Predictors of Response to PEG-IFN Plus Ribavirin Therapy in Previously Untreated, Immunocompetent Patients with Compensated Chronic Hepatitis C [79]

• Non-genotype 1
• Low HCV RNA levels (<2 million RNA copies/mL)
• Absence of cirrhosis/bridging fibrosis
• Duration of therapy (for genotype 1)
• Age 40 years or younger
• Lighter body weight
• Non-black ethnicity
• Adherence
• Absence of steatosis on liver biopsy
• Women
• No alcohol consumption

Interferon:

• If patient has chronic hepatitis C, the treatment of choice is peg interferon plus ribavirin
• Other interferons can be used
Types of Interferon
• Alpha Interferon
It has 4 types
1. Interferon alpha 2a
2. Interferon alpha 2b
3. Interferon alfacon-1 or consensus interferon --- dose is 9 µg SQ thrice a week.; 15 µg thrice a week in nonresponders
4. Interferon alfa-n1---- this is not approved in US but approved by European Union at a dose of 5 MU subcutaneously or intramuscularly three times weekly for 48 weeks.
Alpha interferon 2a and b can be attached to polyethylene glycol tale to make peg interferon which can be given once daily.
• Peg interferon alfa-2b is dosed by weight (1.5 µg/kg) and coupled with 800 mg of ribavirin;
• Peg interferon alfa-2a is given as a fixed dose of 180 µg along with a weight-adjusted, higher dose of ribavirin (1,000 mg if <75 kg and 1,200 mg if >75 kg).
SIDE EFFECTS

• If patient is put on therapy for chronic hepatitis C, "Flu-like" symptoms, such as headache, fatigue, myalgia, and fever are common and are mostly due to interferon. These symptoms improve spontaneously after two to three weeks. Administration of interferon at night and the prophylactic use of acetaminophen (1000 mg) prior to injection may be beneficial. We also advise patients to consume 12 to 16 glasses of water or juice daily.
• hematologic changes during therapy are common. The neutrophil count falls by an average of 1300 to 1600/µL, and usually returns to pretreatment levels within four weeks of cessation of therapy. The relative neutropenia is not generally associated with an increased risk of serious bacterial infections
• Mean platelet values may also decline, but generally stay within the normal range during therapy. Platelet counts below 100,000/µL develop in less than 10 percent of patients, and may in part be due to a blunted thrombopoietin response, which occurs more commonly in patients with cirrhosis
• Psychiatric changes occur in approximately 50 percent of patients including insomnia, irritability, depression, emotional lability, difficulty concentrating, and nervousness. Suicidal ideation and attempts occur in less than 1 percent of patients.
• Nausea occurs in up to one-half of patients, and anorexia in approximately 20 percent.Reversible hair loss occurs in approximately 20 percent of patients probably due to telogen effluvium, as a result of interferon
• Thyroid abnormalities requiring therapy develop in approximately 1 to 7 percent of patients treated with interferon alfa.
• Painless thyroiditis is most common but other thyroid abnormalities can occur, including Graves' disease, permanent hypothyroidism, and increased serum antithyroid antibody concentrations without thyroid dysfunction.
• Thyroid dysfunction is more likely if patients have preexisting antithyroid antibodies, suggesting that interferon alfa in some way exacerbates underlying thyroid autoimmune disease
• Interferon therapy usually can be continued while hypothyroidism is being treated. On the other hand, we have usually stopped interferon in patients who develop clinically apparent hyperthyroidism.
• Hyperglycemia is an uncommon side effect of interferon that is usually not clinically significant. However, it is recommended increasing monitoring of blood glucose in patients with known diabetes.
• Minor side effects can be pruritis, migranous headache, pulmonary disorders, including interstitial pneumonia and bronchiolitis obliterans, Ophthalmologic disorders (retinal hemorrhages, cotton wool spots, loss of color vision, and rarely retinal artery or vein obstruction) and hearing loss can occur

