Hepatitis C - Impact of treatment with direct-acting antivirals on anxiety and depression

Impact of treatment with direct-acting antivirals on anxiety and depression in chronic hepatitis C 
Marta Gallach , Mercedes Vergara, Joao Pedro da Costa, Mireia Miquel, Meritxell Casas, Jordi Sanchez-Delgado, Blai Dalmau, Núria Rudi, Isabel Parra, Teresa Monllor, Meritxell Sanchez-Lloansí, Angelina Dosal, Oliver Valero, Xavier Calvet
Published: December 19, 2018 https://doi.org/10.1371/journal.pone.0208112

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Abstract
Background and aim
Treatment of hepatitis C with direct-acting antiviral agents (DAA) has few side effects. Although pivotal studies suggested that DAA were safe in patients with psychiatric diseases who could not be treated with previous antiviral therapies, their effects on anxiety and depression have not yet been analysed in clinical practice. The aim of our study was to analyse anxiety and depression in the setting of DAA treatment in a clinical practice series.

Methods
All patients starting DAA treatment between November 1, 2014 and October 31, 2015 were eligible. Patients completed the Hospital Anxiety and Depression scale at different times during treatment. The results were plotted on line graphs and evaluated using a linear regression model with repeated measures.

Results
One hundred and forty-five patients were included (11% with major psychiatric disorders; 32% on psychiatric treatment). Sustained virologic response (SVR) was achieved in 97.3% of cases. Anxiety and depression measures did not differ between time points. No differences between patients on psychiatric treatment or with advanced fibrosis or cirrhosis were found at any time point analysed.

Conclusion
DAA treatment had no impact on anxiety or depression during or after chronic hepatitis C infection treatment, even in high-risk patients with major psychiatric disorders.
Read More: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0208112

Treatment of Chronic HCV: Patients’ experiences before, during, and up to one year after directing antiviral therapy”

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The Patient-Reported Outcomes Project (PROP-UP)
Date presented August 28, 2018
“The Patient-Reported Outcomes Project (PROP UP): A multi-site observational cohort study of patients’ experiences before, during, and up to one year after directing antiviral therapy”
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Hepatitis C and Drug Use: Addressing Screening, Treatment, and Stigma

Date presented September 11, 2018
Presentation by Dr. Christian B. Ramers, MPH, AAHIVS. Dr. Ramers will be added soon.

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Hepatitis C - Adverse events from DAAs can persist for months after treatment

Of Interest
March 14, 2018

Side effects associated with different hepatitis C direct-acting antiviral drugs 

March 24, 2018

Patient-Reported Outcomes After HCV Treatment With Sofosbuvir and Velpatasvir, With or Without Voxilaprevir 

May 30, 2018

Prospective Study: No psychiatric side effects with new IFN-free treatment for HCV 

Article

Adverse events from DAAs can persist for months after treatment, study finds

Liz Meszaros, MDLinx | August 21, 2018
Adverse events (AEs) related to treatment with direct-acting antivirals (DAAs) may persist after treatment in a significant number of patients with chronic hepatitis C, according to results from a study published in the European Journal of Gastroenterology and Hepatology. Clinicians and patients should be aware of this possibility.

Abstract: Outcome and adverse events in patients with chronic hepatitis C treated with direct-acting antivirals: a clinical randomized study

“This real-life study is to the best of our knowledge the first to examine the rate of AEs in patients with hepatitis C virus (HCV) genotype (GT) 1 infection, randomized to one of two different DAA regimens in a real-world setting,” noted these authors, led by Christina Sølund, MD, PhD, Department of Infectious Diseases and Clinical Research Centre, Copenhagen University Hospital, Hvidovre, Denmark.

Recently, the development of DAA agents has revolutionized the treatment of chronic hepatitis C, which is estimated to affect more than 70 million people worldwide. Before the advent of DAAs, the standard of care for these patients consisted of treatment with pegylated-interferon and ribavirin (RBV), lasting for 24 to 48 weeks, which not only had significantly lower cure rates and tolerability, but also carried a high incidence of severe AEs.

Now in their second iteration, DAAs have changed the playing field in the treatment of chronic hepatitis C by directly targeting the proteins responsible for viral replication. Improved sustained virologic responses (SVR) of 90% or more and good tolerability and efficacy in patients who have historically been difficult to treat—such as those with liver cirrhosis, liver transplantation, or previous treatment failures—have characterized the second-generation DAAs.

Few studies, however, have compared different DAA regimens. For this reason, Dr. Sølund and colleagues conducted their investigation. They included 96 patients with chronic hepatitis C with either GT1 or GT3, who were randomized to two different treatment arms. The first was comprised of 72 patients infected with GT1, who were treated for 12 weeks with ledipasvir/sofosbuvir/RBV vs paritaprevir/ombitasvir/ritonavir/dasabuvir/RBV. The second group consisted of 24 patients infected with GT3, who were treated with daclatasvir/sofosbuvir/RBV for 12 weeks vs a 24-week course of sofosbuvir/RBV.

Unfortunately, due to a change in national treatment guidelines, the GT3 treatment arm was prematurely terminated. Therefore, efficacy data are available from both GT3 and GT1 patients, but the incidence of AEs is available only for GT1 patients.

Cure was achieved by 97% of GT1 patients and 83% of GT3 patients, with SVR at 12 months. Virologic failure occurred in only one G3 patient.

Adverse events occurred in 97% of GT1 patients with the most common being anemia, fatigue, and headache.

“We found no statistically significant difference in AEs, neither between treatment groups nor in relation to anemia or cirrhosis. The overall rate of AEs was comparable to other real-world studies, but the frequency of the most common AEs, such as anemia (78%), fatigue (74%), headache (74%), pruritus/eczema (46%), and heartburn/abdominal discomfort (38%), was higher in our study,” they added.

Only 3% of GT1 patients discontinued treatment due to AEs. Notably, 45% of patients with AEs thought to be related to a DAA regimen still manifested the AEs at 4 weeks after treatment. At 12 weeks this was still the case in 11% of patients.

“We consider this an important finding that can be used when informing the patient about AEs that might be caused by the DAA regimen, despite the number of patients included in our study being relatively small,” noted the authors. “The low discontinuation rate reflects that AEs possibly induced by DAA treatment are rarely treatment limiting, even when DAA treatment is given in combination with RBV,” they concluded.

This study received support from the Faculty of Health and Medical Sciences, University of Copenhagen and from Hvidovre Hospital Research Foundation, the Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre, the Capital Region of Denmark’s Research Foundation, the Innovation Fund Denmark project 060-2009-3, the Novo Nordisk Foundation, and the Danish Research Council.

https://www.mdlinx.com/infectious-disease/article/2470

Prospective Study: No psychiatric side effects with new IFN-free treatment for HCV

BMC Psychiatry
Direct-acting antiviral treatment in real world patients with hepatitis C not associated with psychiatric side effects: a prospective observational study
Isak Sundberg, Anders Lannergård, Mia Ramklint and Janet L. Cunningham

BMC Psychiatry 2018 https://doi.org/10.1186/s12888-018-1735-6
Received: 26 September 2017
Accepted: 11 May 2018
Published: 29 May 2018

Abstract
Background
Treatment of Hepatitis C virus (HCV) infection has evolved from interferon (IFN)-based treatments to direct-acting antivirals (DAAs). Patients with HCV have an elevated psychiatric morbidity (including substance abuse) and patients with such comorbidity have often been excluded from treatment with IFN. To date, little is known about psychiatric adverse effects of DAA-based regimens. We therefore aimed to study the psychiatric side effects of new IFN-free treatment for HCV (including depressive symptoms and sleep) in real world patients also including those with a history of psychiatric diagnosis, substance abuse or drug dependence.

Methods

Consecutive patients were monitored during treatment with three of the latest DAA agents (sofosbuvir, simeprevir and daclatasvir). Repeated expert psychiatric assessments from baseline to 12 weeks post-treatment were performed with the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I) clinical version and the self-report versions of the Montgomery Åsberg Depression Rating Scale (MADRS-S) and the Pittsburgh Sleep Quality Index (PSQI). Friedman’s test was performed to calculate differences in the MADRS-S and PSQI over time. In a post-hoc analysis Wilcoxon’s test was used to compare baseline depressive symptoms with those at post-treatment. Spearman’s rank correlation test was conducted in another post-hoc analysis to evaluate the correlation between symptoms of depression and HCV viral load at baseline.

Results
At baseline, 15/17 patients (88%) had a history of any psychiatric diagnosis; 11 (65%) had a history of substance abuse or dependence; and 11 (65%) had previously been treated with IFN and six of those had experienced psychiatric side effects. There was no correlation between depressive symptoms and HCV viral load at baseline. Symptoms of depression did not increase during DAA treatment and were lower 12 weeks post-treatment compared with baseline: MADRS-S 10.7 vs. 8.3 (p = 0.01). This observation held when excluding patients taking antidepressant medication. Sleep quality did not significantly change during treatment. Adherence to treatment was estimated to 95% and sustained virological response was 88%.

