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Increased case‐finding and uptake of direct‐acting antiviral treatment essential for micro‐elimination of hepatitis C among people living with HIV: a national record linkage study in Scotland, England, MSM
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17 December 2020 HIV Medicine - A McLeod 1 SJ Hutchinson,1,2 S Smith,1,2 C Leen,3 S Clifford,3 A McAuley,1,2 LA Wallace,1 ST Barclay,4 P Bramley,2,5
JF Dillon,6 A Fraser,7 RN Gunson,8 PC Hayes,9 N Kennedy,10 E Peters,11 K Templeton12 and DJ Goldberg1,2
only 59% of PWID with chronic HCV and who attended HCV treatment services had been treated for their HCV, and co‐infected PWID were almost twice as likely not to be treated for their HCV as those who acquired HIV through heterosexual transmission. …..The Scottish Government has recently committed to the elimination of hepatitis C as a public health concern in Scotland by 2024 [15. In 2018, the BHIVA recommended an accelerated effort to eliminate HCV among PLHIV with targets to cure 80% of all co‐infected patients by 2019 (with 100% of patients assessed for therapy) increasing to 100% by 2021
Abstract
Objectives
Micro‐elimination of hepatitis C virus (HCV) in people living with HIV (PLHIV) and co‐infected with HCV has been proposed as a key contribution to the overall goal of HCV elimination. While other studies have examined micro‐elimination in HIV‐treated cohorts, few have considered HCV micro‐elimination among those not treated for HIV or at a national level.
Methods
Through data linkage of national and sentinel surveillance data, we examined the extent of HCV testing, diagnosis and treatment among a cohort of PLHIV in Scotland identified through the national database of HIV‐diagnosed individuals, up to the end of 2017.
Results
Of 5018 PLHIV, an estimated 797 (15%) had never been tested for HCV and 70 (9%) of these had undiagnosed chronic HCV. The odds of never having been tested for HCV were the highest in those not on HIV treatment [adjusted odds ratio (aOR) = 7.21, 95% confidence interval (CI): 5.15-10.10). Overall HCV antibody positivity was 11%, and it was at its highest among people who inject drugs (49%). Most of those with chronic HCV (91%) had attended an HCV treatment clinic but only half had been successfully treated (54% for those on HIV treatment, 12% for those not) by the end of 2017. The odds of never having been treated for HCV were the highest in those not on HIV treatment (aOR = 3.60, 95% CI: 1.59-8.15).
Conclusions
Our data demonstrate that micro‐elimination of HCV in PLHIV is achievable but progress will require increased effort to engage and treat those co‐infected, including those not being treated for their HIV.
Progress towards micro‐elimination of HCV among HIV‐diagnosed patients
Figure 1 shows the estimated numbers of chronic HCV infections (ever and current) among PLHIV in Scotland. It is estimated that 586 individuals were ever chronic HCV and that 337 had current chronic HCV. The proportion of ever chronic HCV infections among HIV‐diagnosed patients who had also been diagnosed with HCV was 83% (485/586). With regard to the BHIVA targets, 51% (249/485) of those with diagnosed chronic HCV and HIV had been cured of their HCV by the end of 2017, and 91% (441/485) had been assessed at a specialist HCV treatment service. Of all chronic HCV infections (diagnosed and undiagnosed) among HIV‐diagnosed patients, 42% (249/586) had been cured of their HCV.
Introduction
Since the introduction of direct‐acting antiviral (DAA) treatment for hepatitis C virus (HCV) infection, with shorter treatment duration and cure rates exceeding 95%, elimination of the virus is now possible [1, 2. The World Health Organization (WHO) has set the goal of reducing HCV mortality by 65% and new chronic HCV infections by 80% by 2030 [3. Micro‐elimination of HCV in key populations has been proposed as a pragmatic approach to the overall elimination goal [4. Where health systems may not be prepared for the scale‐up of prevention, testing and screening required for full‐scale elimination, micro‐elimination provides a mechanism for incremental progress towards elimination [5. This involves the elimination of HCV in a defined population, e.g. people in specific settings, risk groups or those with co‐infections, in the recognition that different populations may need different services. A key population for micro‐elimination is people living with HIV (PLHIV) and co‐infected with HCV [6.
