Impact On Growth In Pediatric Patients
Growth inhibition was observed in CHC pediatric subjects 5 to 17 years of age during combination therapy for up to 48 weeks with PEGASYS plus ribavirin. At the end of treatment, 43% of subjects were more than 15 percentiles below their baseline weight curve, and 25% of subjects were more than 15 percentiles below their baseline height curve. At the end of 2 years follow-up after treatment, most subjects had returned to baseline normative curve percentiles for weight and height 16% of subjects were more than 15 percentiles below their baseline weight curve and 11% were more than 15 percentiles below their baseline height curve.
The available longer term data on subjects who were followed up to 6 years post-treatment are too limited to determine the risk of reduced adult height in some patients .
Growth inhibition was also observed in CHB pediatric subjects 3 to 17 years of age during therapy with PEGASYS lasting up to 48 weeks. At Week 48 of treatment 11% of subjects were more than 15 percentiles below their baseline weight curve and 6% were more than 15 percentiles below their baseline height curve. At 24 weeks after the end of treatment, 12% of subjects were more than 15 percentiles below their baseline weight curve and 12% were more than 15 percentiles below their baseline height curve. No data are available on longer term follow-up post-treatment in these patients .
Serological And Biochemical Assays
Routine complete blood counts and biochemical tests were performed using a systemic multi-autoanalyzer at baseline and monthly during therapy. The serum HBeAg and anti-HBe antibody levels were measured by radio-immunoassay . HBsAg was quantified by Elecsys HBsAg II assay . HBV viral load was determined by a PCR-based method, namely the Roche Cobas Taqman HBV DNA assay .
Treatment Of Chronic Hepatitis B With Interferon Alfa
- R. MüllerCorrespondenceCorrespondence: R. Müller, Abteilung für Gastroenterologie und Hepatologie, Zentrum für Innere Medizin und Dermatologie, Medizinische Hochschule Hannover, Hannover, F.R.G..AffiliationsAbteilung für Gastroenterologe und Hepatohgie, Zentrum für Innere Medizin und Dermatologie, Medizinische Hochschule Hannover, Hannover, Federal Republic of Germany
- M. SchulzAffiliationsAbteilung für Gastroenterologe und Hepatohgie, Zentrum für Innere Medizin und Dermatologie, Medizinische Hochschule Hannover, Hannover, Federal Republic of Germany
- H. WittenbergAffiliationsAbteilung für Gastroenterologe und Hepatohgie, Zentrum für Innere Medizin und Dermatologie, Medizinische Hochschule Hannover, Hannover, Federal Republic of Germany
- P. Von WussowAffiliationsAbteilung für Klinische Immunologie, Zentrum Innere Medizin und Dermatologie der Medizinischen Hochschule Hannover, Hannover, Federal Republic of Germany
- H. KleinAffiliationsAbteilung für Gastroenterologe und Hepatohgie, Zentrum für Innere Medizin und Dermatologie, Medizinische Hochschule Hannover, Hannover, Federal Republic of Germany
- K. MalmusAffiliationsAbteilung für Gastroenterologe und Hepatohgie, Zentrum für Innere Medizin und Dermatologie, Medizinische Hochschule Hannover, Hannover, Federal Republic of Germany
- F.W. SchmidtAffiliationsAbteilung für Gastroenterologe und Hepatohgie, Zentrum für Innere Medizin und Dermatologie, Medizinische Hochschule Hannover, Hannover, Federal Republic of Germany
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Approved Drugs For Adults
There are currently 7 approved drugs in the United States for adults living with chronic hepatitis B infection. These include 5 types of antiviral drugs that are taken as a pill once a day for 1 year or longer. And there are 2 types of immune modulator drugs called interferon that are given as an injection for 6 months to 1 year.
It is important to know that not everyone needs to be treated. A liver specialist should evaluate your health through a physical exam, blood tests, and an imaging study of your liver . Then you can discuss together whether you are a good candidate for treatment since the approved drugs are most effective when there are signs of active liver disease. In addition, talk to your provider about HBV Clinical Trials since there are several new drugs being tested that are available for infected adults.
All adults, however, should be seen regularly by a liver specialist whether they are on treatment or not.
Package Label Principal Display Panel
Intron® APowder for InjectionSingle-Dose Vial
10 million IU per vial
For Intramuscular/Subcutaneous/Intravenous/Intralesional Use.
