New AASLD/IDSA hepatitis C virus practice recommendations: An online resource

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Abbreviations

AASLD

American Association for the Study of Liver Diseases

FDA

US Food and Drug Administration

HCV

hepatitis C virus

IAS‐USA

International Antiviral Society‐USA

IDSA

Infectious Disease Society of America

Interferon was first approved for the treatment of chronic hepatitis C virus (HCV) infection 25 years ago, although it was effective in only a small proportion of individuals and was fraught with tolerability issues. The landscape of treatment of HCV infection changed slowly over the years until the introduction of the first‐generation protease inhibitors in 2011. Since then, the field of direct‐acting antiviral drugs has evolved rapidly. A second‐generation protease inhibitor and a nucleoside viral RNA polymerase inhibitor were approved in 2013, and several other drugs with various viral and host mechanisms of action are likely to be approved over the next 12–24 months. Eradication of HCV infection is now possible in nearly all treated patients, and interferon‐free therapy should soon be available for most. However, several major obstacles remain before this progressive liver disease can be eliminated, at least in the United States. These include identification of infected persons through widespread risk‐based and birth cohort population testing, linkage to care, and deciding who and when to treat.

The rapid pace of change in testing recommendations, health care coverage and delivery, and available medications makes it difficult for health care providers to keep abreast of the newest and most appropriate care to offer their patients. To provide timely guidance on how each new development changes practice for health care professionals, the Infectious Disease Society of America (IDSA) and the American Association for the Study of Liver Diseases (AASLD) have developed a web‐based process for the rapid formulation and dissemination of evidence‐based, expertly developed recommendations for HCV management. The International Antiviral [formerly AIDS] Society‐USA (IAS‐USA) provides the structure and assistance to sustain the process that represents the work of leading authorities in the diagnosis and treatment of HCV infection. The purpose of this review is to describe the process of how recommendations are developed and how they will be updated over time. (Table 1 provides an overview of this process.)

Table 1.

