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Viral Infections
Table 4: Advantages and Disadvantages of Current Therapies for Table 5: Potential Management of Hepatitis B Antiviral
Chronic Hepatitis B Drug Resistance
Agent Advantages Disadvantages Lamivudine resistance Continue lamivudine and add adefovir (preferred over switch to
Interferon Higher rate of HBsAg loss Parenteral administration adefovir) or tenofovir
Short, fixed treatment duration Frequent and often intolerable side effects Switch to emtricitabine/tenofovir
1
No drug resistance Not indicated in ESLD Adefovir resistance Continue adefovir and add lamivudine or telbivudine (preferred
Lamivudine Oral administration Drug resistance common (~20%/year, over switch strategy)
Excellent tolerance and 65–70% with 4–5 years of therapy) Switch to or add entecavir (if no prior lamivudine resistance)
Use in ESLD Switch to emtricitabine/tenofovir
1
Use in adefovir failures Entecavir resistance Switch to or add adefovir or tenofovir
1
Adefovir Oral administration Less potent, with suboptimal responses Telbivudine resistance Continue telbivudine and add adefovir or tenofovir
1
Excellent tolerance not uncommon Switch to emtricitabine/tenofovir
1
Use in ESLD Drug resistance: delayed and not common
Updated from Keeffe EB, et al.
2,3
1 = not approved by FDA.
Use in lamivudine failures
Entecavir Oral administration Drug resistance: rare in nucleoside-naïve
HBV DNA >2,000IU/ml at week 24 suggest consideration of intensified
Excellent tolerance patients (0.1% at year 1, 0.4% at year 2,
treatment, with a second or alternative agent. Table 5 summarizes the
Highest potency in lowering 1.1% at year 3, and 0.8% at year 4), but
potential management of HBV antiviral resistance.
2
For patients with
HBV DNA levels common in patients with lamivudine
Use in adefovir failures resistance (6% at year 1, 14% at year 2,
lamivudine resistance, which is the most common type of HBV antiviral drug
32% at year 3, and 39.5% at year 4)
resistance encountered, options include switching to or adding adefovir, with
Peg-IFN Higher rate of HBsAg loss Parenteral administration
recent data favoring combination lamivudine plus adefovir. The latter strategy
Fixed duration of treatment Frequent side effects, but fewer than
is favored because the rate of subsequent adefovir resistance is considerably
No drug resistance with interferon higher using the switch strategy in the setting of pre-existing lamivudine
Telbivudine Oral administration Drug resistance: intermediate rates (5% at resistance.
17–19
Potential future therapy of lamivudine resistance may be
Excellent tolerance year 1 and 21.6% at year 2 in HBeAg-
tenofovir or the combination of tenofovir plus emtricitabine.
High potency in lowering positive patients, and 8.6% in HBeAg-
HBV DNA levels negative patients)
Future Treatment of Chronic Hepatitis B
HBsAg = hepatitis B surface antigen; ESLD = end-stage liver disease; HBeAg = hepatitis ‘e’ antigen-positive. HBV =
The indications for treatment and duration of therapy require a better
hepatitis B virus.
understanding of the clinical significance of low HBV DNA levels, including
entecavir therapy is <1% in treatment-naïve patients and 39.5% in after HBeAg seroconversion, which is associated with disease progression.
lamivudine-resistant patients after four years of therapy.
14
Genotypic resistance New and emerging therapies under study for the treatment of CHB hold
with telbivudine occurs at intermediate rates between those of adefovir and promise for improved treatment, e.g. tenofovir, which is in late phase III
entecavir versus lamivudine, with 21.6% of HBeAg-positive patients and 8.6% testing and is promising based on high potency and a low rate of resistance.
of HBeAg-negative patients experiencing resistance after two years of Finally, the role of combination oral HBV antiviral treatment, the prime
therapy.
15
The telbivudine pivotal trial demonstrated that the greater the degree example for the management of co-infection with HIV infection, is
of viral suppression at week 24 of therapy, the better the outcomes after one undergoing clinical trial and holds promise to reduce the rate of resistance and
to two years of therapy, in terms of undetectable serum HBV DNA, HBeAg possibly enhance efficacy. The most important future goal of oral therapy of
seroconversion, ALT normalization, and rate of HBV antiviral drug resistance.
