Add-On Adefovir Is Superior to a Switch to Entecavir as Rescue Therapy for Lamivudine-Resistant Chronic Hepatitis B

Department of Internal Medicine, Gangnam Healthcare Center, Seoul National University Hospital, Seoul, Republic of Korea.
Digestive Diseases and Sciences (Impact Factor: 2.61). 07/2011; 56(7):2130-6. DOI: 10.1007/s10620-010-1561-2
Source: PubMed


Lamivudine (LAM) has been extensively used to treat hepatitis B, but high incidence of drug resistance has required rescue studies. We validated the optimum treatment strategy for LAM-resistant patients by means of a comparative study of add-on adefovir (ADV) and a switch to entecavir (ETV).
We assessed the virologic response in consecutive LAM-resistant patients who received add-on ADV or a switch to ETV.
The mean reduction of serum hepatitis B virus (HBV) DNA levels was significantly less in the ETV group than in the add-on ADV group (-3.45 vs. -4.17; P = 0.047 at week 24 and -3.81 vs. -4.68 log(10) IU/mL; P = 0.044 at week 48). Achievement of undetectable HBV DNA was significantly lower in the ETV group than in the add-on ADV group (P = 0.043). Multivariate analysis showed that add-on ADV, baseline HBV DNA levels, and initial virologic response were significant predictors of HBV DNA negativity (adjusted OR, 2.582; P = 0.008, 0.304; P = 0.001, and 5.928; P = 0.001). Virologic breakthrough was observed for 12 patients, in the ETV group only.
Add-on ADV was more effective and durable than ETV as rescue therapy. Therefore, add-on ADV might be the preferred strategy for LAM-resistant patients who need long-term antiviral treatment.

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    • "ETV, a guanosine analog , was proved to be potent against LAM-resistant HBV not only in vivo (Tenney et al., 2007) but also in vitro (Levine et al., 2002). However, monotherapy with either ADV or ETV was reported to have a higher risk for developing subsequent genotypic resistance to ADV or ETV and even to induce more multi-drug resistant mutants compared with adding-on ADV therapy (Rapti et al., 2007; Chung et al., 2011; Kim et al., 2010). In our study, we found that incidence of drug resistance in the group of switching to ADV or ETV monotherapy was much higher (respectively 23.67% and 18%) than that in the group of adding on ADV (6.94%) or switching to combination of ADV and ETV (0%). "
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    ABSTRACT: Lamivudine (LAM) resistance now poses a major problem in the management of patients with chronic hepatitis B virus (HBV) infection. We retrospectively collected clinical data on chronic HBV-infected patients who had developed LAM resistance under de novo LAM monotherapy and subsequently took nucleos(t)ide analogs as rescue strategy in our hospital. From initiation of rescue therapies to January 2012, incidence of antiviral drug resistance was 23.67%, 18%, 6.94% and 0% (P=0.007) in the group of switching to adefovir dipivoxil (ADV) monotherapy, switching to entecavir (ETV) monotherapy, adding on ADV and switching to combination of ADV and ETV. At month 12, the median levels of serum HBV DNA were respectively 9300IU/mL, 4648IU/mL, 2054IU/mL and 100IU/mL (P<0.001), and the cumulative rates of serum ALT normalization were respectively 75%, 84%, 93% and 100% (P=0.003). Additionally, the strategy of switching to ADV monotherapy induced more single rtA181T mutations. In conclusion, switching to ADV monotherapy has been widely used in real-world clinical practice in China, however, due to the high incidence of drug resistance, switching to neither ADV nor ETV monotherapy is optimal when LAM resistance occurs; combination of ADV and ETV is most effective, whereas the strategy of adding on ADV is rational for most of LAM-resistant Chinese patients with chronic hepatitis B.
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    • "Substitutions resulting in mutations at rtL180M/rtM204V in strains isolated from patients in the ETV group were treated as a consequence of LAM resistance may have resulted in the selection of strains with mutations at positions rtI169T, rtS202I/G, rtT184G or rtM250V. Substitutions at rtS202I/G, rtT184G and rtM205v were found in strains from patients in the ETV group in this study [21,24]. The cumulative probability of genotypic ETV resistance developing over 5 years was 51% in LAM resistant patients [17]. "
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    ABSTRACT: Chronic hepatitis B virus (HBV) infection represents a serious global health problem and resistance to lamivudine (LAM) has become a serious clinical challenge. Previous rescue therapy for the treatment of chronic LAM-resistant hepatitis B infected patients included switching to entecavir (ETV) and adding adefovir (ADV) or tenofovir (TFV). At present, switching to ETV is not recommended for rescue therapy for LAM-resistant chronic hepatitis B (CHB). The aim of this report was to determine whether add-on ADV was a superior rescue strategy in the treatment of CHB patients with LAM resistance. We searched Medline/PubMed, EMBASE, Web of Knowledge, and the Cochrane Library. Relative risks (RRs) of virologic response, virologic breakthrough, normalization of serum alanine aminotransferase (ALT) levels and HBeAg seroconversion rates were studied. Factors predicting virologic response, standardized mean differences (SMD) in HBV DNA levels and safety were reviewed. Six eligible trials (451 patients in total) were included in the analysis. The rate of virologic breakthrough in the ETV group was higher than that in the LAM plus ADV group. There were no statistical differences in virologic response, ALT normalization and HBeAg seroconversion in either group 48 weeks post treatment. LAM plus ADV combination therapy produced faster and greater HBV DNA reduction rates 24 weeks post therapy compared to ETV monotherapy. HBV DNA baseline levels and the initial virologic response (IVR) were predictive of the virologic response. Additionally, combination therapy or monotherapy were both well tolerated. LAM plus ADV combination therapy was more effective and produced longer-lasting effects than switching to ETV monotherapy in treating CHB patients with LAM resistance. However, considering the practical benefits and limitations of ADV, individualized therapy will be needed in patients with prior history of LAM resistant infections.
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