Conclusions
Despite high psychiatric morbidity, including previous substance abuse, patients successfully completed DAA treatment without increasing depressive symptoms or sleep disturbance. Symptoms of depression were significantly reduced 12 weeks after DAA treatment.

Keywords
Hepatitis C virus Direct-acting antiviral Depression Sleep Side effects

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Side effects associated with different hepatitis C direct-acting antiviral drugs

Aim - To evaluate the adverse effects associated with the different direct-acting antiviral drug (DAA) regimens in Egyptian patients. Patients received sofosbuvir (SOF)/ribavirin (RBV), SOF/simeprevir, SOF/daclatasvir (DCV), SOF/DCV/RBV, and paritaprevir/ombitasvir/ritonavir/RBV. SOF/RBV regimen showed the highest rate of side effects while SOF/DCV showed the least.

The adverse effects of interferon-free regimens in 149 816 chronic hepatitis C treated Egyptian patients

D. Attia, K. El Saeed, W. Elakel, T. Elbaz, A. Omar, A. Yosry, M. H. Elsayed, M. El Raziky, M. Anees, W. Doss, Y. El Shazly, H. Wedemeyer and G. Esmat

Version of Record online: 5 MAR 2018 | DOI: 10.1111/apt.14538

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Summary
Background
Interferon-free regimens are associated with high sustained virological response; however, associated adverse effects have yet to be fully reported.

Aim
To evaluate the adverse effects associated with the different direct-acting antiviral drug (DAA) regimens in Egyptian patients.

Methods
This multicenter retrospective study included all adverse effects during and after treatment with DAA regimens of 149 816 chronic hepatitis C treated Egyptian patients. Patients received sofosbuvir (SOF)/ribavirin (RBV) (n = 21 835), SOF/simeprevir (n = 24 215) SOF/daclatasvir (DCV) (n = 58 477), SOF/DCV/RBV (n = 45 188) and paritaprevir/ombitasvir/ritonavir/RBV (n = 101). The duration of treatment varied between 12 and 24 weeks. All changes in the treatment regimens, discontinuation, mortality, and serious side effects were reported.

Results
Adverse effects developed in 2475 (1.7%) (mean age [54 ± 9], male gender [53%]) patients. Serious side effects developed in 68% of these patients, and SOF/RBV was the most common causing regimen (73%, P < 0.001). Anaemia and hyperbilirubinemia were the most common side effects (731/149816, 0.5% and 463/149816, 0.3%, respectively) and SOF/RBV (588/21835, 3% and 353/21835, 1.6%, respectively) showed the highest incidence in the treated patients. Hepatocellular carcinoma and mortality were reported in 0.02% and 0.06% of all treated patients, respectively. Patients with liver cirrhosis showed higher incidence of serious side effects (Log rank P = 0.045) and mortality (Log rank P = 0.025) than patients without liver cirrhosis. Male gender (P = 0.012), lower haemoglobin (P < 0.001), platelets (P < 0.001) and albumin (P = 0.001), higher bilirubin (P = 0.002) and cirrhosis (P < 0.001) were factors associated with serious side effects development.

Conclusion
Adverse effects associated with DAAs are few, anemia being the most common. SOF/RBV regimen showed the highest rate of side effects while SOF/DCV showed the least.

Discussion

View full-text article @ Alimentary Pharmacology & Therapeutics

To our knowledge, this is the first study with such a large cohort of chronic HCV-infected patients treated with DAAs who reported associated adverse effects and related death. This study revealed that interferon-free regimens are associated with minimal side effects, which are mostly non-serious. The most common side effects were haematological complications, with anaemia being the dominant one, particularly with respect to the SOF/RBV regimen. The serious haematological adverse effects were managed with haematopoietic agents, treatment discontinuation or reduction in RBV dose with prolongation of treatment duration. The SOF/RBV regimen showed the highest rate of side effects, with anaemia being the prominent one. The SOF/SIM regimen was associated with hyperbilirubinemia; however, this was not significant and did not require treatment discontinuation or a change in drug dosage. DCV-containing regimens showed the lowest side effects among all regimens. This study also showed that death was highest in the SOF/RBV regimen and pre-treatment thrombocytopenia and higher Child score were the dominant pre-treatment associated pathologies. In this study, HCC was reported in 33 patients, and this was mostly with the SOF/RBV regimen; however, this was not significant. Serious adverse effects as well as death were prominent with liver cirrhosis under the interferon-free regimens irrespective of the regimen.

The initial approval of DAAs by the Egyptian Council Committee of Viral Hepatitis had dramatically improved the SVR rate in Egyptian chronic HCV-infected patients, from 60% to almost 100% in some studies.[5, 8, 10] Our study showed that SVR24 reached 88% in those who developed side effects. Although the majority of the study cohort were cirrhotic patients (81%), side effects development was minimal (1.7%), in comparison to other studies, the entire cohort of which were cirrhotic patients and reported 24% side effects.[16] Serious side effects that led to reduction in the RBV dose and prolongation of the treatment duration or even treatment discontinuation, were observed in only (1.1%) of cases. Anaemia was the most common serious side effect, and was mostly associated with the SOF/RBV regimen. The rate of serious side effects was lower in comparison to that of the Guard-C study, which reported 5.9% serious side effects, while the incidence of anaemia in our study was higher (29.5% vs 25%).[17] Interestingly, our multivariate analysis confirmed that pre-treatment HB (<12.6 g/dL) and lower platelets (124 × 103/μL) were associated with post-treatment serious side effects development, as previously mentioned.[18] Our large cohort also revealed that the pre-treatment higher Child-Pugh score represented in lower albumin <35 g/dL and higher bilirubin >1.2 μmol/dL were also factors associated with post-treatment serious side effects development. Lower albumin was also described by Maan et al and Foster et al as factors associated with post-treatment serious side effects development.[16, 17]

The second common serious side effect was hyperbilirubinemia, which was not significant and was only prominent in the SOF/RBV regimen. Non-specific side effects such as fatigue, headache and abdominal discomfort were the most commonly reported in all regimens, which is line with all previously published data.[5, 7, 8, 10, 16, 19, 20]

Death was reported in only 0.06% of all treated patients, and was mainly associated with the SOF/RBV regimen. Death was in most of the cases secondary to hepatic decompensation. Three patients died due to diabetic coma and one due to myocardial infarction under the SOF/RBV regimen.

Hepatocellular carcinoma was also reported in 0.02% of all treated patients, and most cases were reported in the SOF/RBV regimen. This incidence is, however, lower when compared to other studies.[21, 22] The incidence of HCC on this regimen can be explained by the associated liver cirrhosis in 89% of patients, which is line with previous published data,[23] and 22% were Child-Pugh B, which may favour disease progression and the presence of regenerative nodules before the start of treatment. It is to be noted, that the presence of cirrhosis was associated with increased death rate and was also the common factor detected in all regimens associated with serious side effects development.

The incidence of serious side effects, death and HCC development was highest in the SOF/RBV regimen. This can be explained by the fact that this regimen was the first approved regimen for DAAs, and all patients treated with this regimen were the most sick (lower platelets and higher Child-Pugh score B). On the other hand, SOF/DCV showed the lowest incidence of side effects in comparison to the other regimens.

This study was conducted on a large cohort of Egyptian patients, more than 90% of which are infected with genotype 4.[7] Egypt is one of the countries with the highest prevalence with HCV infection, and the urgency to treat chronic HCV patients is associated with reduction in prevalence, which already started to appear, with 29% reduction in prevalence in 2015.[4] This study has several limitations; although we are reporting the adverse effects of several regimens, many of these regimens may no longer be used in several countries (eg SOF/RBV combination is no longer recommended in the European and American guidelines). Moreover, SIM is also rarely in use today, not due to efficacy but because of economic reasons. We must highlight that SIM is still used in many regions including Egypt. Another point to highlight is that these data were excluded from the database which were reported by the treating physicians. There may be an underreporting of adverse effects because there was no soft data verification by independent physicians; however, this is also accepted in large cohort studies.

In conclusion, the use of PEG-IFN/RBV combination was limited due to eligibility, tolerability and treatment efficacy (40%-69%).[24, 25] The use of interferon-free regimens increased the SVR rate and improved the tolerability and eligibility of treatment. The use of interferon-free regimens is safe and tolerable, with a higher cure rate in patients with genotype 4 than the previously used regimen. Cirrhotic patients are in particularly urgent need of treatment and those regimens are the most safely used, but this requires close monitoring and the use of haematopoietic agents to avoid anaemia, especially with RBV-containing regimens. Regular sonographic assessment for early detection of HCC is also of great importance in patients with liver cirrhosis. Future worldwide studies are required to address the adverse effects caused by the new regimens used today, such as SOF/velpatasvir, grazopervir/elbasvir and glecaprevir/pibrentasvir.

