Wednesday, September 29, 2010

HCV TX New and Old Therapies

Update From HCV Advocate .....
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Make sure you also watch the video
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Video Update on Boceprevir: Top Line Phase III Results: Boceprevir
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Top Line Results: Boceprevir & Telaprevir—Alan Franciscus, Editor-in-Chief
Merck/Schering and Vertex released exciting news about their top-line results from phase III studies in August 2010. Merck’s top-line data included the use of their HCV protease inhibitor, boceprevir, in combination with pegylated interferon and ribavirin in HCV Genotype 1 patients who have never been treated (treatment-naïve) and people who have ‘failed’ a previous course of pegylated interferon plus ribavirin therapy. Vertex’s data included a study with their HCV protease inhibitor, telaprevir, used in combination with pegylated interferon and ribavirin for treatment of HCV Genotype 1 treatment-naïve patients.

This is the data that we have all been waiting to hear about – with one exception—we are still waiting to hear the results of the phase III study of telaprevir triple therapy (pegylated interferon plus ribavirin) for people who have not achieved an SVR with a previous course of pegylated interferon and ribavirin combination therapy.

Unfortunately, the three studies only include top-line results so we will have to wait until AASLD to hear more in-depth information. These results, however, give hope that the new triple combinations of HCV protease inhibitors, pegylated interferon and ribavirin will increase the efficacy for people who have never been treated and for those who have been treated, but didn’t achieve an SVR.
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Boceprevir – Phase III Top Line Results

HCV Sprint 2 This study included 1,097 HCV genotype 1 treatment-naïve patients. There was a 4 week lead-in of PegIntron plus ribavirin (without boceprevir), followed by the triple combination of boceprevir, PegIntron and ribavirin. Duration and continuation of treatment was guided by the type of response to the medications.1

The sustained virological response rates (HCV RNA negative 24 weeks post treatment or SVR) by group are listed below:
If HCV RNA negative at week 8 through week 24, triple therapy was continued for a total treatment duration of 28 weeks; sustained virological response (SVR) = 63%
If HCV RNA positive at week 8 but undetectable at week 24, boceprevir was stopped at week 28 and PegIntron/ribavirin combo therapy was continued for a total treatment duration of 48 weeks; SVR = 66%

The control arm was standard of care – PegIntron plus ribavirin with a treatment duration of 48 weeks; SVR = 38%

There were also 159 African American (AA) patients in the study (AA patients comprised 15% of the patient population). The SVR by response guided treatment duration in the groups listed above included1:
AA – SVR = 42%
AA- SVR = 53%
AA – SVR = 23%

*If patients were HCV RNA positive at week 24 all treatment was stopped.

HCV RESPOND 2This study included 403 HCV genotype 1 treatment-failure patients and included a 4 week lead-in of PegIntron plus ribavirin, followed by the triple combination of boceprevir, PegIntron and ribavirin with a treatment duration based on type of response. The SVR rates and treatment duration are listed below.2
If HCV RNA negative at week 8 and at week 12 the total treatment duration was 36 weeks; SVR = 59%
IF HCV RNA positive at week 8, but undetectable at week 12, boceprevir was stopped at week 36 and the combination of PegIntron/ribavirin was continued for a total treatment duration of 48 weeks; SVR = 66%
Control arm was standard of care – combination of PegIntron plus ribavirin; SVR = 21%
*If patients were HCV RNA positive at week 12 all treatment was stopped.

SIDE EFFECTS
The side effects in both studies were similar across all treatment arms except that anemia was 20 to 27% higher in the arms that included boceprevir. The discontinuation rate from all side effects was similar across arms including the boceprevir containing arms. The use of erythropoietin (a growth factor used to treat anemia) was allowed, which may explain the low discontinuation rate due to anemia.

