HBV Journal Review
April 1, 2014, Vol 11, no 4
by Christine M. Kukka
Despite Antiviral Treatment, Liver Cancer Risk Persists
Researchers have hoped that treating hepatitis B patients with antivirals would reduce both their viral loads and their liver cancer risk. However, a new study that followed 1,378 treated and 1,014 untreated patients over five years found antivirals did not reduce liver cancer rates as hoped.
The study tracked new liver cancer cases among patients infected with the hepatitis B virus (HBV) (average age 47, 65% male) who had been treated primarily with entecavir (Baraclude) for their high viral loads and liver damage. They compared that group's liver cancer occurrence to those of patients whose "inactive" HBV infection did not require treatment.
Among the treated group, 70 patients (6.2%) developed liver cancer during the study period compared to only 11 (1.1%) in the untreated group. Notwithstanding the ability of antivirals to reduce viral load, a life-long history of HBV infection and liver damage appeared to increase cancer risk, despite the reduction in viral load later in life.
What is especially disappointing is that liver cancer developed even in treated patients who had no history of cirrhosis (severe liver scarring) which increases cancer risk. Among the antiviral-treated patients:
- 20 of 223 HBeAg-negative patients who had cirrhosis at the start of treatment developed liver cancer.
- 15 of 316 HBeAg-negative patients who had no cirrhosis also developed liver cancer.
- Among the treated patients who developed liver cancer, 30 were positive for the hepatitis B "e" antigen (HBeAg) and 30 were HBeAg-negative.
How well the antiviral worked in patients also determined who remained cancer-free. Of the 246 patients who failed to achieve low or undetectable viral loads as a result of treatment, 36 (18.8%) patients developed liver cancer over the five-year study.
The risk of cancer was increased overall by male gender, underlying cirrhosis and older age in the treated group. Curiously, having high viral loads (HBV DNA) at the start of treatment did not appear to increase liver cancer risk.
The key message for doctors is that liver cancer risk remains despite a dramatic reduction in viral load, researchers noted. "...Patients on (antiviral) treatment that effectively suppressed viral replication are still at higher risk of liver cancer compared with patients with inactive stage chronic hepatitis B," they concluded in the study published in the March issue of the journal Gut.
Persistent liver damage before the start of antiviral treatment, evidenced by elevated alanine aminotransferase (ALT) levels, may predispose patients to liver cancer, they also noted.
"The inactive group may have more intact immune response to HBV and therefore may also have entered the inactive stage early in life, with a shorter period of high viral replication and active hepatitis," they wrote.
Appears to Help Prevent Liver Cancer
Recent studies show a diet rich in vitamin D can improve liver health in patients with hepatitis B. A new study from Emory University in Atlanta finds that people with high vitamin D levels have lower rates of liver cancer.
The researchers examined vitamin D levels and liver cancer risk among 520,000 participants in the European Prospective Investigation into Cancer and Nutrition between 1992 and 2010.
They compared vitamin D levels in 138 patients diagnosed with liver cancer against other participants who had similar ages and gender.
They found higher vitamin D levels were associated with a 49% reduction in liver cancer risk.
The higher vitamin D levels appeared to confer protection against liver cancer even if patients had pre-existing liver damage or a hepatitis B or C infection, according to the report published in the February issue of Hepatology.
"Given the rising incidence of this cancer in low-risk developed countries and the strong public health interest surrounding the potentially cancer-protective roles of vitamin D, additional studies in different populations are required," they wrote.
The body makes vitamin D when skin is exposed directly to the sun. Skin exposed to sunshine indoors through a window will not produce vitamin D. Very few foods naturally have vitamin D, fortified foods provide most of the vitamin D in American diets. Foods rich in vitamin D include fatty fish and milk. Vitamin D is added to many breakfast cereals, some orange juice brands and some yogurts.
Dandelions May Be the Next Best Herbal Treatment for
Dandelions—viewed by many as a pesky weed—may become an effective treatment for hepatitis B, according to a recent Chinese study published in the January issue of Molecular Medicine Reports.
Dandelions are full of vitamins, including A, B, C and D, and in the past dandelion roots and leaves were used to treat liver problems. Native Americans boiled dandelion in water and took it to treat kidney disease, swelling, skin problems, heartburn, and upset stomach. In traditional Chinese medicine, dandelion has been used to treat a wide array of stomach problems.
