Should we await IFN-free regimens to treat HCV genotype 1 treatment-naive patients? A cost-effectiveness analysis (ANRS 95141)

Journal of Hepatology

Volume 61, Issue 1, Pages 7–14, July 2014

Sylvie Deuffic-Burban, Michaël Schwarzinger, Dorothée Obach, Vincent Mallet, Stanislas Pol, Georges-Philippe Pageaux, Valérie Canva, Pierre Deltenre, Françoise Roudot-Thoraval, Dominique Larrey, Daniel Dhumeaux, Philippe Mathurin, Yazdan Yazdanpanah

Received: August 22, 2013; Received in revised form: February 4, 2014; Accepted: March 6, 2014; Published Online: March 17, 2014

DOI: http://dx.doi.org/10.1016/j.jhep.2014.03.011

Abstract

Background & Aims

In treatment-naive patients mono-infected with genotype 1 chronic HCV, treatments with telaprevir/boceprevir (TVR/BOC)-based triple therapy are standard-of-care. However, more efficacious direct-acting antivirals (IFN-based new DAAs) are available and interferon-free (IFN-free) regimens are imminent (2015).

Methods

A mathematical model estimated quality-adjusted life years, cost and incremental cost-effectiveness ratios of (i) IFN-based new DAAs vs. TVR/BOC-based triple therapy; and (ii) IFN-based new DAAs initiation strategies, given that IFN-free regimens are imminent. The sustained virological response in F3–4/F0–2 was 71/89% with IFN-based new DAAs, 85/95% with IFN-free regimens, vs. 64/80% with TVR/BOC-based triple therapy. Serious adverse events leading to discontinuation were taken as: 0–0.6% with IFN-based new DAAs, 0% with IFN-free regimens, vs. 1–10% with TVR/BOC-based triple therapy. Costs were €60,000 for 12 weeks of IFN-based new DAAs and two times higher for IFN-free regimens.

Results

Treatment with IFN-based new DAAs when fibrosis stage ⩾F2 is cost-effective compared to TVR/BOC-based triple therapy (€37,900/QALY gained), but not at F0–1 (€103,500/QALY gained). Awaiting the IFN-free regimens is more effective, except in F4 patients, but not cost-effective compared to IFN-based new DAAs. If we decrease the cost of IFN-free regimens close to that of IFN-based new DAAs, then awaiting the IFN-free regimen becomes cost-effective.

Conclusions

Treatment with IFN-based new DAAs at stage ⩾F2 is both effective and cost-effective compared to TVR/BOC triple therapy. Awaiting IFN-free regimens and then treating regardless of fibrosis is more efficacious, except in F4 patients; however, the cost-effectiveness of this strategy is highly dependent on its cost.

Keywords: Boceprevir, Chronic hepatitis C, Cost-effectiveness analysis, Direct-acting antivirals, Genotype 1, Interferon-free regimens, Model-based analysis, Telaprevir, Treatment initiation

Source

FDA Hepatitis Update - Changes to the Victrelis (boceprevir) label

You are receiving this message as a subscriber to the FDA hepatitis electronic list serve. The purpose of the list serve is to relay important information about viral hepatitis-related products and issues, including product approvals, significant labeling changes, safety warnings, notices of upcoming public meetings and alerts to proposed regulatory guidances for comment.
Please do not reply to this message.

On February 24, 2014, FDA approved an update to the Victrelis (boceprevir) label to include a new virologic futility rule. Specifically Section 2, Dosage and Administration, Table 1 was revised to state: If a patient has HCV-RNA results greater than or equal to 1000 IU/mL at treatment week 8, then discontinue three-medicine regimen.

This statement is also reflected in subsection 2.4 Discontinuation of Dosing Based on Treatment Futility: Discontinuation of therapy is recommended in all patients with 1) HCV-RNA levels of greater than or equal to 1000 IU per mL at TW8 (treatment week 8); or 2) HCV-RNA levels of greater than or equal to 100 IU per mL at TW12 (treatment week 12); or 3) confirmed detectable HCV-RNA levels at TW24 (treatment week 24).

You can view the complete revised Victrelis label and Medication Guide at Drugs@FDA.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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Boceprevir and telaprevir-based triple therapy for chronic hepatitis C: virological efficacy and impact on kidney function and MELD score

Journal of Viral Hepatitis

Early View (Online Version of Record published before inclusion in an issue)

V. Virlogeux^1,2,3,4, P. Pradat^1,2,3, F. Bailly^1,2,3, G. Funingana¹, F. Gonçalves¹, M. Maynard¹, K. Hartig-Lavie¹, M. Amiri¹, F. Zoulim^1,2,3,5,*

Article first published online: 25 FEB 2014

DOI: 10.1111/jvh.12237

© 2014 John Wiley & Sons Ltd

Keywords: glomerular filtration rate;  hepatitis C virus;  pegylated interferon;  protease inhibitor;  renal function;  ribavirin; triple therapy; virological response

Abstract

Summary

Triple therapy using telaprevir or boceprevir [hepatitis C virus (HCV)-NS3/NS4A protease inhibitors (PI)] in association with PEG-IFN/ribavirin has recently become the new standard of care (SOC) for treatment of HCV genotype 1 patients. Our objective was to assess the efficacy and tolerance of triple therapy in routine clinical practice. A total of 186 consecutive HCV patients initiating triple therapy were enrolled in a single centre study. Clinical, biological and virological data were collected at baseline and during follow-up as well as tolerance and side effect details. Among 186 HCV patients initiating triple therapy, 69% received telaprevir and 31% boceprevir. Sixty-one per cent of patients had cirrhosis. The overall extended rapid virological response (eRVR) rate and sustained virological response (SVR) rate were 57.0% and 59.7%, respectively. IL28B CC phenotype was associated with increased probability of achieving eRVR and SVR, whereas previous non-response was associated with low eRVR and SVR rates. The SVR rate increased from 30.8% in previously non-responders to 59.1% in partial non-responders and 75% in relapsers. SVR rate in naive patients was 62.5%. Glomerular filtration rate assessed by MDRD after 12 weeks of therapy was significantly reduced for both PI (P < 0.001). The model for end-stage liver disease(MELD) score was significantly increased at W12 for telaprevir (P = 0.008) and at W24 for boceprevir (P = 0.027). PI-based triple therapy leads to high rates of virological response even in previously non-responder patients. Renal function after triple therapy is impaired as well as MELD score in all patients. Cautious clinical monitoring should focus not only on haematological and dermatological side effects but also on renal function.

Source

FDA Hepatitis Update - Label update for Victrelis (boceprevir)

You are receiving this message as a subscriber to the FDA hepatitis electronic list serve. The purpose of the list serve is to relay important information about viral hepatitis-related products and issues, including product approvals, significant labeling changes, safety warnings, notices of upcoming public meetings and alerts to proposed regulatory guidances for comment.
Please do not reply to this message.

The Victrelis (boceprevir) label has been updated to include the following information under Section 5 Warnings and Precautions:

5.4 Pancytopenia (Use with Ribavirin and Peginterferon Alfa)

Serious cases of pancytopenia have been reported postmarketing in patients receiving VICTRELIS in combination with peginterferon alfa and ribavirin. Complete blood counts (with white blood cell differential counts) should be obtained at pretreatment, and at Treatment Weeks 2, 4, 8, and 12, and should be monitored closely at other time points, as clinically appropriate.

Refer to the Package Inserts for ribavirin and peginterferon alfa for guidelines for discontinuation of therapy based on laboratory parameters.

Additionally section 6.2 Postmarketing Experience was updated to include agranulocytosis, pancytopenia, thrombocytopenia, pneumonia and sepsis.

The corresponding patient information and Medication Guide were also updated to reflect these changes.

The complete revised label can be viewed at Drugs@FDA.

Victrelis is a product of Merck Sharp & Dohme Corp.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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FDA Hepatitis Update - Victrelis (boceprevir) label changes update contraindications

You are receiving this message as a subscriber to the FDA hepatitis electronic list serve. The purpose of the list serve is to relay important information about viral hepatitis-related products and issues, including product approvals, significant labeling changes, safety warnings, notices of upcoming public meetings and alerts to proposed regulatory guidances for comment.
Please do not reply to this message.

