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Chou R, Bougatsos C, Blazina I, et al. Treatment of Hepatitis C Virus Infection in Adults: Future Research Needs: Identification of Future Research Needs From Comparative Effectiveness Review No. 76 [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2013 Jan. (Future Research Needs Papers, No. 28.)

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Treatment of Hepatitis C Virus Infection in Adults: Future Research Needs: Identification of Future Research Needs From Comparative Effectiveness Review No. 76 [Internet].

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Executive Summary


In 2010 the Agency for Healthcare Research and Quality (AHRQ) charged the Oregon Evidence-based Practice Center (EPC) with conducting a Comparative Effectiveness Review (CER)1 on antiviral treatments for hepatitis C virus (HCV) infection. The CER focused on current, U.S. Food and Drug Administration (FDA)-approved antiviral therapies for antiviral-naïve adults with chronic HCV infection, without HIV or hepatitis B virus coinfection.

The Key Questions addressed in the CER were:

Key Question 1


What is the comparative effectiveness of antiviral treatment in improving health outcomes in patients with HCV infection?


How does the comparative effectiveness of antiviral treatment for health outcomes vary according to patient subgroup characteristics, including but not limited to HCV genotype, age, race, sex, stage of disease, or genetic markers?

Key Question 2


What is the comparative effectiveness of antiviral treatments on intermediate outcomes, such as the rate of sustained virologic response (SVR) or histologic changes in the liver?


How does the comparative effectiveness of antiviral treatment for intermediate outcomes vary according to patient subgroup characteristics, including but not limited to HCV genotype, age, race, sex, stage of disease, or genetic markers?

Key Question 3


What are the comparative harms associated with antiviral treatments?


Do these harms differ according to patient subgroup characteristics, including but not limited to HCV genotype, age, race, sex, stage of disease, or genetic markers?

Key Question 4


Have improvements in intermediate outcomes (SVR, histologic changes) been shown to reduce the risk or rates of adverse health outcomes from HCV infection?

The analytic framework (Figure A) illustrates the targeted population, interventions, and outcomes for the CER.

This figure depicts the analytic framework that outlines the population, interventions and outcomes considered in the review. The above figure is a modified version of a larger framework depicting the impact of both screening and treatment for Hepatitis C in adults. This figure focuses on the treatment portion of the framework. The population includes adult patients with chronic hepatitis C virus (HCV) infection. The interventions include pegylated interferon alfa-2a with ribavirin; pegylated interferon alfa-2b with ribavirin; protease inhibitors pending FDA approval (e.g., telaprevir). Intermediate outcomes include liver function, sustained virologic remission, and histologic improvements. Final outcomes include morbidity and mortality from HCV (including hepatic cirrhosis, hepatocellular carcinoma, liver transplantation rates, quality of life); harms of antiviral therapies including flu-like symptoms, hematologic effects, psychiatric effects. Outcomes also include “quality of life” and “transmission of hepatitis C virus”.

Figure A

Analytic framework from Comparative Effectiveness Review. Note: HCV=hepatitis C virus, QOL=quality of life, SVR=sustained virologic response.

The CER’s objectives were to understand the comparative benefits and harms of the various antiviral regimens to make informed treatment decisions in antiviral-naïve patients with chronic HCV infection, particularly given the availability of new treatment options. The review evaluated the effects of different medication doses, durations of therapy, and dosing strategies, and examined how comparative effectiveness varies depending on HCV genotype, viral load, and other demographic and clinical characteristics. The CER did not evaluate antiviral treatment of HCV-infected patients with HIV or hepatitis B coinfection, pregnant women, or children.

