HBV Journal Review
February 1, 2014, Vol 11, no 2
by Christine M. Kukka
Tests for Antigens and Drug-Resistant Virus Emerge as Valuable Diagnostic Tools
Measuring the amount of hepatitis B surface antigen (HBsAg) in your bloodstream or conducting quick tests for drug-resistant hepatitis B virus (HBV) may soon be part of your office visit in the brave new molecular world of hepatitis B treatment.
Doctors increasingly are measuring HBsAg levels to determine if treatment is needed or if current medications are working. HBsAg tests—along with measuring alanine aminotransferase (ALT) for signs of liver damage and HBV DNA for viral load—may become essential tools to assess hepatitis B progression or remission.
HBsAg is the protein that makes up the outer covering of HBV. When a patient has a high viral load (and is positive for the hepatitis B "e" antigen—HBeAg), there are often large quantities of HBsAg circulating in the blood stream. When viral replication slows and HBeAg disappears, there can be lower quantities of HBsAg.
But experts are learning that high HBsAg levels can increase cancer risk, even in HBeAg-negative patients, according to a study published in the journal Annales de Biologie Clinique. (1) As a result, there is heightened attention on HBsAg as a key indicator of a patient's health. For example:
- In HBeAg-negative patients, HBsAg levels less than 1,000 international units per milliliter (IU/mL) along with low viral load (HBV DNA) under 2,000 IU/mL indicate the patient is an "inactive" patient.
- When patients are treated with pegylated interferon, doctors can tell if the treatment is working if there is a decline in HBsAg levels within 12 weeks. This early indicator can save money if the drug isn't working and help to avoid uncomfortable side effects. Doctors recommend patients with genotypes B and C should stop interferon at week 12 if their HBsAg levels remain at 20,000 UI/mL or higher.
Another team of French researchers, also exploring the implications of HBsAg in an article published in the February 2014 issue of the journal Liver International, suggest that as HBsAg levels decline, so does the risk of liver cancer.
They also suggest that during antiviral treatment, a rapid decline in HBsAg may indicate which patients will eventually clear HBsAg. A 100-fold decline or more of HBsAg over six months of treatment, "... could be a marker of a sustained response after treatment cessation," they wrote.(2)
In another diagnostic breakthrough, researchers writing in the December journal of Clinical Molecular Hepatology promoted the value of a HepB Typer-Entecavir kit that can precisely detect HBV that have viral mutations that can “resist” the antiviral drug entecavir (Baraclude). This diagnostic tool allows doctors to select the most effective antiviral for each individual patient based on the molecular makeup of their HBV.(3)
1. Source: www.ncbi.nlm.nih.gov/pubmed/24235324
2. Source: www.ncbi.nlm.nih.gov/pubmed/24373085
3. Source: www.ncbi.nlm.nih.gov/pubmed/24459645
Experts Issue a Report Card on Side Effects from Antivirals
Hong Kong researchers evaluated the side effects of commonly-used antivirals in the December 2013 issue of the Journal of Gastroenterology and Hepatology. Antivirals disrupt the genetic make-up of HBV, making it difficult for the virus to replicate. While generally safe, patients must take antiviral pills daily over several years and side effects include damage to the mitochondria of the body's cells (called mitochondria toxicity.)
According to the article, mitochondria toxicity can lead to muscle weakness (myopathy), numbness and tingling in fingers and toes (peripheral neuropathy), kidney damage and lactic acidosis—when unhealthy levels of lactate build up because it is not cleared by the weakened mitochondria.
- The antivirals clevudine and telbivudine (Tyzeka) have been found to cause myopathy and kidney problems.
- Both adefovir (Hepsera) and tenofovir (Viread) cause kidney damage (depending on the dose).
- Neuropathy is most commonly found in patients taking a combination of telbivudine and interferon.
- Increased risk of lactic acidosis has been found in patients with impaired liver and kidney function who take entecavir (Baraclude).
However, not all antiviral side effects are bad, the authors noted. Recent research has found that the antiviral telbivudine appears to somehow enhance kidney health.
To date, researchers have not found any harmful side effects from antivirals when they are administered to pregnant women to reduce their high viral loads and lessen the risk of infecting their newborns.
Experts Weigh in on Why They Prefer Either
Four European experts explain why each chooses either antivirals or pegylated interferon to treat hepatitis B patients in a series of articles published in the February 2014 issue of the journal Liver International.