On January 17, 2014, FDA approved changes to the Victrelis (boceprevir) package insert to expand the list of contraindicated medications and update the Drug Interaction section.

Doxazosin, silodosin and tamsulosin, alpha 1-adrenoreceptor antagonists, were added to the section 4Contraindications due to the potential for alpha 1-adrenoreceptor antagonist-associated adverse events such as hypotension and priapism.

In section 7 Drug Interactions the calcium channel blockers, amlodipine, dilitiazem, nisoldipine and verapamil were added.

The complete, revised label will be posted soon to the Drugs@FDA, and DailyMed sites.

Victrelis is a product of Merck & Co.

Richard Klein
Office of Health and Constituent Affairs
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

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--------------------------

Similar Effectiveness of Boceprevir and Telaprevir Treatment Regimens for Hepatitis C Virus Infection, Based on a Nationwide Study of Veterans

Clinical Gastroenterology and Hepatology

Article in Press

George N. Ioannou, Lauren A. Beste, Pamela K. Green

Received 14 October 2013; received in revised form 18 November 2013; accepted 2 December 2013. published online 19 December 2013.
Accepted Manuscript

Abstract

Background

& Aims: We investigated the real-world effectiveness of triple therapy regimens against hepatitis C virus (HCV) and compared rates of sustained virologic response (SVR) between telaprevir- and boceprevir-based regimens in a population-based study.

Methods

We analyzed data on all patients in the Veterans Administration (VA) healthcare system who were infected with HCV genotype 1 and began treatment with pegylated interferon, ribavirin, and either boceprevir (n=3696, 83%) or telaprevir (n=759, 17%) from June 2011 through February 2013.

Results

Patients treated with telaprevir were more likely to have baseline characteristics associated with not achieving SVR than patients treated with boceprevir. Fewer than half of patients eligible for short-duration regimens (28 weeks for boceprevir, 24 weeks for telaprevir) successfully completed treatment (37% for boceprevir, 27.5% for telaprevir); ∼25% discontinued early and the remaining patients were treated for longer durations. Of patients who were supposed to complete 48-week regimens, only 35% of boceprevir- and 34% of telaprevir-treated patients completed >44 weeks. The rate of SVR was 51.5% overall, 42.7% among patients with cirrhosis, 56.8% among treatment-naïve patients, 64.2% among prior relapsers, 31.7% among prior partial-responders, and 29.8% among prior null responders. There were no significant differences in rate of SVR between patients given boceprevir or telaprevir, in the entire population or among subgroups. The most important predictors of failure to achieve SVR were IL28B genotype, high viral load, Black race, diabetes, high APRI or FIB-4 scores, low platelet counts, or low levels of low-density lipoprotein cholesterol. Erythropoietin use was not associated with SVR.

Conclusions

In a nationwide analysis of Veterans with HCV genotype 1 infection, rates of SVR are similar for those treated with boceprevir vs telaprevir. However, rates of treatment completion and SVR in real clinical practice are substantially lower than those in clinical trials.

Keywords: DAA, antiviral therapy, population, APRI, outcome, LDL

Source

HCV Treatment: Where We're At, Where We're Going

Medscape Gastroenterology

Rowen K. Zetterman, MD

December 11, 2013

Hepatitis C Today

Worldwide, 170-200 million people, including 3.2-5 million Americans, are infected with hepatitis C virus (HCV). Clinical outcomes of chronic HCV infection include chronic hepatitis, cirrhosis, hepatocellular carcinoma (HCC), and complications of cirrhosis or HCC that result in the need for orthotopic liver transplantation. After liver transplantation, recurrence of HCV infection in the new graft is virtually uniform and can result once again in end-stage liver disease in need of transplantation.

There are 6 major genotypes of HCV, with genotype 1 accounting for 70%-75% of HCV infections in the United States. Genotype 1a is responsible for two thirds and genotype 1b for one third of genotype 1 infections. In treatment studies to date, genotype 1b is less likely to develop viral drug resistance and therefore has a higher treatment cure rate than HCV genotype 1a. Response to treatment is also influenced by the patient's interleukin 28B (IL28B) polymorphism, which results in a greater response in patients with the IL28B CC genotype than in those with IL28B TT genotype.^[1]

Where We're At With Treatment

Interferon alpha has been used for 20 years to treat patients with HCV. The mechanism of viral efficacy for interferon has yet to be clearly established. Ribavirin was coupled to interferon therapy in 1998 and has resulted in a doubling of HCV treatment response.^[2] Pegylated interferon alpha plus ribavirin has been used since 2001,^[3] producing an overall 40% response for treated patients with HCV genotype 1.

Four classes of direct-acting antiviral (DAA) drugs have been developed, including NS3/4A protease inhibitors, NS5B nucleoside inhibitors, NS5B nonnucleoside inhibitors, and NS5A inhibitors.

In 2011, boceprevir and telaprevir, which are NS3/4A protease inhibitors, were approved for the treatment of patients infected with HCV genotype 1.^[4,5] Pegylated interferon with ribavirin and either boceprevir or telaprevir is the current standard of care for HCV genotype 1, but this combination is less effective for genotypes 2 and 3. Boceprevir and telaprevir must be administered every 8 hours, and the rapid development of viral resistance prevents them from being used without pegylated interferon and ribavirin.^[6,7] The combination of a protease inhibitor plus pegylated interferon and ribavirin results in more anemia and drug interactions than pegylated interferon and ribavirin alone.

The US Food and Drug Administration (FDA) recently approved the protease inhibitor simeprevir with pegylated interferon and ribavirin for the treatment of patients with HCV genotype 1. In addition, the FDA also approved sofosbuvir with pegylated interferon and ribavirin for the treatment of HCV genotype 1, and sofosbuvir and ribavirin for the treatment of HCV genotypes 2 and 3.

Boceprevir and Telaprevir

The current standard of care for HCV genotype 1 is either boceprevir or telaprevir with pegylated interferon and ribavirin. Therapy is 24-48 weeks in duration and results in a sustained viral response (SVR) in 67%-75% of patients. Patients with extended rapid viral response (eRVR) associated with a marked reduction in viral titer by 4 weeks of therapy and HCV absence at 12 weeks may require only 24 weeks of total treatment. Side effects, such as anemia, are frequent, as are drug interactions and medication intolerance.

Some have questioned whether the results of protease inhibitor therapy plus pegylated interferon and ribavirin are actually as good in general use as they were in early trials. A recent evaluation of Veterans Affairs treatment groups found that in similar patients who received either boceprevir or telaprevir, only 50% developed SVR.^[8] With current therapy, treatment response is better in previously untreated patients, those with HCV genotype 1b, patients with IL28B CC genotype, and patients without advanced fibrosis or cirrhosis of the liver.

Where We're Going With Treatment

Simeprevir

Simeprevir, a new oral NS3/4A protease inhibitor, was recently approved by the FDA for the treatment of patients with HCV genotype 1 when administered with pegylated interferon and ribavirin.

Two studies (QUEST-1 and QUEST-2) evaluated oral simeprevir 150 mg/day for 12 weeks coupled with pegylated interferon and ribavirin, compared with pegylated interferon and ribavirin alone.^[9] In the simeprevir group, 80% of patients had an eRVR at 12 weeks (compared with only 12% eRVR for pegylated interferon and ribavirin alone) and went on to receive 12 additional weeks of pegylated interferon and ribavirin. This resulted in a 91% SVR in the eRVR simeprevir group compared with 21% in other patients, including those treated as long as 48 weeks (QUEST-1). In the second trial (QUEST-2), simeprevir 150 mg/day for 12 weeks coupled with pegylated interferon and ribavirin for 24 weeks resulted in an SVR of 81%, compared with only 50% for interferon and ribavirin alone. No difference in response rates in patients with genotype 1a or 1b were found in this study.

In a third study (PROMISE) of patients in whom previous HCV treatment had failed, patients were treated with 12 weeks of simeprevir and 24 or 48 weeks of pegylated interferon and ribavirin. This study found that those with eRVR who had been treated for a total of 24 weeks had a 79% SVR, compared with 37% in those receiving placebo.^[10] Patients with IL28B genotype CC had a 90% SVR, and those with advanced fibrosis had a 77% SVR, but SVR was only 45% in patients infected with HCV containing an NS3 Q80K mutation.

