Hepatitis B: A “GLOBAL” Health Challenge

December 24, 2008

See “2-year GLOBE trial results: telbivudine is superior to lamivudine in patients with chronic hepatitis B,” by Liaw YF, Gane E, Leung N, et al, on page 486.

The Centers for Disease Control and Prevention has reported an 80 percent decline in the incidence of acute hepatitis B virus (HBV) infection in the United States between 1987 and 2004, which is largely attributed to increased use of the highly safe and effective HBV vaccine. 1 However, the estimated prevalence of chronic HBV infection defined as persistently detectable hepatitis B surface antigen for more than six months in the general U.S. population has remained at ~ 0.3%.2 The true prevalence of chronic HBV may be higher. The surveys did not include statistically valid samples of populations wherein HBV is common (ie, Asian-Americans), and immigration of individuals from endemic countries for HBV has increased dramatically during the past 20 years.2

Therefore, as many as 1.1–2.0 million Americans may harbor chronic HBV infection. The morbidity, health care expenditures and mortality associated with chronic HBV infection also seem to be increasing. For example, a 4.9-fold increase in hospitalizations for HBV-related liver disease was noted between 1989 and 1998.3 In addition, the age-adjusted death rate for HBV increased from 0.1 to 0.4 per 100,000 individuals during the same time period in the United States.3

Seven drugs are now available to treat patients with chronic active HBV infection (Table 1). Standard and pegylated interferon enhance the host immune response to HBV, and the oral nucleos(t)ide analogs are direct inhibitors of the HBV polymerase enzyme required for viral replication. All of the one-year licensing trials of these agents have demonstrated significant virologic, biochemical and histologic improvement in the treated patients compared to controls. In addition, long-term follow-up of virologic responders to standard interferon has demonstrated less frequent hepatic complications and a lower rate of mortality compared with nonresponders.4

A randomized, controlled trial in 651 chronic HBV patients with advanced fibrosis also demonstrated a clinically and statistically significant reduction in disease progression with prolonged lamivudine treatment compared with placebo (9 vs 21 percent at 42 months; P less than .001).5 This landmark study, together with multiple cohort studies in patients with decompensated HBV cirrhosis, demonstrate the oral antiviral agents can reduce morbidity and improve clinical outcomes in selected HBV patients as recently summarized at the National Institutes of Health Consensus Development Conference on HBV.6

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Selection of HBV Patients for Antiviral Therapy

Clinical practice guidelines recommend HBV patients with persistently high HBV DNA levels (ie, hepatitis B e antigen [HBeAg] + with greater than 20,000 IU/mL, HBeAg (-) with greater than 2,000 IU/mL) and evidence of ongoing liver injury manifest by elevated serum alanine aminotransferase (ALT) levels and/or moderate to severe inflammation/ fibrosis on liver biopsy be considered for antiviral treatment. 7,8 Currently, young, “immunotolerant” patients (ie, high HBV DNA levels and persistently normal ALT) as well as “inactive carriers” (ie, HBeAg (-), normal ALT, and low or undetectable HBV DNA) are not recommended for treatment, but should undergo serial laboratory and clinical monitoring.

Endpoints for stopping antiviral therapy in HBeAg-positive patients include the development of anti-HBe, which is durable in 70 to 80 percent of patients who seroconvert. However, because this endpoint is achieved in only 12 to 22 percent of treated patients at one year, prolonged antiviral therapy is needed for the majority of HBeAg-positive patients.

Endpoints for treatment in HBeAg-negative patients are more difficult to define because the majority of patients with a therapeutic response at one year relapse after drug cessation. Therefore, prolonged or even indefinite antiviral treatment is needed in many HBeAg-negative patients at risk for progressive liver disease. Patients who lose detectable hepatitis B surface antigen and develop protective anti-HBs may have therapy discontinued, but this endpoint is achieved in less than five percent of treated patients.

