Hepatitis B -- Current and Emerging Therapies (long report)

January 5, 2006

Medscape coverage of: 56th Annual Meeting of the American Association for

the Study of Liver Diseases | Viral Hepatitis

Hepatitis B -- Current and Emerging Therapies

S. Pratt, MD

Introduction

Hepatitis B remains a major healthcare problem worldwide. It is estimated

that 350 million people are chronically infected, 500,000 to 1 million of

whom die from liver disease each year.[1] Patients with chronic hepatitis B

are at increased risk for progression to cirrhosis and end-stage liver

disease as well as for the development of hepatocellular carcinoma (HCC).

The goal of treatment should be to prevent these complications. There are

now 5 drugs approved by the US Food and Drug Administration (FDA) for the

treatment of chronic hepatitis B in the United States: interferon alfa-2b,

pegylated interferon alfa-2a, lamivudine, adefovir, and entecavir. Other

drugs with potent hepatitis B virus (HBV) activity have FDA approval for the

treatment of human immunodeficiency virus (HIV), and these include tenofovir

and emtricitabine. Newer agents continue to be investigated, including

telbivudine and clevudine, and we can expect that these will continue to

move towards approval. Current challenges in hepatitis B include identifying

who should be treated and what drug or combinations should be used for

treatment, and determining the correct endpoints of treatment.

This report discusses some of the more interesting HBV-related research

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

Study of Liver Diseases (AASLD).

Who Should Be Treated?

Patients with elevated aminotransferases, elevated serum HBV DNA levels, and

active histology are obvious candidates for therapy regardless of whether

they are e antigen (Ag)-positive (the " so-called " immunoreactive stage of

disease) or e antigen-negative (most often seen in those who have precore

mutants of HBV). Knowing what to do with patients with normal serum

aminotransferase levels can be more difficult. Three different organizations

have published guidelines on the management of chronic hepatitis B which do

not recommend treating patients with normal serum aminotransferases unless a

liver biopsy shows significant disease activity.[2-4] The challenge is for

the clinician to differentiate a patient in the immunotolerant stage of

disease (typical presentation: younger age, normal serum alanine

aminotransferase [ALT], HBeAg-positive, elevated HBV DNA [>>105 copies/mL],

and normal liver biopsy) from the one third of patients in the immunoactive

stage of disease (typical presentation: older age, elevated serum ALT,

HBeAg-positive, elevated HBV DNA [> 105 copies/mL], and active histology)

who have a normal serum ALT level. The first group does not need immediate

treatment, whereas the second group does. Likewise, the clinician needs to

differentiate between the patient who is an inactive carrier (typical

presentation: older age, normal serum ALT, HBeAg-negative, low HBV DNA

levels [< 104 copies/mL], and histology showing no inflammation but varying

amounts of fibrosis) and the patient who has HBeAg-negative chronic

hepatitis (typical presentation: older age, elevated serum ALT,

HBeAg-negative, elevated HBV DNA [typically > 104 copies/mL], with a normal

serum ALT. Again, the first group of patients does not need immediate

treatment, but the second group does.

During this year's AASLD meeting, 3 studies examined the role of liver

biopsy in patients with normal aminotransferase levels. Wang and

colleagues[5] looked specifically at patients they described as being in the

" immunotolerant stage " of disease with a normal serum ALT level on at least

2 occasions in the 2 years prior to their liver biopsy. The median age of

patients was 26 years (range, 19-26 years), and the median HBV DNA level was

5.1 x 107 copies/mL (range, 4.5 x 104 to 3.4 x 108 copies/mL). Of the 13

patients studied, all of whom had endemically acquired infection, 10 had

increased fibrosis on liver biopsy.

Nguyen and colleagues[6] performed a retrospective cohort study of patients

with an HBV DNA level > 10,000 copies/mL and normal or minimally elevated

serum ALT who were evaluated by liver biopsy. They identified 39 patients

with persistently normal ALT levels and 17 with serum ALT 1-2 times the

upper limit of normal. Sixty percent of patients were HBeAg-negative and 43%

had an HBV DNA > 6 log10 copies/mL. They found that 12% of patients with a

persistently normal serum ALT had significant histology, defined as grade 2,

stage 2, or higher. Multivariate analysis revealed that only age > 45 years

was an independent predictor of significant histology.