Sofosbuvir

Sofosbuvir, a nucleoside polymerase inhibitor, has been approved by the FDA for treatment of genotypes 1 through 6.

The open-label NEUTRINO trial^[11] included patients with genotypes 1, 4, 5, or 6 who were treated with oral sofosbuvir (400 mg daily) and pegylated interferon with weight-based ribavirin for 12 weeks. This resulted in a 92% SVR for genotype 1a, 82% SVR for genotype 1b, 96% SVR for genotype 4, and 100% SVR for the few patients with genotype 5 or 6. Black patients had an SVR of 87%, compared with 91% in Hispanics and Latinos. The treatment response was better in patients with IL28B CC genotype and in those without cirrhosis.

The POSITRON and FUSION trials^[12] evaluated sofosbuvir plus ribavirin in patients with genotype 2 and 3 HCV infections compared with placebo plus ribavirin. SVR was observed at 12 weeks of therapy in 78% of patients with previous treatment failure or patients who were previously unable to take pegylated interferon and ribavirin (POSITRON), and at 16 weeks in 73% of patients with previous treatment failure (FUSION). Both studies observed lower response in patients with genotype 3 and in those with cirrhosis.

Sofosbuvir with weight-based ribavirin oral therapy alone has been evaluated in small numbers of patients with HCV genotype 1. In a phase 2 trial of 25 previously untreated patients with all degrees of fibrosis, 68% achieved an SVR when treated with sofosbuvir 400 mg/day plus weight-based ribavirin compared with a 48% SVR in 25 patients treated with sofosbuvir 400 mg plus ribavirin 600 mg daily.^[13]The study group included 83% black patients, 23% with advanced liver disease, 70% with HCV genotype 1a, and 48% with a body mass index > 30 kg/m².

Drugs Under Development

Nearly 40 other drugs are currently under development and evaluation for the treatment of patients with HCV disease. These drugs include faldaprevir,^[14,15] ledipasvir,^[16] daclatasvir,^[17] asunaprevir,^[18]danoprevir,^[19] alisporivir, and mericitabine, to name a few.

Why Wait to Treat?

Many studies have identified that viral clearance improves overall clinical outcomes of infected patients. In the Veterans Affairs Registry,^[20] patients who developed undetectable HCV RNA levels had a 27% reduction in morbidity and a 45% reduction in overall mortality. Thus, it seems evident that we need to develop treatments that are able to clear HCV from all infected patients. Unfortunately, as many as 50% of infected patients do not respond to or cannot tolerate the current standard of care treatment with pegylated interferon, ribavirin, and boceprevir or telaprevir.

Are gastroenterologists and hepatologists currently recommending treating patients with current therapies, or waiting until new drugs become available? A survey of 337 physicians in 2012 found that one half recommended that previously untreated patients with early or minimal fibrosis should be treated with current therapy, whereas 49% recommended waiting for new therapies.^[21] For patients who had not responded to previous therapy with pegylated interferon and ribavirin, 74% recommended retreating with the available DAA drugs boceprevir or telaprevir plus interferon and ribavirin, and only 26% suggested waiting for new therapies. Because this survey was completed in March 2012, would those same figures hold today?

Should we treat HCV genotype 1-infected patients who have little hepatic fibrosis with current drugs, such as boceprevir or telaprevir, coupled with ribavirin and pegylated interferon? Arguments in favor of treating now include reasonable success in previously untreated patients, especially those with IL28B CC genotype,^[22] recognizing that the response will be reduced in black patients, those with IL28B TT genotype, and those with underlying cirrhosis or high viral loads. On the other hand, waiting means waiting for recently approved medications that appear to have similar efficacy and are associated with less anemia, reduced daily pill numbers, and fewer drug interactions.

Even though response is also reduced with the new drugs in patients with IL28B genotype, overall treatment response with the new drugs seems better than it is with currently available protease inhibitors. Response to simeprevir is affected by the presence of viral Q80K, and it appears that FDA approval will come with a recommendation to consider other treatments for patients infected with the viral Q80K mutation.

What about patients with HCV genotype 1 who have advanced hepatic fibrosis or cirrhosis? Should we be treating them with current protease inhibitors, or should we wait for better therapies? Better side-effect profiles, similar or improved response to treatment with new drugs, the near availability of simeprevir and sofosbuvir for commercial use, and the better response to initial therapy in treatment-naive patients compared with those who have been previously treated suggest that treatment of these patients should be delayed until new drugs are available.^[23]

For patients with HCV genotypes 2 or 3, waiting for sofosbuvir seems reasonable. Boceprevir and telaprevir-based treatments have less effectiveness in treating these HCV genotypes. Although we need more data on the treatment of HCV genotypes 4, 5, and 6, preliminary studies to date suggest that the treatment efficacy of simeprevir and sofosbuvir for these genotypes is similar to that of current therapies.

Pursuit of All-Oral Therapy

Will we ever have effective and completely oral therapies for HCV treatment?

For genotypes 2 and 3, that could happen by early 2014, with sofosbuvir plus ribavirin treatment being approved for HCV genotypes 2 and 3. Although patients with genotype 3 are less likely to achieve SVR than those with genotype 2, additional new drugs and studies of combinations of DAAs may further improve SVR for both genotypes.

The meeting of the American Association for the Study of Liver Diseases (AASLD) in November 2013 included several presentations about oral therapy for HCV treatment. A fixed combination of oral sofosbuvir 400 mg and the NS5A inhibitor ledipasvir 60 mg with ribavirin for 12 weeks achieved a 100% SVR in previously treated patients with HCV genotype 1 infection and advanced fibrosis of the liver.^[24] Oral sofosbuvir plus ribavirin in patients with HCV and HIV infection (CD4 count > 500 cells/µL) resulted in an SVR of 76% in patients with genotype 1, 88% in those with genotype 2, and 67% in those with genotype 3.^[25] A combination of sofosbuvir and simeprevir plus ribavirin for 12 weeks (COSMOS trial) resulted in a 96% SVR in previously treated patients with genotype 1 and a 93% SVR when sofosbuvir and simeprevir were given alone.^[26]

These studies suggest that new DAAs and future combinations of DAAs will identify new treatments for FDA approval that will lead to all oral therapies for HCV infection.

Cost Considerations

What of the cost of new DAAs?

Although the pricing of simeprevir or sofosbuvir has not been established, some have suggested that approximately $80,000 per treated patient will be the likely cost for each of these new drugs. How does that compare with the cost of current standard-of-care treatment with pegylated interferon, ribavirin, and boceprevir or telaprevir?

A presentation at the AASLD meeting suggested that the cost of the current standard of care is $189,000 per SVR achieved.^[27] In a study of 147 patients, of whom 44% achieved SVR, the direct per-patient costs of telaprevir ($55,273), pegylated interferon ($30,418), and ribavirin ($4926) were supplemented by the additional costs for erythropoietin, transfusions, granulocyte colony-stimulating factor, emergency department visits, and hospitalizations, resulting in a median cost of $83,509 per treated patient. Because SVR was achieved in only 44% of those who were treated, the cost of treatment per successful SVR ($83,509 per treated patient × 2.27, because only 44% of treated patients achieved SVR) was approximately $189,000.

A Future of Improved Treatments

The large number of clinical trials of new DAA drugs to treat HCV infection is encouraging. Simeprevir and sofosbuvir should be available sometime in early 2014, to be coupled with pegylated interferon and ribavirin for the treatment of genotype 1, and sofosbuvir plus ribavirin (but without interferon) for genotypes 2 and 3.

The reduced pill burden, shortened treatment time even with pegylated interferon and ribavirin, similar or improved response rates compared with current protease inhibitor/pegylated interferon and ribavirin therapy, apparent reduction of drug interactions with these newer agents, and somewhat diminished effect of genetic response factors (such as IL28B) all suggest a future of improved treatments for the HCV-infected patient. It seems reasonable that many HCV-infected patients can wait for new drugs to become available.

