ACP: Long-Term HBV Suppression Produces Best Outcomes

— PHILADELPHIA--Hepatitis B infection is now largely preventable through immunization, but it is still a problem among adults.


PHILADELPHIA, April 6 - Hepatitis B infection is largely preventable through immunization, but it remains a problem among adults.

Because school age children in the United States have received vaccination for the past several years, cases are generally no longer seen in young children and teenagers, according to Willis Maddrey, M.D., a professor of medicine at the University of Texas Southwestern Medical School in Dallas.

Dr. Maddrey, who is President Emeritus of the American College of Physicians, spoke at the annual meeting of the college about strategies for the diagnosis and treatment of hepatitis B infection.

Early prevention of infection with hepatitis B virus (HBV) is important because the age of acquisition of an infection determines the risk of developing a chronic infection, which can lead to cirrhosis and eventually to hepatocellular carcinoma (HCC). If infected at birth through mother-to-child transmission, a child has a 90% chance of chronicity, dropping to 60% if acquired at age two years, and only 10% at age six. A 25-year-old adult has less than a 5% risk of chronic infection.

Adults may come into contact with the virus if they travel overseas or if a family member is infected, so high risk adults (including immigrants from Africa and Asia) may be appropriate candidates for immunization. In some parts of the world HBV infection prevalence is as high as 10%, so almost every family has some member with the virus.

Dr. Maddrey said the efficacy of vaccination is demonstrated by the experience in Taiwan. In 1984 the carrier rate for hepatitis B surface antigen (HbsAg) was 9.8% but dropped to 0.5% in 1999. The incidence of hepatocellular carcinoma dropped by half from 1981 to 1986 versus 1990 to 1994 (0.7 per 100,000 to 0.36 per 100,000, respectively). The remaining cases may have been caused by hepatitis C virus (HCV), for which there is no vaccine.

Risk of Liver Cancer

The cumulative survival of patients with HBV is related to the severity of the disease. At the end of an 80-month period, about 98% of HbsAg carriers were alive, compared with about 93% of patients with chronic disease. However, only about 55% of patients with cirrhosis survived that long. Dr. Maddrey said the risk of HCC is directly related to a patientÃ¢â‚¬â„¢s viral load, and the risk is even greater with a high viral load in the presence of cirrhosis.

Ã¢â‚¬Å“Everything weÃ¢â‚¬â„¢re doing here is trying to prevent progression [of cirrhosis],Ã¢â‚¬Â he said. The best ways to achieve that goal are to detect the disease early and to knock down the viral load long-term with drugs, possibly for the patientÃ¢â‚¬â„¢s entire life. The liver has a great ability to regenerate, but like a healthy liver, a cirrhotic liver is working all the time doing normal bodily functions, Dr. Maddrey said, Ã¢â‚¬Å“and working people donÃ¢â‚¬â„¢t have enough time to reproduce all the time.Ã¢â‚¬Â Cell regeneration is a good thing he said, but constant cell turnover as a sick liver tries to regenerate can cause errors in DNA replication, leading to HCC.

Effective Therapy of HBV

Effective antiviral therapy for HBV infection exists. It can provide potent sustained suppression of viral replication and prevent emergence of resistant virus.

The hallmark of chronic HBV infection is the presence of HBsAg. The next value to check is the ALT level. A normal level indicates an inactive HBsAg carrier; an elevated ALT indicates chronic hepatitis. Further differentiation of chronic hepatitis comes from the Ã¢â‚¬Å“eÃ¢â‚¬Â antigen, HBeAg. Depending on whether HBeAg is positive or negative, different approaches with the same drugs will be used. A negative HBeAg with a positive anti-HBe titer indicates a positive immune response that has cleared the virus to a large degree.

Finally, the viral load, or HBV DNA level is important. Ã¢â‚¬Å“That turns out to be a relatively magic number in the hepatitis world,Ã¢â‚¬Â Dr. Maddrey advised. HBV DNA
If the HBV DNA >105 and the ALT are elevated, he would biopsy the liver. He recommended against referring to a radiologist because Ã¢â‚¬Å“they use very thin needles and you might as well not stick the liver unless you are going to get something you can use out of it,Ã¢â‚¬Â he said. Ã¢â‚¬Å“But other than that I donÃ¢â‚¬â„¢t have an opinion.Ã¢â‚¬Â He recommended referring to a hepatologist or a gastroenterologist, or, not withstanding his previous statement, to a radiologist if the referring physician can persuade the radiologist to use a larger needle.

The three drugs that Dr. Maddrey uses are Epivir-HBV (lamivudine, GlaxoSmithKline), Hepsera (adefovir, Gilead), and Baraclude (entecavir, Bristol-Myers Squibb). They are all orally administered, tolerated well, and can be used in the long term. He would not use interferon, an injectable drug with significant side effects. Several studies with Epivir show long term viral suppression, which leads to histologic improvement. Unfortunately, viral mutation occurs after six months of therapy, and HBV DNA and ALT levels increase.

At that point, Dr. Maddrey switches patients to Hepsera, or possibly to the newer Baraclude. Ã¢â‚¬Å“They are very good, and they are very safe, and I can show you that they donÃ¢â‚¬â„¢t have this same mutational risk in the same time frame,Ã¢â‚¬Â he noted. Viral mutations with Hepsera show up in the second or third year, and they have not yet been seen with Baraclude. Hepsera has been shown to continuously suppress ALT and HBV DNA levels out to 48 weeks of therapy.

Contrary to past thinking, Dr. Maddrey said, many hepatologists now believe that cirrhosis can be reversible Ã¢â‚¬â€œ not back to a normal state but with a reduction in fibrosis. The key to improving long term outcomes in hepatitis B is maximal suppression of HBV replication. He offered these treatment recommendations:

For HBeAg-positive patients Ã¢â‚¬â€œ
HBV DNA HBV DNA Ã¢â€°Â¥105 and normal ALT: follow, or base treatment on liver biopsy results
HBV DNA >105 and elevated ALT: treat

For HBeAg-negative patients (more difficult to achieve success; HBV DNA cut off is 104)
HBV DNA HBV DNA Ã¢â€°Â¥104 and normal ALT: results uncertain; base decisions on liver biopsy
HBV DNA >104 and elevated ALT: treat

Action Points

  • Point out the need for HBV immunization to patients intending to travel to Africa or Asia, and to patients who have an infected family member.