Telaprevir/Boceprevir
Just In On The Blog
"INCIVEK" Telaprevir
"VICTRELIS" Boceprevir
Updates - Telaprevir And Boceprevir
May 2012
Hepatitis C Therapy Update-Where Are We Now?
April 23
Summary Of The 47th European Association for the Study of the
Liver EASL
Updated
AASLD HCV Guideline Aims To Simplify Use of DAAs
More Data Needed To Fill Gaps
in Understanding
by
Christina Frangou
April 16 2012
The American Association for the Study of Liver Diseases (AASLD) recently published an updated practice guideline on the treatment of chronic infection with hepatitis C virus (HCV) genotype 1 (Ghany MG et al. Hepatology 2011;54:1433-1444).
The guideline, authored by members of the AASLD practice guideline committee, was issued in response to the development of new direct-acting antivirals (DAAs) and the identification of several single nucleotide polymorphisms associated with spontaneous and treatment-induced clearance of HCV infection. The report makes 18 recommendations for clinicians who are considering using the new DAAs to treat patients with HCV. The two
currently approved DAAs have complex prescribing rules, including outlines for response-guided therapy and unusual stopping rules, and many clinicians question how and when the agents are best used.
“We have entered into a very different treatment paradigm. I’d suggest that everyone read the guideline from
the AASLD. It’s a very good overview of where we are today,” said David R. Nelson, MD, a study author and professor of medicine, Division of Gastroenterology, Hepatology and Nutrition at the University of Florida College
of Medicine, in Jacksonville, during a presentation at The Liver Meeting last year.
The authors outline the current state of evidence regarding treatment with boceprevir and telaprevir, and provide some guidance on much-debated issues such as treatment of patients with cirrhosis and the role of interleukin-28B (IL28B) testing.
The guidelines are “very important and very helpful,” said Michal R. Charlton, MD, professor of medicine
and head of the hepatobiliary section at Mayo Clinic, in Rochester, Minn. “The guidelines provide a lens through which clinicians can look to see the optimal approach to managing patients with HCV infection.”
Inside the
Recommendations
According to the authors of the report, the DAAs, in combination with peginterferon alfa and ribavirin, are now the “optimal therapy” for treating HCV genotype 1 chronic infection. Both therapies must be given with
peginterferon and ribavirin, which limits selection of resistant variants and improves antiviral response. Furthermore, boceprevir and telaprevir should not be used to treat patients infected with HCV genotype 2 or 3.
The authors
reiterated the FDA recommendation that treatment-naive patients with cirrhosis treated with either boceprevir or telaprevir in combination with interferon and ribavirin should receive therapy for 48 weeks instead of on a response-guided basis. However, the authors added that this recommendation is “based on limited data and requires further study.”
The report also specifies that the stopping rules differ for telaprevir and boceprevir in treatment-naive patients.
Treatment with telaprevir, peginterferon alfa and ribavirin should be stopped if the HCV RNA level is greater than 1,000 IU/mL at treatment weeks 4 or 12 and/or detectable at treatment week 24. Treatment with boceprevir, peginterferon and ribavirin should be stopped if the HCV RNA level is greater than 100 IU/mL at treatment week 12 or detectable at treatment week 24. For both therapies, the evidence for the discontinuation rules is considered Class 2a, meaning the weight of evidence is in favor of the usefulness of this rule, but there is limited evidence.
Patients who previously received and failed therapy with interferon and ribavirin remain a conundrum with regard to starting DAA therapy. Studies have shown that patients’ response to triple therapy regimens in both boceprevir and telaprevir trials was strongly influenced by the outcome of their earlier treatment with peginterferon and ribavirin. The decision to re-treat patients should depend on their previous response to peginterferon and ribavirin and on reasons why they may have failed, such as inadequate drug dosing or side-effect management, the report said. The authors call on physicians to review old treatment records to document previous treatment response.
This updated document is the first to clarify treatment for patients who fail DAA therapy. The authors say that patients who do not have a virologic response, who experience virologic breakthrough or who relapse on one
protease inhibitor (PI) should not be retreated with the other PI.
Although the evidence is limited, the AASLD did make some recommendations for managing treatment-experienced patients. The AASLD suggests retreatment with boceprevir or telaprevir, together with peginterferon alfa and
weight-based ribavirin, “be considered” for patients who had a virologic relapse or who were partial responders after a previous course of treatment with standard interferon alfa or peginterferon alfa and/or ribavirin.
“Relapsers and partial responder patients can expect relatively high sustained virologic response rates to retreatment with a PI-containing triple regimen and should be considered candidates for retreatment,” the authors wrote.
For previously null responders, telaprevir may be considered but boceprevir cannot be recommended, the committee
found. This finding differs from the FDA label, which indicates that boceprevir can be used in null responders. Null responders were excluded from Phase III trials of boceprevir (Poordad F et al. N Engl J Med 2011;364:1195-1206).
“Given the lack of definitive information for Phase III data, caution is advised in the use of [boceprevir] in null
responders until further supportive evidence becomes available,” according to the AASLD.
Additionally, the decision to re-treat a null responder with telaprevir should be individualized, particularly in patients with cirrhosis, because less than one-third of null responder patients in the telaprevir trial achieved a sustained virologic response (SVR). Moreover, the authors caution that a majority of null responders developed resistance to DAAs.
“Any potential benefit from treating nonresponders must be weighed against the risk for development of antiviral resistance and for serious side effects, and the high cost of therapy,” the report said.The AASLD acknowledged uncertainty about the benefit of the lead-in strategy required for treatment with boceprevir. Theoretically, the lead-in may improve efficacy by lowering HCV RNA levels, thus reducing the rate of viral breakthrough when the PI is introduced. The authors noted, however, that poor responders during the lead-in period can still achieve SVR.
“Thus, a poor response during the lead-in phase should not be used to deny patients access to PI therapy,” the authors said. Patients who develop anemia on PI therapy should be managed by reducing the ribavirin
dose, they added.
The report also specified that IL28B genotype is a significant treatment predictor of response to therapy, but data are
insufficient to determine whether IL28B testing can be used to recommend either interferon and ribavirin alone or a triple therapy with a PI.
“Consideration should be given to ordering the test when it is likely to influence either the physician’s or patient’s decision to initiate therapy,” the authors said.
Telaprevir and boceprevir are not recommended for use in children and adolescents younger than 18 years because safety and efficacy has not been established in this group.
Additionally, the guidelines do not address several important questions about DAAs, Dr. Charlton said. The
report, for example, does not provide detailed and practical information about drug–drug interactions, managing HIV/HCV co-infection and managing side effects, he said.
“Perhaps the highest-impact omission, which was unavoidable, is whether in light of the spectacular report of efficacy and tolerability of PSI-7977 in combination with ribavirin without interferon, patients with early
stages of liver disease should be treated at all with boceprevir or telaprevir,” he said. “In our practice, we are already beginning to advise many patients to wait. … A strong case could be made for waiting for the results of the Phase III
interferon-free studies.”
The committee cautions that the guidelines are “based on data that are presently limited” and the recommendations may need revision as additional data become available.
“There is a paucity of information for many of the subgroups with the greatest unmet need for treatment
(e.g., patients co-infected with HIV and HCV, with decompensated cirrhosis and after liver transplantation),” the committee said.
Source
Dr. Nelson
receives research support from Bayer/Onyx, Bristol-Myers Squibb,
Genentech/Roche, Gilead, Merck, Pharmasset, Tibotec and Vertex Pharmaceuticals;
he serves on the advisory boards of Bayer/Onyx, Genentech/Roche, Gilead, Merck,
Pharmasset and Tibotec; and he is a consultant for Vertex Pharmaceuticals. Dr.
Charlton receives research support from Bristol-Myers Squibb, Genentech/Roche,
Merck and Vertex Pharmaceuticals; he is a consultant for Bristol-Myers Squibb,
Genentech/Roche Gilead, Merck and Vertex Pharmaceuticals.
VA-Taking Your Hepatitis C Triple Therapy 1-page handouts
One-page printable handouts for providers to give to patients
who are taking one of the new hepatitis C drugs--boceprevir or telaprevir--with
tips on how and when to take the medications, and what to do if you miss a dose.
Boceprevir handout
Telaprevir handout
VA National Hepatitis C Resource Centers
March 2012
View List-FDA Alert-Statins and HIV or Hepatitis C Drugs
Protease inhibitors and statins taken together may raise the blood levels of statins and increase the risk of myopathy, kidney damage, and kidney failure, which can be fatal.
View the list of HIV or HCV Drugs which interact with statins Here Or Here
UK consensus guidelines for the use of the protease inhibitors boceprevir and telaprevir in genotype 1 chronic hepatitis C infected patients
Source:
Alimentary Pharmacology & Therapeutics
Volume 35, Issue 6, pages 647–662, March 2012
What Is Triple therapy ?
Peginterferon, plus
Ribavirin, plus
Either Boceprevir (Victrelis) or Telaprevir (Incivek)
Triple therapy is currently only recommended for patients infected with HCV genotype 1.
Will I respond to this treatment?
The best candidates for treatment are:
Patients who have not had any prior treatment for HCV (Naïve)
Patients who were HCV RNA negative on a prior course of peginterferon/ribavirin but then
relapsed after peginterferon/ribavirin was discontinued (Relapse)
Patients who had at least 100-fold decrease in HCV RNA after 12 weeks of a prior
course of peginterferon/ribavirin (Partial Responder)
Patients who are less likely to respond to triple therapy:
Patients who did not have at least a 10-fold decrease after 4 weeks or 100-fold decrease
after 12 weeks of a prior course of peginterferon/ribavirin (Null Responder)
Patients with Cirrhosis
African Americans (compared to other racial groups)
What are my chances for cure of my hepatitis C if I take triple therapy?
1. Naïve 75%
2. Relapser 80 to 90%
3. Partial Responder 50 to 60%
4. Null Responder 30%
*Rates of cure are lower in patients with cirrhosis or African American race.
What are prior relapsers, prior partial responders, and prior null responders?
Resistance
The importance of adherence during triple therapy to prevent resistance is critically important, by following the dosing regimens with the new protease inhibitors resistance is minimized.
A missed or late dose will expose the virus to reduced drug levels, and will promote resistance. The failure to take the protease inhibitors (PIs) with food may also result in less than optimal drug levels. Telaprevir should be dosed with these recommended foods, as for boceprevir the food choice is up to you, although food taken with each dose is still absolutely necessary.
Of Interest
Hepatitis C-New Protease Inhibitor (NS3/4A) Drug Resistance Test
LabCorp has begun offering nationwide its hepatitis C GenoSure NS3/4A assay, which is designed to identify NS3 and NS4A mutations and NS3-associated resistance to a pair of recently approved HCV protease inhibitors.
Side Effects
Boceprevir and telaprevir for hepatitis C: safety management in clinical practice
The addition of direct-acting antiviral agents, telaprevir (TVR) or boceprevir to pegylated interferon (PEG-IFN) and ribavirin (RBV) represents a new era of therapy associated with an improvement in treatment response rates and an impairment of the safety profile compared to PEG-IFN/RBV. An increase in the frequency and severity of anaemia was reported in clinical trials for both drugs, and skin disorders including rash and pruritus occurred more frequently with the TVR-based regimen. These AEs are generally manageable and do not lead to early discontinuation. The management of anaemia has not been clearly established, and the impact of RBV dose reductions and erythropoietin alpha use on treatment efficacy and safety must be clarified. The management of rashes, which were mild and moderate in more than 90% of the cases, is well planned, does not require TVR discontinuation and can be treated using emollients and topical corticosteroids. However, approximately 5% of rashes were severe, and a few cases were classified as severe cutaneous adverse reactions leading to treatment discontinuation. ..... Read more
Dermatological side effects of hepatitis C and its treatment: Patient management in the era of direct-acting antivirals
Dermatological adverse events (AEs) are an existing concern during hepatitis C virus (HCV) infection and peginterferon/ribavirin treatment. HCV infection leads to dermatological and muco-cutaneous manifestations including small-vessel vasculitis as part of the mixed cryoglobulinemic syndrome. Peginterferon/ribavirin treatment is associated with well-characterized dermatological AEs tending towards a uniform entity of dermatitis. New direct-acting antivirals have led to significant improvements in sustained virologic response rates, but several have led to an increase in dermatological AEs versus peginterferon/ribavirin alone. In telaprevir trials, approximately half of treated patients had rash. More than 90% of these events were Grade 1 or 2 (mild/moderate) and in the majority (92%) of cases, progression to a more severe grade did not occur. In a small number of cases (6%), rash led to telaprevir discontinuation, whereupon symptoms commonly resolved. Dermatological AEs with telaprevir-based triple therapy were generally similar to those observed with peginterferon/ribavirin (xerosis, pruritus, and eczema). A few cases were classified as severe cutaneous adverse reaction (SCAR), also referred to as serious skin reactions, a group of rare conditions that are potentially life-threatening. It is therefore important to distinguish between telaprevir-related dermatitis and SCAR. The telaprevir prescribing information does not require telaprevir discontinuation for Grade 1 or 2 (mild/moderate) rash, which can be treated using emollients/moisturizers and topical corticosteroids. For Grade 3 rash, the prescribing information mandates immediate telaprevir discontinuation, with ribavirin interruption (with or without peginterferon) within 7days of stopping telaprevir if there is no improvement, or sooner if it worsens. In case of suspicion or confirmed diagnosis of SCAR, all study medication must be discontinued...Read More...
Drug interactions
Other drugs can interact with telaprevir/boceprevir" these interactions can reduce the PI concentrations which will result in less than desirable drug levels.
Dose reductions
Any dose reductions for toxicity, or treatment interruptions for any reason, are not advised as exposure to less than the full dose will promote the emergence of resistance. If therapy must be stopped because of toxicity, the PI must be stopped completely.
Stopping Rules
The stopping rules for both boceprevir- or telaprevir-based regimens should be strictly adhered to. Developing resistance to these drugs can be minimized as long as stopping rules are adhered.
From CCO
*Free registration is required
For all patients treated with boceprevir, the following futility rules should be employed:
If HCV RNA is ≥ 100 IU/mL at Week 12, all 3 medications should be discontinued.
If the patient has confirmed, detectable HCV RNA at Week 24, all 3 medications should be discontinued.
For all patients treated with telaprevir, the following futility rules should be employed:
If HCV RNA is more then 1000 IU/mL at treatment Week 4 or 12, all 3 medications should be discontinued.
If HCV RNA is detectable at Week 24, pegIFN/RBV should be discontinued.
More information on resistance
In the HCV Advocate July newsletter an article "Resisting Resistance" written by Ms. Lucinda K. Porter, RN., discusses viral resistance and the importance of taking the new protease inhibitors as directed.
Related - Patient video; New hepatitis C Drugs and Resistance
From CCO- Patient management
*Free registration required
The New Elements of HCV Care: Practical Skills to Optimize Protease Inhibitor–Based Therapy
Review the approved indications and proper management of HCV-infected patients with the newly approved protease inhibitors.
CME-Certified Case Vignette:
The New Elements of HCV Care: Practical Skills to Optimize Protease Inhibitor–Based Therapy
Join Graham R. Foster, FRCP, PhD; Paul Y. Kwo, MD; and Fred Poordad, MD, as they discuss optimal management strategies for 8 case scenarios of patients considering or receiving treatment with boceprevir or telaprevir.
Feb 2012
Video
New and experimental oral drugs to treat hepatitis C
Jan 2012
Triple therapy for HCV geno1: telaprevir or boceprevir?
Boceprevir and telaprevir are the first two protease inhibitors available for the treatment of patients infected with hepatitis C virus (HCV) genotype 1. A sustained virological response (SVR) of 70–80% is observed when either of these protease inhibitors is utilized with pegylated interferon (PEG-IFN) and ribavirin (RBV) in treatment naïve patients. Both agents are also highly effective in patients who failed to achieve a SVR during previous treatment with PEG-IFN/RBV. A rapid virological response (RVR) is observed in 56–60% of treatment naïve patients. Patients who achieve a RVR can be treated with a shorter course of therapy (24–28 weeks) and still achieve a SVR rate of 90% or higher. Patients who do not achieve a RVR, those with cirrhosis and certain prior non-responders should be treated for 48 weeks. Although the SVR rates observed with boceprevir and telaprevir are quite similar both globally and within sub-populations, the treatment algorithms for the two agents are unique. The decision of which protease inhibitor to use should assess several factors including the treatment scheme, duration of therapy, adverse event profile, cost and the likelihood of achieving a RVR. The latter is highly dependent upon IFN sensitivity and the IL28B genotype............