Ribavirin
• If patient has chronic Hepatitis C the addition of ribavirin (1000-1200 mg/day) will increase the response rate to 35-50%
• If patient is taking ribavarin, coadministration of antacids containing magnesium, aluminum, and simethicone may decrease the absorption of ribavirin, although the clinical significance of this effect is unknown. No clinically significant food interactions have been reported.
• If patient is taking ribavarin,it is contraindicated in the following groups of patients: Women who are or can become pregnant — Ribavirin is teratogenic and/or embryocidal, accumulates in gonadal tissues, and can be present for six months after therapy is discontinued. Patients with a known hypersensitivity to ribavirin should also not get the drug
• Ribavirin is not recommended for patients with a creatinine clearance below 50 mL/min.
• If patient is taking ribavarin, because anemia is a potential side effect of ribavarin, patients with cardiovascular disease that may be worsened by drug-induced anemia should not be treated.
• A reduction in hemoglobin levels to less than 10 g/dL is observed in approximately 10 percent of patients, and is largely due to hemolysis induced by ribavirin. Hemolysis correlates with the concentration of ribavirin and its metabolites in red blood cells; levels reach a steady-state after three to four weeks of therapy
• If patient has hemoglobinopathies such as thalassemia and sickle-cell anemia may be exacerbated by the hemolysis induced by ribavarin.
• Psychiatric disease, including depression and suicidal behavior can occur
• If patients have a history of stable cardiovascular disease, therapy should be discontinued if the hemoglobin concentration decreases by more than 2 g/dL during any four-week period or if the hemoglobin concentration remains below 12 g/dL after four weeks on a reduced dose.
• If reduction in the dose of ribavirin is done, it associated with a decreased sustained virologic response rate. As a result, there has been increasing experience with using recombinant human erythropoietin to help support the hemoglobin concentration and thereby permit continued use of higher doses of ribavirin



Genotype-1 HCV infection
• Treatment with peginterferon plus ribavirin should be planned for 48 weeks, using ribavirin doses of 1,000 mg for those <75 kg in weight and 1,200 mg for those more than 75 kg.
• Quantitative serum HCV RNA should be performed at the initiation of, or shortly before, treatment and at week 12 of therapy.
• Treatment may be discontinued in patients who do not achieve an EVR at 12 weeks, although the decision should be individualized according to the tolerability of therapy, severity of underlying liver disease, and demonstration of some degree of biochemical and/or virologic response
• Persons whose treatment continues through 48 weeks, and whose qualitative measurement of HCV RNA at that time is negative, should be retested for HCV RNA 24 weeks later to document an SVR.

Genotype-2 or Genotype-3 HCV infection
• Treatment with peg interferon plus ribavirin should be administered for 24 weeks, using a ribavirin dose of 800 mg.
• Persons whose treatment continues for the full 24 weeks, and whose qualitative measurement of HCV RNA at that time is negative, should be retested for HCV RNA 24 weeks later to document an SVR


Management of side effects of antiviral therapy
• Flu-like side effects of IFN can be managed with acetaminophen or nonsteroidal anti-inflammatory drugs and giving interferon injection at night
• Sleep promoting agents can be used for insomnia
• Antidepressants can be used for depression.
• For management of neutropenia, dose reduction suffices, and the addition of granulocyte colony-stimulating factor is generally not recommended, although it may be considered in individual cases of severe neutropenia.
• Ribavirin is contraindicated in pregnancy, necessitating strict precautions and contraception in women of childbearing age and their sexual partners and in HCV-infected men with female partners of childbearing age.
• Treatment with ribavirin should be avoided in patients with ischemic cardiovascular and cerebrovascular disease and in patients with renal insufficiency.
• If anemia occurs, options include ribavirin dose reduction or the addition of erythropoietin

RETREATMENT OF PERSONS WHO FAILED TO RESPOND TO PREVIOUS TREATMENT
1. Nonresponders and partial responders
• Overall, an SVR can be achieved by retreatment with peginterferon alfa and ribavirin in 25 to 40 percent of persons who failed to respond to interferon alfa monotherapy and in about 10 percent who failed to respond to interferon alfa and ribavirin
• Retreatment with peg interferon plus ribavirin with the aim of eradicating HCV is not indicated in patients who have failed to respond to a prior course of peg interferon plus ribavirin, even if a different type of peginterferon is administered
2. Relapsers
Persons who relapse after an initial response will generally achieve another on-treatment response


3. Maintenance therapy
• While eradication of HCV RNA is the primary goal for treatment of persons with chronic hepatitis C, there is accumulating evidence that treatment may have a secondary benefit of reducing progression of fibrosis - thereby delaying evolution to cirrhosis - or possibly reversing early cirrhosis.
• studies have also shown that in treated patients who fail to clear virus, the rate of progression to cirrhosis may be decreased or reversed [99], and there may be a lower frequency of development of HCC [100, 101].