Finally, Lai and colleagues[7] performed a retrospective chart review of all

patients with chronic hepatitis B with HBV DNA levels > 10,000 copies/mL, a

liver biopsy or " clinical cirrhosis, " and lack of treatment prior to biopsy

(except for interferon). They compared patients with persistently normal ALT

levels against those with elevated serum ALT. Fifty-one percent of the

persistently normal ALT group was HBeAg-positive. The only nonhistologic

predictor of fibrosis in the persistently normal ALT group was age > 45

years.

Commentary. These studies highlight the fact that a normal ALT in patients

with chronic hepatitis B does not necessarily correlate with inactive

histology. It is critical that the clinician categorize each patient with

HBV infection into the appropriate disease stage in order to determine the

need for therapy. For HBeAg-positive patients with normal ALT, the effort

should focus on differentiating between the immunotolerant patient and the

immunoreactive patient with normal serum ALT. Clues to differentiating

between these 2 groups include the patient's age (the younger the patient,

the more likely that he/she is in the immunotolerant stage) and the

patient's HBV DNA level (immunotolerant patients generally have markedly

elevated serum HBV DNA levels [>>106 copies/mL]; immunoreactive patients

have elevated HBV DNA levels as well, but less so). Likewise, for HBeAg

-negative patients with normal ALT, the effort should focus on

differentiating between the inactive carriers and those with HBeAg-negative

chronic hepatitis B. A clue to differentiating between these 2 groups is the

serum HBV DNA level, with inactive carriers having lower levels of viremia

(< 104 copies/mL) and HBeAg-negative chronic hepatitis B patients typically

having HBV DNA levels > 104 copies/mL. However, it should be noted that

there is no absolute level of HBV DNA that correlates with active histology,

that none of these clues are absolute, and that the clinician should

maintain a low threshold for performing a biopsy if any doubt regarding the

appropriate categorization of the patient remains.

Approved Therapies for Chronic HBV Infection

Entecavir

Entecavir, a carbocyclic analogue of 2'-deoxyguanosine, is a potent and

selective inhibitor of HBV polymerase. Gish and colleagues[8] reported the

96-week data from a trial comparing entecavir with lamivudine in

HBeAg-positive chronic hepatitis B and durability of response in patients

who achieved a virologic response (undetectable HBV DNA and HBeAg loss) at

48 weeks. They found that 82% of the entecavir-treated patients maintained

their response 24 weeks off treatment compared with 73% of the

lamivudine-treated patients. By 96 weeks of treatment, 80% of the

entecavir-treated patients had undetectable HBV DNA (< 300 copies/mL)

compared with 39% of the lamivudine group (P < .0001). The HBeAg

seroconversion rate at 96 weeks was 31% for entecavir vs 25% for lamivudine

(not statistically significant).

Colonno and colleagues[9] reported the 2-year resistance data for entecavir.

The development of entecavir resistance requires preexisting lamivudine

resistance substitutions. The 1-year entecavir data showed no resistance in

nucleoside-naive patients and resistance of 1% in patients with prior

lamivudine resistance. By 2 years of entecavir treatment, 10% of patients

with prior lamivudine resistance had developed entecavir resistance.

Eighteen patients (out of more than 650 patients naive to nucleoside

therapy) had virologic rebound, defined as a greater than 10-fold increase

in HBV DNA from nadir on entecavir. None of these patients showed evidence

of emerging entecavir resistance substitutions. Thus, there was no

resistance to entecavir after 2 years of treatment in nucleoside-naive

patients.

Commentary. This study highlights the risk of sequential use of antivirals

in treating HBV infection. Therefore, on the basis of these findings, it

seems that patients with lamivudine resistance should not simply be switched

to entecavir monotherapy.

