1. Anna S. F. Lok, MD University of Michigan Ann Arbor, MI
HEPATITIS B
Anna S. F. Lok, MD
University of Michigan
Ann Arbor, MI

2. What is Hepatitis B?
Hepatitis B is an infection of the liver caused by the hepatitis B virus
Telbivudine is furthest along, phase III clinical trials have been completed and the data are being reviewed by FDA
Phase II clinical trials showed that LdT is more potent than LAM in suppressing HBV replication and associated with a lower rate of drug resistance 5% after 1 yr and 18% after 2 yr, but the site of resistant mutation is the same –
The phase II trial included a group that received combination of LdT and LAM
But the combination group fared worse than the group that received LdT alone suggesting an antagonistic effect
The phase III trial confirmed that telbivudine was more potent than lamivudine but the overall benefit was marginal
Resistance rate was approx 40% that of lamivudine
Thus LdT has limited utility as monotherapy

3. How common is hepatitis B?
Worldwide
400 million people are chronic carriers
About 75% of HBV carriers live in Asia
0.5-1 million deaths per year due to HBV
Asia
Liver cancer is the 2nd cancer killer among Asian men and the 5th cancer killer among Asian women
Roughly 40% of Asian men and 15% of Asian women with chronic hepatitis B die of a liver-related illness
Telbivudine is furthest along, phase III clinical trials have been completed and the data are being reviewed by FDA
Phase II clinical trials showed that LdT is more potent than LAM in suppressing HBV replication and associated with a lower rate of drug resistance 5% after 1 yr and 18% after 2 yr, but the site of resistant mutation is the same –
The phase II trial included a group that received combination of LdT and LAM
But the combination group fared worse than the group that received LdT alone suggesting an antagonistic effect
The phase III trial confirmed that telbivudine was more potent than lamivudine but the overall benefit was marginal
Resistance rate was approx 40% that of lamivudine
Thus LdT has limited utility as monotherapy

4. Geographic Distribution of
Chronic HBV Infection
This map depicts the geographic distribution of chronic HBV infection.
As you can see, areas of high prevalence include most of Asia and Africa, as well as Central America and Alaska;
While areas of low prevalence include the United States and Canada, Australia and NZ, and Northwestern parts of Europe.
HBsAg Prevalence
8% - High
2-7% - Intermediate
<2% - Low

5. Hepatitis B and Asian Americans
Less than 0.5% (1 in 200) Americans have chronic hepatitis B
About 10-15% (1 in 8 to 10) Asian Americans have chronic hepatitis B
About 50% (1 in 2) of the people in the US with chronic hepatitis B are Asian Americans
A much higher percent of Asian Americans compared to Americans of other races have hepatitis B
Telbivudine is furthest along, phase III clinical trials have been completed and the data are being reviewed by FDA
Phase II clinical trials showed that LdT is more potent than LAM in suppressing HBV replication and associated with a lower rate of drug resistance 5% after 1 yr and 18% after 2 yr, but the site of resistant mutation is the same –
The phase II trial included a group that received combination of LdT and LAM
But the combination group fared worse than the group that received LdT alone suggesting an antagonistic effect
The phase III trial confirmed that telbivudine was more potent than lamivudine but the overall benefit was marginal
Resistance rate was approx 40% that of lamivudine
Thus LdT has limited utility as monotherapy

6. Why is Hepatitis B so common among Asian Americans?
Hepatitis B is very common in Asia
Many Asian Americans were infected with hepatitis B before they came to the US
Asian Americans born in the US may be infected through their mother or other family members, who are HBV carriers
Telbivudine is furthest along, phase III clinical trials have been completed and the data are being reviewed by FDA
Phase II clinical trials showed that LdT is more potent than LAM in suppressing HBV replication and associated with a lower rate of drug resistance 5% after 1 yr and 18% after 2 yr, but the site of resistant mutation is the same –
The phase II trial included a group that received combination of LdT and LAM
But the combination group fared worse than the group that received LdT alone suggesting an antagonistic effect
The phase III trial confirmed that telbivudine was more potent than lamivudine but the overall benefit was marginal
Resistance rate was approx 40% that of lamivudine
Thus LdT has limited utility as monotherapy

