Issues in the Management of Hepatitis B: An Expert Interview With Yves Benhamou, MD, PhD - Expert Interview

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Expert Interview

Issues in the Management of Hepatitis B: An Expert Interview With Yves

Benhamou, MD, PhD

Posted 11/23/2004

Editor's Note:

Hepatitis B virus (HBV) infection remains a global health problem, and it is

estimated that nearly 2 billion individuals worldwide have been infected

with this virus. Hepatitis B treatment has evolved significantly over the

past decade with the introduction of oral, well-tolerated antiviral

therapies, including the nucleotide/nucleoside analogues. Nucleoside

analogue-based therapy acts by inhibiting the action of the HBV DNA

polymerase, thereby decreasing viral replication. Nucleotide analogues

represent an emerging class of antiviral therapeutics that interfere with

viral replication inside host cells by incorporating into newly synthesized

viral DNA strands and causing the premature termination of viral DNA

synthesis. However, long-term treatment, particularly with nucleoside

analogues, has been linked to progressively increasing rates of viral

resistance because of emergence of resistant HBV mutant strains. Medscape

spoke with Yves Benhamou, MD, PhD, Associate Professor of Hepatology,

Hôpital Pitié-Salpêtrière; Chief of Department, Clinical Research in

Hepatology, Hôpitaux de Paris - Pitié-Salpêtrière, Paris, France, to discuss

the current role of the nucleotide/nucleoside analogues and other therapies

in the treatment of hepatitis B as well as the potential path forward in

this therapeutic arena.

Medscape: What is the rationale for therapeutic strategies involving the use

of nucleotide/nucleoside analogues in the management of hepatitis B, and

what issues are associated with long-term treatment?

Dr. Benhamou: The objectives of treatment for chronic hepatitis B are to

prevent liver disease progression to cirrhosis and hepatocellular carcinoma

in order to reduce liver-related mortality. These objectives are achieved

with the durable control of hepatitis B virus (HBV) replication. Treatment

with nucleotide/nucleoside analogues is effective for the reduction of serum

HBV DNA. Because of the poor rates of hepatitis B e seroconversion with

these therapies, treatment should be maintained for a long period of time.

However, long-term administration of nucleos(t)ide monotherapy may be

limited by the emergence of HBV resistance. Lamivudine is associated with a

high rate of resistance (approximately 15% per year), whereas it is very low

with adefovir dipivoxil (approximately 4% at 3 years). Anti-HBV drugs with a

low resistance profile should be the preferred approach to management,

particularly in hepatitis B e antigen (HBeAg)-negative patients.

Medscape: In this setting, a number of agents have emerged, including

adefovir dipivoxil, a nucleotide analogue that has demonstrated in vivo and

in vitro activity against wild-type and lamivudine-resistant HBV. Data on

the long-term safety and efficacy of this agent in the treatment of

hepatitis B in patients pre- and post transplant with lamivudine-resistant

HBV were presented during this year's meeting of the American Association

for the Study of Liver Diseases. What can you tell us about this study and

what were the key findings?

Dr. Benhamou: Schiff and colleagues[1] reported the results of a study with

adefovir in pre- and posttransplant patients with lamivudine-resistant HBV

infection. They demonstrated the efficacy of adefovir, with reductions in

serum HBV DNA in more than 75% of both pre- and posttransplant patients, and

alanine aminotransferase (ALT) normalization in 84% and 58% of these

patients, respectively. No adefovir resistance was identified. The long-term

safety with adefovir was comparable to results from 1-year studies; the drug

was generally well tolerated. These are important findings for this very

" fragile " population of patients.

Medscape: Data were also presented on the long-term efficacy and safety of

adefovir in hepatitis B e antigen (HBeAg)-positive chronic hepatitis B

patients. What, in your opinion, are the clinically important findings of

this study?

Dr. Benhamou: Marcellin and colleagues[2] presented the results of a nearly

3-year study with adefovir during this year's meeting proceedings that

clearly demonstrated the long-term efficacy and safety of this agent in

HBeAg-positive patients. The proportion of patients with an undetectable

serum HBV DNA level, with HBeAg loss, and who normalized serum ALT increased

over time -- 56%, 51%, and 81% of patients had a serum HBV DNA < 3 log

copies/mL, HBeAg loss, and ALT normalization, respectively. Emergence of

resistance to adefovir was observed in only 2 of 65 patients at week 144.

The safety profile of adefovir was excellent, similar to results from 1-year

studies -- specifically, no renal toxicity was observed with up to 144 weeks

of therapy. In summary, treatment with adefovir over 144 weeks resulted in

significant reductions in serum HBV DNA and ALT levels, with an increased

proportion of patients achieving clinical benefit over time. Safety profile

over 144 weeks was consistent with that found for the first 48 weeks.

Resistance to adefovir is delayed and infrequent.

Medscape: Results of a study to determine the cross-resistance profiles of

several anti-HBV agents against different patterns of lamivudine-resistant

HBV were also presented during this meeting. What were the key findings of

this investigation in terms of differential antiviral efficacy?

