Viral Hepatitis: A Clinical Update

[Guest guest]

Viral Hepatitis: A Clinical Update

Tram T. Tran, MD Disclosures

Hepatitis B

With the ongoing success of universal vaccination programs in this

country and other countries worldwide, such as Taiwan, the incidence

of acute hepatitis B infection has significantly decreased, and lower

rates of hepatocellular carcinoma have been observed.[1] However, the

global health problem of hepatitis B persists in many highly endemic

areas, and those chronically infected number more than 400 million

worldwide.

In the past several years, the clinical options for the treatment of

chronic hepatitis B have expanded to include several oral

medications, as well as two forms of interferon, administered

subcutaneously. These medications have been successful, to varying

degrees, in achieving viral suppression and seroconversion from

hepatitis B e antigen (HBeAg) positive to anti-HBe antibody (anti-

HBeAb) positive. However, true viral eradication has been elusive.

Research presented at this year's Digestive Disease Week (DDW)

meeting focused on the efficacy and long-term data of the currently

available medications; new therapeutic options such as combination

therapy strategies (along the lines of HIV treatment paradigms); and

other clinical predictors of disease in the setting of hepatitis B.

The Role of Serum Aminotransferase Level

One of the most controversial issues in the management of chronic

hepatitis B is the treatment of patients with aminotransferase levels

that are considered to be relatively normal. Current guidelines and

algorithms, along with the known literature, suggest that patients

with elevated aminotransferases (alanine aminotransferase [ALT]),

have a better chance at responding to therapy -- specifically,

achieving seroconversion. However, data from the recently published

REVEAL (Risk Evaluation of Viral Load Elevation and Associated Liver

disease) study[2] suggest that despite normal ALT levels, patients

with high viral replication had an increased risk for the development

of hepatocellular carcinoma and cirrhosis, and that the higher the

hepatitis B virus (HBV) DNA level, the higher the risk, leading some

clinicians to elect to treat these patients, even in the setting of

normal serum ALT.

Terrault and colleagues[3] examined the correlation between

histologic damage and aminotransferase level in 1253 patients from

the phase III trials of treatment-naive HBV disease who were

subsequently treated with the oral antiviral agent entecavir. They

found that two thirds of patients had clinically significant

necroinflammation on liver biopsy, despite ALT values < 2 times the

upper limit of normal (ULN). They also noted that 11%-17% of patients

with ALT < 2 times ULN also had Ishak fibrosis scores > 4. Although

patients with more elevated ALT levels were even more likely to have

inflammation and fibrosis, these data add to the growing body of

literature suggesting that a normal serum ALT should not be used as

the sole determinant of whether to initiate treatment.

Chen and colleagues[4] presented an analysis of a subgroup of

patients from the REVEAL study, which followed a cohort of Taiwanese

individuals chronically infected with hepatitis B for more than 10

years. This subgroup of 1712 patients who all had at least 5 serum

ALT measurements over this time period was assessed for the

trajectory of their ALT values. They found a correlation between ALT

trajectory (low-to-medium, high-to-medium, and medium-to-high) and

the adjusted hazard ratio of developing hepatocellular carcinoma:

4.0, 4.6, and 7.4, respectively, when compared with patients with

persistently normal ALT levels. Serum HBV DNA also remained an

important predictor of hepatocellular carcinoma, even after adjusting

for ALT trajectories.

Awareness and Screening Practices

Despite the availability of efficacious and well-tolerated

medications for the treatment of HBV infection, many patients in high-

risk groups, such as persons from endemic areas, are not consistently

screened, and many of these patients may be eligible for treatment.

Jou and colleagues[5] examined the awareness and screening practices

of primary care practitioners in Wisconsin regarding hepatitis B.

Despite 88% of the survey respondents reporting that HBV infection

was an important general health problem, 17% would not screen

pregnant women, 35% would not screen children born to immigrants, and

23% would not screen household members of hepatitis B carriers.

Vaccination practices also reflected deficiencies in the

understanding of risk factors, highlighting the need for further

educational initiatives in HBV screening and preventative vaccination.

Treatment

There are currently 6 US Food and Drug Administration (FDA)-approved

therapies for the treatment of chronic hepatitis B infection:

standard nonpegylated interferon alfa-2b, pegylated interferon alfa-

2a, lamivudine, adefovir dipivoxil, entecavir, and telbivudine. New

therapies on the horizon include tenofovir,* a potent antiviral used

in the treatment of HIV but which is also active against HBV; and the

use of combination therapy regimens.

