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HBV Journal Review

HBV Journal Review
November 1, 2012, Vol 9, no 11
by Christine M. Kukka

PDF PDF (download)

Hepatitis B Accompanied Humans Out of Africa 33,600 Years Ago

How old is the hepatitis B virus? When did it first infect humans? Where did it originate?

University of Athens researchers compared the timeline of human migration out of Africa with the evolution and dispersal of the hepatitis B virus (HBV) and its various strains (genotypes) and concluded that the virus first infected humans about 33,600 years ago in Africa and followed them on their migration around the globe.

"Our study provides, for the first time, an estimated timescale for the HBV epidemic that closely coincides with dates of human dispersals, supporting the hypothesis that HBV has been co-expanding and co-migrating with human populations for the last 40,000 years," researchers concluded in the October issue of Hepatology.

Each HBV genotype is found in a distinct region of the world, and its subgenotypes are also found in specific geographic areas. Researchers sampled HBV in indigenous populations around the world, in hopes of documenting HBV that may have migrated out of Africa and then evolved in place over thousands of years.

They studied the genotypes and subgenotypes of Australian Aborigines (who have genotype C), Amerindians in South America (genotype F), Amerindians in Central and North America (genotype H). These suggest, "...an ancient introduction of the (genotype) G/H ancestral strains to the Americas, certainly occurring before the recent European colonization."

HBV from isolated people, including Canadian arctic First Nations people (genotype B6), and those in Papua Indonesia and the Pacific islands (a variety of C subgenotypes), form distinct strains resulting from different waves of human migration.

Genotype C, researchers suggest, shows up in the earliest migrating groups out of Africa, including the Aborigines. To test this hypothesis of slow viral evolution, researchers examined the molecular make-up of HBV DNA recovered from a Korean mummy dating back to the 16th century.

The mummy's genotype was C, which may have originated in Australia and worked its way up through Asia with migrating humans, "confirming that HBV is a slow evolving pathogen and that its genotypes and subgenotypes were shaped long before the 16th century."

Genotype A, which originated early in Africa (and can be found among Haitians whose ancestors were transported there as slaves from Africa more than 300 years ago), also journeyed with humans north to Europe about 5,000 years ago, as evidenced by the various HBV genotype A subtypes in Europe.

The researchers suggest the humanoids who migrated out of Africa, carrying the virus, left behind Homo sapiens who died out or were replaced by more recent population expansions, which is why only one HBV genotype A subgroup is now found in Africa.

If HBV has been infecting humans for so long, why has its liver-damaging symptoms remained unnoticed and largely undocumented for centuries?

Because, scientists wrote, it takes about 40 to 60 years for the virus to cause noticeable liver damage and death in humans. Until about 150 years ago, the average human lifespan was less than 40 years.

Surprise Discovery: Diabetes Drug Prevents Liver Cancer

Two separate studies presented at the 2012 Digestive Disease Week convocation show that the common diabetes drug metformin has an unexpected quality—it prevents liver cancer.

Previous studies have suggested that metformin, which helps cells absorb insulin, may prevent several cancers and in one study it slowed liver tumor development in mice with chemically-induced liver tumors.

People with diabetes have a 2.5-fold higher risk of developing liver cancer. The Taiwanese study presented at the conference compared liver cancer rates in diabetics who took metformin and those who did not take the drug. Those who did not take metformin were at far higher risk of liver cancer than those who took it regularly.

For every year of metformin use, patients with diabetes had a 7% decrease in liver cancer. A second study from Mayo Clinic that compared diabetic patients who took metformin against those who did not, found the drug reduced liver cancer risk by an astonishing 60%.

The findings are preliminary and will not result in immediate prescribing of metformin for hepatitis B patients with cirrhosis who are at risk of cancer, but larger studies are underway to verify the findings.

Statins Also Appear to Prevent Liver Cancer

Statins, used to lower cholesterol levels, appear also able to prevent or lower the risk of liver cancer, especially in people with Asian ethnicity, according to a report published in the October issue of Gastroenterology.

Statins lower cholesterol by blocking a chemical in the liver that is needed to generate cholesterol. Mayo Clinic researchers examined numerous studies that compared liver cancer in people who used statins and those who did not. Ten studies involving 4,298 cases of liver cancer in 1.5 million patients were analyzed.

Statin users were less likely to develop liver cancer than non-users in all patient populations, but especially among Asian patients with hepatitis B.

Researchers called for additional studies to see if statins could one day be prescribed to prevent cancer in people with viral hepatitis.