Of the estimated 36.9 million PLHIV worldwide, 2.3 million (6.2%) are also HCV antibody‐positive. The prevalence of HCV antibody positivity varies significantly by risk group, ranging from 4.0% among pregnant or heterosexually exposed HIV patients to 82.4% among HIV‐infected people who inject drugs (PWID) [7. The 2015 European Association for the Study of the Liver (EASL) recommendations on treatment of HCV prioritized DAA therapy for HCV/HIV co‐infected individuals, regardless of fibrosis stage, due to drug interactions between antiretroviral therapy and interferon‐based HCV treatments [8. Treatment of co‐infected PLHIV with DAA therapy has now been shown to be as highly effective as for HCV mono‐infected patients [9. More recently, the British HIV Association (BHIVA) has called for an accelerated effort to eliminate HCV among PLHIV with targets to cure 80% of all patients diagnosed with HIV and HCV co‐infection by 2019, increasing to 100% by 2021 [10.
Scotland is uniquely placed to monitor progress towards micro‐elimination of HCV among PLHIV targets through national surveillance of HIV diagnoses linked to HCV testing, diagnoses and treatment data. Here we demonstrate an approach to monitor progress towards elimination of HCV among PLHIV, using a combination of surveillance data and prediction modelling. These data are important to inform what progress has been made and where further effort is required to reach HCV elimination in this population.
In the first multivariate regression analysis of factors associated with never being tested for HCV, the final model included current age group, deprivation, ethnicity, HIV treatment status, HIV diagnosis setting, HIV attendance and AIDS diagnosis status. The odds of never having been tested for HCV were highest in those who were not on HIV treatment [adjusted odds ratio (aOR) = 7.21, 95% CI: 5.15-10.10], those diagnosed in a GUM clinic (aOR = 3.44, 95% CI: 2.68-4.40), those in the ‘other’ ethnicity group (aOR = 3.46, 95% CI: 2.10-5.70), and those residing in the least deprived SIMD quintile (aOR = 1.83, 95% CI: 1.33-2.52). Using this model to predict the number never tested from the remaining 2079 (41%) of the full cohort, 221 (11%) were predicted as having not been tested. An estimated 797 (16%) of the full cohort were never tested for HCV (Fig. 3). Of those not tested for HCV, 100 were estimated to be HCV antibody‐positive (62 PWID and 38 non‐PWID) (Appendix 2).
Discussion
The Scottish Government has recently committed to the elimination of hepatitis C as a public health concern in Scotland by 2024 [15. In 2018, the BHIVA recommended an accelerated effort to eliminate HCV among PLHIV with targets to cure 80% of all co‐infected patients by 2019 (with 100% of patients assessed for therapy) increasing to 100% by 2021 [10. Utilizing a variety of surveillance initiatives for blood‐borne viruses in Scotland, this is the first study to examine progress towards micro‐elimination of HCV among PLHIV at a national level, including estimating the extent of undiagnosed infection.
In our analysis of HCV testing, it was predicted that around 15% of PLHIV in Scotland have never been tested for HCV. BHIVA guidelines recommend that all ‘patients have an HCV antibody test when first tested HIV antibody positive’ and patients with repeated high‐risk exposures should be tested at least twice a year [16. Similarly, the Scottish Intercollegiate Guidance Network guideline recommends HCV testing for all PLHIV and annual testing for those who continue to be at risk [17. We estimate that around 70 PLHIV of those who have never been tested for HCV have undiagnosed chronic HCV. Diagnosing all co‐infections is essential for micro‐elimination and efforts should be made to increase and maintain HCV testing of PLHIV, particularly those attending specialist HIV services or who continue to inject drugs.
Overall, 11% of PLHIV were also diagnosed HCV antibody‐positive. HCV positivity was highest among PWID at 49%. PWID represent 63% of those diagnosed with both HIV and HCV despite being only 14% of the PLHIV population. This is consistent with the epidemiology of HCV among PWID and highlights a key group for the micro‐elimination of HCV in PLHIV [4. Despite this, only 59% of PWID with chronic HCV and who attended HCV treatment services had been treated for their HCV, and co‐infected PWID were almost twice as likely not to be treated for their HCV as those who acquired HIV through heterosexual transmission.
Men who have sex with men represent the largest risk group among PLHIV and 4% were also diagnosed HCV antibody‐positive. Outbreaks of sexually transmitted HCV among HIV‐positive MSM have been well documented globally, including in other parts of the UK [18. In this study, more than three‐quarters of HIV‐positive MSM had ever been tested for HCV. With the introduction of pre‐exposure prophylaxis to prevent HIV infection, an increase in condomless sex is likely among MSM engaged in the highest risk activity, which may lead to an increase in sexually transmitted HCV [19. Regular HCV testing in this group is essential to diagnose and treat patients infected with HCV and prevent onward transmission.
