HCV Genotypes and Treatment
What Is a Genotype?
Have you ever had a key copied and found that the new key did not work very well or did not work at all?
If so, then you know that even a small difference can be very important. Although the keys may look the same, may be made from the same material, and have the same function, the shape of the new key may not match up as well with the keyhole.
In much the same way, small genetic differences between viruses can make them very different or only slightly different. In the case of hepatitis C, these differences can influence the way the virus responds to treatment.
The hepatitis C virus has 6 major known types (called
hepatitis C.
Molecular differences between genotypes are relatively large, and they have a difference of at least 30% at the nucleotide level. The major HCV genotype worldwide is genotype 1, which accounts for 40-80% of all isolates. Genotype 1 also may be associated with more severe liver disease and a higher risk of HCC. Genotypes 1a and 1b are prevalent in the United States, whereas in other countries, genotype 1a is less frequent. HCV genotype 1, particularly 1b, does not respond to therapy as well as genotypes 2 and 3. Genotype details are as follows:
- Genotype 1a occurs in 50-60% of patients in the United States; this type is difficult to eradicate using current medications
- Genotype 1b occurs in 15-20% of patients in the United States; subtype 1b is also difficult to eradicate using current medications; this type is most prevalent in Europe, Turkey, and Japan
- Genotype 1c occurs in less than 1% of patients in the United States
- Genotypes 2a, 2b, and 2c occur in 10-15% of patients in the United States; these subtypes are widely distributed and are most responsive to medication
- Genotypes 3a and 3b occur in 4-6% of patients in the United States; these subtypes are most prevalent in India, Pakistan, Thailand, Australia, and Scotland
- Genotype 4 occurs in less than 5% of patients in the United States; it is most prevalent in the Middle East and Africa
- Genotype 5 occurs in less than 5% of patients in the United States; it is most prevalent in South Africa
- Genotype 6 occurs in less than 5% of patients in the United States; it is most prevalent in Southeast Asia, particularly Hong Kong and Macao
Standard Therapy
The current standard of care by genotype is listed below:
• Genotype 1: a combination of pegylated interferon, ribavirin and an HCV
protease inhibitor (boceprevir or telaprevir). The standard duration of
treatment is a total of 24, 36 or 48 weeks.
o Pegylated interferon is a subcutaneous injection—once weekly.
o Ribavirin is a pill. The dose is based on body weight (1,000/1,2000mg) and divided
into two equal doses twice a day.
HCV protease inhibitor (boceprevir or telaprevir) is taken every 7 to 9 hours with
food – boceprevir can be taken with a snack or meal; telaprevir is taken with food that is
not low-fat.
• Genotypes 2 and 3: a combination of pegylated interferon and ribavirin taken for 24
weeks.
o Pegylated interferon is a subcutaneous injection—once weekly.
o Ribavirin is a pill. The dose is given 800mg daily—dose is divided into two equal doses.
Ribavirin is taken with food.
Source HCV Advocate
FDA approved direct-acting antiviral agents
In May of 2011 the first two direct-acting antiviral agents to treat hepatitis C- Boceprevir and Telaprevir were FDA approved, increasing SVR and cutting treatment duration in most genotype 1 patients. Both drugs are used with peginterferon and ribavirin.
Telaprevir and Boceprevir SVR Rates Compared To Standard Therapy
Increased SVR in genotype 1 patients with the addition of Telaprevir or Boceprevir .
In genotype 1 patients
Telaprevir
Pegylated interferon + ribavirin alone = 44% SVR
With the addition of telaprevir = 69-75% SVR
Boceprevir
Pegylated interferon + ribavirin alone = 38% SVR
With the addition of boceprevir = 63-66% SVR
Triple therapy for HCV geno1: telaprevir or boceprevir?
February 2012
The duration of protease inhibitor administration and the treatment paradigm are no doubt more streamlined with telaprevir. All patients begin telaprevir and PEG-IFN/RBV at the onset of treatment, receive 12 weeks of telaprevir and either 24 or 48 weeks of PEG-IFN/RBV. In contrast, the initiation of boceprevir is delayed by 4 weeks and is administered for 24, 32 or 44 weeks, whereas PEG-IFN/RBV IL combination is administered for 28, 32 or 48 weeks respectively. In contrast, boceprevir may have a somewhat more tolerable adverse event profile. Both agents exacerbate the anaemia of PEG-IFN/RBV to a similar extent. However, telaprevir is associated with a rash in over 50% of patients and several gastrointestinal symptoms..