Leung and colleagues[6] reported on a head-to-head viral kinetic

study comparing entecavir and adefovir in 69 HBeAg-positive antiviral-

naive patients treated with entecavir 0.5 mg and adefovir 10 mg

daily. Measurements of serum HBV DNA by polymerase chain reaction

(PCR) assay were determined at Weeks 12, 24, 36, and 48. Viral

suppression was greater in the entecavir-treated group, with the

difference noted as early as Day 10, and persisting through 48 weeks.

HBV DNA by PCR was undetectable (< 300 copies/mL) in 58% of patients

treated with entecavir at 48 weeks vs in 19% of adefovir-treated

patients, and mean HBV DNA change from baseline was -7.28 log10

copies/mL for entecavir vs -5.08 log10 copies/mL for adefovir.

Adverse events were comparable between the 2 groups.

Data were also reported on telbivudine, the most recently approved

oral nucleoside analog for the treatment of hepatitis B. Han and

colleagues[7] reported 2-year data from the GLOBE trial, a phase 3

study comparing telbivudine with lamivudine for the treatment of

chronic hepatitis B, which enrolled 1367 patients. Patients were

randomized to telbivudine 600 mg/day vs lamivudine 100 mg/day;

telbivudine was found to be superior to lamivudine in achieving viral

suppression and ALT normalization. Two-year seroconversion rates for

telbivudine were 30% (vs 25% for lamivudine), and viral breakthrough

occurred in 8%-19% of patients on telbivudine vs 16%-33% of patients

on lamivudine. Early viral suppression at 24 weeks was predictive of

2-year efficacy in this study. Data from GLOBE were also presented by

Seifer and colleagues,[8] who analyzed the 165 telbivudine-treated

patients who had > 1000 copies/mL of virus detectable at 48 weeks;

115 of these 165 patients had evaluable HBV DNA on at least 16 weeks

of therapy. Forty-six of the 115 patients had the M204I genotypic

change associated with telbivudine resistance. Standring and

colleagues[9] reported that in vitro phenotypic testing showed that

the HBV variant with this mutation was > 1300-fold resistant to

telbivudine, with sensitivity to adefovir or tenofovir only 3- to 5-

fold reduced. Thus, on the basis of data from GLOBE, telbivudine

appears to be superior to lamivudine; however, development of the

M204I mutation may reduce viral susceptibility. Using these 24-week

viral data may help predict those patients who are at risk of

developing the M204I mutation, and the use of salvage therapy with

adefovir may be indicated in this setting.[10]

Combination Strategies

One of the important lessons learned from the treatment of other

viral diseases, such as HIV infection, was the prevention of viral

resistance by using combination therapies. With the expanded

armamentarium of HBV treatment, interest in combination therapies is

keen, and some early data exploring this concept are starting to

emerge. However, despite the enticing proof-of-concept, combination

therapy is not yet FDA approved and additional studies are needed to

determine whether combination therapy will really yield improvements

in efficacy and resistance without increased toxicity in the setting

of hepatitis B.

Zhou and colleagues[11] evaluated the pharmacokinetic drug-drug

interactions between telbivudine and tenofovir, combining the effects

of an anti-HBV nucleoside analog and an anti-HIV nucleotide analog

with potent anti-HBV activity. Sixteen healthy individuals were given

1 study drug daily for 14 days, and the second drug was then added on

Day 8. Pharmacokinetic studies showed steady-state values were

similar for the 2 drugs, whether administered alone or in

combination. Both drugs were well tolerated, showing no appreciable

pharmacokinetic drug-drug interaction, thus paving the way for

further combination studies with these 2 agents.

Understanding the resistance profiles of these medications has become

an important clinical issue, especially with long treatment durations

indicated for most patients. Interferons, both nonpegylated and

pegylated, are associated with no appreciable viral resistance due to

their different mechanism of action as primarily immunomodulators.