Adefovir

Hadziyannis and colleagues[10] reported 4- and 5-year data from a long-term

study of adefovir, 10 mg/day, in patients with HBeAg-negative chronic

hepatitis B. Seventy patients were followed through 5 years. The results are

summarized in Table 1.

Table 1. Adefovir in HBeAg-Negative Patients: 5-Year Data

Years of Treatment

1 2 3 4 5 P

% of patients with ¡Ý 1 point decrease in Ishak fibrosis 33 46 71 .005

% of patients HBV DNA < 1000 copies/mL 65 67

% of patients ALT normalized 70 69

Cumulative probability of ADV resistance (A181V and/or N236T) 0% 3% 11% 18%

28%

ADV = adefovir; ALT = alanine aminotransferase; A181V and/or N236T =

adefovir-resistant mutations

Four patients had a verified increase in serum creatinine levels. It is

important to note that although the onset of adefovir resistance was delayed

in adefovir-treated patients, by year 5, resistance had developed in 28%. By

year 5 there also appeared to be a plateau in the percentage of patients

with undetectable HBV DNA and normalization of serum ALT.

Commentary. This supports previous findings in that there is a proportion of

patients with HBV infection who have a poor response to adefovir.[20]

Continued treatment in these patients is unlikely to produce any additional

benefit and carries the risk of emerging viral resistance. Two potential

options for managing these patients with inadequate response are to switch

from adefovir to a different therapy or a combination therapy regimen.

Two other studies presented during this year's meeting also assessed the

development of adefovir resistance; one looked at patients with lamivudine

resistance and the second evaluated patients who had received a liver

transplant.[11,12] Lee and colleagues[11] followed 50 patients with

lamivudine resistance who were treated with adefovir for 48 weeks; 19% of

patients developed adefovir resistance, either at A181V/T or N236T. The

decline in serum HBV DNA levels was significantly less in patients who

developed adefovir resistance than in those who did not develop resistance.

Lok and colleagues[12] assessed the rates of virologic response and adefovir

resistance in the NIH HBV-OLT (National Institutes of Health-Hepatitis B

Virus-Orthotopic Liver Transplantation) study. Eighty-one patients with at

least 6 months of treatment with adefovir were included. The investigators

defined an initial virologic response as HBV DNA < 4 log copies/mL after 6

months of treatment. Only 54% of patients achieved an initial virologic

response. Emergence of adefovir resistance was 1.5% at 1 year and 13.3% at 2

years. Six patients developed adefovir-resistant mutations. Development of

resistance was associated with HBV genotype D and with switching to adefovir

monotherapy. Three of the 6 patients with adefovir resistance had viral

rebound, 2 had a flare of their hepatitis, and 1 suffered hepatic

decompensation and died. These studies suggest that patients with lamivudine

resistance may develop adefovir resistance faster than patients without

prior lamivudine resistance. The second study also suggested that for

patients with lamivudine resistance, sequential therapy with adefovir was

more likely to produce adefovir resistance than was add-on therapy. This

important issue was also addressed in 3 other studies presented during these

meeting proceedings.[13-15]

Thibault and colleagues[13] analyzed the incidence of adefovir resistance in

35 HIV/HBV-infected patients treated with adefovir add-on therapy after the

development of lamivudine resistance. Of the 29 patients still enrolled at

year 4, 14 had an undetectable HBV DNA level (< 200 copies/mL). Of the 15

with detectable HBV DNA (median of 3.55 log10), none had developed

adefovir-resistant mutations. This finding suggested that although adefovir

add-on therapy decreased the likelihood of development of adefovir

resistance, approximately 50% of patients failed to achieve full viral

suppression.

