*New Advances in Chronic Hepatitis B*

liver411

Shannan R. Tujios; William M. Lee
Posted: 05/11/2012; Curr Opin Gastroenterol. 2012;28(3):193-197. © 2012 Lippincott Williams & Wilkins

<http://www.medscape.com/viewarticle/762771?src=mp&spon=38>

*Abstract and Introduction*

*Abstract*
*Purpose of review*This article reviews recent developments in the evaluation and treatment of chronic hepatitis B (CHB) based on articles published between December 2010 and January 2012.

*Recent findings* The majority of patients infected with CHB have not been diagnosed and most at-risk individuals have not been immunized. Progression to cirrhosis depends on hepatitis B virus (HBV) genotype, hepatitis B e antigen (HBeAg) presence, persistently high levels of HBV DNA, and elevated alanine aminotransferase, although hepatitis B surface antigen (HBsAg) kinetics may help predict natural history and antiviral response. Antiviral resistance limits the success of nucleos(t)ide analogs and agents such as entecavir and tenofovir with high potency and high genetic barrier to resistance are considered first-line therapy. Specialized treatment of CHB in pregnancy, coinfection, decompensated cirrhosis, and posttransplant is safe and effective.
*Summary* The complications of CHB can now be avoided and reversed with potent antiviral suppression of HBV DNA. For now, treatment is long-term and further studies are needed to discern whether sequential or combination therapy may be superior to current monotherapy for certain patients. Increased awareness should improve screening resulting in more frequent treatment and immunization of at-risk individuals toward eventual CHB eradication.

*Introduction*
It is estimated that over 350 million persons are infected with chronic hepatitis B worldwide resulting in 600 000 deaths each year from cirrhosis and hepatocellular carcinoma.^[1] As over 90% of infected newborns will develop chronic hepatitis, efforts for eradication have focused on universal vaccination and screening those born in endemic areas. Despite the availability of hepatitis B virus (HBV) vaccine since 1981, over 4000 cases of acute HBV are still diagnosed in the United States each year and more than 700 000 have chronic hepatitis B (CHB).^[2..] Currently there are seven approved hepatitis B therapies that can manage 95% of CHB cases yet 67% of US patients and nearly 90% of European patients are unaware of their infection, highlighting the need for increased awareness and treatment to prevent deaths.^[3,4]
*Natural History*
CHB is characterized by four phases: immune tolerance with the presence of hepatitis B e antigen (HBeAg), high HBV DNA with normal alanine aminotransferase (ALT) levels and little liver damage; immune clearance with declining viral loads with elevated ALT levels corresponding to increased hepatic inflammation and fibrosis; an inactive carrier state with loss of HBeAg, low levels of HBV DNA and normal ALT; and reactivation phase with absence of HBeAg but elevated ALT, fluctuating HBV DNA and commonly precore or core promoter mutants. When the virus finally clears, hepatitis B surface antigen (HBsAg) is absent from serum as is HBV DNA, and any residual liver inflammation resolves, whereas cirrhosis does not. Recently, the impact of viral and host factors on rates of HBV DNA clearance and HBsAg seroconversion has been further elucidated. In the Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer-HBV study in Taiwan, a cohort of 3653 men and women positive for HBsAg was followed over 19 years. Annual seroclearance rate for HBeAg was 5.92, 1.97% for HBV DNA, and 2.26% for HBsAg with greater than 10 000 copies/ml. Female gender, ALT at least 45 IU, HBV DNA less than 100 000 copies/ml, HBV genotype B rather than C, and precore mutants all were associated with higher HBeAg seroclearance. After HBeAg clearance, the annual rate of HBV DNA clearance was 3.2% and subsequent annual rate of HBsAg clearance was 6%.^[5.] A recent study of 46 Asian CHB primarily genotype B patients with spontaneous HBsAg seroclearance showed a rapid decline in HBsAg levels in the preceding 3 years. HBsAg titer less than 200 IU/ml with a drop of 1 log or more has a positive predictive value of 100% of HBsAg loss at 3 years.^[6] In HBeAg-negative patients, HBsAg level less than 1000 IU/ml is an independent predictor of HBsAg loss over 5--10 years with highest rate of seroconversion occurring with titer less than 10 IU/l.^[7]

The natural history of CHB in Mediterranean and African countries differs from much of Asia due to the predominance of genotypes A, D, and E as well as the more common mode of transmission being horizontal transmission during childhood. Less than a third of those infected during childhood will develop CHB and most will lose HBeAg rapidly, 14--16% per year. The vast majority of those with elevated ALT levels and histologically active disease are HBeAg negative but are still at risk for cirrhosis and hepatocellular carcinoma. Annual spontaneous clearance of HBsAg is 1% in childhood and up to 2% in adults.^[8] A better understanding of the natural history of CHB as related to genotypes, environmental factors and serological predictors might shed light on underlying molecular mechanisms and potential treatment targets.

