The two major aspects of Knodell's criteria are the degree of inflammation (Grades 1 through 4, with 4 being the more severe) and the degree of fibrosis (Stages 1 through 4). The more advanced the stage of fibrosis reflects the closer the patient is to developing cirrhosis. Cirrhosis itself is classified differently and will not be discussed further here.
To illustrate the influence of the above factors on outcomes of treatment, one can look at patients who have non-type 1 genotype (genotype 2 or 3). This patient population may achieve rates of sustained response (SR) twice as high as those patients with genotype 1. (It is thought that genotypes 4, 5 and 6 may have similar response rates. However, firm conclusions regarding these last three genotypes are difficult to establish because the relative smaller distribution in the population.) For genotypes 2 and 3, a six-month treatment course is as effective as a twelve-month treatment course. Conversely, genotype 1 has a significant increase in sustain viral response at twelve-month versus six months (30 percent vs. 17 percent respectively).
Viral load also affects Hepatitis C outcomes. In general, if the viral load is greater than 2 million copies per milliliter (copies/ml) the response rates decreases in all patients irrespective of their genotype. However, if a patient has less than 2 million copies per milliliter, and a genotype 1, a six-month course of therapy is as effective as a twelve-month course of therapy (32 percent vs. 33 percent respectively).
Thus, patients with HCV are different based upon many different characteristics. Consultation with a trained hepatologist or gastroenterologist experienced with HCV is strongly recommended.
- History of Hepatitis C Treatment
In the 1980's, a group of investigators published results of a study involving six months treatment with interferon (alpha 2b 3 MU SQ TIW for six months). Previously, no adequate therapy for HCV had been identified. These results showed this treatment which resulted in a beneficial outcome. Thus, a treatment for HCV had finally been identified. Unfortunately, only 10 % of patients had a sustained response to this medical regimen. This plan of therapy is now generally referred to as monotherapy. Since only one agent had been identified which was effective against HCV, multiple trials throughout the world searched for the optimum regimen. These investigations assessed variable methods of using the interferons by assessing the response rates to higher doses of interferon, longer treatment regimens, escalating and de-escalating doses. After massive research, the most appropriate treatment regimen derived from these studies of monotherapy is to increase the period of time in which monotherapy was administered. In the 1990's, the standard of care was changed from 6 months of treatment to 12 months of treatment using the same dose (3 million units) and frequency (3 times a week). By doubling the duration of treatment, a doubling of the sustained response was accomplished. In addition, most interferons work equally as well when used in equivalent dose, frequency and duration.
Multiple other medications were tried for the treatment of HCV. Many failed, but ribavirin was noted to have some efficacy. In addition, it had the advantage of being an oral medication. Ribavirin acts against the RNA of the Hepatitis C virus. It should be noted that ribavirin, as a single agent, does not effectively treat patients with hepatitis C. It will improve or normalize their liver function tests and improve the histology in 30 % to 50 % of patients. It does not increase or decrease the HCV viral load. Ribavirin as a single agent was not approved by the FDA because of its lack of improvement in the viral load.
During this period of time, some investigators had tried ribavirin in combination with interferon. This resulted in an improvement in the sustained viral response in HCV patients. The FDA did allow the combination trials to be performed. As a result, combination therapy has become the standard of therapy. Two major research trials performed in the United States and Europe confirmed the improved efficacy of combination therapy. These were published in the New England Journal of Medicine in November 1998.
Selection of patients for combination therapy is based upon viral load, genotype, and liver histology. These three primary characteristics determine the response rates for combination therapy. Patients with non-type 1 (i.e. genotypes 2 and 3) Hepatitis C generally require only 6 months worth of treatment with combination therapy. Patients with type 1 hepatitis C usually require 12 months worth of treatment.
Acute hepatitis C, when identified, is usually treated with 12 weeks of interferon (3 million units alpha 2b subcutaneously TIW). This appears to result in similar long-term response rates as long term therapy for chronic Hepatitis C. The optimal regimen for acute HCV patients is under investigation.
Naive patients are currently treated with 12 months of combination therapy. The dose of ribavirin is based upon the weight of the patient. If the patient is 75 kg in weight or higher, ribavirin is usually dose at 1200 mg per day. If the patient is less than 75 kg, the dose is 1000 mg. Ribavirin tablets are 200 mg in size.
The standard interferon dose is 3 million units injected subcutaneously three times a week. The duration of this treatment is 12 months for patients who have type1 Hepatitis C. Many patients with non-type 1 (genotypes 2,3) Hepatitis C may be treated for six months.
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