Management of hepatitis B: A longitudinal national survey – impact of the Canadian Hepatitis B Consensus Guidelines

1Liver Transplant Unit, London Health Sciences Centre, London, Ontario; 2Extension Marketing Inc, Ile Bizard, Quebec Correspondence and reprints: Dr Paul Marotta, London Health Sciences Centre, 339 Windermere Road, London, Ontario N6A 5A5. Telephone 519-685-8500, fax 519-663-3858, e-mail paul.marotta@lhsc.on.ca Received for publication December 17, 2009. Accepted February 8, 2010 Chronic hepatitis B virus (HBV) infection is a major cause of chronic liver disease in Canada, with approximately 600,000 Canadians infected. HBV has a high premature mortality rate (20% to 25%) if left untreated, and is the fifth leading cause of cancer (1). However, not all HBV-infected patients develop serious complications. The challenge in the management of chronic HBV is to identify individuals who are at a significant risk for the development of adverse consequences, and to offer this select group safe and effective treatment. Once an individual with HBV has been clinically assessed and deemed to require HBV therapy, there are a multitude of choices of agents that differ in cost, adverse effects, resistance profiles and efficacy. Currently, oral nucleoside and nucleotide agents and pegylated interferon-alpha 2a are the first-line choices for the management of HBV. While the therapeutic efficacy and safety of the therapies used to treat HBV are well known, selecting an agent for HBV therapy in Canada is more challenging because many patients do not have access to the most effective drugs due to formulary restrictions. For example, lamivudine (LAM) has largely fallen out of favour with speciality physicians due to its lack of efficacy and high rate of development of resistance; however, it is the agent most readily oriGinAl ArtiCle

available through provincial drug plans.Many Canadians have a significant public component to their drug coverage that typically limits therapeutic choices to the least expensive one, which, unfortunately, may also be the least potent and the one conferring the highest risk for development of resistance.Consequently, despite availability, adequate therapy is often not used in Canadian clinical practice due to public drug coverage restrictions.
Formulary complexity is a major barrier to treatment adoption because less experienced physicians often have difficulty with keeping up to date with the frequently changing restrictions of publicly funded programs and, as a result, are often reluctant to prescribe complex regimens.Additionally, there are structural barriers to treatment in Canada that result from the restrictive funding of laboratory tests and drug therapy, which currently prevent optimal treatment of those who need it.
The development, publication and dissemination of the Canadian HBV Consensus Guidelines (2) was envisioned to assist practising physicians with the associated complexities of HBV management.Close adherence to these guidelines would, in theory, improve the clinical management of HBV and potentially prevent many of the serious manifestations of this disease.
The primary objective of the present investigation was to assess the degree to which Canadian specialist physicians were able to incorporate the recommendations from the Canadian HBV Consensus Guidelines into their daily practice.
Longitudinal surveys have the ability to assess changes in clinical management of a disease over time.They are particularly valuable when they are conducted in conjunction with some form of intervention.In the current investigation, the impact of the Canadian HBV Consensus Guidelines acted as the intervention, and the series of surveys over time after the release of this document provides a picture of the evolving clinical management of HBV.Not only can this type of longitudinal survey detect improvements in management, it can also provide valuable information regarding barriers to the adoption of best-care practices.

Study sample
A representative sample of 80 physicians who manage patients with HBV across Canada were involved in a two-year longitudinal survey.These physicians were necessarily members of the Canadian Association for the Study of the Liver (CASL) and/or the Canadian Association of Gastroenterology and, as part of their membership, received the published consensus document on HBV.Participating physicians were also required to manage a minimum of 12 new HBV referrals per year to qualify for inclusion in the present study.The participating physicians represented a stratified random sample based on geographical HBV population concentrations, with approximately 26%, 50%, 20% and 4% of the physicians from Western Canada, Ontario, Quebec and Atlantic Canada, respectively.Approximately 45% of the sample were qualified as hepatologists, defined as specialist physicians who focus primarily on the treatment of hepatitis and/or liver disease, with the remaining 55% qualified as general gastroenterologists.Approximately 65% of the participating physicians were academic based and 35% were community based.Retention in the longitudinal study was high, with 84% completing all three phases of the investigation.The surveys questioned the same physicians over time, provided that they were available and still met the inclusion criteria (ie, had to see at least 12 new HBV patients per year); the latter is the main reason why the sample in phase I is slightly different than the sample in phase III.