Manolakopoulos and colleagues[14] also showed that a strategy of adefovir

add-on therapy was superior to sequential therapy both in terms of greater

antiviral efficacy and reduction in adefovir resistance. Finally, Lampertico

and colleagues[15] reported on a 2-year analysis of sequential adefovir vs

add-on adefovir therapy in 604 patients with lamivudine resistance enrolled

in a prospective cohort trial. Thirty-one patients had a virologic rebound

(> 1 log increase in HBV DNA compared with treatment nadir and confirmed on

2 occasions), and 3 developed adefovir resistance. Multivariate analysis

showed that adefovir monotherapy (P < .0001) and detectable HBV DNA at week

24 (P < .0001) were associated with virologic rebound.

Commentary. Collectively, these studies suggest that when treating a patient

with lamivudine resistance, adefovir add-on therapy is superior to

sequential therapy. The study by Lampertico and colleagues[15] also

highlighted the important association between insufficient early viral

suppression and the development of virologic rebound and resistance. In a

phase 3 trial comparing 2 nucleoside analogues (telbivudine and lamivudine),

Lai and colleagues[16] found that early (24 weeks) virologic response

correlated both with response and with the likelihood of viral breakthrough

and resistance. Thus, in patients being treated with monotherapy, unless

viral replication can be quickly achieved, there is a greater risk of

developing viral resistance. If monotherapy is to be used, it is critical

that the degree of viral response be monitored. If there is not significant

viral suppression by 24 weeks on therapy, a change in therapy (ie, a switch

to a different agent or addition of a second agent) should be considered to

avoid the development of breakthrough/resistance. These studies highlight

the need for future investigations to explore the role of combination

therapy as a first-line strategy for hepatitis B.

New Therapies for Chronic HBV Infection

Clevudine*

Yoo and colleagues[17,18] presented data from phase 3 trials of clevudine,

an L-nucleoside, in the treatment HBeAg-positive and HBeAg-negative

patients. In the HBeAg-positive study,[17] 243 patients were randomized in a

3:1 ratio to either clevudine 30 mg/day or placebo for 24 weeks of treatment

with 24 weeks of follow-up. Results are reported in Table 2.

Table 2. Clevudine in HBeAg-Positive Chronic Hepatitis B

24 weeks: Clevudine Placebo P

Median decrease in HBV DNA (log10 copies/mL) 5.1 0.27 < .0001

HBV DNA < 300 copies/mL (%) 59 0

Normal ALT (%) 68.2 17.5

HBeAg loss (%) 10.4 12.3

48 weeks (24 weeks post treatment):

Median decrease in HBV DNA (log10 copies/mL) 2.02 0.68 < .0001

HBV DNA < 300 copies/mL (%) 2.9 0

Normal ALT (%) 61.2 NR

HBeAg loss (%) 15.3 12

Five patients in the clevudine group developed nucleotide substitutions,

none of which were associated with viral rebound.

The HBeAg-negative study[18] had a similar design, with 83 patients assigned

to receive either clevudine 30 mg/day or placebo for 24 weeks of treatment

followed by 24 weeks of follow-up. Results are reported in Table 3.

Table 3. Clevudine in HBeAg-Negative Chronic Hepatitis B

24 weeks: Clevudine Placebo P

Median decrease in HBV DNA (log10 copies/mL) 4.25 0.48 < .0001

HBV DNA < 300 copies/mL (%) 92.1 0

Normal ALT (%) 74.6 33.3

48 weeks (24 weeks post treatment):

Median decrease in HBV DNA (log10 copies/mL) 3.11 0.66 < .0001

HBV DNA < 300 copies/mL (%) 16.4 0

Normal ALT (%) 70.5

No viral resistance was seen.

Commentary. These studies show that clevudine is a potent inhibitor of HBV

in both HBeAg-positive and HBeAg-negative patients.

Telbivudine*

Lai and colleagues[19] presented the 52-week data as well as some 76-week

data from the GLOBE study, a phase 3 randomized, blinded 2-year trial of

telbivudine vs lamivudine in chronic hepatitis B. This study enrolled 1367

patients. Results are reported in Table 4.

