Viral suppression is key in hepatitis-B treatment
Interferon therapy achieves sustained response beyond treatment cessation
The primary goal of hepatitis-B treatment is to bring down HBV DNA to low or undetectable levels to prevent cirrhosis and hepatocellular carcinoma. This, according to two specialists, should be achieved along with secondary end points: to normalize ALT, induce HBeAg loss, develop antibodies, and improve liver histology.
Dr. Wasim Jafri, chief of gastroenterology at the Aga Khan University in Karachi, Pakistan, and Dr. Jose Sollano Jr., professor of medicine at the University of Santo Tomas Hospital, discussed how these can be achieved with interferon therapy. The two spoke in a recent symposium organized by Getz Pharma and the Hepatology Society of the Philippines.
"Clearly, we all recognize that the suppression of viral replication is essential in the control of chronic hepatitis-B infection," said Sollano. Among HBeAg-positive patients, this viral suppression with seroconversion is responsible for reducing the associated risks leading to hepatocellular carcinoma and eventually increasing the event-free survival.
Treatment guidelines
The 2007 Guidelines of the American Association for the Study of Liver Diseases (AASLD) recommend interferon other than adefovir and entecavir for HBeAg-positive patients with >20,000 IU/mL and ALT >2xULN (Lok et al., 2007), as does the US algorithm by Keefe et al. (2006). HBeAg-negative patients are to be given the same, but for more than six months.
For compensated cirrhosis, however, the AASLD does not recommend interferon therapy due to possible decompensation, although Keefe suggests using it in very early cirrhosis for a limited duration. The Asian Pacific Association for the Study of the Liver 2005 guidelines also recommend interferons for HBeAg-positive chronic hepatitis B (CHB) for four to six months along with nucleoside analogs, with an increase in treatment duration (one year) for HBeAg-negative patients.
Interferon efficacy
A metaanalysis of 15 randomized controlled trials using interferon five to 10 MIU thrice weekly for four to six months showed that 37 percent of HBeAg-positive patients responded to the treatment, with HBV DNA at < 106 copies/mL, 33-percent loss of HBeAg, and eight-percent loss of HBsAg (Wong et al., 1993). HBV DNA reduction was seen in 28 percent of HBeAg-negative cases, while ALT normalization was seen in 29 percent. Surface-antigen loss, however, was seen only in three percent.
After continuing interferon therapy for another four months (on top of four-month standard therapy) among "nonresponders," Janssen et al. (1999) found a further increase in seroconversion (28 percent, up from 12 percent). "You pull the bars up if you actually prolong immunomodulator therapy, even in the conventional interferon-treated patients," said Sollano.
Extending treatment with a nucleoside analog to two years showed a success rate of 30 percent, but seroconversion rate with interferon was 33 percent, even when the subjects had already been off therapy for a year. Over time, interferon therapy showed a linear seroconversion trend well beyond the four-month (finite) duration of treatment, compared with four years of dose-driven sustained antiviral therapy. These seroconversion rates achieved with interferon would lead to fewer relapses than with lamivudine treatment.
Said Sollano: "It is important to have virus suppression so that your immune system reacts and gets a seroconversion. Hopefully, the HBeAg seroconversion does not happen alone. It should be that when you seroconvert, you have very low levels of the virus so that the remaining virus in the body or liver does not cause more damage. And we know that when you have HBsAg or HBeAg seroconversion or loss, this translates into a better outcome for patients."
Interferon for HBeAg-negative CHB
While there are no large randomized controlled trials involving interferon use in HBeAg-negative CHB, Lampertico et al. (1997) showed ALT normalization and DNA suppression in 33 percent of their patients, compared with only 22 percent in several small studies, using six to 10 million units of interferon for two years.
Overall, the long-term benefit of interferon therapy is in achieving HBsAg clearance in five to 13 percent of treated patients. Over five to seven years, the seroconversion increases to 45 percent. Among patients who had HBsAg loss, more than 90 percent eventually seroconvert to anti-HBs.
Marcellin et al. (2006) showed that this durability of response was maintained in more than 95 percent of initial responders even after two years, as evidenced by undetectable virus levels in the blood. In effect, patients will not need continuous daily antiviral therapy, thus avoiding the possibility of viral resistance associated with nucleoside analogs. M
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