Current and Evolving Treatment Therapies for Chronic Hepatitis B
||Dr. Rajander Reddy
Director of Hepatology and Medical Director of Liver Transplantation at the University of Pennsylvania, Philadelphia, PA
Sunday, July 10, 2005
This session was an update on the treatment options for those living with chronic hepatitis B. Now that there a total of 5 approved drugs for HBV (interferon alpha, PEG interferon, lamivudine, adefovir, and entecavir), it is essential that patients and doctor become as well informed as possible in order to make effective treatment decisions.
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Dr. Reddy started his presentation with the following overview: hepatitis B is a global health problem. The burden of hepatitis B infection in the U.S. includes about 75,000 new infections, 5,000 deaths, 3,100 cases of liver cancer or HCC, and 230 liver transplants due to chronic hepatitis B per year. There are at least 1.25 million Americans who have been chronically infected with the hepatitis B virus (HBV).
Chronic hepatitis B is the 6 th leading indication for liver transplantation in the U.S. (this represents about 5% of all liver transplants). Most liver transplants in the U.S., however, are due to hepatitis C.
The following sections represent the different topics covered by Dr. Reddy, but he has not had the opportunity to review these notes for accuracy. So please be aware that there could be errors or inaccuracies in the following summary. Remember, talk to your health care provider if you have any questions about the management and treatment of your condition!
HBV disease progression – exposure to HBV can result in a chronic infection, and this progression depends on your age at infection. The younger you are, the greater the risk of developing chronic HBV. This is why it is important to institute effective prophylactic measures, such as immunization at birth and young childhood, to prevent HBV transmission.
Chronic HBV infections - need to be prevented because 30% of those with chronic HBV may develop cirrhosis, and 5-10% may develop liver cancer. Of those who develop cirrhosis, 6% will develop liver cancer in 5 years.
Acute flares – these can happen in chronic HBV infections. Physicians may even think it is a new infection. The virus can switch back and forth from a zero to low replication state to a high replication state. An acute flare can cause various symptoms depending on the severity of the flare and the extent of liver disease. Regardless of whether you are being treated or not, you should be followed by a doctor to monitor for possible flares.
HBV Reactivation and Chemotherapy - HBV reactivation is a serious risk if a patient starts any chemotherapy or immunosuppressive therapy, such as steroids. Patients should be started on an oral prophylactic treatment, such as lamivudine, before starting any kind of chemotherapy or immunosuppressive therapy!
Patients should stay on the oral antiviral for the duration of therapy and at least 6 months after therapy is stopped to ensure suppression of the virus. HBV reactivation must be prevented in these therapeutic situations because it could lead to acute liver failure, and possibly even death.
HBV reactivation is an issue even if a person has undetectable viral DNA or has “recovered”. Therefore, patients undergoing chemotherapy or immunosuppressive therapy should be asked whether they have ever been infected with HBV and should also be tested for the hepatitis B surface antigen (HBsAg). It’s not expensive to test for HBV, and it could save lives from liver failure!
Question: What about steroid inhalers or cholesterol-lowering drugs like the statins?
Answer: There is no data on steroid inhalers and HBV reactivation. Statins are not contraindicated in someone with HBV or liver disease; however, doctors regularly monitor the liver enzymes while patients are on a statin.
Clinical Profiles of HBV
- A chronic HBV diagnosis cannot be made without a “hepatitis B surface antigen” blood test (HBsAg).
- It is uncommon to see replicating states in HBV and HCV co-infections. One virus typically dominates over the other.
- ALT – the usual normal range is 5-40. ALTs are different for people depending on their age, lifestyle and overall health. The “normal ranges” have to be adjusted for different health/weight conditions.
- HBeAg-negative is present in the “immune tolerant phase” (the e-antigen test is used to determine if a person’s HBV is actively replicating or reproducing).
- “Immune tolerant phase” – occurs when a person is infected early in life and the body doesn’t recognize the virus as “foreign”, but instead, “tolerates” the virus without attacking it. In this phase, a person has a normal ALT and high viral load - liver biopsies are mostly normal or show moderate disease. The ALT may fluctuate. When it comes to treatment, the risks and potential success should be considered before deciding to treat.
- “Inactive HBsAg carrier state” – represents an infection where the virus is not actively replicating (or reproducing). It includes positive HBsAg, negative HBeAg, normal ALT, low DNA, and normal histology on a liver biopsy. Traditionally, these patients do not benefit from treatment.
