Successful Use of Entecavir in Hepatitis B-associated Membranous Nephropathy

Successful Use of Entecavir in Hepatitis B-associated Membranous Nephropathy Abstract We report the case of a 7-year-old unimmunized boy who presented with generalized anasarca for the first time, along with nephrotic-range proteinuria, hypoalbuminemia, microscopic hematuria and hypertension. Special investigations revealed ELISA test to be positive for hepatitis B surface antigen (HBsAg) and hepatitis B envelope antigen (HBeAg); hepatitis B viral DNA load (HBV DNA) level (real-time polymerase chain reaction) was 54 360 903 IU/ml. For hepatitis B virus (HBV)-related glomerulopathy, he was started on enalapril and lasilactone, and percutaneous renal biopsy was performed, which revealed membranous nephropathy (MN). A diagnosis of MN secondary to HBV infection contracted via horizontal transmission was made. The patient was started on peginterferon alfa-2b (50 μg/week) for 24 weeks. He failed to attain remission and seroconversion after interferon (IFN) therapy. Then, oral therapy with entecavir was started, and he attained remission as well as seroconversion after 3 months of therapy. He maintained his seroconversion status at his 6-month and the recent 12-month (quantitative HBV DNA level was 373 IU/ml) follow-up visit. Entecavir seems a promising drug for HBV-related glomerulopathy, especially in IFN-resistant cases. secondary nephrotic syndrome, membranous glomerulonephritis, hepatitis B virus-related glomerulopathy, antivirals, interferon resistance INTRODUCTION Membranous nephropathy (MN) is caused by subepithelial deposition of immune complexes in the glomerular basement membrane. MN is classified as primary and secondary, caused by infections like hepatitis B virus (HBV) infection or autoimmune diseases like systemic lupus erythematosus [1]. The overall prevalence of MN in children is 8% [2]. Secondary MN accounts for 75% of total MN cases seen in children. Global pediatric prevalence of MN closely follows the prevalence of HBV infection [3]. HBV infects 2 billion people worldwide. Renal involvement is among its common extrahepatic manifestations. Most common clinical presentation of HBV-related nephropathy is nephrotic syndrome. MN is the most characteristic glomerular lesion seen in (>85%) children with chronic HBV infection [3, 4]. Spontaneous remission is known in secondary MN because of HBV infection in children. However, treatment with interferon (IFN) or nucleoside analogs is warranted in presence of high hepatitis B viral DNA load (HBV DNA) levels. This aids in removing immune complexes causing MN and lowering raised HBV DNA titers, which otherwise put the patient at a high risk for hepatocellular carcinoma [4, 5]. We report the case of a patient with HBV-associated MN, resistant to IFN, treated successfully with entecavir, a nucleoside analog. PATIENT’S MEDICAL REPORTS A 7-year-old boy, unimmunized for HBV, presented to our outpatient department with generalized anasarca for the first time for 2 weeks. However, he also had hypertension (blood pressure = 120/70 mm Hg); the rest of his systemic examinations, including fundal examination, was normal. Family history was noncontributory. There was no history of blood transfusions. His laboratory investigations revealed nephrotic-range proteinuria (2.55 g protein/24 h), hypoalbuminemia (serum albumin 1.8 g/dl) and microscopic hematuria. Blood investigations revealed hemoglobin level to be 9.8 mg/dl, white blood cell count to be 10 500/µl and platelet count to be 2.2 lac/µl; dimorphic anemia on peripheral blood film; serum cholesterol level was 385 mg/dl; renal and liver function tests were normal; antinuclear and anti-neutrophilic cytoplasmic antibodies were negative; and C3 levels were normal. We also performed specific investigations for secondary causes of nephrotic syndrome, which revealed hepatitis B surface antigen (HBsAg) to be positive by ELISA, hepatitis B envelope antigen (HBeAg) to be positive by ELISA and negative serology for hepatitis C virus and HIV. Further workup including quantitative HBsAg was done and antigen level was found to be 27 906.7 IU/ml (normal < 0.05); quantitative HBV DNA level by real-time polymerase chain reaction (RT-PCR) using TaqMan technology was 54 360 903 IU/ml (linear range