Table 4. Telbivudine vs Lamivudine in Chronic Hepatitis B

52 weeks: HBeAg+ HBeAg-

LDT LAM P LDT LAM P

PCR-negative (%) 60 40 < .01 88 71 < .01

HBeAg loss (%) 26 23

HBeAg seroconversion (%) 22 21

Resistance 3 8 < .01 2 7 < .01

Primary treatment failure (%) 5 13 0 3

76 weeks:

PCR-negative (%) 69 41 84 67 < .05

eAg seroconversion (%) 33 24

LDT = telbivudine; LAM = lamivudine; HBeAg+ = HBeAg-positive; HBeAg- =

HBeAg-negative; PCR = polymerase chain reaction

Primary treatment failure was defined as an HBV DNA never < 5 log10

copies/mL.

Commentary. Telbivudine had greater potency than lamivudine and will likely

receive approval in the near future. How this agent will fit into treatment

algorithms has not yet been defined.

Other Therapies on the Horizon

Tenofovir. <<Level 3; run-in>>Tenofovir,* like adefovir, is a nucleotide

analogue. It has FDA approval for the treatment of HIV, but also has potent

anti-HBV activity. A recently published study suggested that tenofovir may

be a more potent agent than adefovir.[20] There were no less than 4 studies

presented during this year's meeting assessing the efficacy of tenofovir in

hepatitis B.[21-24] Van Bommel and colleagues[21] prospectively studied the

effectiveness of tenofovir and adefovir in patients with lamivudine

resistance. A total of 88 patients were treated, 35 with tenofovir (32

HBeAg-positive, 24 with HIV/HBV coinfection, all with genotypic resistance

to lamivudine), and 53 with adefovir (49 HBeAg-positive, 32 with genotypic

resistance to lamivudine) for a mean duration of 33 ¡À 7 and 24 ¡À 5.1

months, respectively. Results are reported in Table 5.

Table 5. Adefovir and Tenofovir in Chronic Hepatitis B

ADV

(n = 53) TDF

(n = 35)

HBV DNA < 400 copies/mL, 12 months 32 94

HBV DNA < 400 copies/mL, 18 months 35 100

HBV DNA < 400 copies/mL, 24 months 49 100

Viral resistance (%) 3.7 0

HBeAg loss (%) 21 51

HBsAg loss (%) 6 12

ADV = adefovir; TDF = tenofovir; HBsAg = hepatitis B surface antigen

Patients in the adefovir group showed greater individual variations in HBV

DNA decline. The presence of lamivudine resistance-associated mutations

M180L and M204V at baseline was associated with a lower rate of viral

suppression at month 12 (P = .01) and month 18 (P = .02) in the adefovir

group only; the tenofovir group was unaffected.

Mauss and colleagues[22] performed a multicenter 1:2 matched-pair analysis

comparing patients with HBV/HIV coinfection starting an antiretroviral

regimen including tenofovir plus lamivudine vs patients who had a highly

replicative lamivudine-resistant hepatitis B starting therapy with tenofovir

only. The results are shown in Table 6.

Table 6. Tenofovir Monotherapy and in Combination With Lamivudine in HBV/HIV

Coinfection

TDF

(n = 46) TDF + LAM

(n = 23) P

Median HBV DNA at baseline (copies/mL) 120,000,000 59,000,000 .75

Median HBV DNA, 3 months (copies/mL) 27,950 138,450 .26

Median HBV DNA, 12 months (copies/mL) < 1000 < 1000 .46

Median HBV DNA, 24 months (copies/mL) < 1000 < 1000 .24

Sustained undetectable HBV DNA (%) 83 83

HBeAg loss (%) 25 31.8 .57

HBsAg loss (%) 4.3 4.3

TDF = tenofovir; ADV = adefovir; HBsAg = hepatitis B surface antigen

No resistance to tenofovir was observed. Tenofovir was very effective in

these coinfected patients with or without lamivudine resistance, and

tenofovir monotherapy appeared to be as effective as combination tenofovir

plus lamivudine.

