Torrens et al. BMC Infectious Diseases (2020) 20:702 https://doi.org/10.1186/s12879-020-05426-4 RESEARCH ARTICLE Open Access Beyond clinical outcomes: the social and healthcare system implications of hepatitis C treatment Marta Torrens1,2* , Tokunbo Soyemi3, Darcy Bowman4 and Eberhard Schatz5 Abstract Background: Hepatitis C virus (HCV) infections in people who inject drugs (PWID) can now be treated and cured. However, the impact that HCV treatment has on drug-user health, practices and wellbeing is not known. The aim of this research was to understand the non-clinical impact that HCV treatment has in PWID and their reasons for accessing and completing treatment. Methods: Participants aged 25–67 years who had injected opioids or stimulants (currently or in the past) and had completed direct-acting antiviral treatment were recruited from seven European countries. Participants completed a 30-min online survey administered face-to-face between September 2018 and April 2019. The questionnaire responses were used to assess the mental and physical impact of having completed treatment. Results: Of the 124 participants who completed the survey questionnaire, 75% were male, 69% were over 45 years old and 65% were using opioids and/or stimulants at the start of HCV treatment. Participants reported improvements in the following areas after completing HCV treatment: outlook for the future (79%); self-esteem (73%); ability to plan for the future (69%); belief in their abilities (68%); confidence (67%); empowerment (62%); energy levels (59%); and ability to look after themselves (58%). The most common reasons for starting HCV treatment were: becoming aware of treatments that were well tolerated (77%) and effective (75%); and understanding the potentially severe consequences of HCV (75%). Conclusions: The benefits of HCV treatment go beyond clinical outcomes and are linked to improved drug-user health and wellbeing. Sharing information about well-tolerated and effective HCV treatments, and raising awareness about the potentially severe consequences of untreated HCV are likely to increase the number of PWID who are motivated to access and complete HCV treatment in future. Keywords: Hepatitis C, Outcomes, Experience, People who inject drugs, Mental health, Physical wellbeing * Correspondence: MTorrens@parcdesalutmar.cat 1 Addiction Research Group, Hospital del Mar Medical Research Institute, Barcelona, Spain 2 Department of Psychiatry and Forensic Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Torrens et al. BMC Infectious Diseases (2020) 20:702 Page 2 of 12 Background part in the study in the form of vouchers. Each participant Chronic hepatitis C is an important public health prob- was offered physical or digital vouchers (supermarket or lem, with an estimated 71 million people living with the Amazon) worth 50 euros (£50 in the UK). hepatitis C virus (HCV) across the globe in 2015 [1]. If left untreated, hepatitis C can progress to serious liver Recruitment disease; the estimated probability of cirrhosis at 20 years The aim was to recruit eight injection drug users per after HCV infection is 16% [2]. country in the UK (Brighton and Blackpool), France The recent introduction of simple, highly effective and (Montpellier and Marseille), Germany (Essen and Cologne), well-tolerated direct-acting antiviral (DAA) treatment Italy (Rome) and Spain (Bilbao), and six injection drug regimens for HCV provides an opportunity to reduce users per country in Portugal (Lisbon and Porto) and prevalence and ultimately eliminate HCV infection as a Switzerland (Lugano). Recruitment channels in these coun- public health threat [3]. For example, significant progress tries included patient associations/organisations, referrals towards HCV elimination has been made in Iceland, with from healthcare professionals (HCPs), recruiter panels 81% (603/741) of people identified as HCV-positive cured (local databases of patients and HCPs from a variety of spe- through a 3-year national elimination programme [4]. To cialties), patient referrals and online campaigns. Invitations achieve HCV elimination, treatment of populations at to participate in the survey were sent via these channels in high risk of infection such as people who inject drugs September 2018. A team of local fieldwork partners/re- (PWID), should be prioritised [5]. In Europe, HCV preva- cruiters with experience in healthcare market research con- lence among people with recent injection drug use is be- ducted recruitment in each of the countries. Physicians tween 39.9 and 48.6% whereas HCV prevalence in the (from the recruiter panels) and patient associations/organi- general population is approximately 1.5% [1, 6]. In fact, in- sations were contacted by email or telephone to invite them jection drug use is the main driver of HCV infection in to assist with patient