The results of this study showed a non-significant virologic response in the lamivudine treated group compared to the control group (1 of 13, 7.6% vs. 1 of 33, 3.0%, p=0.502). The results, while not encouraging, are interesting and offer some practical information for the care of these patients. Despite the fact that the standard period of lamivudine treatment is at least one year, the reason we utilized a shorter of period of treatment is to observe whether or not suppression of serum HBV DNA and resultantly, diminished viral load, might induce any antiviral response in highly replicative patients with chronic HBV infection. Another reason is to avoid the risk of development of YMDD mutation, which is usually observed after six months of therapy. Nevertheless, there is still an actual risk of it being detected after three months of therapy. Moreover, a short course of therapy in these patients would be a valuable strategy (in terms of costs and case of administration). The main limitation of the study was our inability to perform immunological studies during and after the lamivudine therapy, which would have provided some important clues.
A recent study found that whereas the relative risk of hepatocellular carcinoma (HCC) among men with HBsAg alone was 9.6 compared to those without HBsAg, the risk increased to 60.2 when they were positive for both HBsAg and HBeAg (12). A more interesting finding in this study was that the adjusted relative risk for those who were seropositive for HBsAg and HBeAg and who had a normal serum alanine aminotransferase level was 61 (14). There is also data to suggest that survival among cirrhotic patients is lower among those who are HBeAg positive (15). Although these patients have a lower virologic response to either therapy, one has to raise the question whether or not these patients should be treated to reduce their substantial risk for HCC based solely on the detection of HBeAg (16). Moreover, treatment of hepatitis B patients in the immune-tolerant phase is important because it may eradicate the virus from the body before significant liver damage is caused by inflammation when the body’s immune system attempts to clear the virus. Thus, facing an over 60-fold increased risk for HCC despite normal aminotransferase levels, therapy should not be withheld from these patients for ethical reasons irrespective of their chance of virologic response (17).
There are millions of patients worldwide, especially in Asia, with perinatally acquired infection, who show normal aminotransferase levels, but more immune-tolerant patients have been encountered in other parts of the world, including the Eastern Mediterranean and the Middle East regions. These non-Asian patients have the same disease specifics (18, 19) and the same treatment difficulties as the Asian patients. Of particular concern is the fact that until now no drug therapy has actually been effective in achieving a sustained response against the hepatitis B virus in the immune-tolerant phase.
There are some evidences to suggest that in patients with HBV infection in the immune- tolerant phase, the response to antiviral therapy whether with lamivudine or interferon is closely related to the serum ALT values. The preliminary results of the study of Dienstag et al. suggested that a three-month course of treatment could induce prolonged suppression of HBV DNA in only 19% of chronic hepatitis B patients (9). Another three-month lamivudine and a famciclovir study also showed that sustained HBeAg seroconversion and/or HBV DNA suppression were more likely in patients with initially high ALT levels (9, 20). In the study of Lai (21), a four-week course of 25 to 300 mg lamivudine was effective in suppression of 94% to 98% of serum HBV DNA in Chinese HBsAg carriers, but with no change in the HBeAg status. HBeAg seroconversion rate after one year of lamivudine treatment is also less than 10% in patients with pre-treatment ALT levels less than two times normal (3, 22). Also, in a recent study of four drug trials, after one year of therapy, the HBeAg loss was 0% (0 of 25 patients) with placebo and 4% (2 of 55) with lamivudine in patients with ALT values <1x the ULN (23). Several studies have suggested that pre-treatment with a short course of corticosteroid may augment the response to subsequent interferon therapy (11, 24). But patients who have persistently normal ALT levels are unlikely to benefit from interferon therapy even with prednisone priming (10, 11, 25, 26). More recent treatment modalities, such as therapeutic vaccination with a preS2/S HBV vaccine (27, 28) and thymosin-alpha1 and famciclovir combination therapy (29), did not have favorable results. Thus, virtually no treatment has been able to effectively cure hepatitis B in patients in the immune-tolerant phase of the viral infection.
It is important to note that ALT levels went up in the treated group. Although there was no significance, this is clearly due to the small sample size. In our study, increase in biochemical activity after lamivudine therapy resulted in three patients: in one with sustained virologic response, in another with ongoing chronic active hepatitis and in a third with temporarily elevated liver enzymes. The cause of the increase in ALT levels in these patients remained unexplained. The most probable explanation might be lamivudine-induced immune reactivity to the infected liver cells. It can also be speculated that lamivudine has partial effect in restoring T-cell responses in chronic hepatitis B. It was shown that lamivudine treatment in chronic hepatitis B can restore cytotoxic T lymphocyte (CTL) reactivity, making CTL susceptible to exogenous stimulation. Both HBV-specific cytotoxic T cell activity and CD8+ T cell frequency were significantly augmented by a 12-month course of lamivudine therapy (22). It has also been known that lamivudine can overcome CTL hyporesponsiveness (30), and this may serve as a bridge to subsequent HBV-specific immune therapies, which may cause changes in the balance between viral replication and the host’s immune response in favor of eradication of chronic HBV infection.
It is therefore likely that lamivudine may have to be administered on a long-term basis. This is feasible because unlike interferon, lamivudine is taken orally once daily and is associated with few adverse events. However, as with all antiviral agents, there is the possibility of escape mutation(s) with prolonged treatment.
In conclusion, in this pilot study, the primary outcome as virological response at month 12 was not affected by the lamivudine treatment. It was observed that a three-month course of lamivudine therapy has a partial and temporary effect on suppression of HBV DNA, probably because of the short course of therapy. A short course of lamivudine monotherapy for patients in the immune-tolerant phase of HBV infection has no far-reaching effect on virologic response. Whether permanent suppression of HBV DNA can be achieved in HBsAg carriers by long-term treatment with lamivudine awaits further controlled trials. But the fact that therapy will inevitably lead to the emergence of the YMDD mutation together with the occurrence of an active liver disease is a limitation for the prolonged therapy. Thus new and safe modalities of therapy are needed for these asymptomatic but viremic patients.