An Old Article but with Clear Explainations...

liver411

Better hepatitis drugs draw nearer

Human ingenuity continues to battle against viral adaptability.

16 February 2001

JOHN WHITFIELD



Short-term use of the only approved oral treatment for hepatitis B -- the drug lamivudine -- rarely clears the virus. After prolonged use the virus usually evolves drug resistance. Researchers have now deduced how this resistance works, and tested new drugs that may help to combat it1.



The problems of resistance and effectiveness have created a pressing need for more, better and different treatments for hepatitis B, says Raymond Schinazi, of Emory University's School of Medicine in Atlanta, Georgia, one of the new study's co-authors. "About 8-10 million individuals who can afford anti-hepatitis B drugs are not taking any medication, and are waiting on the sidelines for a potential cure to emerge from the research labs," he says.



About 5-10% of cases of hepatis B become chronic, leading to permanent liver damage and an increased risk of cirrhosis and liver cancer. Worldwide, some 400 million people carry the virus, and the World Health Organization estimates that it kills one million each year.



Lamivudine jams the enzyme that the hepatitis B virus uses to copy its DNA. But mutations in this DNA-manufacturing enzyme allow the virus to sneak past the drug.



Schinazi's team found that both the mutations that confer resistance also reduce the virus's ability to replicate -- to less than a fifth that of the 'wild-type' strain. These two mutations affect the site in the enzyme where the building blocks of DNA are assembled.



But the researchers also found that a change to another part of the enzyme combined with either of these mutations restored roughly two-thirds of the resistant virus's unmutated virulence. About three-quarters of lamivudine-resistant mutants in hepatitis B patients fall into this 'double mutant' category.



The team exposed six different strains of hepatitis B -- the unmutated original, three bearing single mutants, and two double mutants -- to a battery of 11 different antiviral agents. They conducted their tests in a culture of liver cells.



Several of the drugs proved more effective than lamivudine. Two of them -- adefovir and entecavir -- were effective against all the various mutant strains, though in much higher doses than lamivudine.



"These are promising drugs," says Robert Perrillo, head of gastroenterology and hepatology at the Ochsner Clinic, New Orleans, although he adds that long-term use of adefovir may lead to kidney damage. Entecavir has already shown some effectiveness against hepatitis B (of unknown resistance) in animal and human trials.



Eventually a combination of therapies could be used to suppress the virus and stave off resistance, similar to the treatment for HIV.



A vaccine for hepatitis B already exists but the benefits of vaccinating virus-carriers are controversial, says Perrillo. Schinazi believes that if viral loads could be reduced enough, vaccination might end the need for costly multi-drug treatment. "This is a very exciting approach," he says.

  

   

References

Ono-Nita, S. K. et al. The polymerase L528 mutation cooperates with nucleotide binding-site mutations, increasing hepatitis B virus replication and resistance. Journal of Clinical Investigation 107 (2001).





?Nature News Service / Macmillan Magazines Ltd 2001



  

awei

hehe Adefovir Entecavir and Alkovir(mentioned elsewhere) Good news! Thanks a lot! i want to know more about these things! [ This page was updated by awei on 2001-12-14.17:59:57. ]