References

1. Ge D, Fellay, Thompson AJ, et al. Genetic variation in IL28B predicts hepatitis C treatment induced viral clearance. Nature. 2009;461:399-401. Abstract

2. McHutchison JG, Gordon SC, Schiff ER, et al. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. Hepatitis Interventional Therapy Group. N Engl J Med. 1998;339:1485-1492.Abstract

3. Manns MP, McHutchison JG, Gordon SC, et al, and the International Hepatitis Interventional Therapy Group. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 2001;358:958-965. Abstract

4. Poordad F, McCone J Jr, Bacon BR, et al; SPRINT-2 investigators. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med. 2011;364:1195-1206. Abstract

5. Jacobson IM, McHutchison JG, Dusheiko G, et al; ADVANCE Study Team. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med. 2011;364:2405-2416. Abstract

6. Susser S, Welsch C, Wang Y, et al. Characterization of resistance to the protease inhibitor boceprevir and hepatitis C virus-infected patients. Hepatology. 2009;50:1709-1718. Abstract

7. Reesink HW, Zeuzem S, Weegink CJ, et al. Rapid decline of viral RNA and hepatitis C patients treated with VX-950: a phase Ib, placebo-controlled, randomized study. Gastroenterology. 2006;131:997-1002. Abstract

8. Backus LI, Belperio PS, Shahoumaian TA, Cheung R, Mole LA. Comparative effectiveness of the hepatitis C virus protease inhibitors boceprevir and telaprevir in a large US cohort. Aliment Pharmacol Ther. 2014;39:93-103.Abstract

9. Jacobson IM. Advances in the treatment of hepatitis C virus infection from EASL 2013. Gastroenterol Hepatol (N Y). 2013;9(6 Suppl 3):5-18.

10. Forns X, Lawitz E, Zeuzem S, et al. Simeprevir (TMD435) with peg-interferon-2a/ribavirin for treatment of chronic HCV genotype 1 infection in patients who relapsed after previous interferon-based therapy: efficacy and safety in patient sub-populations in the PROMIS phase III trial. Hepatology. 2013;58 Suppl:737A-738A.

11. Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. 2013;368:1878-1887. Abstract

12. Jacobson IM, Gordon SC, Kowdley KV, et al; POSITRON Study; FUSION Study. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med. 2013;368:1867-1877. Abstract

13. Osinusi A, Meissner EG, Lee YJ, et al. Sofosbuvir and ribavirin for hepatitis C genotype 1 in patients with unfavorable treatment characteristics: a randomized clinical trial. JAMA. 2013;310:804-811. Abstract

14. Sulkowski MS, Bourliere M, Bronowicki JP, et al. Faldaprevir combined with peginterferon alfa-2a and ribavirin in chronic hepatitis C virus genotype-1 patients with prior nonresponse: SILEN-C2 trial. Hepatology. 2013;57:2155-2163. Abstract

15. Zeuzem S, Soriano V, Asselah T, et al. Faldaprevir and deleobuvir for HCV genotype 1 infection. N Engl J Med. 2013;369:630-639. Abstract

16. Lawitz E, Poordad F, Hyland RJ, et al. Once daily sofosbuvir/ledipasvir fixed dose combination with or without ribavirin resulted in 95% sustained virologic response in patients with HCV genotype 1, including patients with cirrhosis: the LONESTAR trial. Hepatology. 2013;58 Suppl:315A-316A.

17. Lok AS. HCV NS5A inhibitors in development. Clin Liver Dis. 2013;17:111-121. Abstract

18. Suzuki Y, Ikeda K, Suzuki F, et al. Dual oral therapy with daclatasvir and asunaprevir for patients with HCV genotype 1b infection and limited treatment options. J Hepatol. 2013;58:655-662. Abstract

19. Marcellin P, Cooper C, Balart L, et al. Randomized controlled trial of danoprevir plus peginterferon alfa-2a and ribavirin in treatment-naïve patients with hepatitis C virus genotype 1 infection. Gastroenterology. 2013;145:790.e.8-800.e.8.

20. McCombs J, Matsuda T, Tonnu-Mihara I, et al. The risk of long-term morbidity and mortality in patients with chronic hepatitis C: results from an analysis of data from a Department of Veterans Affairs clinical registry. JAMA Intern Med. 2013 Nov 5. [Epub ahead of print]

21. Chen EY, Lee WM, Hynan LS, Singal AG. A survey of hepatitis C treatment clinical practice patterns using the newly approved protease inhibitors. J Clin Gastroenterol. 2013;47:800-806. Abstract

22. Shiffman ML, Benhamou Y. Patients with HCV and F1 and F2 fibrosis stage: treat now or wait? Liver Int. 2013;33:105-110. Abstract

23. Ferenci P. Commentary: triple therapy for patients with chronic hepatitis C and advanced fibrosis? Aliment Pharmacol Ther. 2013;38:1407-1408.

24. Gane EJ, Stedman CA, Hyland RH, et al. Once daily sofosbuvir/ledipasvir fixed dose combination with or without ribavirin: the ELECTRON study. Hepatology. 2013;58 Suppl:243A-244A.

25. Sulkowski MS, Rodriguez-Torres M, Lalezari JP, et al. All-oral therapy with sofosbuvir plus ribavirin for the treatment of HCV genotype 1, 2, and 3 infection in patients co-infected with HIV (PHOTON-1). Hepatology. 2013;58 Suppl:313A-314A.

26. Jacobson IM. SVR results of a once-daily regimen of simeprevir (TMC-438) plus sofosbuvir (GS-7977) with or without ribavirin in cirrhotic and non-cirrhotic HCV genotype 1 treatment-naïve and prior null responder patients: the COSMOS study. Program and abstracts of American Association for the Study of Liver Diseases The Liver Meeting® 2013; November 1-5, 2013. Abstract LB-3.

27. Bichoupan K, Martel-Laferriere V, Ng M, et al. Real world costs of telaprevir-based triple therapy, including costs of managing adverse events, at the Mount Sinai Medical Center, NY: $195,000 per SVR12. Hepatology. 2013;58 Suppl:329A-330A.

Source

 

Effects of Ribavirin Dose Reduction vs Erythropoietin for Boceprevir-Related Anemia in Patients With Chronic Hepatitis C Virus Genotype 1 Infection

Gastroenterology

A Randomized Trial

Fred Poordad, Eric Lawitz, K. Rajender Reddy, Nezam H. Afdhal, Christophe Hézode, Stefan Zeuzem, Samuel S. Lee, Jose Luis Calleja, Robert S. Brown, JR., Antonio Craxi, Heiner Wedemeyer, Lisa Nyberg, David R. Nelson, Lorenzo Rossaro, Luis Balart, Timothy R. Morgan, Bruce R. Bacon, Steven L. Flamm, Kris V. Kowdley, Weiping Deng, Kenneth J. Koury, Lisa D. Pedicone, Frank J. Dutko, Margaret H. Burroughs, Katia Alves, Janice Wahl, Clifford A. Brass, Janice K. Albrecht, and Mark S. Sulkowski

Gastroenterology. 2013;145(5):1035-1044.

Abstract and Introduction

Abstract

Background & Aims Treatment of hepatitis C virus (HCV) infection with boceprevir, peginterferon, and ribavirin can lead to anemia, which has been managed by reducing ribavirin dose and/or erythropoietin therapy. We assessed the effects of these anemia management strategies on rates of sustained virologic response (SVR) and safety.
Methods Patients (n = 687) received 4 weeks of peginterferon and ribavirin followed by 24 or 44 weeks of boceprevir (800 mg, 3 times each day) plus peginterferon and ribavirin. Patients who became anemic (levels of hemoglobin approximately ≤10 g/dL) during the study treatment period (n = 500) were assigned to groups that were managed by ribavirin dosage reduction (n = 249) or erythropoietin therapy (n = 251).
Results Rates of SVR were comparable between patients whose anemia was managed by ribavirin dosage reduction (71.5%) vs erythropoietin therapy (70.9%), regardless of the timing of the first intervention to manage anemia or the magnitude of ribavirin dosage reduction. There was a threshold for the effect on rate of SVR: patients who received <50% of the total milligrams of ribavirin assigned by the protocol had a significantly lower rate of SVR (P < .0001) than those who received ≥50%. Among patients who did not develop anemia, the rate of SVR was 40.1%. Eleven thromboembolic adverse events were reported in 9 of 295 patients who received erythropoietin, compared with 1 of 392 patients who did not receive erythropoietin.
Conclusions Reduction of ribavirin dosage can be the primary approach for management of anemia in patients receiving peginterferon, ribavirin, and boceprevir for HCV infection. Reduction in ribavirin dosage throughout the course of triple therapy does not affect rates of SVR. However, it is important that the patient receives at least 50% of the total amount (milligrams) of ribavirin assigned by response-guided therapy. ClinicalTrials.gov number, NCT01023035.

