HBV Journal Review
March 1, 2011, Vol 8, no 3
by Christine M. Kukka
Early Hepatitis B Screening and Treatment Saves Lives and Health Care Dollars
Early diagnosis and treatment of hepatitis B cuts health care costs and decreases death rates among patients infected with the hepatitis B virus (HBV), according to a study by New York School of Medicine and University of Pennsylvania School of Medicine researchers.
Currently, 4,000 U.S. residents die from HBV infection each year and the direct and indirect cost of hepatitis B is estimated at $1 billion annually. While treatment guidelines exist, many infected with HBV are not diagnosed or treated until their infection has advanced, resulting in cirrhosis, cancer, and liver failure. Fewer than 30% of the estimated 2 million people who have hepatitis B in the U.S. know they are infected.
The researchers constructed a model that compared the financial and social costs of treating patients early in their infection against a group that received late care, when cirrhosis and liver cancer require costly medical care and transplants.
They grouped patients by their viral load and age, which often translates into different disease stages. In early care scenarios, people received antiviral drugs and were frequently monitored early in their infection, which kept their viral loads low, resulting in more quality-adjusted life-years.
The researchers found that providing early care avoids more costly, down-stream health problems such as surgery for cancer or liver transplants: “The proportion of patients with resolved infections or low viral loads was 52.5% in the late care scenario, and 80% in the early care scenario after just five years of treatment or lack of treatment,” they wrote in the Feb. 3, 2011 issue of the journal Health Affairs.
The percentage of patients facing cirrhosis and liver cancer, which required transplants, fell from 1.2% after three years of late treatment, to 0.7% after 20 years of early care.
Over 20 years, the number of new liver cancer cases was 572 per 100,000 chronically infected people in the late care scenario, compared to just 194 per 1000,000 in the early care model.
Providing early care also dramatically reduced death rates. Deaths after five years of late care per 100,000 patients were 2,094 compared to 1,628 receiving early care. After 20 years, the death rate was 20,730 per 100,000 among late care patients compared to 11,606 among those receiving early care.
While implementation of current screening and treatment guidelines would be more costly in the short-term, it would save lives and reduce costs in the long run due to reduced liver damage and need for costly surgery and liver transplants.
When Should Doctors Stop Antiviral Treatment?
Doctors and researchers continue to wrestle with when to stop antiviral treatment in hepatitis B patients. Antiviral treatment, administered as daily pills, slows or stops the virus from reproducing. Currently, there are no medical guidelines defining when it’s safe for a patient to stop antiviral treatment.
When antiviral treatment is successful, it lowers a patient’s viral load (the amount of HBV DNA circulating in the bloodstream) to undetectable levels. There is little or no liver damage from the infection, and patients can even lose the hepatitis B “e” antigen (HBeAg) and develop “e” antibodies (called seroconversion) as a result of treatment. But often, when treatment stops, the infection rebounds, as a result, there is no clear roadmap defining when treatment is safe to stop.
- After patients lose HBeAg during treatment, often the HBeAg returns when treatment stops and their viral load rebounds, with resulting liver damage.
- After patients lose HBeAg, between 30% to 50% of them eventually develop HBeAg-negative hepatitis B, which causes liver damage even though HBeAg has disappeared and viral load declines. This occurs due to mutations in the virus.
- Without the suppressing impact of antivirals, the infection and viral load can suddenly “flare” up dangerously, causing life-threatening liver damage.
- A patient’s viral load and liver health should be monitored frequently after antiviral treatment stops to determine if a viral rebound or flare occurs, but this may not occur if patients cannot afford frequent lab tests.
Additionally, if viral load begins to rebound, using the same antiviral against the resurging infection can increase the risk of drug resistance. In many countries, only one antiviral (lamivudine – Epivir HBV) is available so the risk of drug resistance is high.
Long-term therapy appears inevitable, noted scientists writing in the March 2011 issue of the Journal of Gastroenterology and Hepatology, because the risks of relapse and liver damage from stopping treatment are far greater than the risk of developing drug resistance.
But there is no clear consensus about what the end point of antiviral treatment should be.
“For HBeAg-positive patients, the current European Association for the Study of the Liver (EASL) guidelines state that the ideal end-point of therapy is sustained HBsAg loss with or without (HBeAg) seroconversion,” they wrote.
The American Association for the Study of Liver Diseases (AASLD) and Asian Pacific Association for the Study of the Liver (APASL) guidelines identify sustained HBeAg seroconversion as an adequate end-point for antiviral treatment. The APASL guidelines also indicate that the HBeAg seroconversion should be accompanied by undetectable HBV DNA.
The question remains, however, whether treatment-induced HBeAg seroconversion together with a decline in viral load is truly durable. A study of 34 Koreans treated with lamivudine who stopped the antiviral after HBeAg seroconversion showed a relapse rate of 49% after 2 years. A study of 82 patients from Taiwan found 48% had relapsed by 12 months after treatment stopped, with HBV strain or genotype C infections associated with higher rates of relapse. In 125 Chinese patients who stopped lamivudine after HBeAg loss, the 4-year relapse rate was 41%.
