Entecavir treatment for chronic hepatitis B infection in end-stage renal disease and kidney transplantation

Authors

  • Ezequiel Ridruejo MD,

    1. Hepatology Section, Department of Medicine, Centro de Educacón Médica e Investigaciones Clínicas Norberto Quirno “CEMIC,” Ciudad Autónoma de Buenos Aires, Argentina
    2. Liver and Liver Transplant Unit, Hospital Universitario Austral, Pilar, Prov. de Buenos Aires, Argentina
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  • Raúl Adrover MD,

    1. Hepatology Section, Department of Medicine, Centro de Hepatología, La Plata, Prov. de Buenos Aires, Argentina
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  • Cristina Alonso MD,

    1. Liver and Liver Transplant Unit, Hospital Universitario Austral, Pilar, Prov. de Buenos Aires, Argentina
    2. Fresenius Medical Care, Ciudad Autónoma de Buenos Aires, Argentina
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  • Oscar G. Mandó MD,

    1. Hepatology Section, Department of Medicine, Centro de Educacón Médica e Investigaciones Clínicas Norberto Quirno “CEMIC,” Ciudad Autónoma de Buenos Aires, Argentina
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  • Marcelo O. Silva MD

    1. Liver and Liver Transplant Unit, Hospital Universitario Austral, Pilar, Prov. de Buenos Aires, Argentina
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Abstract

BACKGROUND

The prevalence of chronic hepatitis B virus (HBV) infection is high in patients with end-stage renal disease and in kidney transplant recipients, and there is little experience with treatment using the newer antiviral drugs. The aim of this study was to assess the efficacy and safety of entecavir in HBV infection in this difficult-to-treat population.

METHODS

Eleven male patients—1 with stage 4 chronic kidney disease, 7 undergoing hemodialysis, and 3 kidney transplant recipients-were included in the study evaluation. Six were treatment naïve, and 5 were lamivudine resistant. Entecavir was administered at a dose of 0.1–1 mg qd according to the patients' renal function. All were HBsAg positive: 9 were HBeAg (+)/antiHBe (−), and the remaining 2 were HBeAg (−)/antiHBe (+).

RESULTS

After a median treatment of 2 ± 0.86 years, entecavir therapy was associated with a significant decrease in HBV DNA viral load: it was 6.84 ± 1.45 log10 UI/mL (range 5.21–9.04) at baseline and at the time of evaluation had dropped to 1.73 ± 2.11 log10 UI/mL (range <0.78–4.72). The rate of HBV DNA clearance was 54.5% (n = 6). The rate of anti–HBe seroconversion was 77.7% (7/9 HBeAg-positive patients). The rate of anti-HBs seroconversion was 9.1% (1/11 patients). There were no significant changes in renal function or hematological parameters.

CONCLUSIONS

This small study demonstrates that entecavir therapy is safe and efficient in HBV-positive patients with varying degrees of renal dysfunction.

Chronic hepatitis B virus (HBV) infection affects approximately 350 million people worldwide, and one-third of the world population has evidence of past or present infection.1 It continues to be an important cause of morbidity and mortality, with 1,000,000 deaths and 470,000 cases of hepatocellular carcinoma annually, and currently accounts for 5–10% of cases of liver transplantation.1, 2 Although the prevalence of HBV infection in patients with end-stage renal disease (ESRD) has been decreasing recently due to widespread HBV vaccination and the application of infection control procedures, it is still higher than in the general population. The prevalence of HBV infection in hemodialysis units ranges from 0 to 20% according to the region studied.3 Risk factors for HBV acquisition include nosocomial transmission during dialysis procedures, the kidney allograft, and the use of contaminated blood products.4

After kidney transplantation, immunosuppressive regimens lead to enhanced HBV replication. This higher viral load has been associated with increased morbidity and mortality rates compared with both the non-renal disease population and renal patients who are HBV negative. It has also been associated with decreased graft survival among infected patients who underwent kidney transplantation.5, 6