Introduction

Anemia is a well-established adverse event with both pegylated interferon alfa (peginterferon) and ribavirin (RBV) in the treatment of chronic hepatitis C virus (HCV), particularly when these compounds are used in combination.^[1-3] The mechanism of anemia with RBV is hemolysis-associated, peginterferon suppresses bone marrow, and the mechanism of anemia with boceprevir is unknown. The relative contribution of each to the degree of anemia varies by patient, and depends on renal function, RBV exposure, body mass, and degree of liver fibrosis. Roughly 30% of patients in the large phase 3 clinical trials of peginterferon/RBV experienced hemoglobin declines below 10 g/dL^[4,5] and this threshold has been largely recommended in practice guidelines as defining clinically meaningful anemia and the threshold for anemia management.^[6,7]

Chief among the clinical management paradigms that had been developed based on peginterferon/RBV therapy was the dosage-reduction scheme for RBV because data supported the concept that a minimum of 60%−80% of intended RBV dosing and duration was required to achieve optimal rates of sustained virologic response (SVR).^[8,9] These various reports that probability of response was correlated with RBV dosing and that higher dosages of RBV were more effective led many to speculate that RBV dosing should be maintained at all cost. This led to the use of erythropoietin (EPO) and blood transfusions to support anemic patients on therapy to allow for minimal and brief reductions in RBV dosing.

The contribution of EPO in achieving SVR has never been formally studied in a randomized manner in HCV therapy, including its use with the newly approved protease inhibitors.^[10-13] In a phase 3 clinical trial of boceprevir in previously untreated patients with HCV genotype-1, it was noted that patients who became anemic but did not receive EPO had similar SVR rates to those patients who were given the growth factor.^[14] Given the high cost of EPO and potential safety concerns with its off-label use with HCV treatment-induced anemia, there remains a need to assess the utility of EPO vs RBV dosage reduction as the primary anemia-management intervention with current HCV therapy. This study was designed to determine the relative efficacy and safety of RBV dosage reduction vs EPO as the primary anemia management strategy among previously untreated patients with chronic HCV genotype-1 infection who were treated with boceprevir plus peginterferon/RBV.

Methods

Study Design

This randomized, multi-center, open-label clinical trial was designed to compare 2 strategies for the management of anemia (RBV dosage reduction vs EPO use) in adult patients with previously untreated chronic HCV genotype-1 infection who became anemic (hemoglobin ≤10 g/L) during therapy with boceprevir (VICTRELIS, 800 mg 3 times daily; Merck Sharp & Dohme Corp., Whitehouse Station, NJ) plus peginterferon alfa-2b (PegIntron, 1.5 μg/kg/wk; Merck Sharp & Dohme Corp.)/RBV (600−1400 mg/d, based on weight). The study was conducted between December 2009 and October 2011 in accordance with the principles of good clinical practice and was approved by the appropriate Institutional Review Boards and regulatory agencies. All patients provided written informed consent. Patients (n = 687) were enrolled into this study and received 4 weeks of peginterferon/RBV followed by 24 or 44 weeks of boceprevir plus peginterferon/RBV (Supplementary Figure 1). Patients in cohort 1 (n = 111) received 44 weeks of boceprevir/peginterferon/RBV. After a protocol amendment, patients in cohort 2 (n = 576) were eligible to receive response-guided therapy due to the equivalent efficacy, which had been demonstrated in an earlier pivotal phase 3 trial (either 24 weeks of boceprevir/peginterferon/RBV if HCV RNA was undetectable at treatment week 8 and below the lower limit of quantitation [<25 IU/mL] at all subsequent time points, or 44 weeks of boceprevir/peginterferon/RBV if HCV RNA was detectable at treatment week 8 or ≥25 IU/mL at any subsequent time point). Patients with detectable HCV RNA (≥25 IU/mL) and a <2 log₁₀ decline from baseline HCV RNA levels at treatment week 12 discontinued treatment, as did patients with HCV RNA ≥25 IU/mL at treatment week 24. Patients (n = 500) who became anemic (hemoglobin ≤10 g/dL, or if the rate of hemoglobin decline suggested that the value would be ≤10 g/dL before the next protocol-specified visit and the value was <11 g/dL) during the 4-week lead-in phase with peginterferon/RBV or during study treatment with boceprevir/peginterferon/RBV were randomized in a 1:1 ratio to RBV dosage reduction or EPO use for primary anemia management. The randomized treatment was stratified by time to development of anemia (≤16 vs >16 weeks after starting peginterferon/RBV) and by race (black vs non-black). Patients remained in the Treated/Not Randomized arm (n = 187) if they never met the protocol definition of anemia, discontinued treatment before randomization, or if their first hemoglobin value was ≤8.5 g/dL and treatment was continued at the investigator's discretion.

Supplementary Figure 1. Supplementary Figure 1 Study design and patient disposition. Patients (N = 1154) were assessed for eligibility. Eligible patients (n = 687) received 4 weeks of peginterferon/RBV followed by 24 or 44 weeks of boceprevir (800 mg 3 times a day) plus peginterferon/RBV. The study was projected to enroll a sample size of 660 patients to be treated with boceprevir/peginterferon/RBV. Approximately 60% (400 patients) were expected to develop anemia. The precision of the 95% CI for the true difference in SVR rates between the treatments was expected to be approximately ±10%. Patients with detectable HCV RNA (≥25 IU/mL) and a <2 log₁₀ decline from baseline HCV RNA levels at treatment week 12 discontinued treatment, as did patients with HCV RNA ≥25 IU/mL at treatment week 24. Patients remained in the Treated/Not Randomized arm (n = 187) if their hemoglobin values remained >10 g/dL throughout the 28-week or 48-week treatment period or they discontinued treatment before randomization. Patients with hemoglobin ≤10 g/dL during the lead-in phase with peginterferon/RBV or who became anemic (hemoglobin ≤10 g/dL) during study treatment were randomized in a 1:1 ratio to RBV dosage reduction (RBV DR) or EPO use. If the rate of hemoglobin decline suggested that the value would be ≤10 g/dL before the next protocol-specified visit and the value was <11g/dL, then the patient could be randomized to RBV dosage reduction or EPO use. Patients randomized during the lead-in period with peginterferon/RBV might have delayed initiation of boceprevir for up to 2 weeks at the discretion of the investigator if the anemia was significant.

The initial dosage reduction of RBV was 200 mg/d (or 400 mg/d if initial RBV dosage was 1400 mg/d) with a follow-up assessment at 2 weeks. If further dosage reduction of RBV was required, additional steps of RBV dosage reduction (by 200 mg/d) were performed. EPO was provided by the sponsor and was administered subcutaneously at 40,000 IU/wk. Secondary interventions for anemia (use of EPO in the RBV dosage-reduction arm; RBV dosage reduction in the EPO arm) were permitted for hemoglobin ≤8.5 g/dL. Packed red cell transfusions were allowed at the investigators' discretion. Patients were discontinued from the study if the hemoglobin level was ≤7.5 g/dL.

Selection of Patients

Eligibility criteria included no previous treatment for HCV infection, age older than 18 years, weight of 40−125 kg, HCV genotype-1, plasma HCV RNA level ≥10,000 IU/mL, hemoglobin ≤15 g/dL, and no contraindications for the use of EPO. Exclusion criteria were liver disease of cause other than HCV, decompensated liver disease, renal insufficiency, HIV or hepatitis B infection, pregnancy or current breastfeeding, diabetes, hypertension, pre-existing psychiatric conditions, and active or suspected malignancy. Laboratory exclusion criteria were hemoglobin <12 g/dL for females (males: <13 g/dL), neutrophils <1500/mm³ (blacks/African Americans: <1200/mm³), and platelets <100,000/mm³.

Efficacy

The primary efficacy end point was SVR (undetectable plasma HCV RNA at 24 weeks after the end of treatment) for both the RBV dosage-reduction and EPO arms. Plasma HCV RNA levels were measured with the TaqMan 2.0 assay (Roche Diagnostics, Indianapolis, IN), which had a lower limit of quantification of 25 IU/mL and lower limit of detection of 9.3 IU/mL. The lower limit of detection was used for decision making at various points throughout the study.

