Assessment of Alternative Treatment Strategies for Chronic Genotype 1 Hepatitis C: A Systematic Review

Chronic genotype 1 (GT1) Hepatitis C (HCV) infections have been historically difficult to treat, with low cure rates on standard two-drug therapy (Pegylated Interferon + Ribavirin), high rates of side-effects and treatment discontinuation, and low rates of uptake. Recently, the FDA approved two directly acting antivirals (DAAs) -- boceprevir and telaprevir. Used in combination with standard two-drug therapy as triple therapy, these DAAs show higher rates of sustained viral response, though they also are more costly and have more severe side-effect profiles. Moreover, IL-28B patient genotyping can help identify patients least likely to respond to standard therapy, and who stand to benefit the most from triple therapy, and thus for whom the increased risks of side-effects may be most justified.

Investigators with the VA Evidence-based Synthesis Program, HSR&D's Health Economics Resource Center, and Stanford University addressed key questions about the use of triple therapy and genotyping by: 1) conducting an observational analysis of VA data to evaluate the uptake, use, and costs of therapies for HCV; 2) adapting previously developed HCV computer model to more closely reflect VA patient populations with chronic GT1 HCV infections and patterns of care; and 3) performing model-based projections of health outcomes and costs of alternative HCV treatment strategies. Investigators also reviewed the literature (PubMed) from 2000-2012 for information on chronic HCV infections in U.S. Veterans.

Question #1
What are the current usage patterns of directly-acting antivirals and of IL-28B patient genotyping in the VA healthcare system? And how do these patterns differ by VISN?

• Between July 2011 and June 2012, nearly 3,000 Veterans initiated DAA treatment, with approximately 80% using on-formulary boceprevir (boceprevir N=2,366, telaprevir N=501). During this same period, 2,171 Veterans had an IL-28B test.
• There was heterogeneity in the number of people taking up DAA therapies and IL-28B testing across VISNs.
• VISNs differed in their rate of use of IL-28B testing in Veterans receiving DAAs, with a national average just above 10%. For example, VISN 22 had the greatest number of IL-28B tests, while VISNs 8, 16, and 21 had the greatest number of Veterans initiating DAA therapy.
• The median length of boceprevir treatments was just under 28 weeks. Of those who initiated boceprevir, 89% continued to 8 weeks, 81% to 12 weeks, 76% to 16 weeks, and 29% to 32 weeks.
• Telaprevir treatment episodes were much shorter per its therapeutic protocol. The median length of telaprevir treatment was between 12 and 16 weeks. None lasted beyond 28 weeks.

Question #2
What will be the health impacts of using either of two available directly-acting antivirals combined with pegylated interferon and ribavirin (triple therapy)?

Based on simulation modeling analysis over five years depending on treatment uptake rates, universal triple therapy is likely to:

• Reduce the annual number of cases of decompensated cirrhosis by 10-29, the annual number of cases of hepatocellular carcinoma by 5-16, and the annual numbers of liver transplants by 0-1.
• Compared to standard therapy, adoption of universal triple therapy is likely to increase the annual number of quality adjusted life years (QALYs) by 148-213.

Key Question #3
How will the magnitudes of the health impacts measured in Key Question #2 change if IL-28B patient genotyping is used to offer triple therapy to those less likely to benefit from two-drug pegylated interferon and ribavirin?

Based on simulation modeling analysis over five years depending on treatment uptake rates, in comparing IL-28B guided triple therapy to standard two-drug therapy:

• IL-28B guided triple therapy is likely to reduce the annual number of cases of decompensated cirrhosis by 8-26, annual cases of hepatocellular carcinoma by 4-14, and annual numbers of liver transplants by 0-1.
• Compared to standard therapy, IL-28B guided triple therapy is likely to result in annual increase in QALYs of 110-145.

Question #4
What will be the cost and resource use patterns when using either triple therapy or IL-28B-guided triple therapy?

Based on simulation modeling analysis over five years depending on treatment uptake rates, replacement of standard two-drug therapy with triple therapy is likely to:

• Increase total expenditures for HCV treatment and care for Veterans with GT1 HCV by $32-$100 million annually, depending on treatment strategy and uptake patterns.
• At the current uptake rate of 2% per year, universal triple-drug therapy is expected to cost $43 million more than standard two-drug therapy.
• IL-28B guided triple-drug therapy would cost $32 million more than two-drug therapy.

Conclusions
Approximately 3,000 Veterans initiated care with DAAs since their approval, with about 80% receiving boceprevir. Uptake of DAAs and the use of IL-28B testing vary substantially among VISNs, unadjusted for the number of Veterans who are eligible for treatment. The model-based analyses used in this review indicate that use of triple therapy results in better outcomes than standard therapy, but at increased costs. The use of IL-28B to select patients for triple therapy results in modest reductions in anticipated health benefits and costs compared to using triple therapy for all. Assessment of the cost-effectiveness of the use of IL-28B guided therapy or universal therapy with DAAs will require projection of long-term health outcomes and costs.

Future Research
Therapy for HCV is evolving rapidly and important questions remain unanswered. As clinicians use currently approved DAAs more extensively and additional DAAs become available, future research should evaluate the health and economic outcomes that result from the use of these therapies.

This report is a product of VA/HSR&D's Quality Enhancement Research Initiative's (QUERI) Evidence-Based Synthesis Program (ESP), which was established to provide timely and accurate synthesis of targeted healthcare topics of particular importance to VA managers and policymakers — and to disseminate these reports throughout VA.

Reference

Goldhaber-Fiebert JD, Barnett PG, Dally S, Asch SM, Liu S, Cipriano L, Owens DK, Miake-Lye IM, Beroes JB, Shekelle PG. Assessment of Alternative Treatment Strategies for Chronic Genotype 1 Hepatitis C. VA ESP Project #05-226, 2012.

View the full report.

Please feel free to forward this information to others!

Read past HSR&D Management e-Briefs on the HSR&D website.

This Management eBrief is a product of the HSR&D Evidence Synthesis Program (ESP). ESP is currently soliciting review topics from the broader VA community. Nominations will be accepted electronically using the online Topic Submission Form. If your topic is selected for a synthesis, you will be contacted by an ESP Center to refine the questions and determine a timeline for the report.

This Management e-Brief is provided to inform you about recent HSR&D findings that may be of interest. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs. If you have any questions or comments about this Brief, please email CIDER. The Center for Information Dissemination and Education Resources (CIDER) is a VA HSR&D Resource Center charged with disseminating important HSR&D findings and information to policy makers, managers, clinicians, and researchers working to improve the health and care of Veterans.

This report is a product of the HSR&D Evidence-Based Synthesis Program (ESP), which was established to provide timely and accurate synthesis of targeted healthcare topics of particular importance to VA managers and policymakers - and to disseminate these reports throughout VA.

See all reports online.