Patterns of viral load decline with telaprevir-based therapy in patients with genotype 1 chronic HCV infection

J Clin Virol. 2014 Jan 6. pii: S1386-6532(13)00542-8. doi: 10.1016/j.jcv.2013.12.011. [Epub ahead of print]

Picchio G¹, De Meyer S², Dierynck I², Ghys A², Gritz L³, Kieffer TL³, Bartels DJ³, Witek J⁴, Bengtsson L³, Luo D⁴, Kauffman RS³, Adda N⁵, Sarrazin C⁶.

Abstract

BACKGROUND: Telaprevir-based therapy is associated with rapid decline in HCV RNA, enabling the application of early futility rules.

OBJECTIVES: To familiarize physicians with this paradigm, a comprehensive analysis of the most frequent HCV viral load profiles observed during treatment with telaprevir/Peg-IFN/RBV in Phase III trials is provided.

DESIGN: HCV RNA profiles were analyzed from 320 HCV genotype 1 treatment-naïve patients enrolled in the ADVANCE study, and 225 prior Peg-IFN/RBV treatment-experienced patients enrolled in the REALIZE study. Patients received 12 weeks of telaprevir with either 24 or 48 weeks of Peg-IFN alfa-2a/RBV. Patients with missing SVR assessments during follow-up, detectable HCV RNA at end of treatment but who did not have viral breakthrough (vBT), or with early vBT who discontinued telaprevir before time of failure were excluded.

RESULTS: All analyzed patients experienced a rapid decline in HCV RNA (>2.0 log₁₀) by Day 14, irrespective of baseline characteristics and/or prior response to Peg-IFN/RBV (relapse, partial response and null response). Subsequently, HCV RNA continued to decline to undetectable levels in most patients. These patients went on to have one of the following outcomes: sustained virologic response, late vBT (after Week 12, i.e. during the Peg-IFN/RBV phase), or relapse. In the small subset of patients with early vBT or meeting a futility rule before Week 12, HCV RNA usually never became undetectable and/or increased rapidly after reaching the nadir.

CONCLUSIONS: HCV RNA profiles with telaprevir/Peg-IFN/RBV are different from those with Peg-IFN/RBV alone. It is important that clinicians understand these HCV RNA profiles and monitor patient viral load in order to apply futility rules correctly.

Copyright © 2014. Published by Elsevier B.V.

KEYWORDS: HCV RNA, Hepatitis C, Stopping rule, Telaprevir, Viral load

PMID: 24462470 [PubMed - as supplied by publisher]

Source

Treatment of Recurrent Genotype 1 Hepatitis C Post-Liver Transplantation: Single Center Experience with Telaprevir-Based Triple Therapy

Z Gastroenterol. 2014 Jan;52(1):27-34. Epub 2014 Jan 13.

Werner CR¹, Egetemeyr DP¹, Nadalin S², Königsrainer A², Malek NP¹, Lauer UM¹, Berg CP¹.

Abstract

Recurrent HCV infection post-liver transplantation (post-LT) is still a major challenge in the treatment of hepatitis C virus (HCV) infection. In this retrospective analysis we gathered data about treatment response and safety of all 14 post-LT patients who were treated between 2011 and 2013 at our centre with a telaprevir (TVR)-based triple therapy. Seven out of 14 patients completed the full treatment course of 48 weeks. Five patients achieved a SVR 24, while 3 additional HCV RNA-negative patients are still in follow-up (end of treatment, SVR 12 and 22). Four patients discontinued treatment prematurely due to side effects. A virological non-response at TW 4 was seen in 1 patient. Virological breakthrough was observed in 2 patients at TW 16 and 28, respectively; 1 patient displayed a virological relapse after the end of treatment (EOT). Patients with a complicated course post-LT accumulated most of the severe side effects, largely infections. One patient with cholestatic hepatitis died 11 weeks after discontinuation of treatment due to progressive graft failure. In conclusion, TVR-based triple therapy in post-LT patients reveals an acceptable antiviral efficacy. Unfortunately, severe side effects are frequent and often require therapeutic interventions. Therefore, with the approval of less straining DAA like sofosbuvir in sight, TVR-based triple therapy in post-LT patients should be, if possible avoided.

