Genotype refers to the genetic make-up of an organism or a virus. There are at least six distinct HCV genotypes identified. Genotype 1 is the most common genotype seen in the U.S. HCV is an RNA virus related to the flavivirus family. RNA viruses are genetically less stable than DNA viruses and are prone to mutate during replication. It’s a common misconception that hepatitis C is just one virus, but in reality (as a result of mutation over hundreds of years), it’s a group of very closely related strains. They are similar enough to be called HCV, but based on genetic differences, they can be classified into distinct groups called genotypes.

What is a Genotype? (How many different types are there?)
Our special thanks to Sharon Nicholson

One way to understand the terminology of HCV like ‘genotypes’ and ‘subtypes’ is to compare them to things that we can more readily relate to.

Example:

Imagine that Viruses are like canines. Dogs have evolved into different types, just like the thousands of different viruses. Imagine that all terriers are the hepatitis C viruses, Now each type of terrier is representing different genotypes of Hepatitis C.

All terriers are still dogs, but the Australian Terrier is different from the Fox Terrier, just as the Bull Terrier is different from the Border Terrier.

You could take one major terrier type and imagine these as being one of HCV’s main types (genotypes). Like the Schnauzer. There are different types of Schnauzers like the Miniature and the Standard. That represents the different subgroups within each genotype.

Now scientists predict that people who have hepatitis C, have billions of actual viruses circulating within their body. Although there may be one or two predominant sub-types, the infection as a whole is not a single entity and is composed of many different quasispecies.

It’s believed that of the estimated 160,000 Australians with HCV, approx. 35% have subtype ‘1a’, 15% have ‘1b’, 7% have ‘2’, 35% have ‘3’ (mostly being 3a). The remaining people would have other genotypes.

Genotype and Treatment

Current scientific belief is that factors such as which genotype patients carry, their duration of a HCV infection, their HCV viral load, their age, and grade of liver inflammation or stage of fibrosis may play an important role in determining response to interferon treatment. Recent studies have suggested that a person’s HCV subtype is the key-factor that influences their possible response to interferon, or interferon-ribavirin combination treatment.

It is very important to find out which genotype you carry.

Most of us learn about Hepatitis C as one disease, however in actuality it's really several different strains of a virus. They are all similar enough to be called hepatitis C virus, yet different enough to be classified into subgroups.

HCV GENOTYPES are broken down into sub-types, some of which include: 1a, 1b, 1c 2a, 2b, 2c 3a, 3b 4a, 4b, 4c, 4d, 4e 5a 6a 7a, 7b 8a, 8b 9a 10a 11a

Genotype Geography Patterns:

It is believed that the hepatitis C virus has evolved over a period of several thousand years. This would explain the current general global patterns of genotypes and subtypes:

1a - mostly found in North & South America; also common in Australia

1b - mostly found in Europe and Asia.

2a - is the most common genotype 2 in Japan and China.

2b - is the most common genotype 2 in the US and Northern Europe.

2c - the most common genotype 2 in Western and Southern Europe.

3a - highly prevalent here in Australia (40% of cases) and South Asia.

4a - highly prevalent in Egypt

4c - highly prevalent in Central Africa

5a - highly prevalent only in South Africa

6a - restricted to Hong Kong, Macau and Vietnam

7a and 7b - common in Thailand

8a, 8b & 9a - prevalent in Vietnam

10a & 11a - found in Indonesia

Is it necessary to do genotyping when managing a person with chronic hepatitis C?
No. Although persons with genotype 1 respond less often to treatment, genotype should not be a deciding factor on whether or not to treat. With newer therapies, however, treatment regimens might differ on the basis of genotypes.

Why do most persons remain infected?
Persons infected with HCV mount an antibody response to parts of the virus, but changes in the virus during infection result in changes that are not recognized by preexisting antibodies. This appears to be how the virus establishes and maintains long-lasting infection.

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.

Do Genotypes Play a role in Disease Progression?
This is still a controversial area. Many studies have shown genotype 1, especially type 1b to be associated with more advanced liver disease, however these patients are generally older and have a longer duration of infection. Poynard et al assessed factors associated with fibrosis progression in a large study involving 2,235 patients. No link was found between genotype and fibrosis progression.

