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

Final Report, by Christine Kukka, HBV Project Manager

NIH panel says stricter clinical trials and consistent patient monitoring needed to improve treatment for hepatitis B patients

Bethesda, MD – During a recent conference sponsored by the National Institutes of Health (NIH), an impartial panel recommended more long-term and scientific clinical trials focusing on the effectiveness of interferon and antivirals for hepatitis, and urged doctors to formalize how hepatitis B patients are monitored

NIH convened the conference to produce expert guidance to doctors about how hepatitis B should be monitored and treated. Hepatitis B experts testified before the panel during the three-day conference, pushing for clearer treatment guidelines to help physicians provide better quality care to their HBV-infected patients.

While there are five antiviral medications and two interferons approved for hepatitis B treatment, randomized control trials – where some patients are given a placebo instead of medication to accurately assess the drug’s effectiveness – are sorely lacking, the panel pointed out.  “Further controlled trials are needed to substantiate that these agents prevent disease progression to liver failure, cancer, or death," explained panel chair Michael F. Sorrell, MD, professor of medicine at the University of Nebraska Medical Center.

To address these gaps, the panel recommended that researchers conduct large studies, including placebo-controlled trials, to test the effectiveness of single drugs and drug combinations on liver failure, cancer, and death. The panel also pushed for more studies that would better explain the natural history of this complex infection, which is prone to mutations that quickly develop resistance to medications, and can behave dramatically differently in people based on their immune health, age, gender, and viral strain or genotype.



Clarify how to monitor disease progression and effectiveness of treatment: The panel identified elevated HBV DNA (viral load) and elevated levels of ALT (alanine aminotransferase, a liver enzyme that increases when liver cells are damaged or die) as the most important indicators for doctors to monitor when evaluating a patient’s progression to cirrhosis and liver cancer. Older age, male gender, family history of liver cancer, and coinfection with the hepatitis C virus or HIV were also important indicators.

Whom to screen for HBV, no impact on immigration: The panel recommended routine hepatitis B screening of newly-arrived immigrants and their family members from countries where HBV infection prevalence exceeds 2 percent. These practices are intended to identify infection and help people receive treatment, the panel noted, and is not designed to exclude HBV-infected immigrants in any way.

Whom to treat: The panel recommended treatment for patients with liver damage and complications from cirrhosis. However, immediate therapy was not recommended for patients with inactive forms of the disease, such as people in the immune-tolerant stage (with high viral load and normal ALTs, frequently found in children and young adults), and those with low viral load and normal ALTs. However, older adults with high viral load and normal ALTs have been found to have liver damage, so their ALTs should be monitored over time and if their ALT levels fluctuate, they should be treated.

What is the current prevalence of hepatitis B in the U.S.? While some researchers have estimated the true rate of HBV infected residents to be more than 2 million, the consensus statement stuck to current government predictions of infected residents at about 1 million residents. Many are of Asian or Sub-Saharan African descent. Critics claim current population surveys miss many undocumented residents from Africa and Asia, where infection rates are high.

Who has the highest risk of developing liver cancer? Long-term follow-up studies show that the HBV genotype C infection, found among people from Asia and the Pacific Islands, poses an increased risk of cirrhosis and liver. Other risk factors for liver cancer include being male, older, and having a family history of liver cancer. Co-infection with HCV increases the risk of cirrhosis and cancer.

What are the benefits and risks of current treatments for hepatitis B?
Currently, there are seven drugs for hepatitis B treatment, including conventional and pegylated interferon, and antivirals (lamivudine, adefovir, entecavir, tenofovir and telbivudine). While the goal of treatments is to prevent development of liver damage and cancer, “to date, no conclusive evidence from randomized control trials (RCTs) of antiviral treatment has demonstrated a beneficial impact on any of these primary clinical outcomes,” the panel wrote in its report. “This is due to the fact that cirrhosis, liver cancer, and death often do not occur for many years after infection with HBV, and would therefore require long-term investigation of therapy to demonstrate benefit.” As a result, only short-term or “intermediate” treatment outcomes are known, panelists added.

In studies of hepatitis B therapy, a variety of factors including loss of surface antigen (HBsAg), reduced viral load, loss of the “e’ antigen (HBeAg) and development of the HBeAg antibody, normalization of ALT levels and improvement in liver health have been included either separately or together as treatment endpoints, which results in inexact science and no clear findings about which treatment regimen is best.

Due to the vagaries of the studies, and the reliance on “intermediate” results, such as temporary lowering of viral load during antiviral treatment, the panel recommended, “large RCTs, including placebo-controlled, of mono (using one treatment) and combined therapies with effects on clinical health outcomes (documented).”

Antiviral treatment recommended for patients receiving chemotherapy and immune-suppressing drugs: Panelists also stressed that people with resolved HBV infections and those who test positive for HBsAg and have any viral load, should be treated with antivirals prior to chemotherapy or bone marrow transplants. It takes about one month for an antiviral to begin to work, so antiviral treatment should begin about one month before the start of chemotherapy or immune-suppressing drugs.

Goal of treatment: In addition to preventing the development of liver damage and cancer, treatment endpoints should also include a reduction in HBV DNA levels, improvement in ALT level, and loss of HBeAg and HBsAg.

Future research needs: The long duration of illness and the complex course of HBV infection have created major challenges for effective clinical research. While RCTs may be difficult, randomized control trials are still needed, they stressed, even if it means providing a placebo instead of treatment to infected patients. The complex course of chronic HBV infection has resulted in the acceptance of intermediate or short-term end points for treatment, but that approach, “may lead to biased estimates of therapeutic effect,” panelists warned.

“To ensure that the results of different studies are comparable or may be combined for analysis, such studies should be conducted using standardized protocols, including definitions of populations, regimens, clinical definitions, diagnostic methods, intervals and techniques for follow-up, and, most importantly, standard definitions of improvement,” panelists wrote.

Clear monitoring guidelines also needed: While a variety of monitoring practices are recommended, no clear evidence exists for identifying the best monitoring protocol, they added. Researchers must use the same monitoring tests in order to scientifically evaluate how patients fare from treatment, they added.

The NIH consensus report is found at: http://consensus.nih.gov/2008/hebB%20draft


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