIV-negative men who have sex with men attending the sexually transmitted infection outpatient clinic in Amsterdam, 2007 to 2019. Sex Transm Dis 2018; 45:813817.
62. Schmidt AJ, Falcato L, Zahno B, Burri A, Regenass S, Mullhaupt B, Bruggmann P. Prevalence of hepatitis C in a Swiss sample of men who have sex with men: whom to screen for HCV infection?. BMC Public Health 2014; 14:3.
63. Control ECfDPaPublic health guidance on HIV, hepatitis B and C testing in the EU/EEA An integrated approach. Stockholm:ECDC; 2018.
64. World Health OrganizationGuidelines on hepatitis B and C testing. Geneva:World Health Organization; 2017.
65. Scott N, Sacks-Davis R, Pedrana A, Doyle J, Thompson A, Hellard M. Eliminating hepatitis C: the importance of frequent testing of people who inject drugs in high-prevalence settings. J Viral Hepat 2018; 25:14721480.
66. Aebi-Popp K, Wandeler G, Salazar-Vizcaya L, Metzner K, Stockle M, Cavassini M, et al. Rapid decline of antihepatitis C virus (HCV) antibodies following early treatment of incident HCV infections in HIV-infected men who have sex with men. HIV Med 2018; 19:420425.
67. Breskin A, Drobnik A, Pathela P, Chan C, Braunstein S, Bornschlegel K, et al. Factors associated with hepatitis C infection among HIV-infected men who have sex with men with no reported injection drug use in New York city, 2000–2010. Sex Transm Dis 2015; 42:382386.
68. Wandeler G, Gsponer T, Bregenzer A, Gunthard HF, Clerc O, Calmy A, et al. Swiss HIV Cohort StudyHepatitis C virus infections in the Swiss HIV Cohort Study: a rapidly evolving epidemic. Clin Infect Dis 2012; 55:14081416.
69. Midgard H, Weir A, Palmateer N, Lo Re V 3rd, Pineda JA, Macias J, Dalgard O. HCV epidemiology in high-risk groups and the risk of reinfection. J Hepatol 2016; 65: (1 Suppl): S33S45.
70. Zuure F, Davidovich U, Kok G, Depla AC, Hoebe C, van den Hoek A, et al. Evaluation of a risk assessment questionnaire to assist hepatitis C screening in the general population. Euro Surveill 2010; 15:19539.
71. Papatheodoridis GV, Hatzakis A, Cholongitas E, Baptista-Leite R, Baskozos I, Chhatwal J, et al. Hepatitis C: the beginning of the end-key elements for successful European and national strategies to eliminate HCV in Europe. J Viral Hepat 2018; 25: (Suppl 1): 617.
72. Brener L, Murphy DA, Cama EJ, Ellard J. Hepatitis C risk factors, attitudes and knowledge among HIV-positive, HIV-negative and HIV-untested gay and bisexual men in Australia. Sex Health 2015; 12:411417.
73. Clerc O, Darling K, Calmy A, Dubois-Arber F, Cavassini M. Hepatitis C virus awareness among men who have sex with men in Southwest Switzerland. Sex Transm Dis 2016; 43:4448.
74. World Health Organization GHPGlobal hepatitis report. Geneva:World Health Organization; 2017.
75. Martin NK, Boerekamps A, Hill AM, Rijnders BJA. Is hepatitis C virus elimination possible among people living with HIV and what will it take to achieve it?. J Int AIDS Soc 2018; 21: (Suppl 2): e25062.
76. Boettiger DC, Salazar-Vizcaya L, Dore GJ, Gray RT, Law MG, Callander D, et al. Can Australia reach the World Health Organization Hepatitis C elimination goal by 2025 among HIV-positive gay and bisexual men?. Clin Infect Dis 2020; 70:106113.
77. Heffernan A, Cooke GS, Nayagam S, Thursz M, Hallett TB. Scaling up prevention and treatment towards the elimination of hepatitis C: a global mathematical model. Lancet 2019; 393:13191329.
78. Pradat P, Huleux T, Raffi F, Delobel P, Valantin MA, Poizot-Martin I, et al. Dat’AIDS study GroupIncidence of new hepatitis C virus infection is still increasing in French MSM living with HIV. AIDS 2018; 32:10771082.
79. Martin NK, Jansen K, An der Heiden M, Boesecke C, Boyd A, Schewe K, et al. Can HCV be eliminated among HIV-positive men who have sex with men in Berlin? A modeling analysis. J Infect Dis 2019; 220:16351644.
80. Salazar-Vizcaya L, Kouyos RD, Zahnd C, Wandeler G, Battegay M, Darling KE, et al. Swiss HIV Cohort StudyHepatitis C virus transmission among human immunodeficiency virus-infected men who have sex with men: modeling the effect of behavioral and treatment interventions. Hepatology 2016; 64:18561869.
81. Grebely J, Page K, Sacks-Davis R, van der Loeff MS, Rice TM, Bruneau J, et al. InC3 Study GroupThe effects of female sex, viral genotype, and IL28B genotype on spontaneous clearance of acute hepatitis C virus infection. Hepatology 2014; 59:109120.
82. Smith DJ, Jordan AE, Frank M, Hagan H. Spontaneous viral clearance of hepatitis C virus (HCV) infection among people who inject drugs (PWID) and HIV-positive men who have sex with men (HIV+ MSM): a systematic review and meta-analysis. BMC Infect Dis 2016; 16:471.
83. Martinello M, Gane E, Hellard M, Sasadeusz J, Shaw D, Petoumenos K, et al. Sofosbuvir and ribavirin for 6 weeks is not effective among people with recent hepatitis C virus infection: the DARE-C II study. Hepatology 2016; 64:19111921.