- HBeAg-positive chronic HBV – represents the “wild type” HBV infection that includes positive HBsAg, positive HBeAg, negative HBeAb, high ALT and high viral load.
- HBeAg-negative chronic HBV - represents a “precore mutant” HBV infection that includes positive HBsAg, negative HBeAg, positive HBeAb, high ALT, high viral load (one log lower than eAg-positive patients), active histology on liver biopsy. This patient will require treatment for an indefinite period, and there is a relatively high relapse rate when treatment is discontinued.
Natural history / historical studies of HBV -HBV vaccination and its effects on liver cancer and mortality have been studied extensively in Taiwan. Results show that in Taiwan, children from ages 6-14 had a decrease in the incidence of liver cancer from 0.70 to 0.36. Mortality was decreased from 0.80 to 0.34. These studies support the importance of universal HBV vaccination in significantly decreasing the risk of liver cancer and death from chronic HBV infections.
Hepatitis B Virology – the key point to finding a cure for HBV is to eradicate cccDNA. This is a stable intermediate in the virus life cycle and serves as template for viral protein production (i.e. mRNA). There are currently no drugs that get rid of cccDNA. Future treatment research must focus on cccDNA elimination because it is key to getting rid of the virus itself.
Global distribution of HBV genotypes - There are 8 HBV genotypes. Although there are no commercially available tests and doctors do not test for genotypes, research studies have shown that “genotype A” has the best response to therapy. As time goes by, we will start seeing genotype tests being done to determine potential response to therapy and/or risk of liver cancer.
Every genotype can be found on every continent, but there are certain types that are found more frequently in certain geographic areas:
North America – A, B, C, D Europe – A, D, G Asia – B, D
Central America - H, F South America – F Africa- A, D, E
Australia - A, B, C, D
Goals of Therapy
- There are several treatment endpoints. In “wild type”, e-Antigen seroconversion (the loss of e-antigen and appearance of e-antibody), undetectable DNA, normal ALT, and histological improvement are the usual markers of success. Loss of hepatitis B surface antigen would be ideal, but this is rare and isn’t expected.
- Loss of cccDNA is possible with interferon therapy, but not common. A liver biopsy is needed to determine if there has been cccDNA loss. If a patient loses the hepatitis B surface antigen and develops positive surface antibodies, then you don’t usually worry about cccDNA.
- Is “HBsAg seroconversion” the same for someone who spontaneously clears the virus after an acute infection vs. someone who clears the virus after treatment? The end result may be the same, but the extent of possible liver injury is different since the person who was on treatment probably had more liver injury than someone who had an acute infection. But this isn’t known for sure. HBV reactivation isn’t usually seen with HBsAg seroconversion.
- Are the treatment goals the same for e-antigen negative HBV infections (i.e. the precore mutant)? No, since e-antigen seroconversion cannot be a goal in these patients. There is a high relapse rate if treatment is stopped; therefore, long-term treatment is the rule.
- Is the cirrhotic patient different for the e-antigen positive or “wild type” infection? Patients with cirrhosis should be treated indefinitely even after achieving the endpoints.
HBV DNA Assays – There are different types of viral assays (tests) used to measure HBV DNA levels. Some are more sensitive than others. Use of different assays depends on the insurance company’s contract with a lab! Patients should know which type of assay is being used since DNA levels can vary with different types of assays (or at least should use the same lab to obtain consistent results, which is helpful in monitoring or evaluating treatment).
- Qualitative PCR (polymerase chain reaction) – most sensitive
- Quantitative PCR (Amplicore) – 2 nd most sensitive test, but Dr. Reddy prefers this one
- bDNA (Versant) – branched DNA assay
- Hybridization (Abbott and Digene) – not used anymore
[DNA Conversion rate: 1 pg = 283,000 copies]
Clinical significance of viral replication - Viral replication leads to continued inflammation of the liver (will see elevated ALTs) and worsening histology on liver biopsy, including cirrhosis and then liver cancer. BUT, viral replication can also lead directly to liver cancer without the development of fibrosis or cirrhosis!
How high should the DNA levels be to justify treatment? This is an ongoing debate since there are risks associated with treatment as long as mutants and resistance occurs with current therapies. In general, though, high DNA levels are not considered to be good.
There is also no clear answer as to what the viral DNA level needs to be that will determine the risk of developing liver cancer. One of the factors that play a role in the development of liver cancer is the age at which a person is first infected. The American Association for the Study of Liver Diseases (AASLD) is in the process of developing guidelines for liver cancer surveillance based on consideration of lifestyle, age, ethnicity, etc.