Given the conflicting treatment guidelines, scientists called for a consistent antiviral treatment roadmap. They recommended clearance of the hepatitis B surface antigen (HBsAg) as a treatment end point for both HBeAg-positive and –negative patients. They also encouraged development of a patient monitoring schedule in order to quickly identify “flares.”
Newborns Face Higher Risk of Infection If Mothers Have Genotype C, Despite Immunization
Taiwan, where HBV genotypes or strains B and C are most prominent, instituted a universal infant immunization program decades ago against hepatitis B. A recent study shows the program has been highly effective, but immunization at birth appears less effective in children born to mothers with HBV genotype C.
Genotype C has a reputation for causing a higher viral load and more severe liver damage than genotype B.
Researchers compared the rates of HBV infection in newborns born before and after implementation of the immunization program. They compared 107 children infected with HBV despite immunization at birth.
According to their report published in the February 2011 issue of Hepatology, immunized HBV-infected children born to HBsAg-positive mothers with genotype C had a three-fold higher rate of infection than immunized children born to mothers with HBV genotype B.
“In the post-immunization era, most HBV breakthrough infections are due to maternal transmission, and immunized children born to genotype C mothers may have a higher rate of breakthrough infection than those born to genotype B mothers,” they wrote.
In Vitro Fertilization Can Transmit HBV Infection
Chinese researchers have found that unfertilized eggs (oocytes) and fertilized eggs (embryos) used during the in vitro fertilization process can transmit HBV infection, according to a report published in the January 2011 issue of the journal Fertility and Sterility.
Researchers examined the oocytes and embryos for HBV DNA and RNA in:
- 31 couples where the women were HBsAg-negative and the men were HBsAg-positive
- 41 couples with HBsAg-positive women and HBsAg-negative men
- And 39 uninfected couples.
HBV DNA was detected in 3 of 18 male HBsAg-positive/female HBsAg-negative couples (and in 13 of 84 embryos), and in 3 of 14 male HBsAg-negative/female HBsAg-positive couples (and in 15 of 71 oocytes and embryos).
Hepatitis B virus RNA was detected in 9 of 13 male HBsAg-positive/female HBsAg-negative couples (in 39 of 52 embryos) and 8 of 17 male HBsAg-negative/female HBsAg-positive couples (in 30 of 63 oocytes and embryos).
HBsAg, which is present in the nuclei and cytoplasm of oocytes and embryos, was detected in 6 of 10 male HBsAg-negative/female HBsAg-positive couples and in 13 of 20 oocytes and embryos.
No HBV DNA, HBV RNA, and HBsAg were found in 135 oocytes and embryos from 39 HBV-negative couples.
Researchers Identify “Cancer” Protein That Indicates High Risk of Cancer Recurrence
U.S. and Chinese researchers have identified a protein that indicates cancerous tumors may spread within two years, according to a report published in the February 2011 issue of The Journal of Clinical Investigation.
Scientists examined genetic material from various tumors, including liver cancer, and discovered that when high levels of carboxypeptidase E or CPE were present, there was a high risk that an existing cancer would spread.
Scientists in Hong Kong had been studying samples of liver tumor cells from hepatitis B patients among others and found that some of the cells contained high levels of a mutation of the protein CPE. Simultaneously, scientists at the National Institute of Child Health and Human Development were also studying CPE and also identified the same variant, now called CPE-Delta N.
The two teams combined their research into this “cancer protein.” When cancerous liver cells were injected into mice, researchers confirmed that when CPE-Delta N was present, there was a high risk that the cancer would spread within two years.
Additionally, this protein was monitored in liver cancer patients who had tumors removed surgically who had early, stage 2 tumors as well as those with late, or stage 4 tumors. The patients who had lower CPE-Delta N levels—including those with advanced stage 3 and 4 liver cancers—had lower cancer recurrence rates after surgery than those with higher CPE-Delta levels.
In addition to liver cancer, CPE-Delta N has been found in cancers of the head and neck, colon,breast.
The researchers say the discovery could result in more aggressive treatment for liver cancer patients, especially those in the early stages who are found to carry the CPE-Delta N treatment.
Chinese Researchers Find Adefovir as Effective as Entecavir as Frontline Antiviral
Chinese researchers compared the effectiveness of adefovir (Hepsera) and entecavir (Baraclude)—two commonly-used antivirals—in HBeAg-positive patients who had never been treated before. They reviewed six published studies and compared rates of undetectable viral load, normal alanine aminotransferase (ALT) levels that indicate a healthy liver, and loss of HBeAg and development of the “e” antibody (called HBeAg seroconversion) after 48 weeks of treatment.
They found a moderately higher rate of normal ALT levels and undetectable viral load among entecavir-treated patients, however both groups had equal rates of HBeAg seroconversion.