View full-text article - http://onlinelibrary.wiley.com/doi/10.1111/apt.14538/full

Drug Induced Pneumonitis Secondary to Treatment with VIEKIRA PAK® Hepatitis C: Case Report of an Unexpected Life-Threatening Adverse Reaction

Case Rep Med. 2017; 2017: 4895736.
Published online 2017 Mar 20. doi: 10.1155/2017/4895736
PMCID: PMC5376942

Drug Induced Pneumonitis Secondary to Treatment with Paritaprevir/Ritonavir/Ombitasvir and Dasabuvir (VIEKIRA PAK®) for Chronic Hepatitis C: Case Report of an Unexpected Life-Threatening Adverse Reaction

Abstract

VIEKIRA PAK (ritonavir-boosted paritaprevir/ombitasvir and dasabuvir) is an approved treatment for compensated patients with genotype 1 (GT1) chronic hepatitis C virus (HCV) infection. This oral regimen has minimal adverse effects and is well tolerated. Cure rates are 97% in patients infected with HCV GT 1a and 99% in those with HCV GT 1b. We report the first case of life-threatening allergic pneumonitis associated with VIEKIRA PAK. This unexpected serious adverse event occurred in a 68-year-old Chinese female with genotype 1b chronic hepatitis C and Child-Pugh A cirrhosis. One week into treatment with VIEKIRA PAK without ribavirin, she was admitted to hospital with respiratory distress and acute kidney injury requiring intensive care input. She was initially diagnosed with community acquired pneumonia and improved promptly with intravenous antibiotics and supported care. No bacterial or viral pathogens were cultured. Following complete recovery, she recommenced VIEKIRA PAK but represented 5 days later with more rapidly progressive respiratory failure, requiring intubation and ventilation, inotropic support, and haemodialysis. The final diagnosis was drug induced pneumonitis.

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Articles in Press - Liver Toxicity Associated with Sofosbuvir, an NS5A Inhibitor and Ribavirin Use

Journal of Hepatology
Articles in Press

Liver Toxicity Associated with Sofosbuvir, an NS5A Inhibitor and Ribavirin Use
Jessica K Dyson, John Hutchinson, Laura Harrison, Olorunda Rotimi, Dina Tiniakos, Graham R Foster, Mark A Aldersley, Stuart McPherson

Published Online: August 29, 2015

DOI: http://dx.doi.org/10.1016/j.jhep.2015.07.041

Abstract 

Abstract

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Hepatitis C (HCV) is a major cause of end-stage liver disease and hepatocellular carcinoma. There have been rapid advances in HCV treatment with the development of oral direct acting antivirals (DAAs). Studies have shown sustained virological response rates above 90% with combinations of DAAs, including patients with compensated cirrhosis. Thus far, significant drug toxicity has not been seen with these agents, but there is limited experience of using DAAs in decompensated HCV cirrhosis. This report describes the first experience of serious drug-induced hepatotoxicity with the new DAAs. The mechanism underlying these drug reactions is currently unknown. Few patients with decompensated cirrhosis have been treated with DAAs, so the exact pharmacokinetics in this population have not been characterised. In both cases patients were taking or had recently taken other drugs. It is possible that an unknown interaction or reaction to the drug combination caused the hepatotoxicity. Although the association with the DAAs is not proven these cases indicate that patients with advanced liver disease need close monitoring while on DAA therapy and if there is a significant unexplained deterioration in liver function the DAAs should be discontinued.

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15 hepatitis C patients die of drug’s side effects

15 hepatitis C patients die of drug’s side effects

2:48 am, August 05, 2014 

The Yomiuri Shimbun Fifteen hepatitis C patients who were prescribed a drug manufactured by Mitsubishi Tanabe Pharma Corp. have died after developing serious side effects such as liver failure and whole-body dermatitis, according to the drug company and other sources.

About a quarter of the patients who took Telavic, a drug for hepatitis C also sold under the generic name Telaprevir, suffered serious side effects after the drug went on the market in 2011. Mitsubishi Tanabe Pharma, based in Chuo Ward, Osaka, produces and sells Telavic.

Medical experts had pointed out the risk of side effects during clinical tests before the drug was released onto the market. Because of such concerns, it was prohibited to prescribe the drug to liver cancer patients and those who suffer from serious liver cirrhosis.

But in many of the fatal cases, the medicine was prescribed according to doctors’ judgment to patients for whom it was inappropriate.

According to the company, 11,135 people were prescribed the medicine from November 2011, when it went on sale, to September of last year. Among them, 2,588 people, or 23 percent, suffered serious side effects.

Of them, 13 died of liver failure, skin inflammation, kidney disorders or other conditions. By February of this year, two more had died. In all of the fatal cases, medical experts voiced suspicion that the medicine’s side effects had a causal relationship with the deaths.

Because the serious side effects had often been seen during Telavic’s clinical tests, the Health, Labor and Welfare Ministry ordered the company to set up a third-party committee when releasing the drug. The committee found that the medicine had been prescribed to patients who should not have received it.

According to the committee’s report, one doctor began prescribing the medicine to an elderly woman had previously been diagnosed with liver cirrhosis. Though she developed symptoms such as loss of appetite, the treatment continued for about three months.

Although the hepatitis virus could no longer be detected in her body, she died of acute liver failure.

In the case of a man in his 60s, he developed symptoms such as skin inflammation immediately after he began taking the medicine, and the symptoms initially disappeared. But he redeveloped the symptoms on the 50th day after starting to take the medicine, and his condition got worse and worse. Finally, he died due to sores all over his body.

The committee decided it was possible that his doctor had overlooked signs of side effects from the medicine.

Clinical tests have found that side effects of the medicine can be prevented from worsening if doctors monitor skin conditions carefully. Thus the ministry limited authorization to prescribe the medicine to about 800 medical institutions with doctors that specialize in liver and skin diseases.

According to the company, there were problems aside from the fatalities. For example, there were cases in which patients who took the medicine developed skin symptoms—a sign of side effects—but in which doctors, despite specializing in skin diseases, failed to take sufficient measures to prevent worsening of the symptoms.

http://the-japan-news.com/news/article/0001453154

Side effect analysis suggests Gilead's hep C wonder Sovaldi is safer than rivals

Side effect analysis suggests Gilead's hep C wonder Sovaldi is safer than rivals

May 20, 2014 | By Tracy Staton

Gilead Sciences' ($GILD) breakthrough drug Sovaldi isn't just the newest hepatitis C drug to hit the market, or the fastest selling. It's also the safest, according to an early analysis of adverse event reports.

AdverseEvents, a company that specializes in analyzing FDA side effect reports for payers and healthcare providers, put Sovaldi at the top of the heap in a recent look at a range of hep C drugs. The company obtained the Sovaldi-related reports via a Freedom of Information Act request, and after sifting them, identified 407 cases of serious side effects reported by hep C patients or their doctors.

Conclusions, after those flagged side effects were examined? Similar to those often made when looking at a treatment for patients who are already seriously ill. AdverseEvents found 19 deaths and 48 hospitalizations, but "many of those cases appear to be associated with complications from advanced [hepatitis C]," the report states.

Continue reading........

Hepatitis - FDA Label update for Victrelis (boceprevir)

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)

 Pancytopenia is a medical condition in which there is a reduction in the number of red and white blood cells, as well as platelets.

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

Ensuring Treatment Success in HCV: 10 Ways Providers Can Improve Patient Outcomes

 
Greetings,
Here we are with Friday upon us, and another work week about to end.

My weekend plans include purchasing a dozen Halloween cookies to be placed strategically on a cookie sheet for my grandchildren to enjoy.

In protest I have stopped baking until the government shutdown is over, which has allowed nanna some extra time to play with her new smartphone.

How about you? Do you have any weekend plans? Maybe take a long lovely drive or catch up on some reading? Or better yet visit Clinical Care Options (CCO) and check out their new HCV learning activity.

CCO just launched a Video Module offering ten recommendations for improving treatment outcomes in patients receiving HCV therapy. HoChong Gilles RN, MS, FNP, and April G. Long RN, MS, FNP both experienced healthcare professionals present us with information on managing side effects, adherence to therapy, complex treatment regimens and stopping rules.

*Free registration is required

Tips for navigating the CME
Once you launch the program "click next under the video" to view the next segment. If prompted to answer questions during the CME "click next at the bottom of the activity." I have provided a highlight of each discussion below.

Ensuring Treatment Success in HCV: 10 Ways Frontline Providers Can Improve Patient Outcomes

Faculty: HoChong Gilles RN, MS, FNP, April G. Long RN, MS, FNP
Released: 10/4/2013

Introduction  At this time the presenters prompt us to answer the questions provided under the video, simply click next to skip the questions and proceed.

Meet Early and Often to Address Anemia - Medication dose reduction

Adherence Strategies - Tips for taking medications                

Use Care Contracts or “Statements of Understanding” - Consent for care, patient awareness of lab appointments and side effects.                

