Treatment of HBV and HCV:  Beyond year 2000

by Danny Chu, M.D.

 (presented at the CAMS 2000 Annual Scientific Meeting on November 18, 2000)

    Recent advancement and the knowledge gained from the treatment of HIV have helped in treating other viruses such as hepatitis B and C.  It has given researchers a better understanding of viral life cycle and has led to the development of improved therapy.

    Hepatitis B is the 9^th leading cause of death worldwide and there are more than 300 million chronic HBV carriers worldwide.  It affects 15-20% of the population in Asia.  In United State it affects only 0.1% or 1.2 million people.   The disease state is different in Asia and the U.S.  This is due to the difference in the age of transmission.  In Asia, HBV is vertically transmitted from mother to the infant.  Placenta is a potent barrier and transmission occurs at the time of childbirth.  Once the baby is infected, 30-90% will become a carrier.  In the United State, transmission occurs later in life with experimentation with sex and drug.  At this age, only 10% becomes a carrier.  The difference in the carrier states may be due to immature immune systems.  As a result there are more incidence of hepatocellular carcinoma and cirrhosis in the Asian population.

      Hepatitis B can present as an acute, fulminant disease or in an asymptomatic chronic carrier.  There is no recommended therapy for acute hepatitis but Lamivudine has been used in some cases.  The treatments discussed here are for chronic hepatitis B which by definition is a persistently positive HBSAg for greater than six months.

     Treatment is recommended for people with positive HBSAg and elevated ALT and viral DNA level.   The treatment goal is to achieve seroconversion of HBSAg which is rare or loss of HbeAg which would mean less viral infectivity.   Hopefully, this in turn would lead to less instance of cirrhosis and liver cancer.  

     The two most commonly used treatments are Alfa Interferon (IFN) and Lamivudine.  IFN is a family of naturally occurring small protein and glycoprotein which are products of immune cell response to a viral infection.  The mechanism of action is unknown. It is thought to inhibit viral replication, inhibit viral attachment, induce proteases or amplify cytotoxic T-cell.   Therefore, people lacking a competent or under developed immune system do not response well to IFN.  Patient with high ALT and low pre-treatment DNA level reflecting a good endogenous immune response has a good predictive outcome with IFN.  It is given in 5 MU qd or 10 MU TIW for 16 weeks.  There is a loss of eAg and DNA in 20-40% and loss of HBSAg in 5-10%.

     The other main treatment of HBV consists of nucleoside analogues.  They replace naturally occurring nucleoside such as adenosine, guanosine, cytidine, thymidine and uridine, and cause DNA chain termination.  The nucleoside analogues used in the past were not specific for virus and as a result, the drugs were unsafe.   For example, in early 1990, Fialuridine(FIAU) was a promising new drug.   However, usage of the drug for greater than two months led to lactic acidosis, myopathy, neuropathy, pancreatitis and hepatic failure. Mitochondrial toxicity was eventually implicated. These drugs suppress the replication but do not eradicate the HBV.  As a result, stopping the medication may lead to relapse. 

     Lamivudine, an analogue of dideoxycytidine is the nucleoside which have been tested in patients with chronic HBV in long term trials.  There are now data using Lamivudine up to four years.  In the initial study, Lamivudine 100 mg per day was given for one year.  There was 72% normalization of ALT, 16% HbeAg loss or conversion and 55% improvement in histology.  Two year study revealed 27-38% eAg loss with 52% undected DNA.  Three year study revealed 40% eAg loss and four year study revealed 47% eAg loss.  The seroconversion of HbeAg increases if ALT is >2X normal. The side effects are minimal with respects to pancreatitis and lactic acidosis. 

     Resistance is a problem with nucleoside analogue and can be seen as elevation of DNA level.  This occurs only after 9-12 months use of medication and occurs at a rate of 10-15% per year.  With Lamivudine there is a mutation at the YMDD locus with a substitution of either valine or isoleucine for methionine at residue 552.  Substitution of this smaller amino acid side chain may enlarge the nucleotide binding pocket, reducing its affinity for lamivudine.  YMDD variants continue to replicate at low level and often induce little or no liver injury.  Lamivudine should be continued despite the mutant since there is still evidence of improve biochemical and histological improvement.  In the 4 year data consisting of 58 patient, 39 or 69% of the patients developed YMDD mutation.  With continued treatment, 13 out of 39 patient loss their eAg. 

     Lamivudine should be given 100 mg qd with laboratory testing of DNA, ALT, eAg/eAb every month.   Medication should be discontinued when there is an eAg loss. and lab testings rechecked in 3-6 months.  Lamivudine should be restarted if there is an elevation of DNA.  

The other nucleoside analogues are Famciclovir (guanosine), Adefovir Dipivoxil(adenosine), Entecavir(guanosine) and Lobucavir(guanosine).

     The other area of research has been immunomodulatory therapy where the main focus is activation of T-cell. Thymosin alpha1(Zadaxin) which is a thymic derived peptides to stimulate T cell function.  Interleukin-12 has been used to promote T-helper cell.  The use of DNA vaccine as oppose to peptide vaccines can stimulate not only B cell but also T cell response.  This can lead to prolonged expression of viral proteins.

     The last area is gene therapy which will be discussed below with hepatitis C treatment.

     Chronic hepatitis C effects 170 million people worldwide and 2.7 million people in the United States.  Like HBV, it is transmitted by blood and sex.  However, the U.S. Public Health Department did not suggest any change in the sexual practice in monogamous relationship. 

     Current therapy consists of Rebetron, combination Interferon and Ribavirin.  The NIH consensus suggests treatment for patient with elevated ALT and RNA with moderate to severe histology with or without fibrosis.  Patient with mild histology and cirrhosis should be evaluated in individual cases.  Patient with normal ALT and decompensated cirrhosis should not be treated.  The best predictors of response are hepatic histology, genotype and pre-treatment viral load. 

     Randomized trials have shown that Interferon alone for 24 and 48 weeks lead to a sustained response of 6% and 16% respectively.  Rebetron for 24 and 48 weeks lead to a sustained response of 33% and 41%.  The recommendation is treatment for six months for genotype 2,3 and type 1 with viral load less than 2 million copies/ml.  Treatment of 12 months for genotype 1,4 and high viral load greater than 2 million copies/ml.

     Newer drugs consist of pegylated interferon which is IFN conjugated one to one with a 12,000 dalton polyethylene glycol molecule. This reduces the clearance of interferon and can be given subcutaneously once a week as oppose to three times a week.  Monotherapy offers a sustain response of 36% which is still not as good Rebetron but there are current studies combining Pegylated interferon and Ribavirin.  

     The future treatment will focused on stopping the viral cycle.  They are modeled after HIV treatment and are inhibitors of protease, helicase and ribozyme.  Serine protease inhibitor would block cleavage of non-structural proteins while Helicase inhibitor would stop viral replication and transcription by not allowing the RNA to unwind.  The ribozyme cleaves target RNA in a specific manner to stop replication. 

     There are also researches on gene therapy which is being directed to block protein synthesis by preventing translation.  CDNA, a synthetic complementary DNA is made to bind to initiation site of messenger RNA to stop translation.  However, there are no adequate delivery systems of the CDNA since the body has many nucleases to breakdown the CDNA.

     Current therapy for both hepatitis B and C is adequate for selected patients but with newer treatments and combination treatment the future hold optimism for possible eradication of the disease.

 (Dr. Chu is Clinical Instructor, Albert Einstein School of medicine and Attending Physician, Beth Israel Medical Center and NYU Downtown Hospital)