How often would you recommend liver cancer screening for perinatal infection, high DNA? Every 6 months. Although data shows there is no clear advantage for screening between 6 and 12 months, every six months is the general standard of practice. Screening currently includes ultrasound and the blood test, alpha-feta protein or AFP test. The AFP blood test is controversial since it misses so much cancer. Some doctors would rather not use AFP, but others swear by it.
What is the best, most sensitive way to detect liver cancer? MRI is a diagnostic test rather than a surveillance tool. CAT scan exposes a person to increased radiation. Depending on age, you could subject a patient to 46 MRIs over 23 years and they may or may not ever develop cancer. Universally this decision is based on what is cost effective.
- U.S. Algorithm – 2004 (Keeffe, et al.) – These guidelines are a position paper that are used most frequently since they are user friendly and take a more aggressive approach to treatment.
- AASLD ( U.S.) – 2001/updated 2004(Lok & McMahon) – These guidelines are evidence based and considered to take a conservative approach to treatment.
- NIH Conference ( U.S.) – 2000/updated 2001 (Lok & Hoofnagle) – These guidelines are a position paper based on a NIH workshop that focused on HBV treatments in 2000.
- EASL( Europe) – 2003 (deFranchis, et al.) – These guidelines are evidence-based and recommend interferon alpha as a first line treatment.
- APASL ( Asia) – 2003 (Liaw, et al.)- These guidelines are a consensus statement.
Treatment of HBV patients with cirrhosis
- For patients with cirrhosis, treatment should be more aggressive. If they have decompensated cirrhosis, then treat with an oral antiviral and refer for liver transplant evaluation.
- 20% of patients with cirrhosis who had spontaneous e-antigen seroconversion risk reversion, which is why they should be treated indefinitely. If there is no cirrhosis, then the reversion rate is much lower.
- In patients with “wild type” chronic HBV, there is a histologic improvement in cirrhosis after 3 years of lamivudine therapy. This theory is now being debated.
Currently, there are 5 approved drugs for chronic HBV
1. Interferon alpha (IFN) - approved 1991. In 1993, a meta analysis showed that with interferon alpha there was 8% loss of hepatitis B surface antigen, 33% loss of e-antigen (not seroconversion, though), and 37% undetectable HBV DNA (but in 1993 the cut-off for undetectable DNA was <10 6, which is higher than today because tests are now more sensitive).
2. Lamivudine(LAM) – approved 1998
3. Adefovir (ADV) – approved 2002
4. Entecavir (ETV) – approved April 2005
5. PEG interferon (PEG) – approved May 2005
PEG INTERFERON (PEG) – approved May 2005
- With PEG, 32% of eAg positive patients had suppression of viral DNA <100,000 copies and 41% had normalization of ALT. With combination PEG and LAM, eAg seroconversion occurred in 27% and there was 34% DNA suppression. From this data, it appears there is no real advantage for combination treatment with PEG and LAM for e-antigen positive patients. This will probably be the same case with other oral antivirals (according to a study reported by G. Lau in Hepatology 2004).
- Combination of PEG and LAM in eAg negative patients is no better than monotherapy with PEG. With PEG alone, there was 43% DNA suppression <20,000 copies and 59% normalization of ALT. With combination therapy, there was 44% DNA suppression and 60% normalization of ALT (according to a study reported by Marcellin in the New England J. of Medicine 2004).
- With PEG, e-antigen loss by Genotype: A = 47%, B=44%, C = 28%, D = 25%
- Appears there is a greater chance of hepatitis B surface antigen loss in eAg positive patients with PEG than with LAM (3-7% with PEG, and 0-<1% with LAM). But there was no difference between PEG alone or in combination with LAM (according to three different studies by Janssen, Marcellin and Lau).
LAMIVUDINE (LAM) – approved 1998
5 year Asian Trial in e-Antigen positive patients (Lai CL., 1998, NEJM)
After 5 years on LAM:
- Total eAg seroconversion was 50%
- Those with YMDD variant, 38% eAg seroconversion
- Those with non-YMDD variant, 78% eAg seroconversion
**Patients with YMDD mutant had the lowest eAg seroconversion rate.
Who will develop YMDD variant?
- Need to look at viral DNA levels: If there is effective viral suppression with therapy at 24 weeks, then continue LAM.
- If DNA is >10 4 after 24 weeks, then consider adding or switching to Adefovir, because there is a 64% chance of developing the YMDD variant since therapy is less effective in suppressing the virus.
- People who respond by 24 weeks have a much decreased risk of developing YMDD variant while on LAM (i.e. the less virus in you, the less risk of mutations developing).