 Check HbA1c in Every Patient: Diabetic or Otherwise - Keeping diabetes under control

Give Patients the Gift of (Your) Time - Giving patients the time needed to validate side effect and other concerns

Making Educated Partners Out of Friends and Family - Addressing social history - home support.

Use HCV’s Natural History Against It and Build Hope - Providing education about the disease and counseling regarding likelihood of achieving SVR.

Managing the Therapeutic “Betrayal” of Stopping Rules - Addressing a high baseline viral load and just missing the cut off for stopping rules.               

Recommend or Provide Treatments for Common Adverse Events Before They Are Needed - Preventative strategies such as being well hydrated, staying out of direct sunlight, and anal discomfort advice for patients using Telaprevir - Oh boy..........               

Find and Stick With 1 Specialty Pharmacy - The importance of using a pharmacy with a HCV team.

End Matter - Information on taking the CME test, we skip this part folks.

Need to run now friends, time to pick up those cookies I plan on baking this weekend. Stay safe and enjoy your weekend. See you soon... 

 

 

HCV Drug Incivek (telaprevir) - View Rash Grade 1 and 2

Clinical Updates  

          
New treatments of hepatits C and their cutaneous side effects

Nicolas Dupin

18 December 2012
A new era in hepatitis C virus (HCV) treatment has begun with the recent approval by the US Food and Drug Administration of the new HCV direct-acting antivirals (DAAs) boceprevir and telaprevir as part of triple-combination therapy with the existing peginterferon/ribavirin regimen. Phase III trials of DAA-based combination therapy in treatment-naïve and previously treated HCV genotype-1-infected patients indicate that significant improvements in sustained virological response rates can be achieved, compared with peginterferon/ribavirin alone. Furthermore, DAAs offer the potential to reduce overall treatment duration to less than 48 weeks in around half of treatment-naïve patients. Whilst these new drugs are quite efficient for the treatment of hepatitis C, they bring additional patient management considerations for HCV-treating physicians. Dermatological adverse events (AEs), in particular, have been reported with a higher frequency in trials of the HCV protease inhibitors telaprevir¹ than with peginterferon/ribavirin alone. The mechanism of these side effects is currently unclear; although, these preliminary data suggest that the management of dermatological reactions will remain important going forwards.

In phase II/III trials on telaprevir, dermatological AEs were recorded using special search categories (SSC) for 'rash' and 'pruritus'. The majority of events recorded with the 'rash' SSC term can be more accurately described as eczematous dermatitis, associated with pruritus and xerosis. During the telaprevir/placebo treatment phase, rash and pruritus were among the AEs occurring more frequently (>5% difference) with telaprevir than placebo. During the telaprevir/placebo dosing phase, 55% and 51% of patients treated with T12PR had rash and pruritus, respectively, compared with 33% and 26% of placebo-treated patients.²

In the telaprevir trials, rash events were graded by severity into four grades.

Over 90% of rash events with telaprevir were Grade 1 or 2 (mild/moderate).

Of the 746 (55%) cases of rash (SSC), 495, 186 and 65 were Grades 1, 2 and 3, respectively, representing 37%, 14% and 5% of the overall T12PR-treated population.

In the majority (92%) of cases, progression of rash to a more severe grade did not occur.

A small proportion (6% [78/1346]) of all T12PR-treated patients required discontinuation of telaprevir as a result of skin conditions. Following treatment discontinuation, symptoms commonly resolved. Approximately 50% of rash events started during the first 4 weeks, with the remaining 50% starting between weeks 5-12. The median time to onset of rash (any grade) was 25 (range 1-350) days.

A systematic retrospective assessment by expert dermatologists was made of all 221 Grade 3 rash events, rash events leading to discontinuation of any study drugs, or rash serious AEs occurring in phase III telaprevir trials. In total, 208 (94%) of these cases were reported in patients receiving telaprevir-based therapy (n=1257). This assessment revealed 13 patients receiving a telaprevir-based regimen who presented with a suspected severe cutaneous adverse reaction (SCAR).

Three cases of Stevens-Johnson Syndrome (SJS; one definite, one probable and one possible) and 11 cases of drug reaction with eosinophillia with systemic symptoms (DRESS; one definite, two probable, eight possible) were reported (in one patient, both diagnoses were suspected). Among the three SJS cases, one occurred 11 weeks after telaprevir discontinuation and was not considered related to telaprevir. Of the two suspected SJS cases that occurred during the telaprevir treatment phase, one was considered by the expert dermatologists as possible SJS, and the other as probable SJS. Among the 11 suspected cases of DRESS, three were confirmed and one was already published.³ All cases of reported SJS resolved, 10 cases of reported DRESS resolved, one patient was lost to follow up.

Interestingly, the rate of discontinuation of all study drugs as a result of cutaneous AEs was lower in telaprevir phase III trials than in phase II trials, following incorporation of a rash management plan into the study protocols. Although a rash management plan was implemented during the ongoing phase II trials, the majority of patients had already completed the telaprevir dosing period by this time. All patients in phase III trials, however, were treated following the implementation of the rash management plan at the beginning of the trials. The rash management plan outlined in the phase III trial protocols provides clear guidance for HCV-treating physicians on how to classify and manage rash events, with the objective of minimizing the impact of cutaneous reactions while enabling continuation of antiviral therapy where possible.

Grade 1 or 2 (mild or moderate) rash does not require treatment discontinuation, and can be primarily treated using emollients/moisturizers and topical corticosteroids. Regular follow up is important, with advice to the patient to limit exposure to sun/heat and wear loose-fitting clothes. Grade 3 rash requires immediate discontinuation of telaprevir.⁴Symptomatic treatment as above may also be employed. Ribavirin interruption (with or without peginterferon) is required within 7 days of stopping telaprevir if the Grade 3 rash does not improve, or sooner if it worsens.

However, in case of any reasonable suspicion or diagnosis of SJS, toxic epidermal necrolysis (TEN), DRESS (also known as drug hypersensitivity syndrome, or drug hypersensitivity syndrome), erythema multiforme, acute generalized exanthematous pustulosis, or a skin rash that is considered life-threatening, patients in phase III telaprevir trials were required to immediately and permanently discontinue all medication.

In conclusion, while telaprevir is very efficient for treating patients with hepatitis C, it is associated with a high frequency of dermatological AEs that are not severe. However, the pooled data from all patients who received telaprevir reported a few SCARs that may have been life-threatening. Therefore, patients receiving telaprevir with a rash need thorough evaluation of the severity, and physicians should look for alert criteria of both SJS/TEN (rapidly progressing exanthema, skin pain, mucosal involvement at> 2 sites, blisters or epidermal detachment, atypical/typical target) and DRESS (onset from 6-10 weeks after first dose, rapidly progressing exanthema, prolonged fever, facial oedema). While most of mild rash could be managed by a hepatologist, moderate and severe rash need to be evaluated without delay by a dermatologist who will help to optimize the management and monitoring of the patient.

Figure 1.

• Eczema-like eruption
• Grade 2 rash
• Treatment should be pursued
• Patient must be followed frequently
• Topical steroids should be prescribed regularly

Figure 2.

• Extensive rash with target lesions grade 3 rash
• Telaprevir must be stopped definitively

References

1. Jacobson IM, McHutchison JG, Dusheiko G, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med. 2011;364:2405-16.
2. Cacoub P, Bourlière M, Lübbe J, et al. Dermatological side effects of hepatitis C and its treatment: patient management in the era of direct-acting antivirals. J Hepatol. 2012;56:455-63.
3. Montaudié H, Passeron T, Cardot-Leccia N, Sebbag N, Lacour JP. Drug rash with eosinophilia and systemic symptoms due to telaprevir. Dermatology. 2010;221:303-5.
4. Dupin N, Mallet V, Carlotti A, Vallet-Pichard A, Pol S. Severe skin rash in case of readministration of telaprevir in a patient who previously experienced a non severe rash. Hepatology. 2012;55:2042-3.

https://www.dermquest.com/expert-opinions/clinical-updates/2012/new-treatments-of-hepatits-c-and-their-cutaneous-side-effects/

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Podcast Dec 26 2012
FDA Drug Safety Podcast: Serious skin reactions after combination treatment with the Hepatitis C drugs Incivek (telaprevir), peginterferon alfa, and ribavirin

FDA Podcast: Serious skin reactions with Hepatitis C drug Incivek (telaprevir)

FDA Drug Safety Podcast: Serious skin reactions after combination treatment with the Hepatitis C drugs Incivek (telaprevir), peginterferon alfa, and ribavirin

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Run Time: 00:5:46
December 26, 2012

Transcript

Narrator: Welcome to the FDA Drug Safety Podcast from the Division of Drug Information.

Today’s Topic: Serious skin reactions after combination treatment with the Hepatitis C drugs Incivek, active ingredient telaprevir, peginterferon alfa, and ribavirin US Public Health Service CDR Ray Ford from the division will provide you with additional information about this communication.

