Advances in the Management of Hepatitis B - F. Fred Poordad, MD

[Guest guest]

Advances in the Management of Hepatitis B

Disclosures

F. Fred Poordad, MD

Introduction

The treatment of hepatitis B virus (HBV) infection continues to evolve

rapidly. As more data become available, the therapeutic options will

increase, but it may be increasingly difficult to develop consensus

guidelines. Currently, 3 oral agents, as well as interferon, are approved by

the US Food and Drug Administration (FDA) for the treatment of hepatitis B.

Interferon alfa-2b was approved in 1992; lamivudine in 1998; adefovir in

2002; and entecavir was recently approved in 2005. The pegylated interferons

are not yet approved for treatment of hepatitis B in the United States.

There are 2 strains of HBV, one that produces the early or " e " antigen

(wild-type) and one that does not. The latter is often called the precore

mutant due to a translational defect, and worldwide, this variant is an

increasingly prevalent form of the virus, now comprising 30% to 50% of all

hepatitis B cases. The predominant difference in the therapeutic approach to

these 2 viral strains is the endpoint of treatment. In hepatitis B e antigen

(HBeAg)-positive patients, the endpoint of treatment is the disappearance of

HBeAg and, ideally, the development of hepatitis B e antibody (HBeAb). It

may be that HBeAg loss is as good as HBeAb seroconversion in terms of

durability of response. It may also be that in years past, when HBeAg loss

was present without HBeAb development, it was a function of the limitation

of the assay used to detect HBeAb, and that the antibody was indeed present

in more cases than recognized.

Nevertheless, loss of HBeAg is generally accompanied by loss of HBV

replication. Once this endpoint is achieved, the duration of therapy needed

to " solidify " the results is not truly known. With early discontinuation of

therapy, the relapse rate appears to be higher, and there is evidence that

treating for at least an additional 3 months -- but perhaps even up to 1

year -- may yield better sustained response rates.

The current treatment guidelines for HBV infection, which were revised in

2004, are already outdated. The field is evolving at a rapid pace, and what

is accepted as the current standard of therapy will likely change in the

next year. This report focuses on current therapies as well as new concepts

that are evolving in the management of hepatitis B, as based on key data

presented during this year's meeting of the European Association for the

Study of the Liver (EASL).

Antiviral Therapies

Lamivudine

This nucleoside analog became the preferred therapy for patients with

hepatitis B soon after it was approved. Although this antiviral agent is

very effective in decreasing viral load, it was found to be associated with

a high incidence of mutations in the YMDD motif of the HBV DNA polymerase.

Because the incidence of this mutation occurs in approximately 25% of

patients at 1 year and approaches 60% to 70% by year 4 of therapy, the

utility of this agent is limited. The main appeal of this antiviral is the

relatively low associated cost. Unfortunately, given the cross-resistance

found between this agent and other nucleoside analogs that share in-vitro

and likely in-vivo resistance patterns, it is becoming a less viable option

as a single-agent therapy.

A study by Hasan and colleagues[1] presented during this year's EASL meeting

assessed the efficacy and safety of lamivudine in 17 consecutive

immune-competent acute HBV patients; treatment with lamivudine 100 mg/day

was started within 10-33 days of onset of illness. All patients had an

international normalized ratio (INR) >1.5, with mean alanine

aminotransferase (ALT) levels of 3223 ±1405 IU/mL and elevated serum

bilirubin. In 16 of 17 patients, HBsAg was lost within 4 weeks of therapy,

but 1 patient died of fulminant hepatic failure. The study authors concluded

that although larger studies are needed, lamivudine does have a role in

preventing progression to fulminant hepatic failure. However, because 95% of

immune-competent adults clear HBsAg spontaneously, and because there was no

control arm in this study, it is difficult to know whether lamivudine

altered the natural course of illness in these patients. It is reasonable,

however, to offer therapy to all patients with either severe acute HBV

infection or those with acute decompensation of chronic disease.