Durability of e-Antigen loss with LAM
- This ranges from 77 – 90%, depending on which study you look at.
- Relapse rate depends on the duration of treatment after eAg seroconversion – studies show that LAM needs to be continued at least 6 months after eAg seroconversion to decrease risk of relapse (2 months extra LAM after seroconversion = 43% relapse rate; <6 months extra LAM after seroconversion= 20% relapse rate).
ADEFOVIR (ADV) – approved 2002
Adefovir is effective against lamivudine resistance (mutations); has a low incidence of resistance, and has a long to indefinite duration. Only concern is potential kidney toxicity, so patients need to be watched closely while on the drug.
- e-Antigen seroconversion occurs in about 14% of patients in the first year of adefovir treatment (vs. 30% with interferon alpha). This jumps to about 46% seroconversion in the 3 rd year of adefovir treatment.
- Durability of e-Antigen seroconversion is very good with ADV – about 90% when treatment is stopped (studies have evaluated durability up to114 weeks off treatment).
- Surface antigen loss in pre-core HBV (eAg-negative) is about 3.2% (this is not complete eAg seroconversion, though).
- Cumulative incidence of resistance (or development of viral mutations) with adefovir is low (0% first year, 3% 2 nd year, 11% 3 rd year, and 18% 4 th year) compared to lamivudine (24% first year, 42% 2 nd year, and 70% by the 4 th year).
- Clinical profile of resistance depends on comparing pre-treatment (or baseline) ALT and DNA levels with post-treatment values to evaluate any increases (for example, is the DNA increase within a log or two?).
- Adefovir resistance is different than lamivudine resistance.
- Consider starting both ADV and LAM together to avoid developing either resistance.
ENTECAVIR (ETV) – approved March 2005
Entecavir is the most potent oral HBV antiviral to date. It results in the greatest suppression of viral DNA than any other HBV drug at this point. There is also no development of mutations (or resistance) after 1 year of treatment in “wild type” HBV infections.
Entecavir vs. Lamivudine in e-Antigen positive patients after 1 year of therapy
- With Entecavir, DNA suppression <400 copies/ml is 69% vs. 38% for LAM.
- There are no mutations after one year of therapy (vs. 24% resistance with LAM).
- If entecavir therapy is extended beyond 1 year, will there be a higher eAg seroconversion than with lamivudine? Unfortunately, there is no data to answer this question.
Entecavir vs. Lamivudine in e-Antigen negative patients after 1 year of therapy
- With Entecavir, DNA suppression <400 copies/ml is 91% vs. 73% for LAM.
- With Entecavir, there is 70% histologic improvement vs. 61% for LAM.
TENOFOVIR (TDF) - Clinical Trials Only
Tenofovir is a nucleotide analogue similar to adefovir, but shows greater suppression of HBV DNA levels than adefovir. It is approved for HIV therapy, and is in phase III clinical trials for HBV.
- Two studies show that DNA suppression is 5.5 log greater with tenofovir than with adefovir.
- After 48 weeks of treatment, with tenofovir, DNA suppression <400 copies/ml is 92% compared to 34% for adefovir and 58% for lamivudine.
HepeX-B - Clinical Trials
This drug is a mix of two fully human monoclonal antibodies that can be used against the virus (i.e. surface antigen). It is currently being used in the transplant setting.
Therapeutic Advances in the Management of HBV Infections in the Transplant Setting
The advances in HBV treatment strategies has increased access to liver transplantation among HBV patients and also improved their outcomes:
1991 – Interferon approved for HBV to manage the disease.
1993 – High dose HBIG available for pre-transplant treatment.
1995 – Lamivudine and famciclovir available to manage the disease.
1998 – Lamivudine and HBIG used in combination for pre-transplant treatment.
2002 – Adefovir and lamivudine plus HBIG available for pre-transplant treatment; Adefovir and tenofovir available to manage the disease.
2005 – Entecavir, adefovir, and lamivudine plus HBIG available for pre-transplantation.
Dr. Reddy concluded his presentation with the fact that although there have been many advances in the treatment of chronic hepatitis B, there is no “one size fits all” answer because the virus is so tricky. More studies need to be done in order to better evaluate what approach will work best for which patient.
Visit the Hepatitis B Foundation Drug Watch for more information about approved drugs and compounds in development for chronic hepatitis B
This summary is being made available as a courtesy only; therefore, please be sure to speak with your health care provider (or attorney if filing a disability claim) if you have any questions about the information in these notes.