Thursday, February 9, 2012

Study Supports Telaprevir As Rescue Therapy for Hep C Subgroup


Elsevier Global Medical News

Study Supports Telaprevir As Rescue Therapy for Hep C Subgroup

SAN FRANCISCO – Telaprevir is unlikely to be cost effective as a first-line agent in treatment-naive genotype 1 hepatitis C patients with the CC interleukin 28B polymorphism, according to economic modeling of previously published data.

That’s because most of these patients don’t need telaprevir; about two-thirds will have a sustained virologic response (SVR) with standard pegylated interferon alfa/ribavirin therapy. It makes more
economic sense to try that approach first, keeping telaprevir in reserve for patients who relapse or fail to respond, said lead investigator Dr. Ziad Gellad of Duke University, Durham, N.C.

SVR rates with that approach – using telaprevir later, only if needed – are about 90%, the same as if telaprevir was used right from the start. “The same proportion of the population will be cured whether you use telaprevir upfront or whether you use it as rescue.

Maybe it’s worth reconsidering whether everyone needs these expensive drugs,” Dr. Gellad said at the annual meeting of the American Association for the Study of Liver Diseases.

However, patients might not want to endure a 48-week or longer interferon/ribavirin regimen, considering that adding telaprevir from the start might shorten treatment to 24 weeks, and it’s
unclear at this point if insurers would ask them to do so. Current labeling indicates that the drug can be used combination with interferon and ribavirin for bothHCV treatment-naive patients and those
who’ve failed initial dual therapy, suggesting a role as either a first- or secondline agent. Labeling also notes that the CC IL28B genotype – as opposed to the CT or TT genotypes – strongly predicts
response to dual therapy.

There are commercially available screening blood tests for the polymorphism. The patent on the technology is shared by Duke, Merck, and the Duke scientists who discovered it. It’s mostly academic hepatologists who screen for the polymorphism at present, said Dr. Jake Liang, president of the American Association for the Study of Liver Diseases.

Although the study results support the test’s utility, Dr. Gellad, who has no ownership rights to the patent, cautioned that the “use of IL28 screening is still unclear. It may be that there are other pretreatment predictors that will also be helpful, or it may be, as many have argued, that on-treatment response is the best predictor [of outcome], rendering IL28 testing obsolete. This is still a matter of debate.”

Dr. Gellad and his colleagues compared previously published SVR rates, and their associated costs, for three regimens.

The first, which was standard 48 weeks of interferon and ribavirin, cost $54,931 and gave patients an estimated 19.38 quality-adjusted life-years (QALYS).
Interferon/ribavirin for 24 weeks – in individuals with rapid virologic responses – cost $46,785 and gave patients 19.26 QALYS. Modeling included re-treating nonresponders and relapsers with a 48-
week telaprevir-inclusive regimen.

In the third strategy, individuals got 12 weeks of telaprevir in combination with either 24 or 48 weeks of interferon and ribavirin, again based on their virologic responses. The approach cost $68,788
and gave people 19.34 QALYS.

With all three approaches leading to SVRs in about 90% of patients and just over 19 QALYS, paying more for the same ultimate result makes little economic sense, the researchers concluded.
The study “is very important,” said Dr. Liang, also chief of the liver diseases branch of the National Institute of Diabetes and Digestive and Kidney Diseases.
“With dwindling resources, we need to figure out whether a particular treatment is more cost effective than others. We are all very excited about the approval of [direct-acting antivirals like telaprevir] that
clearly enhance treatment response, but perhaps not one size fits all. Maybe this could be a way for us to save sove money,” he said.
Dr. Gellad and colleagues will continue to study the issue and plan to include boceprevir (Victrelis) to their modeling. “The story will get more interesting,” he said.

Dr. Gellad is a consultant to and receives grant support from Merck, maker of boceprevir. He said that the company was not involved in the study. ■


Gellad and colleagues have done a masterful job in analyzing the cost-effectiveness of potentially
competing strategies for initial therapy of previously untreated patients with chronic hepatitis C.

1 Cost, of course, is a critically important factor to consider in any new therapy, and it is important to
determine whether comparable results may be obtained at a lower cost.

They demonstrated that for treatment-naive, genotype-1 patients with the IL28B CC polymorphism, initial treatment with pegylated interferon and ribavirin (PEG/RBV), followed by triple therapy with telaprevir (TVR)/PEG/RBV for those treatment failures, is more cost effective than initially treating with TVR/PEG/RBV. This makes sense, the science is right, and some organizations have embraced this approach. Cost-effectiveness analyses are most important in estimating clinical and economic outcomes for different treatment strategies. TVR response-guided triple (RGT) therapy has been shown in clinical trials to be far superior to PEG/RBV in treatment-naive patients (ADVANCE),
2 and in this study the authors chose to investigate cost-effectiveness in a subgroup of hepatitis C patients with a high probability of treatment success.

The investigators chose to evaluate alternative treatment strategies in genotype-1 patients who
were IL28B CC positive, where sustained virologic response (SVR) rates vary between 64% and 90%.3 Since IL28B CC patients represent only a minority (approximately 33%) of all genotype-1 patients,3 and since the C-allele frequency varies substantially between racial and ethnic populations,4 these findings may have somewhat limited overall applicability.

In this regard, the probability of achieving an SVR in the IDEAL trial utilizing IL28B information is still dependent upon several additional variables, including baseline viral load, ethnicity, and baseline fibrosis score.5 The underlying reasoning in this study implies several assumptions which may or may not translate to the real world. In recommending a cost-effective strategy which may apply to only a small subgroup of patients, additional uncertainty likely exists when we vary at all from the pristine clinical trial populations.
First, the two-step strategy means that at least some patients (perhaps 36% from the PEG/RBV control arm in ADVANCE) will require a subsequent course of triple therapy.
3 This is not an insignificant number, especially considering that 90% would be expected to achieve an SVR with initial TVR-based triple therapy.3 Second, it assumes that 100% of PEG/RBV failures will undergo retreatment, which is not supported by clinical experience or observational data. Some patients may prove ineligible to secondline therapy due to disease progression, and others may prove intolerant to a second course of PEG/RBV. Third, evolution of therapy may demonstrate that these uniquely responsive patients may achieve a comparably high rate of SVR with only 12 weeks of triple therapy without the need for a PEG/RBV tail.Such an investigation is currently ongoing, although final results are not yet available.

Finally, patients may refuse a non–TVR-containing therapy, particularly those who have already been waiting for protease inhibitor approval by the FDA, and may choose to again wait for future treatments rather than embrace a possible twostep option.
In summary, while using a decision-analytic model, the two step approach to antiviral therapy is certainly cost effective and may be reasonably applied in some unique settings, given the assumptions
and patient population studied; it may have less applicability and be more difficult to implement in clinical practice in the real world setting. Only with real world experience, or head-to-head clinical trials, will we know for sure.

DONALD M. JENSEN, M.D., is Professor of Medicine and Director, Center for Liver Diseases, Section of Gastroenterology, Hepatology and Nutrition, University of Chicago Medical Center.

1. Gellad ZF, et al. AASLD 2011.
2. N. Engl. J. Med. 2011;364:2405-
3. Jacobson IM, et al. EASL 2011,
abstract 3002.
4. Ge D, et al. Nature 2009;461.
5. Ge D, et al. Online supplement

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