Merck/Schering has indicated that they expect to complete filing for marketing approval in the U.S. and Europe by the end of 2010.
Source: Merck & Co., press release.
Telaprevir – Phase III Top Line Results

ILLUMINATE
This study included 540 HCV genotype 1 treatment-naïve patients. The aim of this study was to find out if there was a benefit in extending the total treatment duration from 24 weeks to 48 weeks. The study was response guided—patients who were HCV RNA negative at weeks 4 and 12 of treatment were randomized at treatment week 20 to receive either 24 or 48 week total treatment duration. The overall SVR rate of all patients in the study was 72%. When treatment was guided by type of response during therapy, the SVR rates were higher—88% (24 weeks) and 92% (48 weeks). During the period that telaprevir was used 6.9% of the patients discontinued treatment, which is similar to the treatment discontinuation rates usually seen in pegylated interferon plus ribavirin combination therapy. The study validated that a 24 week treatment duration was as effective as a 48 week treatment duration.
The use of erythropoietin was not allowed in this study or in the larger Phase III ADVANCE study.

Source: Vertex Pharmaceutical, INC., press release.

Comments: The results from all three studies are impressive, but the real story will unfold once more data is made available. It is expected that more information will be released at the 2010 AASLD Conference that will be held in Boston, MA on October 29, 2010 to November 2, 2010. Another phase III Vertex study is expected to be released soon—this study examined the use of telaprevir, pegylated interferon and ribavirin to treat HCV genotype 1 people who did not achieve an SVR with a prior course of pegylated interferon plus ribavirin
Medical providers and patients will soon be making important decisions about which drug to take based on the complete data set from all of the Phase III studies of telaprevir and boceprevir. Important issues that will play into the treatment decision process will be the efficacy of the new HCV protease triple therapy, how long someone will need to be treated based on drug and guided by response, frequency and severity of the side effects, cost of the new medications, additional costs of medicines to manage side effects, additional costs of HCV RNA tests (if response guided), overall insurance coverage and limitations, and the willingness and capacity of the medical provider to tackle the new therapies. But the most important issue will be the person living with hepatitis C who will ultimately be in charge of the treatment decision process.

Notes: 1 Boceprevir (800 mg three times a day), PegIntron (1.5 mcg/kg/week) and ribavirin (600-1,400 mg day)2 Triple combination (telaprevir, pegylated interferon, ribavirin). Telaprevir was not given for more than 12 weeks.
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Treating With New and Standard Therapies: Other Studies and Outcomes
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Telaprevir combined with peginterferon/ribavirin associated with high sustained virologic response (SVR) rates in treatment-naive genotype 1

HCV–infected patients SVR rates high regardless of telaprevir dosing (750 mg every 8 hours or
1125 mg every 12 hours) and use of pegIFN alfa-2a vs alfa-2b
SVR rates higher in patients achieving rapid virologic response HCV RNA undetectable at Week 4) and assigned to 24 weeks of treatment compared with those achieving later response and assigned to 48 weeks of treatment
SVR with 24 weeks of treatment: 96% SVR with 48 weeks of treatment: 79%

24 weeks of treatment could be sufficient to cure between 93 and 100% of treatment-naďve chronic hepatitis C virus ( HCV) genotype 1 infected patients if they have a fast antiviral response to Telaprevir ( with Peginterferon and Ribavirin, according to new research presented today at the International Liver Congress 2010, the Annual Meeting of the European Association for the Study of the Liver in Vienna, Austria.

Many Genotype 1 Hepatitis C Patients Can Be Cured with 24 Weeks of Telaprevir plus Pegylated Interferon/ribavirin

The success rate of achieving SVR is higher then it has even been for genotype 1 , and for persons treating a second time.
More than half of genotype 1 chronic hepatitis C patients who were not cured with a previous course of interferon-based therapy achieved sustained virological response(SVR)

-56% of prior treatment null responder patients achieved SVR with a 48-week telaprevir-based regimen--
97% of prior treatment relapsers and 55% of prior treatment partial responders achieved SVR with 24-week or 48-week telaprevir-based regimens-

Also See The Latest Stats :
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5/14/10
7/23/10

More on Boceprevir

Merck announced the completion and results of its two Phase 3 studies for boceprevir for the treatment of chronic hepatitis C virus (HCV) genotype 1 infection. Boceprevir, in combination with PegIntron and Rebetol, is being studied for the treatment of patients with chronic hepatitis C genotype I who have previously been treated (treatment-failure; HCV RESPOND-2) and in patients who are new to treatment (treatment-naïve; HCV SPRINT-2).