Suppression of HBV DNA to low or undetectable levels as well as maintenance of virologic suppression for prolonged periods of time has emerged as an important differentiating feature among the five available oral drugs. The rate of HBeAg seroconversion at one year is similar with the five drugs and increases further during continued treatment (Table 1). However, prolonged use of the oral nucleos(t)ide analogs is also associated with an increased but variable risk of developing drug-resistant strains of HBV. These mutant virions of HBV have characteristic point mutations in the catalytic domain of the HBV polymerase gene that lead to reduced drug binding and efficacy. Although the drug-resistant mutants are less replication competent compared with wild-type HBV, continued drug exposure can lead to additional point mutations, which help to restore replication fitness (ie, compensatory mutations).

The clinical impact of drug resistance is well described in patients with lamivudineresistant HBV who experienced worsening liver histology and biochemical flares after initial improvement.9 In addition, patients who developed lamivudine-resistant HBV in the Liaw et al 5 study had a higher rate of disease progression compared with treated patients with wild-type HBV. Therefore, drugs that effectively suppress HBV replication and also have a low rate of drug resistance during prolonged treatment are preferred.

Antiviral drug resistance is defined by an increase of HBV DNA of more than 1 log 10 from the nadir on two consecutive samples taken one month apart in a compliant patient who initially suppressed HBV DNA.10 Therefore, monitoring of quantitative HBV DNA levels every three or four months during antiviral treatment is recommended. In patients with viral rebound, a confirmatory test to identify the presence and type of drug-resistant HBV is recommended. After genotypic confirmation of drug-resistant HBV, adding or switching to an alternative antiviral agent without crossresistance is recommended to regain control of HBV replication. Based on in vitro testing, the mutant virions associated with nucleotide analog resistance (ie, adefovir, tenofovir) remain sensitive to nucleoside analogs (ie, lamivudine, entecavir, telbivudine) and vice versa.

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The GLOBE Trial Two-Year Data

In this issue of GASTROENTEROLOGY, the two-year results of the GLOBE trial are presented. This study demonstrates therapeutic response rates were significantly better with telbivudine compared with lamivudine in the 921 HBeAg-positive patients (63 vs 48 percent; P less than .001) as well as in 446 HBeAg-negative patients (78 vs 66 percent; P= .007).11

However, the frequency of telbivudineresistant HBV (M204I) in HBeAg-positive patients also increased from five percent at one year to 25.1 percent at two years, whereas the frequency of lamivudine-resistant HBV increased from 11 to 39.5 percent. As in previous studies, a lower baseline serum HBV DNA level (ie, less than109 cp/ml) and higher baseline ALT (ie, greater than or equal to two times the upper limit of normal) were strong and independent predictors of undetectable HBV DNA, ALT normalization and HBeAg seroconversion at two years in telbivudine-treated patients. In addition, the degree of suppression of HBV DNA at 24 weeks was associated with more favorable outcomes at two years. Conversely, the level of residual HBV DNA at week 24 was associated with the risk of telbivudine resistance (ie, if week 24 HBV DNA greater than 4 log10, 42 to 70 percent developed telbivudine resistance by year two).

Although both drugs were generally well tolerated, the telbivudine-treated patients were more likely to experience moderate serum creatine phosphokinase elevations (12.9 vs 4.1 percent; P less than .001). In addition, two telbivudine-treated patients developed symptomatic but reversible myopathy, highlighting the potential for mitochondrial toxicity when the oral nucleos(t)ide analogs are used for prolonged periods of time as has been previously reported in HIV patients.

Adefovir salvage treatment for telbivudine-resistant HBV was associated with improved suppression of HBV replication in a limited number of patients treated in the GLOBE study. However, it remains unclear if it is better to add or switch to a nucleotide analog such as adefovir or tenofovir in slow responders to telbivudine or in patients with telbivudine-resistant HBV. The utility of entecavir, a potent nucleoside analog, in patients with telbivudine-resistant HBV is also unknown, but concerns regarding potential cross-resistance have been raised.