CDR Ford: On December 19, 2012, the FDA issued a Drug Safety Communication informing the public that the Agency has received reports of serious skin reactions, some fatal, in patients taking the hepatitis C drug Incivek in combination with the drugs peginterferon alfa and ribavirin, known as Incivek combination treatment. Significantly, some patients died when they continued to receive Incivek combination treatment after developing a worsening, or progressive rash and systemic symptoms. As a result, FDA has added a boxed warning to the Incivek drug label stating that Incivek combination treatment must be immediately stopped in patients experiencing a rash with systemic symptoms or a progressive severe rash. Consideration should also be given to stopping any other medications that may be associated with serious skin reactions. Typical systemic symptoms and signs may include fever, nausea, diarrhea, mouth sores or ulcers, facial swelling (or edema), red or inflamed eyes, or swelling or inflammation of the liver (or hepatitis). All patients with serious skin reactions should also receive urgent medical care.

FDA received reports from Japan of two cases, one fatal, of a serious skin reaction called toxic epidermal necrolysis (or TEN) in patients who were taking Incivek with peginterferon alfa and ribavirin. In the fatal case, the patient continued the Incivek combination regimen for a period of time after symptoms developed.

The Incivek drug label already contains information on the risk of serious skin reactions. Serious skin reactions, including drug rash with eosinophilia and systemic symptoms (or DRESS) and Stevens-Johnson Syndrome (SJS) have been previously reported in patients taking Incivek combination treatment. These serious skin reactions required hospitalization, and in some cases, death was reported. The signs and symptoms of DRESS may include rash, fever, facial swelling, and evidence of internal organ involvement (e.g., hepatitis). Patients may or may not have eosinophilia. The signs and symptoms of SJS may include fever, lesions, and ulcerations on the eyes or lips.

These types of serious skin reactions (TEN, DRESS, and SJS) may be considered different varieties along a spectrum of serious skin reactions and can be difficult to tell apart from each other. When any of these serious skin reactions occur, it is necessary for healthcare professionals to immediately stop all three components of Incivek combination treatment and the patient should receive urgent medical care. Consideration should also be given to stopping any other medications that may be associated with serious skin reactions.

Incivek’s manufacturer, Vertex Pharmaceuticals Incorporated, agreed at the time of marketing approval to investigate, through genetic analysis, the factors associated with serious skin reactions following Incivek combination treatment. The purpose of the investigation is to determine whether such serious skin reactions may be linked to the genetic makeup of the patient. FDA will continue to communicate to health professionals and the public any relevant information that becomes available about the risk of serious skin reactions associated with Incivek use.

At this time FDA recommends that Healthcare Professionals be aware of the following:

• Make sure your patients know that rash may occur with Incivek combination treatment, and explain the signs and symptoms of severe skin reaction and when to seek care.
• If serious skin reactions occur, all three components of Incivek combination treatment, including peginterferon alfa and ribavirin, must be immediately discontinued, and the patient should receive urgent medical care. Consideration should also be given to stopping any other medications that may be associated with serious skin reactions.
• The FDA is requiring the addition of a statement to the Warnings and Precautions section of Incivek’s label (PDF - 495KB)² that the incidence of anemia is higher, and the median time to onset of anemia is shorter, among patients on Incivek combination treatment compared to those who received peginterferon alfa and ribavirin alone. The shortest reported time to a clinical intervention (such as blood transfusion, ribavirin dose reduction, or initiation of an erythropoiesis-stimulating agent) is 10 days.
• Adverse events involving Incivek, peginterferon alfa, ribavirin and/or any other drugs also suspected to contribute to serious skin reaction should be reported to the FDA MedWatch program at www.fda.gov/medwatch³.

Narrator: Thank you for listening. The FDA is committed to keeping healthcare professionals informed of the latest safety information. A link to this communication, including the complete Data Summary, can be found at www.fda.gov/DrugSafetyCommunications⁴. If you have drug questions, you can reach us at druginfo@fda.hhs.gov.

And follow us on Twitter @FDA_Drug_Info for up to the minute important drug information. Know the moment it happens.

INCIVEK® (telaprevir)-Updates label after reports of a ‘small number of fatal skin reactions’

Vertex discloses Hep C drug deaths
Vertex Pharmaceuticals (Nasdaq: VRTX) has announced that a number of patients have died from serious skin reactions after taking the company’s hepatitis C therapy Incivek.......

Hep C Drug Linked to Fatal Skin Reactions

16 minutes ago

The oral hepatitis C drug telaprevir (Incivek) will now carry a boxed warning about potentially fatal skin reactions in the wake of multiple deaths, its manufacturer said Wednesday.

Press Release

Vertex Announces Update to U.S. Prescribing Information for INCIVEK® (telaprevir)

- Revised label includes Boxed Warning detailing risk of serious skin reactions observed in the post-marketing setting that require treatment discontinuation -

CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) today announced that the INCIVEK^® (telaprevir) label in the United States has been updated to include a Boxed Warning stating that fatal and non-fatal serious skin reactions have been reported in patients taking INCIVEK combination treatment. Fatal cases of serious skin reactions have been reported in patients with progressive rash and systemic symptoms who continued to receive INCIVEK combination treatment after a serious skin reaction was identified.
  
Rash and serious skin reactions are known adverse events associated with INCIVEK combination treatment and were previously included in the warnings and precautions section of the label. Given the severity of the events reported in the post-marketing setting, and the importance of discontinuing INCIVEK combination treatment in the event of one of these reactions, the information has been given greater prominence through a boxed warning.
  
"The safety of people taking our medicines is our first priority, and we are committed to ensuring that patients and physicians are aware of the label update to help them use INCIVEK properly," said Robert Kauffman, M.D., Ph.D., Senior Vice President and Chief Medical Officer at Vertex. "We will continue to educate physicians to follow the rash management plan developed while INCIVEK was in clinical trials and the information contained in the updated label."
  
In Phase 3 clinical trials, less than 1 percent of people who received INCIVEK combination treatment experienced a serious skin reaction. These serious skin reactions required hospitalization and all patients recovered. For serious skin reactions, INCIVEK combination treatment must be discontinued immediately, and patients should be promptly referred for urgent medical care.
The INCIVEK label was also updated to include additional information on the time to onset and management of anemia.
  
About INCIVEK
INCIVEK^® (telaprevir) tablets is an oral medicine that acts directly on the hepatitis C virus protease, an enzyme essential for viral replication. INCIVEK has been prescribed to more than 50,000 patients in the United States. Approximately three out of four U.S. patients who are prescribed a direct-acting antiviral for the treatment of genotype 1 chronic hepatitis C (HCV) receive INCIVEK combination therapy.
  
In Phase 3 clinical studies, 79 percent of people who had not previously been treated for HCV achieved a viral cure following treatment with INCIVEK combination therapy, compared with 46 percent of those who received pegylated-interferon and ribavirin (P/R) alone. Among people who were treated previously but did not achieve a viral cure, in the Phase 3 studies: 86 percent of relapsers achieved a viral cure with INCIVEK combination therapy compared to 22 percent with P/R alone; 59 percent of partial responders achieved a viral cure compared with 15 percent with P/R alone; and 32 percent of null responders achieved a viral cure compared with 5 percent with P/R alone. In addition, many people are eligible to complete treatment with INCIVEK combination therapy in 24 weeks — half the time required for treatment with P/R alone.
  
INCIVEK was approved by the U.S. Food and Drug Administration (FDA) in May 2011 and by Health Canada in August 2011 for use in combination with pegylated-interferon and ribavirin for adults with genotype 1 chronic hepatitis C with compensated liver disease (some level of damage to the liver but the liver still functions), including cirrhosis (scarring of the liver). INCIVEK is approved for people who are new to treatment, and for people who were treated previously with interferon-based treatment but who did not achieve a sustained viral response, or viral cure (relapsers, partial responders and null responders).
  
Vertex developed telaprevir in collaboration with Janssen and Mitsubishi Tanabe Pharma. Vertex has rights to commercialize telaprevir in North America where it is being marketed under the brand name INCIVEK (in-SEE-veck). Janssen has rights to commercialize telaprevir in Europe, South America, Australia, the Middle East and certain other countries. In September 2011, telaprevir was approved in the European Union and Switzerland. Telaprevir is known as INCIVO^® in Europe. Mitsubishi Tanabe Pharma has rights to commercialize telaprevir in Japan and certain Far East countries. In September 2011, telaprevir was approved in Japan and is known as Telavic^®.
  
IMPORTANT SAFETY INFORMATION
Indication
INCIVEK^® (telaprevir) is a prescription medicine used with the medicines peginterferon alfa and ribavirin to treat chronic (lasting a long time) hepatitis C genotype 1 infection in adults with stable liver problems, who have not been treated before or who have failed previous treatment. It is not known if INCIVEK is safe and effective in children under 18 years of age.
  