7. Hepatitis B and Asian Americans
National Health and Nutrition Examination Survey (NHANES)
Survey on prevalence of various diseases in the US
Sampled cohorts representative of US population
African Americans and Hispanics over sampled to ensure sufficient number studied to permit conclusions on prevalence of diseases among those racial/ethnic groups
Reliable data not available for Asian Americans because Asians not over sampled, number studied too small to be conclusive, and Asians lumped as “other racial/ethnic groups”
Telbivudine is furthest along, phase III clinical trials have been completed and the data are being reviewed by FDA
Phase II clinical trials showed that LdT is more potent than LAM in suppressing HBV replication and associated with a lower rate of drug resistance 5% after 1 yr and 18% after 2 yr, but the site of resistant mutation is the same –
The phase II trial included a group that received combination of LdT and LAM
But the combination group fared worse than the group that received LdT alone suggesting an antagonistic effect
The phase III trial confirmed that telbivudine was more potent than lamivudine but the overall benefit was marginal
Resistance rate was approx 40% that of lamivudine
Thus LdT has limited utility as monotherapy

8. Hepatitis B and Asian Americans
NHANES III –
Current and past HBV infection: 4.9%
Chronic HBV infection: 0.4%
Highest prevalence among blacks
5%-15% among immigrants from Central and Southeast Asia, Middle East and Africa
Prevalence data for Asians not available
Telbivudine is furthest along, phase III clinical trials have been completed and the data are being reviewed by FDA
Phase II clinical trials showed that LdT is more potent than LAM in suppressing HBV replication and associated with a lower rate of drug resistance 5% after 1 yr and 18% after 2 yr, but the site of resistant mutation is the same –
The phase II trial included a group that received combination of LdT and LAM
But the combination group fared worse than the group that received LdT alone suggesting an antagonistic effect
The phase III trial confirmed that telbivudine was more potent than lamivudine but the overall benefit was marginal
Resistance rate was approx 40% that of lamivudine
Thus LdT has limited utility as monotherapy

9. Why is it that hepatitis B gets so little attention in the US?
Federal and state governments – public health
Overall prevalence is low: not a very common problem here
Most of those affected by HBV are Asians – who are politically silent (squeaky wheel gets the oil)
NIH, CDC, Scientific organizations – research and education
Not a common problem
With an effective vaccine, hepatitis B will be eradicated in the next generation.. we predicted that in the 1980s
Competition for $$ and attention from other more trendy diseases: HIV, HCV, SARS, avian ‘flu, cancers….
Telbivudine is furthest along, phase III clinical trials have been completed and the data are being reviewed by FDA
Phase II clinical trials showed that LdT is more potent than LAM in suppressing HBV replication and associated with a lower rate of drug resistance 5% after 1 yr and 18% after 2 yr, but the site of resistant mutation is the same –
The phase II trial included a group that received combination of LdT and LAM
But the combination group fared worse than the group that received LdT alone suggesting an antagonistic effect
The phase III trial confirmed that telbivudine was more potent than lamivudine but the overall benefit was marginal
Resistance rate was approx 40% that of lamivudine
Thus LdT has limited utility as monotherapy

10. How is HBV spread?
HBV is more easily spread than HIV (virus that causes AIDS) and HCV
HBV can live outside the human body for up to 7 days
People with chronic hepatitis B can have very large amounts of virus in their blood – serum HBV DNA up to 11 log10 copies/mL (100 billion)
Telbivudine is furthest along, phase III clinical trials have been completed and the data are being reviewed by FDA
Phase II clinical trials showed that LdT is more potent than LAM in suppressing HBV replication and associated with a lower rate of drug resistance 5% after 1 yr and 18% after 2 yr, but the site of resistant mutation is the same –
The phase II trial included a group that received combination of LdT and LAM
But the combination group fared worse than the group that received LdT alone suggesting an antagonistic effect
The phase III trial confirmed that telbivudine was more potent than lamivudine but the overall benefit was marginal
Resistance rate was approx 40% that of lamivudine
Thus LdT has limited utility as monotherapy