© Georg Thieme Verlag KG Stuttgart · New York.

PMID: 24420796 [PubMed - as supplied by publisher]

Source

Adverse events with telaprevir in half of California HIV/HCV group

Provided by IAS

Author: Mark Mascolini

08 January 2014

Half of 24 patients coinfected with HIV and hepatitis C virus had serious adverse events when taking the HCV protease inhibitor telaprevir with pegylated interferon and ribavirin.

Telaprevir was one of the first HCV protease inhibitors licensed for use against infection with genotype 1 HCV, but its impact in people with HIV is still being assessed. Prescribing information warns about serious skin reactions, anemia, fatigue, vomiting, and other possible complications with telaprevir. Its use is contraindicated with strong CYP3A inhibitors and inducers, which include many antiretrovirals.

This retrospective cohort study involved HIV/HCV-coinfected people treated with telaprevir plus pegylated interferon and ribavirin at the University of California, San Diego HIV clinic.

Among 24 consecutive patients, serious adverse events developed in 12 (50%). Seven patients (29%) had to stop HCV therapy because of adverse events, “despite an intensive multidisciplinary monitoring approach.”

The authors suggest that “careful consideration of the risks and benefits of telaprevir-based therapy should be undertaken, given prospects for interferon-sparing therapy in the near future.”

The United States Food and Drug Administration has licensed three other direct-acting HCV antivirals: boceprevir, sofosbuvir, and simeprevir

Source: Edward R. Cachay, David L. Wyles, Francesca J. Torriani, Craig Ballard, Bradford Colwell, Jennifer C. Lin, Lucas Hill, William C. Mathews. High incidence of serious adverse events in HIV-infected patients treated with a telaprevir-based hepatitis C virus treatment regimen. AIDS. 2013; 27: 2893-2897.

For the study abstract
(Downloading the complete article requires a subscription to AIDS or an online payment; the abstract is free.)

Source

Telaprevir in the Treatment of Acute Hepatitis C Virus Infection in HIV-Infected Men

Clin Infect Dis. 2014 Jan 2. [Epub ahead of print]

Fierer DS, Dieterich DT, Mullen MP, Branch AD, Uriel AJ, Carriero DC, van Seggelen WO, Hijdra RM, Cassagnol DG; and the New York Acute Hepatitis CSurveillance Network.

Abstract

Background. There is an international epidemic of hepatitis C virus (HCV) infection among human immunodeficiency virus (HIV)-infected men who have sex with men. Sustained virologic response (SVR) rates with pegylated interferon and ribavirin treatment are higher in these men during acute HCV than during chronic HCV, but treatment is still lengthy and SVR rates are suboptimal. Methods. We performed a pilot study of combination therapy with telaprevir, pegylated interferon, and ribavirin in acute genotype 1 HCV infection in HIV-infected men. Men who were treated prior to the availability of, or ineligible for, telaprevir were the comparator group. The primary endpoint was SVR12, defined as an HCV viral load <5 IU/mL at least 12 weeks after completing treatment. Results. In the telaprevir group, 84% (16/19) of men achieved SVR12 vs 63% (30/48) in the comparator group. Among men with SVR, median time to undetectable viral load was week 2 in the telaprevir group vs week 4 in the comparator group, and 94% vs 53% had undetectable viral loads at week 4. Most patients (81%) who achieved SVR in the telaprevir group received ≤12 weeks of treatment and there were no relapses after treatment. The overall safety profile was similar to that known for telaprevir-based regimens. Conclusions. Incorporating telaprevir into treatment of acute genotype 1 HCV in HIV-infected men halved the treatment duration and increased the SVR rate. Larger studies should be done to confirm these findings. Clinicians should be alert to detect acute HCV infection of HIV-infected men to take advantage of this effective therapy and decrease further transmission in this epidemic.

KEYWORDS: HIV infection, acute HCV, men who have sex with men, telaprevir, treatment

PMID: 24336914 [PubMed - as supplied by publisher]

Source

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

Telaprevir in the Treatment of Acute Hepatitis C Virus Infection in HIV-Infected Men

Clin Infect Dis. 2013 Dec 13. [Epub ahead of print]

Fierer DS, Dieterich DT, Mullen MP, Branch AD, Uriel AJ, Carriero DC, van Seggelen WO, Hijdra RM, Cassagnol DG; for the New York Acute Hepatitis C Surveillance Network.