Papatheodoridis and colleagues[2] compared the outcome of 201 HBeAg-negative

patients who were treated with lamivudine 100 mg/day vs that of 57

interferon-treated HBeAg-negative sustained responders (SR) and 152

HBeAg-negative nonresponders (NR), as well as vs 195 untreated patients. In

the lamivudine-treatment group, patients who developed resistance were

salvaged with adefovir 10 mg/day, and over a 4-year period this " salvage "

occurred in approximately three fourths of patients. Using regression

analysis, it was noted that transplant-free and complication-free survival

were superior in the lamivudine/adefovir and interferon SR groups compared

with the interferon NR and untreated groups. Baseline lack of fibrosis (P <

0001) and younger age (P < .001) were also significantly associated with

complication-free survival at the end of follow-up. However, whereas the

outcome of the lamivudine/adefovir group was superior in terms of

complication-free survival, this was not the case at the end of lamivudine

monotherapy, but rather at the end of the adefovir salvage step (ie, after

the onset of additional antiviral therapy). The study authors concluded that

close follow-up is needed to survey lamivudine-treated patients for

resistance, and that initial therapy with agents associated with low

resistance should ideally be considered instead.

Adefovir

Adefovir is a unique oral agent for HBV infection in that it is a nucleotide

analog of adenosine monophosphate, and as such, does not share

cross-resistance with nucleoside compounds such as lamivudine,

emtricitabine, telbivudine, and entecavir. The latter makes this agent an

optimal choice for patients with resistance to any of these other compounds.

Additionally, as a first-line agent, it appears that each additional year on

therapy continues to yield better results.

During this year's meeting proceedings, Marcellin and colleagues[3]

presented the results of a multicenter study evaluating long-term safety and

efficacy of adefovir 10 mg/day. They reported on the results of 171

HBeAg-positive patients (74% male, 57% Asian, 38% white) treated for up to

144 weeks. HBeAg seroconversion rate improved from 12% at 48 weeks to 29% at

96 weeks, and to 43% by week 144. HBeAg loss occurred in 51% of patients by

week 144, and 56% of patients had serum HBV DNA < 1000 copies/mL at week

144. These findings suggest that therapy with adefovir should be continued

beyond 48 weeks to increase HBeAg loss and seroconversion if it has not yet

occurred. Furthermore, safety was confirmed in that no patient had an

increase in creatinine level from baseline of > 0.5 mg/dL or serum

phosphorus < 1.5 mg/dL. No patient developed resistance at 48 weeks, and

only 2 patients developed resistance by 144 weeks. Seroconversion was

durable in 91% of patients off therapy. These data strongly demonstrate the

very high rate of seroconversion and HBeAg loss achievable with extension of

therapy.

Hadziyannis and colleagues[4] conducted a 192-week multicenter study

assessing the safety and efficacy of adefovir in HBeAg-negative patients.

Sixty-seven patients continued therapy for the full 192-week duration; 81%

were male, 70% white, and 26% were Asian. Patients had a median serum

HBV-DNA level of 7.08 log10 copies/mL and serum ALT of 99 IU/L. Three

patients had serum creatinine increases > 0.5 mg/dL, but all patients

normalized, 2 after discontinuing therapy. Median HBV-DNA decrease was 3.71

log10 copies/mL, with 85% having undetectable (< 1000 copies/mL) HBV DNA by

polymerase chain reaction. Four of 79 patients (5%) had HBsAg

seroconversion. It is important to note that the cumulative incidence of

adefovir genotypic resistance was 0% at 48 weeks, 3% by 96 weeks, 11% by 144

weeks, and 18% by 192 weeks; ie, beyond the first year, resistance in

HBeAg-negative individuals was observed at a rate of 4% to 5% per year.

Resistance to adefovir had not been observed in the first 48 weeks of

therapy in registration studies. Thus, Locarnini and colleagues[5] conducted

a study to determine the incidence of adefovir resistance mutations after

192 weeks of therapy in patients with HBeAg-negative chronic hepatitis B.

This analysis included data from 5 studies and involved a total of 1210

patients. The majority of patients in these studies had received adefovir

monotherapy, although some had received combination therapy with lamivudine.

These investigators performed sequence analysis of HBV DNA, and cumulative

probability of adefovir resistance was calculated using the life table

method. They found that 22 patients had developed adefovir resistance

mutations by 4 years. The incidence of resistance per treatment period was 0

of 629 patients for 0-48 weeks, 2% (6 of 293) during weeks 49-96, 5% (11 of

217) during weeks 97-144, and 8% (5 of 62) during weeks 145-192. Overall,

these findings resulted in a cumulative probability of adefovir resistance

of 15% by week 192 (18% for patients in monotherapy trials). No mutations

conferring resistance to adefovir were observed in patients on combination

lamivudine and adefovir. Only high serum HBV DNA at week 48 (median 4.2

log10 vs 3 log10) was found to be a predictor of adefovir resistance by

regression analysis of various factors. These study findings suggest that

beyond 48 weeks of adefovir therapy, for those patients with viral loads > 4

log10, the yearly incidence of adefovir resistance may be 4% to 5%. The

other important message that may be derived from these findings is that in

patients receiving combination therapy (lamivudine plus adefovir), no

resistance was observed -- which again suggests that in the setting of HBV

therapy, perhaps combination therapeutic regimens are preferred,

particularly if treatment beyond 48 weeks is necessary.