Survey methodology
Identical 30 min telephone interviews were conducted at three distinct times, separated by approximately eight months, to assess the changes in HBV clinical management in the present cohort.The primary outcome was to evaluate whether the published Canadian HBV Consensus Guidelines had an impact on the clinical management of HBV and whether there was an increase in the adoption of the guidelines over time.The first telephone survey (phase I) was completed approximately six months following the publication and distribution of the guidelines, the second interview approximately 14 months following the publication (phase II) and the third and final interviews (phase III) occurred approximately 22 months following the publication of the guidelines.The questionnaire was administered by telephone by a third-party research firm specifically trained in the consistent administration of the survey.

Survey design and testing
The draft questionnaire was developed by prominent specialist physicians with significant expertise in the clinical management of HBV, and consisted of questions aimed at assessing the adoption of key clinical management strategies addressed in the Canadian HBV Consensus Guidelines publication.This particular questionnaire was further refined by a select group of CASL members and was translated into French by a professional translation service for use in French-speaking communities.
All participant responses were tabulated and reported for all assessed physicians (n=80).To investigate differences among groups of participant physicians, the responses from groups identified as hepatologists, gastroenterologists or those specialists within the sample who, as identified by the survey, managed the greatest number of HBV patients (top 20), were compared.

Analyses
Each response was tabulated and statistical significance was determined using 95% CIs that did not cross unity or P≤0.05.Differences among groups were assessed using t tests or c 2 tests as appropriate.

Respondents
Eighty-four per cent of the initial cohort of physicians participated in all three phases of the study.Of the physicians not participating in all phases, 60% no longer met the criteria for participation (ie, did not manage a minimum of 12 new HBV patients per year), 20% no longer managed HBV, 10% could not participate because of scheduling issues and 10% did not participate for unknown reasons.Regional representation (ie, percentage of physicians participating per region) was maintained over the duration of the study timeframe.Table 1 outlines the physician characteristics in greater detail.

Referral patterns and disease characteristics
Fifty-seven per cent of physicians stated that HBV referrals increased steadily from 2007 to 2009 (trend analysis).The source of HBV referrals differed significantly according to specialty.Gastroenterologists were referred HBV patients primarily from general practitioners (86%), while 12% were referred from other specialists.Hepatologists had approximately 71% of their referrals initiated by general practitioners and 25% from other specialists.Of interest, less than 5% of HBV referrals to these cohorts were from public health organizations.Hepatologists are referred twice as many new HBV patients, and maintain care and monitoring of almost four times the number of HBV patients versus gastroenterologists (Figure 1).
When physicians were asked about the health state of their new HBV patients, 50% were believed to possess 'active' disease (ie, potential candidates for treatment with elevated levels of HBV DNA and/or elevated alanine aminotransferase levels).Of the new referrals, 90% had never previously received HBV therapy (ie, treatment naive) and 10% were treatment resistant or refractory; these findings were consistent over the course of the study (phases I to III).The majority (96%) of treatmentresistant patients were LAM resistant (LAM-r); however, physicians reported that some patients (4%) experienced the development of resistance to other agents including adefovir (ADF), entecavir (ETV) and telbivudine (TELB).These resistances were not commonly reported in 2007 (phase I), but became slightly more common in phases II and III.Of the HBV patients deemed to require pharmacological management, only 71% of the treatment-naive patients and 81% of the treatment-resistant/refractory patients were subsequently treated.The main reasons cited for not treating the remaining eligible patients included reimbursement (80%) and affordability (61%) barriers.Public plan reimbursement remains a major obstacle preventing the optimal care of HBV patients (Figure 2); this barrier did not change over the course of the longitudinal survey.Interestingly, hepatologists initiated therapy in 75% and 90% of the eligible treatment-naive patients and treatment-resistant/refractory patients, respectively.This is in sharp contrast to the 68% and 64% of the eligible treatmentnaive and treatment-resistant/refractory patients, respectively, treated by general gastroenterologists.