Abstract

Background. There is an international epidemic of hepatitis C virus (HCV) infection among human immunodeficiency virus (HIV)-infected men who have sex with men. Sustained virologic response (SVR) rates with pegylated interferon and ribavirin treatment are higher in these men during acute HCV than during chronic HCV, but treatment is still lengthy and SVR rates are suboptimal. Methods. We performed a pilot study of combination therapy with telaprevir, pegylated interferon, and ribavirin in acute genotype 1 HCV infection in HIV-infected men. Men who were treated prior to the availability of, or ineligible for, telaprevir were the comparator group. The primary endpoint was SVR12, defined as an HCV RNA level <5IU/mL at least 12 weeks after completing treatment. Results. In the telaprevir group, 84% (16/19) achieved SVR 12 versus 63% (30/48) in the comparator group. Among men with SVR, median time to undetectable viral load was week 2 in the telaprevir group vs week 4 in the comparator group, and 94% vs 53% had undetectable viral loads at week 4. Most patients (81%) who achieved SVR in the telaprevir group received ≤12 weeks of treatment and there were no relapses after treatment. The overall safety profile was similar to that known for telaprevir-based regimens. Conclusions. Incorporating telaprevir into treatment of acute genotype 1 HCV in HIV-infected men halved the treatment duration and increased the SVR rate. Larger studies should be done to confirm these findings. Clinicians should be alert to detect acute HCV infection of HIV-infected men to take advantage of this effective therapy and decrease further transmission in this epidemic.

PMID: 24336914 [PubMed - as supplied by publisher]

Source

Does telaprevir possess a direct antidiabetic effect?

Liver International

Accepted Article (Accepted, unedited articles published online and citable. The final edited and typeset version of record will appear in future.)

Case Reports

Paulino Tallón de Lara¹, Thomas Himschoot¹, Jean-Louis Frossard¹,  Francesco Negro^1,2,*

DOI: 10.1111/liv.12440

This article is protected by copyright. All rights reserved.

Publication History
Accepted manuscript online: 14 DEC 2013 03:48AM EST
Manuscript Accepted: 7 DEC 2013
Manuscript Revised: 30 OCT 2013
Manuscript Received: 15 AUG 2013

This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/liv.12440

Keywords: hepatitis C; insulin resistance;  protease inhibitor;  type 2 diabetes

Abstract

Hepatitis C virus (HCV) induces insulin resistance, which improves upon viral clearance. Telaprevir is a protease inhibitor effective against HCV genotype 1. We report a case whose history suggests that telaprevir may induce some antidiabetic effect independently of its suppression of HCV. A 56-year old woman with obesity, type 2 diabetes treated with sitagliptin and metformin, and HCV-related cirrhosis was given triple therapy with pegylated interferon-alpha, ribavirin and telaprevir. After two weeks of treatment, HCV RNA was no longer detectable but the patient described a pronounced drop in the capillary glucose levels and episodes of hypoglycemia that compelled her to stop all antidiabetic treatment. One month after stopping telaprevir, she had to resume her antidiabetic treatment, despite a persisting virological response. Despite reaching a sustained virological response, her diabetes progressed. Although the suppression of HCV replication may have played a role in reducing glucose intolerance, the fact that this patient resumed her prior antidiabetic treatment upon completing the telaprevir treatment, while still aviremic, suggests that telaprevir may have an additional antidiabetic effect. Further evidence about the possible role and mechanisms of telaprevir as antidiabetic agent is warranted.

This article is protected by copyright. All rights reserved.

Source

Telaprevir Twice Daily is Noninferior to Telaprevir Every 8 hrs for Patients with Chronic Hepatitis C

Gastroenterology. 2013 Dec 4. pii: S0016-5085(13)01728-9. doi: 10.1053/j.gastro.2013.11.047. [Epub ahead of print]

Buti M, Agarwal K, Horsmans Y, Sievert W, Janczewska E, Zeuzem S, Nyberg L, Brown RS Jr, Hezode C, Rizzetto M, Parana R, De Meyer S, De Masi R, Luo D, Bertelsen K, Witek J.