11. How is HBV spread? Mainly through blood and bodily secretions
Infected mother to babies at birth
Contact with blood from carriers through wounds, contaminated household articles such as razors, toothbrushes, or contaminated needles used for tattoos and injecting drugs
Sexual contact with carriers
Telbivudine is furthest along, phase III clinical trials have been completed and the data are being reviewed by FDA
Phase II clinical trials showed that LdT is more potent than LAM in suppressing HBV replication and associated with a lower rate of drug resistance 5% after 1 yr and 18% after 2 yr, but the site of resistant mutation is the same –
The phase II trial included a group that received combination of LdT and LAM
But the combination group fared worse than the group that received LdT alone suggesting an antagonistic effect
The phase III trial confirmed that telbivudine was more potent than lamivudine but the overall benefit was marginal
Resistance rate was approx 40% that of lamivudine
Thus LdT has limited utility as monotherapy

12. How is HBV spread? HBV is not spread by: Hugging or kissing
Coughing or sneezing
Sharing eating utensils
Telbivudine is furthest along, phase III clinical trials have been completed and the data are being reviewed by FDA
Phase II clinical trials showed that LdT is more potent than LAM in suppressing HBV replication and associated with a lower rate of drug resistance 5% after 1 yr and 18% after 2 yr, but the site of resistant mutation is the same –
The phase II trial included a group that received combination of LdT and LAM
But the combination group fared worse than the group that received LdT alone suggesting an antagonistic effect
The phase III trial confirmed that telbivudine was more potent than lamivudine but the overall benefit was marginal
Resistance rate was approx 40% that of lamivudine
Thus LdT has limited utility as monotherapy

13. Outcome of Acute HBV Infection
Recovery
Acute Hepatitis
SubclinicalHepatitis
FulminantHepatitis
Death
Acute Infection
Chronic Infection

14. What is Hepatitis B? Hepatitis B may be ACUTE Recent infection
May have no symptoms, especially in children
Common symptoms: easily tired, poor appetite, nausea, abdominal discomfort, jaundice
Roughly 95% recover, usually in 2-3 months
About 1% severe hepatitis with acute liver failure
About 5% go on to chronic infection, lasts longer than 6 months
Telbivudine is furthest along, phase III clinical trials have been completed and the data are being reviewed by FDA
Phase II clinical trials showed that LdT is more potent than LAM in suppressing HBV replication and associated with a lower rate of drug resistance 5% after 1 yr and 18% after 2 yr, but the site of resistant mutation is the same –
The phase II trial included a group that received combination of LdT and LAM
But the combination group fared worse than the group that received LdT alone suggesting an antagonistic effect
The phase III trial confirmed that telbivudine was more potent than lamivudine but the overall benefit was marginal
Resistance rate was approx 40% that of lamivudine
Thus LdT has limited utility as monotherapy

15. Risk of Chronic HBV Infection
Age at Infection 20 40 60 80
100
Neonates
Infants
Children
Adults %
Risk
Risk of chronic infection
The risk of progression to chronic HBV infection is inversely proportional to the age at infection. Up to 50 to 90% of neonates and infants born to HBeAg positive mothers become HBV carriers, as compared to 20 to 30 % among children infected between the age of 1-5 years, and less than 5% among immunocompetent adults.
McMahon BJ, Alward WL, Hall DB, et al. Acute hepatitis B virus infection: relation of age to the clinical expression of disease and subsequent development of the carrier state. J Infect Dis 1985;151:
Tassopoulos NC, Papaevangelou GJ, Sjogren MH, et al. Natural history of acute hepatitis B surface antigen-positive hepatitis in Greek adults. Gastroenterology 1987;92:
Chang MH, et al. Natural history of hepatitis B virus infection in children. J Gastroenterol Hepatol 2000;15 Suppl:E16-9.

16. Outcome of Chronic HBV Infection
Inactive Carrier State
Chronic Hepatitis
Cirrhosis
HCC

17. What is Hepatitis B? Hepatitis B may be CHRONIC
Long-lasting infection, persists for more than 6 months
Most people have no symptoms
Common symptoms: easily tired, poor appetite, nausea, abdominal discomfort
Can go on to cirrhosis, liver failure, liver cancer, and death
Telbivudine is furthest along, phase III clinical trials have been completed and the data are being reviewed by FDA
Phase II clinical trials showed that LdT is more potent than LAM in suppressing HBV replication and associated with a lower rate of drug resistance 5% after 1 yr and 18% after 2 yr, but the site of resistant mutation is the same –
The phase II trial included a group that received combination of LdT and LAM
But the combination group fared worse than the group that received LdT alone suggesting an antagonistic effect
The phase III trial confirmed that telbivudine was more potent than lamivudine but the overall benefit was marginal
Resistance rate was approx 40% that of lamivudine
Thus LdT has limited utility as monotherapy