Based on the study, researchers recommended that adefovir could be still used as first-line therapy in these patients, according to the report published in the journal Virology. However other medical societies in North America and Europe recommend tenofovir (Viread) or entecavir as first-choice antivirals because they have lower rates of drug resistance than adefovir.
HBeAg-Positive Patients with Genotype B and Elevated ALT Levels Respond Well to Interferon
Researchers followed 88 HBeAg-positive patients who were treated with pegylated interferon (Pegasys) for six months, and then followed for another 24 weeks, to see which patients responded best.
According to the report in the March 2011 Journal of Gastroenterology and Hepatology, 38.6% cleared HBeAg, with some seroconverting weeks after treatment ended. The patients who responded best had ALT levels exceeding 200 international units per milliliter (IU/mL), genotype B, and low levels of HBeAg.
“Genotype-B-infected patients had higher probability of delayed HBeAg clearance and sustained response,” researchers wrote. They added that a rapid decline in HBeAg during the first few weeks of treatment indicated which patients would respond.
Interferon treatment is costly, requires weekly injections, and causes side effects such as depression, so doctors are eager to quickly identify which patients would benefit most from this treatment.
Liver Stiffness Monitoring Provides Accurate Snapshot of Liver Health—Without a Biopsy
For the first time, researchers monitored changes in liver stiffness in 426 hepatitis B patients, using transient elastography, to document changes in liver health over a three-year period. This non-invasive technique is used instead of an invasive liver biopsy to assess the extent of fibrosis or cirrhosis in the liver.
In addition to measuring liver stiffness, researchers monitored viral status, HBV DNA and ALT levels. Of the patients, 38 (9%) were HBeAg-positive, 293 (69%) were HBeAg-negative, 95 (22%) were patients who had cleared HBsAg, and 110 of them were treated with antivirals during the study period.
There was a significant decline in liver stiffness, indicating a decrease in fibrosis, in the antiviral-treated patients who had elevated ALT levels at the start of treatment and who achieved normal ALTs.
Among the untreated patients, only patients with persistently normal ALT over the study period (including those who had cleared HBsAg) had significantly lower liver stiffness measurements after three years.
“In patients with chronic hepatitis B, a significant decline in liver stiffness measurements after three years was observed in treated patients (who achieved normal ALT) and in untreated patients who had persistently normal ALT,” researchers reported in the Journal of Viral Hepatitis.
Doctors Still Failing to Screen Patients for HBV before Starting Chemotherapy
Despite medical guidelines that require doctors to screen patients for active and inactive hepatitis B infection before starting chemotherapy, a study published in the March 2011 issue of the journal Liver International, found that many doctors are failing to screen patients.
The chemotherapy drug rituximab (Rituxan®) is commonly used to treat patients with non-Hodgkin lymphoma and chronic lymphocytic leukemia. It suppresses the immune system, which can result in a resurgence of HBV infection even in patients with inactive or resolved hepatitis B infections.
In order to assess how effective doctors were in conducting HBV screening before starting chemotherapy, researchers screened 524 of 1,429 patients for hepatitis B who had been treated with rituximab for non-Hodgkin lymphoma between August 1997 and September 2009.
The researchers found HBsAg—indicating chronic HBV infection—in 20 of the 524 patients. In contrast, the doctors had conducted limited screening and had identified only eight patients with HBV.
Researchers found that 10 of the 20 HBV-infected patients they identified did indeed experience reactivation of their HBV infection as a result of chemotherapy. Of these 10, only five had been screened for HBV before chemotherapy began.
Even when doctors identified patients with HBsAg, only three of eight patients identified as having hepatitis B were offered antivirals in order to suppress viral replication during chemotherapy.
One patient with HBV who had not been screened developed acute liver failure and died.
Hepatitis B Vaccination’s Protection Continues for More Than Two Decades
For how long does hepatitis B immunization confer protection against infection? Researchers continue to study the lifespan of immunization protection in order to determine if “booster” vaccinations are needed.
In China, researchers followed residents who received the full three doses of vaccine 23 years ago when they were between the ages of 5 and 9 and compared them to an unimmunized control group. The study subjects all live in communities with high rates of HBV infection.
They reported in the January 2011 issue of the journal Vaccine that 48.1% (39 of 81) vaccinees still had sufficient surface antibodies (anti-HBs titers), equal to or higher than 10 mIU/mL at year 23.
The vaccinated subjects who had lower levels of antibodies quickly generated a robust rebound in antibodies after receiving a booster dose, which indicates they still retain a strong “immune memory” of hepatitis B, which enabled them to fight infection. None of the subjects who were vaccinated developed chronic hepatitis B over the 23-year period.
“These results suggest a persisting immune memory and certain protection for 23 years after primary vaccination in children living in highly HBV-endemic areas,” researchers wrote. “Booster doses should be unnecessary for more than 20 years after a full primary immunization in children (as catch-up vaccination) and, also likely, in newborns living in highly HBV-endemic areas.”
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