Summary of the Process and Methods for Guidance Development

Topic	Description
Statement of need	The introduction of direct‐acting agents against HCV in 2011 has rapidly changed the treatment of HCV infection. The ever‐increasing pace of change anticipates numerous, additional therapies in the next few years, requiring timely guidance on how each new development changes practice for health care professionals.
Goal of the HCV Guidance document	The goal of the HCV Guidance document is to provide up‐to‐date recommendations to health care practitioners on the optimal screening, management, and treatment of adults with HCV infection in the United States, considering the best available evidence. The HCV Guidance document is developed in real time with regular updates. The initial recommendations address three areas of priority: 1) screening, testing, and linkage to care; 2) initial treatment regimens for persons in whom the decision to treat has been made; and 3) retreatment regimens and considerations for persons who have not responded to previous therapy with peginterferon/ribavirin (PEG/RBV) with or without an HCV protease inhibitor.
Panel members	The panel members were chosen because of their expertise in the diagnosis, management, and treatment of HCV infection in terms of research and patient care. Members from the fields of hepatology and infectious diseases were included. Members were appointed by the respective sponsor societies after vetting by an appointed sponsor society committee. At least one representative from the HCV community serves on the panel. The panel chairs were appointed, two each from the sponsor societies and one representing the collaborating partner. All panel chairs and members serve as volunteers (not compensated) for defined terms (3 years), which may be renewed.
Conflict of interest management	Financial conflict of interest statements for the prior year of all chairs and members under consideration were reviewed by the sponsor societies and collaborating partner during the vetting processes. Panel members under consideration were given the opportunity to divest themselves of any nonconforming conflicts of interests before being confirmed to the panel. The panel composition was designed to include a balance of members with no substantial financial relationships with commercial entities that have interests in the content of the HCV Guidance document with those who do at the time that the panel member was confirmed. The criteria of the sponsoring societies (e.g., limits on annual compensation from any particular commercial entity, absence of employment with a commercial entity, absence of equity or options in the relevant commercial entity, absence of service on company speakers bureaus and company paid lectureships, etc) were followed. More details on policies in that regard can be found on the organizations' websites.
	At the first in‐person meeting of the full panel, each chair and member read his or her disclosure statement to the group; members were given the opportunity to recuse themselves (or be recused) from particular topic areas where there was a perceived conflict of interest that could not be resolved.
	Panel member direct (personal) financial disclosure information can be found at http://www.hcvguidelines.org/disclosure_information.
Intended audience	HCV treatment practitioners
Sponsors, funding, and collaborating partner	The AASLD and the IDSA are the sponsors of the HCV Guidance document and provide financial support. The IAS‐USA is the collaborating partner responsible for managing the panel and the Guidance process.
Evidence identification and collection	The HCV Guidance document was developed using an evidence‐based review of information that is generally available to the Guidance audience. Data considered included research published in the peer‐reviewed literature or presented at major national or international scientific conferences, safety warnings from the FDA or other regulatory agencies or from manufacturers, drug interaction data, prescribing information from FDA‐approved products, and registration data for new products under FDA review. Unpublished or presented reports, data on file, and personal communications are generally not considered.
	Panel members were appointed based on their collective broad knowledge of available data and current research in the field, and were responsible for initially identifying and discussing these data, including recent reports from scientific conferences.
	In addition, an initial literature search was conducted on November 4, 2013, to ensure that the panel addressed all relevant published data. A total of 3939 unique citations were retrieved. Medical subject headings and free text terms were combined to maximize retrieval of relevant citations from the PubMed, Scopus, EMBASE, and Web of Science databases. Inclusion criteria included articles published in English from 2010 to the present. Exclusion criteria included review articles, mice, rats, and in vitro studies.
	The panel members monitor for new evidence regularly and the literature search is be updated as needed.
Grading of the evidence and recommendations	The HCV Guidance document is presented in the form of recommendations. Each recommendation is graded in terms of the quality of the evidence and the strength of the recommendation, using a scale adapted from the American College of Cardiology and the American Heart Association Practice Guidelines (). A summary of the supporting (or conflicting) evidence follows each recommendation.
Data review and synthesis and preparation of recommendations and supporting information	The panel was initially divided into three subsections: 1) Testing and Linkage to Care; 2) Choice of Regimen in Treatment‐Naïve Patients For Whom the Decision to Treat Has Been Made, and 3) Retreatment for Patients in Whom Previous Treatments Have Failed.
	Treatment for unique populations with HCV infection is discussed separately. Subgroups were assigned to collect, review, and prepare initial draft recommendations. Each subgroup has two subgroup leaders (one liver specialist and one infectious diseases specialist). Draft recommendations were reviewed at the first full panel meeting in October 2013. Subgroups then met regularly by conference call and presented their updated recommendations and supporting evidence at each of three full‐panel conference calls.
	Final approval of all recommendations are made by full‐panel, general consensus. Each initial recommendation and its grade was subject to panel survey (agree, disagree, and opportunity for comment, for each recommendation and grade) to separately identify any disagreement or inconsistency.
	The sponsor societies have final review and approval of each recommendation prior to release on the HCV Guidance website.
Update process	The HCV Guidance document will be expanded to cover more management issues on an ongoing basis for each section posted; the panel members will regularly monitor for data that may warrant modification of the guidelines. Updates may be prompted by new publications or presentations at major national or international scientific conferences, new drug approvals (or new indications, dosing formulations, or frequency of dosing), new safety warnings, or other information that may have a substantial impact on the clinical care of patients.
	Updated recommendations and grades, once agreed upon by the full panel and approved by the sponsor societies, are posted on the HCV Guidance website.
Abbreviations	Commonly used abbreviations with their expansions are listed at http://www.hcvguidelines.org/full-report/methods-table-3-commonly-used-abbreviations-and-their-expansions.
Opportunity for comments	Evidence‐based comments may be submitted to the panel by sending an e‐mail to hcvguidance@iasusa.org or by clicking on the “Send a comment to the panel” button at www.hcvguidelines.org/contact‐us. Note: the panel will consider evidence‐based comments about the recommendations, grades, and evidence summary, but should not be contacted for individual patient management questions.

These recommendations are referred to as “HCV Guidance” rather than as a guideline, because the rapidity of change in the field does not allow for the rigorous and time‐consuming process required by the AASLD and the IDSA to develop their practice guidelines. We felt that the timeliness of recommendations and the dynamic nature of a web‐based resource would better serve providers and patients at this time. However, it is anticipated that these recommendations will eventually be developed as a formal practice guideline and will be published in the journals of the sponsoring societies in alternating years.

Despite the aforementioned limitations, the process for developing the AASLD/IDSA HCV Guidance document is rigorous. Five co‐chairs (two from AASLD, two from IDSA, and one from IAS‐USA) were selected by the governing boards of the sponsoring societies. These co‐chairs reviewed nominations for panel members and selected 10 HCV experts from each association. Community representatives were also added to the panel, and other experts were added ad hoc as subjects under development required. Co‐chairs had either no potential conflicts of interest or divested themselves of all such interests at the onset of the process. Panel members were encouraged to do likewise, with a goal of having at least half of the panel members without conflicts. Potential conflicts were reviewed by the members' respective societies according to their specific conflict of interest policies. These criteria are available on the AASLD and IDSA websites (http://www.aasld.org; http://www.idsociety.org). In addition, for this particular activity, participation in industry speakers' bureaus or single company‐sponsored activities with companies who have a hepatitis drug that is approved or in development was considered to be an exclusion from participation on the panel. A listing of the panel members and their conflicts is available on the panel's website (http://www.hcvguidelines.org/panel).

