The Hepatitis Viruses Virus Chronic Disease (%) A 0 B 5-10 C > 85 D * 45 E 0 F ** G ** *Infects only hepatitis B patients.**Data not yet available.Alter MJ, et al.Gastroenterol Clin North Am.1994;23:437-455.Alter MJ. Semin Liver Dis. 1995;15:5-14.
Annual Hepatitis B Infections in the United States HBV Acute Infections 300,000 5% to 10% chronicity Chronic Hepatitis B 15,000 - 30,000 1.0-1.25 million people in the United States are chronic carriers of HBVMMWR. 1991;40:1-17.Alter MJ, et al. Gastroenterol Clin North Am. 1994;23:437-455.
Annual Hepatitis C Infections in the United States HCV Acute Infections 180,000 Asymptomatic Symptomatic 112,500 37,500 Chronic Liver Disease 93,000 Cirrhosis 30,700 Deaths 9,000MMWR. 1991;40:1-17.Alter MJ, et al. Gastroenterol Clin North Am. 1994;23:437-455.
The Hepatitis Epidemic Nationwide prevalence of chronic viral hepatitis HCV--3.5 million HBV--1.0 million-1.25 million Most patients are asymptomatic until irreversible liver damage occurs Diagnosis depends on a high index of suspicion and proper screeningMMWR. 1991;40:1-17.Alter MJ, et al. Gastroenterol Clin North Am. 1994;23:437-455.
Chronic Hepatitis C Importance of DetectionChronic hepatitis C is a progressive diseaseTreatment is available
Chronic Hepatitis C Progression of the Disease 10-25 years Acute Hepatitis C (150,000/yr) >85% Chronic Hepatitis C (>127,500/yr) 20% - 50% Cirrhosis (>25,000/yr) up to 20% up to 20%Hepatic Failure Hepatocellular(up to 5,000/yr) CarcinomaAlter MJ, et al. Gastroenterol Clin North Am . 1994;23:437-455. (up to 5,000/yr)Davis GL, et al. Gastroenterol Clin North Am. 1994;23:603-613.Koretz RL, et al. Ann Intern Med. 1993;119:110-115.Takahashi M. et al. Am J Gastroenterol. 1993;88:240-243.National Instiitute of Health Consensus Development Statement; March, 1997.
Screening for Viral Hepatitis Patients depend on their Primary Care Physician to detect chronic viral hepatitiseven in the absence of symptoms.
The Hepatitis Epidemic in PerspectivePatients acquire the infection at a younger ageThe acute infection is usually asymptomaticChronic infection is asymptomatic until irreversibleliver damage has occurredLiver test abnormalities may be minimal or evenabsent despite significant liver inflammation on biopsy
Chronic Hepatitis C Clinical PresentationAsymptomatic Minimal to moderate elevation of ALT (SGPT) or AST (SGOT)Positive hepatitis C antibody test with normal liverenzymes Any degree of liver enzyme abnormality should be evaluated!
Screening for Viral Hepatitis in the Primary Care Setting Serum ALT alone is not sufficient for screening with risk factors for hepatitis >70% of patients who were HBsAg-positive and 4% of patients who were HBeAg-positive had normal or near normal ALT (SGPT) Chronic active hepatitis can be found in 35% of anti-HCV-positive blood donors with normal ALT (SGPT) ALT (SGPT) may be intermittently normal in a significant number of patients with chronic viral hepatitisde Franchis R, et al. Ann intern Med. 1993;118:191-194.Esteban JI, et al. Ann Intern Med. 1991;115:443-449.
Screening for Chronic Viral Hepatitis Anti-HCV HBsAg Who should be screened? Risk factors for hepatitis Abnormal liver testsHerrera JL. South Med J. 1994;87:677-684. JL.
Hepatitis C Antibody Test Anti-HCV A positive test suggests viremia until proven otherwise Sensitivity 94% to 100% May take 4 to 6 weeks to become positive in patients with acute hepatitis C A positive test in a patient with elevated liver enzymes and risk factors for hepatitis C is usually diagnosticGross JB, et al. Mayo Clin Proc. 1995;70:296-297.Alter MJ. Semin Li.ver Dis . 1995;15:5-14.de Medina M, et al. Semin Liver Dis. 1995;15:33-40.