We all wait for the better SVR rates and shorter treatment duration . Vertex expects to ask for Food and Drug Administration approval during the second half of 2010. What I am personally and maybe even selfishly excited about is that people I know with advanced liver disease (who have treated more then once) may now have a 50 to 97% chance of clearing HCV.

The information below is from hepc.org/Australia and pertains to

Treating With FDA Approved Pegylated Interferon and Ribavirin

Learn The Lingo :
Rapid Viral Response (RVR) Complete Early Viral Response (cEVR) Partial Early Viral Response (pEVR) Non-response (non-EVR) .

Rapid or early response: part of a approach to hep C treatment .

Treatment for hep C has come a long way over the last 20 years.

"Its really moved pretty fast is the last 6 years, the 1st Phase 1 clinical trial for Telaprevir was started in June, 2004."

Treatment can lead to a complete cure and it can reduce your
chance of long-term complications such as liver failure and liver cancer, improve your quality of life and prevent you from spreading hep C.

Current Treatment

From June 1st 2010 Guidelines: Treatment goals in patients with HCV infection are to delay or prevent progression of fibrosis and to prevent the development of cirrhosis For chronic HCV infection, pegylated interferon and ribavirin is the standard treatment .

Since 2004, standard treatment for hep C has consisted of weekly injections of pegylated interferon with twice-daily oral doses of ribavirin for six or 12 months. This treatment gives a cure rate of 50–80%, but it has its problems – it’s time consuming
and can have unpleasant side effects

"The 50 percent was and is for geno 1's"

The latest development is the move to response guided
treatment which can be tailored to the individual person to maximise the chance of a cure while minimising the side effects .

Contraindications To Treatment .

From June 1st 2010 Guidelines:
Absolute contraindications to treatment of HCV infection include active alcohol or substance abuse, active autoimmune hepatitis or other condition known to be exacerbated by interferon and ribavirin, known hypersensitivity to medications used to treat HCV infection, and pregnancy or lack of compliance with adequate contraception. For ribavirin only, renal failure is an absolute contraindication.

Other absolute contraindications to treatment of HCV infection are severe concurrent cardiopulmonary disease; uncontrolled major depressive illness, psychosis, or bipolar disorder; and untreated hyperthyroidism.

Relative contraindications to treatment of HCV infection include laboratory values suggesting decompensated cirrhosis, and baseline hematologic and biochemical indices.
How do you know if you have been cured of
hepatitis C?

You are cured of hep C when there is no more virus in your blood.
Your doctor will be able to tell you that you are cured if you have a sustained viral response (SVR) to treatment which means that no hep C virus can be detected in your blood six months after you finish treatment.

Research has shown that an SVR to treatment is a good indication that you have cleared the virus for good.
How can you tell how successful your
treatment is going to be?


Not everyone has the same results from antiviral treatment for hep C. For example, women do better than men, younger people do better than older people, people with a normal body weight do better than those who are overweight or obese, and people with less liver damage have a better chance of successful treatment.
Your iron levels and your alcohol consumption can also affect how well you will go on the treatment Two of the most important factors that will predict whether you will have an SVR are the strain of hep C virus (genotype) you have and the amount of virus in your blood (viral load) before you start treatment


How can your genotype affect your treatment success?

From New Guidelines June 1st 2010/ HCV genotype and virologic response to treatment determine the duration of treatment. Patients with genotypes 1 and 4 are treated for 48 weeks, and those with genotypes 2 and 3 are treated for 24 weeks. Multidrug regimens may be developed in the future, using new agents in combination with current therapies.


There are six known strains of hep C virus, known as genotypes 1-6. Each of these can be further divided into subtypes, such as genotype 1a, 1b, 2a, etc. Some genotypes are easier to treat than others. Your doctor can do a genotype test to determine your viral genotype and help decide the dose of treatment, how long you should stay on it and how likely you are to reach an SVR.