Research gaps and limitations of the existing literature identified in the CER are summarized below, organized according to the most relevant element of the population, intervention, comparator, outcome, and timing (PICOT) framework:

Population-Related Gaps

  1. Need for studies enrolling broader spectrum of patients, including those with medical and psychological comorbidities seen in clinical practice (relevant to all Key Questions).
  2. Need for studies of treatment in screen-detected patients, to understand applicability to this population (relevant to all Key Questions).
  3. Need for studies designed using an effectiveness paradigm, to understand real-world effects of antiviral regimens, including effects related to the poorer treatment adherence than observed in efficacy trials (relevant to all Key Questions).
  4. Need for studies on effects of newer triple therapy regimens with a protease inhibitor in subgroups defined by age, body weight, baseline fibrosis stage, and other important factors (relevant to Key Questions 2b, 3b).

Intervention-Related Gaps

  1. Need for head-to-head studies comparing triple therapy with newer protease inhibitors (telaprevir and boceprevir) (relevant to Key Questions 1a, 1b, 2a, 2b, 3a, and 3b).
  2. Need for trials evaluating the boceprevir regimen approved by the FDA in antiviral-naïve patients without baseline cirrhosis (relevant to Key Questions 1a, 1b, 2a, 2b, 3a, and 3b).
  3. Need for studies that evaluate the usefulness of genomics and other methods for individualizing treatment decisions in patients with HCV infection (relevant to Key Questions 1b, 2b, and 3b).

Comparator-Related Gaps

  1. Need for more studies on clinical outcomes in patients who experience SVR following antiviral treatment versus those who do not experience SVR that are methodologically rigorous, including adequate controlling for potential confounders (relevant to Key Question 4).

Outcome/Timing-Related Gaps

  1. Need for studies assessing important long-term clinical outcomes associated with current antiviral treatments for chronic HCV infection (relevant to Key Questions 1a and 1b).
  2. Need for methodologically rigorous studies on effects of achieving a SVR on long-term quality of life (relevant to Key Question 4).
  3. Need for studies with long-term followup of patients exposed to telaprevir and boceprevir to understand the long-term harms (relevant to Key Questions 3a and 3b).

Other Issues

  1. Need for studies not funded by pharmaceutical companies, as almost all studies of antiviral therapies were funded by pharmaceutical companies; studies have found that industry-funded studies tend to report more favorable results than studies not funded by industry (relevant to all Key Questions).


We began by generating an initial list of evidence gaps as identified in the CER. The Principal Investigator of this Future Research Needs report also served as the Principal Investigator of the CER and provided insight into the identified future research needs. We reviewed all notes available from Key Informant interviews and Technical Expert Panels discussions undertaken as part of the CER processes. The preliminary list of evidence gaps was supplemented and refined through input from stakeholders selected to represent a variety of perspectives, including clinicians, researchers, policymakers, payers, research funders, and consumer advocates, and was subsequently prioritized into a top-tier list of research needs. This was accomplished through an initial Webinar and phone discussion with stakeholders, followed by two rounds of Web-based prioritization using questionnaires, based on the Delphi method. SurveyMonkeyÔ was used to create and deliver the surveys and organize stakeholder responses.

For the initial questionnaire, we asked stakeholders to describe their stakeholder perspective(s) and to describe any additional gaps missing from the initial list that they thought were important, within the scope of the original CER. We initially asked the stakeholders to consider the following criteria when ranking gaps as high, medium, or low priority:

  • Burden of disease
  • High public interest
  • Vulnerable populations
  • Utilization of existing resources
  • Potential impact
  • Their own reasoning

In the second and final questionnaire, we asked the stakeholders to rank the evidence gaps in order of priority, using the Effective Health Care (EHC) Program Selection Criteria to rank clinical importance and significance, which included:

  • Appropriateness
  • Importance
  • Desirability of research/Avoidance of unnecessary duplication
  • Feasibility
  • Potential impact

The top five gaps that received the most stakeholder endorsements were to be classified as the top-tier research needs, followed by the second-tier gaps. Any gaps raised by the stakeholders that fell outside the scope of the CER were not prioritized.