Klausen and colleagues[23] presented a retrospective review of 21

HBV/HIV-coinfected patients with highly replicative hepatitis B, 10 of whom

had lamivudine resistance, who were treated with tenofovir for an average of

27 months (range, 12-39 months). They found that tenofovir was equally

effective in patients with and without lamivudine resistance. No viral

breakthrough or resistance was seen.

Finally, van Bommel and colleagues[24] studied the effectiveness of

tenofovir in 14 lamivudine-resistant patients who had a suboptimal response

to adefovir. They defined suboptimal response as a decline in the HBV DNA of

< 3 log or a high level of HBV DNA (> 6 log10) in the absence of adefovir

resistance mutants. All subjects were switched directly from adefovir to

tenofovir. At this time, the mean HBV DNA level was 6.6 log10 copies/mL; 10

of 14 patients had elevated serum ALT. Mean reduction in HBV DNA on adefovir

was 0.9 log10 copies/mL, and mean decrease in HBV DNA on tenofovir was 3.1

log10 copies/mL at 3 months and 3.9 log10 copies/mL at 6 months. Thirteen

patients reached HBV DNA levels below the limit of detection (400

copies/mL).

Commentary. Despite being similar molecules and having similar mechanisms of

action, there are clear differences between tenofovir and adefovir. The

studies discussed above add additional weight to the belief that tenofovir

has potentially greater antiviral activity compared with adefovir. Some

clinicians have suggested that this difference may be due to dosing

differences between the 2 drugs.[20] However, just simply increasing the

dose of adefovir in the subset of patients with a poor response increases

the likelihood of toxicity, a risk not justified given the availability of

other effective agents. Tenofovir also appears to be more effective than

adefovir in avoiding the development of drug resistance. The rate and level

of HBV DNA suppression observed in these studies makes the development of

tenofovir resistance unlikely.

Concluding Remarks

With the availability of effective agents, it is critical that all potential

candidates for hepatitis B therapy be identified. Data reported during this

year's meeting proceedings reinforced the knowledge that a normal serum ALT

level does not always mean inactive histology. In the appropriate clinical

setting, and with increasing age (> 40 years) and elevated HBV DNA levels (>

104 copies/mL), a liver biopsy should be performed to determine with

certainty whether a patient may benefit from treatment. When in doubt,

clinicians should perform the biopsy.

We continue to learn more regarding the currently available approved

therapies for hepatitis B. Lamivudine should not be used as a monotherapy;

the risk of developing lamivudine resistance is too high and the development

of lamivudine resistance limits treatment options down the line. Patients

who develop lamivudine resistance should be treated with add-on therapy as

opposed to sequential therapy regimens. Adefovir, although an effective

agent, is increasingly associated with some challenges in management. There

is a subset of patients with an inadequate response to therapy with

adefovir. It is on the basis of this group with inadequate response that we

are now observing the late development of resistance (28% at 5 years in

HBeAg-negative patients). Patients with inadequate response to adefovir at

24 weeks should be considered for an alternative therapy or a combination

therapy regimen. Entecavir has greater potency than lamivudine and this is

reflected in the absence of resistance in nucleoside-naive patients at 96

weeks. However, we can expect that resistance of some degree will likely

eventually develop in these patients. We also now know that entecavir

resistance occurs at a high rate in patients with prior lamivudine

resistance: 10% at 2 years. Thus, it seems entecavir monotherapy should not

be used in patients with lamivudine resistance. Tenofovir appears to be more

potent (and, as a result, more likely to avoid the development of

resistance) than its fellow nucleotide analogue adefovir. This agent may

have a role in the management of those patients with an inadequate response

to adefovir or as first-line therapy. Telbivudine and clevudine are also

effective therapies in hepatitis B that are currently in the pipeline for

approval for general use in as yet undefined roles in this setting. It is

hoped that in future AASLD meetings, we will begin to see data from studies

assessing the effectiveness of combination therapies as the initial

treatment strategy in naive patients.

*The US Food and Drug Administration has not approved this medication for

this use.

References<cut>

http://www.medscape.com/viewarticle/518701

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January 5, 2006