Dec 2011 Updates and Information
HCV Handout
Triple Therapy for HCV with Incivek, Pegasys and ribavirin is a major advance.
About 70% of previously untreated genotype one patients succeed with triple therapy. In addition, triple therapy permits the majority of patients to succeed with 24 instead of 48 weeks of treatment. 30-40% of nonresponders to Pegasys plus ribavirin are successful with triple therapy. Incivek is an inhibitor of HCV protease enzyme. The virus needs this enzyme to reproduce. Incivek reduces the viral level by 99.9% in less than one week. Incivek must be given with Pegasys and ribavirin or the virus quickly develops resistance.
Incivek is taken with fatty food such as cheese, peanut butter or meat every eight hours for the first 12 weeks of treatment. Pegasys is injected every week for at least 24 weeks. Ribavirin is taken with food twice daily every day for at least 24 weeks. Blood tests are checked before starting treatment, after 2 weeks and 4 weeks of treatment. Blood tests are then performed every 4 weeks while on treatment. Patients who test undetectable for HCV-RNA after 4 and 12 weeks of treatment have an excellent chance of cure of HCV with 24 weeks of triple therapy.
Incivek interacts with many other medications. Some medicines cannot be used at all and others must be dose adjusted.
Atorvastin (Brand name: Lipitor) cannot be combined with Incivek. Simvastin (Brand name: Zocor) cannot be used with Incivek. Lovastatin (Brand name: Mevacor) cannot be used either. All statin drugs are likely to be dangerous when combined with Incivek.
Ergot derivatives such as dihydroergoamine, ergonovine, ergotamine and methylergonovine cannot be taken with Incivek.
Rifampin must be avoided as well as Pimozide (Brand name: Orap).
Incivek potentiates sildenafil (Brand name: Viagra or Revatio). It will increase the risk of side effects of similar medications such as Levitra or Cialis.
Sedatives like alprazolam (Brand name Xanax) are increased by Incivek causing respiratory depression and increased sedation.
Alfuzosin (Brand name: UroXatral) cannot be used with Incivek. Cisapride (Brand name: Propulsid) must not be used with Incivek.
St. John’s wort must be avoided if you are taking Incivek.
Incivek interacts with many other drugs including methadone, hormonal birth control products, BP medicines like amlodipine (Brand name: Novasc). There are extensive interactions with medications used for HIV.
Depo Provera, oral birth control pills and NuvaRing do not work correctly with Incivek and pregnancy can occur. Patients on Incivek must use barrier methods of birth control like condoms and copper IUDs.
It is essential to take all of the medications on time, especially the telaprevir and Pegasys. If doses are skipped the treatment will fail. Set your alarm for 7AM, 3PM and 11PM and carry the alarm with you so you do not forget to take your medicine. If you skip doses your chance of success will fall significantly.
Flu like symptoms are common with Pegasys. Fever, chills, and body aches start four hours after the injection and last for 24-48 hours. Irritability, insomnia, loss of appetite and depression may occur. Bacterial infections are harder to treat in patients taking Pegasys. If you are coughing up yellow or green material or have other signs of infection you must start antibiotics immediately. Autoimmune diseases such as thyroid disease can be triggered or worsened by Pegasys.
Ribavirin causes birth defects. Females must avoid pregnancy during treatment and for 6 months after completion of treatment. Males must avoid getting a woman pregnant during treatment and for 6 months after completion of treatment.
Incivek causes anemia and rash in some patients. The rash can usually be treated with antihistamines like Benadryl, Claritin or Atarax. Creams like 1% hydrocortisone cream may help and some patients will have to stop Incivek if the rash is severe.
Patients who permanently eradicate their HCV with triple therapy will reduce their risk of liver failure, liver cancer and premature death from liver disease.
Source
Nov 2011
Hepatitis C -Direct-acting antivirals (DAAs) Telaprevir and Boceprevir
Telaprevir and boceprevir are new medications that can be added to a peg-interferon/ribavirin regimen for people with genotype 1 hepatitis C mono-infection. This is called “triple therapy”—since it is a combination of three medications: peg-interferon, ribavirin and either telaprevir or boceprevir. Telaprevir and boceprevir are not prescribed on their own (without peg-interferon and ribavirin) and they are not prescribed together.
Ontario first province to reimburse new chronic hepatitis C treatment VICTRELIS™ Now Available for Eligible Patients in Ontario
MONTREAL, - Ontarians living with chronic hepatitis C now have publicly funded access to a new treatment option, as Ontario becomes the first province to reimburse VICTRELIS™ (boceprevir). The treatment qualified for a pre-approval rapid review under the Ontario Drug Benefit Act (ODBA), as it successfully met a pre-determined set of criteria, including offering substantial improvements of significant outcomes for the treatment of a serious disease.
Boceprevir is a first-in-class oral hepatitis C virus (HCV) protease inhibitor for the treatment of chronic hepatitis C genotype 1 infection. It is to be used in combination with peginterferon alpha and ribavirin (peg/riba) in adult patients (18 years and older) with compensated liver disease, including cirrhosis, who are previously untreated or who have failed previous therapy.2 When added to peg/riba, boceprevir can significantly increase a patient’s chance of clearing the virus from the body.3,4 The treatment was authorized for use in Canada in July of this year.
“The Canadian Liver Foundation is pleased that Ontario’s public drug program has agreed to reimburse boceprevir for the treatment of chronic hepatitis C,” says Dr. Morris Sherman, Chairman of the Canadian Liver Foundation. “Boceprevir represents a major advance in our ability to cure this disease, and as a result, fewer patients will have to struggle with the consequences of end-stage liver disease, liver transplants and liver cancer. We applaud the research efforts that led to this breakthrough and hope other provinces will follow Ontario’s lead and rapidly reimburse this important treatment.”
Eligibility criteria for boceprevir can be accessed through the following link:
http://www.health.gov.on.ca/english/providers/program
Nov 20
Treatment Update
Source- CCO
The Beckoning Future: How Hepatitis C Drugs in Development May Affect Practice Today and Tomorrow
Review the current benefits and limitations with protease inhibitor-based HCV therapies, and the emerging data on potential future regimens and the advances they represent.
The New Elements of HCV Care: Practical Skills to Optimize Protease Inhibitor–Based Therapy
Review the approved indications and proper management of HCV-infected patients with the newly approved protease inhibitors.
* Free Registration Required
Oct 15
Hey Doc, Victrelis-boceprevir or Incivek-telaprevir?
Oct 10 2011
Janssen’s new hepatitis C treatment Incivo has been launched in the UK, one of two new drugs set to advance treatment
.Incivo (telaprevir) is a new direct acting antiviral protease inhibitor (PI), for genotype-1 chronic hepatitis C, and can help clear the virus from many more patients when added to standard treatment, peginterferon alfa and ribavirin.Trials show that adding Incivo clears the virus in almost twice as many previously untreated patients (79% vs. 46%) and almost four times as many who had previously relapsed following treatment (84% vs. 22%). The drug also halved the current total treatment duration to six months in many (58%) previously untreated patients in trials.
Treatment of chronic hepatitis C: The new standard of care for the future
Treatment results for hepatitis C genotype 1 disease with PegIFN and ribavirin are suboptimal. In the last several decades, significant research has allowed many patients, about 50% with genotype 1 and about 80% with genotype 2 or genotype 3, to be virologically cured by attaining SVR.6 The remaining nonresponders to the standard-of-care regimen are left with no other treatment option to cure their infection. If treatment is considered, it is recommended that a hepatitis C genotype be secured prior to initiating therapy. With continued efforts to gain more knowledge of the HCV life cycle and its viral structure, the first generation of drugs known as specifically targeted antiviral therapy for hepatitis C (STAT-C) or direct-acting antivirals (DAAs) have emerged to improve SVR cure rates and reduce the treatment duration of therapy. FDA-approved DAA drugs for HCV genotype 1 disease are the protease inhibitors boceprevir and telaprevir.
Oct 2 2011 - Help, How Do I Take Incivek ?
Sept
2011 practice guideline by the American Association for the Study of Liver Diseases
From CCO
Pocket Guide For Using
Telaprevir and Boceprevir
Telaprevir-Incivek/Boceprevir-Victrelis-Paying For Hepatitis C Treatment
Telaprevir is currently priced at USD 49,200 for 12 weeks of therapy, while boceprevir is priced at USD 1,100 per week, for a total treatment cost of anywhere between USD 26,400 to USD 48,400 depending on individual patient response to therapy
AJN, American Journal of Nursing: September 2011 - Volume 111 - Issue 9 - p 22 doi: 10.1097/01.NAJ.0000405053.00454.26 Drug Watch
Two New Drugs for Chronic Hepatitis C
Aschenbrenner, Diane S. MS, RN
Free Access
Author Information Diane S. Aschenbrenner is the course coordinator for undergraduate pharmacology at Johns Hopkins University School of Nursing in Baltimore, MD. She also coordinates Drug Watch: dianea@son.jhmi.edu.
Abstract *
Two new protease inhibitors that specifically target the hepatitis C virus have recently been approved: telaprevir (Incivek) and boceprevir (Victrelis). Both drugs are added to standard chronic hepatitis C treatment to improve the therapeutic response; they're not used as monotherapy.
* Food containing 20 g of fat must be eaten 30 minutes before taking telaprevir.
* Boceprevir can be taken just before, during, or just after a meal, with no dietary restrictions.
For years the standard of care in patients with chronic hepatitis C has been 48 weeks of treatment with peginterferon alfa and ribavirin, although fewer than 50% of patients using this therapy are cured of the condition. Two new direct-acting antiviral drugs have recently been approved to treat this chronic illness: telaprevir (Incivek) and boceprevir (Victrelis). Both drugs are protease inhibitors specific for the hepatitis C virus, and neither of the new drugs produces cross-reactivity or cross-resistance with any of the protease inhibitors used to treat HIV.
Telaprevir is added to standard therapy in patients with hepatitis C who've not previously received interferon-based therapy or who've had a poor response to previous treatment.
The Food and Drug Administration (FDA) reported in May that in the various clinical trials to determine the safety and efficacy of telaprevir, a sustained virologic response was achieved 20% to 45% more often in patients taking telaprevir than in patients receiving only standard therapy. This was true across all of the studies and patient groups. Treatment with telaprevir shortens the recommended duration of therapy from 48 weeks to 24 weeks.
Telaprevir must be taken concurrently with peginterferon alfa and ribavirin. In studies its most common adverse effects were rash; fatigue; pruritus (all occurring in approximately 50% of patients); anemia; gastrointestinal symptoms (nausea, diarrhea, vomiting, and altered taste); and anorectal symptoms such as hemorrhoids, discomfort, and pruritus. Nurses who work with patients prescribed telaprevir need to provide specific patient education related to the duration of therapy. Telaprevir is taken orally three times a day, with seven to nine hours between doses, and should be taken with food that contains 20 g of fat (to promote absorption of the drug). The food should be eaten no more than 30 minutes before each dose of telaprevir. Examples of foods that contain 20 g of fat are a bagel with cream cheese, nuts (1/2 C), peanut butter (3 T), ice cream (1 C), American or cheddar cheese (2 oz.), potato chips (2 oz.), and trail mix (1/2 C). If a missed dose is discovered within four hours of the time the drug is normally taken, the dose may be made up then.
In studies of boceprevir used in combination with peginterferon alfa and ribavarin, it too significantly increased the rates of sustained virologic response. Adverse effects are similar to those of telaprevir. A major difference between these two direct-acting antivirals, however, is how the drugs react with food. Although food does increase the bioavailability of boceprevir, the amount of fat in the food doesn't affect the drug's absorption, nor is the timing of the food as important: boceprevir may be taken just before, during, or immediately after a meal. Both men and women who are capable of reproducing should be instructed to use two forms of birth control while taking either drug and for six months after stopping it.
For more information on telaprevir and boceprevir, see the FDA's complete prescribing information: http://1.usa.gov/iZRoW7 and http://1.usa.gov/jUQ9ov.
Aug 19
Update; Check out two new videos;
Patient Video; New HCV New Drugs and Resistance
Telaprevir Alone or With Peginterferon and Ribavirin Reduces HCV RNA in Patients With Chronic Genotype 2 But Not Genotype 3 Infections
Aug 17
Use of New HCV Protease Inhibitors ‘Not That Simple’
“These therapies are game changers in terms of how they work and the improvements in response rates,” said Dr. Jensen. “There are also a lot of differences that, as gastroenterologists, we are not used to dealing with.”
Incivek/Victrelis; New approvals may change treatment for hepatitis C
The recent approvals of the new medications for hepatitis C are expected to revolutionize treatment.
Boasting sustained viral response rates of up to 75% in treatment-naive patients, telaprevir (Incivek, Vertex Pharmaceuticals) and boceprevir (Victrelis, Merck) are being heralded within the infectious disease community, but many clinicians are urging judicious use.
The FDA approved telaprevir in May, based on results of trials that looked at the use of telaprevir 750 mg assigned three times daily for 12 weeks combined with peginterferon and ribavirin. This medication increased sustained virological response rates by 20% to 40% across a broad range of disease and demographic characteristics.
Aug 8
Hepatitis C-New Protease Inhibitor (NS3/4A) Drug Resistance Test
LabCorp and Monogram Biosciences are pleased to announce the launch of HCV GenoSure NS3/4A, a protease inhibitor drug resistance assay for the clinical management of patients with hepatitis c.
HCV GenoSure NS3/4A provides a comprehensive sequence-based analysis of a patients hepatitis C virus to assess drug resistance (or susceptibility) to the NS3/4A protease inhibitors, boceprevir, and telaprevir. It also includes a detailed understanding of the viral population for the entire region of non-structural proteins NS3 and NS4A for hepatitis C virus genotype 1a or 1b.
View Complete PDF At NATAP
New Protease Inhibitor (NS3/4A) Drug Resistance Test -
Boceprevir-Victrelis-Telaprevir "INCIVEK" Which pegylated interferon ?
In HCV treatment failures, SVR was 64% with boceprevir vs. 21%
with placebo, combined with standard therapy, Dr. Steven Flamm said.
"This study clearly establishes that boceprevir seems to have equivalent response with peginterferon 2a as was reported with peginterferon 2b. We await similar data for telaprevir with the peginterferon 2b product, as the registration trials were all done with peginterferon 2a."
peginterferon 2a = PEGASYS
peginterferon 2b = Peg-Intron
Telaprevir/INCIVEK
FDA approves Telaprevir / INCIVEK For The Treatment Of Hepatitis C
Telaprevir/Incivek Prescribing Information
Medication Guide
Boceprevir/Vicrelis
Vicrelis/Boceprevir IS NOW FDA Approved May 13 2011
VICTRELIS™- Boceprevir: Prescribing Information and Medication Guide
Patient Assistance Programs
INCIVEK/Telaprevir and VICTRELIS (Boceprevir) Patient Assistance Program
More Than Two-Thirds of Surveyed U.S. Clinicians Plan to Prescribe Incivek and Victrelis to Patients with Treatment-Naive Hepatitis C Virus Genotype 1
Boceprevir vs. Telaprevir: What We Know and Don't Know;
New Treatments for Chronic Hepatitis C Infection
June 5 2011
The newly approved HCV protease inhibitors boceprevir and telaprevir promise to revolutionize HCV treatment.
Hepatitis C virus (HCV) treatment will change dramatically with the FDA's recent approval of two new oral HCV protease inhibitors, boceprevir and telaprevir. When used in combination with current standard therapy (peginterferon and ribavirin [PR]), these new drugs substantially improve cure rates and often reduce the overall duration of therapy. Although data are still emerging, these new drugs are likely to benefit HIV-coinfected patients as well.
Boceprevir
Boceprevir (Victrelis) was approved by the FDA on May 13, 2011, for the treatment of chronic HCV genotype 1 infection both in patients who are treatment-naive and in those with prior treatment failure.1 The approval was based on two large, manufacturer-sponsored, phase III, randomized, controlled trials.