Read more...
For Patients That Have Treated Previously
In clinical trials the SVR in patients who have treated previously with telaprevir was at 65% and for boceprevir 66%.
Although before Merck presented new data at this months liver meeting (AASLD) the trials with boceprevir did not include null responders. Vertex’s phase III REALIZE trial did test telaprevir in null responders, which produced a 31% SVR rate.
The new data presented at the 2011 November liver meeting from Merck showed that in an interim analysis, 38 per cent (16/42) of prior null responders achieved a sustained virologic response (SVR), meaning they were able to clear the virus from the body ,when treated with boceprevir in combination with peginterferon alfa and ribavirin.
View Press Release
Other factors that contribute to decreased SVR rates in both the new drugs and standard Peg-IFN/RBV treatment, include IL28B genotype ( IL28B for the new drugs -(in Clinical trials) , high baseline HCV RNA levels, cirrhosis or bridging fibrosis, and black or Latino ethnicity.
More on IL28B genotype
IL28B is a gene related to the interferon system. A genetic region near the IL28B gene is referred to as an IL28B genotype.
There are three variations of IL28B genotypes:
CC, CT or TT.
People with the two copies of the C allele of the gene respond best to treatment, while those with two copies of the T allele are most resistant. Those with one copy of each allele fall in the middle.
To learn more see;
Hey, I have a question about this IL28B gene and hepatitis c treatment.........
These variations have been associated with a person's response to treatment for hepatitis C with pegylated-interferon and ribavirin.
The CC variation is more frequent in Caucasians compared to African Americans (39 percent versus 16 percent), which may partially explain the lower response to treatment observed among African Americans in most clinical trials of pegylated-interferon and ribavirin.
A genetic factor: a single nucleotide polymorphism in the IL28b gene that has been shown to reduce the response to therapy, and may also cut the rate of spontaneous clearance
The IL28B polymorphism is the strongest pretreatment predictor of sustained virologic response in patients with HCV genotype 1. Personalized HCV treatment regimens based on pretreatment factors such as IL28B or on-treatment response may improve the efficacy and tolerability of treatment.
Re-treatment options with standard therapy
There are no effective re-treatment options with standard therapy . Patients who do not achieve a viral cure after treatment with 48 weeks of Peg-IFN/RBV therapy. Re-treatment with an additional 48 weeks of Peg-IFN/RBV results in SVR in only 5% to 20% of patients. Consequently.
Again, the recently FDA Approved Direct-acting antivirals, such as telaprevir or boceprevir, have proven effective for patients with genotype 1 who do not respond to first-line pegylated interferon alfa-ribavirin therapy or who relapse after the standard treatment.
New Study Telaprevir
In October of 2011 Vertex announced a Phase 3b study called CONCISE that will evaluate the potential for treatment with INCIVEK- (telaprevir) combination therapy to be shortened to 12 weeks in people with genotype 1 chronic hepatitis C who have the 'CC' variation near the IL28B gene.
The study is expected to enroll 350 people in the United States and Europe who are new to treatment or who have relapsed after at least one prior course of treatment with pegylated-interferon and ribavirin alone. The primary endpoint of the study is the proportion of patients who achieve a sustained viral response 12 weeks after the last planned dose of study drug (SVR12). Click here for more information.
EASL 2012-Updated May 9
Summary Of The 47th European Association for the Study of the
Liver EASL
The promise of all oral hepatitis C drug regimens were the highlight of the liver conference this year. For the
hepatitis C patient the drug developments in Interferon-free regimes will become the long awaited revolution in HCV treatment.........
May 2012
A special supplementary issue of Gastroenterology with full text viral hepatitis review articles and commentaries available through open access. Click here to view an index of articles.
March 2012
Treatment of chronic hepatitis C genotype 1 with triple therapy comprising telaprevir or boceprevir
A significant increase in the number of patients with CHC to be treated is expected for 2012, with triple
therapy regimens that are more complex. These expected developments represent
a significant challenge and will stretch current resources.