Safety

Safety analyses were based on all patients who were treated with any study medication. The proportion of patients with dosage modification/discontinuation due to adverse events, treatment-related serious adverse events, World Health Organization grade 3/4 neutropenia, and hemoglobin <10 g/dL were summarized by treatment. An adverse event was considered common if it occurred in a frequency ≥25% in either study arm. An exploratory analysis also examined safety in cirrhotic patients.

Statistical Analysis

The primary objective was to compare the effect on SVR of the 2 anemia management strategies. Key secondary objectives were to determine the safety and tolerability of EPO use vs RBV dosage reduction and to define predictors of SVR.

For the primary efficacy comparison, a 95% confidence interval (CI) for the difference in the SVR rates between the 2 treatment arms was computed using a Mantel-Haenszel approach adjusting for stratification factors as well as protocol amendment cohort. SVR rates were summarized for various subgroups using descriptive statistics (number and percentage) and exact 95% CIs. Exploratory analyses included calculation of P values using the χ² test to compare SVR rates in some subgroups and the proportions of requiring secondary anemia intervention, and the Cochran-Armitage trend test for SVR rates by total RBV dosage. For safety analyses, adverse events were summarized using descriptive statistics (number and percentage).

All authors were involved in the collection, analysis, or interpretation of the data; revision of the manuscript; and the decision to submit the manuscript for publication. All authors had access to the study data, and reviewed and approved the final manuscript. All authors vouch for the completeness and accuracy of the data and analyses, as well as the fidelity of the study to the protocol.

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Management of anemia induced by triple therapy in patients with chronic hepatitis C: Challenges, opportunities and recommendations

J Hepatol. 2013 Dec;59(6):1323-30. doi: 10.1016/j.jhep.2013.07.014. Epub 2013 Jul 15.

Romero-Gómez M, Berenguer M, Molina E, Calleja JL.

Source

UCM Digestive Diseases and CIBERHD, Hospital Universitario de Valme, Universidad de Sevilla, Sevilla, Spain.

Abstract

The addition of protease inhibitors, boceprevir or telaprevir, to peginterferon+ribavirin (PegIFN/RBV) increases the frequency as well as the severity, and hence, clinical relevance of anemia, which has now become one of the major complications associated with triple therapy. Most significant factors associated with anemia in patients receiving triple therapy include older age, lower body mass index (BMI), advanced fibrosis, and lower baseline hemoglobin. The variability in inosine triphosphate pyrophosphatase (ITPA) gene, which encodes a protein that hydrolyses inosine triphosphate (ITP), has been identified as an essential genetic factor for anemia both in dual and triple therapy. The correct management of anemia is based on anticipation, characterization and therapeutic management. Basically, anemia can be characterized in 3 types: ferropenic (mostly in fertile women), thalassemic type hemolytic anemia, and anemia from chronic processes. Functional deficit of iron should also be excluded in patients with normal ferritin and lower saturation of transferrin. Ribavirin dose reduction and epoetin, sequentially, are indicated in the management of anemia. Epoetin non-response can be caused by lack of time, type of anemia, functional iron deficit or erythropoietin resistance. In the transplantation setting, adding a protease inhibitor to PegIFN/RBV results in a significant increase in the incidence and severity of anemia and, as a consequence, a greater need for epoetin, transfusions, and ribavirin dose reductions. Packed red cell transfusions are utilized when hemoglobin decreases to less than 7.5g/dl and/or there are clinical symptoms and/or there is no response to other therapeutic measures.

Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

KEYWORDS: Anemia, BMI, Boceprevir, EPO, Epoietin, GWAS, HCV, Hepatitis C virus, ITPA, Pegylated interferon, Protease inhibitor, Ribavirin, SNP, Telaprevir, body mass index, erythropoietin, genome-wide association study, hepatitis C virus, inosine triphosphate pyrophosphatase, sRfT, single nucleotide polymorphisms, transferrin soluble receptor

PMID: 23867320 [PubMed - in process]

Source

The Efficacy, Limitations, and Outcomes of Our Current Interferon-Based Therapies for Hepatitis C

Gastroenterology
Volume 145, Issue 6 , Pages 1488-1490, December 2013

Paul Y. Kwo, Margaret S. Sozio

published online 28 October 2013.

Philip S. Schoenfeld, Section Editor, John Y. Kao, Section Editor

Chou R, Hartung D, Rahman B, et al. Comparative effectiveness of antiviral treatment for hepatitis C virus infection in adults: a systematic review. Ann Intern Med 2013;158:114–123.

Hepatitis C affects approximately 3.2 million Americans and is a major cause of complications related to chronic liver disease, such as cirrhosis and hepatocellular cancer (Gastroenterology 2002;123:2082–2099). It is also the leading indication for liver transplantation in the United States (Gastroenterology 2010;138:513–521). Treatment for hepatitis C has evolved from interferon in the early 1990s, to dual therapy with pegylated interferon and ribavirin in the early 2000s, to triple therapy with the addition of direct-acting antiviral agents for genotype 1 in 2011 (Hepatology 2009;49:1335–1374).

A number of studies have examined the effectiveness of therapies for hepatitis C and a recent meta-analysis has now examined advantages and disadvantages of interferon-based therapy for hepatitis C (Ann Intern Med 2013;158:114–123). Specifically, a meta-analysis of antiviral therapy for hepatitis C in treatment-naïve patients with genotypes 1, 2, 3, or 4 was performed to determine if patient characteristics or type of antiviral therapy affected sustained virologic response (SVR) rate. In addition, the harmful effects of therapy as well as clinical outcomes were examined.

The authors noted a slightly higher likelihood of SVR in 7 studies across genotypes 1–4 with pegylated interferon alfa-2a therapy compared with pegylated interferon alfa-2b with an absolute difference of 8 percentage points and a pooled relative risk (RR) of 0.87 (95% confidence interval [CI], 0.80–0.95). When the SVR rates were examined from 6 trials, lowering the dose of pegylated interferon alfa-2b from the standard dose of 1.5 μg/kg resulted in slightly lower SVR rates in genotype 2/3 patients with pooled RR of 0.90 (95% CI, 0.81–0.99). Comparison of weight-based dosing of ribavirin with fixed dosing in patients with genotypes 2 and 3 found no effect on SVR across 3 trials, although one showed lower SVR rates with reduced doses of ribavirin in patients with advanced fibrosis. Moreover, the SVR rates in genotypes 2 and 3 did not improve by extending treatment from 24 to 48 weeks in 2 trials. Higher SVR rates were noted in genotype 2/3 patients when treatment duration was 24 weeks versus truncating therapy at 12–16 weeks (pooled RR, 1.2; 95% CI, 1–1.3). However, the SVR rate was not affected by 12- to 16-week treatment durations in those patients with rapid virologic response.

Boceprevir, 1 of 2 currently approved protease inhibitors, in conjunction with pegylated interferon alfa-2b and ribavirin, was shown to have higher SVR rates than dual therapy. A 4-week lead-in with dual therapy followed by 44 weeks of triple therapy with boceprevir had an absolute increase in SVR of 31 percentage points (95% CI, 23–39) compared with dual therapy. Changing the regimen to eliminate the lead in period or shortening the length of treatment did not improve SVR. Six trials looked at the use of the protease inhibitor telaprevir in treating hepatitis C. Telaprevir was used with either pegylated interferon alfa-2a or -2b and ribavirin for the first 8–12 weeks, followed by dual therapy for the duration of treatment. Forty-eight weeks of telaprevir-based triple therapy increased the SVR rate by 22 percentage points (95% CI, 13–31). Three trials with telaprevir found response-guided therapy, defined as undetected HCV viral load at weeks 4 and 12 for a total treatment of 24 weeks, was more effective than dual therapy. One trial with boceprevir showed similar efficacy between response-guided therapy (defined as undetected HCV viral load at weeks 8 and 24) for a total of 28 weeks of treatment and fixed duration therapy for 48 weeks. Regardless of treatment regimen, SVR rates were lower in advanced fibrosis, higher viral loads, older patients, and black patients across boceprevir and telaprevir studies by approximately 10% compared with those without these features of poor response. Retrospective analyses of boceprevir and telaprevir registration trials have demonstrated that the presence of the favorable interleukin (IL)-28B CC genotype is associated with a higher likelihood of SVR and a 24- to 28-week treatment duration, although these datasets are incomplete (J Hepatol 2011;54:S542–S543; J Hepatol 2011;54:S6–S6).

