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Georgetown U. Researchers Said to Identify Markers That Lead to HBV Drug Resistance


A team of researchers at Georgetown University Medical Center said it has stumbled upon a genetic marker that might eventually help physicians better treat patients with hepatitis B.

The scientists claim to have discovered a way to predict which patients with the disease will have a positive response to a commonly prescribed treatment, and which patients will likely develop resistance or reject the drug outright.

Hepatologists usually resist prescribing the drug, lamivudine, until patients become clinically ill. Physicians fear the drug, which is considered to be highly efficacious, may eventually lose its potency, and may even engender a resistance to other HBV treatments. Indeed, resistance to lamivudine occurs in approximately two-thirds of treated patients.

“We have long struggled with one tough question: How do you treat those HBV-positive people who have the best chance at responding to lamivudine treatment and determine those who will fail treatment?,” said John Gerin, professor of microbiology and immunology at Georgetown University Medical Center. He explained that physicians currently “wait until you get sick and then … see if lamivudine works.”

However, results of Gerin’s study may eventually offer physicians a more palatable option. “With a precise, predictive system in place, we can give patients immediate and targeted treatment rather than forcing them to wait until they become very ill,” he said.

Together with Brent Korba, a professor of microbiology at Georgetown, and colleagues from S. Giovanni Battista Hospital in Torino, Italy, Gerin followed 26 HBV-positive people through 21-48 months of lamivudine treatment. Seven of them, classified as “responders,” enjoyed “permanent remission.” Twelve patients, considered “breakthroughs,” experienced initial success but then “slid back” into active infection as a result of lamivudine resistance, Gerin reported. The remaining seven didn’t respond to lamivudine treatment at all.

The researchers detected two separate genetic polymorphisms in the viral genome in every breakthrough and non-responding patient prior to treatment; none of the responders had these markers.

Gerin said he looked at a region of the virus “that hasn’t been routinely studied in depth before.” He said his lab studied the polymerase protein made by the virus, which has five domains. After extracting the virus, his lab performed PCR-based amplification and outsourced the samples for sequencing. The researchers focused on the first and last domains in the protein — the A and E domains — and, since the domains contain polymorphisms, “they are predictive of treatment failures,” he said.

“Frankly, we were stunned to see that we could in fact clearly distinguish markers between the three groups and link them directly to that patient’s degree of success with lamivudine,” said Gerin, who presented his study this week at the 16th International Conference for Antiviral Research in Savannah, Ga.

Gerin told SNPtech Reporter that the next step for his team is to extend the study. “We need to see if other ... investigators can reproduce these same findings. The results were highly significant statistically, but … others need to repeat it.”

Asked if the results of his trial represent the first step to creating a viable diagnostic for HBV, Gerin said, “very definitely. This would predict treatment failure, not treatment success. That’s important, too, because you don’t want to start a patient on a drug if he’s not going to be successful.” He said doing otherwise increases the risk of sparking accumulated toxicity and creating mutant forms of the virus that might develop resistance to other drugs.

Although his research may lead to biomarkers, Gerin said he hasn’t observed interest among drug makers. “It’s much too early,” he said. “I don’t think any of them know about our study until we presented it here today.”

Approximately 1.3 million people in the United States are chronically infected with HBV, of whom between 20 and 30 percent acquired the infection in childhood, according to the Centers for Disease Control and Prevention. Additionally, 1 out of 20 people in the county will become infected with the virus at a point in their lives. HBV is spread through sexual contact, needle sharing, or from an infected mother to her baby during birth, the CDC said.

Chronic hepatitis B can lead to progressive liver disease, liver failure, or primary liver cancer. It affects more than 400 million people worldwide. The highest rate of HBV occurs in people aged 20 to 49, and death from chronic liver disease occurs in 15-25 percent of chronically infected individuals. The HBV vaccine is considered the best protection against the virus, and infants are routinely given it as part of their standard immunizations.

“In an era of skyrocketing medical costs, the cost savings in not treating patients who will not respond may be a profound public health advantage,” said Gerin.

— KL

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