A systematic review of community based hepatitis C treatment

Each year in Australia less than 2 % of people infected with hepatitis C virus (HCV) are treated and globally treatment uptake rates are similarly low [1]. Barriers to HCV treatment include; difficulty in accessing a treatment service, not being offered treatment once in a treatment service and toxic pegylated interferon based treatment with poor efficacy [2–5]. Stigma is also a significant barrier to treatment in health care settings [6].

Fortunately the HCV treatment landscape is changing; pegylated interferon, ribavirin and protease inhibitor regimens of 6–12 months duration, which generate serious adverse effects in about 10 % of people and achieve cure in only 70 % are being replaced by all oral, well tolerated interferon free, direct acting antiviral (DAA) therapy, often for 12 weeks duration, with cure in more than 95 % [7, 8]. Although treatment tolerability and efficacy as a barrier to HCV treatment has been overcome, in the vast majority of countries HCV antiviral costs remain prohibitive. For DAA therapy to have maximum impact on the HCV epidemic, it must be affordable and accessible. To date, in most developed and many developing countries specialist physicians have provided HCV treatment, usually from tertiary hospital outpatient clinics. Such clinics often have rigid appointment scheduling and do not always provide multidisciplinary care. The reassuring safety profile and high efficacy of DAA therapy means HCV treatment could now be provided in a diverse range of clinical settings. HCV treatment could be provided in community-based clinics, including opioid substitution therapy (OST) clinics or using telehealth, with a variety of service providers including nurses, general practitioners and specialists. Increasing treatment accessibility may significantly improve HCV treatment uptake and cure, but a key issue is a lack of quality information about which model of care is most efficacious.

The Australian government has recently made a landmark decision to fund DAA therapy for every Australian infected with hepatitis C from 1st March 2016 [9]. In addition, a new model of care will be implemented in order to facilitate access to treatment. General practitioners will be able to prescribe DAA, albeit after authorization from a specialist [10]. As the new Australian model of care unfolds, it is timely to reflect upon the available evidence regarding hepatitis C treatment in the community.

To gain data that may inform HCV service delivery policy, we reviewed the literature to compare treatment uptake rates in community based treatment services with conventional tertiary services, and to compare sustained virological response (SVR) outcomes in patients treated with standard interferon with or without ribavirin, or pegylated interferon and ribavirin, in the community with patients treated in conventional tertiary settings.

Treatment could include pegylated interferon and ribavirin, with or without DAA or interferon-free. Health care provider could be a specialist or general practitioner or nurse; the use of telehealth was permitted.

A narrative review of the included studies was performed. This review is registered with the PROSPERO database (registration number CRD42015025505).

The flow diagram of the study analysis is shown in Fig. 1. The search generated 1499 citations, 413 duplicates were then deleted. Of the remaining 1086 citations, 967 were excluded based on the abstract. Full text articles were retrieved for 119 citations. A further 8 articles were included after citations searching. Thirteen of the 127 articles fulfilled the inclusion criteria. A summary of data from included articles is shown in Table 1, below.

Study	Year	Country	Design	Intervention	Facility	n	Rx uptake	SVR
							n (%)	n (%)
Arora	2011	USA	Prospective cohort study of treatment outcome	Telehealth to support primary care (in community and prison)	Tertiary	146		84/146 (58)
					Primary total (Prisoners)	261 (106)		152/261 (58)
Bruce	2012	USA	Randomised controlled trial of treatment uptake and outcome	Directly observed therapy in OST clinic vs self administered treatment in tertiary clinic	Tertiary	9	4/9 (44)	1/4 (33)
					Primary	12	12/12 (100)	6/12 (75)
Chen	2014	Taiwan	Prospective cohort study of treatment outcome	Telecare	Tertiary	150		99/150 (66)
					Telecare	148		102/148 (69)
Gigi	2013	Greece	Retrospective cohort study of treatment uptake	Rx in OST clinic	Tertiary	643 Ab+	276/643 (43)
					Primary	204 Ab+	17/204 (8)
Jou	2013	USA	Retrospective cohort study of treatment outcome	Analysis of data by Rx site	Academic	1905		760/1905 (40)
					Community	1165		455/1165 (39)
Kramer	2010	USA	Retrospective cohort study of treatment uptake		Specialist clinic	24,853	3537 (14)
					Primary Care clinic	1929	251 (13)
Kuo	2015	Taiwan	Prospective cohort study of treatment uptake and outcome	Rx in community	Pre intervention	18	4/18 (22)	2/4 (50)
					Post intervention		3/16 (19)	3/3 (100)
Moriarty	2001	New Zealand	Observational study of treatment uptake	Rx co-located at NSP site	Tertiary	51	1 (2)
					Primary		4 (8)
Moussalli	2010	France	Observational study of treatment uptake	Rx in OST clinic	Pre intervention	337	2/337 (0.6)
					Post intervention		85/335 (25)	37/85 (44)
Myers	2011	Canada	Observational study of treatment outcomes		Academic	133		79/133 (59)
					Community	250		120/250 (48)
Nazareth	2013	Australia	Retrospective cohort study of treatment outcomes	Telehealth	Tertiary	528		311/528 (59)
					Telehealth	50		36/50 (72)
Niederau	2014	Germany	Prospective cohort study of treatment outcome	Analysis of adherence to guidelines by Rx site	Hospital based	621		290/621 (47)
					Private practice	3778		1744/3778 (46)
Rossaro	2013	USA	Retrospective cohort study of treatment outcomes	Telehealth	Tertiary	40		16/37 (43)
					Telehealth	40		21/38 (55)

