Antiviral T-cell responses and therapy in chronic hepatitis B.

Hepatitis B virus (HBV) infection is a major global health concern and is the most common cause of chronic liver disease worldwide. It is estimated that there are between 350 and 400 million individuals with chronic HBV infection. For many of these individuals, the current forms of therapy are suboptimal. The first problem is the limited lack of efficacy. Many patients either will not respond or will fail to have a durable sustained virologic response after treatment with either of the two available classes of agents, interferon-a and the nucleos(t)ide analogs (lamivudine or adefovir). Interferon alone, while effective in a subset of patients (33% for treated patients compared with 12% of untreated patients with respect to loss of HBeAg) [1], is notable for the substantial toxicity suffered by many patients. Lamivudine and adefovir, while better tolerated, similarly offer rates of HBeAg seroconversion in the range of 12–30% [2–6]. Since patients without virologic suppression can have substantial benefits in terms of histologic improvement [5–7], therapy with either lamivudine or adefovir is often continued so long as the patient has evidence of continued virologic suppression and a biochemical response to therapy. This leads to the second major problem, which is that long term use of lamivudine is accompanied by a progressive risk of viral resistance conferred by mutations in HBV polymerase [8,9]. The percent of patients with such resistance mutations increases with the duration of nucleoside therapy, from 14% at 1 year to as high as 38 and 67%, respectively, after 2 and 4 years [4]. Resistance to adefovir was recently reported as well [10], suggesting that neither agent alone will be successful as long term monotherapy. Both agents are also expensive, and particularly in developing nations there is a need for a less expensive therapy that is of short duration. New strategies may improve the efficacy and reduce the emergence of drug resistance. Drawing from the lesson of antiretroviral therapy of HIV, some studies have addressed the possibility of combination therapy. However, combinations of interferon and lamivudine to date have yielded mixed results, perhaps due to variations in the patient selection [11–13]. Although other drugs are in phase I/II trials, no agents have yet provided a highly durable sustained virologic response in the majority of treated patients. Therefore, it is important to understand the mechanisms involved to obtain long-lasting viral suppression and disease remission. The immune system appears to play a key role in the course and outcome of hepatitis B. In patients with self-limited acute hepatitis B, both CD4 þ T-helper and CD8 þ cytotoxic T-cell (CTL) responses to viral antigens are strong and multispecific, whereas these responses are weak or undetectable and narrowly focused in chronically infected patients [14]. The immune system also appears to be important for maintaining recovery. In patients with spontaneous resolution of HBV infection these strong and broad antiviral T-cell responses are usually maintained for decades after clinical recovery [15,16]. Patients with either inactive or resolved hepatitis B can experience reactivation with return of high levels of HBV antigens and DNA upon immunosuppression [17], emphasizing the importance of virus-specific immunity in maintaining control of viral replication. It is commonly held that the immune response is also important to response to treatment, at least as defined by HBeAg seroconversion. It has been known for years that spontaneous elevations in serum alanine aminotransferase (ALT) during chronic HBV infection may be followed by HBeAg seroconversion, which has been presumed to represent the augmentation of HBV-specific immunity. Similarly, pretreatment ALT values are predictive of HBeAg seroconversion, with a higher baseline ALT associated with a higher likelihood of such a response [18]. This suggests that patients with a stronger endogenous immune response against HBV have a better response to antiviral agents. Moreover, CTL directed to specific epitopes of the HBV, rarely detected in chronic hepatitis B carriers, have been noted to appear in the peripheral blood