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Genotypes

There are 6 known genotypes and more than 50 subtypes of hepatitis C.    The genotype of infection is helpful in defining the epidemiology of hepatitis C. Knowing the genotype or serotype (genotype-specific antibodies) of HCV is helpful in making recommendations and counseling regarding therapy. Patients with genotypes 2 and 3 are almost three times more likely to respond to therapy with alpha interferon or the combination of alpha interferon and ribavirin. Furthermore, when using combination therapy, the recommended duration of treatment depends on the genotype. For patients with genotypes 2 and 3, a 24-week course of combination treatment is adequate, whereas for patients with genotype 1, a 48-week course is recommended. For these reasons, testing for HCV genotype is often clinically helpful. Once the genotype is identified, it need not be tested again; genotypes do not change during the course of infection.

Considering HCV Treatment?—
Know Your Genotype and Viral Load

Alan Franciscus,
Editor-in-Chief, HCV Advocate-In the past, many reports listed the overall sustained virological response rates (SVR) of HCV medications regardless of genotype—this was misleading because SVR rates are dramatically affected by genotype. Now, many physicians quote the pivotal trial results of currently available HCV therapies by genotype.  However, a physician recently pointed out that the amount of HCV-RNA in the blood (viral load) also affects treatment response rates and commented that this is an important consideration to include along with genotype when interpreting HCV treatment response rates.  In this article, I will review the current data available on sustained virological response rates broken down by genotype and viral load.

HCV RNA – Viral Load

HCV Viral load tests measure the amount of HCV circulating in the blood.  HCV viral load is expressed as either copies per milliliter of blood or as a standard unit of measurement called International Units (IU).  HCV viral load tests are used to confirm active HCV infection, to predict medical treatment response, and to measure how well HCV medications are working.

A low viral load (LVL) is defined as <2 million copies/ml or 800,000 IU/ml and a high viral load (HVL) is defined as >2 million copies/ml or 800,000 IU/ml.  Even though the pivotal pegylated interferon combination trails used different assays, in general a low viral load (LVL) is defined as < 2,000,000 copies/ml or 800,000 IU/ml.  For exact conversion by assay please refer back to the May Advocate.

Genotype

HCV has many different strains called genotypes.  There are enough genetic differences to classify them into six major genotypes:  1, 2, 3, 4, 5, and 6. Genotype information is important when considering HCV treatment since some genotypes respond more favorably to medications than others with, non-1 genotype responding more favorably.  Genotype also determines the length of therapy needed with genotype 2 and 3 requiring only 24 weeks in comparison to genotype 1 and 4 require 48 weeks.  At this time there is not enough data to make definitive recommendations on other genotypes.

Genotype and Viral Load

Breaking HCV down by genotype and viral load in the United States further clarifies the issues of treatment response rates: genotype 1 comprises 74% of the overall population—49.5% with a high and 24.5% with a low viral load. That means that two-thirds of patients with genotype 1 have genotype 1 high viral load or to look at it another way—one-half of the U.S population with hepatitis C have genotype 1 high viral load.  This contrasts with 26% of the population with genotype non-1—of which 17.4% have a high and 8.6% have a low viral load.

Therefore in the United States, regardless of genotype, two thirds of the hepatitis C population has a high viral load.

Clinical Trials – Prospective vs. Retrospective

The most reliable research results come from a prospective study, which is carefully planned and conducted in a standard manner with well-defined patient populations as well as a protocol that includes predetermined primary and secondary endpoints.  This is considered the gold standard of clinical research.  On the other hand, a retrospective study looks back in time, which is subject to bias because certain assumptions are made that may not be valid.  For instance, a retrospective study may look at previous study results and try to ascertain if treatment response rates would be improved using a higher dose of the study drug. However, you can not draw any concrete conclusions since you did not actually study the tolerability at a higher dose in all participants.  Retrospective studies are, however, useful in determining what should be studied prospectively and therefore do have a role in medical science.  

Standard of Care – PEG Plus Ribavirin

Pegylated interferon and ribavirin is now the standard of care for the treatment of hepatitis C.  There are two available pegylated interferon combinations, Peg Intron (pegylated interferon alpha 2b – Schering Plough) plus Rebetol (Schering’s branded ribavirin) and Pegasys (pegylated interferon alpha 2a – Roche) plus Copegus (Roche’s branded ribavirin).  There have not been any large head to head trials of these pegylated products but in their development programs both companies compared their pegylated combination to standard interferon plus ribavirin with almost fifty percent of the same investigator sites, so some accurate comparisons can be drawn from the data between the two PEG products as it relates to efficacy or effectiveness in certain genotype and viral load groups.