Recombinant Immunoblot Assay (RIBA) Confirmatory assay for hepatitis C Not mandatory in classical cases Consider obtaining in anti-HCV (+) patients and: Suspected autoimmune hepatitis Hypergammaglobulinemia Normal liver enzymes levelsNakatsuji Y, et al. Hepatology. 1992;16:300-305.
Indeterminate RIBA RIBA assay tests for bands of reactivity to 4 HCV antigens 2 or more bands reactive = positive 0 bands reactive = negative 1 band reactive = INDETERMINATE Up to 57% of patients with indeterminate RIBA results are infected with the hepatitis C virus Patients with "indeterminate" RIBA test results should undergo HCV RNA testingde Medina M, et al. Semin Liver Dis. 1995;15:33-40.Zanella A, e al. Hepatology. 1995;21:913-917.Chemello L, et al. Hepatology. 1993;17:179-182.
Hepatitis C RNA Tests Measure the presence of the actual virus, not the antibodies Helpful in patients with normal liver enzymes and positive anti-HCV and RIBA: A positive RNA test indicates the presence of viremia RNA tests are expensive and require special handlingDavis GL, et al. Hepatology. 1994;19:1337-1341.
Hepatitis C RNA Tests HCV RNA by PCR Most sensitive and specific test to detect HCV viremia Detects low levels of viremia Qualitative test HCV RNA by bDNA (Quantitative HCV RNA) Less sensitive than PCR requires >350,000 viruses/cc blood to be positive Quantitative test Useful in following response to treatmentde Medina M, et al. Semin Liver Dis. 1995;15:33-40.Urdea MS. Bio/Technology. 1994;12:926-928.
Diagnosis of Hepatitis C Anti-HCV (+) and RIBA (+) Serum ALT levels are usually elevated, but may be normal
LIVER ENZYMES ARE NOT LIVER FUNCTION TESTS! In chronic hepatitis, there is poor correlation between the magnitude of the liver enzyme elevations and the degree of liver injury
Approach to the Patient With(+) Anti-HCV and Normal ALT RIBA positive or indeterminate HCV RNA by PCR positive Liver Biopsy abnormal histology Consider Treatment
Assessing Liver Function Clinical Tests of Liver Function Prothrombin time Serum albumin Serum bilirubinThese tests are insensitive and nonspecificAbnormalities occur only after significant, usuallyirreversible, liver damage has occurred
Assessing Severity of Disease Ultrasound Excellent test to evaluate the biliary tree and detect focal lesions in the liver - Not a good test to assess liver function Cannot differentiate a normal liver from chronic hepatitis, fibrosis, or early cirrhosis Most accurate in the advanced stages of liver disease Cannot reliably distinguish between fatty liver, cirrhosis, and acute hepatitisNeedleman L, et al. AJR. 1986;146:1011-1015.Zakim D, et al, eds. Hepatology: A Textbook of Liver Disease. 2nd ed. 1990:667-689.
Assessing Severity of Disease Liver BiopsyOnly accurate method for determining severity andactivity of the diseaseHistology findings do not always correlate withsymptoms, liver enzyme levels, or ultrasound findingsBiopsy results may help in the decision to proceed withtreatment
Treatment of Chronic Hepatitis C Patient Selection Anti-HCV and RIBA (+) and Abnormal Liver Biopsy ALT levels are of secondary importance.
Chronic Viral Hepatitis Treatment INTRON -A (Interferon alfa-2b, recombinant) forInjection is the only product demonstrated to besafe and effective for the treatment of chronichepatitis B and C in patients with compensatedliver disease
Chronic Viral Hepatitis Treatment Interferon therapy forms the backbone
In 1957 Isaacs and Lindenmann did an experiment using chicken cell cultures and found a substance that interfered with viral replication was therefore named interferon Nagano and Kojima also independently discovered this soluble antiviral protein
Interferons are naturally occurring proteins and glycoproteins made by cells in response to an appropriate stimulus Interferons play an important role in the first line of defense against viral infections Interferons are part of the non-specific immune system substances that have antiviral properties in adjacent, noninfected cells.
Secreted by eukaryotic cells in response to viral infections, tumors, and other biological inducers Structurally, they are part of the helical cytokine family which are characterized by an amino acid chain that is 145-166 amino acids long. Produce clinical benefits for disease states such as hepatitis, various cancers, multiple sclerosis, and many other diseases.