Lamivudine, now with extensive long-term data, has been shown to be

associated with significant resistance (24% at 1 year, increasing to

70% by Year 4 of therapy) due to the development of the YMDD

mutation, and is no longer a preferred first-line treatment choice by

most clinicians. In the setting of lamivudine resistance, current

data suggest that the addition of an oral nucleotide analog, such as

adefovir, to ongoing lamivudine therapy, is a better option than

sequential monotherapy, which could lead to the development of

multidrug-resistant HBV in the long term. Adefovir has a reported 29%

5-year resistance rate in naive HBeAg-negative patients , and if

resistance develops, the virus is still responsive to therapy with a

nucleoside analog, such as lamivudine or entecavir.[12] Entecavir

resistance at 4 years has recently been reported at < 1%; in vitro

studies suggest the entecavir-resistant mutants should be responsive

to adefovir or tenofovir.[13]

Prophylactic Antiviral Therapy for Prevention of Chemotherapy-Induced

HBV Reactivation

Current guidelines[14] recommend that patients in high-risk groups

who are to undergo chemotherapy or cytotoxic immunosuppressive

therapy be screened for hepatitis B. If chronically infected, it is

recommended that preemptive prophylaxis with antiviral therapy be

initiated at the time of chemotherapy and maintained for 6 months

afterward. This strategy is recommended because of the approximate

20%-50% risk of HBV reactivation in HBV-infected individuals

undergoing chemotherapy, which may lead to a severe disease flare,

fulminant hepatitis, and delays in the treatment of the underlying

malignant process.

Alsohaibani and colleagues[15] performed a meta-analysis of clinical

trials evaluating the efficacy and safety of lamivudine prophylaxis

in HBV carriers undergoing chemotherapy, and identified 12 clinical

trials involving a total of 715 patients. Mortality in the lamivudine-

treated group due to HBV reactivation was 0% vs 5% in the

nonprophylaxed group (P < .05), and fewer patients on lamivudine

required disruption of their chemotherapy (11% vs. 31%). No

significant adverse events and no resistance were noted with

lamivudine in this setting.

Hepatitis C

For the past several years, the standard of care for the treatment of

hepatitis C has been combination therapy with pegylated interferon

and ribavirin. Pegylated interferon is an immunomodulator, with some

antiviral properties, whereas ribavirin is a nucleoside analog,

which, when given in conjunction with pegylated interferon, yields

sustained viral response rates in approximately 50% of patients

treated. The current focus in the field of HCV treatment is on the

STAT-C (specifically targeted antiviral therapy for HCV) therapies,

which include new agents that target specific steps in the viral

replication cycle. Agents in this category include protease

inhibitors and polymerase inhibitors. The hope is that these

therapies will increase the efficacy of therapy, especially in those

difficult-to-treat patients such as the nonresponders/relapsers to

standard treatment. Research is also continuing toward the goal of

optimizing and individualizing current therapy in order to achieve

maximal efficacy, as emphasized in presentations at DDW 2007.

Novel Treatments

Valopicitabine (NM283),* a ribonucleoside analog that targets the

viral RNA polymerase, is currently undergoing study for the treatment

of hepatitis C. Gitlin and colleagues[16] reported preliminary 24-

and 48-week results with combination valopicitabine and pegylated

interferon alfa-2a in treatment-naïve patients infected with

hepatitis C virus (HCV) genotype 1. It is important to note that the

higher valopicitabine dose had to be reduced per protocol due to

gastrointestinal side effects. However, by Week 24, 49%-68% of

patients achieved undetectable HCV RNA to < 20 IU/mL, with continued

viral suppression through to Week 48, and with acceptable

tolerability. Sustained virologic response rates, not yet available,

are eagerly awaited. Results of a phase 2a study designed to assess

the potential for a pharmacokinetic drug interaction between

valopicitabine and pegylated interferon alfa-2b in treatment-naive

patients with HCV 1 infection were also reported by -

and colleagues,[17] and revealed no treatment-limiting side effects

or pharmacokinetic interaction.

The efficacy of another HCV polymerase inhibitor, R1479,* and its

prodrug R1626* was evaluated in comparison to placebo in a 14-day

dose-ranging study involving 47 treatment-naive patients chronically

infected with HCV genotype 1.[18] This novel nucleoside analog

targeting HCV polymerase demonstrated a decrease in viral load,

without evidence of viral rebound or resistance. Phase 2 studies are

now under way.

Other new agents in development include celgosivir,*[19] a potent

inhibitor of alpha-glucosidase I, a host enzyme required for viral

assembly and release; and HCV-796,* another inhibitor of HCV RNA-

dependent RNA polymerase.[20] Preliminary data presented at DDW 2007

regarding these agents suggest the need for further studies and

suggest the potential of these agents for the treatment of chronic

hepatitis C.

Predicting Response to Therapy

The ability to predict which patients have a better chance of

responding to therapy is instrumental in the clinical management of

hepatitis C. The early viral response (EVR; defined as a 2-log or

greater decline in viral load at 12 weeks of therapy), and more

recently, the rapid viral response (RVR; defined as undetectable

viral load at Week 4 of therapy) have allowed for stratification of

patients by likelihood of response and relapse. These

strategies/rules may allow clinicians to discontinue therapy earlier

in those who have little chance of responding to therapy, sparing

them unnecessary side effects and associated costs, and may also

allow for intensification of therapy in those patients who have a

higher likelihood of relapse.