referrals. In this communication, they Europe, with approximately 80% of new cases attributable were provided with a letter detailing information about the to this high-risk behaviour [7]. Although DAA therapy study, invited to help refer suitable patients and given can cure the majority of people living with HCV, there are details of the referral incentive. The incentive consisted of still some physical and psychological barriers that prevent donations ranging from 100 to 1000 euros or £100–£1000 people, including PWID, from accessing HCV care and in the UK (depending on how many participants were re- treatment [8, 9]. The psychological impact of living with ferred) to charities and addiction centres for their support hepatitis C is well-documented with many people experi- in referring participants. Physical or digital vouchers (super- encing depression and anxiety [10, 11]. These symptoms, market or Amazon) worth 50 euros (£50 in the UK) were which are very common among PWID, may affect peo- offered to participants who referred other participants to ple’s willingness to initiate HCV treatment [12, 13]. the survey. In Portugal, there were no incentives given for There is a gap in knowledge on the factors that en- referrals due to country regulations. No healthcare profes- courage PWID to start DAA treatment and on the im- sionals were paid any referral incentives. Physicians were pact treatment has on drug-user health, practices and invited to tell patients about the study and provide them wellbeing. Therefore, the aim of this investigation was to with the recruiter’s contact details. Patients were free to survey injection drug users who have received DAA contact the recruiter if they were interested in participating. treatment in order to gain insights on the non-clinical The recruiters also advertised the study and provided infor- impact that HCV treatment has had on their life, and on mation about how to take part via various channels includ- wider society. Additionally, the study aimed to ascertain ing the recruiter panel website, social media and patient the main reasons these participants were motivated to association forums, newsletters and websites. access and complete HCV treatment, as well as survey the participants’ opinions on the factors that may en- Survey courage more PWID to engage in HCV care. The survey questionnaire was developed by Incite, an in- dependent international market research consultancy Methods (Supplementary File 1). The authors, who have a wide Study population knowledge of hepatology and addiction, contributed to Participants included in this study were aged between 25 the development of the questionnaire and decisions on and 67 years, were either injecting opioids or stimulants which outcomes to measure. They reviewed the final regularly (at least once a week), injecting occasionally (less version to ensure alignment with the research objectives than once a week) or had previously injected opioids or and that the questions were appropriate for participants. stimulants. The participants had also received a confirmed The survey comprised of 25 questions relating to partici- diagnosis of hepatitis C (self-reported) and completed pants’ sociodemographic characteristics, injecting behav- DAA treatment. Participants were incentivised to take iours and HCV treatment. The survey also included Torrens et al. BMC Infectious Diseases (2020) 20:702 Page 3 of 12 seven questions on the perceived impact of HCV treat- outcomes: outlook for the future (79%); self-esteem ment on different aspects of the participants’ lives. The (73%); ability to plan for the future (69%); belief in their survey was hosted online on the Confirmit platform. abilities (68%); and confidence (67%). A small number of Once participants had agreed to participate, the online participants reported a negative impact (defined as either survey was conducted in-person (as a face-to-face inter- some negative impact or significant negative impact) on view) in the native language at a convenient location psychological health (3%) and their ability to be open (e.g. a café, HCV nurse’s office, rehabilitation centre, with others (1%). For all mental health-related outcomes drug addiction clinic or patient’s home). The interviews except psychological/mental health, the percentage of were carried out by moderators (non-HCPs) with experi- people who reported a positive impact with HCV treat- ence working in healthcare market research, including ment was higher in participants who no longer used opi- patient research. All moderators had received training oids/stimulants at the time of the survey compared with on how to ask questions on topics of a sensitive nature. those who did (Fig. 1b). At the beginning of every interview, participants were For physical health, a positive impact on energy levels