18. How can hepatitis B be diagnosed?
The only way to know is to have a blood test
Most people with hepatitis B have no symptoms until late stages of liver disease
Tests for hepatitis B or liver enzymes are not included in most routine check-ups
Hepatitis B may be present even if liver enzymes were tested and were normal
Telbivudine is furthest along, phase III clinical trials have been completed and the data are being reviewed by FDA
Phase II clinical trials showed that LdT is more potent than LAM in suppressing HBV replication and associated with a lower rate of drug resistance 5% after 1 yr and 18% after 2 yr, but the site of resistant mutation is the same –
The phase II trial included a group that received combination of LdT and LAM
But the combination group fared worse than the group that received LdT alone suggesting an antagonistic effect
The phase III trial confirmed that telbivudine was more potent than lamivudine but the overall benefit was marginal
Resistance rate was approx 40% that of lamivudine
Thus LdT has limited utility as monotherapy

19. Serological Markers of HBV Infection 
HBsAg Acute/Chronic infection
Anti-HBc IgM Recent infection
HBeAg High infectivity
Anti-HBe Low infectivity
Anti-HBs Immunity
Anti-HBc IgG + HBsAg Chronic infection
Anti-HBc IgG + anti-HBs Resolved infection

20. Acute HBV Infection HBV DNA HBeAg Anti-HBe Anti-HBs Anti-HBc HBsAg
Anti-HBc IgM
Months Years

21. Chronic HBV Infection HBV DNA HBeAg Months Years Anti-HBe HBsAg
Anti-HBc IgM
Anti-HBc
Anti-HBe
HBsAg

22. Serum HBV DNA is the most reliable marker of HBV replication and infectivity
Fluctuating levels, serial tests important for clinical assessment
Virus persists at low levels even after recovery
Reactivation can occur spontaneously and more often when immune system is suppressed
HBV DNA levels do not always correlate with ALT levels or histologic activity of liver disease
Persistently high serum HBV DNA levels are associated with increased risk of cirrhosis and HCC
Telbivudine is furthest along, phase III clinical trials have been completed and the data are being reviewed by FDA
Phase II clinical trials showed that LdT is more potent than LAM in suppressing HBV replication and associated with a lower rate of drug resistance 5% after 1 yr and 18% after 2 yr, but the site of resistant mutation is the same –
The phase II trial included a group that received combination of LdT and LAM
But the combination group fared worse than the group that received LdT alone suggesting an antagonistic effect
The phase III trial confirmed that telbivudine was more potent than lamivudine but the overall benefit was marginal
Resistance rate was approx 40% that of lamivudine
Thus LdT has limited utility as monotherapy

23. Hepatitis B Vaccines
Genetically engineered hepatitis B surface antigen only
3 doses: month 0, 1, 6
Immune response: 50% after 1 dose % after 3 doses
Duration of protection: >15 years, dependent on initial antibody response
Factors associated with poor response: older age, chronic medical illness (cirrhosis, kidney failure, diabetes), decreased immune response, smoking, obesity, genetics
Telbivudine is furthest along, phase III clinical trials have been completed and the data are being reviewed by FDA
Phase II clinical trials showed that LdT is more potent than LAM in suppressing HBV replication and associated with a lower rate of drug resistance 5% after 1 yr and 18% after 2 yr, but the site of resistant mutation is the same –
The phase II trial included a group that received combination of LdT and LAM
But the combination group fared worse than the group that received LdT alone suggesting an antagonistic effect
The phase III trial confirmed that telbivudine was more potent than lamivudine but the overall benefit was marginal
Resistance rate was approx 40% that of lamivudine
Thus LdT has limited utility as monotherapy