What about Genotypes and Treatment?
Research has shown people with genotypes 2 or 3 have a higher sustained response rate (60-70%) to combination therapy than genotype 1 (20-30%). However other factors such as stage of fibrosis or cirrhosis, viral load, age, gender, duration of disease and excessive alcohol consumption also influence response to therapy.

Furthermore the duration of treatment is also influenced by genotype. Previously untreated patients with genotype 1 double their chance of a sustained response when treated for 12 months instead of 6 months. Conversely 12 months treatment for patients with genotypes 2 or 3 does not improve response rates over 6 months treatment.

Can Genotypes be used in studying the Modes of Transmission?
Genotyping has been used to study the ways hepatitis C is transmitted. It has been used to identify the source of infection in cases of patient-to-patient transmission and is also useful in the study of other modes eg. vertical (mother to baby), sexual transmission and needle stick injury.

June 11, 2008

Determining HCV Treatment Success: Early Response Trumps Genotype

As presented at the April 2008 meeting of the European Association for the Study of the Liver, a rapid virological response can help clinicians customize the length of treatment for Hepatitis C – regardless of genotype.

by Nicole Cutler, L.Ac.

There is much debate among experts about the duration of treatment required for treating the Hepatitis C virus (HCV). As prescribed by physicians worldwide, the standard duration of a prescription for pegylated interferon (Pegasys or PegIntron) plus weight-based ribavirin differs depending on the patient’s genotype. However, recently announced research suggests that duration of treatment is best based on the individual’s virological response at specific intervals rather than their genotype.

The standard course of treatment is established by analyzing the results of large clinical trials. As determined by computational averages, these trials provide analysts with an ideal regimen for the population as a whole. In general, the standard duration of treatment is 24 weeks for HCV genotypes 2 and 3, and 48 weeks for HCV genotype 1. Despite this traditionally used model for determining treatment length, researchers have been finding that the best approach for Hepatitis C may veer away from this standardization and lean towards individual customization.

Historically, HCV genotype is the single most important predictor of a person’s outcome from treatment with pegylated interferon and ribavirin. Defined as a sustained viral response, a successful outcome is when the virus is undetectable in the blood six months after treatment ends.

The statistics consistently demonstrate that while about 50 percent of those with genotype 1 will achieve a sustained virologic response (SVR), between 70 and 90 percent of patients with genotype 2 or 3 will achieve SVR. Regardless of HCV genotype, experts have observed that patients who respond quickly to drug treatment are also more likely to be cured by them. Because pegylated interferon and ribavirin therapy is costly and carries the risk of serious side effects, scientists are continuously exploring new ways of predicting SVR so that the length of treatment can be customized for each patient.

The week of April 23-27, 2008, the 43rd annual meeting of the European Association for the Study of the Liver was held in Milan, Italy. Along with the myriad of revelations at this meeting, researchers presented a retrospective analysis of three randomized trials that demonstrated a rapid virologic response (RVR) to be superior to HCV genotype at predicting sustained virologic response.

Upon studying the outcomes of three trials, which, collectively, followed nearly 1,400 people receiving treatment for HCV, analysts compared these two factors for predicting SVR:

1. HCV genotype
2. RVR – defined as undetectable viral load after only four weeks of treatment

Among those achieving RVR in just four weeks of treatment, most (over 86 percent) achieved SVR independent of their HCV genotype. The value of this information applies to the scientists who calculate treatment time and to the physicians administering pegylated interferon and ribavirin treatment for HCV. The researchers recommended including RVR into the computations for treatment duration. In addition, they advise using an individual’s response to treatment after just one month to customize drug regimens regardless of genotype.

The debate over exactly how much medication for how long continues to churn in the Hepatitis C scientific community. By varying the treatment duration based on an individual’s early response, unnecessary side effects and costs of interferon and ribavirin can be spared. As factors other than genotype emerge as predictive of future treatment success, clinicians gain more insight into guiding their patients toward a customized, best possible outcome.

References:
Dalgard, Olav, et al., A Randomized Controlled Trial of Pegylated Interferon Alfa and Ribavirin for 14 vs. 24 Weeks in Patients with HCV Genotype 2 or 3 and Rapid Virological Response, Hepatology, January 2008.