For the top-tier research needs, a research librarian then searched the Ovid pre-MEDLINE, MEDLINE, and the Cochrane Central Register of Controlled Trials databases using the search strings developed for the original CER.1 The searches for the CER were conducted through August 2012. We also searched using National Institute of Health’s and Current Controlled Trials. We searched for ongoing studies of currently approved treatments or studies of unapproved treatments in phase 3 or 4 of clinical testing conducted in treatment-naïve, HCV-infected individuals. We did not look for studies that would fall outside the scope of the treatment CER, such as studies conducted in treatment-experienced patients, patients with HIV or hepatitis B virus coinfection, or children.1

Our research team then proposed study designs to address the top-tier gaps, described research considerations, and provided example research questions with accompanying PICOT specifications.


Of 14 stakeholders invited to participate in the project, eight agreed to participate. Seven stakeholders completed the first questionnaire and six stakeholders completed the second (final) questionnaire. No participating stakeholders reported significant conflicts of interest that precluded participation, as determined by AHRQ and our team.

The participating stakeholders identified themselves as representing clinicians (71.4%), researchers (57.1%), policymakers (14.3%), payers (14.3%), and consumer advocate (14.3%) stakeholder perspectives (Figure B). Individuals could represent more than one area. While no stakeholder identified themselves as a “research funder,” we did include one stakeholder from a Federal agency that funds clinical research. Some may be hesitant to identify themselves as research funders due to concerns that their opinions would be seen as representative of their funding organization.2

This figure is a pie chart depicting the perspectives of the participating stakeholders. Perspectives were self-selected by the stakeholders in the project’s first questionnaire, and stakeholders could choose more than one perspective if they felt that they represented several stakeholder perspectives. The greatest representation was of clinicians (71.4%), followed by researchers (57.1%), with equal numbers of policymakers, payers, and consumer advocates (14.3% each). No stakeholder self-identified as a research funder.

Figure B

Stakeholder perspectives.

The final, ranked prioritization of the top-tier research needs are shown in Table A, followed by the second-tier research needs. There were tie scores for the first and fifth place rankings, so instead of the top five needs, our list includes the top seven needs. In addition, there was not a clear demarcation between top-tier and second-tier research needs, and several of the gaps overlapped. In particular, our research team thought that research need #7 (the lack of studies of clinical outcomes among patients who experience SVR that adequately controlled for potential confounders) and research need #8 (the need for rigorous studies conducted in U.S. applicable settings evaluating the association between SVR and improved clinical outcomes) had considerable overlap in terms of scope. Therefore, even though research need #8 is categorized as second tier, we combined it with research need #7 in our discussion of study designs for top-tier research needs.

Table A. Final prioritization of research needs.

Table A

Final prioritization of research needs.

We identified 46 ongoing studies that may potentially address a future research need. Among these ongoing studies, one focused on patients with cirrhosis, one enrolled intravenous drug users, four were efficacy trials of new (not yet approved) interferon-free treatment regimens in antiviral-naïve patients, and three evaluated long-term virologic outcomes and harms associated with antiviral treatments. We did not include studies of alisporivir (also known as DEB025), a cyclophilin inhibitor, as research was suspended in April 2012 by the FDA due to safety concerns.3 We identified no ongoing studies that evaluated long-term clinical outcomes associated with antiviral treatments or that enrolled screen-detected patients. No study clearly was designed using an effectiveness framework, though details on methods were fairly limited. Although the remainder of the ongoing studies enrolled treatment-naïve individuals, they were less relevant to the top-tier research needs. Most studies were short-term, interferon-based efficacy studies with SVR as the primary outcome.

We propose both randomized controlled trials (RCTs) and cohort studies as applicable and ideal study designs for addressing top-tier research needs #1 (effectiveness paradigm), #2 (broader populations), #4 (screen-detected patients), and #6 (important long-term clinical outcomes). For research needs #3 (new drugs) and #5 (comparative effectiveness of liver fibrosis testing), we propose RCTs; and for #7 (controlling for adequate confounders) and #8 (association between achieving an SVR and improvements in clinical outcomes), we propose cohort studies.