Treatment options for HBV include standard and pegylated interferons and nucleos(t)ide analogs. In the general population, peginterferon, entecavir, and tenofovir are considered the first treatment options.1, 7 These and other drugs have been used in ESRD and kidney transplant populations. Experience with interferons is limited in this setting. They have been associated with significant toxicity and poor efficacy in dialysis patients and are contraindicated after kidney transplantation due to poor efficacy and risk of graft rejection.8, 9 Lamivudine has been used for a long time and has been demonstrated to be safe. Even though lamivudine is initially effective (HBV DNA negativization rates of 43–78%, HBeAg negativization rates of 0–25%), when given for long periods, rates of resistance are extremely high (∼60%).10–14 Adefovir has been demonstrated to be safe and effective in patients who have HBV infection with varying degrees of renal dysfunction, but experience is restricted to a low number of lamivudine-resistant patients.15–17

Entecavir is a potent HBV inhibitor, it is safe and effective for the treatment of chronic hepatitis B infection, and it is recommended as first-line therapy in the most recently published guidelines.1, 7 Kamar et al.18 recently reported their experience with entecavir in eight kidney-transplanted patients infected with HBV strains resistant to lamivudine and adefovir. Their results showed a favorable outcome with no relevant adverse events.18

Apart from the study just mentioned,18 little information exists about the use of entecavir in this particular population with ESRD and kidney transplantation. We therefore aimed to assess the efficacy and safety of entecavir in a small group of patients with chronic HBV infection, ESRD, and/or kidney transplantation.

Patients and Methods

We retrospectively reviewed clinical records from four different liver and kidney units in Buenos Aires, Argentina, between January 1, 2006 and September 1, 2009. Patient records were selected according to their hepatitis B status. Diagnosis of chronic HBV infection was defined as a positive serum HBsAg and detectable HBV DNA for more than 6 months, independent of ALT levels and HBeAg status. Quantitative HBV DNA was determined by the Cobas Taqman HBV Real Time PCR test (Roche Molecular Systems, Branchburg, NJ) with a limit of detection of 6 IU/mL (0.78 log). HBsAg/anti-HBs/HBeAg/anti-HBe/anti-HBc were assessed by the Microparticule Enzyme Immunoassay assay (MEIA; Abbott Diagnostics Division, Wiesbaden, Germany). HIV and hepatitis D virus (HDV) co-infected patients were excluded from the analysis.

ESRD was defined according to international guidelines.19

Patients treated for more than 6 months were included in the analysis. Among them we compared baseline with after treatment last available serum HBV DNA levels and HBeAg and HBsAg status.

Entecavir doses were prescribed as recommended by the manufacturer.20 Three naïve hemodialysis patients received 0.05 mg/d, four lamivudine-resistant hemodialysis patients received 0.1 mg/d, two naïve kidney transplant patients received 0.5 mg/d, one lamivudine-resistant kidney transplant patient received 1 mg/d, and one naïve ESRD patient received 0.15 mg/d. Treatment duration was defined according to current stopping rule guidelines: discontinuation after 24–48 weeks of anti-HBe seroconversion in HBeAg-positive patients and indefinitely in HBeAg negative/anti-HBe-positive patients.1

At baseline and after 6 months, the following parameters were recorded: liver function tests, serum HBV DNA levels; HBsAg, anti-HBs, HBeAg, and anti-HBe titers; and serum creatinine and cellular blood counts.

We report our virologic and serologic results with continued treatment up to September 1, 2009.

Statistical analysis

Microsoft Excel 2007 software (Microsoft, Seattle, Wash.) was used for the database. STATA statistical software was used for the analysis (version 7.0, Stata, College Station, Texas). Data were compared using non-parametric tests (Wilcoxon) for paired data. A p-value less than 0.05 was considered statistically significant.