It has become clear that patients with HBV-related cirrhosis should be

treated to improve fibrosis, prevent decompensation, and suppress virus in

the pretransplant setting. Schiff and colleagues[6] conducted a study

involving 226 patients with lamivudine resistance who were awaiting liver

transplantation; adefovir 10 mg/day was added to their therapeutic regimen.

Eighty-eight percent of patients were male, 70% were white, and median age

was 52 years. Median HBV-DNA level at baseline was 7.4 log10 copies/mL and

Child-Pugh score was 10. Adefovir resistance was seen in 3 patients, all of

whom had been switched to adefovir monotherapy. Two percent of patients

discontinued therapy due to renal dysfunction. At study end, 118 (52%)

patients were stable or improved and were not transplanted. Another 27% of

patients were transplanted, and the remainder discontinued (for various

reasons) prior to study completion. These findings suggest the safety of

adefovir in this setting, its effectiveness as lamivudine salvage, and the

potential problem of developing lamivudine resistance in the setting of

advanced cirrhosis.

Entecavir

Entecavir, the most recently approved of the oral antiviral therapies for

hepatitis B, is a nucleoside analog of 2'-deoxyguanosine. In 3 separate

studies submitted to the FDA for registration, this agent was evaluated in

HBeAg-positive (0.5-mg dose), HBeAg-negative (0.5-mg dose), and

lamivudine-resistant patients (1-mg dose), and was found to be equivalent to

lamivudine in terms of HBeAg seroconversion, but superior in terms of viral

suppression. In HBeAg-negative patients, viral suppression was also found to

be superior to that observed with lamivudine (5.04 log10 vs 4.53 log10).

Shouval and colleagues[7] presented the results of analyses of baseline

demographics in HBeAg-positive and -negative patients during this year's

EASL meeting. Subgroups were analyzed and found to have some demographic

differences. The study evaluating HBeAg-positive patients had a higher

proportion of Asian patients vs those of European origin, which is in

contrast to the demographic distribution in the HBeAg-negative analysis.

Regardless of demographic factors such as sex, race, past interferon

therapy, or region of study (Asia, Europe, North America, South America),

entecavir response was comparable or superior to that achieved with

lamivudine with respect to histologic improvement and viral suppression (to

HBV DNA levels < 400 copies/mL) in both HBeAg-positive and HBeAg-negative

chronic hepatitis B patients. None of the baseline factors assessed appeared

to influence response to entecavir.

A summary of the safety data from 3 phase 3 and 1 phase 2 clinical trials of

entecavir was presented by Manns and colleagues[8] during these meeting

proceedings. Subjects received entecavir in doses of either 0.5 mg daily

(nucleoside-naive) or 1.0 mg daily (lamivudine-refractory). The proportion

of patients experiencing any adverse events on treatment was comparable in

both treatment-naive and lamivudine-resistant groups, and there was no

difference between the entecavir and lamivudine treatment arms (entecavir, n

= 862; lamivudine, n = 858). Although not statistically significant, there

were fewer discontinuations due to adverse events and on-treatment ALT

flares in the entecavir-treated groups.

Entecavir is predominantly eliminated by the kidney. In this setting, Yan

and colleagues[9] assessed the impact of renal impairment on the

pharmacokinetics of single-dose entecavir. Patients were assigned to 1 of 6

groups based on renal function, ranging from normal to severe impairment

requiring continuous dialysis. The study authors found that dose adjustments

were required when entecavir was administered to patients with renal

insufficiency. The first dose adjustment was recommended for creatinine

clearance below 50 mL/minute. However, it is interesting to note that the

mean AUC (area under the curve) from time 0 to 336 hours after dosing nearly

doubled from that observed in the group with creatinine clearance > 80

mL/minute (normal renal function) when compared with that observed in

patients with creatinine clearance of 50-80 mL/minute (27.9 vs 51.46). This

latter group with mild renal impairment may need to be monitored closely in

clinical practice for potential toxicity.