24. Indications for HBV Vaccines
Hepatitis B immune globulin and HB vaccine to infants of HBsAg+ mothers
All infants
All children and adolescents who were not vaccinated at birth
Vaccination of adults at risk of infection
Occupational
Sexual / household contacts
Injection drug users
Long-term residence in high prevalence areas
Telbivudine is furthest along, phase III clinical trials have been completed and the data are being reviewed by FDA
Phase II clinical trials showed that LdT is more potent than LAM in suppressing HBV replication and associated with a lower rate of drug resistance 5% after 1 yr and 18% after 2 yr, but the site of resistant mutation is the same –
The phase II trial included a group that received combination of LdT and LAM
But the combination group fared worse than the group that received LdT alone suggesting an antagonistic effect
The phase III trial confirmed that telbivudine was more potent than lamivudine but the overall benefit was marginal
Resistance rate was approx 40% that of lamivudine
Thus LdT has limited utility as monotherapy

25. HBV Vaccine: Safety
Worldwide, more than 500 million individuals have received HB vaccine over the past 20 years
Most common adverse event – soreness and erythema at the injection site
Systemic symptoms – transient low-grade fever, headache, malaise and myalgia in ~10%

26. Impact of HBV vaccination on HBV infection rates in Taiwanese children30
HBsAg+
Anti-HBc+ 20 % 10
Impact on HBV infection rates in children
Taiwan is one of the first few countries in the world that started universal infant hepatitis B vaccination. Since 1984, all newborns from HBsAg+ mothers were vaccinated against HBV. From 1986, universal vaccination of all newborns was implemented. From 1987, universal vaccination was extended to children of preschool age. In 1991, “catch up” program was implemented for all first graders.
This comprehensive HBV vaccination program has been shown to result in significant decrease in the prevalence of HBsAg from 9.3% in 1984 to 0.7% in 1999, and of anti-HBc from 26% in 1984 to 2.9% in 1999, among children aged 15 years or less. This study showed that universal vaccination program reduces the rate of chronic carriers as well as the total HBV infection rate.
Chen HL, Chang MH, Ni YH, et al. Seroepidemiology of hepatitis B virus infection in children: ten years of mass vaccination in Taiwan. JAMA. 1996;276:906-8.
Ni YH, Chang MH, Huang LM, et al. Hepatitis B virus infection in children and adolescents in a hyperendemic area: 15 years after mass hepatitis B vaccination. Ann Intern Med 2001;135: 
1984
1994
1999
Vaccination of infants born to HBsAg+ mother
Universal vaccination of infant/preschool children
Ni YH, Ann Intern Med 2001;135:796

27. Impact of HBV Vaccination on Incidence of HCC in Taiwanese Children
Universal Vaccination of Newborns
Chang MH, NEJM 1997;336:1855

28. Hepatitis B Factors affecting disease activity and progression
VIRUS
Genotype
Molecular Variants
HOST
Gender
Age
Immune Response
Genetics
ENVIRONMENT
Alcohol
HCV, HDV, HIV
Carcinogens
It remains unclear what governs the outcome of individual patients with hepatitis B, but virus, host and environmental factors all play a role and likely interact with each other.

29. Stages of chronic HBV infection Inactive-carrier state
Immune
Immune
Low replicative
Reactivation
tolerance
clearance
phase
phase
HBeAg + (wild)
HBeAg - / anti-HBe + (PC/CP variants)
<
>
<
>
>105 cp/ml
HBV-DNA
<105 cp/ml
cp/ml
cp/ml
ALT
Normal /
mild CH
moderate/severe CH
Normal/mild CH
moderate/severe CH
cirrhosis
Inactive cirrhosis
cirrhosis
HBeAg +
Chronic hepatitis
Inactive-carrier state
HBeAg –
Chronic hepatitis

30. Unique Aspects of Hepatitis B among Asians
Clinical Manifestations/Natural history
Immune tolerant phase
Frequent exacerbations and reactivations
Increased risks of HCC

31. Immune Tolerant Phase
First years of perinatally acquired HBV infection
Asymptomatic
High HBV DNA levels but normal ALT
Very low rates of spontaneous/treatment-induced HBeAg seroconversion

32. Immune Clearance Phase
HBeAg → anti-HBe seroconversion
Predictors : ALT, age, gender, HBV genotype
Annual rate = 5-15%
Hepatitis Flares
⅔ HBeAg seroconversion preceded by flares
¼ flares followed by HBeAg seroconversion
More common in men
Increased risk of cirrhosis