In Australia about half the people with hep C (54%) have genotype 1, about a third (37%) have genotype 3, and genotype 2 accounts for approximately 5%. The rest of the cases of hep C in Australia is made up of people who have migrated from different countries: generally,
genotype 4 is from Central Africa and the Middle East, genotype 5 from South Africa, and genotype 6 from South East Asia. l If you have genotype 1 or 4 you are generally given 12 months of treatment and have about a 50% chance of a cure. If you have genotypes 2 or 3 you are generally given six months of treatment and have a 70–80% chance of a cure.

Along with hep C genotype, rapid or early reduction in viral load is seen as an important predictor of treatment

This information below is still very important for all those people treating now with Pegylated Interferon and Ribavirin alone "

As mentioned above this entry has been edited/updated on June 9th as a result of the published article "Management of Hepatitis C " in the June 1st issue of the American Family Physician.

How can your viral load affect your treatment success?

From June 1st 2010 Guidelines-

"The quantitative HCV RNA level is used to assess response to therapy and as a guide to discontinue treatment," the review authors write.

"A negative viral load test after four weeks of therapy is predictive of sustained virologic response.

In contrast, failure to achieve a 100-fold reduction in viral load by week 12 of therapy has a strong negative predictive value for sustained virologic response and suggests that treatment is likely ineffective and should be stopped."

Hep C viral load is the amount of hep C virus in your blood. The results of the viral load test, known as an _HCV RNA quantitative test”, are given as the number of International Units of virus in each millilitre of blood (IU/mL). l Most people with chronic hep C have between 50,000 and five million IU of hep C virus in each millilitre of their blood. When the test cannot detect any virus in your blood, the level is “undetectable”

A high viral load is considered to be above 400,000 IU/mL

A low viral load is considered to be below 400,000 IU/mL l Changes in viral load are sometimes expressed in terms of logs: a 1-log change means a 10-fold increase or decrease; a 2-log change is a 100-fold increase or decrease. k .Viral load cannot tell you how serious your infection is or how much damage the infection has caused your liver. k Its main purpose is to predict how well you will do on antiviral therapy and to monitor how well you are doing once you start. The lower your viral load when you start treatment the better your chance of an SVR.

Viral load monitoring during treatment An early decrease in viral load while you are on treatment indicates that it is working. Research shows that people who respond early and rapidly also have a better chance of being cured.

Rapid viral response (RVR) : a viral load of less than 50 IU/mL four weeks into treatment. If you have an RVR your chance of cure is better than 85% and your doctor may recommend that you shorten your treatment .

From June 1st Guidelines:

"A negative viral load test after four weeks of therapy is predictive of sustained virologic response (SVR).


Complete early viral response (cEVR): a viral load of less than 50 IU/mL 12 weeks into treatment. If you have a complete EVR you have a good chance of being cured .

Partial early viral response (pEVR): a drop in viral load of at least 2-log (e.g. from 600,000 IU/mL down to 6,000 IU/mL) at 12 weeks of treatment, but still detectable virus in your blood. In people with genotype 1 the chance of viral clearance is low and treatment is generally stopped.

If the virus in your blood is still detectable at week 24, you have a poor chance of having an SVR: it’s very unlikely (only a 1–2% chance) that you will clear the virus and
therefore treatment is generally stopped.

Non-response (non-EVR): no significant drop
in viral load in the first 12 weeks of treatment.
Treatment modifications .

Genotype 1 or 4 Treatment modifications RVR at 4 weeks and low viral
load before treatment -Your doctor may consider
reducing treatment to 24 weeks
Genotype 1 or 4 No EVR at 12 weeks-Your doctor may consider
stopping treatment depending on how well you are coping with side effects k

June 1st 2010 Guidelines: In contrast, failure to achieve a 100-fold reduction in viral load by week 12 of therapy has a strong negative predictive value for sustained virologic response and suggests that treatment is likely ineffective and should be stopped."

Genotype 2 or 3

RVR at 4 weeks and low viral load before treatment Your doctor may consider reducing treatment to 16 weeks .