Medication Guide for patient enclosed.Dosage and Administration: See package insert.Reconstitute as directed in package insert.Read accompanying directions.Discard unused portion.
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What Will I Need To Do If I Am On Hepatitis B Medications
- Take oral medications every day to avoid developing resistance.
- See your provider on a regular basis
- If you have cirrhosis or high risk of liver cancer, get liver imaging on time as prescribed by your provider
- Have periodic laboratory tests to monitor HBV viral load and liver enzymes to monitor disease activity and response to medications
- You may need blood tests every 3-6 months initially and at least once a year thereafter if virus is undetected in blood.
Hbsag Clearance Rates In Different Treatment Periods
To evaluate the effect of Peg-IFN treatment courses on HBsAg clearance, we analysed the clearance rate among IHCs with baseline HBsAg < 1000 IU/mL after Peg-IFN treatment. The HBsAg clearance rates were 29% after 24 weeks of treatment, 39% after 48 weeks of treatment, and 43% after 96 weeks of treatment , suggesting that HBsAg clearance increased with longer Peg-IFN treatment, although the difference did not reach statistical significance . This finding may be related to the small sample sizes and significant heterogeneity in the 24-week and 48-week groups.
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Pregnancy: Use With Ribavirin
Ribavirin may cause birth defects and/or death of the exposed fetus. Patients must avoid pregnancy while taking PEGASYS and ribavirin combination therapy. Ribavirin therapy should not be started unless a confirmed negative pregnancy test has been obtained immediately prior to initiation of therapy. Women of childbearing potential and men must use two forms of effective contraception during treatment and for at least 6 months after treatment has concluded. Routine monthly pregnancy tests must be performed during this time .
Serious Depression And Other Mood Disorders
Interferons can cause or worsen serious depression or other mental illness. The risk for each condition is higher if youve had that condition before. Its not known why interferons can cause mood disorders.
Symptoms may include:
- flu-like symptoms
- skin changes such as bruising, flaking, and redness
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Factors Associated With Responses In Hbeag
Baseline factors associated with the e seroconversion and the sustained off-treatment combined response among HBeAg-positive CHB patients were analyzed . By univariate analysis, the baseline ALT 200IU/L and HBsAg < 25,000IU/mL were associated with e seroconversion among HBeAg-positive patients. After multivariate analysis, baseline ALT 200IU/L remained associated with e seroconversion. By univariate analysis, baseline HBV DNA < 2.5×107IU/mL, ALT 200 U/L, and HBsAg < 250IU/mL were associated with the combined response among HBeAg-positive patients. After multivariate analysis, only baseline HBV DNA of < 2.5×107IU/mL and HBsAg level of < 250IU/mL remained independently associated with the combined response among HBeAg-positive patients.
Table 2 Univariate and multivariate analysis of baseline factors associated with 48 weeks of off-treatment HBe seroconversion and combined response among HBeAg-positive chronic hepatitis B.
On-treatment HBsAg level on weeks 12 was available in 34 HBeAg-positive cases. Of them, 22 patients had at least 10% of decline compare to their pretreatment level. Genotype was available in 39 cases. Of them, 22 were genotype B, 17 were genotype C. Nether on-treatment HBsAg decline nor genotype of HBV was associated with response in the subgroup patients .
Serological Virological And Combined Responses
Among the 118 HBeAg-positive CHB patients, HBeAg seroconversion rates were 19.5% and 30.5% at EOT and 48 weeks after EOT . The ALT normalization rates were 38% and 45% and the combined response rates were 11% and 21.2% at EOT and 48 weeks after EOT, respectively . The median HBV DNA reduction at EOT and 48 weeks post EOT were both -2.6log IU/mL as compared with the baseline levels.
Figure 1: Off-treatment responses among HBeAg-positive and HBeAg-negative chronic hepatitis B patients.
Cumulative HBe seroconversion rate and HBe seroreversion rate among HBeAg-positive CHB patients Cumulative combined response rate and relapse rate among HBeAg-positive CHB patients Cumulative virological response rate and relapse rate among HBeAg-negative CHB patients Cumulative HBV DNA undetectable rate and relapse rate among HBeAg-negative CHB patients . *The black bar means patients who had already achieved response at EOT. The delay response indicated patients achieving response after EOT.