*Screening and Vaccination*
In countries such as the United States and Canada with lower disease prevalence, screening, and treating high-risk groups has been shown to be costeffective and suggests that screening should include immigrants from areas with prevalence less than the currently recommended 2%.^[9..,10]
Guidelines recommend hepatitis A and B immunizations for all persons with chronic liver disease. Although vaccination rates in the United States have increased over the past decade with 68% of 2 year olds having detectable surface antibody, currently only 20% of chronic liver disease patients have been immunized against hepatitis A and 32% against hepatitis B.^[11.] Due to 25 outbreaks of acute hepatitis B since 1996 in long-term care facilities traced to glucose monitoring and high prevalence of nonalcoholic fatty liver disease, vaccination is now recommended for all diabetic patients ages 19--59 years.^[12]
*Treatment Indications and Endpoints*
The goal of antiviral therapy is to suppress HBV DNA replication and reduce necroinflammatory activity to prevent progression to cirrhosis and hepatocellular carcinoma. Surrogate markers for clinical success include normalization of ALT, improvement of histology, HBeAg loss, and ultimately HBsAg loss. HBsAg levels appear to correspond to transcriptional activity of covalently closed circular DNA but pangenotypic multicenter trials are needed to identify clinical thresholds of who should be treated and for how long.^[13.,14,15,16.] Currently there are seven approved therapies including /a/-2a interferon, pegylated interferon, lamivudine, adefovir, entecavir, telbivudine, and tenofovir. Pegylated interferon, entecavir, and tenofovir monotherapies have the highest efficacy and lowest risk for resistance and are recommended first-line treatment in naive patients. The benefits, disadvantages, and long-term success rates with each have been documented in detail previously.^[17]

*Treatments*
Although the development of novel antiviral therapies has slowed, more information becomes available on the three preferred first-line therapies.

*Pegylated Interferon*
Approximately 30% of HBeAg-positive patients treated with pegylated interferon will achieve HBeAg seroconversion though current ability to predict an individual's response is limited. Recent genome-wide association studies identified polymorphisms of the interleukin (IL) 28B gene as a potent predictor of sustained viral response in interferon treatment of hepatitis C. Two hundred and five HBeAg positive CHB patients treated with pegylated interferon were analyzed for IL28B polymorphisms. The favorable AA or CC IL28B genotypes strongly predicted HBeAg seroconversion with 50% compared with 29% responding to interferon. However, end of treatment response was also reliant on viral characteristics with HBV genotype A achieving HBsAg seroconversion irrespective of IL28B genotype.^[18.] HBV viral load and HBsAg decline at week 12 predicts sustained response to interferon in HBeAg-negative patients. Monitoring HBV DNA and HBsAg kinetics provides the ability for response-guided therapy with a stopping rule for those not responding to interferon.^[19..] However, stopping rules with HBV DNA and HBsAg decline need to be validated in HBeAg-positive patients and across genotypes.

*Entecavir*
Long-term follow-up studies continue to show that entecavir effectively suppresses HBV DNA incurring very little resistance. In over 100 patients followed for 3 years, 92.1% had undetectable HBV DNA, 43.9% had HBeAg seroconversion, and 92% had normal ALT levels. The cumulative rate of entecavir-resistant mutations was 1.2% at year 3.^[20.] In contrast to previous studies of interferon treatment and despite undetectable HBV DNA with entecavir monotherapy, monitoring decline in HBsAg titer at 12 and 24 weeks was not predictive of virologic response, or HBeAg seroconversion at 2 years.^[21.] HBsAg levels appear to have little clinical utility in determining response with nucleos(t)ide therapy at this time.

*Tenofovir*
After 3 years of treatment with tenofovir monotherapy, viral suppression with HBV DNA less than 400 copies/ml was achieved in 72% of HBeAg- positive patients and 87% of HBeAg-negative patients with normalization of ALT in 74 and 81%, respectively. No resistance was reported and 8% of HBeAg-positive patients lost HBsAg.^[22.] A prospective study of 60 patients with lamivudine resistance treated initially with either change to or addition of adefovir demonstrated the benefit of tenofovir rescue therapy. At 96 weeks, 64% of patients were HBV virus negative on tenofovir and while potent, it is less than seen in naive patients. The decreased efficacy may be due to underlying adefovir resistance mutations.^[23.] Tenofovir added to entecavir therapy was studied as a rescue strategy in 57 CHB patients with multidrug resistance or prior partial response. Fifty-one patients had undetectable HBV DNA after a mean of 6 months proving this to be an effective and safe strategy in a difficult-to-treat population.^[24.]
*Virological Breakthrough*

In a large retrospective review of 11 000 CHB patients on nucleos(t)ide therapy, mean adherence rate to therapy was 87.8% with 1-year persistence of 81%. Although adherence to CHB therapy is high, new, and younger age patients tend to be less compliant.^[25..] In a study of 148 CHB patients on nucleos(t)ide therapy with mean follow-up of 3 years, 39 patients had at least one virologic breakthrough with 38% having no genotypic resistance and 10 patients with further HBV DNA decline while continued on current treatment.^[26.] Medication nonadherence is a common cause of intermittent virologic breakthrough and should be addressed before changing therapy.