Willems and colleagues[21] analyzed a subpopulation of patients with

HCV genotype 2/3 disease who were treated with pegylated interferon

alfa-2a plus ribavirin and did not achieve a RVR in 2 large previous

clinical studies, to determine whether an intensified regimen of

pegylated interferon alfa-2a plus ribavirin would have utility in

this setting. They found that sustained virologic response, which is

defined as remaining HCV PCR negative for 6 months after completion

of therapy, was higher in those patients subsequently treated for 48

weeks as compared with 24 weeks (76% vs 65%), and relapse rates were

lower with the longer duration of therapy (4% vs 24%). Higher doses

of ribavirin (1000/1200 mg daily vs 800 mg daily) also added to

treatment success.

In another study involving HCV genotype 2/3 patients, Shiffman and

colleagues[22] examined response rates in patients with and without

cirrhosis. They reported that if RVR was achieved, then a sustained

viral response was highly likely for both cirrhotic and noncirrhotic

patients (sustained virologic response > 87%) with 24 weeks of

therapy. However, if a RVR was not achieved, patients with cirrhosis

had a sustained virologic response of only 30% with the currently

recommended 24-week regimen, suggesting that earlier or longer

therapy in cirrhotic patients may be necessary for treatment

optimization.

Insulin resistance has recently been linked to treatment failure in

hepatitis C. Two studies presented during DDW 2007 examined the role

of diabetes and the metabolic syndrome in determining response to

therapy in patients with hepatitis C. Elgouhari and colleagues[23]

conducted a case-controlled retrospective analysis of 61 hepatitis C

patients with diabetes mellitus treated with combination pegylated

interferon plus ribavirin; subjects were matched to controls without

diabetes. They found that diabetic patients had higher body mass

indexes, were more likely to have advanced fibrosis, and were less

likely to achieve a sustained virologic response. Multivariate

analysis showed diabetes and HCV genotype to be predictors of

treatment failure. Hanouneh and colleagues[24] assessed the role of

the metabolic syndrome, a condition whose underlying mechanism is

related to insulin resistance, in 251 HCV-infected patients

undergoing antiviral therapy. They found that after adjusting for

ethnicity, genotype, sex, degree of fibrosis, and steatosis, patients

with metabolic syndrome were 2.8 times more likely to fail to respond

to therapy than those without metabolic syndrome.

Durability of Response

Unlike in hepatitis B, a sustained virologic response in hepatitis C

(remaining HCV undetectable for 6 months after the completion of

therapy) is considered complete viral " cure " due to the low reported

rates of HCV recurrence.

Swain and colleagues[25] reported on a long-term study following 997

patients who took part in 9 randomized trials of pegylated interferon

given alone or in combination therapy with ribavirin. In >99% of all

patients who achieved a sustained virologic response, the response

was durable, with a mean follow-up of 4.1 years after treatment

cessation. Eight patients became HCV RNA detectable, with no clear

demographic or viral characteristic particular to this group.

Therefore, sustained virologic response appears to be highly durable

in HCV.

Extrahepatic Manifestations

Extrahepatic manifestations of hepatitis C can include

cryoglobulinemia, vasculitis, Behcet's disease, lichen planus,

glomerulonephritis, lymphoma, and porphyria cutanea tarda. In

particular, cryoglobulinemia is one of the most common of these

extrahepatic diseases and can present with a wide array of clinical

symptoms.

Al Sibae and colleagues[26] reported on 43 HCV-infected patients with

cryoglobulinemia presenting in a large academic center. They found

that the majority of these patients were women, over age 50, had HCV

genotype 1, and 25% had concomitant evidence of autoimmune disease,

reflecting possible cross-reacting antibodies.

Conclusion

Research in the areas of viral hepatitis B and C are continuing to

refine treatment strategies, with a focus on individualizing care,

and with special consideration to patterns of viral resistance, side

effects, and predictors of response. The evolving therapeutic

landscape for hepatitis B has provided exciting new options for viral

suppression, in the hopes of reducing disease progression and the

development of hepatocellular carcinoma -- although the goal of viral

eradication remains elusive. For hepatitis C, although viral " cure "

is possible, enhancing response rates with fewer associated side

effects and the use of viral-specific targets appear to be the

current strategies in therapy.