Interferons are released by macrophages, lymphocytes, and tissue cells infected with a virus. 1. When a tissue cell is infected by a virus, it releases interferon. 2. Interferon will diffuse to the surrounding cells. 3. When it binds to receptors on the surface of those adjacent cells, they begin the production of a protein that prevents the synthesis of viral proteins. 4. This prevents the spread of the virus throughout the body.
3 TYPES OF INTERFERONS: 1. alpha, 2. beta and 3. gamma. Viral infection is the stimulus for alpha and beta expression and is used to mobilize our 1st line of defense against invading organisms Alpha interferons are produced by leukocytes Beta interferons are produced by fibroblasts gamma (immune interferon) are produced by certain activated T cells & NK cells
Interferons are broken down into recombinant versions of a specific interferon subtype and purified blends of natural human interferon. & many of these are in clinical use and are given intramuscularly or subcutaneously Recombinant forms of alpha interferon include: • Alpha-2a drug name Roferon • Alpha-2b drug name Intron A • Alpha-n1 drug name Wellferon • Alpha-n3 drug name AlferonN • Alpha-con1 drug name Infergen Recombinant forms of beta interferon include: • Beta-1a drug name Avonex • Beta-1b drug name Betaseron Recombinant forms of gamma interferon include: • Gamma-1b drug name Acimmune
Non-glycosylated Protein chain that is 165 amino acids long Produced using recombinant DNA technology Short half life, short terminal elimination of half life, a large volume of distribution, and a larger reduction in renal clearance. These problems were resolved by pegylating alpha-2a resulting in peginterferon alpha-2a that is named Pegasys.
Pegasys is recombinant interferon alpha-2a that is covalently conjugated with bis- monomethoxy polyethylene glycol (PEG)Background: • First developed by Davis, Abuchowski and colleagues in the 1970s • In early 1990s PEG attached to alpha-2a, but it lacked the required profile of improving pharmacokinetics • Pegylation of interferon alpha-2b was achieved with the addition of a linear PEG, designed to degrade to allow the full potency of the interferon, while achieving a longer half-life. • Increasing the size with PEG, the absorption and ½ life are prolonged and the clearance of the interferon is decreased. • Goal of pegylation is to decrease clearance, retention of biological activity, get a stable linkage and enhance water solubility.
INTRON -A (Interferon alfa-2b, recombinant) for Injection Mechanism of Action Suppresses viral replication Increases the ability of the immune system to recognize and attack the virus Decreases inflammation in the liver by attacking the virusJohnson HM, et al. Sci Am. May 1994:68-75.
Interferon Treatment for Chronic Hepatitis C 3 million units subcutaneously or intramuscularly three times per week for 24 weeks ALT response rate of 45%, Sustained ALT of 14% 3 million units subcutaneously or intramuscularly three times per week for 48 weeks ALT response rate of 45%, Sustained ALT of 35%Poynard; Meta-Analysis of Interferon Randomized Trials; Hepatology;1996; 24:778-789
Treatment of Chronic Hepatitis C Predicting Response to Interferon PATIENTS LIKELY TO RESPOND Mild histologic disease Low pretreatment viral load Viral genotype Short duration of disease Younger ageLin R, et al. Aust N Z J Med. 1991;21:387-392.Pagliarlo L, et al. Hepatology. 1994;19:820-828.Lau JYN, et al. Lancet. 1993;341:1501-1504.Okada SI, et al. Hepatology. 1992;16:619-624.Causse X, et al. Gastroenterology. 1991;101:497-502.
Treatment of Chronic Hepatitis C Response According to Histology Initial Sustained Histology Response Response Mild CAH 93% 35% Severe CAH or 33% cirrhosisLin R, et al. Aust N Z J Med. 1991;21:387-392.
Chronic Viral Hepatitis Who Should Be Treated?All patients with compensated chronic hepatitis Bor C should be evaluated for possible treatmentEvaluation should be done even if: ALT is normal or near normal Patient has no symptoms Ultrasound and tests of liver function are normal
Treatment of Chronic Hepatitis B With Interferon Alfa-2b INTRON -A (Interferon alfa-2b, recombinant) for Injection is demonstrated to be safe and effective for the treatment of chronic hepatitis B in patients with compensated liver disease Careful interpretation of the patients serologic profile is needed for proper patient selection All HBsAg (+) patients should be referred for further evaluation and consideration for treatmentPerrillo RP, et al. Gastroenterol Clin North Am. 1994;23:581-601.Alter MJ, et al. Gastroenterol Clin North Am. 1994;21:437-455.McMahon BJ, et al. Arch Intern Med. 1990;150:1051-1054.