33. Stages of chronic HBV infection Inactive-carrier state
Immune
Immune
Low replicative
Reactivation
tolerance
clearance
phase
phase
HBeAg + (wild)
HBeAg - / anti-HBe + (PC/CP variants)
<
>
<
>
>105 cp/ml
HBV-DNA
<105 cp/ml
cp/ml
cp/ml
ALT
Normal /
mild CH
moderate/severe CH
Normal/mild CH
moderate/severe CH
cirrhosis
Inactive cirrhosis
cirrhosis
HBeAg +
Chronic hepatitis
Inactive-carrier state
HBeAg –
Chronic hepatitis

34. Inactive HBsAg Carrier State
HBsAg+ > 6 months
HBeAg- , anti-HBe+
Serum HBV DNA < 103 copies/ml
Persistently normal ALT
Outcome dependent on liver damage accrued prior to entering inactive carrier state and any subsequent reactivation

35. HBeAg – Chronic Hepatitis B
HBsAg +
HBeAg –
Serum HBV DNA > copies/ml
Elevated ALT / moderate-severe inflammation on biopsy
Frequently associated with precore or core promoter mutations that prevent or decrease HBeAg production

36. Risk factors for progression to cirrhosis
Viral factors Host Factors External Factors
Persistently high HBV DNA levels
HBV precore/CP variant?
HBV genotype (C > B)
Older age
Male gender
Advanced fibrosis
Persistent ALT elevation
Recurrent hepatitis flares
HDV, HCV coinfections
HIV coinfection
Alcohol

37. Risk factors for progression to HCC
Viral factors Host Factors External Factors
Persistently high HBV DNA levels
HBV CP variant
HBV genotype (C > B)
Older age
Male gender
Asians??
Advanced fibrosis
Persistent ALT elevation
Recurrent hepatitis flares
HDV, HCV coinfections
HIV coinfection
Family history of HCC
Alcohol
Aflatoxin
Smoking

38. What can patients do to protect their liver?
Do not drink alcohol
Do not take any herbal medicine that might hurt the liver
Eat a balanced diet, exercise regularly, avoid getting overweight
Hepatitis B is a chronic health problem, HBV levels and severity of liver damage can change with time, see their doctor and get tested at least once a year even if they have no symptoms
Telbivudine is furthest along, phase III clinical trials have been completed and the data are being reviewed by FDA
Phase II clinical trials showed that LdT is more potent than LAM in suppressing HBV replication and associated with a lower rate of drug resistance 5% after 1 yr and 18% after 2 yr, but the site of resistant mutation is the same –
The phase II trial included a group that received combination of LdT and LAM
But the combination group fared worse than the group that received LdT alone suggesting an antagonistic effect
The phase III trial confirmed that telbivudine was more potent than lamivudine but the overall benefit was marginal
Resistance rate was approx 40% that of lamivudine
Thus LdT has limited utility as monotherapy

39. Treatment of Chronic Hepatitis B
Goals
Suppression of HBV replication
Decrease hepatic necroinflammation and fibrosis
Prevent progression to cirrhosis, liver failure and HCC
The goals of hepatitis B treatment are:
Sustained suppression of HBV replication
Remission of liver disease
And
Prevention of progression to cirrhosis, liver failure and hepatocellular carcinoma

40. Treatment of Chronic Hepatitis B Definition of Response
HBeAg+ patients
Serum HBV DNA decrease to <100,000 copies/ml
Loss of HBeAg ± anti-HBe seroconversion
Normalization of ALT level
HBeAg- patients
Serum HBV DNA decrease to undetectable by PCR
On-treatment response – initial / maintained
Off-treatment sustained response – FU mo 6 or 12
Before I compare the efficacies of various treatments, it is important to review the definition of treatment response.
Response is usually defined as decrease in serum HBV DNA to levels that are not detectable by hybridization assays, or levels around 100,000 copies/ml and normalization of ALT. For HBeAg+ patients, response should include loss of HBeAg.
For HBeAg- patients, many investigators feel that viral suppression should be to lower levels than 100,000 copies, but a consensus has not been reached on how low it should be.
It is also important to differentiate between response observed while patients are on treatment versus sustained response observed 6-12 months off treatment
Lok A et al., Gastro 2001;120:1828