of assay ≥20–<1.7 × 108; 1 IU/ml = 5.82 copies/ml); anti-HBeAb was negative; and anti-HBc IgM (hepatitis B core antibodies) was negative, confirming chronic HBV infection (Table 1). Renal ultrasound was normal. Table 1. Laboratory investigations Serial number Test Baseline; pretreatment After IFN alfa-2b; 24 weeks posttreatment After entecavir till date 1 HBsAg (ELISA) Positive Positive Positive 2 HBeAg (ELISA) Positive Positive Negative 3 Anti-HBeAb (ELISA) Negative Negative Positive 4 Anti-HBc IgM Negative 5 Quantitative HBV DNA (RT-PCR) 54 360 903 IU/ml 11 524 620 IU/ml 373 IU/ml 6 24-h urine protein 2.55 g/TV 1.89 g/TV 0.2 g/TV 7 Serum albumin 1.8 g/dl 2.2 g/dl 4.2 g/dl 8 Serum cholesterol 385 mg/dl 315 mg/dl 280 mg/dl Serial number Test Baseline; pretreatment After IFN alfa-2b; 24 weeks posttreatment After entecavir till date 1 HBsAg (ELISA) Positive Positive Positive 2 HBeAg (ELISA) Positive Positive Negative 3 Anti-HBeAb (ELISA) Negative Negative Positive 4 Anti-HBc IgM Negative 5 Quantitative HBV DNA (RT-PCR) 54 360 903 IU/ml 11 524 620 IU/ml 373 IU/ml 6 24-h urine protein 2.55 g/TV 1.89 g/TV 0.2 g/TV 7 Serum albumin 1.8 g/dl 2.2 g/dl 4.2 g/dl 8 Serum cholesterol 385 mg/dl 315 mg/dl 280 mg/dl Table 1. Laboratory investigations Serial number Test Baseline; pretreatment After IFN alfa-2b; 24 weeks posttreatment After entecavir till date 1 HBsAg (ELISA) Positive Positive Positive 2 HBeAg (ELISA) Positive Positive Negative 3 Anti-HBeAb (ELISA) Negative Negative Positive 4 Anti-HBc IgM Negative 5 Quantitative HBV DNA (RT-PCR) 54 360 903 IU/ml 11 524 620 IU/ml 373 IU/ml 6 24-h urine protein 2.55 g/TV 1.89 g/TV 0.2 g/TV 7 Serum albumin 1.8 g/dl 2.2 g/dl 4.2 g/dl 8 Serum cholesterol 385 mg/dl 315 mg/dl 280 mg/dl Serial number Test Baseline; pretreatment After IFN alfa-2b; 24 weeks posttreatment After entecavir till date 1 HBsAg (ELISA) Positive Positive Positive 2 HBeAg (ELISA) Positive Positive Negative 3 Anti-HBeAb (ELISA) Negative Negative Positive 4 Anti-HBc IgM Negative 5 Quantitative HBV DNA (RT-PCR) 54 360 903 IU/ml 11 524 620 IU/ml 373 IU/ml 6 24-h urine protein 2.55 g/TV 1.89 g/TV 0.2 g/TV 7 Serum albumin 1.8 g/dl 2.2 g/dl 4.2 g/dl 8 Serum cholesterol 385 mg/dl 315 mg/dl 280 mg/dl A clinical possibility of HBV-related glomerulopathy was considered. The patient was initially started on enalapril and lasilactone. Percutaneous renal biopsy was performed. Light microscopy (PAS and H&E staining) showed diffuse global basement membrane thickening with focal increase in mesangial matrix and cellularity, capillary loop stiffening and lifting up of podocytes at places. Extensive vacuolization was seen in the tubules, indicating proteinuria. Direct immunofluorescence (DIF) showed capillary loop positivity for IgG, C3, kappa and lambda (2–3+) consistent with a membranous pattern. DIF for IgA, IgM and C1q was negative. Electron microscopy showed presence of transmembranous and epimembranous immune complex deposits with laying down of basement membrane between deposits. Effacement of the foot processes was seen (Fig. 1). Hence, a diagnosis of MN secondary to HBV infection was made. Fig. 1. View largeDownload slide (A and B) Light microscopy (PAS and H&E stain) showing enlarged glomerulus with eosinophilic refractile thickening of the glomerular capillary walls (black arrows), mild neutrophilic infiltration and a cellular crescent. (C) Electronmicroscopy showing highly osmiophilic, dense deposits present in the lamina densa of the glomerular capillary basement membrane (white arrows) in a segmental pattern. (D) Immunofluorescence showing 3+ positivity for IgG (D1), C3 (D2), kappa (D3) and lambda (D4) in the glomerular capillary walls in an interrupted fashion with mesangial staining and presence of staining in the Bowman’s capsule. Fig. 1. View largeDownload slide (A and B) Light microscopy (PAS and H&E stain) showing enlarged glomerulus with eosinophilic refractile thickening of the glomerular capillary walls (black arrows), mild neutrophilic infiltration and a cellular crescent. (C) Electronmicroscopy showing highly osmiophilic, dense deposits present in the lamina densa of the glomerular capillary basement membrane (white arrows) in a segmental pattern. (D) Immunofluorescence showing 3+ positivity for IgG (D1), C3 (D2), kappa (D3) and lambda (D4) in