Under current guidelines, either antivirals or interferon can be used as a first-line treatment for hepatitis B. Interferon, which spurs the immune system to fight the infection, requires a weekly injection over a 48-week period. It is costly and often accompanied by body aches and flu-like symptoms. In contrast, antivirals are daily pills that stop the virus from replicating for as long as the medication is used.
Why I treat my HBeAg-negative patients with pegylated interferon: Researchers from Athens University Medical School explained why they prefer interferon to treat this common, but aggressive form of chronic hepatitis B.
Antivirals are safe, they admitted, but they must be used long-term, possibly as lifelong treatment in older people with HBeAg-negative hepatitis B. In contrast, a 48-week treatment with interferon can offer a permanent solution. About one-fourth of HBeAg-negative patients treated with interferon eventually clear HBsAg, thus minimizing future liver damage and cancer.
However, interferon is effective only in patients with certain HBV strains or genotypes. Longer treatment may improve the odds for those with hard-to-treat genotypes, but more study is needed.
Why I treat HBeAg-negative patients with antivirals: Researchers from Italy promoted antiviral treatment—primarily entecavir and tenofovir—in patients who may not respond to interferon because of their genotype or its cost.
Long-term antiviral treatment, they wrote, suppresses HBV replication in more than 95% of patients after five years. These patients achieve normal, healthy livers, and even patients with fibrosis and cirrhosis experience dramatic improvements.
The drawbacks are the long-term treatment required and the costs associated with lifelong medication and side effects that may emerge from long-term treatment.
Why I treat HBeAg-positive patients with pegylated interferon: An expert from the National Taiwan University College of Medicine acknowledged that while many patients prefer antiviral pills because of their convenience, "...a finite duration of pegylated interferon (treatment) is still an attractive strategy."
He noted that interferon continues to boost the immune system even after the weekly injections end after 48 weeks. "In addition, the rate of HBeAg/HBsAg loss or seroconversion increases over time in patients who respond to interferon therapy," he wrote. "Nevertheless, these benefits are limited to 30% of all patients, and significant adverse (side) effects are still a concern."
Therefore, doctors should select patients who would benefit most from interferon based on their age, liver health, viral load, genotype, and viral mutations. Additionally, they should monitor patients' viral load, HBsAg levels and HBeAg status after 12 weeks of interferon treatment to determine if treatment should continue.
"Understanding these factors can help determine personalized interferon therapy for patients," he noted. "In the near future, the treatment paradigm of chronic hepatitis B should be tailored based on HBV DNA level, HBV genotype and HBV mutants and host (age, gender, ALT level and host genetic polymorphisms) factors, disease status (fibrosis) and the selection of (appropriate) antiviral agents…."
Why I treat HBeAg-positive patients with antivirals: A researcher from Barcelona explained that he uses antivirals in most HBeAg-positive hepatitis B patients because they are easy-to-take and can be prescribed to all patients regardless of genotype.
The current leading antivirals—entecavir and tenofovir—have few side effects and have low rates of drug resistance. As a result, nearly all HBeAg-positive patients (who generally have high viral loads) who take them as prescribed are able to achieve almost undetectable viral loads. "Tolerance is excellent and the safety profile is good, whereas interferon can be associated with adverse events that affect the patients' quality of life," he wrote.
"There is considerable evidence to show that antivirals modify the natural history of chronic hepatitis B and increasing evidence that they reduce the risk of liver cancer," he wrote. "The need for long-term, perhaps indefinite treatment in patients who do not achieve HBeAg seroconversion (loss of HBeAg and gaining of the "e" antibody) exists, but this is offset by their excellent tolerance and safety profile."
Doctors Explain Which Medical Guidelines They Follow, Or
There are three sets of hepatitis B treatment guidelines available worldwide (from America, Asia and Europe) and sometimes they agree, and often they conflict.
Confronted with varying treatment recommendations, a team of expert doctors from the University of Michigan Health System in Ann Arbor detailed which they followed when caring for their own patients in the January 2014 issue of the journal of Clinical Gastroenterology and Hepatology.
All three guidelines give guideposts forwhen antiviral treatment should begin—when ALT levels are elevated indicating liver cell damage, or viral load is high, or when a liver biopsy uncovers fibrosis or cirrhosis. But there is much gray area and little consensus about exactly how high viral load or ALT levels should be to trigger treatment, or when to perform a liver biopsy. For example:
- American guidelines suggest treatment should start when HBV DNA levels exceed 20,000 IU/mL.