Researchers Uncover New Ways to Prevent Viral Replication

Two collaborating research groups from the University of Colorado Boulder and the Xiamen University in China may have uncovered an "Achilles heel" in the hepatitis B tumor-promoting protein called HBx that could allow new drugs to stop HBV replication.

The two studies, published in the October Proceedings of the National Academy of Sciences, identified two prime targets in liver cells that the HBx needs to enable viral replication.

The "host targets" of HBx in human liver cells, which are used for viral replication, are two small cell proteins known as Bcl-2 and Bcl-xL that help inhibit cell death.

HBx uses a "motif"--a strand of protein building blocks known as amino acids that resemble those seen in some cell death-causing proteins—to interact with the Bcl-2 and Bcl-xL to generate an increase in calcium in the host cell. The calcium elevation triggers both viral HBV replication and cell death.

When the researchers introduced gene mutations into the motif, HBx could not bind to the Bcl-2 and Bcl-xL proteins, nor could it reproduce in the liver cells and damage them. Also, when either Bcl-2 or Bcl-xL proteins in the liver cells were weakened, HBx was less able to finesse an increase in calcium and viral replication in the infected liver cell.

Now that researchers have identified the motif and the two HBx targets, scientists can start developing drugs that target the motif and two proteins to prevent HBV replication.

In one of the studies, researchers used a tiny roundworm known as C. elegans, a widely used animal model in biomedical research, to identify HBx host targets within the cell. This roundworm has never been used in hepatitis research and scientists hope this new model will "galvanize" hepatitis B research into identifying host "targets" in liver cells that HBV must bind to in order to replicate.

HBV Genotype D Associated with “Spontaneous” Viral Mutations

What role do genotypes play in viral mutations and loss of the hepatitis B e antigen (HBeAg)? A group of University of Miami researchers examined the HBV DNA of 213 southern Florida, multi-ethnic residents who had a mix of HBV genotypes to see how genotype influenced disease progression.

Patients were predominantly male (67%); 61 (31%) were African-American, 60 (28%) were Hispanic, 37 (17%) were Haitian, 27 (19%) were white, and 14 (6.6%) were of Asian ethnicity.

Genotype A was found in 101 (69%), D in 25 (17%), F in 9 (6%), G in 7 (5%), C and E in 6 (4%) each, B in 4 (3%), and H in 2 (1%) patients. Interestingly, a mix of genotypes were found in 11 patients.

Genotype A was more prevalent in all ethnicities except among Asians. Among HBeAg-negative patients (59%), basal core mutations, precore, and a combination of the two mutations were found in 30 (37.5%), 13 (16.3%), and 14 (17.5%), respectively. Genotype D was associated with higher rate of HBeAg- negative status and mutations.

PC mutations were more common in genotype D than genotype A. Researchers, reporting in the October issue of the Journal of Clinical Gastroenterology, found that 100% and 79% of Asians and Haitians had spontaneous mutations, with no drug resistance-related mutations. All Haitians with genotype D had precore mutations.

Antivirals Safe in Patients with Severe Cirrhosis

Researchers are studying whether antivirals are safe to treat vulnerable patients with severe hepatitis B-related liver damage. They reviewed eight studies involving 511 patients with decompensated cirrhosis--when the liver is extensively scarred and unable to function properly, which can lead to life-threatening complications.

According to their report published in the journal Digestive Diseases and Sciences, lamivudine (Epivir-HBV) and telbivudine (Tyzeka) significantly decreased patients' death rate, improved liver health, and promoted HBeAg seroconversion (loss of the "e" antigen and development of the "e" antibody).

In an unrelated article published in the journal Clinical Gastroenterology and Hepatology, researchers evaluated the effectiveness of lamivudine, entecavir (Baraclude) and tenofovir (Viread) in patients with moderate and cirrhosis. They followed 227 patients, 104 of whom had decompensated cirrhosis (severe). Seventy-two received tenofovir, 77 received entecavir, and 74 received lamivudine for two or more years.

Undetectable HBV DNA (less than 400 copies/mL) were achieved in 91.5%, 92.5%, and 77% of patients receiving tenofovir, entecavir, or lamivudine respectively, with 86.8%, 92.1%, and 71.8% achieving normal ALT levels with tenofovir, entecavir, and lamivudine respectively.

Liver biopsies showed improved liver health in 8.5% receiving tenofovir, 15.6% receiving entecavir, and 27.4% received lamivudine.

Lamivudine had to be changed to another drug in 32.4% of the patients because of drug resistance. Researchers recommend tenofovir and entecavir for long-term use in patients with either compensated or decompensated cirrhosis.