Peg Intron Plus Rebetol

Firstly, I reviewed the data on Peg Intron 1.5µg/kg plus 800mg Rebetol.  Schering only conducted one combination trial, the data for which was published in The Lancet vol. 358, September 22^nd, 2001 by Michael Manns.  There is also additional supplemental information available from the FDA web site review of the Mann’s data www.fda.gov as well as the US FDA package insert (USPI) for Peg Intron.  Here are the results:

Sustained Virologic Response for Genotype 1

Sustained Virologic Response for Genotype 2/3

It is clear from the above table that the perceived advantage of Peg Intron plus Rebetol in genotype 1 in not entirely accurate.  The overall SVR for genotype 1 patients with Peg Intron is totally driven by the improved efficacy in genotype 1 low viral load patient.  Patients with genotype 1 and a high viral load (1/2 of the U.S. population with hepatitis C), will not get any increased efficacy or effectiveness over Rebetron with Peg Intron plus Rebetol combination therapy in the doses studied.  It is also interesting to note that the genotype non-1 efficacy in high viral load patients is also no better than Rebetron.  In summary two thirds of the patients in the United States with hepatitis C have no increased efficacy with Peg Intron plus Rebetol in the doses studied in Schering’s development program.

One could argue that if higher doses of Rebetol were used in the original trial then the results would be better across all patients but is that really true?  A retrospective analysis of the pivotal trial which is included in the Lancet publication looked at a subset of patients that recieved >10.6mg/kg of Rebetol.  Because everyone in the prospective trial recieved only 800mg of Rebetol, the retrospective analysis was only looking at a subset of patients that were lighter, probably female who have prognostic factors in their favor for an SVR.  To extrapolate the results from that subset across all patients is not a medically sound approach to a retrospective analysis and so Schering is now trying to prospectively look at this and a very large trial known as the WIN-R trial is underway.  According to FDA documents the reason that Schering did not originally study higher doses of Rebetol in the Peg Intron 1.5µg/kg arm is that they were concerned about potential drug toxicities.  The original pivotal trial had a dose modification rate of 42% with only 800mg Rebetol, which is sure to increase with higher doses of Rebetol.  This issue however may be overcome in the WIN-R trial as it does allow for the use of growth factors such as erythropoietin (EPO) and granulocyte macrophage colon-stimulating factor (GM-CSF). But how available are they to the general population with hepatitis C?

Pegasys plus Copegus

Now let’s review the data on Pegasys 180µg plus 1000-1200mg Copegus.  Roche conducted two trials, the first is published in the New England Journal of Medicine 2002; 347(13):975-82 and the second was presented at EASL 2002 by Hadziyannis and is awaiting publication.  Here are the results:

Sustained Virologic Response for Genotype 1

Sustained Virologic Response for Genotype 2/3

The data for Pegasys plus Copegus shows a marked improvement over standard interferon plus ribavirin combination in all patient types regardless of genotype or viral load. So why the difference in the results between the PEGs?

A Peg is Not a Peg

Many people refer to the two pegylated interferons as though they are the same products but manufactured by different companies—based upon the prospective data that is available to date this doesn’t seem to be the case.  Interestingly, the information that was brought to my attention as it relates to the differences in the PEG’s efficacy in high viral load patients may explain the differences in the PEG’s.  It is believed that this difference is a result of the different types of pegylation processes used by each company.  Peg Intron is the result of earlier pegylation technology using a smaller linear peg that weakly attaches to the interferon molecule, which is the reason that Peg Intron comes in a powered form that requires reconstitution—it is unstable.  This type of pegylation helped in the fact that Peg Intron doesn’t need to be dosed three times a week, but it still acts similarly to standard interferon with periods at the end of each week when there is no detectable Peg Intron.  It has not been determined how much interferon is needed to suppress the hepatitis C virus but one could theorize that if there is no drug in the body of someone with a high viral load—there is an opportunity for the virus to replicate, mutate and bounce back.  This may explain the lack of improvement in response rates of Peg Intron over standard interferon in patients with a high viral load regardless of genotype.

Pegasys on the other hand is the result of later pegylation technology which uses a larger branched peg that very tightly attaches to the interferon, which explains why it is stable enough to be made in a ready made liquid formulation—it is very stable.  This type of pegylation provides Pegasys with constant suppression of the hepatitis C virus from the first dose injected to when therapy is completed.  Levels of Pegasys gradually increase until around week 5-8 when steady state is established.  We know that the hepatitis C virus replicates trillion of virions a day and that constant suppression of the virus is critical, especially in patients with a high viral load (>2 million copies/ml).

In summary, we have known for a while that it is not enough to just look at overall treatment response rates.  We now know, however, that viral load and genotype should also be separated out when reporting treatment response rates.  Patients and health care providers should be carefully reviewing all data, including medication, viral load and genotype as well as carefully questioning how the prospective data is being marketed and which can be misleading.