- Asian guidelines start treatment when viral load exceeds 20,000 IU/mL for HBeAg-positive patients and 2,000 IU/mL for HBeAg-negative patients.
- And, European guidelines recommend a minimum of 2,000 IU/mL to initiate treatment no matter what the patient's HBeAg status is.
When do these doctors start treatment? When patients have moderate (compensated) cirrhosis, they follow American guidelines but they don't wait for HBV DNA to reach 20,000 IU/mL. They start treating when HBV DNA is much lower (at 2,000 IU/mL) because of the risk of liver cancer in these cirrhotic patients.
In non-cirrhotic patients, they follow American guidelines and start treatment when HBV DNA levels exceed 20,000 IU/mL and ALT levels are greater than twice the upper limits of normal.
For patients in the gray zone, with moderately elevated viral loads and ALT levels, the doctors recommend liver biopsies to determine the true health of their livers, especially if patients are 40 or older.
When do they order a liver biopsy? All guidelines agree that neither treatment nor a biopsy is needed in patients with normal ALT and low viral load. These doctors order a biopsy when patients have slightly elevated ALT levels, especially in patients age 40 or older. (European guidelines recommend a biopsy in these patients once they reach age 30.) Treatment is recommended if moderate to severe inflammation and/or fibrosis is found.
If patients have high viral load, even though their ALT levels are normal (called the immune-tolerant stage), the doctors would not treat or biopsy until the patient reached age 40, when liver damage and cancer risks increase.
Do they treat pregnant women with high viral loads to prevent infection of newborns? European and Asian guidelines promote treating women with high viral loads with antivirals to prevent mother-to-child infection.
"We defer treatment in women who have plans to be pregnant unless they have active or advanced liver disease," they wrote. "We discuss the benefits and risks of ... antiviral treatment with women who have HBV DNA level(s) greater than (10 million) IU/mL during the second trimester of pregnancy.
"We recommend starting antiviral treatment around week 30 if the patient agrees and (we) prefer tenofovir (Viread)…. We stop treatment immediately after delivery and emphasize the importance of monitoring for postpartum flares. We discuss the potential risk of exposing the infant to the antiviral medication if treatment is continued, but we do not advise against breastfeeding."
How often do these doctors monitor their patients? They monitor patients under age 30 in the immune-tolerant stage every six to 12 months and older patients every three to six months. "We monitor HBeAg-negative patients every three months over a one-year period before determining they are truly in the inactive carrier phase, at which time we decrease monitoring to every 6 to 12 months."
What treatments do these doctors use? Pegylated interferon and the antivirals tenofovir and entecavir are recommended as first treatments by the American guidelines and the doctors follow their recommendations. However, despite their good experience with interferon, fewer than 10% of their patients select interferon. "We are more enthusiastic in recommending interferon to young patients, particularly those who are hesitant to commit to a long duration of treatment and young women who are planning to start a family within the next two to three years," they wrote.
When it comes to antivirals, they believe entecavir and tenofovir are equally effective. "We prefer entecavir in patients who are at increased risk of (kidney damage) such as patients with decompensated cirrhosis, older patients, and patients with hypertension or diabetes. We prefer tenofovir in young women who might become pregnant during the course of treatment," they wrote.
They avoid prescribing lamivudine, telbivudine, and adefovir because of their higher rates of drug resistance. "In addition, we systematically have switched patients from adefovir to tenofovir because tenofovir is more potent. For patients taking lamivudine plus adefovir because of prior lamivudine resistance, we have switched them to tenofovir if they have undetectable HBV DNA levels or to the combination pill Truvada (containing the antiviral emtricitabine plus tenofovir). We have switched most patients taking lamivudine to tenofovir, except for a few who had been on lamivudine for many years with undetectable HBV DNA levels because the risk of antiviral drug resistance in these patients is very low."
When do the doctors stop antiviral treatment? These doctors continue antiviral treatment indefinitely in those who have cirrhosis and in many older patients (older than 60) unless they clear HBsAg.
For HBeAg-positive patients without cirrhosis, the doctors won't stop treatment until 12 months after the patients have achieved HBeAg seroconversion in order to "consolidate" the HBeAg loss.
In HBeAg-negative patients, they stop treatment after HBsAg loss, but this has occurred in only one patient they have treated in the past five years.