Chronic Viral Hepatitis End Points of TherapySuppression or reduction of viremiaCessation or diminution of necro-inflammatoryactivity in the liverCurePrevention of cirrhosisPrevention of hepatocellular carcinoma
Chronic Viral Hepatitis Treatment DecisionsPatient follow-up: Liver enzymes not helpful Patients are usually asymptomatic Serial liver biopsiesRisk of progression to cirrhosis andhepatocellular carcinoma
Common Reasons Why Chronic Viral Hepatitis Is Not Treated "The ALT elevation is minimal" ALT levels do not correlate with necro-inflammatory activity "The patient is asymptomatic" Symptoms usually occur when irreversible liver damage is present "The liver biopsy does not look too bad" These are the patients most likely to respond "The patient may never develop cirrhosis" 50% will progress to severe chronic hepatitis or cirrhosis "Too many side effects" Side effects requiring discontinuation of therapy are infrequentDavis GL, et al. Gastroenterol Clin North Am. 1994;23:603-613.
Interferon Side-Effect ProfileSide effects requiring discontinuation of therapy: <3%Side effects or cytopenias requiring dose reduction: <2%Flu-like syndrome is the most common side effect Treatable Usually diminishes after the 2nd or 3rd week of treatment
monotherapy not very effective cumbersome dosing (TIW) multiple side effects
Interferon Therapy WarningsUse with caution with patients with debilitating conditions: Cardiovascular disease Pulmonary disease Coagulation disorders Severe myelosuppression Diabetes mellitus prone to ketoacidosis
Chronic Hepatitis C: Most Common* Adverse Experiences With Interferons Flu-like symptoms Gastrointestinal symptoms Alopecia Irritability, depression* Occur in >10% of patients. 3 MIU TIW
Adverse Experiences: Modification/Discontinuation of Interferons Adverse Event Moderate Severe Interferes with daily Fatigue Requires bed rest routine Daily, with Vomiting more than Nausea occasional vomiting twice daily Granulocytopenia <750/mm <500/mm Thrombocytopenia <50,000/mm Recommendation Reduce doseCausse X, et al. Gastroenterology. 1991;101:497-502.Davis GL, et al. N Engl J Med. 1989;321:1501-1506.Marcellin P, et al. Hepatology. 1991;13:393-397.
Take-Home Messages About 85% of people who are infected by the hepatitis C virus (HCV) go on to develop chronic hepatitis C - "persistent, detectable serum HCV RNA for a period > than 6 months". Chronic HCV infection has a variable course but usually includes many symptom-free years before complications such as cirrhosis, liver failure, and hepatocellular carcinoma develop. The specific HCV genotype is an important predictor of clinical outcome with Genotype 1 being associated with the poorest response to antiviral treatment.
Take-Home Messages The recommended regimen for patients who meet the criteria for antiviral treatment is dual therapy with "pegylated" interferon plus ribavirin (pegylated refers to the addition of polyethylene glycol to delay renal clearance). A sign that patients have responded to therapy is the elimination of the viral RNA from the serum - this is known as a viral response. A sustained viral response (SVR) is defined as the "absence of detectable HCV RNA from the serum in the six months after the end of therapy".
Many times interferons and peginterferons are used in combination with Ribavirin It is a purine nucleoside analogue with a modified base and a D-ribose sugar moiety 1st made in 1970 by Drs. Joseph Witkowski and Roland Robins It inhibits the replication of a variety of RNA and DNA viruses and is serves as an immunomodulator to enhance type 1 cytokine production. This increases the end of treatment response and reduces post-treatment relapse. Mechanism is not well known, but there are 4 proposed mechanisms
By attaching a protective barrier called polyethylene glycol (PEG) to interferon, pegylated interferon can survive in the body longer than the un-pegylated form, thus reducing dosing frequency. Pegylation was developed to overcome disadvantages of standard interferon.
Shields IFN from enzymatic degradation thus lowers systemic clearance Achieve higher/sustained serum [interferon] Allows less frequent dosing - While regular interferon is injected 3 times a week, pegylated interferon is generally taken once a week.