Summary: Response-guided treatment recommendations

Having a treatment schedule designed around how you respond to treatment is possible because the diagnostic tests are now available for genotyping and accurately measuring viral load.
The main diagnostic test to measure as accurately as possible the levels of virus in your blood is the supersensitive polymerase chain reaction (PCR), TaqMan HCV test.

Give yourself the best chance There are effective treatments for chronic hep C. Getting the correct treatment at the correct time gives you a chance of clearing the virus from your bloodstream.

Recent research and advances in sensitive diagnostic tests have allowed doctors to make changes to the standard treatment to get you the best results: not all people with hep C should
be treated the same. With viral load testing and
genotyping, your doctor can tailor both your treatment dose and your treatment duration to avoid the downsides of treatment and give you a better chance of an SVR.
June 1st guidelines:

Recommendations for diagnosis and treatment of hepatitis C virus HCV infection in the family practice setting are provided in a review published in the June 1 issue of the American Family Physician. The review discusses chronicHCV nfection in adults but does not cover special groups, such as children, pregnant women, transplant recipients, and persons coinfected with hepatitis B virus or HIV.

"An estimated 170 million persons, or 3 percent of the world's population, are chronically infected with the ... HCV," write Thad Wilkins, MD, and colleagues from Medical College of Georgia in Augusta. "In the United States, the prevalence of hepatitis C antibody is 2 percent in adults 20 years and older, but the prevalence is higher in groups at increased risk (e.g., 8 to 9 percent in persons undergoing hemodialysis). HCV, a single-stranded RNA virus, is transmitted through percutaneous exposure to infected blood."
Serious morbidity, including cirrhosis or hepatocellular carcinoma, and mortality may result from chronic HCV infection.

At-risk populations should be tested for hepatitis C, and positive test results should be confirmed using polymerase chain reaction to quantify virus. In the general population, namely asymptomatic adults who are not at increased risk for infection, the US Preventive Services Task Force (USPSTF) recommends against routine screening for HCV infection.
The USPSTF also found insufficient evidence to recommend for or against routine screening of adults at high risk for HCV infection.
Treatment of patients with chronic HCV infection should include counselling them to abstain from alcohol use. Although no vaccine currently exists to prevent HCV infection, persons infected with HCV should be vaccinated against hepatitis A and B. Persons with chronic HCV infection and cirrhosis should periodically undergo ultrasound imaging as surveillance for hepatocellular carcinoma, according to recommendations from the American Association for the Study of Liver Diseases
Recommendations for Practice
Specific clinical recommendations for practice, and their accompanying level of evidence rating, are as follows:

Screening for HCV infection should not be performed in the general population of persons who are not at increased risk (level of evidence, A)

Persons with HCV infection should be vaccinated against hepatitis A and B (level of evidence, C).
Abstinence from alcohol is recommended for persons with chronic HCV infection (level of evidence, C).

Persons with chronic HCV infection and cirrhosis should avoid hepatotoxic drugs (level of evidence, C).

For persons with chronic HCV infection and cirrhosis, surveillance for hepatocellular carcinoma should be considered (level of evidence, C).

For chronic HCV infection, pegylated interferon and ribavirin is the standard treatment (level of evidence, C, because the outcome is a surrogate marker, namely sustained virologic response, rather than mortality).

"Other interferons (consensus interferon and albinterferon alfa-2b) and ribavirin alternatives (taribavirin) are being developed to improve the effectiveness, safety, and tolerability of therapy for chronic HCV infection," the review authors conclude.

" New protease inhibitors (telaprevir and boceprevir) are actively being investigated in phase 3 clinical trials. In the future, multidrug regimens will probably be used in combination with interferon and ribavirin."
The review authors have disclosed no relevant financial relationships.Am Fam Physician. 2010;81:1351-1357.
Abstract Authors and DisclosuresJournalistLaurie Barclay, MD Freelance writer and reviewer Medscape, LLC Disclosure: Laurie Barclay, MD, has disclosed no relevant financial relationships. .

For further details on any of the information in
this article call the Hep C Helpline:
9332 1599 (Sydney) or 1800 803 990
(regional NSW).
Mary Sawyer is a Sydney-based health and
medical writer.


The Hep C Review Edition 65 June 2009 17 feature

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