While viral load – the amount of HBV DNA that is detectable in the circulation in the blood – is increasingly becoming accepted as a good measuring stick for hepatitis B infection, its uses have become complex and varied, and in some cases, controversial.

“Viral load is a surrogate for clinical outcome,” said virologist Brent Korba, Ph.D., professor of microbiology and immunology at Georgetown University, “and routinely used to decide who should be treated with powerful antiviral drugs, when they should be treated and for what duration, as well as to gauge their effectiveness against HBV.”

High viral load increases the risk of liver-related complications, including cirrhosis and liver cancer, from chronic HBV infections.

“There’s a great deal of evidence showing that the amount of viral DNA in a person correlates with outcome. But is therapy-induced reduction the same as natural reduction?” asks Timothy Block, Ph.D., HBF president and professor and director of the Drexel Institute for Biotechnology and Virology Research.

Robert Gish, M.D., medical director of the liver transplant program at California Pacific Medical Center, said that viral DNA load is increasingly becoming a surrogate for the liver biopsy and serum liver enzyme levels to decide who should be treated when, for how long and as a way to measure drug effectiveness. He called it an “effective way to predict who will get cancer and cirrhosis – the best we have.”

For now, the gold standard remains liver biopsy, in which a small piece of the liver is removed and examined for reductions in liver inflammation and fibrous tissue, two hallmarks of HBV infection.

It is, however, an invasive procedure that requires a hospital setting.

Measuring viral load, on the other hand, is a simple blood test and is much easier on the patient than a liver biopsy. The ability to reliably detect viral DNA has been possible for only the past five to seven years.

But is viral load an effective surrogate by itself? Is it simply enough to lower the viral load in treating a patient? Should a patient be treated until DNA is eliminated? What about drug resistance and the dangers of being on a drug for too long?

“There’s no question that the lower the level of viral DNA you can achieve, the better it is for the patient,” said Korba. “The drugs are so good now. We have powerful new drugs that can drop viral DNA within the first three months of therapy and the ability to track that reduction.

“Treating until DNA is no longer detectable is the ideal, as is keeping it eliminated, but that’s not the response seen from most patients,” Block said.

He noted that for patients without indication of active disease, physicians tend to not want to treat right away out of concerns for developing drug resistance. Still, putting a patient on a constant on-off cycle of antiviral drugs may not be a good long-term plan. “The drugs seem safe, but long-term studies have yet to be done – they are too new, and drugs affect individuals differently at age 20 and at age 50.

“It’s clear that if viral load is above 10,000 copies of viral DNA per ml, there is a statistically increased risk of severe liver disease,” said W. Thomas London, M.D., senior member at Fox Chase Cancer Center, noting that this is the new opinion coming out of a recent conference at the National Institutes of Health.

“Currently available drugs for hepatitis B aren’t reliably getting all patients’ levels below that,” he noted. “It won’t do much good to have federal guidelines mandating that chronic, lifetime therapy should reduce HBV viral loads below several hundred copies per ml because it may be too difficult to achieve this.”

The question now is, ‘How low should we go’?

“Intuitively, you would want to go as low as possible,” Korba said. But there may be a threshold for HBV. Reducing viral load beyond that threshold may not have much clinical benefit, he contends.

Nevertheless, while knowing how low is ‘good enough’ for viral load reduction remains to be determined, almost everyone agrees it is an important clinical bench mark in the treatment of hepatitis B. This is a race to the bottom that we want to win.

Steve Benowitz, science writer, Philadelphia, PA

BInformed, Summer 2006.