Dr. Benhamou: Delaney and colleagues[3] presented very important data on the

cross-resistance profiles of anti-HBV candidates against different patterns

of frequently observed lamivudine-resistant HBV (L180M+M204V,

V173L+L180M+M204V, M204I, and L180M + M204I). Eleven anti-HBV compounds

(including entecavir, telbivudine, and emtricitabine) were tested in cell

lines. Lamivudine, emtricitabine, telbivudine, and clevudine demonstrated >

100-fold cross-resistance, whereas acyclic phosphonate nucleotides,

including adefovir and tenofovir, retained near wild-type efficacy. Although

variable, all patterns of lamivudine-resistant HBV were significantly less

susceptible to entecavir compared with wild-type HBV (M204I mutant HBV

showed the greatest fold reduced susceptibility to entecavir). This in-vitro

study showed that only nucleotide analogues are effective against wild-type

and different patterns of lamivudine-resistant HBV. Entecavir demonstrated

varying levels of resistance to the 4 different patterns of

lamivudine-resistant HBV. These findings are very important in clinical

practice. One year of therapy with adefovir has demonstrated efficacy

against lamivudine-resistant HBV. The results presented by Delaney and

colleagues showed that nucleotide analogues did not cross-resist with

lamivudine-resistant-associated mutations and may then represent the

alternative therapy to new nucleoside-associated HBV resistance.

Medscape: Were there any other data presented during the meeting that would

help put this information into clinical context? Also, how do you view the

path forward in terms of the treatment of patients with chronic hepatitis B?

Dr. Benhamou: Results of 1-year studies with entecavir in HBeAg-positive

and -negative patients, and in patients with lamivudine resistance, were

also presented during this year's meeting.[4-6] Results of these studies

demonstrated the efficacy and safety of entecavir in HBV infection. The dose

of entecavir used for the treatment of lamivudine-resistant HBV was twice as

high as the dose used for the treatment of HBeAg-positive and -negative

patients (1 mg vs 0.5 mg per day). No mutations associated with resistance

to entecavir were detected at week 48. Although these are very interesting

results, a longer study period is necessary to evaluate the long-term

efficacy, tolerability, and resistance rate associated with this agent.

Results of another study evaluating the use of combination therapy with

lamivudine (100 mg/day) and pegylated interferon alfa-2a (180 mcg/day) in

HBeAg-positive patients did not show the superiority of the combination

therapy regimen compared with pegylated interferon monotherapy.[7] However,

the rate of HBeAg seroconversion was higher in interferon-treated patients

(with and without lamivudine) compared with in the lamivudine monotherapy

group.

Future research in anti-HBV strategies will focus on:

The durability of the virologic response -- ie, prevention of the long-term

emergence of resistance. Combination therapies with nucleoside and

nucleotide analogues could represent the best option.

The improvement of HBe (and hepatitis B s antigen) seroconversion rate.

These strategies will likely involve immunotherapy.

References

Schiff E, Lai C-L, Neuhaus P, et al. Long-term safety and efficacy of

adefovir dipivoxil (ADV) in the treatment of chronic hepatitis B in patients

pre- and post-liver transplantation (OLT) with lamivudine-resistant (LAM-R)

hepatitis B virus (HBV). Hepatology. 2004;40:660A. [Abstract #1143]

Marcellin P, Chang TT, Lim S, et al. Long term efficacy and safety of

adefovir dipivoxil (ADV) 10 mg in HBeAg-positive chronic hepatitis B (CHB)

patients: increasing serologic, virologic, and biochemical response over

time. Hepatology. 2004;40:655A. [Abstract #1135]

Delaney W, Yang H, Qi X, et al. In vitro cross-resistance of adefovir,

lamivudine, telbivudine (L-DT), enetecavir, and other anti-HBV compounds

against four major mutational patterns of lamivudine-resistant HBV.

Hepatology. 2004;40:244A. [Abstract #181]

Chang TT, Gish R, de Man R, et al. Entecavir is superior to lamivudine for

the treatment of HDeAg+ chronic hepatitis B: results of phase III study

ETV-022 in nucleoside-naïve patients. Hepatology. 2004:40:193A. [Abstract

#70]

Shouval D, Lai C-L, Lok A, et al. Entecavir demonstrates superior histologic

and virologic efficacy over lamivudine in nucleoside-naïve HBeAg- chronic

hepatitis B: results of phase III trial ETV-027. Hepatology. 2004;40:728A.

[Abstract #LB 07]

Sherman M, Yurdaydin C, Sollano J, et al. Entecavir is superior to continued

lamivudine for the treatment of lamivudine-refractory, HBeAg+ chronic

hepatitis B: results of phase III study ETV-026. Hepatology. 2004;40:664A.

[Abstract #1152]

Lau G, Piratvisuth T, Luo KX, et al. Peginterferon alfa-2a (40KD)

monotherapy and in combination with lamivudine is more effective than

lamivudine monotherapy in HBeAg-positive chronic hepatitis B: results from a

large, multinational study. Hepatology. 2004;40:171A. [Abstract #20]

Disclosure: Yves Benhamou, MD, PhD, has disclosed that he has received

grants for clinical research from Gilead and Roche.

Medscape Gastroenterology 6(2), 2004. © 2004 Medscape