We propose the following example research questions utilizing these study designs to address the top-tier research needs:

Research Need #1

  • What is the comparative effectiveness of different antiviral regimens in patients recruited from community settings, using broad inclusion criteria?
  • How does the efficacy of antiviral drugs change with lower treatment adherence?

Research Need #2

  • How do outcomes of antiviral treatments differ in patients with HCV who are IV drug users versus patients without IV drug use?

Research Need #3

  • What is the comparative effectiveness of oral antiviral regimens without interferon for HCV versus interferon-based regimens?

Research Need #4

  • How does the efficacy of antiviral treatment for HCV differ in patients identified through screening versus those identified based on symptoms or abnormal liver tests?

Research Need #5

  • What is the comparative effectiveness of antiviral treatments in patients selected for therapy based on a liver biopsy versus those selected for treatment without undergoing a liver biopsy?

Research Need #6

  • What are the effects of antiviral therapy on clinical outcomes in patients at higher risk for disease progression?

Research Needs #7 and #8

  • How do outcomes differ among U.S. patients with HCV infection who experience an SVR versus those who do not experience an SVR after antiviral therapy?


Based on the 2012 CER, and with the input of stakeholders, we identified 12 evidence gaps, seven of which were prioritized as top-tier research needs, and the remainder as second-tier research needs based on the priority rankings of stakeholders. Most of the research gaps did not suggest new research questions to be addressed; rather they primarily identified the need for more applicable and methodologically rigorous studies. In fact, a number of the research gaps (such as the need for studies that evaluate an effectiveness paradigm, studies that evaluate patients with important comorbidities, and studies that are not funded by the pharmaceutical industry) are relevant across many research questions applicable to understanding the comparative effectiveness of antiviral treatments for HCV. Nonetheless, we suggested specific research questions that could address each of these needs.

A limitation of our report is the omission of potentially important research needs due to the requirement of the needs to be within the scope of the original CER. For example, the CER did not evaluate patients with HIV or hepatitis B virus coinfection, or patients who had previously been treated for HCV infection. It also excluded children. Because the CER did not evaluate the state of the evidence for these populations, the extent of research gaps and availability of research was not known. Such areas could be the subject of nominations for future CERs in the EHC program. The precedent for this limitation was initially discussed with the stakeholders during the webinar, which precluded any out of scope gaps from being raised at subsequent opportunities.

Another limitation is that we also had a small sample of stakeholders, with limited representation of some stakeholder perspectives. In addition, standardized and validated methods for selecting stakeholders and synthesize diverse stakeholder viewpoints are not yet available, but would be helpful for Future Research Needs projects.

The rapidly evolving nature of antiviral HCV treatments suggests that even a CER completed this year will need to be updated in the near future. Stakeholders emphasized that all-oral, interferon-sparing regimens are expected within the next few years and will likely have a major impact on clinical practice.


Future research needs as prioritized by a stakeholder group representing diverse perspectives focused on the need for more methodologically rigorous and applicable research to better understand the comparative effectiveness of antiviral treatments for HCV infection in antiviral-naïve patients. Clinical trials of all-oral, interferon-sparing regimens are ongoing and illustrate the rapidly evolving nature of HCV treatments.


Chou R, Hartung D, Rahman B, Wasson N, Cottrell E, Fu R. Treatment for Hepatitis C Virus Infection in Adults. Comparative Effectiveness Review No. 76. Rockville, MD: Agency for Healthcare Research and Quality; Nov, 2012. (Prepared by Oregon Evidence-based Practice Center under Contract No. 290-2007-10057-I). AHRQ Publication No. 12(13)-EHC113-EF. www​.effectivehealthcare​
Chang SM, Carey T, Kato EU, Guise JM, Sanders GD. Identifying Research Needs for Improving Health Care. Ann Intern Med. 2012;31:0003–4819. [PubMed: 22847017]


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