Results

From our records we identified 11 patients with chronic HBV infection and ESRD. All were men, with a mean age of 53 ± 15.8 yr. Nine patients were HBeAg positive/anti-HBe negative, whereas the other two were HBeAg negative/anti-HBe positive. Six patients were naïve to anti-HBV treatment. Five patients received lamivudine and were considered resistant to it, as HBV DNA remained positive despite appropriate antiviral dosage; 2 discontinued treatment and 3 were still on treatment. Two HBV patients who were also co-infected with hepatitis C virus (anti-HCV and HCV RNA positive) did not receive anti-HCV therapy.

Seven patients underwent a liver biopsy before starting entecavir therapy, which was scored according to the Metavir scale.21 The Metavir score showed a mean activity index of A2.5 ± 0.7 (A1–A3) and a mean fibrosis score of F2.8 ± 1 (F1–F4). Two patients had histological cirrhosis. None of the patients had clinical evidence of decompensated liver disease.

According to international guidelines, 1 patient had CKD stage 4, 7 had ESRD stage 5 (and were undergoing hemodialysis), and 3 were kidney transplant recipients. The mean dialysis duration was 6 ± 4.4 years and elapsed mean time since transplantation was 8.5 ± 5.8 years.

Mean entecavir treatment period was 2.1 ± 0.8 years, with a mean dose of 0.24 ± 0.3 mg/d. Individual doses are shown in TableI.

Table I. Baseline characteristics and results obtained with treatment.
PatientRenal StatusMetavir ScoreBaseline HBeAg StatusBaseline HBV DNA Levels (IU/mL)ETV Doses (mg/d)ETV Treatment Duration (yr)HBV DNA at EvaluationHBsAg/HBeAg Status at Evaluation
  1. KT, kidney transplant; HBV, hepatitis B virus; HD, hemodialysis; ESRD, end-stage renal disease; ETV, entecavir; ND, not done.

 1KTA3 F3Positive6,872,8520.52.683.02 log reductionAnti-HBe seroconversion
 2KTA2 F2Positive7,840,20612.623.22 log reductionUnchanged
 3HDA3 F3Positive640,000,0000.052.37UndetectableAnti-HBe seroconversion
 4HDA1 F1Positive240,0000.13.27UndetectableAnti-HBe seroconversion
 5KTA3 F4Positive1,100,000,0000.51.067.14 log reductionAnti-HBe seroconversion
 6ESRDNDPositive640,000,0000.152.39UndetectableAnti-HBs and antiHBe seroconversion
 7HDNDNegative291,0000.051.52UndetectableUnchanged
 8HDNDPositive13,700,0000.050.682.41 log reductionUnchanged
 9HDA3 F4Positive326,4600.10.630.78 log reductionAnti-HBe seroconversion
10HDNDPositive164,9550.12.15UndetectableAnti-HBe seroconversion
11HDA3 F3Negative687,2850.12.29UndetectableUnchanged

Baseline HBV DNA viral load was 6.84 ± 1.45 log10 UI/mL (range 5.21–9.04), and after treatment the last evaluation was 1.73 ± 2.11 log10 UI/mL (range <0.78–4.72; p = .0033). At this time point, six patients were HBV DNA negative (54.5%). The mean time up to HBV DNA negativization was 1.08 ± 0.5 years.

Nine patients were HBeAg positive/ anti-HBe negative before initiation of treatment with entecavir. Seven of 9 (77.7%) HBeAg-positive patients seroconverted to HBeAg negative/antiHBe positive (p = .0082). The mean time up to anti-HBe seroconversion was 0.97 ± 0.6 yr. Only one patient (No. 6) obtained anti-HBs seroconversion and HBsAg negativization after 2.16 yr of treatment (p = .31). Baseline data and individual patient treatment results are presented in TableI.

Baseline ALT values were elevated in 7 patients (63.6%), with a mean value of 103.3 ± 129.6 IU/mL (range 15–450). Last ALT values were elevated in 3 patients (27.2%), with a mean value of 33.3 ± 18.7 IU/mL (range 17–75).