reassured on the anonymity of their responses to en- and fatigue/tiredness with HCV treatment was reported courage open and honest feedback. All responses pro- in 59 and 53% of participants, respectively (Fig. 1a). Few vided by the participant were inputted onto a tablet or participants reported a negative impact on their physical laptop by the moderator. Data were collected on the wellbeing, with the most common negative outcomes Confirmit platform. Incite researchers and analysts col- being tiredness/fatigue (6%) or inability to maintain a lated and analysed the data using Q Research Software. healthy weight (6%). Additionally, most participants (82%) reported that HCV treatment had no impact on Data collection pain. Among participants who used opioids/stimulants The surveys were carried out from 13 September 2018 at the start of therapy, the parameter with the greatest to 11 April 2019 and took 30 min to complete on numerical difference between participants who no longer average. used opioids/stimulants at the time of the survey and those who did was the ability to maintain a healthy Results weight (44% compared with 30%) (Fig. 1b). Baseline characteristics of participants In this study, 124 participants completed the survey Self-perceived impact of HCV treatment on lifestyle, questionnaire. The target for the minimum number of ability to engage in wider society and ability to maintain participants per country was met with 100 respondents personal relationships from the UK, Germany, France, Italy and Spain (20 per Over half (58%) of participants reported a positive country), 15 from Portugal and 9 from Switzerland. Of impact in their ability to look after themselves and the 124 participants who completed the survey, the ma- just under half (47%) reported a positive impact on jority (75%) were male and aged over 44 years old (69%). their ability to fulfil daily commitments to others Many received a confirmed HCV diagnosis before 2008 (Fig. 2). Overall, 46% reported a positive impact on (73%) and concurrent illnesses were common (Table 1). their ability to enjoy/explore new interests and hob- Overall, 65% of participants were using opioids and/or bies with many participants starting new activities stimulants at the start of HCV treatment, and the other after completing treatment: 6% started a sport or 35% had a history of injection drug use. Most partici- hobby; 13% obtained a new job; 19% enrolled in an pants were recruited through a patient association/or- education or training course; and 30% became an ganisation (62%) or through a referral from an HCP advocate regarding HCV and/or drug use (e.g. advis- (20%). The majority (78%) received treatment less than ing patients, companies or healthcare professionals) 3 years ago and treatment was most often received from (Supplementary Fig. 1). For the parameters related to a secondary care hospital (73%). maintaining personal relationships, 35–41% of partic- ipants reported a positive impact with HCV treat- Self-perceived impact of HCV treatment on mental health ment; the majority reported no impact. and physical wellbeing Participants reported on the impact (significant positive, Accommodation and employment status before HCV some positive, some negative, significant negative or treatment and during survey none) of HCV treatment on various mental and emo- There were few changes to the participants’ accommo- tional treatment-related outcomes (Fig. 1a). A positive dation before and after HCV treatment: living in their impact (defined as either a significant positive impact or own home from 36 to 44%, respectively; in a family some positive impact) with HCV treatment was reported home from 22 to 25%; in shared accommodation from by a high proportion of participants on the following 18 to 13%; in a halfway house from 10 to 9%; homeless Torrens et al. BMC Infectious Diseases (2020) 20:702 Page 4 of 12 Table 1 Baseline characteristics of survey participants (N = 124) Table 1 Baseline characteristics of survey participants (N = 124) Characteristics % (Continued) Age, years Characteristics % 18–29 2 Recruiter panel 13 30–44 30 Patient referral 3 45–60 64 Online campaign 2 > 60 5 Year started most recent HCV treatment Sex ≥ 5 years ago 8 Male 75 4 years ago 5 Female 25 3 years ago 10 Year HCV diagnosis was received 2 years ago 19 Before 1999 40 1 year ago 33 1999–2003 15 This year 26 2004–2008 18 Where most recent HCV treatment was received 2009–2013 13 Secondary care/hospital 73 2014–2018 15 Addiction clinic 14 Comorbidities (more than one could be selected) GP/PCP 5 HBV 13 Prison 2 HIV 24 Other 3 a Cardiovascular disease 7 HCV treatment most recently received (more than one could be selected) Diabetes 2 SOF/VEL 27 Other 13 LDV/SOF 23 Currently injecting drugs SOF 14 ≥ once a week 17 GLE/PIB 6 < once a week 17 DCV 5 No longer injecting 66 EBR/GZR 