The present Swiss Association for the Study of the Liver (SASL) expert opinion statement
is not intended as guideline but shall provide some guidance on the management
of CHC genotype 1 and the use of TPV and BOC
March 2012
Protease inhibitors: Silver bullets for chronic hepatitis C infection?
Recent trials evaluated the safety and efficacy of two protease inhibitors, boceprevir (Victrelis) and telaprevir (Incivek), added to standard care with pegylated interferon and ribavirin, in patients with chronic hepatitis C virus (HCV) infection. These drugs open the door for triple therapy and other new therapies involving combinations of other direct-acting antiviral agents to
become the new standard of care for this population.
Key points
Standard care with the combination of pegylated interferon and ribavirin produces a sustained virologic response in about 40% of patients infected with HCV genotype 1, the most prevalent genotype in North America.
New phase 3 trials showed that the addition of an oral protease inhibitor (boceprevir or telaprevir) increased the sustained virologic response rates to 70% in patients infected with HCV genotype 1. Boceprevir and telaprevir must be used in
combination with pegylated interferon and ribavirin; they should not be used as monotherapy because of concern about the development of drug-resistant mutations.
The main side effects of boceprevir were anemia and dysgeusia. Adverse events associated with telaprevir included rash, pruritus, anemia, and diarrhea.
The treatment of hepatitis c virus (HCV) infection is on the brink of major changes with the recent approval of the first direct-acting antiviral agents, the protease inhibitors boceprevir (Victrelis) and telaprevir (Incivek).
Both drugs were approved by the US Food and Drug Administration (FDA) Advisory Panel for Chronic Hepatitis C in May 2011 and are believed to significantly improve treatment outcomes for patients with HCV genotype 1 infection.
This review summarizes the results of recent phase 3 clinical trials that evaluated the safety and efficacy of these new agents
Continue Reading....
An update on treatment of genotype 1 chronic hepatitis C virus infection: 2011 practice guideline by the American Association for the Study of Liver Diseases
These recommendations provide a data-supported approach to establishing guidelines. They are based on the following: (1) a formal review and analysis of the recently published world literature on the topic (MEDLINE search up to
June 2011); (2) the American College of Physicians' Manual for Assessing Health Practices and Designing Practice Guidelines;1
(3) guideline policies, including the AASLD Policy on the Development and Use of Practice Guidelines and the American Gastroenterological Association's Policy Statement on the Use of Medical Practice Guidelines;2
and (4) the experience of the authors in regard to hepatitis C.
Intended for use by physicians, these recommendations suggest preferred approaches to the diagnostic, therapeutic, and preventive aspects of care. They are intended to be flexible, in contrast to standards of care, which are
inflexible policies to be followed in every case. Specific recommendations are based on relevant published information. To more fully characterize the quality of evidence supporting recommendations, the Practice Guidelines Committee of
the AASLD requires a Class (reflecting benefit versus risk) and Level (assessing strength or certainty) of Evidence to be assigned and reported with each recommendation (Table 1, adapted from the American College of Cardiology
and the American Heart Association Practice Guidelines).3, 4
Continue Reading...
May 2012
Will Interferon-Free Regimens Prevail?
Many promising small molecule inhibitors directed against hepatitis C virus (HCV) proteins (direct-acting antiviral [DAA] agents) and compounds targeting host cell factors (host-targeting agents [HTAs]) are currently in the drug
development and...
March 2012
EASL:Hepatitis C-NEW DATA SUGGESTS INTERFERON-FREE THERAPY AROUND THE CORNER
June 2011
What’s Next for Hepatitis C
Source
By Jessica Wapner
Posted: June 9, 2011
Without question, the recent approvals of telaprevir (Vertex) and boceprevir (Merck) for the treatment of hepatitis C infection marks the beginning of a new time for hepatitis C. This advance is genuinely significant, and after all the me-too drugs and incremental gains we’ve all grown used to reading about, it’s exciting to see two medications that are making a real difference for a large portion of the 170 million people worldwide infected with the virus. The drugs are protease inhibitors; they work by blocking the enzyme that enables the virus to survive in a host.