Fried MW, et al., Rapid virological response is a more important predictor of sustained virological response (SVR) than genotype in patients with chronic hepatitis C virus infection, Program and abstracts of the 43rd Annual Meeting of the European Association for the Study of the Liver, Journal of Hepatology, April 2008.

http://clinicaloptions.com , RVR a Better Predictor of SVR Than HCV Genotype in HCV-Infected Patients With Peginterferon alfa-2a Plus Ribavirin, Clinical Care Options LLC, 2008.

Mangia, Alessandra, et al., Individualized Treatment Duration for Hepatitis C Genotype 1 Patients: A Randomized Controlled Trial, Hepatology, January 2008.

www.hcvadvocate.org , Adjustment of Treatment Duration Based on Early Response, Liz Highleyman, HCV Advocate, The Hepatitis C Support Project, March 2008.

www.hivandhepatitis.com , Duration of Pegylated Interferon plus Ribavirin May Be Tailored Based on Early Patient Response, Liz Highleyman, hivandhepatitis.com, 2008.

www.hivandhepatitis.com , HCV Genotype Is the Strongest Predictor of Sustained Virological Response after Retreatment of Hepatitis C Patients: Final Results of EPIC 3, hivandhepatitis.com , 2008.

www.natap.org , Virological response at 4 and 12 weeks predict high rates of sustained virological response in genotype 1 patients treated with peginterferon alfa-2a (40KD) plus ribavirin, Jules Levin, EASL, April 2007.

Posted by Editors at June 11, 2008 12:26 PM

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May 01, 2008

Highly Effective Against HCV Genotype 1

When tested on people with Hepatitis C genotype 1, R7128 proved to be an effective addition to combination therapy after just four weeks' time. In addition to its anti-viral effect, polymerase inhibitor R7128 received good marks for safety and minimal side effects.

R7128 is Safe, Effective in Short-Term for Patients With Hepatitis C Virus Genotype 1: Presented at EASL

By Emma Hitt, PhD

www.docguide.com

MILAN, Italy -- April 29, 2008 -- R7128, a potent inhibitor of hepatitis C virus (HCV) polymerase, appears effective and well tolerated at week 4 after initiation of treatment in combination with pegylated interferon alfa-2a (PEG-INF)/ribavirin, according to interim findings of a randomised trial of patients with genotype 1 HCV, researchers reported here at the 43rd Annual Meeting of the European Association for the Study of the Liver (EASL).

John McHutchison, MD, Associate Director, Duke Clinical Research Institute, Durham, North Carolina, described how the study sought to evaluate the efficacy and safety of R7128 at a dose of 500 mg BID (n = 20) and 1500 mg BID (n = 20), compared with placebo (n = 10) at 4 weeks; each arm also received PEG-INF/ribavirin. Patient characteristics were similar among study arms.

R7128 demonstrated a dose-dependent effect on efficacy parameters. Patients in the placebo group had a 2 log10 reduction in HCV RNA, compared with a 3 log10 reduction of in the 500-mg BID arm and a 5 log10 reduction in the 1500-mg BID arm. Rapid viral response was achieved in 10%, 30%, and 95% of patients in the placebo arm, the 500-mg BID, and the 1500-mg BID R7128 arms, respectively. alanine aminotransferase normalisation was achieved in 60%, 80%, and 70% of the 3 arms, respectively.

R7128 was generally well tolerated, with no apparent serious adverse events associated with R7128. The most common mild adverse events with the 1500-mg BID dose included fatigue (40% vs 20% in placebo), chills (35% vs 20% in placebo), and headache (65% vs 40% in placebo). No evidence of additional haematologic adverse events with R7128 was noted. In addition, amylase, bilirubin, blood urea nitrogen, and creatinine measurements were comparable at week 4 among treatment arms, with no evidence of renal toxicity.

Dose reductions and discontinuations were similar among treatment arms. One patient receiving R7128 1500 mg BID discontinued all treatment due to anorexia, diarrhea, and weight loss on study day 24.

"We observed a significant antiviral effect of R7128 in combination with PEG-INF [plus ribavirin] at week 4," Dr. McHutchison concluded. "Approximately 85% of patients receiving R7128 achieved undetectable HCV RNA by week 4."