CLINICAL TRIALS
Treatment-Naive Patients
In the SPRINT-2 trial,2 1097 treatment-naive patients with HCV genotype 1 infection (159 blacks; 938 nonblacks) underwent a 4-week lead-in period of PR and then received one of the following:
Among nonblacks, sustained virologic response (SVR) rates were significantly higher in the boceprevir groups (67%–68%) than in the control group (40%). Blacks had lower SVR rates in all three groups, but B+PR still outperformed PR in this population; SVR rates were 42% in the RGT group, 53% in the fixed-duration group, and 23% among controls. Overall, 44% of patients in the RGT group had undetectable HCV RNA from week 8 to week 24 and therefore received shorter-duration therapy (28 weeks total).
Previously Treated Patients
The RESPOND-2 trial3 involved 403 patients with HCV genotype 1 infection who had a partial response to — or a relapse following — prior PR therapy. Of note, so-called prior null-responders (patients who had not previously achieved a 2 log IU/mL drop in HCV RNA by week 12) were not included in this trial. Patients received 4 weeks of lead-in therapy with PR (which, in this trial, consisted of peginterferon α-2b and ribavirin). Treatment arms were the same as in SPRINT-2, except that here, the RGT arm involved B+PR for 32 weeks beyond lead-in, with an additional 12 weeks of PR alone if HCV RNA was detectable at week 8. SVR rates were significantly higher in the boceprevir groups (59% in the RGT group; 66% in the fixed-duration group) than in the control group (21%).
DOSING
Boceprevir should be prescribed only in combination with PR and should be taken at a dose of 800 mg (four 200-mg capsules) three times daily with food. PR should be administered alone for a 4-week lead-in period. Response-guided therapy is recommended for patients without cirrhosis who are treatment-naive or who have had partial response to, or relapse following, prior interferon/ribavirin therapy. Guidelines for treatment duration in such patients, as recommended in the package insert,1 are shown in Table 1.
Because patients with compensated cirrhosis have relatively poor results with therapy, the recommended boceprevir-based treatment for this population is 4 weeks of PR followed by 44 weeks of B+PR. In addition, 44 weeks of B+PR should be considered for previously untreated patients who have a poor response to lead-in PR, defined as a <1 log IU/mL reduction in HCV RNA at week 4. Although the efficacy of boceprevir in prior null-responders has not been studied, if treatment is considered for such an individual, 4 weeks of PR followed by 44 weeks of B+PR should be given.
B+PR treatment should be stopped based on futility in any patient with an HCV RNA level 100 IU/mL at treatment week 12 or confirmed detectable HCV RNA at treatment week 24.
DRUG INTERACTIONS
Boceprevir is a strong inhibitor of CYP3A4/5 and should not be administered with drugs that are highly affected by this pathway, such as alfuzosin, rifampin, simvastatin, carbamazepine, phenytoin, and oral midazolam.
ADVERSE EVENTS
In phase II and III clinical trials,1 49% of patients in the boceprevir groups had hemoglobin values <10 g/dL, compared with 28% of those in the control groups. Use of erythropoiesis-stimulating agents to treat anemia was more frequent in the boceprevir groups (43%) than in the control groups (24%). However, the rate of study-drug discontinuation because of anemia was low (1%). Decreased neutrophil and platelet counts were more common in the boceprevir groups, as was dysgeusia (35%–44% in boceprevir groups vs. 11%–16% in control groups).
Telaprevir
Telaprevir (Incivek) was approved by the FDA on May 23, 2011, based on data from manufacturer-sponsored trials in treatment-naive and treatment-experienced patients chronically infected with HCV genotype 1.4 In these trials, PR consisted of peginterferon α-2a and ribavirin.
CLINICAL TRIALS
Treatment-Naive Patients
In the phase III ADVANCE trial,5 1088 treatment-naive patients were randomized to one of three treatments (none of which involved a lead-in period):
In the phase III ILLUMINATE study,7 researchers examined two treatment durations among patients who had achieved eRVR with a 12-week course of T+PR, followed by PR alone. In all, 322 patients were randomized at week 20 to receive a total of 24 or 48 weeks of therapy. SVR rates were 92% and 88%, respectively, demonstrating noninferiority of the 24-week regimen in this patient group.
Previously Treated Patients
In the phase III REALIZE trial,8 662 patients with prior PR treatment failure (i.e., relapse, partial response, or null response) were randomized to 48 weeks of therapy with one of the following approaches:
DOSING
Telaprevir should be prescribed only in combination with PR and should be taken at a dose of 750 mg (two 375-mg tablets) three times daily with food. It should be administered for 12 weeks in all patients, followed by PR alone for an additional 12 or 36 weeks, depending on viral response and prior response status. Guidelines for treatment duration, as recommended in the package insert,4 are shown in Table 2.
Prior partial-responders should receive T+PR for the first 12 weeks, followed by an additional 36 weeks of PR alone. Treatment-naive patients with cirrhosis who have undetectable HCV RNA at weeks 4 and 12 may also benefit from an additional 36 weeks of PR. If therapy is considered for prior null-responders, T+PR for 12 weeks followed by an additional 36 weeks of PR should be given.
Therapy should be stopped in any patient with an HCV RNA level 1000 IU/mL at treatment week 4 or week 12 or confirmed detectable HCV RNA at treatment week 24.
DRUG INTERACTIONS
Telaprevir inhibits CYP3A and should not be administered with drugs that are highly affected by this pathway, including alfuzosin, rifampin, HMG CoA reductase inhibitors (atorvastatin, lovastatin, simvastatin), and oral midazolam.
ADVERSE EVENTS
The main adverse effects of telaprevir are rash, anemia, nausea and other gastrointestinal symptoms, dysgeusia, and anorectal discomfort. In clinical trials, rash developed in 56% of patients who received T+PR, compared with 34% who received PR alone. Severe rash was reported in 4% of those receiving T+PR, versus <1% of those who received PR alone.4 Patients with mild to moderate rashes may continue therapy with careful monitoring. Telaprevir should be stopped if a rash progresses and becomes severe, or if systemic symptoms develop.
PR treatment is associated with decreased hemoglobin concentrations, and the addition of telaprevir is associated with an additional decrease. In clinical trials, 36% of patients who received T+PR had hemoglobin values <10 g/dL, compared with 17% of those who received PR alone.4 (Use of growth factors — allowed in the boceprevir studies — was not permitted in the telaprevir trials.9) However, the rate of telaprevir discontinuation because of anemia was low: Among patients receiving T+PR, 4% stopped telaprevir, and 1% discontinued T+PR.
Boceprevir vs. Telaprevir: What We Know and Don't Know
Not surprisingly, emergence of drug-resistance mutations has been observed in patients who have received these agents. Drug resistance may become undetectable after HCV protease inhibitors are stopped, but we do not yet know whether these resistant variants would reemerge if therapy were restarted.
Improving HCV Therapy for HIV-Coinfected Patients
HCV treatment in HIV-coinfected individuals has traditionally been challenging, given their low rates of SVR. However, emerging data from a recent phase II, randomized trial demonstrate that telaprevir may improve virologic responses in HIV-infected patients with genotype 1 HCV infection.11 In that study, 60 patients were treated with PR plus telaprevir or placebo for 12 weeks, followed by PR alone to complete 48 weeks of therapy. In an interim analysis involving 59 patients, 70% of those in the telaprevir group had undetectable HCV RNA at week 4, compared with 0% in the control group. At week 12, the numbers were 68% versus 14%. Table 3 shows results stratified by receipt of antiretroviral therapy (ART); notably, only those receiving tenofovir/FTC/efavirenz or tenofovir/FTC + ritonavir-boosted atazanavir were eligible for the portion of the study examining responses in ART-treated patients. Currently, neither telaprevir nor boceprevir is approved for treating chronic HCV infection in HIV-positive patients. Although these findings suggest that telaprevir may be beneficial, longer-term results are still pending.
Little is known about drug interactions between HCV protease inhibitors and ART. Use of efavirenz reduces telaprevir levels; as a result, in the ongoing phase II study summarized above, the dose of telaprevir was increased to 1125 mg every 8 hours in the efavirenz group. In healthy-volunteer studies, ritonavir-boosted atazanavir had less effect on telaprevir exposure than did other HIV protease inhibitors.12 Coadministration of efavirenz reduces trough concentrations of boceprevir, but the clinical implications are not clear.13 Interactions between boceprevir and commonly used HIV protease inhibitors have not yet been reported.
Conclusions and Future Challenges
Use of boceprevir or telaprevir together with PR will revolutionize HCV treatment, leading to improved outcomes and a shorter duration of treatment for many patients. As we take stock of this breathtaking advance, we should also pause to consider some unanswered questions:
Finally, boceprevir and telaprevir are administered with peginterferon/ribavirin, and patients who cannot tolerate these medications will not benefit from the newly approved drugs yet. Fortunately, many new anti-HCV drugs — including polymerase and NS5A inhibitors — are being investigated in clinical trials. Hopefully, they will eliminate interferon from our HCV toolbox in the future.
— Isaac I. Bogoch, MD, and Rajesh T. Gandhi, MD
Dr. Bogoch is a Fellow in the Division of Infectious Diseases at Massachusetts General Hospital in Boston. He reports no conflicts of interest.
Published in Journal Watch HIV/AIDS Clinical Care May 27, 2011
Citation(s): 1. Victrelis (boceprevir) capsules [prescribing information]. Whitehouse Station, NJ: Merck; 2011. (http://www.merck.com/product/usa/pi_circulars/v/victrelis/victrelis_pi.pdf)
2. Poordad F et al. for the SPRINT-2 investigators. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med 2011 Mar 31; 364:1195.
5. Jacobson IM et al. Telaprevir in combination with peginterferon and ribavirin in genotype 1 HCV treatment-naïve patients: Final results of phase 3 ADVANCE study. Hepatology 2010 Oct; 52(S1):427A.
6. Hofmann WP and Zeuzem S. A new standard of care for the treatment of chronic HCV infection. Nat Rev Gastroenterol Hepatol 2011 May; 8:257.
8. 65% of people whose prior treatment for hepatitis C was unsuccessful achieved SVR (viral cure) with telaprevir-based therapy in phase 3 REALIZE study [press release]. Cambridge, MA. Vertex; Sep 7 , 2010. (http://investors.vrtx.com/releasedetail.cfm?ReleaseID=505239)
9. Pawlotsky J-M. The results of phase III clinical trials with telaprevir and boceprevir presented at the Liver Meeting 2010: A new standard of care for hepatitis C virus genotype 1 infection, but with issues still pending. Gastroenterol 2011 Mar; 140:746.
12. van Heeswijk R et al. Pharmacokinetic interactions between ARV agents and the investigational HCV protease inhibitor TVR in healthy volunteers. 18th Conference on Retroviruses and Opportunistic Infections (CROI), Boston , Feb/Mar 2011. Abstract 119. (http://www.retroconference.org/2011/Abstracts/41437.htm)
13. Kasserra C et al. Clinical pharmacology of BOC: Metabolism, excretion, and drug-drug interactions. 18th Conference on Retroviruses and Opportunistic Infections (CROI), Boston , Feb/Mar 2011. Abstract 118. (http://www.retroconference.org/2011/Abstracts/41140.htm)
Getting Ready; Telaprevir or Boceprevir ?
You know folks, as I begin writing this (and I have no talent for writing by the way) I can't help but wonder if hepatitis C patients who are preparing to treat are ready to choose between the two new drugs; Telaprevir "INCIVEK" or Boceprevir "VICTRELIS". More importantly I wonder if patients understand the dire need for an experienced physician to be on board for this complicated three drug regimen of difficult to tolerate drugs (maybe more including rescue drugs) which willinvolve treating for 24 to 48 weeks. . I ask you, are you ready ? Do you have an experienced physician ? Have you moved your family out of the house and into the garage in order not to hurt them, kidding. You, the patient will decide which drug to use, a difficult decision no doubt. Both drugs are so close in comparison, with each drug closely being scrutinized, your decision will be determined by the efficacy and safety provided by the recent clinical data. Although, the final decision for some patients may hinder on either enrolling in clinical trial (when available) or taking advantage of the drug companies patient assistance programs(when in place).
Yes, boceprevir is here,(FDA Approved) and the temptation to begin treatment is upon us, with telaprevir only a whisper away you may be asking yourself what to do, which drug to use, or wishing someone would make a decision for you. Nope, that's up to you and only you. Coupled with the assistance from your physician, and your own particular scenario, you will ultimately make the final decision. That's how the medical world works today, the same is true for all medical care from cancer treatments to knee surgery, its up to you folks, so lets get started.
What we know to date is that clinical data has suggested that telaprevir is significantly more effective in comparison to boceprevir. If we look at patients who were not previously treated, we know that telaprevir achieved a sustained virologic response of 79 percent when used along with standard treatment. Boceprevir also used in combination with standard therapy has a 63 percent sustained virologic response in naïve patients. As for duration of treatment, in telaprevir 58% of naïve patients can shorten treatment to 24 weeks, compared to 28 weeks in 44% of boceprevir patients.
If we check out the stats in patients that have treated previously the SVR for telaprevir is 65% and boceprevir is 66%. As mentioned on the blog boceprevir did not include null responders in their trial. Vertex’s phase III REALIZE trial did test telaprevir in null responders, which produced a 31% SVR rate.
.
Author Courtney McQueen from The AIDS Beacon writes; Although the rates for telaprevir appear higher than those for boceprevir, it is not clear whether telaprevir is actually more effective.
Patients who received the standard treatment of just ribavirin plus Pegasys in the telaprevir trials had a higher cure rate than patients in the boceprevir trials who received just ribavirin plus PegIntron. As a result, it is possible that the differences in cure rates between the trials are actually due to Pegasys versus PegIntron, or other differences between the studies. Some studies have found that Pegasys is more effective than PegIntron.
Trials in which telaprevir and boceprevir are compared directly will be necessary before determining whether one drug is more effective than the other.
The concern in relation to side effects or safety in telaprevir is the significance of the rash, which was reported in 56% of patients using telaprevir. We can compare that to 32% of patients reporting a rash receiving standard of care. The rash was found to be mild to moderate although severe in 1% of patients and resulted in stopping treatment for 6% of patients. You must be aware of the symptoms of the rash, which will add to the stress often experienced with treating HCV. The drug ribavirin also causes a rash, what seasoned patients refer to as the "Riba Rash", hated it. . Physicians will be on alert folks, but you must also be persistent and diligent in reporting it to your treatment nurse and doctor.
. Anemia was seen more often in patients receiving telaprevir then those treating only with standard therapy. (36% telaprevir vs.15% standard of care patients) and sometimes more severe. In 3% of patients telaprevir was discontinued because of anemia.(remember that 3%)
. In boceprevir anemia was seen in about 50 % of patients compared to 30% receiving standard therapy. This is important, in the telaprevir trials patients were not allowed rescue drugs, in that they were not allowed to treat the anemia with erythropoietin (EPO)-a drug that stimulates the production of red blood cells. In comparison the boceprevir trials did allow rescue drugs and (EPO) was used, or patients were able to lower their dose of ribavirin . This raises the question of how severe the anemia could have been in the boceprevir clinical trials. So in retrospect those 3% of patients who had to discontinue telaprevir because of anemia were real numbers. This is the second time boceprevirs stats have not been clear, the same applies to those SVR numbers in previously treated patients, as mentioned null responders were not included in boceprevir trials.
. The protocol for treating with boceprevir can be viewed here and here.
*After FDA approval of telaprevir this blog will post the prescribing information.
.The newly FDA approved boceprevir has been projected to cost around $1,100 per week, with telaprevir costing close to the same.(Not including Interferon/ribavirin). According to consumers reports the cost of standard of care is at roughly $600 per week which breaks down to $500 for the Peginterferon and $100 for ribavirin.
Reuters reported yesterday that Merck the maker of Boceprevir made a deal with Roche to promote Victrelis/boceprevir in the US and research treatments for hepatitis c.
Just In On The Blog
"INCIVEK" Telaprevir
"VICTRELIS" Boceprevir
Updates - Telaprevir And Boceprevir
May 2012
Hepatitis C Therapy Update-Where Are We Now?
April 23
Summary Of The 47th European Association for the Study of the
Liver EASL
Updated
AASLD HCV Guideline Aims To Simplify Use of DAAs
More Data Needed To Fill Gaps
in Understanding
by
Christina Frangou
April 16 2012
The American Association for the Study of Liver Diseases (AASLD) recently published an updated practice guideline on the treatment of chronic infection with hepatitis C virus (HCV) genotype 1 (Ghany MG et al. Hepatology 2011;54:1433-1444).