Among the 83 HBeAg-negative patients, the virological response rates were 85.5% and 27.7% and the ALT normalization rate were 45% and 49% at EOT and 48 weeks after EOT, respectively. The HBV DNA undetectable rates were 55.4% , and 13.3% at EOT, and 48 weeks after EOT, respectively . The median reductions in HBV DNA were 4.3log IU/mL at EOT and 1.1log IU/mL at 48 weeks after EOT as compared with the baseline levels.
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Treatment Duration And Dose
The dose and duration of PEG-IFN is recommended to be 180 µg weekly for 48 weeks for both HBeAg negative and HBeAg disease . In the phase III registration trial of HBeAg negative patients, 48 weeks of treatment with PEG-IFN-2a resulted in a sustained off-treatment virological response of 20% and HBsAg loss 3% . In the long term follow up study, 23% of patients had persistent viral suppression after 5 years . In addition, the rate of HBsAg loss increased to 9% at 3 years and 12% at 5 years . It was noted that higher rates of HBsAg clearance at 5 years post-treatment occurred when patients had HBV DNA less than 2,000 IU/mL at 1-year post-treatment .
Extended therapy in HBeAg negative patients was explored in an Italian multicentre centre study , which compared 128 mostly genotype D patients randomised to 48 or 96 weeks of extended therapy with PEG-IFN-2a . Significantly higher sustained off-treatment viral suppression, defined as HBV DNA < 2,000 IU/mL at 12 months post treatment , and HBsAg loss occurred in those in the 96 week extended therapy arm compared to the 48 weeks standard arm. The study reported that extended therapy was tolerated well, and that the rate of adverse events was comparable to 48 weeks treatment . Extended therapy with PEG-IFN may be an option, but needs further validation.
Carcinogenesis Mutagenesis Impairment Of Fertility
Studies with INTRON A have not been performed to determine carcinogenicity.
Interferon may impair fertility. In studies of interferon administration in nonhuman primates, menstrual cycle abnormalities have been observed. Decreases in serum estradiol and progesterone concentrations have been reported in women treated with human leukocyte interferon.12 Therefore, fertile women should not receive INTRON A therapy unless they are using effective contraception during the therapy period. INTRON A therapy should be used with caution in fertile men.
Mutagenicity studies have demonstrated that INTRON A is not mutagenic.
Studies in mice , rats , and cynomolgus monkeys injected with INTRON A for up to 9 days, 3 months, and 1 month, respectively, have revealed no evidence of toxicity. However, in cynomolgus monkeys injected daily for 3 months with INTRON A, toxicity was observed at the mid and high doses and mortality was observed at the high dose.
However, due to the known species-specificity of interferon, the effects in animals are unlikely to be predictive of those in man.
INTRON A in combination with REBETOL should be used with caution in fertile men. See the REBETOL prescribing information for additional information.
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Why Interferons Cause Long
Interferon treatment for hepatitis C would typically last 2448 weeks . Interferons caused many long-term side effects partly because of this long treatment time.
Using the drug for this length of time gave side effects a chance to develop and get worse.
The more common long-term side effects of interferons are typically less severe. These side effects can include:
- swelling or other reactions at the injection site
- flu-like symptoms such as headache, tiredness, and weakness
- low levels of white blood cells
- loss of appetite
If you have these side effects and youre concerned that they relate to your interferon exposure, call your doctor. They can assess you and determine if the interferons or something else is causing your symptoms.
Should All Patients With Chronic Hepatitis B Be On Treatment
Not all patients with chronic hepatitis B need to be on treatment. The decision to treat HBV is based on several factors including blood tests results, the patient’s age, and the risk of developing cirrhosis or liver cancer. Sometimes a liver biopsy is needed to see if there is significant liver damage to make a decision.
Hepatitis B medications are recommended for patients with detected HBV virus on a blood test and evidence of liver damage. Liver damage can be detected with a liver enzyme known as ALT. People with cirrhosis should be considered for treatment even if the liver enzymes appear normal.
Chronic hepatitis B may change over time. Patients can go through different phases with low amounts of virus and normal level of ALT followed by high viral loads and ALT levels. These bursts of virus activity usually don’t cause any symptoms but may cause liver damage overtime. It is important that people with chronic hepatitis B have blood tests on a regular basis to see if treatment is needed.