In a study of 84 patients treated with lamivudine, adefovir, or entecavir who stopped therapy after reaching defined endpoints, 42% of HBeAg- positive and 47% HBeAg-negative patients had virologic relapse with HBV DNA more than 1000 copies/ml at a mean of 4.3 months. Preexisting lamivudine resistance, increased time to undetectable HBV DNA, and higher HBsAg level at end of treatment corresponded to relapse suggesting those with lamivudine resistance will need indefinite antiviral therapy.^[27]
*Treatment in Special Populations*

Clinical trials typically exclude patients that are pregnant, coinfected, or posttransplant yet these CHB patients are commonly encountered in practice in need of treatment.
*Pregnancy*
Recent analysis of 2356 children born to HBsAg-positive mothers revealed 9.26% of those born to HBeAg-positive mothers were HBsAg positive despite receiving hepatitis B immunoglobulin (HBIG) and three doses of recombinant HBV vaccine. Conversely, rate of CHB infection was so low (<1%) in those children born to HBeAg-negative mothers, HBIG did not appear to offer any additional protection to vaccination but may prevent infantile fulminant hepatitis.^[28] In order to decrease vertical transmission, HBeAg-positive mothers with high HBV viral loads can be treated with antiviral therapy in the third trimester. Both tenofovir and telbivudine are class B with no apparent teratogenicity. Telbivudine has been reported to decreaseHBsAg positivity at 7 months from 8% to zero.^[29..]

*Coinfection With HIV or Hepatitis Delta*
With 8.4% of HIV patients testing positive for HBsAg, CHB is 20 times more prevalent in HIV-infected patients than the general US population. Only a third of eligible HIV patients have been vaccinated and homosexual men comprise over 70% of HIV/HBV coinfected patients.^[30] When selecting highly active antiretroviral therapy, medications active against HBV such as tenofovir, lamivudine, or emtricitabine are usually selected. In a recent study of 451 consecutive CHB patients, 246 HIV-positive patients had similar clinical presentation and degree of liver fibrosis as the 205 HIV-negative patients. Tenofovir used alone or in combination was noted to be equally efficacious in suppressing HBV DNA. In contrast to previous studies, HBsAg loss was more often seen in HIV-positive patients. HIV status did not seem to impact success of antiviral therapy.^[31]
Hepatitis D virus (HDV) co-infection can lead to more rapid disease progress and precipitate decompensation. A recent study showed sustained HDV response in up to 25% of patients treated with 48 weeks of peginterferon with or without adefovir.^[32..]

*Decompensated Cirrhosis*
In a phase 2 trial, 112 patients with decompensated liver disease were randomized to receive tenofovir, emtricitabine/tenofovir, or entecavir to gauge tolerability and efficacy. All treatments were well tolerated and resulted in clinical improvement.^[33.] Similarly a meta-analysis of 22 studies of antiviral therapy in decompensated CHB cirrhosis showed improved virological, biochemical, and clinical parameters at 1 year with all agents but cautions resistance limits utility of lamivudine and telbivudine and adefovir has slow onset and weak viral suppression.^[34] A recent prospective randomized trial compared entecavir with adefovir in patients with decompensated cirrhosis. Both entecavir and adefovir demonstrated clinical improvement and tolerability but entecavir was superior in HBV DNA suppression and ALT normalization.^[35.]

*Posttransplant*
HBIG and antiviral therapy have reduced the recurrence rates of CHB to less than 1% posttransplant. However, HBIG is expensive and requires regular injections. In a prospective study, 80 CHB patients undergoing liver transplant received entecavir monotherapy. Only 26% had undetectable HBV DNA at time of transplant but 91% were HBsAg negative at 2 years and 98.8% had undetectable HBV DNA suggesting that an HBIG free, entecavir monotherapy regimen is effective posttransplant.^[36..]

*Conclusion*
In the past year, determinants of the natural history of CHB continue to be defined in order to better select patients in need of long-term antiviral therapy. Studies support the safety and efficacy of potent antivirals with low development of resistance among a variety of patient populations. Increased awareness is needed for screening, treating, and vaccinating at-risk individuals for effective control of CHB.
*Sidebar*
*Key Points*

* Initial selection of peginterferon, entecavir, or tenofovir in
  treatment of chronic hepatitis B (CHB) is preferred.
* HBsAg kinetics may be helpful in determining the natural history of
  CHB infection and response to peginterferon but current use in
  nucleos(t)ide treatment is limited.
* Screening, vaccinating, and treatment of high-risk individuals are
  necessary to impact the CHB epidemic.

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  Papers of particular interest, published within the annual period of
  review, have been highlighted as:
  .of special interest
  .. of outstanding interest
  Additional references related to this topic can also be found in the
  Current World Literature section in this issue (pp. 288--291).

*Acknowledgements*
None.**
Curr Opin Gastroenterol. 2012;28(3):193-197. © 2012 Lippincott Williams & Wilkins