The guideline, authored by members of the AASLD practice guideline committee, was issued in response to the development of new direct-acting antivirals (DAAs) and the identification of several single nucleotide polymorphisms associated with spontaneous and treatment-induced clearance of HCV infection. The report makes 18 recommendations for clinicians who are considering using the new DAAs to treat patients with HCV. The two
currently approved DAAs have complex prescribing rules, including outlines for response-guided therapy and unusual stopping rules, and many clinicians question how and when the agents are best used.
“We have entered into a very different treatment paradigm. I’d suggest that everyone read the guideline from
the AASLD. It’s a very good overview of where we are today,” said David R. Nelson, MD, a study author and professor of medicine, Division of Gastroenterology, Hepatology and Nutrition at the University of Florida College
of Medicine, in Jacksonville, during a presentation at The Liver Meeting last year.
The authors outline the current state of evidence regarding treatment with boceprevir and telaprevir, and provide some guidance on much-debated issues such as treatment of patients with cirrhosis and the role of interleukin-28B (IL28B) testing.
The guidelines are “very important and very helpful,” said Michal R. Charlton, MD, professor of medicine
and head of the hepatobiliary section at Mayo Clinic, in Rochester, Minn. “The guidelines provide a lens through which clinicians can look to see the optimal approach to managing patients with HCV infection.”
Inside the
Recommendations
According to the authors of the report, the DAAs, in combination with peginterferon alfa and ribavirin, are now the “optimal therapy” for treating HCV genotype 1 chronic infection. Both therapies must be given with
peginterferon and ribavirin, which limits selection of resistant variants and improves antiviral response. Furthermore, boceprevir and telaprevir should not be used to treat patients infected with HCV genotype 2 or 3.
The authors
reiterated the FDA recommendation that treatment-naive patients with cirrhosis treated with either boceprevir or telaprevir in combination with interferon and ribavirin should receive therapy for 48 weeks instead of on a response-guided basis. However, the authors added that this recommendation is “based on limited data and requires further study.”
The report also specifies that the stopping rules differ for telaprevir and boceprevir in treatment-naive patients.
Treatment with telaprevir, peginterferon alfa and ribavirin should be stopped if the HCV RNA level is greater than 1,000 IU/mL at treatment weeks 4 or 12 and/or detectable at treatment week 24. Treatment with boceprevir, peginterferon and ribavirin should be stopped if the HCV RNA level is greater than 100 IU/mL at treatment week 12 or detectable at treatment week 24. For both therapies, the evidence for the discontinuation rules is considered Class 2a, meaning the weight of evidence is in favor of the usefulness of this rule, but there is limited evidence.
Patients who previously received and failed therapy with interferon and ribavirin remain a conundrum with regard to starting DAA therapy. Studies have shown that patients’ response to triple therapy regimens in both boceprevir and telaprevir trials was strongly influenced by the outcome of their earlier treatment with peginterferon and ribavirin. The decision to re-treat patients should depend on their previous response to peginterferon and ribavirin and on reasons why they may have failed, such as inadequate drug dosing or side-effect management, the report said. The authors call on physicians to review old treatment records to document previous treatment response.
This updated document is the first to clarify treatment for patients who fail DAA therapy. The authors say that patients who do not have a virologic response, who experience virologic breakthrough or who relapse on one
protease inhibitor (PI) should not be retreated with the other PI.
Although the evidence is limited, the AASLD did make some recommendations for managing treatment-experienced patients. The AASLD suggests retreatment with boceprevir or telaprevir, together with peginterferon alfa and
weight-based ribavirin, “be considered” for patients who had a virologic relapse or who were partial responders after a previous course of treatment with standard interferon alfa or peginterferon alfa and/or ribavirin.
“Relapsers and partial responder patients can expect relatively high sustained virologic response rates to retreatment with a PI-containing triple regimen and should be considered candidates for retreatment,” the authors wrote.
For previously null responders, telaprevir may be considered but boceprevir cannot be recommended, the committee
found. This finding differs from the FDA label, which indicates that boceprevir can be used in null responders. Null responders were excluded from Phase III trials of boceprevir (Poordad F et al. N Engl J Med 2011;364:1195-1206).
“Given the lack of definitive information for Phase III data, caution is advised in the use of [boceprevir] in null
responders until further supportive evidence becomes available,” according to the AASLD.
Additionally, the decision to re-treat a null responder with telaprevir should be individualized, particularly in patients with cirrhosis, because less than one-third of null responder patients in the telaprevir trial achieved a sustained virologic response (SVR). Moreover, the authors caution that a majority of null responders developed resistance to DAAs.
“Any potential benefit from treating nonresponders must be weighed against the risk for development of antiviral resistance and for serious side effects, and the high cost of therapy,” the report said.The AASLD acknowledged uncertainty about the benefit of the lead-in strategy required for treatment with boceprevir. Theoretically, the lead-in may improve efficacy by lowering HCV RNA levels, thus reducing the rate of viral breakthrough when the PI is introduced. The authors noted, however, that poor responders during the lead-in period can still achieve SVR.
“Thus, a poor response during the lead-in phase should not be used to deny patients access to PI therapy,” the authors said. Patients who develop anemia on PI therapy should be managed by reducing the ribavirin
dose, they added.
The report also specified that IL28B genotype is a significant treatment predictor of response to therapy, but data are
insufficient to determine whether IL28B testing can be used to recommend either interferon and ribavirin alone or a triple therapy with a PI.
“Consideration should be given to ordering the test when it is likely to influence either the physician’s or patient’s decision to initiate therapy,” the authors said.
Telaprevir and boceprevir are not recommended for use in children and adolescents younger than 18 years because safety and efficacy has not been established in this group.
Additionally, the guidelines do not address several important questions about DAAs, Dr. Charlton said. The
report, for example, does not provide detailed and practical information about drug–drug interactions, managing HIV/HCV co-infection and managing side effects, he said.
“Perhaps the highest-impact omission, which was unavoidable, is whether in light of the spectacular report of efficacy and tolerability of PSI-7977 in combination with ribavirin without interferon, patients with early
stages of liver disease should be treated at all with boceprevir or telaprevir,” he said. “In our practice, we are already beginning to advise many patients to wait. … A strong case could be made for waiting for the results of the Phase III
interferon-free studies.”
The committee cautions that the guidelines are “based on data that are presently limited” and the recommendations may need revision as additional data become available.
“There is a paucity of information for many of the subgroups with the greatest unmet need for treatment
(e.g., patients co-infected with HIV and HCV, with decompensated cirrhosis and after liver transplantation),” the committee said.
Source
Dr. Nelson
receives research support from Bayer/Onyx, Bristol-Myers Squibb,
Genentech/Roche, Gilead, Merck, Pharmasset, Tibotec and Vertex Pharmaceuticals;
he serves on the advisory boards of Bayer/Onyx, Genentech/Roche, Gilead, Merck,
Pharmasset and Tibotec; and he is a consultant for Vertex Pharmaceuticals. Dr.
Charlton receives research support from Bristol-Myers Squibb, Genentech/Roche,
Merck and Vertex Pharmaceuticals; he is a consultant for Bristol-Myers Squibb,
Genentech/Roche Gilead, Merck and Vertex Pharmaceuticals.
VA-Taking Your Hepatitis C Triple Therapy 1-page handouts
One-page printable handouts for providers to give to patients
who are taking one of the new hepatitis C drugs--boceprevir or telaprevir--with
tips on how and when to take the medications, and what to do if you miss a dose.
Boceprevir handout
Telaprevir handout
VA National Hepatitis C Resource Centers
March 2012
View List-FDA Alert-Statins and HIV or Hepatitis C Drugs
Protease inhibitors and statins taken together may raise the blood levels of statins and increase the risk of myopathy, kidney damage, and kidney failure, which can be fatal.
View the list of HIV or HCV Drugs which interact with statins Here Or Here
UK consensus guidelines for the use of the protease inhibitors boceprevir and telaprevir in genotype 1 chronic hepatitis C infected patients
Source:
Alimentary Pharmacology & Therapeutics
Volume 35, Issue 6, pages 647–662, March 2012
What Is Triple therapy ?
Peginterferon, plus
Ribavirin, plus
Either Boceprevir (Victrelis) or Telaprevir (Incivek)
Triple therapy is currently only recommended for patients infected with HCV genotype 1.
Will I respond to this treatment?
The best candidates for treatment are:
Patients who have not had any prior treatment for HCV (Naïve)
Patients who were HCV RNA negative on a prior course of peginterferon/ribavirin but then
relapsed after peginterferon/ribavirin was discontinued (Relapse)
Patients who had at least 100-fold decrease in HCV RNA after 12 weeks of a prior
course of peginterferon/ribavirin (Partial Responder)
Patients who are less likely to respond to triple therapy:
Patients who did not have at least a 10-fold decrease after 4 weeks or 100-fold decrease
after 12 weeks of a prior course of peginterferon/ribavirin (Null Responder)
Patients with Cirrhosis
African Americans (compared to other racial groups)
What are my chances for cure of my hepatitis C if I take triple therapy?
1. Naïve 75%
2. Relapser 80 to 90%
3. Partial Responder 50 to 60%
4. Null Responder 30%
*Rates of cure are lower in patients with cirrhosis or African American race.
What are prior relapsers, prior partial responders, and prior null responders?
- 1Prior relapsers: These patients had a viral load so low that it could not be measured at the end of their previous treatment. However, their viral load was higher when it was measured 6 months after treatment
- 2Prior partial responders: These patients' viral loads were greatly reduced after 12 weeks of their previous treatment. However, their viral load was high enough to be measured at the end of treatment
- 3Prior null responders: These patients' viral loads did not go down much during their previous treatment for chronic hepatitis C
Resistance
The importance of adherence during triple therapy to prevent resistance is critically important, by following the dosing regimens with the new protease inhibitors resistance is minimized.
A missed or late dose will expose the virus to reduced drug levels, and will promote resistance. The failure to take the protease inhibitors (PIs) with food may also result in less than optimal drug levels. Telaprevir should be dosed with these recommended foods, as for boceprevir the food choice is up to you, although food taken with each dose is still absolutely necessary.
Of Interest
Hepatitis C-New Protease Inhibitor (NS3/4A) Drug Resistance Test
LabCorp has begun offering nationwide its hepatitis C GenoSure NS3/4A assay, which is designed to identify NS3 and NS4A mutations and NS3-associated resistance to a pair of recently approved HCV protease inhibitors.
Side Effects
Boceprevir and telaprevir for hepatitis C: safety management in clinical practice
The addition of direct-acting antiviral agents, telaprevir (TVR) or boceprevir to pegylated interferon (PEG-IFN) and ribavirin (RBV) represents a new era of therapy associated with an improvement in treatment response rates and an impairment of the safety profile compared to PEG-IFN/RBV. An increase in the frequency and severity of anaemia was reported in clinical trials for both drugs, and skin disorders including rash and pruritus occurred more frequently with the TVR-based regimen. These AEs are generally manageable and do not lead to early discontinuation. The management of anaemia has not been clearly established, and the impact of RBV dose reductions and erythropoietin alpha use on treatment efficacy and safety must be clarified. The management of rashes, which were mild and moderate in more than 90% of the cases, is well planned, does not require TVR discontinuation and can be treated using emollients and topical corticosteroids. However, approximately 5% of rashes were severe, and a few cases were classified as severe cutaneous adverse reactions leading to treatment discontinuation. ..... Read more
Dermatological side effects of hepatitis C and its treatment: Patient management in the era of direct-acting antivirals
Dermatological adverse events (AEs) are an existing concern during hepatitis C virus (HCV) infection and peginterferon/ribavirin treatment. HCV infection leads to dermatological and muco-cutaneous manifestations including small-vessel vasculitis as part of the mixed cryoglobulinemic syndrome. Peginterferon/ribavirin treatment is associated with well-characterized dermatological AEs tending towards a uniform entity of dermatitis. New direct-acting antivirals have led to significant improvements in sustained virologic response rates, but several have led to an increase in dermatological AEs versus peginterferon/ribavirin alone. In telaprevir trials, approximately half of treated patients had rash. More than 90% of these events were Grade 1 or 2 (mild/moderate) and in the majority (92%) of cases, progression to a more severe grade did not occur. In a small number of cases (6%), rash led to telaprevir discontinuation, whereupon symptoms commonly resolved. Dermatological AEs with telaprevir-based triple therapy were generally similar to those observed with peginterferon/ribavirin (xerosis, pruritus, and eczema). A few cases were classified as severe cutaneous adverse reaction (SCAR), also referred to as serious skin reactions, a group of rare conditions that are potentially life-threatening. It is therefore important to distinguish between telaprevir-related dermatitis and SCAR. The telaprevir prescribing information does not require telaprevir discontinuation for Grade 1 or 2 (mild/moderate) rash, which can be treated using emollients/moisturizers and topical corticosteroids. For Grade 3 rash, the prescribing information mandates immediate telaprevir discontinuation, with ribavirin interruption (with or without peginterferon) within 7days of stopping telaprevir if there is no improvement, or sooner if it worsens. In case of suspicion or confirmed diagnosis of SCAR, all study medication must be discontinued...Read More...
Drug interactions
Other drugs can interact with telaprevir/boceprevir" these interactions can reduce the PI concentrations which will result in less than desirable drug levels.
Dose reductions
Any dose reductions for toxicity, or treatment interruptions for any reason, are not advised as exposure to less than the full dose will promote the emergence of resistance. If therapy must be stopped because of toxicity, the PI must be stopped completely.
Stopping Rules
The stopping rules for both boceprevir- or telaprevir-based regimens should be strictly adhered to. Developing resistance to these drugs can be minimized as long as stopping rules are adhered.
From CCO
*Free registration is required
For all patients treated with boceprevir, the following futility rules should be employed:
If HCV RNA is ≥ 100 IU/mL at Week 12, all 3 medications should be discontinued.
If the patient has confirmed, detectable HCV RNA at Week 24, all 3 medications should be discontinued.
For all patients treated with telaprevir, the following futility rules should be employed:
If HCV RNA is more then 1000 IU/mL at treatment Week 4 or 12, all 3 medications should be discontinued.
If HCV RNA is detectable at Week 24, pegIFN/RBV should be discontinued.
More information on resistance
In the HCV Advocate July newsletter an article "Resisting Resistance" written by Ms. Lucinda K. Porter, RN., discusses viral resistance and the importance of taking the new protease inhibitors as directed.
Related - Patient video; New hepatitis C Drugs and Resistance
From CCO- Patient management
*Free registration required
The New Elements of HCV Care: Practical Skills to Optimize Protease Inhibitor–Based Therapy
Review the approved indications and proper management of HCV-infected patients with the newly approved protease inhibitors.
CME-Certified Case Vignette:
The New Elements of HCV Care: Practical Skills to Optimize Protease Inhibitor–Based Therapy
Join Graham R. Foster, FRCP, PhD; Paul Y. Kwo, MD; and Fred Poordad, MD, as they discuss optimal management strategies for 8 case scenarios of patients considering or receiving treatment with boceprevir or telaprevir.
Feb 2012
Video
New and experimental oral drugs to treat hepatitis C
Jan 2012
Triple therapy for HCV geno1: telaprevir or boceprevir?
Boceprevir and telaprevir are the first two protease inhibitors available for the treatment of patients infected with hepatitis C virus (HCV) genotype 1. A sustained virological response (SVR) of 70–80% is observed when either of these protease inhibitors is utilized with pegylated interferon (PEG-IFN) and ribavirin (RBV) in treatment naïve patients. Both agents are also highly effective in patients who failed to achieve a SVR during previous treatment with PEG-IFN/RBV. A rapid virological response (RVR) is observed in 56–60% of treatment naïve patients. Patients who achieve a RVR can be treated with a shorter course of therapy (24–28 weeks) and still achieve a SVR rate of 90% or higher. Patients who do not achieve a RVR, those with cirrhosis and certain prior non-responders should be treated for 48 weeks. Although the SVR rates observed with boceprevir and telaprevir are quite similar both globally and within sub-populations, the treatment algorithms for the two agents are unique. The decision of which protease inhibitor to use should assess several factors including the treatment scheme, duration of therapy, adverse event profile, cost and the likelihood of achieving a RVR. The latter is highly dependent upon IFN sensitivity and the IL28B genotype............
Dec 2011 Updates and Information
HCV Handout
Triple Therapy for HCV with Incivek, Pegasys and ribavirin is a major advance.