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Perspective

The two-year GLOBE trial results clearly demonstrate telbivudine is a more potent and effective agent than lamivudine in chronic HBV patients. A prior study also demonstrated more rapid viral suppression with telbivudine compared with adefovir at 24 weeks in 135 HBV patients. 12 However, the rising incidence of telbivudineresistant HBV at two years will inevitably increase further. In comparison, entecavir use for up to five years has been associated with effective suppression of HBV replication and a very low rate of drug resistance (ie, less than one percent).13

In addition, tenofovir, a potent nucleotide analog, was shown to be superior to adefovir and there has been no evidence of tenofovir-resistant HBV in treated patients through two years nor in lamivudine-resistant HBV patients treated with tenofovir for four years.14,15 Therefore, both tenofovir and entecavir can rapidly and persistently suppress HBV replication in HBV patients and are associated with lower rates of drug resistance compared with the other oral agents.

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What Are the First-Line Agent(s) for HBV?

Practice guidelines currently recommend using entecavir, tenofovir or pegylated interferon as first-line agents for chronic HBV patients requiring treatment.7,8 Although pegylated interferon is only suitable for patients with compensated disease owing to its side effects, it is associated with the highest one-year rate of HBeAg seroconversion and does not lead to drug-resistant strains of HBV (Table 1).

Lamivudine is a second-line agent for HBV because of its high rate of drug resistance (ie, 75 percent at five years) and its proven inferiority compared to telbivudine and entecavir in large, randomized, controlled trials. Similarly, adefovir is considered a secondline drug because of its weaker inhibition of HBV replication compared with tenofovir and its increasing risk of drug resistance with prolonged use (ie, 28 percent at five years).

Finally, although telbivudine is a more potent suppressor of HBV replication compared with lamivudine, it is also a second-line agent for HBV owing to the increasing rate of drug resistance at two years.

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Are There Unique Therapeutic Niches for Telbivudine?

The utility of telbivudine in combination with other nucleotide analogs in previously untreated HBV patients has not been adequately studied. However, studies of other nucleoside/nucleotide combinations (ie, lamivudine plus adefovir) in previously untreated patients have failed to demonstrate incremental antiviral or therapeutic responses compared with monotherapy.16 In addition, telbivudine and lamivudine combination therapy should be avoided owing to its proven inferiority to telbivudine monotherapy and development of cross-resistant HBV.17 Finally, pegylated interferon and telbivudine combination therapy should be avoided because 17 percent of HBV patients treated in a pilot study developed a moderately severe peripheral neuropathy.

Telbivudine and tenofovir are Pregnancy Category B (ie, no animal risk but unknown human risk) and lamivudine, adefovir and entecavir are in Pregnancy Category C (ie, known risk in animals but unknown human risk). Therefore, telbivudine may be preferred in women of reproductive age or in pregnant women requiring antiviral therapy to minimize fetal risk. However, experience in pregnancy is limited, with only one telbivudine-treated patient reported among the 9,899 women enrolled in the Antiretroviral Pregnancy Registry.18

In addition, telbivudine or telbivudine and adefovir combination therapy may be preferred for HIV and HBV coinfected patients who do not need highly active antiretroviral therapy because these agents are not expected to cause HIV resistance. However, confirmatory safety and efficacy data in this setting are lacking, and evolving recommendations suggest both viruses should be treated under these circumstances.19

In summary, the two-year GLOBE trial data demonstrate telbivudine is superior to lamivudine in patients with chronic active HBV infection. However, the rising incidence of telbivudine-resistant HBV will likely limit its long-term utility in the management of chronic HBV. The GLOBE trial also demonstrates the importance of monitoring quantitative HBV DNA levels during treatment and the potential utility of early viral kinetics in defining optimal treatment regimens. Nonetheless, additional drugs that target other steps in the HBV replication cycle or host immune response are needed as we strive to improve clinical outcomes in the large number of chronic HBV patients at risk for adverse hepatic outcomes both in the United States and abroad.

ROBERT J. FONTANA
Department of Internal Medicine
University of Michigan Medical Center
Ann Arbor, Michigan

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References

1. Centers for Disease Control and Prevention. A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States. MMWR 2006;55:1–41.


