Experimental Treatments for Hepatitis B Virus (HBV) Infection

3 Nucleoside Analog Drugs: Emtricitabine (FTC, Coviracil), Entecavir and Clevudine (L-FMAU)

Chronic hepatitis B infection is a common viral infection that is transmitted by the same routes that HIV is transmitted.   In the US, approximately 10% of patients with HIV infection are co-infected with HBV (hepatitis B virus).  There are two FDA-approved treatments for chronic hepatitis B: lamivudine (3TC, Epivir-HBV) and interferon alfa-2b (Intron A).  (Note Epivir also is used to treat HIV.)  However, newer treatments also are needed. 

Early study results (ìphase I/IIî) of emtricitabine (FTC, Coviracil) for chronic hepatitis B were presented by Dr. A. T. Robertson of Triangle Pharmaceuticals.  This drug is a ìnucleoside analogî with activity against both HIV and HBV (hepatitis B virus) and is dosed once daily.  A total of 49 patients with chronic hepatitis B (without HIV) were given 56 days of FTC in doses of 25, 50, 100, 200 or 300 mg once daily.  The results showed a ìdose-dependentî decrease in the HBV DNA viral load (greater decreases with higher doses).  For the same doses listed above, in order, the decreases were 1.7 log (52-fold decrease), 2.1 log (125-fold), 2.2 log (169-fold), 2.45 log (316-fold), and 2.52 log (331-fold).  FTC was tolerated well and no ìdose-relatedî toxicities were reported.

Reference
Roberston AT and others.  Antiviral activity of emtricitabine in a phase I/II dose escalation trial, FTCB-101.  Abstract 1407.

There were two presentations about the experimental drug entecavir (BMS-200475), a nucleoside analog drug for chronic hepatitis B.  In one study, 28 days of oral entecavir was given to 32 patients.  Women represented 9% and non-Caucasians represented 62%.  The results showed a ìdose-dependentî decrease in HBV DNA viral load.  The decreases for the three daily doses were: 0.1 mg (2.3 log or 177-fold decrease); 0.5 mg (2.8 log or 630-fold decrease); and 1.0 mg (2.4 log or 263-fold decrease).  Responses were similar among those who had previous unsuccessful treatment for HBV and those who were never treated.  The drug was tolerated well without any ìdose-relatedî adverse events (side effects) or abnormal blood tests.  Entecavir is under development by Bristol-Myers Squibb.

In a second study of entecavir, an animal model for chronic hepatitis B infection was used: woodchucks infected with WHV (woodchuck hepatitis virus).  Without any treatment, more than 75% of infected woodchucks die by age 3 years, usually from primary liver cancer due to WHV.  By age 4 years, more than 95% have died due to WHV-related primary liver cancer.  In the current study, 11 woodchucks were treated with entecavir for 14 or 36 months.  The results showed that the survival rate at age 3 and 4 years was normal (same as WHV-uninfected) for the treated woodchucks.  (Note that in chronic HBV infection in humans also is associated with an increased risk of primary liver cancer.)

References
Colonno RJ and others.  Long-term therapy with entecavir (BMS-200475) in the woodchuck model of chronic hepatitis infection.  Abstract and poster 172.

De Man RA and others.  Safety and efficacy of oral entecavir given for 28 days in subjects with chronic hepatitis B.  Abstract 1408.

Early study (ìphase Iî) results of clevudine (L-FMAU) were presented.  This nucleoside analog drug is under development by Triangle Pharmaceuticals.  Previous studies showed benefits for this drug in the same animal model of chronic hepatitis B described above, called WHV.  In the current study, 12 healthy (no viral infection) men took a dose of 150, 300, 600, 900 or 1,200 mg.  ìDose-dependentî blood concentrations (increasing blood levels with increasing doses) occurred.  Clevudine was ìtolerated well.î  Based upon the results, future ìphase I/IIî studies of patients with chronic hepatitis B are planned by Triangle Pharmaceuticals.

Reference
Blum MR and others.  Phase I pharmacokinetic and safety evaluation of clevudine (L-FMAU), a new agent under development for the treatment of hepatitis B virus (HBV) infection.  Abstract 510.