Rx treatment, OST opioid substitution therapy, Ab + HCV antibody positive

Five of the included studies were from the US, two were from Taiwan and there was one study each from Australia, New Zealand, Greece, France, Germany and Canada. The interventions to provide treatment in the community were diverse and included telehealth and treatment provision from primary care clinics, opioid substitution therapy (OST) clinics or needle exchange programs. Treatment consisted of pegylated interferon and ribavirin in all studies but for Moriarty [11] and Gigi [12], in which standard interferon with or without ribavirin was also included.

This systematic review has identified publications, which contain a comparison between HCV treatment uptake rates or SVR outcomes in community and tertiary treatment services. Of the thirteen publications included, only one was a randomized controlled trial and the remainder were observational studies. The interventions that resulted in HCV treatment provision in the community were diverse, and included; telehealth, integrated HCV services in OST clinics or NSEP services, private medical practice and outreach services staffed by specialists or nurses.

Of the six studies that measured treatment uptake as an outcome (see Table 2), three demonstrated an increase in uptake at the community site [11, 13, 22]. Interestingly, two of these studies were conducted in OST clinics, and the third in a NSEP service. Two studies demonstrated similar treatment uptake rates between the community and tertiary services [14, 23]. The large study by Kramer et al. investigated the treatment uptake within the Veterans Affairs Healthcare in the United States according to whether treatment was provided from a primary care provider clinic or a specialist clinic. It is not known what proportion of the primary care provider clinics may have been OST providers as well. One study demonstrated decreased treatment uptake at the community site [12]. The authors attributed this difference to a difficulty in collaboration between OST staff and hospital based specialists.

The factors contributing to increased treatment uptake in the community sites varied according to the study; provision of non invasive fibrosis assessment (Fibrotest-Actitest) (Mousalli), multidisciplinary services (Mousalli, Moriarty, Bruce), modified directly observed therapy (Bruce) and gaining trust (Moriarty), led to improved management of HCV in the community setting.

Of the nine studies that measured SVR as an outcome (see Table 3), four demonstrated higher SVR rates in the community group [16, 17, 22, 23]. Possible reasons for this include that the community services were more convenient for the patients and offered a “one stop shop” where multiple needs could be met, or that HCV treatment was integrated into a developed patient-provider relationship. Another explanation is that the availability of multidisciplinary services may have helped mitigate factors associated with poor adherence or SVR outcomes in PWID such as unstable housing, poor social functioning and ongoing drug use [24]. Four studies demonstrated similar outcomes between the two treatment settings [15, 18–20]. One study from Canada in which 250 patients were treated in the community and 133 in an academic centre, demonstrated lower SVR rates in patients treated in the community [21]. The difference was due to SVR outcomes in genotype one patients only. Patient characteristics including level of fibrosis, rates of dose modification and treatment cessation for genotype one infected patients were similar in the community and academic sites, and an explanation for the difference in SVR between treatment sites was not apparent.

Modelling studies indicate that treatment uptake is the major limiting factor to substantial reductions in disease burden. Current treatment rates in Australia of 3 per 1000 PWID annually would need to be scaled up to 40 per 1000 PWID annually to halve HCV prevalence by 2030. [25]. The advent of DAA therapy has made the elimination of HCV a tangible concept since treatment is simple and well tolerated, but for this to be achieved a significant change in service delivery would be required, and has been undertaken.

Nine of ten studies reporting SVR outcomes demonstrated similar or superior SVR rates were achieved in the community. Further, findings in this review suggest that decentralising HCV services and providing HCV treatment in the community, particularly OST clinics, may increase treatment uptake. Numerous cohort studies conducted in OST clinics indicate that HCV treatment in this setting can be successful, even in the peginterferon based treatment era [19, 26, 27]. The key components of successful HCV treatment delivery in the community need to be identified, to inform policy and ensure that integrated services are adequately resourced.

This review was limited by the lack of published data that compares outcomes of HCV treatment delivered in the community with treatment delivered in conventional tertiary settings. Some studies included in the review have a small number of participants and therefore lack statistical power. There was only one small randomised controlled trial comparing community and tertiary based treatment, and this study also provided DOT to the patients in the community arm, rendering the relative contribution of both interventions difficult to assess. This review investigated interferon based HCV treatment and therefore the findings may not be applicable to HCV treatment with DAA. A large randomised controlled trial addressing the effect of community provision of HCV DAA treatment – the Prime Study based in Melbourne, Australia – is underway (clinicaltrials.gov NCT02555475). It is likely that any treatment outcome difference between hospital and community care may become less pronounced as treatment becomes easier with DAA therapy.

In conclusion, this review demonstrates that the limited data available supports the safety of peginterferon based HCV treatment in the community, and the potential for community based treatment to increase treatment uptake. The paucity of high quality data available to assess the effect of HCV treatment in the community on HCV treatment uptake is striking. This variable is a key component in the hepatitis C cascade of care, and further studies are warranted to clarify how best to structure HCV service delivery in the era of DAA.

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Not applicable.