Important Safety Information
INCIVEK^® (telaprevir) should always be used in combination with peginterferon alfa and ribavirin. INCIVEK combination treatment may cause serious side effects including skin rash and serious skin reactions, anemia (low red blood cell count) that can be severe, and birth defects or death of an unborn baby.
  
Skin rashes are common with INCIVEK combination treatment. Sometimes these skin rashes and other skin reactions can become serious, require treatment in a hospital, and may lead to death. Patients should call their healthcare provider right away if they develop any skin changes during treatment with INCIVEK.
Their healthcare provider will decide if they need treatment or if they need to stop INCIVEK or any of their other medicines. Patients should not stop taking INCIVEK combination treatment without talking with their healthcare provider first.
Patients' healthcare providers will do blood tests regularly to check for anemia. If anemia is severe, the healthcare providers may tell them to stop taking INCIVEK.
  
INCIVEK combined with peginterferon alfa and ribavirin may cause birth defects or death of an unborn baby. Therefore, a patient should not take INCIVEK combination treatment if she is pregnant or may become pregnant, or if he is a man with a sexual partner who is pregnant. Females who can become pregnant and females whose male partner takes these medicines must have a negative pregnancy test before starting treatment, every month during treatment, and for 6 months after treatment ends. Patients must use two forms of effective birth control during treatment and for 6 months after all treatment has ended. These two forms of birth control should not contain hormones, as these may not work during treatment with INCIVEK.
  
INCIVEK and other medicines can affect each other and can also cause side effects that can be serious or life-threatening. There are certain medicines patients cannot take with INCIVEK combination treatment. Patients should tell their healthcare providers about all the medicines they take, including prescription and non-prescription medicines, vitamins and herbal supplements.
The most common side effects of INCIVEK combination treatment include itching, nausea, diarrhea, vomiting, anal or rectal problems (including hemorrhoids, discomfort , burning or itching around or near the anus), taste changes and tiredness. There are other possible side effects of INCIVEK, and side effects associated with peginterferon alfa and ribavirin also apply to INCIVEK combination treatment. Patients should tell their healthcare provider about any side effect that bothers them or doesn't go away.
  
Please see full Prescribing Information including Boxed Warning, and the Medication Guide for INCIVEK available at www.INCIVEK.com.

About Hepatitis C
Hepatitis C is a serious liver disease caused by the hepatitis C virus, which is spread through direct contact with the blood of infected people and ultimately affects the liver.¹ Chronic hepatitis C can lead to serious and life-threatening liver problems, including liver damage, cirrhosis, liver failure or liver cancer.¹ Though many people with hepatitis C may not experience symptoms, others may have symptoms such as fatigue, fever, jaundice and abdominal pain.¹ Unlike HIV and hepatitis B virus, chronic hepatitis C can be cured.² If treatment is not successful and a person does not achieve a viral cure, they remain at an increased risk for progressive liver disease.^3,4

More than 170 million people worldwide are chronically infected with hepatitis C.⁵ In the United States, up to 5 million people have chronic hepatitis C and 75 percent of them are unaware of their infection.^6,7 Hepatitis C is four times more prevalent in the United States compared to HIV.⁷ The majority of people with hepatitis C in the United States were born between 1945 and 1965, accounting for 82 percent of people with the disease.⁸ Hepatitis C is the leading cause of liver transplantations in the United States and is reported to contribute to 15,000 deaths annually.^9,10 By 2029, total annual medical costs in the United States for people with hepatitis C are expected to more than double, from $30 billion in 2009 to approximately $85 billion.¹¹

About Vertex
Vertex creates new possibilities in medicine. Our team discovers, develops and commercializes innovative therapies so people with serious diseases can lead better lives.
  
Vertex scientists and our collaborators are working on new medicines to cure or significantly advance the treatment of hepatitis C, cystic fibrosis, rheumatoid arthritis and other life-threatening diseases.
Founded more than 20 years ago in Cambridge, Mass., we now have ongoing worldwide research programs and sites in the U.S., U.K. and Canada. Today, Vertex has more than 2,000 employees around the world, and for three years in a row, Science magazine has named Vertex one of its Top Employers in the life sciences
  
Vertex's press releases are available at www.vrtx.com.
  
Special Note Regarding Forward-Looking Statements
This press release contains forward-looking statements as defined in the Private Securities Litigation Reform Act of 1995, including, without limitation, Dr. Kauffman's statements in the third paragraph of this press release. While the company believes the forward-looking statements contained in this press release are accurate, there are a number of factors that could cause actual events or results to differ materially from those indicated by such forward-looking statements. Those risks and uncertainties include the risks listed under Risk Factors in Vertex's annual report and quarterly reports filed with the Securities and Exchange Commission and available through Vertex's website at www.vrtx.com. Vertex disclaims any obligation to update the information contained in this press release as new information becomes available.
(VRTX-GEN)
  
References:
¹ Centers for Disease Control and Prevention. Hepatitis C Fact Sheet: CDC Viral Hepatitis. Available at: http://www.cdc.gov/hepatitis/HCV/PDFs/HepCGeneralFactSheet.pdf Updated June 2010.
Accessed September 21, 2012.
² Pearlman BL and Traub N. Sustained Virologic Response to Antiviral Therapy for Chronic Hepatitis C Virus Infection: A Cure and So Much More. Clin Infect Dis. 2011 Apr;52(7):889-900.
³ Morgan TR, Ghany MG, Kim HY, Snow KK, Lindsay K, Lok AS. Outcome of sustained virological responders and non-responders in the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) trial. Hepatology. 2008;50(Suppl 4):357A (Abstract 115).
⁴ Veldt BJ, Heathcote J, Wedmeyer H. Sustained virologic response and clinical outcomes in patients with chronic hepatitis C and advanced fibrosis. Annals of Internal Medicine. 2007; 147: 677-684.
⁵ Ghany MG, Strader DB, Thomas DL, Seeff, LB. Diagnosis, management and treatment of hepatitis C; An update. Hepatology. 2009;49 (4):1-40.
  
⁶ Chak, E, et. al. Hepatitis C Virus Infection In USA: An Estimate of True Prevalence. Liver Intl. 2011;1096 -1098.
  
⁷ Institute of Medicine of the National Academies. Hepatitis and liver cancer: a national strategy for prevention and control of hepatitis B and C. Colvin HM and Mitchell AE, ed. Available at: http://www.iom.edu/Reports/2010/Hepatitis-and-Liver-Cancer-A-National-Strategy-for-Prevention-and-Control-of-Hepatitis-B-and-C.aspx Updated January 11, 2010. Accessed September 21, 2012.
⁸ Smith, BD, et al. Hepatitis C Virus Antibody Prevalence, Correlates and Predictors among Persons Born from 1945 through 1965, United States, 1999-2008. AASLD 2011 Annual Meeting.
⁹ Volk MI, Tocco R, Saini S, Lok, ASF. Public health impact of antiviral therapy for hepatitis C in the United States. Hepatology. 2009;50(6):1750-1755.
  
¹⁰ Ly KN, et al. The Increasing Burden of Mortality From Viral Hepatitis in the United States Between 1999 and 2007. Ann Intern Med. 2012;156:271-278.
  
¹¹ Pyenson B, Fitch K, and Iwasaki K. Consequences of Hepatitis C Virus (HCV): Costs of a Baby Boomer Epidemic of Liver Disease. Milliman, Inc. May 2009. Available at: http://www.vrtx.com/assets/pdfs/MillimanReport.pdf

Vertex Pharmaceuticals Incorporated
Media:
Erin Emlock, 617-341-6992
mediainfo@vrtx.com
or
Nikki Levy, 617-341-6992
mediainfo@vrtx.com
or
Investors:
Michael Partridge, 617-341-6108
or
Kelly Lewis, 617-961-7530
Source: Vertex Pharmaceuticals Incorporated


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Anemia Management During PI-based HCV Therapy: Ribavirin Dose Reduction is the Right Course of Action

Anemia Management During PI-based HCV Therapy: Ribavirin Dose Reduction is the Right Course of Action

Mark S. Sulkowski, MD - 12/12/2012 More from this author

Source - CCO

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Anemia in Patients Treated With PIs
Clinicians have now been using boceprevir and telaprevir in combination with peginterferon/ribavirin for approximately 1.5 years since their approval, and the biggest obstacle faced by clinicians is the increase in anemia with both of the HCV protease inhibitors (PIs). Although we all have previous experience with anemia management from when peginterferon/ribavirin was the standard of care, the addition of PIs has compounded this issue.

The prescribing information for the PIs recommends reducing ribavirin for anemia management; however, many clinicians have been reluctant to take this approach for fear of compromising a patient’s ability to achieve an SVR—an idea left over from the days of the 80-80-80 rule that was coined more than a decade ago to describe response to therapy with standard interferon 3 times weekly plus ribavirin.

