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NIH Consensus Development Conference: Management of Hepatitis B
October 20-22, 2008

Tuesday Reports, by Christine Kukka, HBV Project Manager


When to Treat, Antiviral Resistance, and Use of Antivirals During Pregnancy

Researchers at NIH Conference Find Few Valid Scientific Studies Confirm Benefits of Hepatitis B Treatment


When to treat, antiviral resistance, and use of antivirals during pregnancy
BETHESDA, MD--Hepatitis B experts examined who should be treated, when, and the benefits and risks of antiviral treatment during the second day of the National Institutes of Health’s Consensus Development Conference on hepatitis B.

When to treat:
Anna S.F. Lok, professor of internal medicine and director of clinical hepatology at the University of Michigan Health System, recommended treatment when there was life-threatening liver disease, a high risk of “adverse outcome in the near future,” and active inflammation and cirrhosis.

Despite the lack of credible, randomized clinical trials, Lok cited the life-saving benefits of using antiviral therapy in the face of sudden liver failure and decompensated cirrhosis.

Older age, male gender, and a long period of elevated viral load and ALT levels are also triggers for treatment, she explained. The hardest challenge is whether to treat younger patients, under age 40, who have normal ALT levels and moderately elevated viral loads.  More studies are showing that even moderately elevated ALTs and viral load are producing liver damage, even in younger adult patients.

Monitoring for antiviral resistance
Experts also pressed for the need to create a standardized method for monitoring patients to identify when they develop resistance to antiviral medications. Marc Ghany, MD, investigator for the Liver Diseases Branch of the National Institute of Diabetes and Digestive and Kidney Diseases at NIH, recommended monitoring viral load, and other biochemical features every three months after treatment begins.

It may be beneficial to test a patient’s HBV before treatment begins to see if they already have certain mutations that would enable viral resistance, he said, but the test is expensive ($300) and is currently not performed in the U.S.

“But if viral load begins to rise,” he said, “the tests should be repeated and then a test should be performed to test for genotype resistance (viral resistance).” If resistance is found, doctors can start a second antiviral, or switch to more potent antiviral, or they can stop treatment and observe what happens. However, if a patient has cirrhosis, antivirals should not be stopped because a life-threatening resurgence of ALT and viral load can occur.

Side effects from lengthy antiviral treatment identified
Researchers are finding that prolonged treatment, beyond two years with antivirals not only inhibits replication of the virus, but also interferes with cellular replication and causes myopathy, lipoatrophy, pancreatitis, nephrotoxicity and neuropathy. Researchers reviewed the risk from each antiviral, and called for additional study into the risks of renal insufficient from the agents.

Use of antivirals during pregnancy to prevent mother-to-child transmission of HBV infection
Despite immediate treatment with HBIG (hepatitis B antibodies) and immunization, between 5 to 10% of infants born to infected mothers with high viral load develop chronic HBV infection.

Lamivudine, which has been safely used in the third trimester of pregnancy to prevent perinatal transmission of HIV, is beginning to be used in HBV-infected women with high viral load during the third trimester of pregnancy to prevent transmission.

Researchers reviewed the potential side effects of the five available antiviral agents, and recommended that lamivudine may be the safest for use during pregnancy, given its safe record from HIV use. Tenofovir (Viread), which is a stronger antiviral than lamivudine, was not promoted because doctors are concerned about its potential impact on fetal bone development.

Reactivation of hepatitis B when chemotherapy or immune-stimulants are used:
Jay Hoofnagle, director of the NIH’s Liver Disease Research Branch, detailed the alarming occurrence of HBV reactivation, which can lead to death, among patients with inactive or resolved hepatitis B when they are treated for non-hepatic cancers with chemotherapy or bone marrow replacement. Because antivirals can take up to a month to be effective, in some cases doctors have used antivirals to help these reactivating patients belatedly. Hoofnagle stressed the need for additional studies, and close collaboration with oncologists and other doctors who may be unaware of this risk.


Researchers at NIH Conference Find Few Valid Scientific Studies Confirm Benefits of Hepatitis B Treatment
BETHESDA, MD--Hepatitis B experts at the National Institutes of Health’s Consensus Development Conference found themselves defending the shortage of evidence-based research studies that justify the use of antivirals and interferon to treat patients infected with the hepatitis B virus (HBV).

The confrontation arose during the NIH consensus conference, when physicians and researchers specializing in hepatitis B presented evidence to a panel that will decide future priorities for funding research and clinical trials.

One expert, whose job was to critique available hepatitis B studies of what worked and what didn’t, found little proof that antiviral treatment or interferon were effective at preventing either cirrhosis or liver cancer. At issue is the lack of randomized control studies, which use a control group that receives a placebo instead of treatment, in order to show the effectiveness of treatment.

The research and clinical trials were weak and failed to adequately follow patients for several years or use control groups, according to the report, and antiviral medications did not reduce death and pegylated interferon failed to prevent cirrhosis in HBeAg-positive patients.

Timothy J. Wilt, MD, MPH, professor of medicine at the Center for Chronic Disease Outcomes Research at the Minneapolis VA Medical Center, levied a harsh judgment on the clinical outcomes in the studies. He took researchers to task for not consistently tracking outcomes such as viral load (HBV DNA), ALT levels that indicate liver damage, and loss of the “e” antigen (HBeAG) or surface antigen (HBsAg), development of HBeAg or HBsAg antibodies, and specific improvements in liver health (histology) measured by liver biopsies.

His critique exposed the inconsistent studies, which have been performed by different researchers around the world over the past two decades, in a field of care that lacks many firm benchmarks or goals. Some studies, for example, define reductions in viral load or ALT as a goal, others focus on “seroconversion” (loss of HBeAg and development of the “e” antibody), and others track improvements in liver health.

“Available drugs have not been demonstrated to improve clinical outcomes or resolve hepatitis B,” Wilt explained in his analysis.

“How do you not treat cirrhotic patients without putting them in jeopardy?” responded Jules L. Dienstag, MD, hepatitis B expert and dean of medical education at Harvard Medical School, to the charge that researchers did not use a control group.

Members of the panel picked up on Wilt’s findings of a lack of valid, randomized control studies and asked if treating with antivirals, which can lead to antiviral resistance, may be causing more harm than good.

Dienstag explained there was no cure for hepatitis B and physicians did not have the luxury to be able to follow patients for decades or use control groups, which would have essentially assigned patients who received placebos to death from liver disease.

“There are people who didn’t die because we used antivirals,” he told the panel. “You’re asking for scientific outcomes that are measured in decades, which is very difficult.”

Dienstag and others explained that treatment goals have changed over the years as more knowledge was gained about the infection and more antivirals developed. Physicians can point to tangible improvements in liver biopsy results as a result of treatment, he said, but they cannot prove that they were able to prevent development of cirrhosis.

“True, we don’t have many controlled trials,” Dienstag said, “but it wasn’t until antivirals came along 10 years ago that we even realized that cirrhosis was reversible.”

While pharmaceutical companies are required to perform randomized control trials for 12 months in order to win U.S. Food and Drug Administration approval for drugs, after that initial controlled trial, doctors and researchers often test the drugs in less rigorous clinical trials.


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