2 Use of opioids/stimulants at start of HCV treatment TEL 2 Users 65 SOF/VEL/VOX 2 Non-users 34 OBV/PTV/r 2 Did not remember 1 DSV 2 Substances used BOC 2 Opioids (e.g. heroin, morphine) 92 Other/unknown 23 Stimulants (e.g. cocaine, amphetatmine) 85 a The treatment regimen received by participants was at the discretion of their Both opioids and stimulants 78 treating physician and was a function of the timing of the research, and/or regulatory approvals and reimbursement in each country Other substances 58 BOC Boceprevir, DCV Daclatasvir, DSV Dasabuvir, EBR Elbasvir, GLE Glecaprevir, Country GP General practitioner, GZR Grazoprevir, HBV Hepatitis B virus, HCP Healthcare professional, HCV Hepatitis C virus, HIV Human immodeficiency virus, LDV UK 16 Ledipasvir, OBV Ombitasvir, PCP Primary care physician, PIB Pibrentasvir, PTV Paritaprevir, r Ritonavir, SOF Sofosbuvir, TEL Telaprevir, VEL Velpatasvir, Germany 16 VOX Voxilaprevir France 16 Italy 16 from 5 to 2%; rehabilitation/detox centre from 5 to 4%; Spain 16 and in prison from 2 to 0% (Supplementary Fig. 2). Em- Portugal 12 ployment status remained largely the same before and Switzerland 7 after completing HCV treatment: on benefits from 35 to Recruitment channel 31%, respectively; out of work from 44 to 41%; employed Patient association/organisation 62 (full- or part-time) from 24 to 23%; retired from 8 to 7%; HCP referral 20 and volunteer/peer work from 6 to 5% (Supplementary Fig. 3). Torrens et al. BMC Infectious Diseases (2020) 20:702 Page 5 of 12 Fig. 1 a The impact of HCV treatment on participants’ mental health and physical wellbeing (N = 124). b The positive impact (defined as either a significant positive impact or some positive impact) of HCV treatment on mental health and physical wellbeing among participants who used opioids/stimulants at the start of treatment (n = 80). Those who no longer used opioids/stimulants at the time of the survey (n = 43, green) were compared with those who still did (n = 37, orange) Torrens et al. BMC Infectious Diseases (2020) 20:702 Page 6 of 12 Fig. 2 The impact of HCV treatment on the ability of participants to maintain personal relationships and aspects of their lifestyle (N = 124) Self-reported emotions felt after completing treatment consequences of HCV, were their main reasons for start- The most common emotions reported by participants ing therapy (Fig. 5a). Only 35% of individuals identified after completing treatment were: happy (73%), relieved that suffering symptoms of HCV was a motivation to start (71%), optimistic (53%); and proud (53%) (Fig. 3a). treatment. In the sub-population of individuals not using Among participants who used opioids/stimulants at the opioids/stimulants at the start of HCV treatment, 71% start of therapy, the most common emotions felt after were concerned about the long-term consequences of the treatment were: relieved (70% in participants who no disease (Fig. 5b). For those who were drug users at the longer used drugs at the time of the survey, 68% in users start of HCV treatment, the most frequently reported rea- at the time of survey) and happy (67% in non-users, 65% son to start therapy was ‘to get rid of the virus’. The par- in users) (Fig. 3b). The emotions with the greatest nu- ticipants agreed that raising awareness of effective and merical difference between participants who no longer well-tolerated treatments (98%), raising awareness about used opioids/stimulants at the time of the survey and the risk and severity of HCV (96%), hearing about the those who did were: successful (42% in non-users, 19% positive experiences of others (94%) and having a support- in users), free (53% in non-users, 24% in users) and opti- ive HCP (93%) were the factors that were most likely to mistic (60% in non-users, 38% in users). encourage others to start and complete HCV treatment (Fig. 6). The factor that was the least likely to encourage Motivations for starting HCV therapy others was financial payments/incentives (41%). During the survey, 84 participants reported that some- one else encouraged them to start treatment. Of those 84 participants: 75% were encouraged by an HCP; 21% Discussion by a family member; 19% by a social worker; 18% by a This survey analysis shows that there are additional friend; 17% by an advocate or key worker; 12% by their benefits to HCV treatment in PWID other than cure; partner; and 11% by one of their peers (Fig. 4). many participants experienced a positive impact on The majority of participants (≥75%) stated that becom- other outcomes, mainly in their subjective psycho- ing aware of treatments that were effective and well toler- logical/mental health. These results align with previ- ated, as well as understanding the potentially severe ous studies which demonstrate that HCV treatment Torrens et al. BMC Infectious Diseases (2020) 