"We have, however, discontinued treatment in several patients who can no longer afford or are no longer willing to commit to long-term treatment if they have completed at least five years of treatment with undetectable HBV DNA levels in the past three years," they reported. "Although all patients experienced virologic relapse after treatment was stopped, most patients continue to have low HBV DNA levels and normal ALT levels and have not required resumption of treatment."
"Guidelines provide an evidence-based framework for managing patients; however, management of individual patients must be flexible, taking into account the patient's preference and other medical or psychosocial conditions, evolution in knowledge over time, and the provider's experience," they concluded.
Truvada Effective in Lowering Viral Load in Young Adults with High Viral Load
An international study found the antiviral combination of tenofovir and emtricitabine (Truvada) was most effective in treating younger adult hepatitis B patients with high viral load and normal ALT levels.
Doctors historically have not treated this group because there appeared to be no sign of liver damage. However, doctors now know that high viral loads may increase patients’ risk of liver damage and cancer as they age, despite their normal ALT levels.
Most participants in the study were Asian and the average age was 33. Nearly all were HBeAg-positive and had HBV DNA levels at around 10 million IU/mL. Sixty-four patients were treated with tenofovir (300 mg daily) and 62 were treated with the combination pill containing tenofovir (300 mg) and emtricitabine (200 mg).
After 192 weeks of treatment, 55% of patients treated with just tenofovir and 76% of patients treated with the combination Truvada pill had nearly undetectable HBV DNA levels (less than 69 IU/mL). None of the patients developed drug resistance.
HBeAg seroconversion (loss of HBeAg and development of “e” antibodies) occurred in three patients in the tenofovir group. None of the patients in either group lost HBsAg.
Researchers reported that women in the study fared better than men from either treatment and that Truvada was superior to tenofovir alone in lowering viral load. However, HBeAg seroconversion and HBsAg clearance rates remained low in both groups, according to their report published in the January 2014 issue of the journal Gastroenterology. (1)
An unrelated study in Spain also explored the success of long-term antiviral treatment in 33 HBeAg-positive patients (older, with an average age of 42) with high viral loads. The patients were treated longer, for nearly four years, 37% with lamivudine, 24% with tenofovir and 21% with entecavir.
This group appeared to have more success, with 19 (57%) achieving HBeAg seroconversion and 27% clearing HBsAg. No patient regained HBsAg during three years of follow-up after treatment ended, according to the report published in the January issue of the journal of Gastroenterology and Hepatology.
However, seven of the patients developed drug resistance to lamivudine and one developed adefovir resistance.
“Treatment with (antivirals) achieves a high seroconversion rate (57.57%) and a considerable percentage of HBsAg clearance (27.27%),” researchers concluded. (2)
1. Source: www.ncbi.nlm.nih.gov/pubmed/24462735
2. Source: www.ncbi.nlm.nih.gov/pubmed/24462611
Hepatitis B Causes Most Liver Cancer Deaths in China
Researchers writing in the Asian Pacific Journal of Cancer Prevention, examined the five leading causes of preventable liver cancer in China and found hepatitis B leads the list, causing 66% of liver cancer deaths in men and 58% in women.
Their data, pulled from the 3rd National Death Causes Survey of 2005, found hepatitis B caused most liver cancer deaths, followed by:
- Hepatitis C
- Aflatoxin, a poisonous fungus found in soil and decaying matter that can contaminate rice, corn and other grains
- Alcohol abuse, which affected men more than women
- And smoking
Overall, 86% of liver cancer deaths were attributable to these five factors. “Our findings provide useful data for developing guidelines for liver cancer prevention and control in China and other developing countries,” researchers wrote.
Smoking Shortens Survival after Liver Cancer Surgery
A Chinese study found that heavy smokers who have hepatitis B face a higher risk of death and cancer recurrence after they undergo surgery for liver cancer.
Smoking affects more than lungs—the liver must metabolize more than 40 tobacco-related compounds and several of them are known to cause cancer in the liver. In this study, researchers followed 302 patients who underwent surgery to remove liver tumors and compared survival of smokers to nonsmokers.
Survival without recurrence of liver cancer was 34 months in nonsmokers and 26 months in current smokers. Even former smokers had lower survival rates that were similar to current smokers, probably due to the cumulative effects of years of smoking, according to the report published in January issue of PLoS One.
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