Hepatitis B treatment strategies

Hepatitis B virus (HBV) is a transmissible, fibrogenic and oncogenic virus for which there are a continually expanding number of well-tolerated treatment options. The decision to treat patients with chronic hepatitis B (CHB) should be based on rapidly emerging data and knowledge of the clinical consensus regarding CHB. There is no way to predict reliably which patients will experience the sequelae of CHB – complications of cirrhosis and hepatocellular carcinoma (HCC) – or time-to-onset of these clinical endpoints. Recent information about the predictive value of alanine aminotransferase (ALT) levels and viral load prompts reconsideration of established guidelines. New antiviral medications, alone or in combination, may alter the risk/benefit ratio of treatment for certain CHB groups. When HBV DNA is detectable in serum, clinicians should aim for complete viral suppression rather than wait for a rise in viral titer, signs of hepatic decompensation or HCC.

Current US guidelines call for treatment of chronic HBV infection with interferon alfa-2b lamivudine or adefovir when the ALT values are more than twice the upper limit of normal and HBV DNA levels exceed 10 copies/ml. There are several reasons for the conservative nature of these recommendations. ALT as a marker of necroinflammation and response to treatment is used to identify those patients who might demonstrate the best response to, and therefore benefit most from, antiviral therapy. Secondly, many epidemiologic and treatment studies, until recently, used branched or hybrid DNA assays to quantify viral load. This excluded a considerable number of patients with serological evidence of low-level viral replication. Finally, side effects of interferon therapy, rapid emergence of viral resistance to lamivudine and lack of long-term experience with newer therapeutic agents led to a more restrictive selection of treatment candidates. Some of these agents led to a more restrictive selection of treatment candidates. Some of these agents include entecavir, a new highly active HBV drug approved in early 2005, peginterferon alfa-2a, approved later the same year, telbivudine, an investigational L-nucleoside expected to be approved in 2006, and both tenofovir and emtricabine, HIV medications that appear to have good activity against HBV. Present guidelines do not include any of these agents.

Clinicians should not use rigid ALT threshold levels as a guide to initiate antiviral treatment. ALT levels fluctuate significantly in CHB such that even patients who repeatedly have normal measurements are at risk for cirrhosis and HCC. ALT reflects not only damage caused by HBV, but the innate host immune response and possibly other insults, such as alcohol use and steatosis form one or more metabolic conditions common in the general population. In fact, some authors question "normal" ALT values and suggest lower limits due to the prevalence of live disease in the United States. In some groups of CHB patients, ALT levels do not predict histological activity, and at least 25 percent of patients with normal ALT levels have evidence of inflammation on biopsy. The outcome of some trials indicates that ALT levels predict antiviral response. However, this does not preclude need for treatment based on viral titer, albeit low, particularly with the introduction of newer and effective therapeutic agents.

Treatment candidacy of CHB based on HBV DNA cutoff implies that there is a safe level of viremia. Conversely, recent long-term, prospective data from Taiwan shows a "dose-response" relationship between HBV DNA titers and development of HCC in HBeAg-negative patients. Multiple regression analyses showed that patients with an HBV DNA titer of 10-10 copies/ml had a hazard ration of 2.6 for development of HCC when accounting for age, alcohol use, ALT and the presence of cirrhosis. Titers below 10 showed a non-significant trend toward higher incidence of HCC. The authors state that HBV DNA titer was also related to the presence of cirrhosis a baseline, although they do not report the data. There are no studies to date that relate viral load to progression of cirrhosis, complications of cirrhosis or HCC incidence in HBeAg-positive patients. We do no know, however, that detection of HBeAg in and of itself is associated with a 60-fold increase to the risk of HCC. The distinction between HBeAg-negative and HBeAg-positive patients is more important to determine the endpoint of therapy than the indication for treatment.

The available data justify treatment of any patient with the presence of HBsAg, without anti-HBs and with a detectable serum HBV DNA. Patients without HBeAg-negative without HBV DNA should receive careful monitoring with biochemical and sensitive HBV DNA assays every three to six months, as these values can significantly fluctuate while patients remain asymptomatic. In the absence of biochemical evidence of inflammation (i.e. ALT<twice the upper limit) and when clinicians are hesitant to initiate treatment for HBV DNA titers less than 10-10, patients undergo liver biopsy to rule out histologic damage, another indication for antiviral treatment.

Endpoints and possible risks of therapy should be considered upon initiation of treatment. Group describe why the high rate of viral resistance to lamivudine should strongly discourage clinicians from using it as initial monotherapy in any patient population. Peginterferon could be considered for monotherapy or in combination with adefovir, but is limited by its adverse effects and patient acceptance. The impressive antiviral effects and resistance profiles of adefovir and entecavir should make either of them first-line agents for both HBeAg-positive and HBeAg-negative patients, as well as cirrhosis HBV patients. Peginterferon alfa-2a is an option in no cirrhotic HBeAg-positive patients but is contraindicated in cirrhotics. With the initial use of these agents, the goal of therapy should be complete suppression of HBV DNA to mitigate the emergence of resistant viral species. HBeAg-positive patients who seroconverst should be treated for six additional months (but no less than one year) and then followed closely for relapse. Other patients should be treated for 24 weeks and, if there is persistent viremia at the end of this time, treatment should continue for an additional six months with both adefovir and entecavir. In refractory cases, emtricabine can be added or tenofovir and entecavir can be combined (the combination of adefovir with tenofovir should be avoided due to overlapping resistance mutations and potentially additive toxicities). "Watchful waiting" should give way to aggressive suppression of virus as the goal of HBV treatment. There should always be a healthy respect for resistance planted in the back of our minds as we plan HBV therapy.

The high cost of caring for patients with complication from CHB warrants an aggressive approach to treatment, especially in the clinical areas where there are few or no data. ALT levels should not be used to determine the need for treatment. Patients with low HBV DNA levels may be referred for biopsy or may be treated directly. All HBV cirrhotics should be managed with aggressive treatment. Lamivudine should not be used as initial monotherapy in any patient group, and combination therapy should be liberally utilized with the goal of complete viral suppression and avoidance of drug resistance. Novel anti-HBV therapeutic agents, as well as viral and host factors, should be studied to delineate further the pathogenesis of this complex disease.