No difference in rates of withdrawal from therapy was found between pegylated interferon alfa-2a and-2b. Boceprevir-based triple therapy was associated with higher rates of neutropenia compared with dual therapy (33% vs 18%), anemia (25% vs 12%), and dysgeusia (35% vs 13%), whereas telaprevir-based triple therapy was found to be associated with higher risk of anemia (52% vs 39%) and rash (49% vs 35%). However, there were no differences in rates of withdrawal with bocepravir-based therapies compared with dual therapy. Three studies of telaprevir for 24 weeks showed no difference in withdrawal rates compared with dual therapy, whereas only 1 trial of telaprevir-based treatment for 24–48 weeks found higher rates of withdrawal compared with dual therapy (RR, 3.8; 95% CI, 2.6–5.7).

Examination of the literature found no studies that compared long-term outcomes between treatment regimens, although no difference was found in 6-month mortality among the available regimens that were compared. Nineteen cohort studies looked at associations between SVR, regardless of the treatment regimen used, and long-term outcomes and found lower all-cause mortality with SVR. One study that controlled for confounders showed lower all-cause mortality in patients who achieved SVR stratified by genotypes: Genotype 1 had a hazard ratio (HR) of 0.71 (95% CI, 0.60–0.86), genotype 2 had a HR of 0.62 (95% CI, 0.44–0.87), and genotype 3 had a HR of 0.51 (95% CI, 0.35–0.75), versus those who did not achieve SVR.

Comment

Hepatitis C, particularly genotype 1, has traditionally been difficult to treat with pegylated interferon and ribavirin owing to suboptimal SVR rates and associated side effects. However, with improved understanding of viral kinetics and identification of polymorphisms including IL-28B, clinicians may now identify patients who are at greater likelihood of achieving SVR with interferon-based therapies, with overall SVR rates for hepatitis C genotypes 1–3 of approximately 70% using protease-based triple therapy for genotype 1 and dual therapy for genotypes 2 and 3 (Nature 2009;461:399–401). Moreover, additional classes of direct-acting antivirals are in development in combination with pegylated interferon/ribavirin, as well as without pegylated interferon and ribavirin with SVR rates in some trials are >90% and treatment durations ranging from 8 to 24 weeks (N Engl J Med 2012;366:216–224).

In their meta-analysis, Chou et al analyze available data from pegylated interferon-based trials from the past 6 years to provide an overview for the practitioner treating hepatitis C with interferon based therapies. As with any meta-analysis, there are limitations in the quality and heterogeneity of the studies, making it more difficult at times to draw conclusions. In addition, further data have become available that make comparing across studies difficult including the IL-28B genotype status in genotype 1 populations, and the recognition that genotype 3 remains more problematic to treat compared with genotype 2 (Aliment Pharmacol Ther 2008;28:397–404). However, the analysis by Chou et al confirms many of today's standard practices and clarifies much of the available data.

Chou et al found that pegylated interferon alfa-2b had slightly lower rates of SVR in genotypes 1–4 than pegylated interferon alfa-2a; however, the absolute difference was low (8 percentage points) and the 95% CI approached 1 (0.80–0.95). Similar findings were noted in a Cochrane database review, where the absolute difference was 6 percentage points with a RR of 1.11 (95% CI, 1.04–1.19), again across all genotypes (Hepatology 2010;51:1176–1184). However, the largest available trial with 3070 genotype-1–infected patients showed no difference in SVR between pegylated interferon alfa-2a and -2b (N Engl J Med 2009;361:580–593). To date, major society guidelines have not recommended one interferon over another; therefore, clinicians may choose either interferon to treat their HCV- infected patients (Hepatology 2011;54:1433–1444).

Chou et al's study suggested that weight-based dosing of ribavirin does not improve SVR in genotypes 2 or 3. However, given that genotype 3 is more difficult to treat than genotype 2, even in the direct acting antiviral era, additional studies should address whether weight-based dosing of ribavirin may lead to better SVR rates in combination with interferon or a direct-acting antiviral than flat-dose ribavirin in genotype 3 (N Engl J Med 2013;368:1867–1877). Of note, the 2 pegylated interferons differ with regard to ribavirin dose for genotypes 2/3 with pegylated interferon alfa 2a being combined with 800 mg of ribavirin and pegylated interferon alfa 2b being combined with 800–1400 mg of ribavirin.

It was demonstrated that 24 weeks of dual therapy for genotype 2 or 3 is as efficacious as 48 weeks, confirming current recommendations. In addition, 12–16 weeks of therapy for genotypes 2 or 3 in patients with rapid viral response provided similar rates of SVR as compared with treatment for 24 weeks, although a study of almost 1500 subjects, which showed that 24 weeks of treatment with fixed dose ribavirin was superior to 16 weeks in patients with rapid viral response, was not included in that analysis (N Engl J Med 2007;357:124–134). Additionally, relapse rates are higher in groups treated for 12–16 weeks (6%–30% compared with 3%–13% with 24 weeks of treatment), and this should be taken into account when deciding duration of treatment in this population. In our practice treating genotypes 2 and 3, we consider the overall likelihood of patient response to treatment in conjunction with whether they have achieved rapid virologic response to decide whether or not to consider shortening therapy. In the era of pegylated interferon and ribavirin, we are willing to truncate therapy in genotype 2 patients who achieve rapid viral response and do not have cirrhosis and we use weight-based ribavirin regardless of pegylated interferon type. For genotype 3, we encourage all patients to complete 24 weeks of therapy with weight-based ribavirin regardless of type of interferon.

Both telaprevir and boceprevir were found to be more efficacious at treating hepatitis C than dual therapy. However, triple therapy with telaprevir resulted in a higher rate of anemia and rash compared with dual therapy, with no change in withdrawal rates in patients treated for 24 weeks. Triple therapy with boceprevir also had no increased rates of withdrawal compared with dual therapy, although boceprevir regimens were associated with higher rates of neutropenia, anemia, dysgeusia, and thrombocytopenia. More recently, studies have suggested that real-world experiences with triple therapy in a less selective population may result in higher rates of withdrawal from therapy. One preliminary study of veterans with hepatitis C treated with either boceprevir or telaprevir found approximately 10% higher rates of withdrawal overall, although side effects were similar. Futility rates in the veteran population treated with telaprevir were double that seen in clinical trials (Clin Gastroenterol Hepatol 2013;11:1021–1027). Moreover, a recent report has suggested that those with platelet counts <100,000/mL and an albumin <3.5 g/dL are at increased risk for significant side effects with triple therapy (J Hepatol 2013;59:434–441). The meta-analysis paper did not comment on the efficacy of pegylated interferon alfa-2a compared with interferon alfa-2b in triple therapy. One trial has been reported with pegylated interferon alfa-2a and boceprevir with a similar SVR rate noted in nonresponders to that found with pegylated interferon-alfa-2b–based therapy with bocepravir (Clin Gastroenterol Hepatol 2013;11:81–87.e84; N Engl J Med 2011;364:1207–1217). One trial with telaprevir utilized both pegylated interferons and found no difference in SVR rates (Gastroenterology 2011;140:459–468 e451).