41. Randomized controlled trial of lamivudine in patients with advanced liver disease
HBeAg+ and/or serum HBV DNA >700,000 gEq/mL
% with disease progression
21%
Placebo
P=0.001 9%
This slide shows the rate of disease progression between the treated patients and controls
Lamivudine
Time to disease progression (months)
Placebo (n=215) ITT population
Lamivudine (n=436) p=0.001
Liaw YF, NEJM 2004; 351:1521

42. Licensed HBV therapies and those under development
Phase III
Phase II
Phase I
Interferon -2b
Lamivudine
Adefovir
Entecavir
Peg IFN a-2a
Emtricitabine (FTC)*
Tenofovir (TFV)*
FTC+ TFV*
Emtricitabine
PegIFN -2b
Telbivudine (LdT)
Clevudine
Tenofovir
Pradefovir
Valtorcitabine (LdC)
LB80380
Remofovir (MB06866)
Elvucitabine (Fd4C)
BAM 205
IL-12
MCC 478
FLG
There are a number of drugs that are either available, or in various phases of study. Today, due to time restraints, I will focus my efforts on data which has emerged over the past year on already available agents and ongoing developments in the area of nucleoside research. I will briefly mention some promising concept drugs, albeit these are several years away from clinical application.

43. Who Should be Treated?
Not a question of who to treat but when – treat now or monitor and treat when indicated
All HBV carriers are potential treatment candidates
A patient who is not a treatment candidate now can be a treatment candidate in the future
Changes in HBV replication status and/or activity/stage of liver disease
Availability of new and better treatments
A more promising compound is tenofovir, which is active against HIV and HBV, both wild type and lamivudine resistant
In vitro studies showed that it has similar potency as adefovir
Tenofovir has been approved for HIV
At the approved dose of 300 mg it results in greater degree of viral suppression than 10 mg doses of adefovir
And there have been reports that patients with primary nonresponse to adefovir experience 2-3 log decrease in serum HBV DNA when switched to tenofovir

44. When to start treatment?
Benefits
Risks
Likelihood of
sustained response
cirrhosis and HCC
Side effects
Drug resistance
Patient’s age
Co-morbid illness
Costs
So, where do we go from here?
The first question we have to ask when managing pts with hep B is who should be treated
Given the limitations of current treatments, we must balance the benefits against the risks.
Treatment should be considered for pts with more active or advanced liver disease and those with higher likelihood of response
Side effects and risks of drug resistance must be considered
Likelihood of cirrhosis / HCC in the next yrs
Likelihood of sustained viral suppression after a defined course of treatment

45. What should be the primary treatment?
Long-term Benefits
Long-term Risks
Antiviral potency
Durability of response
Side effects
Drug resistance
Contraindications
Ease of administration
Duration of Rx
Costs of Rx & monitoring
Patient and provider preference
Having made a decision on who to treat, the next question is what Rx
In view of the need for long term treatment, it is important to balance the long term benefits against the risks

46. IFN Lamivudine Adefovir Entecavir
Parenteral
Oral
Finite duration
Long duration
More durable response
Primary nonresponse in 25%
More potent than LAM
Higher rate of HBsAg loss
Effective vs. LAM- R mutants
Activity vs. LAM-R mutants lower
No resistant mutants
Resistant mutants
15-30% yr 1
70% yr 5
0 yr 1, 29% yr 5
~15-20% yr 2 (LAM-R pts switched to ADV only)
0 yr 1, <1% yr 2
~10% yr 2 (LAM-R pts)
Frequent side effects
(Nephrotoxic at high doses)
(Limited track record)
There are a number of drugs that are either available, or in various phases of study. Today, due to time restraints, I will focus my efforts on data which has emerged over the past year on already available agents and ongoing developments in the area of nucleoside research. I will briefly mention some promising concept drugs, albeit these are several years away from clinical application.

47. When can treatment be stopped?
IFN treatment: finite duration, 12 mos
Nucleoside/tide analogues
HBeAg+ patients: 6-12 mos after HBeAg seroconversion (~50% after 5 yr Rx)
HBeAg- patients: endpoint not defined, ?until HBsAg loss (~5% after 5 yr)
Cirrhosis patients: endpoint not defined, ?life-long

48. Hepatitis B can be a deadly disease BUT It can be prevented, and it can be treated
GET TESTED