20:702 Page 7 of 12 Fig. 3 a Emotions felt by participants after completing HCV treatment (N = 124). Participants were able to select more than one emotion. b Emotions felt by participants who used opioids/stimulants at the start of treatment (n = 80). Those who no longer used opioids/stimulants at the time of the survey (n = 43, green) were compared with those who still did (n = 37, orange) Torrens et al. BMC Infectious Diseases (2020) 20:702 Page 8 of 12 Fig. 4 The person who encouraged each participant to start HCV treatment (N = 84). Participants were able to select more than one person has a transformative effect on patients’ quality of life of previously underserved populations, thus maximising and mental wellbeing [14–17]. efforts towards HCV elimination [30]. Despite these benefits, global HCV treatment uptake There is still a need to understand what motivates among PWID is low [18, 19]. There are many system- PWID to engage in care. Qualitative research has illus- level and provider-level reasons for this low treatment trated that eliminating the virus is not the only factor uptake but at an individual level, lack of awareness of that motivates PWID to start therapy [31]. The results HCV diagnosis, previous negative experiences with of our survey suggest that awareness of the availability of healthcare systems, stigma and physical/psychological effective and well-tolerated treatments and the poten- co-morbidities have been identified as common barriers tially severe consequences of untreated HCV are key for PWID [20–22]. Another key barrier is lack of know- motivators. This highlights the importance of developing ledge or misinformation about HCV and how it is programmes and initiatives that include patient educa- treated [20]. Until 2013, the only treatments that were tion to ensure that more PWID are treated for HCV available for HCV were interferon (IFN)-based and re- [32]. In the Netherlands, education and awareness cam- quired weekly injections for up to 1 year [23]. These paigns targeted at PWID have already been proven to be IFN-based regimens were associated with many side ef- successful at engaging more individuals into care, with fects and low efficacy rates, particularly among PWID 257 additional PWID diagnosed with chronic HCV when [24, 25]. Negative experiences of these poorly tolerated these interventions were used compared to the control regimens have been shared among drug user communi- group [33]. An interesting topic for further research ties which has resulted in many people being fearful of would be to survey PWID who decline HCV treatment treatment side effects [26, 27]. to understand which factors influence their decision With the advent of well-tolerated and orally adminis- making. tered DAA drugs, HCV treatment has become simpler Even in the era of simple DAA treatments that are and the majority of infected individuals, including effective in many patient populations, management of PWID, can be treated and cured [28]. There is now con- HCV among PWID is often perceived as challenging sensus among the medical community that all patients because this population is usually stigmatised by soci- should be able to access care and that treating PWID in ety and can find healthcare services difficult to access particular is a priority to reduce HCV transmission [5, [21, 22, 34]. However, findings from this survey sug- 29]. Pangenotypic regimens that are currently available gest that the majority of PWID reported a positive require minimal pre-, during and post-treatment moni- impact on their ability to engage in wider society and toring and can be used effectively to treat large numbers explore new interests/hobbies after HCV treatment. Torrens et al. BMC Infectious Diseases (2020) 20:702 Page 9 of 12 Fig. 5 a Reasons for participants to start treatment (N = 124). b Top three motivations for starting HCV treatment among participants using opioids/stimulants at the start of their treatment (n = 80, orange) and non-using participants (n = 42, green). Participants were asked to rank their top three motivations (ranking 1 to 3), those who provided rankings for all three of their top motivations were included in the analysis Torrens et al. BMC Infectious Diseases (2020) 20:702 Page 10 of 12 Fig. 6 Potential initiatives that participants agreed would help other PWID to start and complete HCV treatment (N = 124) Previous studies have also shown similar positive out- many participants, there was variation in the time between comes beyond HCV cure that are valued highly completing treatment and completing the survey. In among PWID [16, 31]. addition, this study only presents data on the aspects of In this analysis, there was wide variation in injecting life mentioned in the survey and so there may be more patterns between participants, with different numbers benefits of