Of PLHIV diagnosed with chronic HCV, 90% had attended a specialist HCV treatment clinic for assessment by the end of 2017, which, while high, suggests the BHIVA target of 100% of co‐infections assessed by April 2019 may have been missed. Of those who had attended HCV treatment services, one‐third had not received any treatment for their HCV. Only half of those with chronic HCV had achieved an SVR by the end of 2017. This indicates a key challenge in achieving the BHIVA treatment targets of 80% treated by 2020 target and for micro‐elimination in general.
There are several reasons why co‐infected PLHIV may have sub‐optimal HCV treatment uptake despite being engaged with other services. Response rates for co‐infected patients treated with pegylated interferon and ribavirin were 10-20% lower than in HCV mono‐infected patients, and drug interactions between HCV and HIV treatments had been documented [20. Either of these factors may have had an impact on treatment uptake among co‐infected patients, but with the introduction of DAA therapy, these particular barriers have been overcome [21. A number of interventions have been identified as increasing uptake of HCV treatment among PWID, the most common route of transmission for co‐infected patients in Scotland. In a 2017 systematic review, it was found that an on‐site total care concept, including non‐invasive liver assessment, psychiatric evaluation, education and motivational interviewing, had the greatest increase in treatment initiations (38% vs. 2% before the intervention), followed by integration of HCV services with drug and psychiatric services, which showed a significant but lower increase in treatment initiations (32% vs. 19% in the control group). While neither of these studies considered co‐infected individuals, it is logical to assume that these approaches would also benefit that group if the approach could include these additional services and HIV/HCV treatment [22. While GUM clinics represent the most common setting for HIV diagnoses at 40%, this setting accounts for lower HCV activity, and while there was an increase in HCV testing in GUM clinics between 1999 and 2011, there was a reduction in the number of positive results [11, 13. Similarly, a number of studies have shown limited evidence for sexual transmission of HCV among GUM attendees (with the exception of PWID) [23, 24. At a time when sexual health services are experiencing acute funding challenges, integrating services in GUM clinics may be difficult to implement, [25
To meet the BHIVA treatment target, significant increase of treatment among co‐infected patients is essential, which highlights the challenges for micro‐elimination of HCV among PLHIV. Scotland has already seen a significant scale‐up of treatment for HCV in recent years as a result of the Hepatitis C Action Plan [26. In 2006, less than 10% of those with chronic infection had attended a specialist HCV treatment clinic and around 450 were initiated onto treatment per year. By the end of the Action Plan in 2010, the numbers treated per year had more than doubled and to achieve the Scottish Government elimination goal this will increase to 3000 patients initiated onto therapy per year [15.
In comparison to these increases, the number of patients needed to be treated to eliminate HCV among PLHIV is relatively small and achievable. Between 2015 and 2017, HIV co‐infected patients were among the groups prioritized for DAA treatment in Scotland, along with patients with F2-F4 hepatic fibrosis, patients with severe extra‐hepatic manifestations of HCV and/or patients with significant psychosocial morbidity as a consequence of HCV (with all patients eligible for DAA treatments since 2017) [27. DAA treatment has been available for several years, so the fact that the majority are in contact with HIV services and treatment uptake remains relatively low represents a system failure. The reasons for this are probably multi‐faceted, including: HIV and HCV services being separated in different healthcare silos; increased pressures on HIV and sexual health services; lack of knowledge that the previous clinical barriers to treatment have been overcome; and patients not prioritizing their HCV infection. At the very least, referral pathways between HIV services and specialist HCV treatment clinics should be reviewed to ensure that these reflect current treatment guidance and facilitate access to HCV treatment. Education of HIV services staff and PLHIV about DAA and HCV elimination may be required, and delivery of HCV treatment through HIV services could be considered as a method of achieving micro‐elimination.
The BHIVA recognized that while rapidly increasing treatment is possible, the challenges of treating the most vulnerable patients, such as those who are currently homeless, may also require some short‐term specialist services [10, 28. The importance of these most vulnerable groups to the HCV elimination goals cannot be overstated. The recent outbreak of HIV among PWID in Scotland’s largest city has clearly demonstrated how quickly blood‐borne viruses can spread among injecting networks, particularly among homeless people and those who inject in public. Around 60% of those infected with HIV in the outbreak were co‐infected with chronic HCV [29.
