Predictors of response

• ALT/AST
• HBV-DNA concentration.
• Active histological changes (necrosis, inflammation, fibrosis)
• Short disease duration prior treatment
• HIV neg., absence of renal failure

IFNa and atypical forms

• Children: Rate of response similar to those of adults if ALT/AST elevated.(6M IU/m2 (BSA), TIW X 4-6 months.
• HBV-DNA+ + normal ALT/AST level: Poor response - treatment not indicated.
• HBV-DNA+ + HBeAg neg. (precore mutation): Possible long-term remissions.
• HBV-related glomerulonephritis: remission rate (liver + kidney) with IFN a.
• Immunosuppressed patients: Beneficial effect if normal CD4 counts (HIV) or low dose of immunosuppressive drugs (transplant recipients).
• Decompensated liver disease: Poor prognosis - Low IFN doses if mildly decompensated

New therapies

• VACCINE: No practical approaches are available at the present time.
• NUCLEOSIDES ANALOGUES (famcyclovir, lamivudine, etc.):
• Short Term Tx: Rapid decrease in serum HBV and decrease ALT/AST, clearance of HBeAg
  
  But rapid return to pretreatment levels when stopped. (Long term treatment under evaluation - viral resistance is a concern)
• POSSIBLE COMBINATION APPROACH:
• IFNa
  • Clearance of serum markers
  • Induction of remission
• Antiviral(s)
  • Sustained inhibition of viral replication
  • Amelioration of disease

Chronic Delta Hepatitis.
It is the less common form of chronic viral hepatitis. HDV is a defective RNA virus that only replicates in the presence of HBsAg in serum.

IFN a TREATMENT:
Greater than or equal to 5M IU, DAILY OR 9-10M IU, TIW X 12 MONTHS: Leads to sustained improvement + HBsAg disappearance in 15-25% of patients.

Chronic Hepatitis C.
Hepatitis C is the most common cause of chronic viral hepatitis in the Western world. Ranks second, slightly below chronic alcoholism as a cause of cirrhosis, end-stage liver disease, and hepatocellular carcinoma in the United States. Half the patients with chronic HCV infection have normal or only minimally elevated serum aminotransferase concentrations, but can have a marked degree of hepatitis as indicated by histologic evidence

Indication for treatment with IFNa

• Chronic hepatitis C
• Elevated serum aminotransferase level
• Anti-HCV+ in serum
• Histological evidence

Therapy with IFN alpha

• "The only therapy of proven benefit for patients with chronic hepatitis C is interferon alpha."
• 6 month therapy:
  • NORMAL ALT/AST in 40-50% of patients.
  • SUSTAINED response in 15-25% of patients.
• 12+ month therapy (12, 18, 24):
  • SUSTAINED response ~ 25% of patients.
• Initial higher doses (5M IU daily or TIW), have shown a higher rate of sustained response in some studies.
• Increasing doses after 3 months for partial responders (5 to 10 M IU TIW), is an alternative to stopping therapy. However, relapses are common after stopping treatment.

Patterns of response

TYPE OF RESPONDER:
• Complete + Sustained (x 6 months after Tx. end.) -- PATTERN = HCV-RNA neg. within 1 to 4 weeks / Long term F/U - maintenance of remission. (If treated X for 6 months +)
• Relapse -- PATTERN = Prompt return to initial parameters.
• Partial or no response -- PATTERN = Remain Pos. for HCV-RNA throughout the duration of therapy.

Predictors of response

• Patient Less than 45 years of age.
• Disease duration less than 5 yrs.
• No cirrhosis or minimal fibrosis.
• Low iron concentration in liver.
• Low HCV-RNA serum levels
• Genotypes 2 or 3 (as opposed to 1).
• Low genetics diversities.

The most important independent predictors for response to IFN a therapy are the HCV-RNA serum level and the genotype (> 40% response with type 2 and 3).

IFNa and atypical forms

• Acute Hepatitis C:
  • If untreated: 80-100% pts. develop chronic hep. C.
  • IFNa treatment: 36-61% develop chronic hep. C.
• Children:
  • Similar response vs. Adults: Treat early for a better response.
• Associated vasculitis/cryoglobulinemia:
  • Improvement of extrahepatic features/frequent relapse.
• Immunosuppressed/Decompensated:
  • Experimental/Lower long term resp. rate
• Solid organ transplant:
  • Rarely effective
• Retreatment:
  • Long term treatment + high dose IFN for patients with transient positive response in 1st course.
• HCV-RNA+ and ALT/AST = Normal
  • No treatment indicated.

New Therapies
Corticosteroids, IFNg, thymosin, ursodiol, acyclovir: Little or no evidence of long term benefit.

Ribavirin alone:
Markers return to pretreatment levels when treatment stopped.

Ribavirin + IFNa:
More promising, 40-77% long-term response, lower rate of relapses.

Complementary and Alternative Medicine for Chronic Liver Disease.
Leonard B. Seeff, MD, from the National Institute of Health (NIH) in Bethesda, Maryland, gave a report on the recent NIH Symposium focusing on the issue of botanical preparations and herbal preparations available to treat chronic liver diseases. He spoke at the postgraduate course in Dallas held in conjunction with the annual meeting of the American Association for the Study of Liver Disease (AASLD).

Dr. Seeff presented data showing that most patients with chronic liver disease use some type of alternative medicine products and that "conventional" Western science needs to examine these products to find out which ones are effective and helpful and which ones may be harmful. He pointed out some herbal products that appeared to be beneficial and deserve further study.

Some of the potentially beneficial herbal products listed by Dr Seeff included milk thistle and sho-saiko-to (TJ-9) as mentioned above. In addition, he noted that Glycyrrhizin (licorice root extract), a product used in Japan for the treatment of hepatitis, appears to have anti-inflammatory properties and improves ALT levels when given intravenously. Some studies have been reported using glycyrrhizin in pill form for the treatment of viral hepatitis. One study gave interferon only or interferon plus glycyrrhizin to patients that had failed to respond to interferon. ALT levels normalized in 33% of those receiving interferon only, but in 64% of those receiving the glycyrrhizin in addition to the interferon. HCV-RNA became undetectable in 38.5% of those receiving the herbal product, but in only 13% of those treated with interferon only.

Another interesting product is Compound 861. This is a liquid medicine that contains 10 herbs based on traditional Chinese medicine. This compound appears to be anti-fibrotic (prevents or improves the scar tissue in the liver). A study in China gave this compound to patients with hepatitis B and found improvement in most patients.

The NIH has allocated funds to be used for research related to herbal products. Hopefully we will soon be able to tease out those products that are effective from those who may not help at all or even be harmful.