In an intriguing study presented during this meeting, Bifano and

colleagues[10] evaluated the pharmacokinetic interactions between entecavir

coadministered with lamivudine, adefovir, or tenofovir, and found no change

in AUC for drug exposure, Cmax, or Cmin for any of the compounds. This

finding lends support for the concomitant use of these agents when

warranted, and will likely have more implications for HIV/HBV-coinfected

individuals.

Entecavir resistance was not observed in the registration studies. To date,

analyses indicate that resistance occurs in the presence of lamivudine

resistance where substitutions at rtL180 and/or rtM204 predispose to

additional substitutions at rtT184, rtS202, and/or rtM250. Given this

context, Colonno and colleagues[11] evaluated over 600 patients, both

nucleoside-naive and lamivudine-resistant, who had completed at least 1 year

of entecavir therapy. Entecavir-resistant substitutions were not found in

any of the 430 randomly selected nucleoside-naive patients. However, 1% of

lamivudine-resistant subjects developed viral rebound on entecavir, with

another 6% showing genotypic resistance by week 48. Although the study

authors concluded that genotypic mutations will not necessarily lead to

clinical resistance, they noted that these various mutations did lead to a

range of entecavir susceptibility changes. Further follow-up of these

patients will be necessary to evaluate clinical resistance. However, if one

applies the patterns observed with other nucleoside/nucleotide agents as a

learning platform, it is very likely that genotypic mutations will

eventually lead to clinical resistance and viral rebound.

In a highly selective cross-sectional analysis of 28 studies chosen from

among 612 potential publication sources, Dienstag and colleagues[12]

attempted to assess overall efficacy of lamivudine, adefovir, and entecavir.

They applied established statistical techniques using a prospectively

defined analysis protocol to compare phase 3 data with entecavir with

combined data from published trial results of lamivudine, adefovir, and

placebo. After considering the relevant histologic, virologic, biochemical,

and serologic endpoints from those studies that satisfied the inclusion

criteria, they found that entecavir was superior to adefovir and lamivudine

with regard to HBeAg seroconversion or viral suppression, respectively.

Unfortunately, this type of analysis has little utility for clinicians

because these studies were conducted at different timepoints, using

different assays, different primary endpoints, different comparator arms,

and different patient populations. Because lamivudine was the comparator arm

in the registration studies for entecavir, it may be concluded that

entecavir was superior to lamivudine in suppressing virus with equivalent

HBeAg seroconversion, and that adefovir was superior to placebo in its

registration studies. Without direct comparisons in prospective studies

conducted in the same study population, no other valid conclusions can be

drawn.

Interferons and Combination Therapies

Interferon was first approved in the early 1990s for the treatment of

hepatitis B. The main advantage of interferon is that it is effective in

those patients with short-duration infection, low viral load, high serum ALT

levels, and competent immune systems. Interferon does also offer the

potential for clearing HBsAg, which does not generally happen with the oral

antiviral agents. The disadvantages associated with interferon are that so

few patients fit the " ideal " candidate demographics, and that the side

effects are quite significant. With the standard, nonpegylated interferon

alfa formulation, HBeAg clearance occurs in approximately one third of

patients and is associated with hepatitis B surface antigen (HBsAg) loss in

5% to 10% of patients. The finite treatment course of 4-12 months associated

with interferon has been appealing, and relapse rates have been low. The

pegylated interferons are now the standard of care for the treatment of

hepatitis C, and given the convenience of once-weekly dosing, treatment of

hepatitis B with these molecules is the next logical step in the therapeutic

armamentarium. Although not currently approved in this setting in the United

States, pegylated interferon alfa-2a is approved for treatment of hepatitis

B in the European Union. Results of several studies published in 2004

suggested that pegylated interferon alfa may be more effective than

lamivudine (and standard interferon) in HBeAg-positive patients.