84. Naggie S, Marks KM, Hughes M, Fierer DS, Macbrayne C, Kim A, et al. AIDS Clinical Trials Group (ACTG) A5327 Study TeamSofosbuvir plus ribavirin without interferon for treatment of acute hepatitis C virus infection in HIV-1-infected individuals: SWIFT-C. Clin Infect Dis 2017; 64:10351042.
85. Rockstroh JK, Bhagani S, Hyland RH, Yun C, Dvory-Sobol H, Zheng W, et al. Ledipasvir-sofosbuvir for 6 weeks to treat acute hepatitis C virus genotype 1 or 4 infection in patients with HIV coinfection: an open-label, single-arm trial. Lancet Gastroenterol Hepatol 2017; 2:347353.
86. Martinello M, Orkin C, Cooke G, Bhagani S, Gane E, Kulasegaram R, et al. Shortened duration pan-genotypic therapy with glecaprevir-pibrentasvir for six weeks among people with acute and recent HCV infection ILC Vienna; 2019.
87. El Sayed A, Barbati ZR, Turner SS, Foster AL, Morey T, Dieterich DT, Fierer DS. New York Acute Hepatitis C Surveillance NetworkSofosbuvir in the treatment of early HCV infection in HIV-infected men. HIV Clin Trials 2017; 18:6066.
88. Garvey LJ, Smith CJ, Stingone C, Ghosh I, Rodger A, Jain L, et al. Fall in HCV incidence in HIV+MSM in London following wider acess to DAA therapy. 26th Conference on Retroviruses and Opportunistic Infections. 2019; Seattle [abstract 0085].
89. Vogel M, Page E, Matthews G, Guiguet M, Dominguez S, Dore G, et al.Use of week 4 HCV RNA after acute HCV infection to predict chronic hcv infection [abstract 640].17th Conference on Retroviruses and Opportunistic Infections; 16-19 February 2010; San Francisco, California, USA.
90. Mosley JW, Operskalski EA, Tobler LH, Buskell ZJ, Andrews WW, Phelps B, et al. Transfusion-transmitted Viruses Study and Retrovirus Epidemiology Donor Study GroupsThe course of hepatitis C viraemia in transfusion recipients prior to availability of antiviral therapy. J Viral Hepat 2008; 15:120128.
91. Calleri G, Cariti G, Gaiottino F, De Rosa FG, Bargiacchi O, Audagnotto S, et al. A short course of pegylated interferon-alpha in acute HCV hepatitis. J Viral Hepatitis 2007; 14:116121.
92. Santantonio T, Fasano M, Sinisi E, Guastadisegni A, Casalino C, Mazzola M, et al. Efficacy of a 24-week course of PEG-interferon alpha-2b monotherapy in patients with acute hepatitis C after failure of spontaneous clearance. J Hepatol 2005; 42:329333.
93. De Rosa FG, Bargiacchi O, Audagnotto S, Garazzino S, Cariti G, Calleri G, et al. Twelve-week treatment of acute hepatitis C virus with pegylated interferon- alpha -2b in injection drug users. Clin Infect Dis 2007; 45:583588.
94. Martinello M, Hellard M, Shaw D, Petoumenos K, Applegate T, Grebely J, et al. Short duration response-guided treatment is effective for most individuals with recent hepatitis C infection: the ATAHC II and DARE-C I studies. Antivir Ther 2016; 21:465.
95. Matthews GV, Hellard M, Haber P, Yeung B, Marks P, Baker D, et al. Australian Trial in Acute Hepatitis C Study GroupCharacteristics and treatment outcomes among HIV-infected individuals in the Australian Trial in Acute Hepatitis C. Clin Infect Dis 2009; 48:650658.
96. Vogel M, Nattermann J, Baumgarten A, Klausen G, Bieniek B, Schewe K, et al. Pegylated interferon-alpha for the treatment of sexually transmitted acute hepatitis C in HIV-infected individual. Antivir Ther 2006; 11:10971101.
97. Dominguez S, Ghosn J, Valantin MA, Schruniger A, Simon A, Bonnard P, et al. Efficacy of early treatment of acute hepatitis C infection with pegylated interferon and ribavirin in HIV-infected patients. Aids 2006; 20:11571161.
98. Kowdley KV, Gordon SC, Reddy KR, Rossaro L, Bernstein DE, Lawitz E, et al. ION-3 InvestigatorsLedipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med 2014; 370:18791888.
99. Feld JJ, Jacobson IM, Hezode C, Asselah T, Ruane PJ, Gruener N, et al. ASTRAL-1 InvestigatorsSofosbuvir and velpatasvir for HCV genotype 1, 2, 4, 5, and 6 Infection. N Engl J Med 2015; 373:25992607.
100. Zeuzem S, Ghalib R, Reddy KR, Pockros PJ, Ben Ari Z, Zhao Y, et al. Grazoprevir-elbasvir combination therapy for treatment-naive cirrhotic and noncirrhotic patients with chronic hepatitis C virus genotype 1, 4, or 6 infection: a randomized trial. Ann Intern Med 2015; 163:113.
101. Matthews GV, Bhagani S, Van der Valk M, Rockstroh JK, Kim A, Thurnheer C, et al. on behalf of the REACT study groupShort duration sofosbuvir-velpatasvir is inferior to standard duration therapy in the treatment of recently acquired HCV infection: results from the REACT study. CROI 2020. 121.

The names of all contributing authors are listed in the Acknowledgements.

Keywords:

acute hepatitis C virus; directly acting antivirals; hepatitis C; HIV; MSM

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