Hospital Valle Hebron and Ciberehd del Institut Carlos III, Barcelona, Spain. Electronic address: mbuti@vhebron.net.

Abstract

BACKGROUND & AIMS: We performed an open-label, multi-center, Phase 3 study of the safety and efficacy of twice-daily telaprevir in treatment-naïve patients with chronic hepatitis C virus (HCV) genotype 1 infection, including those with cirrhosis.

METHODS: Patients were randomly assigned to groups given telaprevir 1125 mg twice-daily or 750 mg every 8 hrs, plus peg-interferon alfa-2a and ribavirin for 12 weeks; patients were then given peg-interferon alfa-2a and ribavirin alone for 12 weeks if their week 4 level of HCV RNA was <25 IU/mL, or for 36 weeks if their level was higher. The primary objective was noninferiority of telaprevir twice-daily vs every 8 hrs in producing a sustained virologic response 12 weeks after the end of therapy (SVR12) (based on a -11% lower limit of the 95% lower confidence interval for the difference between groups).

RESULTS: At baseline, of 740 patients, 85% had levels of HCV RNA ≥800,000 IU/mL, 28% had fibrosis (F3-4), 14% had cirrhosis (F4), 57% were infected with HCV genotype 1a, and 71% had the non-CC IL28B genotype. Of patients who received telaprevir twice-daily, 74.3% achieved SVR12, compared with 72.8% of patients who received telaprevir every 8 hrs (difference in response, 1.5%; 95% confidence interval, -4.9% to 12.0%), so telaprevir twice-daily is noninferior to telaprevir every 8 hrs. All subgroups of patients who received telaprevir twice-daily vs those who received it every 8 hrs had similar rates of SVR12. Most frequent adverse events (AEs) in the telaprevir phase were fatigue (47%), pruritus (43%), anemia (42%), nausea (37%), rash (35%), and headache (26%); serious AEs were reported in 9% of patients. Rates of AEs and serious AEs were similar or slightly higher among patients receiving telaprevir every 8 hrs.

CONCLUSIONS: Based on a phase 3 trial, telaprevir twice-daily is noninferior to every 8 hrs in producing SVR12, with similar levels of safety and tolerability. These results support use of telaprevir twice-daily in patients with chronic HCV genotype 1 infection, including those with cirrhosis. ClinicalTrials.gov number: NCT01241760.

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

KEYWORDS: AEs, AUC, BMI, C(max), C(max,ss), C(min), C(trough,ss), CI, DAA, DRESS, ESA, G1, HCV, ITT, IU, LLOQ, OPTIMIZE, P, Peg-IFN, PK, PP, PR, R, RBV, RVR, SD, SE, SSC, SVR, TVR, adverse events, area under curve, bid, body mass index, clinical trial, confidence interval, drug reaction with eosinophilia and systemic symptoms, e-diary, eRVR, electronic diary, erythropoiesis-stimulating agents, every 12 hours, every 8 hours, extended rapid virologic response, genotype 1, hepatitis C virus, intent-to-treat, international unit, lower limit of quantification, maximum concentration, maximum steady-state concentration, peginterferon, peginterferon alfa/ribavirin, per-protocol, pharmacokinetics, predose concentration, predose steady-state concentration, protease inhibitor, q12h, q8h, rapid virologic response, ribavirin, special search category, standard deviation, standard error, sustained virologic response, telaprevir, twice daily

PMID: 24316262 [PubMed - as supplied by publisher]
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

 

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.

Source

Effect of fibrosis on adverse events in patients with hepatitis C treated with telaprevir

Alimentary Pharmacology & Therapeutics

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

Original Article

You have free access to this content

K. Bichoupan^1,*, J. M. Schwartz², V. Martel-Laferriere¹, E. R. Giannattasio², K. Marfo²,  J. A. Odin¹, L. U. Liu¹, T. D. Schiano¹, P. Perumalswami¹, M. Bansal¹, P. J. Gaglio², H. Kalia², D. T. Dieterich¹, A. D. Branch¹, J. F. Reinus²

Article first published online: 24 NOV 2013

DOI: 10.1111/apt.12560

© 2013 John Wiley & Sons Ltd

Summary

Background

Data about adverse events are needed to optimise telaprevir-based therapy in a broad spectrum of patients.