Kidney function remained stable within the entire treatment period in the nonhemodialysis patients when we compared baseline and last treatment values: serum creatinine of 1.5 ± 1.1 mg/dL (range 0.8–3.3) vs. 1.72 ± 1.3 mg/dL (range 0.8–3.8; p = .35). There were no significant changes in the other laboratory values.

There were no adverse events related to entecavir. In transplanted patients, no rejection episodes occurred under treatment. Two patients died during treatment, due to cardiovascular causes, unrelated to liver disease or to entecavir treatment. Patient No. 1 died at 78 years old after 2.6 years of treatment; his last viral load was 6,420 UI/mL (3.81 log10) and he was anti-HBe positive. Patient No. 10 died at 54 years old after 0.68 years of treatment; his last viral load was 5,3571 UI/mL (4.72 log10) and he was anti-HBe negative.

Discussion

In this small study, we have demonstrated that treatment with entecavir therapy can significantly decrease serum HBV DNA, can induce HBV DNA negativization, and can also significantly induce anti-HBe seroconversion in chronic HBV-positive organ transplant recipients.

Entecavir has been commercially available since 2005. It is currently recommended as first-line treatment with peginterferon alfa-2a and tenofovir, since they have demonstrated superior efficacy, tolerability, and better resistance profiles in both HBeAg-positive and HBeAg-negative patients in different clinical trials.1, 7

Pivotal studies have demonstrated that entecavir is an antiviral agent of high clinical potency. A dose of 0.5 mg/d in treatment-naive patients suppressed HBV DNA to undetectable levels by year 1 in 67% of HBeAg-positive and in 90% of HBeAgnegative patients.22, 23 The mean reduction in HBV DNA at year 1 from baseline was 6.9 log10 copies/mL (∼6.2 log10 IU/mL) in HBeAg-positive patients receiving entecavir vs. 5.0 log10 copies/mL (∼4.3 log10 IU/ mL) in HBeAg-negative patients.23 A recent report showed that prolonging treatment resulted in better HBV DNA suppression. After 96 wk of entecavir, 80% of patients achieved HBV DNA levels <300 copies/mL (∼59 IU/mL). In addition, approximately 12% of patients achieved HBeAg seroconversion by week 96.24

Entecavir has a high genetic barrier to resistance and a strong resistance profile. Recently reported results of more than 6 years of therapy showed that in nucleos(t)ide-naive patients, the cumulative probability of genotypic resistance to entecavir was 1.2% whereas the 6-year cumulative risk of genotypic resistance to entecavir among lamivudine-refractory patients was 57%.25

As previously mentioned, to our knowledge, the only published experience with entecavir use in kidney-transplanted patients was reported by Kamar et al.18 There are no other reports with the use of entecavir in hemodialysis or in naïve kidney transplanted patients. In our study, with prolonged entecavir treatment we obtained a significant HBV DNA reduction, a 54.5% HBV DNA negativization rate, and a 77.7% antiHBe seroconversion rate.

Lamivudine is the most used therapy in this population. It is effective and safe, but the very high levels of resistance preclude its use in many patients.10–14 Most of the experience with adefovir is restricted to lamivudine-resistant patients. It is not the most potent anti-HBV drug, and it has a medium to high levels of resistance. Thus it should not be used as the first option, but given its efficacy, it can be used in lamivudine-resistant patients.15–17 There is no experience with tenofovir in this setting, and there is concern about nephrotoxicity; it use should be restricted to clinical trials.26

Although this is a small cohort of patients, our results suggest that long-term treatment with entecavir in HBV-positive patients with varying degrees of renal dysfunction appears to be safe and effective. We obtained significant reductions in serum HBV DNA levels, even in lamivudine-resistant patients. Surprisingly, we saw a high HBeAg seroconversion rate, for which we do not have a clear explanation. Serum creatinine levels and other laboratory parameters did not change throughout treatment.

Given these results, entecavir might be considered an efficient and safe treatment option for patients who have chronic HBV infection with ESRD and kidney transplantation.

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