16
chronic hepatitis B is to avoid the development of resistance by using drug(s)
The reduced efficacy and higher rates of resistance seen in patients with serum with a high genetic barrier to resistance or using combination therapy. ■
1. Yim HJ, Lok ASF, Natural history of chronic hepatitis B virus infection: 2006;295:65–73. ETV resistance in nucleoside-naïve and lamivudine refractory patients
what we knew in 1981 and what we know in 2005, Hepatology, 9. Liaw YF, Sung JJY, Chow WC, et al., Lamivudine for patients with [abstract], J Hepatol, 2007;46(Suppl. 1):S294.
2006;43:S173–81. chronic hepatitis B and advanced liver disease, N Eng J Med, 15. Lai CL, Gane E, Hsu CW, et al., Two-year results from the GLOBE trial
2. Keeffe EB, Dieterich DT, Han SB, et al., A treatment algorithm for the 2004;351:1521–31. in patients with hepatitis B: greater clinical and antiviral efficacy for
management of chronic hepatitis B virus infection in the United 10. Fung SK, Wong F, Hussain M, Lok ASF, Sustained response after a telbivudine (LDT) vs. lamivudine [abstract], Hepatology, 2006;44
States: An update, Clin Gastroenterol Hepatol, 2006;4:936–62. 2-year course of lamivudine treatment of hepatitis B e antigen- (Suppl. 1):22A.
3. Lok AS, McMahon B, Chronic hepatitis B, Hepatology, 2007;45: negative chronic hepatitis B, JViral Hepat, 2004;11:432–8. 16. Di Bisceglie A, Lai CL, Gane E, et al., Telbivudine GLOBE trial:
507–39. 11. Hadziyannis S, Sevastianos V, Rapti IR, Tassopoulos N, Sustained maximal early HBV suppression is predictive of optimal two-year
4. EASL Jury, EASL International Consensus Conference on Hepatitis B. biochemical and virological remission after discontinuation of 4 to 5 efficacy in nucleoside-treated hepatitis B patients [abstract 112],
13–14 September, 2002: Geneva, Switzerland. Consensus statement years of adefovir dipivoxil (ADV) treatment in HBeAg-negative Hepatology, 2006;44(Suppl. 1):230A–231A.
(Long version), J Hepatol, 2003;39:S3–S25. chronic hepatitis B [abstract], Hepatology, 2006;44(Suppl. 1): 17. Peters M, Hann HW, Martin P, et al., Adefovir dipivoxil alone or in
5. Liaw YF, Leung N, Guan R, et al., Asian-Pacific consensus statement 231A–2A. combination with lamivudine in patients with lamivudine resistance
on the management of chronic hepatitis B: a 2005 update, Liver Int, 12. Keeffe EB, Zeuzem T, Koff RS, et al., Report of an international and chronic hepatitis B, Gastroenterology, 2004;126:91–101.
2005;25:472–89. workshop: Roadmap for management of patients receiving oral 18. Lee YS, Suh DJ, Lim YS, et al., Emergence of rtA181V/T and rtN236T
6. ACT-HBV Asia-Pacific Steering Committee Members. Chronic therapy for chronic hepatitis B, Clin Gastroenterol Hepatol, 2007;5: mutations after 48 weeks of adefovir dipivoxil therapy in patients
hepatitis B: treatment alert, Liver Int, 2006;26:47–58. 890–97. with lamivudine-resistant chronic hepatitis B [abstract], Hepatology,
7. Iloeje UH, Yang HI, Su J, et al., Predicting cirrhosis risk based on the 13. Hadziyannis S, Tassopoulos N, Chang TT, et al., Long-term adefovir 2005;42(Suppl. 1):578A.
level of circulating hepatitis B viral load, Gastroenterology, 2006;130: dipivoxil treatment induces regression of liver fibrosis in patients with 19. Lok AS, Fung SK, Han SH, et al., Virological response and resistance
678–86. HBeAg-negative chronic hepatitis B: results after 5 years of therapy to adefovir (ADV) therapy in liver transplant (OLT) patients [abstract],
8. Chen CJ, Yang HI, Su J, et al., Risk of hepatocellular carcinoma across [abstract], Hepatology, 2005;42(Suppl. 1):754A. Hepatology, 2005;42(Suppl. 1):232A.
a biological gradient of serum hepatitis B virus DNA level, JAMA, 14. Colonno RJ, Rose RE, Pokornowski K, et al., Four year assessment of
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