About 70% of previously untreated genotype one patients succeed with triple therapy. In addition, triple therapy permits the majority of patients to succeed with 24 instead of 48 weeks of treatment. 30-40% of nonresponders to Pegasys plus ribavirin are successful with triple therapy. Incivek is an inhibitor of HCV protease enzyme. The virus needs this enzyme to reproduce. Incivek reduces the viral level by 99.9% in less than one week. Incivek must be given with Pegasys and ribavirin or the virus quickly develops resistance.
Incivek is taken with fatty food such as cheese, peanut butter or meat every eight hours for the first 12 weeks of treatment. Pegasys is injected every week for at least 24 weeks. Ribavirin is taken with food twice daily every day for at least 24 weeks. Blood tests are checked before starting treatment, after 2 weeks and 4 weeks of treatment. Blood tests are then performed every 4 weeks while on treatment. Patients who test undetectable for HCV-RNA after 4 and 12 weeks of treatment have an excellent chance of cure of HCV with 24 weeks of triple therapy.
Incivek interacts with many other medications. Some medicines cannot be used at all and others must be dose adjusted.
Atorvastin (Brand name: Lipitor) cannot be combined with Incivek. Simvastin (Brand name: Zocor) cannot be used with Incivek. Lovastatin (Brand name: Mevacor) cannot be used either. All statin drugs are likely to be dangerous when combined with Incivek.
Ergot derivatives such as dihydroergoamine, ergonovine, ergotamine and methylergonovine cannot be taken with Incivek.
Rifampin must be avoided as well as Pimozide (Brand name: Orap).
Incivek potentiates sildenafil (Brand name: Viagra or Revatio). It will increase the risk of side effects of similar medications such as Levitra or Cialis.
Sedatives like alprazolam (Brand name Xanax) are increased by Incivek causing respiratory depression and increased sedation.
Alfuzosin (Brand name: UroXatral) cannot be used with Incivek. Cisapride (Brand name: Propulsid) must not be used with Incivek.
St. John’s wort must be avoided if you are taking Incivek.
Incivek interacts with many other drugs including methadone, hormonal birth control products, BP medicines like amlodipine (Brand name: Novasc). There are extensive interactions with medications used for HIV.
Depo Provera, oral birth control pills and NuvaRing do not work correctly with Incivek and pregnancy can occur. Patients on Incivek must use barrier methods of birth control like condoms and copper IUDs.
It is essential to take all of the medications on time, especially the telaprevir and Pegasys. If doses are skipped the treatment will fail. Set your alarm for 7AM, 3PM and 11PM and carry the alarm with you so you do not forget to take your medicine. If you skip doses your chance of success will fall significantly.
Flu like symptoms are common with Pegasys. Fever, chills, and body aches start four hours after the injection and last for 24-48 hours. Irritability, insomnia, loss of appetite and depression may occur. Bacterial infections are harder to treat in patients taking Pegasys. If you are coughing up yellow or green material or have other signs of infection you must start antibiotics immediately. Autoimmune diseases such as thyroid disease can be triggered or worsened by Pegasys.
Ribavirin causes birth defects. Females must avoid pregnancy during treatment and for 6 months after completion of treatment. Males must avoid getting a woman pregnant during treatment and for 6 months after completion of treatment.
Incivek causes anemia and rash in some patients. The rash can usually be treated with antihistamines like Benadryl, Claritin or Atarax. Creams like 1% hydrocortisone cream may help and some patients will have to stop Incivek if the rash is severe.
Patients who permanently eradicate their HCV with triple therapy will reduce their risk of liver failure, liver cancer and premature death from liver disease.
Source
Nov 2011
Hepatitis C -Direct-acting antivirals (DAAs) Telaprevir and Boceprevir
Telaprevir and boceprevir are new medications that can be added to a peg-interferon/ribavirin regimen for people with genotype 1 hepatitis C mono-infection. This is called “triple therapy”—since it is a combination of three medications: peg-interferon, ribavirin and either telaprevir or boceprevir. Telaprevir and boceprevir are not prescribed on their own (without peg-interferon and ribavirin) and they are not prescribed together.
Ontario first province to reimburse new chronic hepatitis C treatment VICTRELIS™ Now Available for Eligible Patients in Ontario
MONTREAL, - Ontarians living with chronic hepatitis C now have publicly funded access to a new treatment option, as Ontario becomes the first province to reimburse VICTRELIS™ (boceprevir). The treatment qualified for a pre-approval rapid review under the Ontario Drug Benefit Act (ODBA), as it successfully met a pre-determined set of criteria, including offering substantial improvements of significant outcomes for the treatment of a serious disease.
Boceprevir is a first-in-class oral hepatitis C virus (HCV) protease inhibitor for the treatment of chronic hepatitis C genotype 1 infection. It is to be used in combination with peginterferon alpha and ribavirin (peg/riba) in adult patients (18 years and older) with compensated liver disease, including cirrhosis, who are previously untreated or who have failed previous therapy.2 When added to peg/riba, boceprevir can significantly increase a patient’s chance of clearing the virus from the body.3,4 The treatment was authorized for use in Canada in July of this year.
“The Canadian Liver Foundation is pleased that Ontario’s public drug program has agreed to reimburse boceprevir for the treatment of chronic hepatitis C,” says Dr. Morris Sherman, Chairman of the Canadian Liver Foundation. “Boceprevir represents a major advance in our ability to cure this disease, and as a result, fewer patients will have to struggle with the consequences of end-stage liver disease, liver transplants and liver cancer. We applaud the research efforts that led to this breakthrough and hope other provinces will follow Ontario’s lead and rapidly reimburse this important treatment.”
Eligibility criteria for boceprevir can be accessed through the following link:
http://www.health.gov.on.ca/english/providers/program
Nov 20
Treatment Update
Source- CCO
The Beckoning Future: How Hepatitis C Drugs in Development May Affect Practice Today and Tomorrow
Review the current benefits and limitations with protease inhibitor-based HCV therapies, and the emerging data on potential future regimens and the advances they represent.
The New Elements of HCV Care: Practical Skills to Optimize Protease Inhibitor–Based Therapy
Review the approved indications and proper management of HCV-infected patients with the newly approved protease inhibitors.
* Free Registration Required
Oct 15
Hey Doc, Victrelis-boceprevir or Incivek-telaprevir?
Oct 10 2011
Janssen’s new hepatitis C treatment Incivo has been launched in the UK, one of two new drugs set to advance treatment
.Incivo (telaprevir) is a new direct acting antiviral protease inhibitor (PI), for genotype-1 chronic hepatitis C, and can help clear the virus from many more patients when added to standard treatment, peginterferon alfa and ribavirin.Trials show that adding Incivo clears the virus in almost twice as many previously untreated patients (79% vs. 46%) and almost four times as many who had previously relapsed following treatment (84% vs. 22%). The drug also halved the current total treatment duration to six months in many (58%) previously untreated patients in trials.
Treatment of chronic hepatitis C: The new standard of care for the future
Treatment results for hepatitis C genotype 1 disease with PegIFN and ribavirin are suboptimal. In the last several decades, significant research has allowed many patients, about 50% with genotype 1 and about 80% with genotype 2 or genotype 3, to be virologically cured by attaining SVR.6 The remaining nonresponders to the standard-of-care regimen are left with no other treatment option to cure their infection. If treatment is considered, it is recommended that a hepatitis C genotype be secured prior to initiating therapy. With continued efforts to gain more knowledge of the HCV life cycle and its viral structure, the first generation of drugs known as specifically targeted antiviral therapy for hepatitis C (STAT-C) or direct-acting antivirals (DAAs) have emerged to improve SVR cure rates and reduce the treatment duration of therapy. FDA-approved DAA drugs for HCV genotype 1 disease are the protease inhibitors boceprevir and telaprevir.
Oct 2 2011 - Help, How Do I Take Incivek ?
Sept
2011 practice guideline by the American Association for the Study of Liver Diseases
From CCO
Pocket Guide For Using
Telaprevir and Boceprevir
Telaprevir-Incivek/Boceprevir-Victrelis-Paying For Hepatitis C Treatment
Telaprevir is currently priced at USD 49,200 for 12 weeks of therapy, while boceprevir is priced at USD 1,100 per week, for a total treatment cost of anywhere between USD 26,400 to USD 48,400 depending on individual patient response to therapy
AJN, American Journal of Nursing: September 2011 - Volume 111 - Issue 9 - p 22 doi: 10.1097/01.NAJ.0000405053.00454.26 Drug Watch
Two New Drugs for Chronic Hepatitis C
Aschenbrenner, Diane S. MS, RN
Free Access
Author Information Diane S. Aschenbrenner is the course coordinator for undergraduate pharmacology at Johns Hopkins University School of Nursing in Baltimore, MD. She also coordinates Drug Watch: dianea@son.jhmi.edu.
Abstract *
Two new protease inhibitors that specifically target the hepatitis C virus have recently been approved: telaprevir (Incivek) and boceprevir (Victrelis). Both drugs are added to standard chronic hepatitis C treatment to improve the therapeutic response; they're not used as monotherapy.
* Food containing 20 g of fat must be eaten 30 minutes before taking telaprevir.
* Boceprevir can be taken just before, during, or just after a meal, with no dietary restrictions.
For years the standard of care in patients with chronic hepatitis C has been 48 weeks of treatment with peginterferon alfa and ribavirin, although fewer than 50% of patients using this therapy are cured of the condition. Two new direct-acting antiviral drugs have recently been approved to treat this chronic illness: telaprevir (Incivek) and boceprevir (Victrelis). Both drugs are protease inhibitors specific for the hepatitis C virus, and neither of the new drugs produces cross-reactivity or cross-resistance with any of the protease inhibitors used to treat HIV.
Telaprevir is added to standard therapy in patients with hepatitis C who've not previously received interferon-based therapy or who've had a poor response to previous treatment.
The Food and Drug Administration (FDA) reported in May that in the various clinical trials to determine the safety and efficacy of telaprevir, a sustained virologic response was achieved 20% to 45% more often in patients taking telaprevir than in patients receiving only standard therapy. This was true across all of the studies and patient groups. Treatment with telaprevir shortens the recommended duration of therapy from 48 weeks to 24 weeks.
Telaprevir must be taken concurrently with peginterferon alfa and ribavirin. In studies its most common adverse effects were rash; fatigue; pruritus (all occurring in approximately 50% of patients); anemia; gastrointestinal symptoms (nausea, diarrhea, vomiting, and altered taste); and anorectal symptoms such as hemorrhoids, discomfort, and pruritus. Nurses who work with patients prescribed telaprevir need to provide specific patient education related to the duration of therapy. Telaprevir is taken orally three times a day, with seven to nine hours between doses, and should be taken with food that contains 20 g of fat (to promote absorption of the drug). The food should be eaten no more than 30 minutes before each dose of telaprevir. Examples of foods that contain 20 g of fat are a bagel with cream cheese, nuts (1/2 C), peanut butter (3 T), ice cream (1 C), American or cheddar cheese (2 oz.), potato chips (2 oz.), and trail mix (1/2 C). If a missed dose is discovered within four hours of the time the drug is normally taken, the dose may be made up then.
In studies of boceprevir used in combination with peginterferon alfa and ribavarin, it too significantly increased the rates of sustained virologic response. Adverse effects are similar to those of telaprevir. A major difference between these two direct-acting antivirals, however, is how the drugs react with food. Although food does increase the bioavailability of boceprevir, the amount of fat in the food doesn't affect the drug's absorption, nor is the timing of the food as important: boceprevir may be taken just before, during, or immediately after a meal. Both men and women who are capable of reproducing should be instructed to use two forms of birth control while taking either drug and for six months after stopping it.
For more information on telaprevir and boceprevir, see the FDA's complete prescribing information: http://1.usa.gov/iZRoW7 and http://1.usa.gov/jUQ9ov.
Aug 19
Update; Check out two new videos;
Patient Video; New HCV New Drugs and Resistance
Telaprevir Alone or With Peginterferon and Ribavirin Reduces HCV RNA in Patients With Chronic Genotype 2 But Not Genotype 3 Infections
Aug 17
Use of New HCV Protease Inhibitors ‘Not That Simple’
“These therapies are game changers in terms of how they work and the improvements in response rates,” said Dr. Jensen. “There are also a lot of differences that, as gastroenterologists, we are not used to dealing with.”
Incivek/Victrelis; New approvals may change treatment for hepatitis C
The recent approvals of the new medications for hepatitis C are expected to revolutionize treatment.
Boasting sustained viral response rates of up to 75% in treatment-naive patients, telaprevir (Incivek, Vertex Pharmaceuticals) and boceprevir (Victrelis, Merck) are being heralded within the infectious disease community, but many clinicians are urging judicious use.
The FDA approved telaprevir in May, based on results of trials that looked at the use of telaprevir 750 mg assigned three times daily for 12 weeks combined with peginterferon and ribavirin. This medication increased sustained virological response rates by 20% to 40% across a broad range of disease and demographic characteristics.
Aug 8
Hepatitis C-New Protease Inhibitor (NS3/4A) Drug Resistance Test
LabCorp and Monogram Biosciences are pleased to announce the launch of HCV GenoSure NS3/4A, a protease inhibitor drug resistance assay for the clinical management of patients with hepatitis c.
HCV GenoSure NS3/4A provides a comprehensive sequence-based analysis of a patients hepatitis C virus to assess drug resistance (or susceptibility) to the NS3/4A protease inhibitors, boceprevir, and telaprevir. It also includes a detailed understanding of the viral population for the entire region of non-structural proteins NS3 and NS4A for hepatitis C virus genotype 1a or 1b.
View Complete PDF At NATAP
New Protease Inhibitor (NS3/4A) Drug Resistance Test -
Boceprevir-Victrelis-Telaprevir "INCIVEK" Which pegylated interferon ?
In HCV treatment failures, SVR was 64% with boceprevir vs. 21%
with placebo, combined with standard therapy, Dr. Steven Flamm said.
"This study clearly establishes that boceprevir seems to have equivalent response with peginterferon 2a as was reported with peginterferon 2b. We await similar data for telaprevir with the peginterferon 2b product, as the registration trials were all done with peginterferon 2a."
peginterferon 2a = PEGASYS
peginterferon 2b = Peg-Intron
Telaprevir/INCIVEK
FDA approves Telaprevir / INCIVEK For The Treatment Of Hepatitis C
Telaprevir/Incivek Prescribing Information
Medication Guide
Boceprevir/Vicrelis
Vicrelis/Boceprevir IS NOW FDA Approved May 13 2011
VICTRELIS™- Boceprevir: Prescribing Information and Medication Guide
Patient Assistance Programs
INCIVEK/Telaprevir and VICTRELIS (Boceprevir) Patient Assistance Program
More Than Two-Thirds of Surveyed U.S. Clinicians Plan to Prescribe Incivek and Victrelis to Patients with Treatment-Naive Hepatitis C Virus Genotype 1
Boceprevir vs. Telaprevir: What We Know and Don't Know;
New Treatments for Chronic Hepatitis C Infection
June 5 2011
The newly approved HCV protease inhibitors boceprevir and telaprevir promise to revolutionize HCV treatment.
Hepatitis C virus (HCV) treatment will change dramatically with the FDA's recent approval of two new oral HCV protease inhibitors, boceprevir and telaprevir. When used in combination with current standard therapy (peginterferon and ribavirin [PR]), these new drugs substantially improve cure rates and often reduce the overall duration of therapy. Although data are still emerging, these new drugs are likely to benefit HIV-coinfected patients as well.
Boceprevir
Boceprevir (Victrelis) was approved by the FDA on May 13, 2011, for the treatment of chronic HCV genotype 1 infection both in patients who are treatment-naive and in those with prior treatment failure.1 The approval was based on two large, manufacturer-sponsored, phase III, randomized, controlled trials.
CLINICAL TRIALS
Treatment-Naive Patients
In the SPRINT-2 trial,2 1097 treatment-naive patients with HCV genotype 1 infection (159 blacks; 938 nonblacks) underwent a 4-week lead-in period of PR and then received one of the following:
- Boceprevir plus PR (B+PR) for 24 weeks, with an additional 20-week course of PR alone if HCV RNA was detected between weeks 8 and 24 (the response-guided therapy [RGT] group)
- B+PR for 44 weeks (the fixed-duration group)
- PR plus placebo for 44 weeks (the control group)
Among nonblacks, sustained virologic response (SVR) rates were significantly higher in the boceprevir groups (67%–68%) than in the control group (40%). Blacks had lower SVR rates in all three groups, but B+PR still outperformed PR in this population; SVR rates were 42% in the RGT group, 53% in the fixed-duration group, and 23% among controls. Overall, 44% of patients in the RGT group had undetectable HCV RNA from week 8 to week 24 and therefore received shorter-duration therapy (28 weeks total).
