Entecavir plus tenofovir combination as rescue therapy in pre-treated chronic hepatitis B patients: An international multicenter cohort study

Liver Unit, IFI Institute for Interdisciplinary Medicine, Asklepios Klinik St. Georg Hamburg, Germany.
Journal of Hepatology (Impact Factor: 11.34). 03/2012; 56(3):520-6. DOI: 10.1016/j.jhep.2011.09.018
Source: PubMed


Long-term viral suppression is a major goal to prevent disease progression in patients with HBV. Aim of this study was to investigate the efficacy and safety of entecavir plus tenofovir combination in 57 CHB partial responders or multidrug resistant patients.
Investigator-initiated open-label cohort study. Quantitative HBV-DNA measurement and resistance testing (line-probe-assays and direct-sequencing) at baseline and every 3 months.
Fifty seven patients (37 HBeAg+), median age 45 years, previously treated with a median of three lines of antiviral therapy (range 1-6), 24/57 with advanced liver disease, were included. Median ALT at baseline was 1.0 ULN (range 0.3-22) and HBV-DNA 1.5 × 10(4)IU/ml (range 500-1 × 10(11)IU/ml). Median treatment duration of combination therapy was 21 months. HBV-DNA level dropped 3 logs (median, range 0-8 log; p<0.0001), 51/57 patients became HBV-DNA undetectable, median after 6 months (95% CI, 4.6-7). The probability for HBV DNA suppression was not reduced in patients with adefovir or entecavir resistance or in patients with advanced liver disease. Viral suppression led to decline in ALT (median 0.7 ULN; range 0.2-2.4; p=0.001). Five patients lost HBeAg (after 15, 18, 20, 21, and 27 months, respectively), one patient showed HBs-seroconversion. Patients with advanced disease did not show clinical decompensation, two patients with cirrhosis and undetectable HBV DNA developed HCCs. No death, newly induced renal impairment or lactic acidosis were reported.
Rescue therapy with entecavir and tenofovir in CHB patients harboring viral resistance patterns or showing only partial antiviral responses to preceding therapies was efficient, safe, and well tolerated in patients with and without advanced liver disease (249).

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    • "The substitution rtP177G and rtF249A reduced susceptibility to TDF in an in vitro study, but no clinical findings have yet been reported.18 Moreover, rescue therapy with ETV and TDF in CHB patients harboring viral resistance patterns (for LAM, ADV, or ETV) or showing only partial antiviral responses to preceding therapies was efficient in patients both with and without advanced liver disease.19 To date, there have been no confirmed reports of resistance selection during treatment with TDF for CHB.9–12 "
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    ABSTRACT: Tenofovir disoproxil fumarate (TDF) is widely used to treat hepatitis B virus (HBV) patients in the USA and Europe. No confirmed report of resistance selection during treatment with TDF in treatment-naïve and nucleoside/nucleotide analog-treated chronic hepatitis B patients has yet been reported. Here, we report for the first time a patient with chronic hepatitis B and cirrhosis who emerged with virologic breakthrough during combination therapy with TDF and entecavir (ETV), against ETV-resistant virus. A 51-year-old Japanese woman with hepatitis B e-antigen (HBeAg), whose genotype was C, received ETV monotherapy continuously followed by TDF and ETV combination therapy, because her HBV DNA levels had been >3.5 log copies/mL. At the start of combination therapy, amino acid substitutions of the reverse transcriptase (rt) gene, rtL180M, rtT184I/M, and rtM204V, were detected. After this, serum HBV DNA decreased to less than 2.1 log copies/mL and remained at this level until 31 months of combination therapy, when it again began to increase. Amino acid substitutions of rtL180M, rtS202G, and rtM204V emerged and were associated with an increase in serum HBV DNA at virologic breakthrough. Long-term therapy with TDF against the ETV-resistant virus has the potential to induce virologic breakthrough and resistance, and careful follow-up should be carried out.
    Drug Design, Development and Therapy 06/2014; 8:869-73. DOI:10.2147/DDDT.S65349 · 3.03 Impact Factor
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    • "TDF safe and effective in patients with prior failure of LAM and in patients with suboptimal response to ADV or entecavir (ETV) therapy.9,10 The combination of ETV and TDF is highly efficient and safe in patients with partial responses to preceding therapies.11 However, long-term data of efficacy and safety of TDF in treatment-experienced patients is not sufficient. "
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    ABSTRACT: We investigated the efficacy and safety of tenofovir disoproxil fumarate (TDF)-based treatment in chronic hepatitis B (CHB) patients who failed previous antiviral therapies. Seventeen patients who failed to achieve virological responses during sequential antiviral treatments were included. The patients were treated with TDF monotherapy (four patients) or a combination of TDF and lamivudine (13 patients) for a median of 42 months. Hepatitis B virus (HBV) DNA and hepatitis B e antigen (HBeAg) were measured, and renal function was also monitored. Prior to TDF therapy, 180 M, 204 I/V/S, 181 T/V, 236 T, and 184 L mutations were detected. After TDF therapy, the median HBV DNA level decreased from 4.6 log10 IU/mL to 2.0 log10 IU/mL and to 1.6 log10 IU/mL at 12 and 24 months, respectively. HBV DNA became undetectable (≤20 IU/mL) in 14.3%, 41.7%, and 100% of patients after 12, 24, and 48 months of treatment, respectively. HBeAg loss was observed in two patients. Viral breakthrough occurred in five patients who had skipped their medication. No significant changes in renal function were observed. TDF-based rescue treatment is effective in reducing HBV DNA levels and is safe for patients with CHB who failed prior antiviral treatments. Patients' adherence to medication is related to viral rebound.
    Gut and Liver 01/2014; 8(1):64-9. DOI:10.5009/gnl.2014.8.1.64 · 1.81 Impact Factor
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    • "As post-treatment ALT flares are possible, children should be carefully monitored and a reinstitution of lamivudine treatment (in patients who have not developed resistance) or an alternative therapy (tenofovir if possible for the age) should be started in the rare cases with severe and protracted ALT elevation (A1) [115]. For children with cirrhosis, who need antiviral treatment to be continued , switch to tenofovir (if P12 years of age), alone or in combination with entecavir (if P16 years of age) or maintenance of lamivudine (if <12 years of age) despite an incomplete VR is recommended (C2) [171] [172]. Combination therapy with IFN-a and lamivudine is promising, but further data are needed in children (C2). "

    Journal of Hepatology 10/2013; 59(4):814-829. DOI:10.1016/j.jhep.2013.05.016 · 11.34 Impact Factor
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