In a laboratory, researchers treated animal liver cells with dandelion (Taraxacum mongolicum) and found the compound protected the injured liver cells and also inhibited HBV DNA replication.
"The results demonstrate the potent antiviral effect of Taraxacum mongolicum against HBV," they wrote. This protective effect may be achieved by its ability to reduce liver cell damage and its antiviral properties may block HBV DNA replication, they concluded, supporting the traditional use of dandelions in the treatment of hepatitis.
Kidney Problems Are Prevalent with Hepatitis B Even Before Treatment Starts
Doctors have found signs of kidney problems in hepatitis B patients treated with antivirals, which reduce the ability of HBV to replicate, and have suspected that renal (kidney) function could be affected by the medication.
However, a new study, published in the February issue of the journal Liver International, found that kidney problems were quite prevalent—affecting 64.6% of 268 untreated hepatitis B patients, many of whom had inactive infection.
The doctors, based in France, followed the patients (58% male, average age 47) over two years. Among them, 59.6% were "inactive" carriers.
"Renal (kidney) abnormalities are highly prevalent in our population and pre-exist before the initiation of any anti-hepatitis B virus treatment," they wrote. This emphasizes the need for:
- A baseline renal evaluation in all patients
- And regular kidney function monitoring before and during treatment to diagnose and manage any kidney impairment and adjust medication doses as needed.
HBV Genotype H Appears to Cause Immediate Chronic Infection in Adults
Japanese researchers have found a case of a hepatitis B strain (genotype) that appears to cause an immediate chronic infection in adults.
Infants and children who are infected with HBV often develop chronic infections because their young immune systems do not recognize the virus and fight off infection. Most adults, however, are able to fight off a hepatitis B infection following an acute and brief infection unless their immune systems are compromised.
In the March issue of the World Journal of Gastroenterology, researchers describe a 47-year-old man who developed a new HBV infection. However, after the initial bout of infection, the man developed a chronic or persistent infection. Researchers found he was infected with HBV genotype H. This genotype has been found primarily in Southern and Central America.
"This case suggests that there is a risk of persistent infection by HBV genotype H following acute hepatitis," researchers wrote. They recommended additional studies on patients with genotype H and suggested that doctors may consider performing HBV genotype tests on patients with new, acute infections to fine-tune their treatment response.
HBV Genotype E Has the Worst Response to Pegylated
An Italian study published in the March issue of the Journal of Infection finds that HBV genotype E has the worst response to pegylated interferon (Pegasys) treatment.
Certain HBV genotypes (including A and B) appear to be more responsive to weekly injections with pegylated interferon than others. Researchers studied how effectively the drug, which spurs the immune system to fight infection, worked in 63 patients with this genotype, which is most prevalent in West and Central Africa.
Forty-one had low viral load and were treated with only interferon, 10 had high viral load and were treated sequentially with interferon and the antiviral entecavir, and 12 genotype E patients with inactive infection were followed as the control group.
Only 17.9% of those treated solely with interferon responded to treatment, with only one patient losing HBsAg. All patients with high viral load showed no response at all to interferon. "The HBV E genotype evidences the worse response to pegylated interferon and maybe requires novel treatment options," researchers wrote.
Cancer-Causing YMDD Mutations Found Frequently in HBV Genotype C
Chinese researchers followed 1,424 hepatitis B patients who had different stages of infection—ranging from asymptomatic/inactive carriers to those with cirrhosis and liver cancer—to see what role viral mutations played.
HBV have a weak genetic blueprint that allows the virus to mutate easily. Among the more common mutations, not related to any antiviral treatment, is the YMDD mutation, which can lead to more severe liver damage and liver cancer.
The researchers looked for YMDD mutations in the varying stages of liver disease among the 1,424 patients who had both genotypes B and C, and they found a higher YMDD mutation rate among genotype C patients.
"The difference in spontaneous YMDD mutation rates in patients with liver diseases infected with genotype C strains at different stages was statistically significant," they noted in the February issue of the Journal of Medical Virology, which made genotype C patients at higher risk of liver cancer.
High Iron Levels Found in Patients with Liver Failure
Researchers continue to investigate why hepatitis B patients with high iron (ferritin) levels often have liver damage. Another insight into this mystery was recently reported in the March issue of the Archives of Medical Research.
Chinese researchers compared ferritin (a protein that stores iron) levels in 55 healthy people, 46 people with chronic HBV and 71 patients with liver failure admitted to a hospital, and followed them for four months.