In a study presented during this year's EASL meeting, Cooksley and

colleagues[13] followed up on previous findings suggesting that certain

baseline factors, such as viral genotype, affect treatment response in

patients with chronic hepaitis B. These investigators evaluated the effect

of HBV genotypes on treatment outcomes in HBeAg-positive patients treated

with combination pegylated interferon and lamivudine, pegylated interferon

plus placebo, or lamivudine monotherapy. They found that pegylated

interferon alone or in combination with lamivudine was more effective than

lamivudine monotherapy in achieving HBeAg seroconversion (32% > 27% > 19%,

respectively; P < .001 [with pegylated interferon], P = .023 [with

combination therapy]). Multivariate analysis showed that high serum ALT, low

HBV-DNA levels, and low HBeAg levels were predictors of seroconversion (P <

001). Genotype A was most successfully treated with pegylated interferon

alone (52% HBeAg seroconversion); combination pegylated interferon and

lamivudine was not as effective in this patient population (22% HBeAg

seroconversion). It is likely that the finding of a 52% seroconversion rate

in the HBV genotype A group was a statistical " blip " because it involved

such a small group of patients and was a much higher rate of seroconversion

than that seen in the group treated with combination pegylated interferon

and lamivudine. This large discrepancy was not observed for the other viral

genotypes, and except for this one arm of the study, no real difference in

response was noted between the HBV genotypes.

In results of a study published by Marcellin and colleagues[14] last year,

pegylated interferon-based therapy was shown to be more effective than

lamivudine monotherapy for the treatment of HBeAg-negative disease. The

study endpoint was viral suppression < 20,000 copies/mL. This endpoint made

it difficult to gauge the effectiveness of the therapy, because it

represented a unique cut-off value for HBV DNA, and had not previously been

used in other studies. A more important endpoint is viral suppression < 400

copies/mL. In this study by Marcellin and colleagues, this endpoint (ie,

rate of sustained suppression of HBV DNA to < 400 copies/mL) was achieved at

72 weeks in 19% of patients who received pegylated interferon monotherapy,

in 20% of patients who received pegylated interferon plus lamivudine, and in

only 7% of patients in the lamivudine-only group. During this year's EASL

meeting, Marcellin and colleagues[15] presented follow-up data for this

trial. They presented 96-week data (48 weeks after the end of treatment) for

57% of the patients for whom data were available from the original study

group. These data were similar to that obtained at the 72-week follow-up,

although more than 40% of the dataset was missing, making it less robust. At

week 96, HBV DNA suppression to < 400 copies/mL occurred in 17%, 14%, and 8%

of patients in the pegylated-interferon-only,

pegylated-interferon-plus-lamivudine, and lamivudine-only groups,

respectively. The rationale for using pegylated interferon-based therapy for

the treatment of the HBeAg-negative patient derives from the finite

treatment course -- although less than 20% of patients will have long-term

viral suppression. The downside to this approach, of course, is that the

majority of patients will not have prolonged benefit, and will have to

experience the potential adverse events associated with interferon-based

therapy for 1 year.

In yet further follow-up, Farci and colleagues[16] evaluated on-treatment

predictors of response from this same cohort studied by Marcellin and

colleagues.[14] This study involved 177 patients with HBeAg-negative chronic

hepatitis B who received 48 weeks of pegylated interferon alfa therapy. They

found that patients with lower HBV DNA levels 12 weeks into therapy had

higher rates of ALT normalization and viral suppression (< 20,000 copies/mL)

at week 72 of follow-up. Patients who did not achieve a 1-log10 reduction in

viral load, or those with > 7 log10 at week 12, had less than a 20% chance

of responding. However, because the association was not strong (that is, the

association was not sufficient to allow discrimination based on HBV DNA

levels at week 12 as to which patients were likely/unlikely to have a

response to pegylated interferon alfa at week 72), a 12-week stopping rule

could not be recommended by the study authors. If reliable predictors of

response, particularly a strong negative predictive value, could be

achieved, it would serve as a very useful tool. Only then would it make more

sense to subject patients with HBeAg-negative disease to a limited course of

interferon-based therapy until the clinician could predict response or lack

of response.

Further analysis of this same database by Fried and colleagues[17] revealed

that the rate of HBeAg seroconversion in patients who received pegylated

interferon monotherapy was slightly better than that observed in patients

receiving combination pegylated interferon and lamivudine (32% vs 27%), even

though viral suppression was much more robust in the combination therapy

group (69% of patients achieved suppression of HBV DNA < 400 copies/mL vs

only 25% of the pegylated interferon monotherapy group). This lack of

correlation between viral suppression and loss of HBeAg (or seroconversion)

was also observed in the studies with entecavir, in which a 6- to 7-log10

decline in viral load vs only a 4-log10 decline in the lamivudine control

group yielded the same seroconversion rates. These findings suggest that

there is more to seroconversion than just profound viral suppression.