Aim

To investigate adverse events of telaprevir-based therapy in patients with and without advanced fibrosis or cirrhosis in a real-world setting.

Methods

Data on 174 hepatitis C-infected patients initiating telaprevir-based therapy at Mount Sinai and Montefiore medical centres were collected. Biopsy data and FIB-4 scores identified patients with advanced fibrosis. Multivariable fully adjusted models were built to assess the effect of advanced fibrosis on specific adverse events and discontinuation of treatment due to an adverse event.

Results

Patients with (n = 71) and without (n = 103) advanced fibrosis were similar in BMI, ribavirin exposure, gender, prior treatment history, haemoglobin and creatinine, but differed in race. Overall, 47% of patients completed treatment and 40% of patients achieved SVR. Treated patients with and without advanced fibrosis or cirrhosis had similar rates of adverse events; advanced fibrosis, however, was independently associated with ano-rectal discomfort (P = 0.03). Three patients decompensated and had advanced fibrosis. The discontinuation of all treatment medications due to an adverse event was significantly associated with older age (P = 0.01), female gender (P = 0.01) and lower platelets (P = 0.03).

Conclusions

Adverse events were common, but were not significantly related to the presence of advanced fibrosis or cirrhosis. More critical monitoring in older and female patients with low platelets throughout treatment may reduce adverse event-related discontinuations.

Continue here to read full article (Free) …..

Role of Ritonavir in the Drug Interactions Between Telaprevir and Ritonavir-Boosted Atazanavir

Clin Infect Dis. 2013 Nov 8. [Epub ahead of print]

Gutierrez-Valencia A, Ruiz-Valderas R, Torres-Cornejo A, Viciana P, Espinosa N, Castillo-Ferrando JR, Lopez-Cortes LF.

Source

Enfermedades Infecciosas, Microbiología y Medicina Preventiva, Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla.

Abstract

Background. Detrimental bidirectional pharmacokinetic interactions have been observed when telaprevir (TVR) and ritonavir (RTV)-boosted human immunodeficiency virus (HIV) protease inhibitors are coadministered in healthy volunteers. Our aim was to evaluate the role of RTV in the bidirectional TVR and atazanavir (ATV) interactions.

Method. An open-label, sequential study was carried out in hepatitis C virus (HCV)/HIV-coinfected patients on a RTV-boosted ATV-based (ATVr) antiretroviral regimen (300/100 mg every 24 hours) and triple therapy for chronic C hepatitis genotype 1 (TVR, 1125 mg every 12 hours, pegylated interferon-alpha and ribavirin). Pharmacokinetic profiles were acquired before and after switching from ATVr to unboosted ATV (200 mg every 12 hours). The plasma levels of both drugs were determined by liquid chromatography coupled with mass spectrometry. Pharmacokinetic parameters were calculated by noncompartmental analysis and compared by geometric mean ratios and their 90% confidence intervals.

Results. Fourteen white HCV/HIV-coinfected males were enrolled in this study. After RTV was withdrawn, the TVR AUC_0-12 (area under the concentration-time curve), maximum concentration (C_max), and minimum concentration (C_min) values increased by 19% (7%-30%), 12% (0.9%-29%), and 18% (2%-34%), respectively, without any changes in the TVR terminal half-life. The ATV AUC_0-12, C_max, and C_min values were 39% (13%-66%), 19% (8%-59%), and 48% (1%-96%) higher, respectively, with a significantly shorter terminal half-life (22.6 hours vs 10.4 hours).

Conclusions. RTV is responsible for the adverse interactions that occur when TVR and ATVr are administered together, possibly by influencing either the absorption phase or first-pass metabolism of TVR. The boost effect of TVR on ATV exposure is higher than on RTV, despite its shorter terminal half-life. The coadministration of TVR and unboosted ATV results in increased exposure of both drugs compared with their coadministration with RTV. Clinical Trials Registration. ClinicalTrials.gov: NCT01818856. European Medicines Agency EudraCT no. 2012-002515-25.