Patients with liver failure had significantly higher ferritin levels at admission compared to the healthier two groups. "Elevated (ferritin) levels were associated with increased severity of liver disease and three-month mortality rate," they reported.
Researchers encouraged emergency admission doctors to screen these patients' ferritin levels to improve diagnosis and treatment.
Vietnamese-Americans at High Risk of Undiagnosed Hepatitis B and C
A University of California Irvine Medical Center study finds hepatitis B and C infection rates remain high, and often undiagnosed and untreated, among Vietnamese-Americans.
The study evaluated 1,405 Vietnamese-American adults in Orange County who had been screened at community health centers for both hepatitis B and C and HIV. (Often, doctors screen for only hepatitis B in Asian-Americans.) The average age was 51, 55% were women, most were married, and nearly all had been born in Vietnam. Researchers found:
- 124 (8.8 %) were chronically infected with hepatitis B. Twelve percent of them thought they had already been tested and found to be hepatitis B-negative
- 81 (5.8 %) had hepatitis C, including four (0.3 %) with HBV/HCV coinfections. About one-third of those with hepatitis C thought they had been previously tested and found to be negative.
- 15.4% of those screened had never been vaccinated against hepatitis B
"This large serial survey and screening in the Vietnamese-American community confirmed the rates of HBV and HCV infection to be as high as
8.8 % and 5.8 %, respectively," researchers wrote in the January issue of the Journal of Immigrant and Minority Health.
Entecavir Performance Is Mediocre in Lamivudine-Resistant
After an eight-year study, Chinese researchers have concluded that entecavir is not a highly effective antiviral to use in patients who have already developed drug resistance to lamivudine (Epivir-HBV).
Researchers followed 32 lamivudine-resistant patients who were then treated with a 1 mg daily pill of entecavir for eight years.
After eight years, the percentage of patients with HBV DNA with less than 300 copies/mL finally reached 62.5% (20/32), but improvement was slow.
However, there were frequent incidents of "viral breakthrough," when patients had a resurgence in viral load. After eight years, 28.1% (9/32) of patients had experienced breakthroughs.
Over the study period, 10 patients lost the hepatitis B surface antigen (HBsAg) and four patients lost HBeAg, according to the report published in the Chinese journal of hepatology (PMID: 24636288).
They concluded that HBV DNA suppression from extended entecavir treatment was lackluster in this group, and that the economic cost was high as were virological breakthroughs.
A Simple Platelet Count Test Could Be Best Indicator of
Looking for a quick and easy test for fibrosis? Forget ALT levels, viral load, HBeAg status or expensive scanning procedures such as transient elastography. Researchers from China say a simple platelet count test may be the best indicator as to whether a patient has fibrosis (inflammation of the liver)—short of an invasive liver biopsy.
Experts have been looking for years for a non-invasive, inexpensive test that can quickly and accurately indicate when patients have fibrosis. To date, a lot of lab tests have provided misleading information, according to a study published in the January issue of ISRN Gastroenterology.
For example, doctors used to think that normal ALT levels meant the liver was healthy and free of fibrosis or cirrhosis, but new studies show that 29% of hepatitis B patients with normal ALT levels have significant fibrosis. When doctors rely on ALT levels alone, fibrosis is missed and many patients who need treatment don't get it.
Researchers have also found no significant link between HBeAg status or viral load and liver fibrosis. Many patients become HBeAg-negative over time and develop lower viral loads as they age, which is often when fibrosis develops or worsens.
In this recent study, researchers performed biopsies on 157 patients and looked at their blood tests to see if there was some other lab test that consistently indicated when fibrosis was present. They examined albumin levels, prothrombin time, globulin, platelet counts, ALT levels and performed other tests that could alone or taken together provide a more accurate snapshot of when fibrosis was present.
Their study found that low platelet counts and albumin levels, especially in older patients, were accurate indicators of significant fibrosis.
Platelets help the blood clot and are smaller than red or white blood cells. Albumin, made by the liver, helps move small molecules through the blood, including bilirubin, calcium, progesterone, and medications.
"In conclusion, ALT is a poor marker when considering antiviral therapy because of its poor correlation with significant liver injury in patients with chronic HBV infection," they wrote. "Lower levels of platelet count were independently associated with significant fibrosis. If a liver biopsy is considered to assess disease activity and fibrosis, it can be recommended for patients with chronic HBV infection, particularly for an older age group and patients with normal ALT and lower platelet count and albumin."
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