The Need to Dose Reduce
The point I’d like to make is that our understanding of anemia with ribavirin has evolved and we need to move beyond this entrenched concept. Here’s the new thinking for the management of anemia with triple therapy including telaprevir or boceprevir: We need to dose reduce ribavirin in patients with anemia, and we need to do it relatively aggressively. The foundation of this statement are data showing that ribavirin dose reduction does not impair a patient’s likelihood of achieving SVR; on the contrary, it is often key to successful therapy by keeping patients on therapy rather than discontinuing due to anemia complications.

How low can you go and how soon can you dose reduce? One of the most critical findings from recent analyses is that ribavirin dose reduction even during the first 4 weeks of PI administration did not affect the likelihood of response; furthermore, ribavirin dose reduction for anemia while HCV RNA is still detectable also was not associated with worse outcomes. These data give us comfort that we can reduce ribavirin for anemia early in the course of therapy if necessitated by significant anemia.

Many clinicians cling to the idea that more ribavirin is always better, but this idea ignores one of the realities of ribavirin pharmacokinetics—there is wide variability in exposure between individuals. In other words, 2 patients ingesting that same dose of ribavirin can have markedly different plasma exposures. Renal clearance of ribavirin is one of the major drivers of this variability. Several published studies as well as the US Food and Drug Administration analysis of anemia in the telaprevir and boceprevir registration trials clearly demonstrate that the degree of anemia is related to the plasma ribavirin concentrations. In other words, the development of anemia is a marker of higher ribavirin exposure. In the large IDEAL trial of peginterferon/ribavirin, anemic patients actually had a higher SVR rate than nonanemic patients, including those who reduced their ribavirin dose from 1000 or 1200 mg/day to 600 mg/day. The same pattern was observed in the SPRINT-2 trial of boceprevir-based therapy, where SVR rates were higher for individuals who developed anemia when compared with individuals who did not develop anemia. This concept of anemia indicating adequate ribavirin plasma concentration is key in approaching ribavirin dose reductions with confidence. When ribavirin is reduced, we can think of this as an adjustment of the ribavirin dose for that unique patient to a more tolerable level.

My Approach to Anemia Management
In my practice, we monitor our patients taking PI-based therapy pretty closely. I generally recommend complete blood count monitoring every 2 weeks while a patient receives triple therapy. If the patient has a large decline in hemoglobin from baseline or if hemoglobin levels are < 10 g/dL, I drop the ribavirin dose to 600 mg/day. Some clinicians prefer to drop by 200 mg/day increments but, in my experience, that is not aggressive enough and I would rather drop the ribavirin dose to 600 mg/day and then attempt to increase the dose once the patient’s hemoglobin level stabilizes. In my view, it’s better to be safe than sorry; in the case of anemia, a less aggressive approach may lead to the need for epoetin alfa or blood transfusions or, in the worst case scenario, treatment discontinuation. I do use some erythropoietin in my practice but generally reserve that approach for patients who fail the initial strategy of ribavirin dose reduction. I don’t think that there is any rationale to use epoetin alfa as a primary means of preventing ribavirin dose reduction.
If these strategies are followed, I believe you can limit the number of patients who take epoetin alfa, avoid blood transfusions, and most importantly, prevent treatment discontinuation due to anemia. Keep in mind that the most important part of the old 80-80-80 rule was staying on therapy for at least 80% of the treatment duration. Staying on treatment is the key to success with triple therapy.

Your Thoughts?
How do you manage anemia during PI-based therapy? Have recent clinical trial analyses changed your management strategy?

Topics: HCV - Treatment

 

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• Will Dropping Interferon Be the Magic Bullet for Reducing HCV Mortality?
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Hepatitis C-Managing Adverse Effects and Complications in Completing Treatment

Top Antivir Med. 2012 Oct;20(4):125-8.

HCV Treatment Complications Volume 20 Issue 4 October/November 2012

Perspective

Managing Adverse Effects and Complications in Completing Treatment for Hepatitis C Virus Infection

Sherman KE.

Source
University of Cincinnati College of Medicine, Cincinnati, OH, USA.

Download PDF

The addition of direct-acting antivirals (DAAs) to hepatitis C virus (HCV) treatment regimens has made treatment more effective and patient management more complex. Shepherding patients through a full course of HCV therapy requires motivation and involvement on the part of the patient and the physician. Indeed, physician inexperience and lack of confidence in guiding patients through the challenges of treatment appears to be a primary reason for early discontinuation of therapy. Among the many complications of HCV treatment that must be managed efficiently and effectively are depression and other psychiatric disorders; hematologic abnormalities including DAA- and ribavirin-associated anemia and peginterferon alfaassociated neutropenia and thrombocytopenia; rash and drug eruptions, including telaprevir-associated rash; and weight loss. Practical considerations in management of these common complications are offered.

In clinical trials, treatment with a direct-acting antiviral (DAA) in combination with peginterferon alfa and ribavirin for 48 weeks produced a sustained virologic response (SVR) in approximately 65% to 75% of patients with genotype 1 or 4 hepatitis C virus (HCV) infection. Peginterferon alfa and ribavirin treatment for 24 weeks produced an SVR in approximately 70% to 85% of patients with HCV genotype 2 or 3 infection. SVR rates in clinical practice are not as high, in large part because early discontinuation of HCV therapy is frequent for reasons unrelated to treatment futility (ie, stopping treatment for failure to achieve specific reductions in plasma HCV RNA level by specific time points).

Major reasons for early discontinuation of anti-HCV therapy are discussed herein. Physician Inexperience Treating HCV infection with available regimens can be daunting to both patient and physician, and physician inexperience can result in a lack of confidence in initiating and following through with treatment.

A recent analysis in a study population receiving peginterferon alfa and ribavirin therapy showed that treatment was discontinued in 44% of patients, with physician reasons accounting for 75% of discontinuations and patient reasons accounting for 25%.1 Whereas treatment futility accounted for 33% of physician discontinuations, no reason for discontinuation was given for 39% of cases. Comorbidities and lack of adherence were cited as reasons in 5% of cases each.

Patients often cited adverse effects as a reason for stopping treatment, but some also reported that they got the sense from their physician that they should stop or were encouraged to stop. In the WIN-R (Weight-Based Dosing of Peginterferon alfa-2b and Ribavirin) trial, which was performed at 236 community and academic sites, 41.3% of subjects discontinued therapy.2

Clinicians who are inexperienced and not confident in their ability to guide a patient through the treatment course may discontinue treatment early, depriving the patient of a chance for cure. As health care providers, we need to move past any such hesitancy in order to provide effective treatment and management.

Psychiatric Complications
Depression is the most common psychiatric complication encountered in HCV patients, with mild to moderate depression found in as much as 80% of patients. Bipolar disorder and schizophrenia are also not infrequently encountered.

There is little evidence to support a benefit of preemptive antidepressant therapy in all patients undergoing HCV treatment, though a recent randomized trial of HCV patients without psychiatric history suggested that major depression risk was decreased in a group of patients randomized to receive escitalopram prior to interferon- based therapy.3 For patients who are actively depressed, antidepressant treatment is likely to be required. Mild and moderate depression can be assessed by and readily treated by the HCV physician and in most cases, referral to psychiatry is not necessary.

The primary issue for the HCV physician is to determine whether the depression is manageable in the context of HCV treatment. The physician should become comfortable with the use and effects of several antidepressants, including sertraline, paroxetine, and mirtazapine.

A thumbnail guideline for use of these agents is to use sertraline if the depression is characterized by sadness and crying episodes and paroxetine if it is characterized by anger. Mirtazapine is especially useful in patients who are suffering weight loss, because it is associated with significant appetite stimulation and weight gain. All of these drugs have potential interactions with telaprevir and boceprevir and should be started at the lowest possible therapeutic dose. Psychiatric assistance is needed for patients with more severe depression—eg, those with suicidal ideation—and HCV treatment should be delayed until such patients are stable.

The most effective way to manage such patients is not to refer to psychiatry and wait for clearance, but to form a partnership with the psychiatrist throughout the duration of the patient’s treatment. Psychiatric expertise also usually is needed for patients with bipolar disorder or schizophrenia prior to starting HCV treatment. It is important that these patients have a commitment to psychiatric care. A contract with such patients sometimes ensures that they will stay with their psychiatric care.