Elevated ALTs and Body Mass Index Increases Diabetes Risk

People infected with HBV who have a higher body mass index (BMI) and elevated alanine aminotransferase (ALT) levels are at higher risk of diabetes (insulin resistance) according to a study published in a recent Chinese medical journal (PubMed 23044237).

Researchers compared 68 hepatitis B patients with and without diabetes with a group of uninfected people who had normal ALT levels.

Compared to the healthy people in the study, people infected with HBV with elevated ALT levels had higher rates of diabetes.

Diabetes was detected in 44.12% (30 of the 68) hepatitis B patients. The levels of ALT and BMI were significantly different between the hepatitis B patients with diabetes and without diabetes.

Researchers concluded that elevated ALT and high BMI in hepatitis B patients also increased their risk of diabetes.

Mutations in Surface Antigen Increase Liver Cancer Risk in Older Patients

A team of Korean researchers followed 195 patients (average age 44, 72.3% male, 56% HBeAg-positive, all genotype C, and 40.5% with cirrhosis) for seven years to see which patients developed liver cancer.

They found that those who had a pre-S mutation (a mutation in the hepatitis B surface antigen (HBsAg) that enables it to avoid detection by most lab tests) were at higher risk of liver cancer.

They reported in the journal Digestive Diseases and Sciences that 22.6% of the 195 patients had the surface antigen mutation. Patients with the surface mutation had significantly higher liver cancer diagnoses at five years than those without the mutation (26.5% vs. 5.7 %).

Patients older than 50 with the mutation were at notably higher risk of liver cancer (58.3 %) compared to those without the surface antigen mutation (16.1%).

Researchers called for heightened cancer surveillance in older patients with the surface mutation, also called “occult” hepatitis B.

Many with HIV Also Infected with “Occult” Hepatitis B

A study of 298 HIV-infected South Africans found most who were coinfected with hepatitis B tested negative for the surface antigens and had “occult” hepatitis B. Only a sensitive lab test that screened for HBV DNA was able to identify their HBV infection.

Increasingly, physicians and researchers are discovering that mutations in HBV and other dynamics make it difficult to identify hepatitis B infections in HIV- and hepatitis C-infected people, unless a highly sensitive HBV DNA test is used.

In this study published in PLoS One, researchers stressed the need to test people at risk of hepatitis B using sensitive nucleic acid testing, so the infection can be identified and appropriately treated.

Patients with Genotype A, and Past Interferon Treatment, More Likely to Clear HBsAg During Antiviral Treatment

Japanese researchers followed 442 HBeAg-positive patients and 349 HBeAg-negative patients who were treated with antivirals over nine years to see which ones were able to clear the virus.

Eighteen (4.1%) of HBeAg-positive patients and 20 (5.7 %) of the HBeAg-negative patients cleared surface antigen over the nine years.

Among HBeAg-positive patients who cleared the virus were patients who:

  • Had been previously treated with interferon

  • Had genotype A

  • Experienced a 0.5 log IU/mL decline or more of HBsAg levels within six months of starting treatment

  • And lost HBeAg after six months of treatment.

Among HBeAg-negative patients, those most likely to clear the virus during antiviral treatment:

  • Had also been treated with interferon

  • Had genotype A

  • Had experienced a significant decline in HBsAg during the first six months of treatment

  • And had low HBsAg levels, less than 730 IU/mL, when they started treatment, according to the report in the Journal of Gastroenterology.

Electronic Reminders Spur Physicians to Test Asian-Americans for HBV

Studies repeatedly have found that primary care physicians fail to adequately screen Asian-American patients for hepatitis B--because doctors don't know they should or they forget Asian-Americans are at high risk of hepatitis B.

A new study by the University of California Davis School of Medicine found that building in hepatitis B screening reminders into electronic medical record systems improves hepatitis B screening.

According to the report published in the journal of Digestives Diseases and Sciences, the record system was primed to remind providers to screen for HBV when patients had Chinese or Vietnamese surnames and there was no history of HBV testing in the patient's records.

The study revealed that when prompted by the electronic record, physicians tested 41% of at-risk patients for hepatitis B, while physicians who did not receive electronic reminders only checked 1% if their patients for hepatitis B.

As a result of these prompts, four (13.3 %) of patients tested were found to be HBsAg-positive, 14 (46.7 %) were immune, and 12 (40 %) were vulnerable to HBV and required immunization.

"(Electronic) provider prompts significantly increased HBV testing in Chinese and Vietnamese patients when compared to 'usual care,'" researchers wrote. "(Electronic) prompts are a promising intervention that could significantly increase screening for HBV."



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