As this study starts with the HIV diagnosis database, it has not been possible to consider here patients who are infected with HIV but who remain undiagnosed. It is, however, estimated that the undiagnosed HIV population is low in Scotland [11. A study in England covering the pre‐DAA era examined co‐infection from the other perspective (i.e. starting with HCV‐diagnosed patients and examining factors associated with HIV infection) found that rates of co‐infection were highest among MSM and reported lower co‐infection rates than we describe [30. These differences may relate to the sexually transmitted outbreaks of HCV among MSM that have been described in England but which, so far, have not been seen in Scotland, and the HIV outbreaks among PWID in Scotland that have not been observed in England. A number of studies have examined HCV treatment in co‐infected cohorts and we have found results consistent with these. A study of HCV screening of patients in HIV care in the United States found that 77.9% were not tested for HCV and that only 17.8% were initiated onto treatment [31. A prospective cohort in Spain found that while more than 60% were started on HCV treatment, recent PWID and those on opioid substitution therapy had lower rates compared with other groups, which is consistent with our results [32. An Australian cohort of co‐infected patients also found that rapid scale‐up of DAA treatment was possible in a short time and these results demonstrate that micro‐elimination in this population is possible [33. These studies do not take into account patients who are not in HIV care, which is a key strength of our study, as this group has significantly lower HCV testing and treatment uptake.
Our analysis has been limited to the data collected on the HIV and HCV surveillance databases. There are probably numerous factors beyond those analysed here that may have an impact on HCV testing or treatment among PLHIV. This was a particular issue in our attempts to predict the number of HCV infections among those who had not been tested. Only PWID status was associated with positivity and so it was not possible to use a prediction model for positivity among the non‐PWID group. This has affected the precision of the undiagnosed HCV estimates and these should be interpreted accordingly. Similarly, we may have underestimated the extent of migration within the study cohort as we know that, for example, 40% of those diagnosed with HIV in 2017 were infected outside Scotland [11. Only those reported as being known or presumed to have migrated were excluded. As we have used data linkage in this study, it has not been possible to include those tested or diagnosed anonymously and our PLHIV cohort includes only those who have a Community Health Index number. There may be some in this cohort who have been tested for HCV anonymously and who we are unable to link. However, as they have undergone named testing for HIV they may be less likely to use anonymous HCV testing. While the HCV diagnoses database includes all antibody‐ and/or PCR/antigen‐positive individuals in Scotland, those who received a negative antibody test result during the acute phase may be under‐represented. Similarly, the HCV diagnoses and test databases include both venous blood and dried blood spot samples, but rapid near‐patient tests which are not undertaken or confirmed in a laboratory are not included and so some testing activity may have been missed. We have not been able to determine the individual reasons why someone may have chosen not to accept treatment or the specific support that this patient group may require to increase treatment rates. Further qualitative work may provide insights into this subject. All linkage studies carry the possibility for error and there may be records that have been matched incorrectly and others that have not been matched despite belonging to the same person [34. However, the use of this study design has allowed for a rapid assessment of Scotland’s position with regard to micro‐elimination of HCV among PLHIV and progress towards the BHIVA targets and can be repeated to monitor progress towards elimination.
Conclusion
Bringing together a variety of data sources, we have demonstrated an approach to measuring progress towards micro‐elimination in PLHIV. We found that a significant minority of PLHIV had yet to be tested for HCV despite guidance recommending annual testing for those who continue to be at risk. This should be included in the routine monitoring of CD4 and viral loads. Whilst the vast majority of co‐infected patients have had contact with specialist HCV services, only half had been successfully treated by the end of 2017, 2 years after the prioritization of DAAs for PLHIV in Scotland. Our data demonstrate that micro‐elimination of HCV in PLHIV is achievable but progress towards this goal will require increased effort to engage and treat those co‐infected, including those not being treated for their HIV.
Attendance at specialist services and HCV treatment
Of the 485 ever chronic HCV group, 441 (91%) had attended a specialist HCV treatment clinic. Of those who had attended such a clinic, 293 (66%) had been treated at least once and 249 (85%) of these had achieved an SVR. The odds of never being treated for HCV (Table 3) were highest in those who were not on HIV treatment (aOR = 3.60, 95% CI: 1.59-8.15), those residing in the most deprived areas (aOR = 2.64, 95% CI: 1.04 to 6.71) and PWID (aOR = 2.09, 95% CI: 1.04-3.78).
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