Acute Hepatitis C

Acute hepatitis C is diagnosed on the basis of symptoms such as jaundice, fatigue, and nausea, along with marked increases in serum ALT (usually greater than 10-fold elevation), and presence of anti-HCV or de novo development of anti-HCV. Diagnosis of acute disease can be problematic because anti-HCV is not always present when the patient presents to the physician with symptoms. In 30 to 40 percent of patients, anti-HCV is not detected until 2 to 8 weeks after onset of symptoms. Acute hepatitis C can also be diagnosed by testing for HCV RNA, but another approach is to repeat the anti-HCV testing a month after onset of illness.

 Chronic Hepatitis C

Chronic hepatitis C is diagnosed when anti-HCV is present and serum aminotransferase levels remain elevated for more than 6 months. Testing for HCV RNA (by PCR) confirms the diagnosis and documents that viremia is present; almost all patients with chronic infection will have the viral genome detectable in serum by PCR. Diagnosis is problematic in patients who cannot produce anti-HCV because they are immunosuppressed or immunoincompetent. Thus, HCV RNA testing may be required for patients who have a solid-organ transplant, are on dialysis, are taking corticosteroids, or have agammaglobulinemia. Diagnosis is also difficult in patients with anti-HCV who have another form of liver disease that might be responsible for the liver injury, such as alcoholism, iron overload, or autoimmunity. In these situations, the anti-HCV may represent a false-positive reaction, previous HCV infection, or mild hepatitis C occurring on top of another liver condition. HCV RNA testing in these situations helps confirm that hepatitis C is contributing to the liver problem. 

Differential Diagnosis

The major conditions that can be confused clinically with chronic hepatitis C include

•Autoimmune hepatitis

•Chronic hepatitis B and D

•Alcoholic hepatitis

•Nonalcoholic steatohepatitis (fatty liver)

•Sclerosing cholangitis

•Wilson's disease

•Alpha-1-antitrypsin-deficiency-related liver disease

•Medication-induced liver disease.

The Future of Hepatitis C: Research

Basic Research
A major focus of hepatitis C research is developing a tissue culture system that will enable researchers to study HCV outside the human body. Animal models and molecular approaches to the study of HCV are also important. Understanding how the virus replicates and how it injures cells would be helpful in developing a means of controlling the virus and in screening for new drugs that would block it.

Diagnostic Tests
More sensitive and less expensive assays for measuring HCV RNA and antigens in the blood and liver are needed. Although current tests for anti-HCV are quite sensitive, a small percentage of patients with hepatitis C test negative for anti-HCV (false-negative reaction), and a percentage of patients who test positive are not infected (false-positive reaction). Also, there are patients who have resolved the infection but still test positive for anti-HCV. Convenient tests to measure HCV in serum and to detect HCV antigens in liver tissue would be helpful. 


New Treatments
Most critical for the future is the development of new antiviral agents for hepatitis C. Most interesting will be specific inhibitors of HCV-derived enzymes such as protease, helicase, and polymerase inhibitors. Drugs that inhibit other steps in HCV replication may also be helpful in treating this disease, by blocking production of HCV antigens from the RNA (IRES inhibitors), preventing the normal processing of HCV proteins (inhibitors of glycosylation), or blocking entry of HCV into cells (by blocking its receptor). Nonspecific cytoprotective agents might also be helpful for hepatitis C by blocking the cell injury caused by the virus infection. Further, molecular approaches to treating hepatitis C are worthy of investigation; these consist of using ribozymes, which are enzymes that break down specific viral RNA molecules, and antisense oligonucleotides, which are small complementary segments of DNA that bind to viral RNA and inhibit viral replication. All of these approaches remain experimental and have not been applied to humans. The serious nature and the frequency of hepatitis C in the population make the search for new therapies of prime importance. 

Prevention
At present, the only means of preventing new cases of hepatitis C are to screen the blood supply, encourage health professionals to take precautions when handling blood and body fluids, and inform people about high-risk behaviors. Programs to promote needle exchange offer some hope of decreasing the spread of hepatitis C among injection drug users. Vaccines and immunoglobulin products do not exist for hepatitis C, and development seems unlikely in the near future because these products would require antibodies to all the genotypes and variants of hepatitis C. Nevertheless, advances in immunology and innovative approaches to immunization make it likely that some form of vaccine for hepatitis C will eventually be developed.
http://www.niddk.nih.gov/health/digest/pubs/chrnhepc/chrnhepc.htm

Issues For Partners, Parents, Family And Friends

Except for blood to blood contact, the virus is quite difficult to pass on.
Each person's razor blades and toothbrushes should be kept separate. Blood spills should be washed up with paper towels and bleach and cuts or grazes should be cleaned and covered with water proof dressings.
Blood stained items should be placed in plastic bags before disposal in the garbage.