Previously Treated Patients
The RESPOND-2 trial3 involved 403 patients with HCV genotype 1 infection who had a partial response to — or a relapse following — prior PR therapy. Of note, so-called prior null-responders (patients who had not previously achieved a 2 log IU/mL drop in HCV RNA by week 12) were not included in this trial. Patients received 4 weeks of lead-in therapy with PR (which, in this trial, consisted of peginterferon α-2b and ribavirin). Treatment arms were the same as in SPRINT-2, except that here, the RGT arm involved B+PR for 32 weeks beyond lead-in, with an additional 12 weeks of PR alone if HCV RNA was detectable at week 8. SVR rates were significantly higher in the boceprevir groups (59% in the RGT group; 66% in the fixed-duration group) than in the control group (21%).
DOSING
Boceprevir should be prescribed only in combination with PR and should be taken at a dose of 800 mg (four 200-mg capsules) three times daily with food. PR should be administered alone for a 4-week lead-in period. Response-guided therapy is recommended for patients without cirrhosis who are treatment-naive or who have had partial response to, or relapse following, prior interferon/ribavirin therapy. Guidelines for treatment duration in such patients, as recommended in the package insert,1 are shown in Table 1.
Because patients with compensated cirrhosis have relatively poor results with therapy, the recommended boceprevir-based treatment for this population is 4 weeks of PR followed by 44 weeks of B+PR. In addition, 44 weeks of B+PR should be considered for previously untreated patients who have a poor response to lead-in PR, defined as a <1 log IU/mL reduction in HCV RNA at week 4. Although the efficacy of boceprevir in prior null-responders has not been studied, if treatment is considered for such an individual, 4 weeks of PR followed by 44 weeks of B+PR should be given.
B+PR treatment should be stopped based on futility in any patient with an HCV RNA level 100 IU/mL at treatment week 12 or confirmed detectable HCV RNA at treatment week 24.
DRUG INTERACTIONS
Boceprevir is a strong inhibitor of CYP3A4/5 and should not be administered with drugs that are highly affected by this pathway, such as alfuzosin, rifampin, simvastatin, carbamazepine, phenytoin, and oral midazolam.
ADVERSE EVENTS
In phase II and III clinical trials,1 49% of patients in the boceprevir groups had hemoglobin values <10 g/dL, compared with 28% of those in the control groups. Use of erythropoiesis-stimulating agents to treat anemia was more frequent in the boceprevir groups (43%) than in the control groups (24%). However, the rate of study-drug discontinuation because of anemia was low (1%). Decreased neutrophil and platelet counts were more common in the boceprevir groups, as was dysgeusia (35%–44% in boceprevir groups vs. 11%–16% in control groups).
Telaprevir
Telaprevir (Incivek) was approved by the FDA on May 23, 2011, based on data from manufacturer-sponsored trials in treatment-naive and treatment-experienced patients chronically infected with HCV genotype 1.4 In these trials, PR consisted of peginterferon α-2a and ribavirin.
CLINICAL TRIALS
Treatment-Naive Patients
In the phase III ADVANCE trial,5 1088 treatment-naive patients were randomized to one of three treatments (none of which involved a lead-in period):
- Telaprevir plus PR (T+PR) for 8 weeks, followed by PR alone. Patients who had extended rapid virologic response (eRVR; defined as undetectable HCV RNA at weeks 4 and 12) stopped PR at week 24, whereas those without eRVR continued therapy until week 48.
- T+PR for 12 weeks, followed by PR alone. Patients with eRVR stopped PR at week 24, whereas those without eRVR continued therapy until week 48.
- PR for 48 weeks (control group)
In the phase III ILLUMINATE study,7 researchers examined two treatment durations among patients who had achieved eRVR with a 12-week course of T+PR, followed by PR alone. In all, 322 patients were randomized at week 20 to receive a total of 24 or 48 weeks of therapy. SVR rates were 92% and 88%, respectively, demonstrating noninferiority of the 24-week regimen in this patient group.
Previously Treated Patients
In the phase III REALIZE trial,8 662 patients with prior PR treatment failure (i.e., relapse, partial response, or null response) were randomized to 48 weeks of therapy with one of the following approaches:
- T+PR for 12 weeks, followed by PR alone for 36 weeks
- Lead-in PR for 4 weeks, followed by T+PR for 12 weeks, and then PR alone for 32 weeks
- PR for 48 weeks (control group)
DOSING
Telaprevir should be prescribed only in combination with PR and should be taken at a dose of 750 mg (two 375-mg tablets) three times daily with food. It should be administered for 12 weeks in all patients, followed by PR alone for an additional 12 or 36 weeks, depending on viral response and prior response status. Guidelines for treatment duration, as recommended in the package insert,4 are shown in Table 2.
Prior partial-responders should receive T+PR for the first 12 weeks, followed by an additional 36 weeks of PR alone. Treatment-naive patients with cirrhosis who have undetectable HCV RNA at weeks 4 and 12 may also benefit from an additional 36 weeks of PR. If therapy is considered for prior null-responders, T+PR for 12 weeks followed by an additional 36 weeks of PR should be given.
Therapy should be stopped in any patient with an HCV RNA level 1000 IU/mL at treatment week 4 or week 12 or confirmed detectable HCV RNA at treatment week 24.
DRUG INTERACTIONS
Telaprevir inhibits CYP3A and should not be administered with drugs that are highly affected by this pathway, including alfuzosin, rifampin, HMG CoA reductase inhibitors (atorvastatin, lovastatin, simvastatin), and oral midazolam.
ADVERSE EVENTS
The main adverse effects of telaprevir are rash, anemia, nausea and other gastrointestinal symptoms, dysgeusia, and anorectal discomfort. In clinical trials, rash developed in 56% of patients who received T+PR, compared with 34% who received PR alone. Severe rash was reported in 4% of those receiving T+PR, versus <1% of those who received PR alone.4 Patients with mild to moderate rashes may continue therapy with careful monitoring. Telaprevir should be stopped if a rash progresses and becomes severe, or if systemic symptoms develop.
PR treatment is associated with decreased hemoglobin concentrations, and the addition of telaprevir is associated with an additional decrease. In clinical trials, 36% of patients who received T+PR had hemoglobin values <10 g/dL, compared with 17% of those who received PR alone.4 (Use of growth factors — allowed in the boceprevir studies — was not permitted in the telaprevir trials.9) However, the rate of telaprevir discontinuation because of anemia was low: Among patients receiving T+PR, 4% stopped telaprevir, and 1% discontinued T+PR.
Boceprevir vs. Telaprevir: What We Know and Don't Know
- A 4-week lead-in period of PR is given with boceprevir but not with telaprevir.
- In treatment-naive patients with genotype 1 HCV infection, both boceprevir and telaprevir improve SVR rates and, for many patients, reduce the duration of treatment. Neither drug is indicated for treatment of non–genotype 1 HCV infection.
- In previously treated patients, telaprevir improves SVR rates in both prior responders and prior null-responders. Boceprevir has been studied only in patients who had at least a partial response to PR therapy in the past — and has been shown to improve SVR rates in this population.
- Both boceprevir and telaprevir are approved for three-times-daily dosing, and the pill burden is considerable. Telaprevir may be effective when dosed at 1125 mg twice daily,10 but larger studies are needed.
- In a retrospective subgroup analysis of the boceprevir phase III trials, patients with the favorable IL28B genotype (C/C) had higher response rates than those with unfavorable genotypes. This was particularly true among previously untreated patients.1 In a retrospective subgroup analysis of the telaprevir trials, patients with any IL28B genotype appeared to have higher SVR rates with T+PR than with PR alone.4
- A head-to-head trial comparing the drugs has not been performed, so we do not yet know which one is better.
Not surprisingly, emergence of drug-resistance mutations has been observed in patients who have received these agents. Drug resistance may become undetectable after HCV protease inhibitors are stopped, but we do not yet know whether these resistant variants would reemerge if therapy were restarted.
Improving HCV Therapy for HIV-Coinfected Patients
HCV treatment in HIV-coinfected individuals has traditionally been challenging, given their low rates of SVR. However, emerging data from a recent phase II, randomized trial demonstrate that telaprevir may improve virologic responses in HIV-infected patients with genotype 1 HCV infection.11 In that study, 60 patients were treated with PR plus telaprevir or placebo for 12 weeks, followed by PR alone to complete 48 weeks of therapy. In an interim analysis involving 59 patients, 70% of those in the telaprevir group had undetectable HCV RNA at week 4, compared with 0% in the control group. At week 12, the numbers were 68% versus 14%. Table 3 shows results stratified by receipt of antiretroviral therapy (ART); notably, only those receiving tenofovir/FTC/efavirenz or tenofovir/FTC + ritonavir-boosted atazanavir were eligible for the portion of the study examining responses in ART-treated patients. Currently, neither telaprevir nor boceprevir is approved for treating chronic HCV infection in HIV-positive patients. Although these findings suggest that telaprevir may be beneficial, longer-term results are still pending.
Little is known about drug interactions between HCV protease inhibitors and ART. Use of efavirenz reduces telaprevir levels; as a result, in the ongoing phase II study summarized above, the dose of telaprevir was increased to 1125 mg every 8 hours in the efavirenz group. In healthy-volunteer studies, ritonavir-boosted atazanavir had less effect on telaprevir exposure than did other HIV protease inhibitors.12 Coadministration of efavirenz reduces trough concentrations of boceprevir, but the clinical implications are not clear.13 Interactions between boceprevir and commonly used HIV protease inhibitors have not yet been reported.
Conclusions and Future Challenges
Use of boceprevir or telaprevir together with PR will revolutionize HCV treatment, leading to improved outcomes and a shorter duration of treatment for many patients. As we take stock of this breathtaking advance, we should also pause to consider some unanswered questions:
- How will clinicians choose between these new agents?
- Do all patients need the new drugs, or can some patients, such as those with favorable host and viral factors, be treated with PR alone?
- Does boceprevir require the 4-week PR lead-in period for maximum effectiveness?
- Should prior null-responders be treated with telaprevir-based therapy — which is expected to have a response rate of approximately 30% — or should they wait for development of better therapies in the future?
- How should liver-transplant patients with graft HCV reinfection be treated?
- How should patients with decompensated cirrhosis, in whom PR therapy is contraindicated, be treated?
Finally, boceprevir and telaprevir are administered with peginterferon/ribavirin, and patients who cannot tolerate these medications will not benefit from the newly approved drugs yet. Fortunately, many new anti-HCV drugs — including polymerase and NS5A inhibitors — are being investigated in clinical trials. Hopefully, they will eliminate interferon from our HCV toolbox in the future.
— Isaac I. Bogoch, MD, and Rajesh T. Gandhi, MD
Dr. Bogoch is a Fellow in the Division of Infectious Diseases at Massachusetts General Hospital in Boston. He reports no conflicts of interest.
Published in Journal Watch HIV/AIDS Clinical Care May 27, 2011
Citation(s): 1. Victrelis (boceprevir) capsules [prescribing information]. Whitehouse Station, NJ: Merck; 2011. (http://www.merck.com/product/usa/pi_circulars/v/victrelis/victrelis_pi.pdf)
2. Poordad F et al. for the SPRINT-2 investigators. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med 2011 Mar 31; 364:1195.
- Medline abstract (Free)
- Medline abstract (Free)
5. Jacobson IM et al. Telaprevir in combination with peginterferon and ribavirin in genotype 1 HCV treatment-naïve patients: Final results of phase 3 ADVANCE study. Hepatology 2010 Oct; 52(S1):427A.
6. Hofmann WP and Zeuzem S. A new standard of care for the treatment of chronic HCV infection. Nat Rev Gastroenterol Hepatol 2011 May; 8:257.
- Medline abstract (Free)
8. 65% of people whose prior treatment for hepatitis C was unsuccessful achieved SVR (viral cure) with telaprevir-based therapy in phase 3 REALIZE study [press release]. Cambridge, MA. Vertex; Sep 7 , 2010. (http://investors.vrtx.com/releasedetail.cfm?ReleaseID=505239)
9. Pawlotsky J-M. The results of phase III clinical trials with telaprevir and boceprevir presented at the Liver Meeting 2010: A new standard of care for hepatitis C virus genotype 1 infection, but with issues still pending. Gastroenterol 2011 Mar; 140:746.
- Medline abstract (Free)
- Medline abstract (Free)
12. van Heeswijk R et al. Pharmacokinetic interactions between ARV agents and the investigational HCV protease inhibitor TVR in healthy volunteers. 18th Conference on Retroviruses and Opportunistic Infections (CROI), Boston , Feb/Mar 2011. Abstract 119. (http://www.retroconference.org/2011/Abstracts/41437.htm)
13. Kasserra C et al. Clinical pharmacology of BOC: Metabolism, excretion, and drug-drug interactions. 18th Conference on Retroviruses and Opportunistic Infections (CROI), Boston , Feb/Mar 2011. Abstract 118. (http://www.retroconference.org/2011/Abstracts/41140.htm)
Getting Ready; Telaprevir or Boceprevir ?
You know folks, as I begin writing this (and I have no talent for writing by the way) I can't help but wonder if hepatitis C patients who are preparing to treat are ready to choose between the two new drugs; Telaprevir "INCIVEK" or Boceprevir "VICTRELIS". More importantly I wonder if patients understand the dire need for an experienced physician to be on board for this complicated three drug regimen of difficult to tolerate drugs (maybe more including rescue drugs) which willinvolve treating for 24 to 48 weeks. . I ask you, are you ready ? Do you have an experienced physician ? Have you moved your family out of the house and into the garage in order not to hurt them, kidding. You, the patient will decide which drug to use, a difficult decision no doubt. Both drugs are so close in comparison, with each drug closely being scrutinized, your decision will be determined by the efficacy and safety provided by the recent clinical data. Although, the final decision for some patients may hinder on either enrolling in clinical trial (when available) or taking advantage of the drug companies patient assistance programs(when in place).
Yes, boceprevir is here,(FDA Approved) and the temptation to begin treatment is upon us, with telaprevir only a whisper away you may be asking yourself what to do, which drug to use, or wishing someone would make a decision for you. Nope, that's up to you and only you. Coupled with the assistance from your physician, and your own particular scenario, you will ultimately make the final decision. That's how the medical world works today, the same is true for all medical care from cancer treatments to knee surgery, its up to you folks, so lets get started.
What we know to date is that clinical data has suggested that telaprevir is significantly more effective in comparison to boceprevir. If we look at patients who were not previously treated, we know that telaprevir achieved a sustained virologic response of 79 percent when used along with standard treatment. Boceprevir also used in combination with standard therapy has a 63 percent sustained virologic response in naïve patients. As for duration of treatment, in telaprevir 58% of naïve patients can shorten treatment to 24 weeks, compared to 28 weeks in 44% of boceprevir patients.
If we check out the stats in patients that have treated previously the SVR for telaprevir is 65% and boceprevir is 66%. As mentioned on the blog boceprevir did not include null responders in their trial. Vertex’s phase III REALIZE trial did test telaprevir in null responders, which produced a 31% SVR rate.
.
Author Courtney McQueen from The AIDS Beacon writes; Although the rates for telaprevir appear higher than those for boceprevir, it is not clear whether telaprevir is actually more effective.
Patients who received the standard treatment of just ribavirin plus Pegasys in the telaprevir trials had a higher cure rate than patients in the boceprevir trials who received just ribavirin plus PegIntron. As a result, it is possible that the differences in cure rates between the trials are actually due to Pegasys versus PegIntron, or other differences between the studies. Some studies have found that Pegasys is more effective than PegIntron.
Trials in which telaprevir and boceprevir are compared directly will be necessary before determining whether one drug is more effective than the other.
The concern in relation to side effects or safety in telaprevir is the significance of the rash, which was reported in 56% of patients using telaprevir. We can compare that to 32% of patients reporting a rash receiving standard of care. The rash was found to be mild to moderate although severe in 1% of patients and resulted in stopping treatment for 6% of patients. You must be aware of the symptoms of the rash, which will add to the stress often experienced with treating HCV. The drug ribavirin also causes a rash, what seasoned patients refer to as the "Riba Rash", hated it. . Physicians will be on alert folks, but you must also be persistent and diligent in reporting it to your treatment nurse and doctor.