According to Dr. McHutchison, two additional cohorts will be enrolled in the current 4-week triple combination study: a 1000-mg BID arm in treatment-naive patients with genotype 1 HCV and a 1500-mg BID arm in treatment-experienced patients with genotype 2 or 3 HCV. Both arms will also receive PEG-INF/ribavirin. An international phase 2b study is also underway to evaluate R7128 in triple combination for up to 12 weeks.

Funding for this study was provided by Roche.

[Presentation title: Potent Antiviral Activity of the HCV Nucleoside Polymerase Inhibitor R7128 With PEG-IFN and Ribavirin: Interim Results of R7128 500mg BID for 28 Days. Abstract 66]

http://www.hepatitis-central.com

April 29, 2008

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Improves Outcome for Hep C Genotype 4

Currently approved for treating contagious diarrhea in children, nitazoxanide has been found to make pegylated interferon-based treatment for Hepatitis C genotype 4 more effective. Prompting new trials in the U.S. and Europe, this drug is now being evaluated for Hepatitis C genotype 1.

Nitazoxanide Demonstrates Activity in Treatment-Naive Patients With Hepatitis C Virus Genotype 4: Presented at EASL

By Emma Hitt, PhD

www.docguide.com

MILAN, Italy -- April 29, 2008 -- Nitazoxanide significantly improves response to pegylated interferon (PEG-IFN)-based therapy in patients with chronic hepatitis C virus genotype 4 (HCV-4), according to new research findings presented here at the 43rd Annual Meeting of the European Association for the Study of the Liver (EASL).

Jean-Francois Rossignol, MD, Research Scientist, and Cofounder, Romark Institute For Medical Research, Tampa, Florida, reported the results of a randomised trial of nitazoxanide, an oral agent that targets host-cell interactions with HCV. Dr. Rossignol and colleagues sought to evaluate the antiviral activity and safety of nitazoxanide in combination with PEG-IFN alfa-2a, with or without ribavirin.

A total of 120 patients with chronic HCV-4 were sequentially randomised to 1 of 3 treatment arms. The first arm was a standard-of-care arm: PEG-IFN alfa-2a plus ribavirin (RBV) for 48 weeks. The second arm was nitazoxanide for 12 weeks followed by nitazoxanide plus PEG-IFN alfa-2a for 36 weeks. The third arm was a triple therapy consisting of nitazoxanide for 12 weeks followed by nitazoxanide combined with PEG-IFN alfa-2a plus RBV for 36 weeks.

PEG-IFN alfa-2a was injected by clinical investigators at 180 mcg/kg/week while ribavirin was dosed at 1000 to 1200 mg/day. Nitazoxanide was administered at 500 mg twice daily with food.

Patients were previously untreated, with the exception of 12 interferon-experienced patients included in each of the nitazoxanide-containing arms.

During the monotherapy lead-in phase with nitazoxanide, a modest (0.25 log10) but statistically significant decrease in HCV ribonucleic acid (RNA) from baseline to week 12 was observed (P = .0032). Out of 76 patients, 5 had a drop in HCV RNA of greater than 1 log10 from baseline to week 12; and 1 patient had undetectable HCV RNA, with a 5.4 log10 decline in HCV RNA and normalised alanine aminotransferase (ALT) test results at week 12. There was no significant change in overall ALT measurements during the lead-in period.

Among the interferon-naive patients (n = 96), the patients receiving the triple regimen (nitazoxanide plus PEG-IFN plus RBV) achieved a higher sustained viral response (SVR) than the patients receiving the standard of care (79% vs 50%; P = .023). In the nitazoxanide arm without RBV, the SVR was 61%. The rapid viral response (RVR) was also higher in patients receiving the triple therapy compared with those receiving the standard of care (64% vs 38%; P = .048).

In the interferon-experienced patients (n = 24), no efficacy differences were observed between the 2 nitazoxanide-containing arms (not compared with standard of care).

"Adverse events in the overall population were characteristic of those typically observed with pegylated interferon and ribavirin, with no additional effects resulting from nitazoxanide," Dr. Rossignol noted here on April 25. "Additional clinical trials of nitazoxanide in interferon-naive patients and nonresponders to pegylated interferon plus ribavirin have been initiated in patients with HCV genotype 1 in the United States and Europe."

