Lamivudine (LAM), adefovir (ADV), entecavir (ETV), and telbivudine are 4 approved nucleoside or nucleotide analogs for treating chronic HBV infection. These drugs have inhibitory effects on HBV polymerase/reverse transcriptase activity but not directly on covalently closed circular DNA (cccDNA) synthesis, thus prolonged therapy is usually required to ensure maintained or sustained HBV suppression. LAM was the first drug to have been approved and has been used extensively for more than a decade with an excellent safety record. However, LAM resistance has become a serious clinical challenge because its incidence increases with increasing duration of therapy, and it is associated with virologic/biochemical breakthrough, hepatitis flare, and even hepatic decompensation or mortality.1 ADV and ETV are associated with a delayed and low incidence of resistance in treatment-naïve patients; both drugs have antiviral activity against LAM-resistant HBV, although ETV displays some level of cross-resistance.2
Clinical studies show ADV monotherapy or ADV add-on LAM combination therapy is effective in both compensated and decompensated patients with LAM resistance.3–5 Among these studies, one small randomized controlled trial showed that 1 year of ADV monotherapy was as effective as ADV add-on LAM combination therapy. Although none of the patients experienced a virologic rebound during ADV monotherapy or combination therapy, elevated serum ALT levels of 5 to 10 times the upper limit of normal occurred within 12 weeks in 7 (37%) of the 19 patients who were switched to ADV monotherapy; none of these ALT increases were associated with increases in HBV-DNA.5 Probably on the basis of this finding, it was recommended that LAM therapy be continued for 2 to 3 months to minimize the risk of ALT flare during the transition to ADV therapy.6 However, subsequent studies in Asian patients with compensated and decompensated liver cirrhosis show that switching to ADV monotherapy is not associated with an increased risk of ALT flare and is a reasonably safe and cost-effective approach.7, 8 The strategy of switching to ADV monotherapy was therefore included in the 2005 Asian-Pacific guidelines for patients with LAM resistance.9 Shortly afterward, the alarming problem of ADV resistance emerged. Case series studies have shown that, compared with LAM-naïve patients, ADV resistance occurs earlier and more frequently (up to 18% at 48 weeks and 25% at 24 months) in patients with LAM resistance who were switched to ADV monotherapy.10–12 In contrast, no ADV resistance was demonstrated during ADV add-on LAM combination therapy for up to 2 years.11, 13
In this issue of HEPATOLOGY, Rapti et al.14 report their results of a randomized controlled study of ADV therapy in 42 patients with genotype D HBV infection who had genotypic LAM resistance with virological and clinical breakthrough. The patients were randomized (1:2) to receive 10 mg/day ADV monotherapy or ADV add-on LAM combination therapy for a median duration of 37.5 (9-53) months. No ALT flares were recorded after either switching to or adding on ADV to LAM. Therapeutic efficacy, in terms of undetectable HBV-DNA and ALT normalization in the first 12 months of ADV therapy, was similar between the 2 regimens. Patients with a baseline HBV-DNA level < 107 copies/ml experienced significantly earlier and more frequent decline of serum HBV-DNA to undetectable levels. Of the 7 patients with positive samples by PCR assay during combination therapy, genotypic LAM-resistant strain HBV persisted in all patients at month 12, in 4 at month 18, in 3 at month 24, and in 2 at month 36. No evidence of ADV resistance was detected in the 28 patients undergoing ADV add-on LAM combination therapy during a median duration of 40 (9-53) months. In contrast, ADV-resistant mutation was detected in 3 patients (21%) upon viral/biochemical breakthrough at 15 to 18 months after switching to ADV monotherapy. Although the number of patients in this study was relatively small, the randomized controlled study design and sufficiently long and careful follow-up evaluations provide solid evidence supporting the notion that ADV add-on LAM combination therapy prevents or delays ADV resistance. With these findings, switching to ADV monotherapy is clearly no longer an appropriate rescue therapy for LAM resistance.
