Current Evidence and Recommendations
Lamivudine, adefovir dipivoxil, entecavir, telbivudine, and tenofovir disoproxilfumarate are NAs registered for the treatment of chronic hepatitis B. All NAs are given once daily per oral at a fixed dosage (Table 1). Because all NAs are excreted mostly or fully by the kidneys, dose adjustment is required in patients with estimated glomerular filtration rate below 50 mL/min/1.73 m2. Data on the use of NAs in patients with estimated glomerular filtration rate below 30 mL/min/1.73 m2 or on dialysis are scarce.
Owing to differences in genetic barrier, current guidelines recommend entecavir and tenofovir as preferred first-line NAs for the treatment of chronic hepatitis B.[12–14] Entecavir is registered to be used at a dose of 0.5 mg daily for treatment-naïve patients and 1.0 mg daily for lamivudine-refractory patients. It should be noted that entecavir was given at 1.0 mg daily during extended follow-up of the original registration trial. However, real-life cohort studies suggest that entecavir 0.5 mg daily is not associated with increased risk of drug resistance and treatment failure in treatment-naïve patients.[40,41] Although entecavir at a dose of 1.0 mg daily is superior to continuing lamivudine in lamivudine-refractory patients, up to 50% of such patients develop entecavir resistance in 5 years; therefore, this cannot be recommended. This is due to partial cross-resistance between lamivudine and entecavir.
Tenofovir is given at a dose of 300 mg daily. In the follow-up study of the registration trial, no patient developed tenofovir resistance in 5 years. The rate of tenofovir resistance may have been underestimated because patients with HBV DNA above 400 copies/mL at week 72 were allowed to add emtricitabine as a fixed dose combination tablet (Truvada®, Gilead, Foster City, CA). However, post hoc analysis suggests that resistance should be very rare, even if the patients were continued with tenofovir monotherapy.
In most countries, tenofovir is more commonly used for the treatment of lamivudine resistance or patients exposed heavily to different NAs. Because of different mutational pathways, it comes as no surprise that tenofovir is a highly effective treatment for lamivudine resistance. What is less certain is its efficacy in patients with adefovir resistance. In vitro studies showed that the rtA194T mutation confers partial resistance to tenofovir. Around 60 to 90% of adefovir-experienced patients can achieve undetectable HBV DNA with tenofovir and/or emtricitabine treatment (Table 2).[44–48] A retrospective study showed that only 33% of patients with adefovir resistance at baseline had undetectable HBV DNA in 1 year, but the findings were not confirmed by others.[45,46,48] The inconsistent use of add-on emtricitabine in different studies makes it difficult to determine the role of combination treatment in this context.
NAs are largely safe. No specific side effects are associated with lamivudine and entecavir. Adefovir and tenofovir may damage renal tubular cells and cause nephrotoxicity, though the risk appears small and the effect is mostly reversible. Tenofovir treatment has been reported to cause greater loss in bone mineral density in patients infected with human immunodeficiency virus. The same phenomenon has not been reported in patients with chronic hepatitis B.
During NA treatment, patients should be monitored for drug adherence, resistance, and side effects. The most important monitoring test for treatment efficacy and drug resistance is HBV DNA. When a drug with low genetic barrier to resistance is used, undetectable HBV DNA must be maintained to prevent the development of drug resistance. For drugs with high genetic barrier to resistance, complete viral suppression appears less important.[6,40] In any case, drug adherence should be enquired in case of incomplete virological response.
Patients on telbivudine treatment should be monitored for muscle symptoms. The role of creatine kinase levels monitoring dubious, as most patients with elevated creatine kinase do not have myopathy. Patients treated with adefovir or tenofovir should have renal function and phosphate level monitoring. There is currently insufficient data to support routine bone mineral density assessment.
Combination treatment may be in the form of NA plus interferon or using two NAs together. In the pivotal peginterferon studies, although the combination of peginterferon and lamivudine resulted in greater HBV DNA reduction during treatment, there was no meaningful advantage over peginterferon monotherapy in ALT normalization, HBeAg seroconversion, posttreatment HBV DNA level, and histological improvements.[18,19,21,22] Studies combining peginterferon and more potent NAs (entecavir and tenofovir) are under way.
De novo combination of lamivudine and adefovir does not improve viral suppression over lamivudine alone, although this reduces, but not abolishes lamivudine resistance. Furthermore, adefovir resistance was not reported in this study. Combining telbivudine and lamivudine again does not achieve greater reduction in HBV DNA than telbivudine monotherapy, but may even increase the risk of telbivudine resistance. This suggests that NAs with the same resistance pattern should not be combined.
Research in this disappointing field is reignited when new and potent NAs become available. Combination of entecavir and tenofovir is highly effective in patients with multidrug resistance, though it is uncertain if tenofovir monotherapy may be as good. In a recent clinical trial, 379 treatment-naïve patients were randomized to receive entecavir monotherapy (n = 186) or entecavir plus tenofovir (n = 198). By week 96, 76% in the monotherapy arm and 83% in the combination arm had HBV DNA below 50 IU/mL (p = 0.088). In a post hoc subgroup analysis, combination therapy was superior to entecavir monotherapy in patients with positive HBeAg and baseline HBV DNA over 8 log IU/mL. However, because the subgroup analysis was not planned a priori, the findings can only be considered exploratory and have to be confirmed in another study focusing on patients with high viral load. The efficacy of tenofovir monotherapy and higher dose entecavir (1.0 mg) has to be evaluated before combination therapy can be recommended for this group of patients.
Although NAs are largely safe and effective during long-term treatment, patients may wish to stop for convenience and financial reasons. Currently guidelines recommend that it is possible to stop NAs in HBeAg-positive chronic hepatitis B after sustained HBeAg seroconversion and undetectable HBV DNA for at least 6 to 12 months.[12,13,14] In HBeAg-negative cases, the risk of virological relapse is high. NAs can only be stopped after HBsAg seroclearance. The Asian Pacific guideline is unique in recommending stopping NAs after at least 2 years of treatment if HBV DNA remains undetectable for at least three visits 6 months apart. However, observational studies consistently showed that a significant proportion of patients would still have relapse despite fulfilling the guideline criteria.[8,10]
Currently, there is limited knowledge on the predictors of virological relapse. For HBeAg-positive disease, a longer duration of consolidation antiviral therapy after HBeAg seroconversion can reduce the chance of relapse. In a small retrospective study of 53 HBeAg-negative patients who stopped lamivudine after treatment for 12 to 76 months, all patients who had HBsAg below 100 IU/mL and decline of > 1 log continued to have suppressed HBV DNA 12 months later. In contrast, all patients with HBsAg above 100 IU/mL and less than 1 log decline developed virological relapse. The results have to be replicated and tested in other NAs in a prospective manner before they can be applied in the clinic.
Semin Liver Dis. 2013;33(2):122-129. © 2013 Thieme Medical Publishers