Chou et al's study did not evaluate therapy in treatment experienced patients, but this remains an important area of investigation. SVR rates in patients with genotype 1 who were previously treated with dual therapy increased to 55%–66% with boceprevir compared with 21% with pegylated interferon and ribavirin (N Engl J Med 2011;364:1207–1217). Telaprevir also had improved response rates in previously treated patients, with SVR rates ranging from 29% to 88% SVR in null responders and relapsers, respectively, compared with 5%–24% SVR in patients treated with dual therapy (N Engl J Med 2011;364:2417–2428) Thus, in the treatment of nonresponders, relapsers to a previous course of interferon-based therapy will have a high opportunity for SVR with telaprevir- or bocepravir-based therapy. Null responders require new approaches and some centers have used a 4-week pegylated interferon lead-in as a tool to gauge interferon responsiveness in difficult to treat populations with those who have greater than a log₁₀ continuing with addition of either boceprevir or telaprevir and those with less than a log₁₀ reduction stopping therapy altogether. The polymorphism IL-28B plays little role in nonresponders with accurate viral kinetics and is not required. In those without viral kinetics who have been treated, a lead-in can be used to determine interferon responsiveness. No direct-acting antiviral therapy that has been approved by the US Food and Drug Administration is available for treatment of genotypes 2 or 3al, though sofosbuvir, a nucleotide polymerase inhibitor, is expected to be approved with ribavirin. A recent study looking at 16 weeks of sofosbuvir and ribavirin in treatment-experienced patients with genotypes 2 or 3 found response rates of 73% compared with response rates of 25% in historical controls (N Engl J Med 2013;368:1867–1877).

Although no studies comparing long-term outcomes of different treatment regimens are available in the literature, Chou et al reviewed 19 cohort studies evaluating long-term outcomes associated with SVR. Although the quality of the studies ranged from poor to fair, all studies found a lower risk of all-cause mortality in patients who achieved SVR, regardless of fibrosis level, with HRs ranging from 0.07 to 0.71 depending on the study and genotype. This supports the findings in long-term histologic follow-up studies, where interferon therapy has been associated with reduced rates of fibrosis (Gastroenterology 2002;122:1303–1313). These longer-term clinical outcomes are important and will constitute an important endpoint for hepatitis C therapeutic trials. This compliments ongoing efforts to improve therapies for hepatitis C and the recent recommendations of population-based screening for hepatitis C by the US Centers for Disease Control and Prevention to identify those who will benefit from therapy (MMWR Recomm Rep 2012;61:1–32).

Preliminary studies suggest that newer, interferon-free therapies will be more efficacious, better tolerated with markedly improved safety profiles, and associated with shorter treatment duration, although many parts of the world will continue to use interferon as part of hepatitis C therapy for years to come. With better outcomes available to more hepatitis C–infected individuals, the meta-analysis by Chou et al provides further evidence that successful therapy for hepatitis C improves clinical outcomes, supports the importance of diagnosing and treating hepatitis C in the general population, and, in addition, confirmed many of the findings in current practice guidelines. Although response rates are better with triple therapy, “difficult-to-treat” groups remain difficult to treat—confirming the continued need for better therapies that are better tolerated, especially in those with cirrhosis. The meta-analysis confirms our current practice in the treatment of hepatitis C in the United States, although this is about to undergo a dramatic change. However, many countries that still utilize interferon-based therapy will benefit from this analysis and all of those who treat hepatitis C can tell their patients that SVR is indeed associated with better outcomes that will only improve as we move forward to reduce the worldwide burden of chronic hepatitis C.

PII: S0016-5085(13)01503-5

doi:10.1053/j.gastro.2013.10.029

© 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.

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Management of anemia induced by triple therapy in patients with chronic hepatitis C: Challenges, opportunities and recommendations

Journal of Hepatology

Volume 59, Issue 6, Pages 1323-1330, December 2013

Manuel Romero-Gómez, Marina Berenguer, Esther Molina, José Luis Calleja

Received 6 May 2013; received in revised form 20 June 2013; accepted 8 July 2013. published online 17 July 2013.

Summary
The addition of protease inhibitors, boceprevir or telaprevir, to peginterferon+ribavirin (PegIFN/RBV) increases the frequency as well as the severity, and hence, clinical relevance of anemia, which has now become one of the major complications associated with triple therapy. Most significant factors associated with anemia in patients receiving triple therapy include older age, lower body mass index (BMI), advanced fibrosis, and lower baseline hemoglobin. The variability in inosine triphosphate pyrophosphatase (ITPA) gene, which encodes a protein that hydrolyses inosine triphosphate (ITP), has been identified as an essential genetic factor for anemia both in dual and triple therapy. The correct management of anemia is based on anticipation, characterization and therapeutic management. Basically, anemia can be characterized in 3 types: ferropenic (mostly in fertile women), thalassemic type hemolytic anemia, and anemia from chronic processes. Functional deficit of iron should also be excluded in patients with normal ferritin and lower saturation of transferrin. Ribavirin dose reduction and epoetin, sequentially, are indicated in the management of anemia. Epoetin non-response can be caused by lack of time, type of anemia, functional iron deficit or erythropoietin resistance. In the transplantation setting, adding a protease inhibitor to PegIFN/RBV results in a significant increase in the incidence and severity of anemia and, as a consequence, a greater need for epoetin, transfusions, and ribavirin dose reductions. Packed red cell transfusions are utilized when hemoglobin decreases to less than 7.5g/dl and/or there are clinical symptoms and/or there is no response to other therapeutic measures.

Abbreviations: BMI, body mass index, ITPA, inosine triphosphate pyrophosphatase, HCV, hepatitis C virus, GWAS, genome-wide association study, SNP, single nucleotide polymorphisms, sRfT, transferrin soluble receptor, EPO, erythropoietin

Keywords:Hepatitis C virus, Anemia, Boceprevir, Telaprevir, Pegylated interferon, Ribavirin, Epoietin, Protease inhibitor

Introduction

Anemia is a major complication of antiviral therapy in chronic hepatitis C. With dual therapy, and despite its negative impact on quality of life, it was a desirable effect due to its association with higher sustained viral response rates. In patients treated with triple therapy, the impact of anemia on outcome is controversial; its incidence though is significantly higher and the management in this scenario is more complex, frequently requiring ribavirin dose reduction, epoetin and, in some cases, blood transfusions, jeopardizing the final efficacy of triple therapy.

In this review, we will try to answer the questions that physicians face regarding the management of anemia among patients treated with telaprevir or boceprevir triple therapy. We highlight the most relevant aspects with regards to the incidence of anemia, its clinical course, factors implicated in its development, characterization, and management.

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Triple combination therapy for hepatitis C with telaprevir exhibits greater early antiviral activity than with boceprevir

Original article

José M Benito, Clara Sánchez-Parra, Ivana Maida, Antonio Aguilera, Norma I Rallón, Fernanda Rick, Pablo Labarga, José V Fernández-Montero, Pablo Barreiro, Vincent Soriano

Corresponding author name: Pablo Barreiro
Corresponding author e-mail: pmbarreiro@gmail.com

doi: 10.3851/IMP2614

Date accepted: 01 April 2013
Date published online: 03 May 2013

Abstract

Background: Achievement of early viral suppression is important in patients with chronic HCV infection treated with telaprevir (TLV) or boceprevir (BOC) to avoid selection of drug resistance and attain cure. No head-to-head studies comparing TLV and BOC have been performed so far.

Methods: All consecutive individuals who initiated triple HCV therapy with TLV or BOC outside clinical trials at three European clinics were evaluated. Rapid virological response (RVR) was defined as unquantifiable HCV RNA (<25 IU/ml) at week 4 for TLV and at week 8 for BOC (4 weeks after lead-in).

Results: A total of 106 patients were evaluated, 33 treated with BOC and 73 with TLV. Median age, gender, body mass index, baseline HCV RNA, HCV subtype 1a (45% versus 42%) and IL28B-CC alleles (29% versus 23%) did not differ significantly in BOC and TLV groups, respectively. HIV coinfection was more prevalent in patients on TLV than BOC (24% versus 44%). Conversely, more patients on BOC than TLV had previously failed pegylated interferon plus ribavirin (82% versus 64%). RVR was achieved by 82% of patients on TLV versus 59% on BOC (P=0.001). Multivariate logistic regression analysis confirmed that TLV use was the strongest predictor of RVR (OR 3.54 [95% CI 1.23, 10.24]; P=0.02), others being HCV subtype 1b versus 1a (OR 3.26 [95% CI 1.17, 9.09]; P=0.02) and low baseline HCV RNA (OR 0.41 [95% CI 0.16, 1.03]; P=0.06). Prior interferon exposure, HIV coinfection or absence of advanced liver fibrosis did not influence the likelihood of RVR.

Conclusions: Compared to BOC, triple therapy with TLV produces greater RVR rates. TLV might be a better option in more difficult-to-cure patients, such as those with high baseline HCV RNA and/or HCV 1a subtype. HIV coinfection does not influence early HCV RNA responses.

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