Of note is that the study by Rapti et al.14 enrolled patients with virological and biochemical breakthrough. Half their patients had a serum HBV-DNA level > 107 copies/ml at the onset of ADV therapy, a level found to be associated with insufficient virological response. Thus, the efficacy in terms of decline of serum HBV-DNA to undetectable level by sensitive PCR assay is insufficient even in patients who received combination therapy, as was demonstrated in earlier case series studies.10, 13, 15 This is consistent with the observation of Lampertico et al.13 that HBV was more rapidly and consistently suppressed in patients starting ADV early during the phase of genotypic resistance than in patients starting ADV later during the phase of phenotypic resistance (median HBV-DNA = 7.3 log10 copies/ml). These findings clearly indicate that ADV should be added to LAM as soon as genotypic resistance is detected when the serum HBV-DNA level usually has not increased to a level too high to be suppressed successfully.
Some problems associated with ADV add-on LAM combination therapy deserve attention. It has been shown that maintained LAM therapy provides a continuing selective advantage to a LAM-resistant strain over wild-type HBV and that LAM-resistant HBV may persist in the majority of patients after 1 year of ADV add-on LAM combination therapy.4, 5, 15 In addition, compensatory mutations may emerge and restore replication fitness of the virus during continuing LAM therapy.1 The study by Rapti et al.14 has also shown that a LAM-resistant strain may persist up to 36 months in patients on combination therapy, and is a possible reason for suboptimal viral response. Perhaps the potency of ADV at the licensed, but actually suboptimal, daily dose of 10 mg is insufficient to suppress LAM-resistant strain HBV. This notion is supported by a study showing the superiority of 300 mg tenofovir treatments, another acyclic nucleotide analog, to 10 mg ADV in patients with LAM resistance.16 Likewise, a higher daily ETV dose of 1.0 mg is required to treat patients with LAM-resistant HBV more effectively, despite the fact that ETV is more potent than ADV in the activity of HBV suppression. In addition, genotypic ETV resistance and virologic breakthrough may also occur, as was detected in 10 and 2, respectively, of the 141 LAM-resistant patients during 52 weeks of ETV therapy; and it was only observed in patients with LAM-resistant virus (M204 V/I and/or L180M) that had an additional substitution at residues T184, S202, or M250.17 Considering the selection advantage of LAM-resistant strains, it is conceivable that switching to ETV monotherapy is more appropriate than ETV add-on LAM combination therapy for LAM-resistant patients.18 On the other hand, the potential of developing multidrug resistance may be a concern, as dual resistance to LAM and ADV or ETV has been reported;19, 20 the former was associated with a 59-fold decrease in susceptibility to combination of the 2 drugs.19 Studies are needed to explore whether the duration of continuing LAM during ADV therapy can be shortened to terminate LAM resistance earlier but still be able to prevent resistance to the add-on agent.
In summary, drug resistance is a serious challenge in antiviral therapy of chronic hepatitis B although nucleoside (nucleotide) analogs with different resistance profiles are available. It is now clear that rescue therapy should be instituted as soon as genotypic resistance is detected. Therefore, careful monitoring during direct antiviral therapy is mandatory for early detection and early rescue of drug resistance. Although both initiation of ADV add-on LAM combination therapy and switching to ETV monotherapy are better strategies for managing LAM resistance, insufficient efficacy and potential multidrug resistance are unsolved problems. Tenofovir administered 300 mg daily appears to be superior to ADV administered 10 mg daily in suppressing LAM-resistant strain HBV, and no tenofovir resistance has been detected.16 However, the data for tenofovir are still limited, and the drug has not been approved for hepatitis B patients. Because cost is a concern and a large number of patients are currently being and will be treated with LAM, the least expensive drug, LAM resistance remains a serious clinical challenge for the foreseeable future. In addition, ADV and even ETV monotherapy in LAM-naïve patients will engender drug resistance if the duration of therapy is long enough. It is therefore very important to select the right patients and the right antiviral agent(s) and to start antiviral therapy at the right time to prevent or reduce drug resistance. In other words, it is very important to ensure there is a clear indication for starting therapy and to take measures to maximize antiviral activity and genetic or pharmacological barriers to resistance.1 The study by Rapti et al.14 proved the concept that combination therapy prevents or delays drug resistance and underscores the need to evaluate de novo combination of antiviral agents to maintain long-term and complete viral suppression. Such studies are needed to determine the optimal strategy for the antiviral therapy of chronic hepatitis B.