Treatment of LAM-r HBV patients
Regarding the treatment of LAM-r HBV patients (Figure 5 TDF monotherapy represents the largest growth segment in this population, with the main differences demonstrated on a regional level.In Ontario, LAM-r patients with public funding receive either ADF or TDF in combination with LAM (42% versus 24%, respectively), whereas patients with private insurance receive either TDF as monotherapy or in combination with LAM (40% versus 32%, respectively).In Quebec, both publicly and privately reimbursed LAM-r patients receive TDF plus LAM (53% versus 51%, respectively) followed by TDF monotherapy (13% versus 23%, respectively) or ADF plus LAM (23% versus 19%, respectively) (Figure 6).In Western Canada, publicly funded patients primarily receive ADF plus LAM (75%) and privately funded patients receive either ADF plus LAM (36%), ETV (28%), TDF plus LAM (19%) or TDF (10%).

Treatment coverage
Sixty-four per cent of the new HBV patients treated had public drug coverage only (Figures 7 and 8).Therapy for HBV patients varied significantly depending on whether HBV therapy coverage was publicly or privately funded (Figures 9 and 10).For example, in 2009, 58% of treatment-naive HBV patients with public coverage were treated with LAM, whereas only 10% of treatment-naive HBV patients with private insurance were treated with LAM.HBV patients residing in Quebec were the exception because drug access was similar across all payers (Figures 4 and 6).Specifically in Quebec, the use of the various agents was very similar regardless of whether the patient had public or private reimbursement coverage.What changed over time was the shift from agents such as LAM and ADV to the newer, more potent agents ETV and TDF.
Approximately 10% of all treated patients receive some form of financial assistance from pharmaceutical companies that are involved in the manufacturing and marketing of specific HBV therapies.The presence of co-pay programs was cited as a factor influencing treatment choices by 80% of respondents and remained consistent from 2007 to 2009 (phases I to III).

Advantages and disadvantages of the various treatment options
When physicians were asked to name the key advantages of each of the various agents used to treat HBV (Table 2), potency, efficacy and duration of treatment were the key components of differentiation.Similarly, when asked to outline the key disadvantages of each, cost, resistance profile and adverse events clearly divided the agents.ETV was consistently identified to be the most costly agent.With the exception of TDF and the interferons, all agents were cited as having the potential for patients to develop resistance.Adverse events were more commonly cited for the interferons and ADF.
Only the interferons were cited as having a short and finite duration of treatment (2007 to 2009: 59%, 79% and 65% mention), whereas all of the oral agents were cited as most often requiring lifelong administration.The interferons were cited as being efficacious in a select subpopulation of patients (ie, young, hepatitis B e antigen positive, elevated alanine aminotransferase levels and moderate to low HBV DNA levels), but the associated adverse events were often mentioned as a barrier to widespread use (2007 to 2009: 85%, 88% and 88%).The key advantages to LAM were that it was well tolerated and less costly than the other agents used (2007 to 2009: 56%, 45% and 53%, and 45%, 55% and 65%, respectively).The key disadvantage associated with the use of LAM was the high rate of resistance development (2007 to 2009: 93%, 95% and 98% mention).The main advantage cited for ADF was that it was effective for the treatment of LAM-r patients (2007 to 2009: 52%, 51% and 55%) and the disadvantages were similar in terms of the percentage they were mentioned (2007 to 2009: range 23% to 43%) and included the risk of adverse events, the elevated cost compared with the other HBV agents, its lack of potency and the increased risk of resistance development.ETV was found to be relatively potent, with a good resistance profile (2007 to 2009: 80%, 81% and 88%, and 45%, 43% and 38%, respectively).High cost was cited as the main disadvantage associated with ETV (2007 to 2009: 56%, 63% and 60%, respectively); however, in 2009, 73% of physicians began mentioning the issue of cross-resistance with LAM.The key advantage cited for TELB was potency (2007 to 2009: 67%, 31% and 25%, respectively) and, by 2009, 32% of physicians stated that TELB offered no distinct advantage over other existing agents.The key disadvantage associated with TELB was the development of resistance (2007 to 2009: 78%, 75% and 80%, respectively).TDF was found to be highly potent and had a favourable resistance profile (2007 to 2009: 78%, 75% and 80%, and 51%, 35% and 61%, respectively).The key disadvantages for TDF were similar in terms of the percentage they were mentioned, and included the elevated cost, the risk of adverse events and poor public reimbursement (2007 to 2009: range 20% to 38%).