2. Centers for Disease Control and Prevention. Recommendations for identification and public health management of persons with chronic hepatitis B virus infection. MMWR 2008;57:1–16.


3. Kim WR, Ishitani MB, Dickson ER. Rising burden of hepatitis B in the United States: Should the ‘other’ virus be forgotten? Hepatology (Abstract) 2002;36:222A.


4. Niederau C, Heintges T, Lange S, et al. Long-term follow-up of HBeAg-positive patients treated with interferon alfa for chronic hepatitis B. N Engl J Med 1996;334:1422–1427.


5. Liaw YF, Sung JJ, Chow WC, et al. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med 2004;351:1521–1531.


6. National Institutes of Health. Consensus Development Conference statement, management of hepatitis B. October 20–22, 2008. Available at: http://www.natap.org/2008/HBV/102308_01.htm. Accessed November 5, 2008.


7. Keeffe EB, Dieterich KT, Han SHB, et al. A treatment algorithm for the Management of Chronic Hepatitis B virus infection in the United States: 2008 update. Clin Gastroenterol Hepatol 2008; 6:1315–1341.


8. Lok ASF, McMahon BJ. AASLD practice guideline: chronic hepatitis B. Hepatology 2007;45:507–539.


9. Dienstag JL, Goldin RD, Heathcote EJ, et al. Histological outcome during long-term lamivudine therapy. Gastroenterology 2003;124: 105–117.


10. Ghany M, Liang TJ. Drug targets and molecular mechanisms of drug resistance in chronic hepatitis B. Gastroenterology 2007; 132:1574–1585.


11. Liaw YF, Gane E, Leung N, et al. 2-year GLOBE trial results: telbivudine is superior to lamivudine in patients with chronic hepatitis B. Gastroenterology 2008;136:486–495.


12. Chan HLY, Heathcote EJ, Marcellin P, et al. Treatment of hepatitis B e-antigen positive chronic hepatitis with telbivudine or adefovir. Ann Intern Med 2007;147:745–754.


13. Han SH, Chang TT, Chao YC, et al. Five years of continuous entecavir for nucleoside-naïve HBeAg (+) chronic hepatitis B: results from study ETV 901. Hepatology 2008;48(4 Suppl 1): 705A (abstract).


14. Snow-Lampart A, Chappell BJ, Curtis M, et al. Week 96 resistance surveillance for HBeAg positive and negative subjects with chronic HBV infection randomized to receive Tenofovir DF 300 mg q d. Hepatology 2008;48(4 Suppl 1):197A (abstract).


15. Van Bommel F, Wunsche T, Mauss S, et al. Comparison of adefovir and tenofovir in the treatment of lamivudine-resistant hepatitis B virus infection. Hepatology 2004;40:1421–1425.


16. Sung JJ, Lai JY, Zeuzem S, et al. Lamivudine compared with lamivudine and adefovir for the treatment of HBeAg positive chronic hepatitis B. J Hepatol 2008;48:728–735.


17. Lai CL, Leung N, Teo EK, et al. A 1-year trial of telbivudine, lamivudine, and the combination in patients with hepatitis B e antigen-positive chronic hepatitis B. Gastroenterology 2005;129: 528–536.


18. Antiretroviral Pregnancy Registry. Available at: www.apregistry.com. Accessed October 1, 2008.


19. Hammer SM, Eron JJ, Reiss P, et al. Antiretroviral treatment of adult HIV infection. JAMA 2008;300:555–570.

Address requests for reprints to: Robert J. Fontana, MD, Associate Professor of Medicine, 3912 Taubman Center, Ann Arbor, MI 48109- 0362. E-mail: rfontana@med.umich.edu; fax: 734-936-7392.

The author discloses the following: Dr Fontana has been a consultant or on the Speaker’s Bureau for Roche Laboratories, Bristol-Meyers-Squibb, Gilead Sciences, and GlaxoSmithKline.
© 2009 by the AGA Institute

0016-5085/09/$36.00
doi:10.1053/j.gastro.2008.12.018