treatment that are not described. Finally, we re- of participants injecting drugs before and after HCV port results from a survey of PWID who had volunteered treatment. This highlights the complexity of this pa- and were therefore motivated to participate. We cannot tient population and should be considered when guarantee that the findings are representative of all people interpreting the results. For example, for some out- who use drugs. comes such as overall outlook for the future, ability It is also important to highlight the specific strengths of to plan for the future and empowerment, there was a this research. For example, this is one of the first analyses large difference in the number of participants who re- that focus on the self-perceived impact of HCV treatment ported a positive impact with HCV treatment between on mental health and physical wellbeing in people who in- those who used drugs at the time of the survey and ject drugs. Many of the outcomes that we report on have those who did not. It is not clear why this is the case not been measured in clinical trials and so these findings however it suggests that injection drug use could also add breadth to the literature on patient-level benefits of have an impact on these outcomes. Previous research HCV treatment. In addition, information from this survey has demonstrated that stopping drug use can improve allows us to gain insights on a high-risk and highly stigma- an individual’s mental and physical health, and there- tised population that is usually excluded from healthcare fore their quality of life [35, 36]. programmes and large randomised controlled clinical tri- The results of this research should be interpreted in als. One of the benefits of this study was that recruitment light of several limitations. First, given the nature of the of participants was driven by patients with the majority re- data, it was not appropriate to conduct statistical analyses cruited through patient associations/organisations. A pos- so we cannot draw reliable statistical comparisons be- sible reason for this is that PWID visit community-based tween different categories of patients. Therefore, our re- organisations more regularly than other healthcare set- sults should be viewed as indicators for future studies. tings [37]. In general, this survey shows that having a var- The cross-sectional nature of the survey must also be iety of different recruitment channels is valuable when taken into account when analysing these results as for recruiting PWID. Torrens et al. BMC Infectious Diseases (2020) 20:702 Page 11 of 12 Conclusions Competing interests In this survey analysis, we show that the benefits of HCV Tokunbo Soyemi and Darcy Bowman are employees of Gilead Sciences Europe Ltd. and may own stock or stock options. Marta Torrens has received treatment among PWID go beyond clinical outcomes and consultancy fees from AbbVie, Esteve, Gilead Sciences, Lundbeck, Merck are linked to improved health and wellbeing. In addition, Sharp & Dohme and Servier. The Correlation European Harm Reduction our results suggest that awareness of effective and well- Network receives funding from Gilead Sciences for hepatitis C-related re- search and activities. tolerated HCV treatments, as well as understanding the potentially severe consequences of untreated HCV are the Author details 1 main reasons PWID are motivated to access and complete Addiction Research Group, Hospital del Mar Medical Research Institute, Barcelona, Spain. 2Department of Psychiatry and Forensic Medicine, HCV treatment. Universitat Autònoma de Barcelona, Barcelona, Spain. 3Medical Affairs, Gilead Sciences Ltd, London, UK. 4Public Affairs, Gilead Sciences Ltd, London, UK. 5 Correlation European Harm Reduction Network, Amsterdam, The Supplementary information Netherlands. Supplementary information accompanies this paper at https://doi.org/10. 1186/s12879-020-05426-4. Received: 3 June 2020 Accepted: 16 September 2020 Additional file 1: Supplementary File 1. Survey Questionnaire Additional file 2: Supplementary Figure 1. Impact of HCV treatment on participants’ ability to engage in wider society (N = 124). References Supplementary Figure 2. Participants’ living situation at the start of 1. World Health Organization. Global hepatitis report; 2017. https://www.who.int/ HCV treatment and during the survey (N = 124). Supplementary Figure hepatitis/publications/global-hepatitis-report2017/en. Accessed 28 Aug 2020. 3. Participants’ employment status at the start of HCV treatment and 2. Thein H-H, Yi Q, Dore GJ, Krahn MD. Estimation of stage-specific fibrosis during the survey (N = 124). progression rates in chronic hepatitis C virus infection: a meta-analysis and meta-regression. Hepatology. 2008;48(2):418–31. 3. Chen Q, Ayer T, Bethea E, et al. 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