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Making Treatment Decisions in an Evidence-Free Zone

By Lei Chou

New drug development; treatment strategies; natural history; long-term outcomes: The lack of support for research on hepatitis B virus is putting millions of people with the virus at risk.

People living with chronic hepatitis B (HBV) and their doctors have been struggling with a lack of clear guidelines for making treatment decisions—despite advances in new treatment options made during the last decade. High cost, indefinite duration, potential long-term side effects, and the emergence of drug resistance—all have raised the stakes on finding optimal HBV treatment strategies. In the cold light of evidence-based science, the lack of research on HBV natural history and on long-term clinical outcomes was brought into sharp relief at the NIH Consensus Development Conference on the Management of Hepatitis B held October 20–22, 2008, in Bethesda, Maryland.

The NIH Consensus Development Program has convened meetings to develop evidence-based consensus statements on medical controversies since 1977. Sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases and the Johns Hopkins School of Medicine, this meeting seated a 12-member panel with no financial or career interest in the field of HBV research to formulate a statement aimed to widely disseminate strong, evidence-based recommendations for general practice. A report based on a systemic literature review was submitted by the Minnesota Evidence-based Practice Center to the panel, and leading HBV experts provided 1-1/2 days of presentations on the topic. The evidence report, meeting webcasts, and the draft consensus statement can be accessed at: 2008/2008HepatitisBCDC120main.htm.

“The data available are insufficient to provide patients, clinicians, researchers, and policymakers with high-quality information with which to make accurate prognostic and treatment decisions.”

—Evidence Report/Technology Assessment No. 174, Management of Chronic Hepatitis B

Although the verdict rendered by the evidence report came as no surprise to people who follow HBV research, the blunt assessment on the current state of research data in HBV clinical management is no less sobering. The lack of clear clinical guidance creates a potential danger to patients that is not merely theoretical. For example, many people with HBV remained on lamivudine monotherapy for years in the belief that even suboptimal viral suppression could improve long-term outcomes. Eventually, data emerged showing that cross-resistance rendered subsequently approved drugs less effective, leaving many with fewer treatment options than if they had waited or switched to a combination therapy approach.

To be fair, the decade-long, fluctuating, and mostly silent and complex disease progression in chronic HBV presents a very difficult challenge for research measuring long-term clinical outcomes such as those of liver cirrhosis and cancer. Studies with the duration, size, and diverse treatment strategies required to fully answer these questions would be very expensive. Such large investments are unlikely to be made by the private sector, which has only sponsored small trials with short follow-up periods intended primarily for drug approval or for increasing market share after approval has been obtained.

Public financing for HBV research recently received a boost with the establishment of a national HBV clinical trials network. But with a first-year budget of only $3 million to be shared among 13 trial sites (and an annual $7 million in each of the following seven years) its funding is woefully insufficient to develop the definitive treatment guidance that is needed: longterm clinical outcomes comparing people who start treatment with people who wait; the safety and duration of benefit while off treatment; improved understanding of different disease progression patterns in people infected at birth versus those infected in adulthood and in those with different genotypes; identification of more accurate biomarkers for disease progression and reactivation; and the establishment of an HBV replicon system to speed identification of new drug targets.

What’s more, the argument for increasing federal investment in HBV research is seriously hampered by the lack of visible demand. There is still no national chronic HBV surveillance program, and the recent CDC recommendation to increase chronic HBV screening came with no additional funding. A vicious cycle created by this data void is what confronts people living with HBV in need of treatment. With no compelling evidence to back up the need for a public assistance program like the Ryan White CARE Act and AIDS Drug Assistance Program, HBV advocates face a major challenge ahead. One hopeful approach would be to support the new administration’s healthcare reform proposal that could increase affordable insurance coverage and eliminate exclusions based on preexisting conditions.

It is clear that the field of HBV research can benefit with the involvement of more advocates. If the paucity of new data on HBV at a recent major medical conference on liver disease in San Francisco is any indication, people living with chronic HBV and their clinicians will continue to struggle with making treatment decisions for years to come.

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