The most profound seroconversion rates were reported by Wursthorn and

colleagues[18] in a small trial assessing the virologic and serologic

outcome in patients with chronic hepatitis B treated with combination

pegylated interferon alfa-2b (1.5 mcg/kg/week) and adefovir (10 mg/day).

This study involved 26 patients treated for 48 weeks; 23 of these patients

(the majority were men and 15 were HBeAg-positive) had been analyzed and

found to have 54% HBeAg loss, 28% seroconversion, and, most impressively, a

2.2-log10 reduction in closed circular (ccc) DNA in paired liver biopsies

(cccDNA is a key intermediate in HBV replication and intracellular cccDNA is

the reservoir responsible for the persistence of chronic hepatitis B

infection and for disease reactivation after stopping therapy). All subjects

in this study will be continued for an additional 96 weeks of adefovir

monotherapy after the 48 weeks of combination therapy.

Other Therapies on the Horizon

A number of other agents are currently under study (not yet approved) for

the treatment of hepatitis B. Valtorcitabine, a prodrug of L-deoxycytidine

(LdC), was evaluated by Lim and colleagues[19] in a phase 1/2 dose-finding

and safety study involving doses ranging from 50 mg/day to 1200 mg/day.

Dose-related reductions in HBV DNA were consistently observed, with a high

of 3.04 log10 copies/mL at 900 mg/day. Trials involving valtorcitabine in

combination with telbivudine (L-thymidine; LdT) are expected. However, both

of these agents are nucleoside analogs and thus may share resistance

profiles.

Tenofovir disoproxil fumarate, a prodrug of tenofovir, has been found to be

a potent inhibitor of HBV in transfected HepG2 cells in culture. Qi and

colleagues[20] set out to evaluate the activity of tenofovir against

wild-type, lamivudine-resistant, and adefovir-resistant HBV strains in

vitro, as well as to assess intracellular metabolism of tenofovir. Tenofovir

was found to be very effective against lamivudine-resistant HBV strains;

adefovir-resistant strains conferred a 3- to 4.6-fold reduced susceptibility

to tenofovir in vitro. The half-life of tenofovir was greater than 40 hours

in human primary hepatocytes. Tenofovir will be evaluated in phase 3

registration studies later this year.

Concluding Remarks

As the landscape of hepatitis B therapy evolves, many options will become

available to the clinician. Currently, there is no clear-cut first-line

therapy for treatment-naive individuals. In HBeAg-positive patients,

lamivudine, adefovir, and entecavir are all currently viable options.

However, lamivudine is being used less often due to the high associated

resistance rates. Entecavir demonstrated excellent viral suppression and

moderate HBeAg seroconversion in clinical studies, but will be even more

appealing if 96- and 144-week data show still higher seroconversion rates.

Adefovir has also demonstrated excellent seroconversion rates beyond 1 year,

with relatively low resistance. Although the subset of interferon candidates

is quite small at present, once pegylated interferon is approved for use in

this setting in the United States, this agent will offer a viable option as

well.

There is no " true " endpoint to therapy for the HBeAg-negative patient, and

thus the choice of long-term therapy will be determined on the basis of the

agent with the lowest cumulative resistance rates. Future studies will need

to focus on combination therapy regimens in this patient group in an effort

to reduce the development of resistance. The lamivudine-resistant population

is currently eligible for treatment with adefovir or entecavir. The low

seroconversion rates associated with entecavir in this patient population

and the potential for cross-resistance with lamivudine make adefovir a more

likely choice in this setting. Pegylated interferon can have utility, but

with poor long-term suppression off-drug and a significant adverse-event

profile, this agent may not be the first-line option of clinicians.

Newer nucleoside/nucleotide agents will be evaluated further, with tenofovir

representing the most promising of these agents on the horizon. Combination

therapy regimens involving the use of a nucleoside and nucleotide agent

perhaps makes the most clinical sense in terms of decreasing resistance to

either class of drug. Although this approach will add to the cost of

therapy, minimizing emergence of resistant strains of HBV is a worthwhile

expense.

Supported by an independent educational grant from Gilead.

References<CUT>

http://mp.medscape.com/cgi-bin1/DM/y/ho6A0F2mbH0D1T0Gcou0Ex