. Anemia was seen more often in patients receiving telaprevir then those treating only with standard therapy. (36% telaprevir vs.15% standard of care patients) and sometimes more severe. In 3% of patients telaprevir was discontinued because of anemia.(remember that 3%)
. In boceprevir anemia was seen in about 50 % of patients compared to 30% receiving standard therapy. This is important, in the telaprevir trials patients were not allowed rescue drugs, in that they were not allowed to treat the anemia with erythropoietin (EPO)-a drug that stimulates the production of red blood cells. In comparison the boceprevir trials did allow rescue drugs and (EPO) was used, or patients were able to lower their dose of ribavirin . This raises the question of how severe the anemia could have been in the boceprevir clinical trials. So in retrospect those 3% of patients who had to discontinue telaprevir because of anemia were real numbers. This is the second time boceprevirs stats have not been clear, the same applies to those SVR numbers in previously treated patients, as mentioned null responders were not included in boceprevir trials.
. The protocol for treating with boceprevir can be viewed here and here.
*After FDA approval of telaprevir this blog will post the prescribing information.
.The newly FDA approved boceprevir has been projected to cost around $1,100 per week, with telaprevir costing close to the same.(Not including Interferon/ribavirin). According to consumers reports the cost of standard of care is at roughly $600 per week which breaks down to $500 for the Peginterferon and $100 for ribavirin.
Reuters reported yesterday that Merck the maker of Boceprevir made a deal with Roche to promote Victrelis/boceprevir in the US and research treatments for hepatitis c.
Treating Hepatitis C In 2011 With Boceprevir Or Telaprevir
April 2011
April 2011
Melissa Palmer, M.D. on Telaprevir (Vertex Pharmaceuticals) & Boceprevir (Merck), the new protease inhibitor treatments for hepatitis C (HCV).
Dr. Palmer is the author of the best-selling book "Dr. Melissa Palmer's Guide to Hepatitis & Liver Disease." Her website is http://www.liverdisease.com/
May 11
DDW;Video New Hepatitis C Drugs Come With A Warning
Andrew Muir, MD, director of GI/hepatology research at Duke University, told MedPage Today Senior Editor John Gever that these drugs offer the promise of nearly doubling response rates compared with the current standard of care. But he warned that clinicians need to be careful with the new agents -- they should never be given as monotherapy, but must be given along with pegylated interferon and ribavirin. Nor should physicians simply substitute the other drug in patients who don't respond adequately to the first one tried, Muir emphasized.
Clinical Care has a new set of slides ready to download;Slideset: Future Generations: Understanding the Similarities and Differences Among Direct-Acting Antivirals for Hepatitis C Free registration required
New Drugs for Hepatitis C on the Horizon
With the promise of two new drugs to fortify the current treatment protocol, doctors see promise of a better-tailored cocktail, similar to HIV treatments, to beat back this common and often debilitating infection
By Katherine Harmon
March 30, 2011
http://www.scientificamerican.com/
Some 3.2 million Americans have chronic hepatitis C, an infection that can linger in the body for years before producing symptoms. It can eventually lead to serious liver scarring and cancer. And most infections in the U.S. are the disease's particularly tough breed, known as genotype 1, which has a cure rate of less than 40 percent with the best current treatment.
Two new drugs for this type, however, are now racing toward approval by the U.S. Food and Drug Administration, which could come as soon as late May. Both compounds are protease inhibitors and are expected to hit the market at about the same time. At EASL, the european liver meeting I am at some striking news about other drugs will emerge today & I will report it later today.
Hepatitis C is spread through contact with blood and occasionally other bodily fluids, and 65 to 70 percent of people infected with the disease are unaware that they have it, according to John Ward, director of the Division of Viral Hepatitis at the U.S. Centers for Disease Control and Prevention. In the U.S. about one in 30 baby boomers has hepatitis C, and one in four people with HIV has the infection, he noted at a 2010 talk. The disease is responsible for some $33.3 billion in medical costs each year.
"We've been waiting for these drugs for a long time," says Darryn Potosky, a hepatologist at the University of Maryland Medical Center, who often has to tell patients they face steep odds of beating the disease.
If the new drugs come to market, patients would take one or the other in addition to the current two-drug treatment regimen. "It seems hepatitis C therapy is moving in the direction of HIV therapy, with multiple drug cocktails," Potosky says. And with that come "hopes that we can tailor treatments to patients."
Two new studies of one of the drugs, boceprevir, will be published in the March 31 issue of the New England Journal of Medicine. Both phase III trials were funded by Schering-Plough (now part of Merck), which makes the drug. There have not yet been any studies comparing boceprevir and the other new protease inhibitor, telaprevir (made by Vertex), but given the drugs' similarity, experts say they both seem promising.
In the new boceprevir trials, adding the drug to the current standard treatment (of interferon and ribavirin) effectively doubled the percentage of patients who were able to suppress the virus-an effect called sustained viral response, which is a mark of being effectively "cured."
"Patients with hepatitis C genotype 1 infection can anticipate a significant therapeutic advance," says Donald Jensen, a professor of medicine at the University of Chicago Medical Center, who wrote an editorial on the new research for the same issue of NEJM. But because these new drugs will each need to be used in combination with the existing two-drug regimes, they "will be associated with more side effects and more complexity."
Long road to safety
Doctors have long hoped for a safe and effective drug to beat hepatitis C (HCV) genotype 1-which, among strains of the disease, is "the most common and the hardest to treat at the same time," Potosky says. Some 70 to 80 percent of people infected with hepatitis C in the U.S. have this type.
With excitement building for these new drugs to arrive in the market, those who have been working on the problem have not forgotten that getting to this point "has been painstakingly slow," says Stuart Gordon of Henry Ford Hospital in Detroit, who coauthored one of the new studies.
Just finding the right compounds was challenging, he notes. An early protease-inhibitor contender, made by Boehringer Ingelheim, was found to be too toxic, and "many of the HCV polymerase inhibitors had to stop their development because of unacceptable side effects," Gordon notes.
And because the new treatment regime must be shown to be better than the current standard of care, which is a 48-week course, "the sheer time involved in conducting these large trials" made for slow going. But a payoff might be near.
One new trial, of 1,097 patients with hepatitis C genotype 1 who had never been treated, found that after 24 or 44 weeks of adding boceprevir to their drug regimen some two-thirds of non-black patients showed they were effectively suppressing the virus. The drug combo was not as effective for black patients, who are less likely to have a gene alteration that is linked to responsiveness to one of the drugs. But adding boceprevir still boosted response rates in these patients from 23 percent to more than half in the 44-week treatment group.
In the other trial, 403 patients with the disease who had not responded to traditional treatment-either showing no improvement or relapsing-were studied. Adding boceprevir to the standard treatment for 32 or 44 weeks resulted in sustained viral response rates in 59 and 66 percent of patients, respectively, compared with 38 percent in the control group.
The studies were both somewhat unusual in that they started patients out with a month-long lead-in period in which patients received the two drugs already available-before boceprevir was introduced to some groups. This "allowed some prediction capability of both subsequent response as well as risk of developing resistant variants," Jensen explains.
Early studies showed that although a protease inhibitor given on its own was very effective initially, it often led to resistant strains of the virus in a matter of days, Gordon says. Even with interferon and ribavirin, resistance "remains a concern," he says. To keep it to a minimum, "clinicians must follow such patients very closely during therapy because if the viral level starts to rise after initially declining, then the protease inhibitor must be stopped to prevent the development of even more resistant strains."
Potosky notes that the extent of resistance will only become clear with time-and as more people take the new drugs. And just as they monitor HIV patients for telltale resistance patterns, doctors should be able to detect early signs of resistance in people being treated for hepatitis C as well.
Adding boceprevir also increased the amount of side effects patients experienced. More than 40 percent of subjects taking this third drug required treatment for anemia in one of the studies, and in the other, severe anemia led doctors to decrease dosage in some 20 percent of subjects. Even though some of these cases were serious, few patients dropped out of treatment.
With boceprevir and telaprevir likely in the home stretch to reach potentially millions of hepatitis C patients in the U.S., doctors and researchers are now turning their focus to the many challenges that remain.
Aside from keeping resistance low and dialing down side effects, the next steps are to try to simplify the treatment regimen. "Everyone wants to get rid of interferon and ribavirin because both have toxicity that make them often difficult to tolerate," Gordon notes. Interferon also currently is usually administered via injection, so moving to an all-oral, once-a-day dosing would make treatment better and more consistent.
Gordon also looks forward to finding ways to help special populations of patients, including those who have HIV, end-stage liver disease or renal disease, as well as children, "who are currently not eligible for our current therapies."
Boceprevir
Related
A Better Way to Unbind Prometheus? Boceprevir for the Treatment of Chronic Hepatitis C Infection
EASL
Telaprevir Improved SVR Rates in People Whose Prior Treatment For Hepatitis C Was Unsuccessful
Hepatitis C; Telaprevir, Boceprevir Boost SVR in Hep C
Found In The March GI and Hepatology News ; Download PDF
March 8th
We are on the verge of triple-drug regimens that will improve response rates for genotype 1 hepatitis C to where rates for genotype 2/3 have been,while shortening the duration of therapy to 24 weeks for many patients,which can lower both cost and side effects.However, therapy will be more complex and will require closer monitoring to manage side effects and monitorfor and prevent resistance.
DR. ROBERT S. BROWN JR. is the Frank Cardile Professor ofMedicine and Surgery and Chiefof the Center for Liver Diseaseand Transplantation at ColumbiaUniversity College of Physicians and Surgeons, New York.
Hepatitis C: Treatment Guidelines " With The GOOD gene", The Cost Of Treatment Telaprevir/Boceprevir
Hepatitis C; resistance to protease inhibitors
Feb 10 2011
Only people who have experienced a chronic illness understand the fear and apprehension felt with each step up the ladder, climbing closer to either medical treatment or a possible cure. These millions of people who are living with chronic hepatitis C or just newly diagnosed are often left out in the cold, alone, with many unanswered questions. Enter the sleepless nights, anxiety, waking each day wondering if treatment will work/or is it working, what about the side effects/I can't take these side effects, whats the availability/should I have waited for the new drugs, do I have the right specialist/I hate my doctor; what the hell am I doing? I understand.
According to the CDC each year in the U.S. approximately 8,000 - 10,000 people die from hepatitis C-related liver disease. The estimate is that 3.2 million persons in the United States have chronic hepatitis C . The estimate does not included those people who have yet to be diagnosed. Quoted from the article;" Prevalence and Challenges of Liver Diseases in Patients with Chronic Hepatitis C Virus Infection" published in Clinical Gastroenterology and Hepatology were these facts; "A recent report commissioned by the Institute of Medicine (IOM) of the National Academies highlighted shortcomings in care for viral hepatitis, including the estimate that up to 75% of HCV-infected persons have not even been diagnosed."
In 2010 an article was published at (Bloomberg) which reported on a hepatitis C clinic located in Los Angeles, where patients are waiting for new drugs before embarking on treatment. You can view the article here.... 'Warehoused' Hepatitis C Patients
As the HCV community waits with anticipation for these new drugs to enter the market they slowly sift through the information available hoping to better understand these new agents.
This sure isn't easy, abstracts are difficult to understand, articles in the media leave out important facts, this leaves us with relevant data undiscovered.
The information we miss, overlook, is found in pages and pages of data. Hidden among abstracts only deciphered easily by a professional. With hunger we read and digest the information at our "reader friendly" HCV websites, HCV Advocate, HIV and Hepatitis
and Natap.
Today this blog will highlight information from the must read entry entitled "New Future Hepatitis C Treatments: Interferon-sparing combinations"
The information points out that "Genotype 1 patients who do not respond to this new triple therapy (telaprevir or boceprevir/PEG-IFN plus ribavirin) will have developed resistance to protease inhibitors"
The Facts;
"In the 30–40% of Genotype 1 patients who do not respond to this new triple therapy will have developed resistance to protease inhibitors, which will limit future treatment options. Therefore, although the addition of a single DAA=(Direct-acting antivirals) to PEG-IFN and ribavirin may improve cure and shorten the treatment duration of SOC=( PEG-IFN/ribavirin), this approach will not meet the needs of many difficult-to-treat patient groups."
Once again the good news; The SVR for persons treating for the first time (geno 1) with telaprevir-PEG-IFN/ribavirin is at 75%.
The SVR rates treating with telaprevir in genotype 1 for patients who "failed to respond to prior therapy" are a little more complex. However, 65% of people overall achieved a sustained viral response.
In the Phase III REALIZE trial you can view the breakdown between relapsers, partial responders, and null responders here, also included are the SVR rates treating with boceprevir.
With these SVR rates so high, the majority of patients will likely take a chance and go on to treat with either telaprevir or boceprevir.
Another worthy mention in the highlighted blog entry is the drug RG7128, which is a nucleoside polymerase inhibitor, by adding this drug to RG7227 a protease inhibitor, it provides additive viral suppression of the HCV virus and completely prevented the development of phenotypic resistance to the protease inhibitor.
A little back story on the drug; Danoprevir
Danoprevir = (RG7227 formerly R7227 also known as ITMN-191) is an investigational protease inhibitor, which targets the hepatitis C virus, used in combination with the standard of care for HCV infection; peg-interferon alpha-2a and ribavirin. It has demonstrated rapid and profound reductions in HCV RNA, data has shown Direct-acting Drugs Danoprevir plus RG7128 Suppress HCV without Interferon.
The first study of combination of DAAs=(Direct-acting antivirals) in patients was the proof-of-concept INFORM-1 study completed last year .
In this randomised, placebo-controlled double-blind trial, 87 patients with HCV Genotype 1 infection were randomised to receive up to 13 days of either oral combination therapy with RG7128, a nucleoside polymerase inhibitor, and RG7227/danoprevir, an NS3/4A protease inhibitor or with matched placebos.
Both agents had already been administered to patients for 12 weeks in combination with SOC.
Direct drug interactions between RG7128 and danoprevir were considered very unlikely, because of the different mechanisms of action and routes of elimination and the lack of overlapping toxicities identified in any of the preclinical or human clinical studies.
This combination achieved profound antiviral suppression, greater than the additive effects of either treatment alone.
The median reduction in HCV RNA from baseline was 5 logs, falling below the level of detection in 88% in the cohort who received the highest dose of both RG7128 (1000 mg b.i.d.) and danoprevir (900 mmg b.i.d.).
No evidence of the emergence of resistance to either compound was observed during this study. This combination was well tolerated, with no serious adverse events, treatment-related dose modifications, discontinuations or study withdrawals. ,
More information can be found here.
Recently medscape published a guide for physicians ;"Hepatitis C: New Direct-acting Antivirals in Development : Treatment Guidelines" which is highlighted here on the blog.
A quick summary;
Owing to the side-effect cost of DAAs and the risk of development of drug-resistant viral strains, it will be necessary to guide treating physicians through a growing maze of confounding factors. These will likely not only include new drugs but also important predictive tests and relevant mutation analysis.
One such predictive test is the IL28B genetic polymorphism, which has recently been reported to be associated withSVR by three separate groups [Ge et al. 2009; Suppiah et al. 2009; Tanaka et al. 2009].
The IL28B genotype will become a commercially available polymerase chain reaction assay in 2010 and may be helpful for decisions using SOC treatment. It is unknown if the C/C, C/T, and T/T alleles of IL28B will be associated with response rates to DAAs and this information will need to be carefully collected in ongoing trials.
UPDATED As reported On Feb 25 2011
Scripps Health ;IL28B Genetic Testing to Hepatitis C Patients Now Available
In this proposed system;
Class I
patients would be those with a very high chance of SVR with SOC therapy for 24 weeks, that is, treatment naïve, interferon-tolerant patients with genotype 2/3, or genotype 1 infection with low viral loads or the C/C IL28B allele [Thompson et al. 2009].
As these patients would have an 80–90% probability of cure without the risk of additional side effects or the additional cost of DAAs, they might be well served to be treated with current SOC alone. These patients represent approximately 20–25% of the US population with HCV [Ghany et al. 2009].
Class II
Patients might be those who are treatment naïve, interferon-tolerant with genotype 1 who have high viral loads and/or have C/T or T/T IL28B alleles. These patients would be less likely to have an SVR with current SOC but would have approximately a 75–80% chance of an SVR with the addition of an NS3/4 protease inhibitor followed by consolidation therapy for a total of 24 weeks (if an RVR is attained). The added cost of DAA therapy and the risk of side effects would need to be considered in these patients, who represent the majority of the US HCV population (40–50%) [Ghany et al. 2009].