With patients who have bipolar disorder, it is best to try to initiate HCV treatment during a hypomanic phase. It is difficult to start and maintain therapy in a manic or actively delusional patient even with the help of a psychiatrist. There is evidence from several small studies that partnering with psychiatry can help in getting patients with bipolar disorder or schizophrenia through an HCV treatment course. In one study, 22 patients with psychiatric disorders and 17 control patients were treated with peginterferon alfa and ribavirin in an interdisciplinary setting that included psychiatry. The outcomes in the 2 groups were similar, with SVR being achieved in 50% and 58.6%, respectively.4

Hematologic Toxicities Anemia
Anemia beyond that associated with ribavirin alone is a major adverse effect with both telaprevir and boceprevir. For example, anemia occurred in 37% and 41% of patients receiving telaprevir in the ADVANCE (A New Direction in HCV Care: A Study of Treatment-Naive Hepatitis C Patients with Telaprevir)5 and ILLUMINATE (Illustrating the Effects of Combination Therapy with Telaprevir)6 trials, respectively, compared with 19% of patients receiving peginterferon alfa and ribavirin alone. No erythrocyte-stimulating agents were used in the telaprevir trials, with anemia being managed by ribavirin dose reduction. Similarly, 49% of patients in each of the 2 boceprevir arms in the SPRINT-2 (Serine Protease Inhibitor Therapy 2) trial developed anemia, compared with 29% of patients receiving peginterferon alfa with ribavirin and placebo.7 Treatment was discontinued because of anemia in 2% of each boceprevir group and in 1% of placebo patients.

Dose reductions were implemented in 20% to 21% of boceprevir patients and in 13% of placebo patients, and epoetin alfa was used to treat anemia in 43% of boceprevir patients and 24% of placebo patients.

Ribavirin dose reduction should be considered the first strategy for treating anemia in patients receiving DAAcontaining regimens, because it does not appear to compromise response, and is less expensive and safer than initiating epoetin alfa treatment or other erythrocyte-stimulating growth factors. In a recent trial in 500 patients receiving boceprevir-containing regimens, patients with hemoglobin levels dropping below or about to drop below 10 g/dL were randomized to receive a 200 mg/d to 400 mg/d reduction in ribavirin dose or to get an addition of 40,000 U/wk of subcutaneous epoetin alfa.8 SVR rates were approximately 70% in both groups, suggesting no difference between the 2 approaches with regard to compromising response.

In addition, a retrospective analysis of outcomes in the ADVANCE and ILLUMINATE telaprevir trials showed slightly, but not statistically significantly lower SVR rates in patients with ribavirin dose reduced to a range of 800 mg/d to 1000 mg/d, or 600 mg/d, than in patients with no ribavirin dose reductions (all SVR rates were between 74% and 79%).9 Similar outcomes were observed in an analysis of previously treated patients in the REVEAL (Risk Evaluation of Viral Load Elevation and Associated Liver Disease) study of telaprevir.

Neutropenia
Neutropenia is common during peginterferon alfa and ribavirin therapy and is attributed primarily to peginterferon alfa. Considerable anecdotal evidence, analyses of clinical trials, and one large single center experience indicate that there is no increased risk of infection associated with neutropenia, even when the absolute neutrophil count (ANC) drops below 500/μL.10,11 Neutropenia should be managed with filgrastim (5-10 μg/kg) only when the ANC drops below 500/μL and before any reduction in peginterferon alfa dose.

Thrombocytopenia
Thrombocytopenia is a frequent cause of treatment discontinuation in clinical practice. Platelet counts plummet during the first 6 weeks to 8 weeks in some patients, and physicians justifiably become alarmed. However, it does not appear that a declining platelet count should prompt substantial concern until it reaches about 30,000/ μL.

When platelet counts are in the range of 20,000/μL to 30,000/μL, the thrombocytopenia should be managed by peginterferon alfa dose reduction. In the absence of substantial anemia, the ribavirin dose should not be changed, because ribavirin increases platelet count when compared with use of peginterferon alfa alone.12

Eltrombopag is a platelet growth factor that is very expensive, sometimes difficult to get insurance approval for, and not widely used. However, its use can be considered in a patient who has a platelet count of 20,000/μL to 30,000/μL in whom no further peginterferon alfa dose reductions can be made and who is otherwise doing well.

A study reported several years ago showed that starting eltrombopag treatment in patients with low platelet counts prior to beginning HCV therapy was successful in increasing platelet counts such that they remained at high levels throughout the course of therapy.13 This approach would be very expensive and is not a US Food and Drug Administration–approved use of eltrombopag, but the drug can be effective in adjunctive therapy for thrombocytopenia.

Dermatologic Issues
Peginterferon alfa, ribavirin, and telaprevir, but not boceprevir, are associated with rash. Peginterferon alfa can cause dermatitis, local reactions, and exacerbation of psoriasis. The local reactions are rare but can be quite severe.

Treatment should be stopped in patients who develop a depression or ulcer at the injection site; if treatment continues, the lesion will continue to widen and deepen. Psoriasis may progress from tiny patches to that covering large portions of the body. In such cases, aggressive treatment with topical steroids should be started in consultation with a dermatologist. Light therapy sometimes helps. Treatment with injectable methylprednisolone or other injectable steroids has been successful at more advanced stages of psoriasis, but should not be used for initial treatment.

Ribavirin is associated with drug eruption that often occurs between 6 weeks and 16 weeks and up to 20 weeks of therapy. It frequently overlaps with telaprevirassociated rash, which is the rash of greatest concern.

Telaprevir is associated with eczematous rash and drug rash with eosinophilia and systemic eruptions (DRESS). A summary of data from telaprevir placebo-controlled phase II and III trials indicates that rash occurred in approximately 56% of telaprevir patients compared with approximately 35% of control patients, with rash being mild in severity in 37% of telaprevir patients, moderate in 14%, and severe in 5%.14 Rash was typically pruritic and eczematous, covering less than 30% of the total body surface area.

Rash started within the first 4 weeks of treatment in approximately 50% of patients, but was observed at any time during treatment. Progression of rash to greater severity occurred in less than 8% of patients. Grading of skin eruptions is important. It was learned in the telaprevir trials that even experienced clinicians overestimate the percentage of body surface area affected by rash compared with dermatologist findings.

A mild eruption is a localized eruption with limited distribution in separate, isolated sites on the body.15 A moderate eruption is a diffuse rash that involves less than 50% of body surface area. Severe rash affects more than 50% of body surface area or is accompanied by substantial systemic symptoms, mucous membrane ulceration, target lesions, or epidermal detachment.

Severe cutaneous adverse reaction (SCAR) comprises DRESS (usually involving fever and increased liver enzymes); Stevens-Johnson syndrome with toxic epidermal necrolysis; acute generalized exanthematous pustulosis; and erythema multiforme.

Figure 1 illustrates DRESS. The patient’s skin was peeling off in layers, and he had lesions in the mouth, dramatic swelling of the lips, and a very high eosinophil count.

Figure 1. Drug rash with eosinophilia and systemic eruptions (DRESS). This patient’s skin is peeling off in layers, he had oral lesions in his mouth with blisters, and his lips were swollen. He had a high eosinophilic count.

DRESS requires immediate hospitalization. Mild rash developing in patients receiving telaprevir should be managed conservatively with topical steroids. For moderate rash without mucosal involvement, management includes stopping telaprevir, especially if the patient has had more than 8 weeks of treatment, but continuing peginterferon alfa and ribavirin. If the physician suspects that the rash is caused by ribavirin, the drug can be held for 1 week to 2 weeks and then restarted at a lower dose. For patients with severe rash or SCAR, all HCV treatment should be stopped.

Weight Loss
Weight loss associated with peginterferon alfa treatment is fairly common. Body weight loss of more than 10% is considered serious. Serious weight loss is more common among patients who have HCV and HIV coinfection. Primary management HCV treatment should be discontinued in most cases if the platelet count drops below 20,000/μL. In patients who have hemophilia, the threshold for stopping therapy is much higher (eg, about 50,000 cells/μL).consists of calorie supplementation using milk shakes or nutrition drinks. As noted above, the antidepressant mirtazapine is often effective in promoting weight gain.

Conclusion
With the availability of DAAs, the management of HCV treatment has become more, not less, complex. Specific management techniques are evolving as we learn more about both safety and efficacy of the currently available regimens. The decision to initiate therapy now, versus waiting for next-generation therapies that may not contain peginterferon alfa, is also complex. In general, patients with stage 1 or 2 hepatic fibrosis are unlikely to progress to cirrhosis (stage 4) within 3 to 5 years and may choose to wait for newer therapies. However, these patients do represent a potential public health risk to others, and there is no guarantee that newer therapies will truly be more efficacious with fewer adverse effects than current therapy. In contrast, patients with stage 3 fibrosis and compensated cirrhosis should probably be offered treatment now. Effective treatment may prevent hepatic decompensation. A patient with decompensated disease (ascites, bleeding varices, encephalopathy) is not a candidate for the current generation of HCV antiviral therapies. Management of treatment with the next generation of DAAs may be easier, but it is likely that challenges will continue for decades to come.

Financial Affiliations: Dr Sherman has served as a consultant to Abbott Molecular, Fibrogen Inc, Kadmon Corporation, and Merck Pharmaceuticals. He has served on data and safety monitoring boards and endpoint adjudication committees for MedPace Inc and Janssen Therapeutics. His institution has received research support from Abbott Laboratories, Anadys Pharmaceuticals, BMS, Boehringer-Ingelheim Corp, Genentech Inc, Gilead Sciences, Inc, Norvartis, and Vertex Pharmaceuticals, Inc. (Updated 10/22/12)

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