There are some medications which can cause hepatitis B “reactivation” which can lead to life threatening liver failure. These medications are used to treat some cancers, inflammatory conditions and hepatitis C. Reactivation reactions can be prevented and it is important to let your provider know you have HBV before you start any new medications.
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Dental And Periodontal Disorders
Dental and periodontal disorders have been reported in patients receiving ribavirin and interferon combination therapy. In addition, dry mouth could have a damaging effect on teeth and mucous membranes of the mouth during long-term treatment with the combination of REBETOL and interferon alfa-2b. Patients should brush their teeth thoroughly twice daily and have regular dental examinations. In addition, some patients may experience vomiting. If this reaction occurs, they should be advised to rinse out their mouth thoroughly afterwards.
Pegylated Interferon Alpha Versus Nucleoside Analogues
PEG-IFN and NAs are the main forms of antiviral treatment for CHB. NAs were developed during the 1980s for the treatment of HIV, but subsequently were found to have additional efficacy in treating CHB. There are advantages and disadvantages of therapy with PEG-IFN compared to NAs. PEG-IFN treatment has the benefit of finite treatment duration, a higher rate of HBeAg and HBsAg seroconversion, a higher chance of sustained off-treatment response, and no drug resistance . On the other hand, PEG-IFN therapy is not well tolerated because adverse effects are common and can occasionally cause significant morbidity or mortality. Pregnancy and decompensated cirrhosis are absolute contraindications. Administration by subcutaneous injection is difficult for some patients. The advantages of NAs are that it is an oral medication, is a potent anti-viral, and has relatively few adverse effects. NAs are safe to use in cirrhosis and some are safe in pregnancy. The newer NAs, entecavir monohydrate and tenofovir disoproxil fumarate also have little or no drug resistance . The main disadvantage of NAs are that rates of HBeAg and HBsAg seroconversion are lower, and sustained off-treatment responses are rare . As a result, the treatment duration is usually indefinite.
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Chinese Herbal Medicine Active Component Kurorinone Alone
The Chinese herbal medicine active component kurorinone, when used alone, appeared to be equivalent to interferon alfa in its effect on seroreversion of HBeAg and HBV DNA . Neither of the 2 studies employing kurorinone19,24 reported seroreversion data on HBsAg, so we were not able to include that endpoint in this subanalysis.
Warning: Risk Of Serious Disorders
Risk of Serious Disorders
Alpha interferons, including PEGASYS , may cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. Patients should be monitored closely with periodic clinical and laboratory evaluations. Therapy should be withdrawn in patients with persistently severe or worsening signs or symptoms of these conditions. In many, but not all cases, these disorders resolve after stopping PEGASYS therapy .
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On Treatment Factors For Sustained Response
Predictors of treatment success with PEG-IFN in HBeAg negative patients are not well established. In 518 patients from the original phase III trial , the best PPV was 50%, which was associated with HBV DNA decrease to less than 20,000 copies/mL at 12 weeks . Although HBsAg levels correlate with sustained viral suppression its use as a predictor is poor. In the aforementioned Greek study, the best PPV was 45% which occurred when HBsAg decline was greater than 10% at 24 weeks . Table 2 provides a summary of on treatment factors predicting treatment success or failure with PEG-IFN in HBeAg negative disease.
Interferon Alpha 2b Plus Ribavirin For Chronic Hepatitis B
|The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.|
|First Posted : January 12, 2006Last Update Posted : January 12, 2006|
Hepatitis B virus causes a wide spectrum of liver diseases, such as fulminant or acute hepatitis, chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. The number of individuals infected with this virus has been estimated to be as high as 350 million. Thus, in addition to global hepatitis B vaccination, effective treatment of chronic hepatitis B is also needed.
Currently, there are no effective antiviral treatments to cure HBV infection in patients with chronic hepatitis B. Five drugs have been approved for the treatment of chronic hepatitis B at present: conventional interferon alpha, lamivudine, adefovir dipivoxil, pegylated IFN alpha and recently entecavir. Overall, satisfactory virologic and serologic responses could be achieved using pegylated IFN alpha alone in around 20-44% of these patients. Nevertheless, better treatment options are still needed for the remaining > 50% non-responders.
|Drug: interferon alpha 2b plus ribavirinDrug: interferon alpha 2b plus placebo||Phase 2Phase 3|
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