Class III
Patients would be those requiring 48 weeks of total therapy in order to attain an SVR with SOC and protease inhibitor therapy, such as relapsers and nonresponders of all genotypes, and those in Class I who do not attain an RVR. It would be important to establish a limit on exposure to protease inhibitor therapy in this group as many who are interferon refractory would not clear virus permitting the emergence of resistance. Although this period will require refinement in the future it appears to be 12 weeks based on the data we have presented herein. These patients are prevalent in practices but actually do not represent a majority of the infected population, certainly no more than 20%. It would be anticipated that half of these patients would not attain an SVR based on the data seen in treatment-failure patients Table 2.
Class IV
Patients would include Class IIIs who do not become undetectable by week 12, interferon-intolerant patients and all treatment failures fromtreated Classes I and II. This could be up to 30% of the US population infected with HCV based on the SVR rates proposed above. These patients would probably be best served by waiting for the availability of combination therapy with an NS3/4 protease and either an NS5B polymerase, an NS5A inhibitor, a cyclophilin inhibitor, or another interferon-free combination regimen.
The goal of therapy in these patients would be viral eradication but this is not likely to be an attainable outcome for most. Instead, viral suppression with cessation of histological injury will likely be the new goal in these patients. As such, the risks for resistance and the cost of long-term therapies will need to be major considerations in this population Table 3.
A summary from "New Future Hepatitis C Treatments: Interferon-sparing combinations"
The addition of a protease inhibitor to PEG-IFN plus ribavirin will increase the cure rate in both treatment-naïve and treatment-experienced patients and is likely to become the new SOC. However, there will still be a large ‘unmet need’, including patients unable to or unwilling to receive IFN or ribavirin therapy and previous non-responders to SOC
.
The rationale for combining different DAAs is to increase viral suppression and prevent or delay the emergence of antiviral resistance.
.
The ultimate goal is to develop a short-duration, IFN-free oral combination, with excellent tolerability and efficacy in both treatment-naïve and treatment-experienced patients.
With boceprevir or telaprevir in some cases resulting in a 67% to 75 % cure; it appears the time is right to consider treatment. Thousands and thousands of people now have a better chance of clearing HCV. It may not be one hundred percent yet folks, but its getting there.
Latest Updates
Feb 3
Protease Inhibitor–Resistant Hepatitis C Virus Mutants With Reduced Fitness From Impaired Production of Infectious Virus
Hepatitis C virus Resistance to Protease Inhibitors;
Halfon P, Locarnini S; Journal of Hepatology (Jan 2011)
Hepatitis C Drugs Boceprevir and Telaprevir: I'm Still Waiting Jan 10th Yesterday in a press release we heard from Vertex discussing their new drugs and the big 2011 plan. Additional information is available in a web cast presentation, at the Vertex website. The news coming from Vertex is encouraging for both the ongoing and new clinical trials. Vertex is conducting a Phase 2 trial evaluating multiple 12-week, response-guided regimens of telaprevir dosed in combination with their HCV polymerase inhibitor, VX-222. *Note : Response guided therapy is intended to enable the physician to determine the duration of combination therapy based on a patients viral response during treatment The study currently includes three treatment arms. The Four Drug Combination: Telaprevir, VX-222, Pegasys and Ribavirin Two of the treatment arms are fully enrolled and are evaluating four-drug combinations of telaprevir (1,125 mg; BID), VX-222 (400 mg or 100 mg; BID), Pegasys® (pegylated-interferon alfa-2a) and Copegus® (ribavirin). Approximately two-thirds of the people in the four-drug treatment arms have received eight weeks or more of treatment. More than one-third of patients have received 10 weeks or more of treatment, with some people having completed all therapy. Interim data from both of the four-drug treatment arms are expected in the first quarter of 2011. The Three Drug Combination: Interferon-free regimen of Telaprevir, VX-222 and Ribavirin In November 2010, Vertex announced the planned addition of a three-drug treatment arm to evaluate the potential of an all-oral, interferon-free regimen of telaprevir (1,125 mg), VX-222 (400 mg) and ribavirin dosed twice daily. Enrollment in this new treatment arm is anticipated to begin in the first quarter of 2011. Not Mentioned However, not mentioned was that in October of 2010 the VX-222/telaprevir combo being tested in low doses was stopped because of viral breakthrough. Just recently in a higher dose of the VX-222/telaprevir combo was halted in part of the Vertex study. Additional Trials Vertex and Tibotec also plan to conduct several additional clinical trials of telaprevir in 2011 that aim to expand the future patient population for telaprevir-based regimens. HIV Co-Infection Trial Phase 3 HCV/Human Immunodeficiency Virus Co-Infection Trial: Vertex recently completed enrollment in a Phase 2 clinical trial of telaprevir-based regimens in people who are infected with genotype 1 hepatitis C virus and the human immunodeficiency virus (HIV), also known as HCV-HIV co-infection. If positive, results from this trial could support the planned initiation of a Phase 3 study of telaprevir-based regimens in people co-infected with HCV and HIV in 2011. The Phase 3 trial will be designed to generate data that, if positive, could support the submission of a supplemental NDA for this population. Vertex Is Initiating A Short-Duration Study: Regimens involving less than six total months of therapy Phase 2 Short-Duration Treatment Study: In 2011, Vertex and Tibotec plan to initiate a clinical trial to evaluate the role of telaprevir as part of hepatitis C treatment regimens involving less than six total months of therapy. One part of the trial may evaluate a telaprevir-based treatment regimen as short as 12 total weeks in duration for certain subsets of patients. Phase 2 Post Transplant Study: Vertex recently completed a drug-drug interaction study of telaprevir with immunosuppressive agents commonly used following a liver transplant. . If All Goes Well Vertex Will Initiate A phase 2 study for recurrent hepatitis C following a liver transplant Based on results from this study, Vertex and Tibotec plan to initiate in 2011 a Phase 2 study of telaprevir-based regimens in people with recurrent hepatitis C following a liver transplant The Launch Vertex is getting ready for the launch of telaprevir, and hired more than 200 new employees. According to the website; " The sales and commercial leadership team is in place, and more than 100 field-based employees have been hired to date and are prepared to support the future use of telaprevir across the United States following the planned launch." Not Mentioned What was not mentioned is that the Shasun pharmaceutical chemical manufacturer obtained a contract from Vertex Pharma for manufacturing telaprevir. As reported Vertex will supposedly source the entire supply from Shasuns UK subsidiary. On Jan 5th Shasun announced; "The supply of the Hepatitis C drug to Vertex by Shasun Chemicals is set to take off earlier than anticipated. The product is set to launch in June-July next year. "Commercial supplies have already started and we are preparing for the launch this year," says Vimal Kumar, Managing Director of Shasun Chemicals, in an exclusive interview with CNBC-TV18's Udayan Mukherjee and Mitali Mukherjee. Although Shasun did not name the Vertex drug as telaprevir. The validation of the contract came from a snippet on Pharma-Markets website, not vertex. Who is Shasun ? Shasun Chemicals is a pharmaceutical chemical manufacturer headquartered in Chennai, India and one of the largest producers of Ibuprofen worldwide. The company was incorporated in 1976 - and has facilities in both India and the UK. Their products are exported across North America, Europe, Latin America, and Asia. According to their website they have positioned themselves in order to develop and supply their products for the U.S. Market. In 2008 the pharmaceutical manufacturer opened development facilities in Piscataway, NJ. Outsourcing to India According to the article ; List of Companies Outsourcing Pharmacy Work to India it appears outsourcing to India is a popular practice for drug companies as it provides a cheap labor for manufacturers. In 2008 the drug company Merck felt the heat when Sen. Sherrod Brown of Ohio requested information about their outsourcing practices to India . The Senators concern began after hearing of an announcement made by Merck's Richard Spoor stating that by 2010, Merck plans to outsource about 35 percent of the company's pharmaceutical ingredients and packaging. The senator also sent a letter to the FDA, which expressed his concern about how countries with weaker safety standards might produce contaminated drug ingredients. On the topic of safety standards: Drug Trials In India: Cheaper and Weak Ethical Controls. The average cost in America for a pharmaceutical company to develop a drug for FDA approval is close to $802 million with the time taking 10 to 15 years. With these high costs and long wait times, the pharmaceutical industry in the US is now looking at outsourcing. Noted at the website Chemical and Engineering ;"In recent years, major U.S. drug companies have been laying off people by the thousands while, at the same time, headcounts at contract pharmaceutical research firms in India, China, and Russia have surged. It would seem the two phenomena are linked. But, as with much involving the pharmaceutical industry, things aren’t that straightforward." We don’t really have a concern or a position concerning R&D (or research and development) capabilities leaving the U.S.,” Goldhammer says. “It’s up to each company to decide what’s best for them.” He adds that even though there may appear to be a very large number of experienced drug R&D scientists who have relocated from the U.S. to China or India, it has on the whole little impact on R&D capabilities in the U.S. “We have a very deep pool of talent in this country,” he says. You may want to read the full 2009 article, its compelling The confidence I once had in pharmaceutical companies is gradually fading, with news reported on insider trading, Roche paying off nurses to recruit patients, to the report from ProPublica that 83.8% of doctors have some sort of relationship with drug companies. I was angry and confused when I read that Mr. Sam Waksal, whose insider trading lead to spending time in prison along with Martha Stewart; was then able to go on to purchase Three Rivers Pharmaceuticals. He mentioned in an article that the backbone of his new enterprise is comprised of treatments for hepatitis C, and cancer. Is it just me, or have the ethics in America's health care system and pharmaceutical industry changed? If so we must change with it, the time has come to be the wise patient because the day of being the good and trusting patient is over. I assume that the consequences of those few employees/physicians have reflected negatively on the majority of virtuous pharmaceutical companies. Its evident that they have taken the heat for a few individuals who were morally deficient. Personally, for the first time in my life, this long ago "hippie" has become a little cynical and disillusioned. When I treated HCV ten years ago I did so with an illiterate combination of fear, desperation and blind ambition. From the moment I was diagnosed I was determined to clear the virus, which I did treating with a combination of Intron A and a side of ribavirin. After discovering I was a genotype 2 I felt confident that therapy just might work. In 1991 Shering's "Intron A" was FDA approved and in 2000 I began treatment in an extraordinarily unnecessary trial. The protocol was for a year which is unheard of with my genotype with a lead in of high dosed "Intron A" at 5 million units/daily for a month and then three times a week for eleven months in combination with 800 mg of Ribavirin. The recommendations for my genotype were to treat for six months, while people with genotype 1 treated for 12 months. The standard dose or protocol was for 3 million units of interferon, three times a week. I understood those stats and decided to treat, I was too hyped up to wait. Over the years I realized how fortunate I was to have achieved my SVR status; I do not regret my choice, instead I rejoice. In January 2001, the (FDA) approved the use of peglayted interferon in the U.S. Yes, if I knew then, what I know now, I most certainly would have waited. Over the past year or so I have been diligently reading updates on a few investment sites and their accompanied blogs. The author Adam Feuerstein who is not an investor but a contributor at the The Street, for me, has been instrumental in bringing a clearer understanding of both drugs. Although, I read with caution because until the data is published in a peer reviewed journal there is no bottom line. However, Mr. Feuersteins articles are backed by published data. The recent news/research/data on telaprevir and boceprevir is staggering, HCV therapy has come a long way folks, with impressive cure rates in people who are difficult to treat; genotype 1, treatment-experienced or people treating for a second time, null responders, relapsers, different ethnic groups and even people with surmountable liver damage. The good news is that Boceprevir is moving along and assuming all goes well telaprevir will be following close behind . However, the majority of us have little preference on which drug reaches the market first, we still continue to absorb the data before deciding on which drug to use or when and how to proceed with treatment. In the next few months there will be comparisons, not a head to head study, we can only dream, but articles/data from reputable websites. Then the work begins, as we are given the laborious task of steadily reading through the generous information made available to us by our few devoted HCV advocates, pun intended. In both boceprevir and telaprevir response-guided therapy will be implemented, enabling therapy to be individually tailored, by adapting the treatment duration according to individual patient response. If the drug of choice is boceprevir your physician may be using a 4 week lead-in strategy of peg/RBV before adding the oral protease inhibitor drug boceprevir. Assuming this protocol is used it can help to identify the responsiveness to interferon before adding boceprevir. Another new addition to HCV therapy was discussed in detail by HCV advocate in two articles "The Gene that Predicts—by Alan Franciscus." and IL28B Gene Highlighted at AASLD—Liz Highleyman . With the groundbreaking discovery of the IL28B gene comes a little concern for us. On the website is an article put together by information I compiled from data, reports with a speculation of what insurance companies may do with this new discovery; Is IL28B Testing A Threat To Telaprevir Or To Patients ? The reality is once you begin HCV therapy you will transform into your own advocate. You and you alone will need to address the protocol and over see your blood work. Before choosing a physician , entering into a clinical trial, or starting therapy ask the hard questions, do the homework, ask for all copies of your blood work and learn what they mean. Ask the treating physician how many patients he has treated with HCV and for how long. If possible go through a teaching hospital/university which is on the cutting edge of these therapies. Report all side effects as they occur and know this folks, trust your gut instinct. That may be the most valuable advice I can offer folks, trust yourself, and listen to your body. | On Jan 6th 2011 Boceprevir Receives FDA Priority Review and EMA Accelerated AssessmentTelaprevir "Gets FDA Priority Review" In U.S. and Canada/Jan 20 Vertex (Telaprevir) and Merck (Boceprevir) . Excerpt From Nature; Comparison of hepatitis drugs zeros in on null responders In its RESPOND-2 study, Merck defines a null responding patient — someone who is faring the worst under the current standard of care — as a patient whose viral load decreased less than 1 log after four weeks of standard treatment. That's a considerably different criteria from the US Food and Drug Administration, which defines null responders as 'less than a 2 log10 reduction in HCV RNA at week 12'. Vertex used the FDA's definition of null responder in its study, REALIZE. Since both companies are trying to show that their protease inhibitor works better for patients for whom current options have failed, there is a remote chance that Merck's numbers might paint an artificially rosier picture." The original article from In Vito ; Notes from AASLD: Apples and Oranges and Null Responders ________________________________________________ HCV Protease Inhibitors—Telaprevir and Boceprevir. Both drugs finished their phase III clinical studies in 2010. When boceprevir and telaprevir were combined with pegylated interferon and ribavirin the studies showed an increase in the number of people who can be cured. In addition some people who achieved a rapid and dramatic decrease in HCV RNA (viral load) early on in treatment were able to shorten the duration of treatment. The higher response rates were seen in people who had never been treated (treatment naïve) and in people who had been treated before but did not achieve an SVR. The added good news is that in the groups that traditionally have had poor treatment response rates—African Americans, Hispanics and people with cirrhosis—the treatment response rates are vastly improved. Of note: Vertex completed their application to the Food and Drug Administration (FDA) for marketing approval of telaprevir—approval is expected by mid-2011. http://www.hcvadvocate.org/news/newsLetter/2011 /advocate0111.html#1 Audio From AASLD/Nov 4 2010 AASLD:Hepatitis C/HBV /PIs Boceprevir/Telaprevir ( Link To Capsule Summaries from CCO) . 2010 Annual Meeting of the American Association for the Study of Liver Diseases *October 29-November 2, 2010 Boston, Massachusetts *CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs. . From Podium to Practice: Updates in HCV Treatment From Podium to Practice: Updates in HBV Treatment Merck Announces Pivotal Phase III Data for Boceprevir will be Presented at the American Association for the Study of Liver Diseases 2010 Annual Meeting Telaprevir the REALIZE Study From HCV Advocate Oct 23/New Fact Sheets . Boceprevir Telaprevir . Top Line Results: Boceprevir & Telaprevir HCV The Difficult To Treat: Re-Cap Telaprevir/Boceprevir FDA Issues Guidance for Development of Directing-acting Antiviral Drugs for Hepatitis C STAT-C drugs block specific steps of the viral lifecycle. For example, HCV protease inhibitors (such as telaprevir and boceprevir) interfere with an enzyme encoded by the NS3/4A gene that processes proteins before they can be assembled into new virions (virus particles). HCV polymerase inhibitors disrupt the action of another enzyme, encoded by the NS5B gene, that copies viral genetic material. , The HCV lifecycle and how drugs work is explained more fully in the December 2009 HCV Advocate |