Panel members were divided into topic subgroups and given an aggressive timeline for development of recommendations. In each instance, the panel was asked to recommend what it considers to be the best possible management option for a given patient at the present time—or, put another way, what the expert panel member would recommend if a colleague called to ask what to do with a particular patient. Recommendations are evidence‐based and rapidly updated as new data become available in the form of peer‐reviewed publications, results of clinical trials presented at national or international meetings (published in abstract form), or submissions to the US Food and Drug Administration (FDA). At times, treatment regimens may be endorsed that are not specifically stated in a drug's package label, though such recommendations will be supported by study data in all cases. Readers should consult prescribing information and other resources for further information. Recommendations are graded with regard to the level of the evidence and strength of the recommendation using a scale adapted from the American College of Cardiology and the American Heart Association Practice Guidelines (http://my.americanheart.org/idc/groups/ahamah‐public/@wcm/@sop/documents/downloadable/ucm_319826.pdf) (Table 2). For each patient group, a particular treatment regimen was judged to be recommended (favored), alternative (not favored, but appropriate in some circumstances), or not recommended. These recommendations were reviewed and vetted by all panelists and co‐chairs before publication on the HCV Guidance website (www.hcvguidelines.org). To date, the AASLD/IDSA HCV Guidance document includes recommendations for testing, linkage to care, initial therapy, treatment of nonresponders to prior therapy, and treatment of individuals in what has been termed “difficult to treat” groups such as human immunodeficiency virus–coinfected patients, compensated and decompensated cirrhosis, liver transplant recipients, and persons with renal failure. Future topics scheduled for publication later this year include: who to treat, when to treat, monitoring therapy, and treatment of acute HCV infection. The important issue of cost has not been addressed in the recommendations to date. While obviously important and a topic of considerable recent discussion in the lay press, cost‐benefit data are currently limited. Such information will be added as it becomes available.

Table 2.

Grading System Used to Rate the Level of the Evidence and Strength of the Recommendation for Each Recommendation

	Description
Classification
I	Conditions for which there is evidence and/or general agreement that a given diagnostic evaluation, procedure, or treatment is beneficial, useful, and effective
II	Conditions for which there is conflicting evidence and/or a divergence of opinion about the usefulness and efficacy of a diagnostic evaluation, procedure, or treatment
IIa	Weight of evidence and/or opinion is in favor of usefulness and efficacy
IIb	Usefulness and efficacy are less well established by evidence and/or opinion
III	Conditions for which there is evidence and/or general agreement that a diagnostic evaluation, procedure, or treatment is not useful and effective or if it in some cases may be harmful
Level of evidence
A	Data derived from multiple randomized clinical trials or meta‐analyses
B	Data derived from a single randomized trial, or nonrandomized studies
C	Consensus opinion of experts, case studies, or standard of care

Recommendations are based on scientific evidence and expert opinion. Each recommended statement includes a letter (A, B, or C) that represents the strength of the recommendation and a roman numeral (I, II, or III) that represents the level of the evidence that supports the recommendation.

Adapted from the American College of Cardiology and the American Heart Association Practice Guidelines (http://circ.ahajournals.org/content/early/2013/11/11/01.cir.0000437738.63853.7a.full.pdf+html?sid=03916dda‐ac3b‐4734‐a9b0–5fda0e41a432).

Financial support for the AASLD/IDSA HCV Guidance process comes solely from the membership‐based societies and not by pharmaceutical companies or other commercial interests. The guidance development process is generally consistent with that used to develop other IAS‐USA guidelines (https://www.iasusa.org/about/program‐development‐policy). The Centers for Disease Control and Prevention provided financial support for the gathering and review of evidence related to HCV screening and testing recommendations and interventions to implement HCV screening in clinical settings.

The HCV Guidance document should be considered a “living” document in that new sections will be added and updated frequently as new information and treatments become available. Notation of such updates will be provided, and download of the document or any portion of it will be dated as a reference. It is our hope that this dynamic document will make the selection of the best treatment regimen for chronic HCV infection more straightforward for providers in a time of rapid evolution of management strategies. We also hope that this document will encourage health care providers who have not treated the disease previously to consider offering treatment to their patients.