There are 2 types of pegylated interferons – Peg-interferon alfa-2a, & Peg-interferon alfa-2b. The major difference between the two is how they are dosed: 2a – The dose of pegylated interferon alfa-2a (Pegasys) is the same for all patients, regardless of weight or size. 2b – The dosing of pegylated interferon alfa-2b (PegIntron) is based on an individual’s weight.
Peginterferon alfa-2b linear molecule weight 12 kDa Peginterferon alfa-2a larger, branched molecule weight 40 kDa While logic might lead one to assume that a dosage customized for each individual would deliver safer and more effective results, the data does not completely support this view.
Peg alfa-2b Peg alfa-2aVolume of 20 L 8LdistributionAbsorption half-life 4.6 50(h)Mean elimination 40 80half-life (h)
Comparing Pegylated Interferons for Hepatitis C by Laura Dean, MD., National Center of Biotechnology Information (NCBI) created on October 1, 2007. Data are limited, but indirect analysis suggests that there is no significant difference between the efficacy of peginterferon alfa-2a (Pegasys®) plus ribavirin and alfa2b (PEG-intron®) plus ribavirin in eliminating the hepatitis virus RNA from patients serum
In the August 2006 Journal of Hepatology, a small Argentine study compared the pharmacokinetics, pharmacodynamics, and antiviral activity of Pegasys and PegIntron in participants with chronic Hepatitis C genotype1. The researchers found that patients receiving PegIntron had greater decreases in HCV viral load after 8 weeks of therapy, despite lower levels of interferon in the blood of these participants. Interestingly, this trial was sponsored by Schering-Plough, the manufacturer of PegIntron.
At the 38th annual Digestive Disease Week in May 2007, Roche announced results of a small study demonstrating that all patients who discontinued treatment with PegIntron and ribavirin due to adverse events within the first 12 weeks were able to complete 12 weeks of treatment with Pegasys and ribavirin. The researchers concluded that Pegasys may be an option for those who are unable to tolerate the side effects of PegIntron.
3 studies presented at the 43rd European Association for the Study of Liver Diseases (EASL) held in Milan, Italy in April of 2008 showed that Pegasys had a better cure rate for Hepatitis C than PegIntron. The results of two Italian and one German trial demonstrated that when the dosage of ribavirin was kept at a constant, the cure rate for Hepatitis C was greater in those treated with Pegasys than Pegintron.
Also presented at the 43rd EASL were the results of the IDEAL (Individualized Dosing Efficacy vs. flat dosing to assess optimal pegylated interferon therapy) trial sponsored by Schering- Plough. Over 3,000 participants with Hepatitis C genotype 1 were recruited. While relapse after the end of treatment was lower for pts. receiving PegIntron, the end of treatment response was higher for pts. taking Pegasys.
In total, the IDEAL results demonstrated a similar sustained virologic response, safety and tolerability between the two pegylated interferons. This study is being criticized by experts because those receiving Pegasys received a different starting dose of ribavirin than those on PegIntron. In addition, ribavirin dose reduction protocol for side effects was not uniformly administered between these two treatment arms
An adjusted indirect analysis of trials comparing dual therapy with Pegasys or PegIntron versus dual therapy with non-pegylated interferon was then conducted. After analyzing 16 trials for sustained virological response and withdrawal due to side effect rates, no statistically significant differences between dual therapy with pegylated interferon alfa-2a and dual therapy with pegylated interferon alfa-2b were found.
A recent systematic review by the Cochrane Collaboration of randomized clinical trials comparing the 2 pegylated interferons, which included a meta-analysis of SVR rates in 8 trials with a total of 4293 participants, found that Pegasys was slightly but significantly more effective than PegIntron (relative risk 1.10; P = 0.004), with similar results for all subgroups; adverse event profiles were similar.
No studies directly compared the effects of different doses or durations of the two pegylated interferons. The optimal dose of peginterferon alfa-2b, when used as part of dual therapy with ribavirin, is 1.5 mcg/kg/week (the FDA-approved dose). Studies comparing different doses of peginterferon alfa-2a have not been published. Almost all trials evaluated the FDA-approved dose of 180 mcg/week. In patients with HCV genotype 1 infection, 48 weeks of dual therapy appears to be more effective than shorter courses. In patients with HCV genotype 2 or 3 infection, shorter courses may be sufficient, eg. 12 week-course of therapy appears to be as effective as 24 weeks.