And yet, much more remains. Here’s a look at what is still needed in the realm of hepatitis C care:
First, HCV comes in a variety of genotypes. The nucleotide sequence in one strain of hepatitis C varies up to 35% from another strain. Genotypes 1 and 4 have been the most difficult to treat, until the advent of the new drugs, which work excellently for patients with genotype 1. Genotypes 2 and 3 have traditionally responded well to the previous standard drugs (pegylated interferon plus ribavirin), with 80–90% of patients having the virus cleared from their body. The problem is that peg-IFN and ribavirin cause harsh side effects, and a lot of patients aren’t eligible because of pre-existing conditions, including, sometimes, depression. So there is a need for additional drugs that work in the other genotypes. Plus, even among genotype-1 patients, the new combination does not clear the virus in everyone.
Second-generation protease inhibitors are already in development and will likely be available in the next five years or so. These compounds will probably be less genotype-specific. Location could be a problem here. Genotype-1 is in North America, Europe and Asia. Genotypes 4 and 5 are prevalent in Africa, genotype 6 in Hong Kong, Macau and Vietnam, genotype 7 in Thailand, genotype 8 in Vietnam, and genotypes 10 and 11 in Indonesia. Will drug developers be willing to create new protease inhibitors for HCV patients in Vietnam and Indonesia? A non-specific inhibitor would do the trick, but whether the drugs will reach these patients of course remains to be seen.
There’s also the question of why not all genotype-1 patients respond to telaprevir and boceprevir (either of which is given in combination with peg-IFN and ribavirin). There are several possible explanations, according Ralf Bartenschlager, of Heidelberg University, and Charlie Rice, of Rockefeller University, both of whom were integral in the basic science that led to the new drugs. Interactions between these and other drugs might interfere with their potency. Patients not sticking with their treatment is another component. Some patients might metabolize the drugs too quickly, clearing them from their system before they have a chance to work their magic. And there might be variants of HCV that are already resistant to the new drugs. The virus can also become resistant during the course of treatment.
And HCV is, of course, a virus, capable of mutating any time. There could be hundreds of more genotypes in five years. It might be impossible to create a protease inhibitor that is nonspecific enough to work in everyone without losing the drug’s power.
Which leaves the looming issue of a vaccine. Hepatitis B has one; why not hepatitis C?
The variety of genotypes is one reason. That many varieties makes vaccination just as hard as creating a universal protease inhibitor. Developing a vaccine might not be possible until scientists come to thoroughly understand the origins of hepatitis C – where it came from, how it got into people, and how it made its way around the world. There’s an amazing tale to be told about that, but because no one wants to ruin a good story, I’ll save it for another time.
All of this focus on medications leads naturally to the question of prevention. Dirty needles are the primary route by which HCV is spread. (The virus is also spread through sex, but less easily, and through maternal transmission to the fetus.) So what’s going to be done about that? Helping people get off addictive injection drugs and to not start in the first place. Needle and syringe exchange programs. Increased access to treatment for chronic opiate addiction. There are few if any profits to be made in preventing dirty needle drug use, but when it comes to reducing the worldwide incidence of hepatitis C virus (3% of the world is infected), it’s really the only definite approach. And! It’s not genotype-specific.
Article Of Interest
The Origin Of Hepatitis:HCV and HBV Protons, Electrons, and Hepatitis C
More On Genotypes
Can persons become infected with different genotypes?
Yes. Because of the ineffective immune response described above, prior infection does not protect against reinfection with the same or different genotypes of the virus. For the same reason, there is no effective pre- or postexposure prophylaxis (i.e, immune globulin) available.
What is a Quasispecies?
As the virus continues to replicate in each person, there is the potential for quasispecies to form. Quasispecies are very closely related mutations of the original virus they were infected with. Over time the diversity of quasispecies increases and may affect response to treatment. View more here - HCV and Quasispecies
Links
Summary Of The 47th European Association for the Study of the Liver EASL - 2012
For a summary of the AASLD Nov 2011 Meeting Click Here .
Updates On Interferon Free Combinations, Click Here
For The Hepatitis C Treatments in Current Clinical Development, Click Here and Here
Related On The Web Site
Treatment and Genotype 4
Telaprevir Genotype 2
Individualizing Treatment Duration in Hepatitis C Virus Genotype 2/3-infected Patients
Role of HCV genotypes in severity of liver disease