DISCUSSION
The management of HBV is complex and evolving rapidly with new findings in diagnosis and treatment.Diagnostic testing has improved dramatically over the past five years, as has the development of efficacious therapeutic agents.Case findings are increasing in Canada due to changing immigration patterns, increasing disease volumes and the evolving education of health professionals.Consensus guidelines provide the best evidence in a concise format and enable health care professionals to stay abreast of current best-practice management strategies; however, the impact of guidelines has not previously been studied among HBV specialty care providers.The present study reports the first longitudinal data from a large cohort of physicians treating HBV, with the expressed intent of evaluating the impact, uptake and adherence to Canadian HBV Consensus Guidelines.The present cohort was chosen from the membership of the CASL and the Canadian Association of Gastroenterology who are actively involved in treating chronic HBV, and who received the guideline publication as members of affiliate organizations.
The primary strength of our stratified, random populationbased sample of physicians was that it represented a large, geographically diverse cohort, capturing a representative Canadian sample of treating physician specialists from both academicand community-based practices.Furthermore, retention in the 22-month investigation was high, with 84% of the cohort completing all three phases of the investigation.
The Canadian HBV Consensus Guidelines were published and disseminated in June 2007.Initially, the recommendations were followed by 90% of the hepatologists and 100% of the general gastroenterologists who were interviewed.Over time, however, 85% of hepatologists and 93% of general gastroenterologists were following the guidelines, suggesting that the therapeutic arena had changed, as had the clinical experience of the respondents.The treatment of chronic HBV is complex and continues to evolve.
Several factors must be taken into account when selecting the most appropriate agent for an individual patient including treatment efficacy, safety, tolerability, resistance profiles, mode of administration and affordability.The agent selected for treatment should be chosen with consideration given to patient characteristics, stage of disease, affordability and patient preference -not solely as a result of restrictive public reimbursement.Finally, when selecting a nucleoside or nucleotide agent, it is important to note that an agent with both high potency and a high barrier to resistance would be expected to yield the best long-term results for the HBV-infected patient.
There are several variables to consider when managing HBV, for which The Canadian HBV Consensus Guidelines have provided several recommendations.Most of the physicians who participated in the present research stated that the consensus guidelines provided valuable guidance for the management of their patients with chronic HBV.DISCLOSURE: Kurt Lucas operates an independent, private research company, and provides services for the pharmaceutical and medical device industries as well as nonprofit organizations (eg, The Ontario Rheumatology Association).He is not employed by any pharmaceutical company.
FUNDING: Funding for this project was provided through unrestricted research grants from several pharmaceutical companies, all of whom have products that were discussed as part of this research.These include Bristol-Myers Squibb, Gilead, Novartis and Roche Canada.

Figure 7 )Figure 10 )
Figure 7) Source (public, private or none) of drug reimbursement for chronic hepatitis B patients treated

Figure 8 )
Figure 8) Source (public, private or none) of drug reimbursement according to region for chronic hepatitis B patients treated.Atl Atlantic Canada; ODB Ontario Drug Benefit Program; Ont Ontario; Private Private insurance; Public Public insurance; QC Quebec; RAMQ Régie de l'assurance maladie du Québec; West Western Canada