KEYWORDS: atazanavir, drug interactions, pharmacokinetics, ritonavir, telaprevir

PMID: 24145880 [PubMed - as supplied by publisher]

Source

Detection of low HCV viraemia by repeated HCV RNA testing predicts treatment failure to triple therapy with telaprevir

Aliment Pharmacol Ther. 2013 Nov 10. doi: 10.1111/apt.12544. [Epub ahead of print]

Maasoumy B, Cobb B, Bremer B, Luk K, Halfon P, Aslam S, Manns MP, Cornberg M, Wedemeyer H.

Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.

Abstract

BACKGROUND: Early on-treatment virological response is one of the most important predictors for sustained virological response (SVR) to treatment of chronic hepatitis C virus (HCV) genotype 1 infection with triple therapy including HCV protease inhibitors (PI). Treatment duration (24 vs. 48 weeks) is based on HCV RNA results at weeks 4 and 12 of PI therapy when HCV RNA must be 'undetectable' to allow shorter therapy.

AIM: To analyse the reliability of HCV RNA measurements at key decision time points (weeks 4 and 12) and the predictive value of concordant or discordant assay results for SVR.

METHODS: Weeks 4 and 12 samples of patients receiving telaprevir-containing triple therapy were initially tested with the AmpliPrep/COBAS-TaqMan_HCV-Test-v1.0 (limit of detection; LOD = 15IU/mL) and retested with the AmpliPrep/COBAS-TaqMan_HCV-Test-v2.0 (LOD = 15IU/mL) and the High_Pure/COBAS-TaqMan_HCV-Test-v2.0 (LOD = 20IU/mL).

RESULTS: Concordance among the three test results in classifying samples as HCV RNA 'undetectable' or 'detectable' was only 55% at week 4, but 85% at week 12. Retesting of 'undetectable' week 4 samples with the respective other assays revealed positive HCV RNA results in 32-50%. In 30%, HCV RNA was 'undetectable' by all three tests at week 4 and all of these patients achieved SVR. In contrast, treatment failure occurred in 62% of patients with at least one 'detectable' result, including cases with one or two other 'undetectable' tests at week 4.

CONCLUSIONS: A single 'undetectable' HCV RNA result at week 4 is not always associated with achieving SVR. Repeated testing in difficult-to-treat patients may identify those at risk for treatment failure.

© 2013 John Wiley & Sons Ltd.

PMID: 24206524 [PubMed - as supplied by publisher]

Source

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.

Continue reading full article here (Free) …..

High incidence of serious adverse events in HIV-infected patients treated with a telaprevir-based hepatitis C virus treatment regimen

AIDS: 28 November 2013 - Volume 27 - Issue 18 - p 2893-2897 doi:

10.1097/01.aids.0000432466.15885.14
Clinical Science: Concise Communication

Cachay, Edward R.^a,b; Wyles, David L.^a,b; Torriani, Francesca J.^a,b; Ballard, Craig^c; Colwell, Bradford^c; Lin, Jennifer C.^b; Hill, Lucas^c; Mathews, William C.^a

Abstract

Objectives: To report the rates of grade IV adverse events and hepatitis C virus (HCV) treatment discontinuation associated with the use of telaprevir, pegylated interferon, and ribavirin.

Design: Retrospective cohort analysis.

Methods: The study included patients coinfected with HIV and HCV who underwent HCV treatment in a clinic-based setting with telaprevir, pegylated interferon, and ribavirin. The United States of America National Institutes of Health Division of AIDS grading system was used to rate severity of adverse events.

Results: Of the 24 consecutive patients treated for HCV using telaprevir/pegylated interferon/ribavirin, 50% (12/24) developed serious adverse events and 29% (7/24) discontinued HCV treatment due to adverse events, despite an intensive multidisciplinary monitoring approach.

Conclusion: In this HIV clinic-based experience, a high rate of grade IV adverse events and treatment discontinuations were observed associated with HCV telaprevir-based treatment. Careful consideration of the risks and benefits of telaprevir-based therapy should be undertaken, given prospects for interferon-sparing therapy in the near future.

Source