Nitazoxanide was initially developed as an antiprotozoal, antiviral, and antibacterial agent, and is approved for the treatment of diarrhoea caused by Cryptosporidium and Giardia in children. Nitazoxanide has since shown activity against HCV and hepatitis B virus.

[Presentation title: Randomized Controlled Trial of Nitazoxanide-Peginterferon-Ribavirin, Nitazoxanide-Peginterferon and Peginterferon-Ribavirin in the Treatment of Patients With Chronic Hepatitis C Genotype 4. Abstract 68]

December 31, 2008

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Hepatitis C Genotype Guides Health Plans

Because the suggested treatment length and success rates vary between genotypes, this is typically one of the first distinctions made after a Hepatitis C diagnosis. In order to assure the correct course of therapy is approved, health insurance companies are demanding to know their members' Hepatitis C genotype.

Genotype Testing Is Crucial to Course of Therapy for Hepatitis C Patients

December 30, 2008

Reprinted from SPECIALTY PHARMACY NEWS, a monthly newsletter designed to help health plans, PBMs, providers and employers manage costs more aggressively and deliver biotechs and injectables more effectively.

By Angela Maas, Managing Editor, (amaas@aispub.com)

With hepatitis C patients, the length of treatment depends upon which of the six hepatitis C genotypes the person has. According to Beckie Fenrick, Pharm.D., director of clinical pharmacy at Blue Cross and Blue Shield of Florida, the treatment regimen for genotypes 2 and 3 is generally 24 weeks, while the regimen for 1, 4, 5 and 6 is 48 weeks. The most common genotypes in the U.S. are 1, 2 and 3.

Many health plans require physicians to provide the organization with the genotype information so they can be sure the patient is receiving the appropriate length of therapy. According to Enoch Strollo, vice president of sales and marketing for BioPlus Specialty Pharmacy, genotype testing costs typically between $450 and $600, and health plans typically cover this expense.

Some plans that spoke to SPN say they require genotype testing either before therapy begins or shortly thereafter.

According to Beverly Franklin-Thompson, Northeast regional pharmacy director for BlueCross BlueShield of Tennessee, BCBST allows patients to immediately begin treatment but then requires the physician to follow up with the patient's genotype. "This minimizes impediments to treatment initiation, allowing a patient to immediately fill the prescriptions for the hepatitis C medications," she says. After a physician notifies BCBST of the patient's genotype, "an approval for a specific duration of treatment is granted," she explains. "A nurse contacts the prescriber to assure that certain tests are being performed and to obtain the results of those tests so that the duration of treatment can be determined and authorization loaded. No prior authorization is required to begin therapy; however, to continue treatment beyond the first few months, clinical parameters such as genotyping must be obtained."

The Florida Blues plan requires physicians to determine patients' genotype so it can make sure patients undergo the appropriate length of therapy. The plan also has practitioners notify it of patients' viral loads at the 12-week mark. If there has been "an appropriate reduction, the approval for additional weeks occurs," Fenrick explains. CIGNA HealthCare also requires a follow-up lab test after the first 12 weeks of therapy, says Todd Cooperman, Pharm.D., director of specialty pharmacy clinical program development.

Mark Leeper, vice president of marketing and clinical program development for PrecisionRx Specialty Solutions, WellPoint, Inc.'s specialty pharmacy, says that when a plan does not require genotype testing, "we do highly encourage it." He explains that "a member's hepatitis C genotype will drive treatment and monitoring. Type 1 genotype is more difficult to treat and requires members to stay on the therapy longer. Also, changes in viral load are influenced by genotype. We conduct baseline information on viral load, and then repeat testing for all genotypes at four, 12 and 24 weeks. For Type 1, we continue testing at 36 weeks and 48 weeks. This schedule is important to allow physicians to adjust dosing to respond to the patient's viral load."

He says if those patients with genotype 1 "don't respond by week 12, they are unlikely to respond, and continuing with therapy is not productive."

Sara Deno, Pharm.D., a manager of clinical services for BioScrip, Inc., who also oversees the adherence and therapy optimization program BioScripCare for hepatitis C, says that plans can structure prior authorizations so that patient response is checked at various intervals.

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URL for Article Source:
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Posted by Editors at December 31, 2008 09:26 AM