the glomerular capillary walls in an interrupted fashion with mesangial staining and presence of staining in the Bowman’s capsule. The patient was started on peginterferon alfa-2b (50 µg subcutaneously/week) for 24 weeks. He failed to attain remission (nephrosis persisted; 24-h urine protein was 1.89 g after completion of IFN therapy) as well as seroconversion after IFN therapy (repeat HBsAg and HBeAg were positive; anti-HBeAb was negative; quantitative HBV DNA level by RT-PCR was 11 524 620 IU/ml) (Table 1). Therefore, oral entecavir (0.5 mg daily) was started. After 3 months of therapy, the patient attained remission (24-h urine protein =0.2 g) as well as seroconversion (HBeAg-negative). He maintained his seroconversion status at 12 months of follow-up (HBeAg-negative; anti-HBeAb-positive; quantitative HBV DNA level by RT-PCR was 373 IU/ml at the 12-month follow-up visit) (Table 1). No adverse reaction was observed during IFN/entecavir therapy. DISCUSSION MN is the most common form of HBV-related glomerulopathy, especially in children. It has a male preponderance and presents as nephrotic syndrome with preserved renal function, as seen in the index case. The pathogenesis is attributed to deposition of immune complexes of viral antigen and host antibody [2, 6]. The diagnosis is based on detection of HBV in blood and exclusion of other causes of glomerular disease. The index patient had HBV-associated MN with high HBV DNA titers, which was resistant to IFN therapy. Cytokine therapy like IFN alfa-2b monotherapy is often the first choice in HBV-related glomerulopathy because of its defined course and ability for HBV DNA suppression. IFN accelerates clearance of virus and improves proteinuria through its action on cytokine and T-cell pathways [7]. However, in most controlled studies on children, IFN therapy was effective only in 20–50% of treated patients [3, 7]. Other options available are nucleoside and nucleotide analogs. Their advantages include enteral administration and more profound HBV DNA suppression as compared with IFN. Furthermore, they are efficacious even in cases nonresponsive to IFN therapy [4]. Entecavir is a guanosine analog. Compared with lamivudine, it results in more potent viral suppression and better histologic improvement, in both HBeAg-positive and HBeAg-negative patients [8, 9]. Its dual action inhibits HBV DNA polymerase at the priming and elongating steps of DNA synthesis. Entecavir was found to be safe in adult patients with kidney diseases, but the dose needs to be adjusted in renal failure. A virological response (defined as serum HBV DNA level of <2000 IU/ml) as well as a combined response (defined as virological response plus serological response for HBeAg-positive hepatitis B) were achieved in the index case [10]. Unfortunately, resurgence of HBV DNA levels can occur if the drug is discontinued prematurely or if resistance develops. CONCLUSION Entecavir seems a promising drug therapy for HBV-related glomerulopathy, especially in IFN-resistant cases in children. However, prospective studies are needed to validate this and identify the best target patients. What is known Secondary MN, caused by HBV, requires treatment with IFN or nucleoside analogs in presence of high HBV DNA levels. What is new Entecavir seems a promising drug for HBV-related glomerulopathy, especially in IFN-resistant cases. Compliance with ethical standards Ethical approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors. Informed consent: Informed consent was obtained from all individual participants included in the study. REFERENCES 1 Kidney Disease Improving Global Outcomes (KDIGO) Glomerulonephritis Work Group . KDIGO clinical practice guideline for glomerulonephritis . Kidney Int Suppl 2012 ; 2 : 139 – 274 . CrossRef Search ADS 2 Ayalon R , Beck LH Jr . Membranous nephropathy: not just a disease for adults . Pediatr Nephrol 2015 ; 30 : 31 – 9 . Google Scholar CrossRef Search ADS PubMed 3 Bhimma R , Coovadia HM. Hepatitis B virus-associated nephropathy . Am J Nephrol 2004 ; 24 : 198 – 211 . Google Scholar CrossRef Search ADS PubMed 4 Elewa U , Sandri AM , Kim WR , et al. Treatment of hepatitis B virus-associated nephropathy . Nephron Clin Pract 2011 ; 119 : c41 – 9 . Google Scholar CrossRef Search ADS PubMed 5 Igarashi T , Shimizu A , Igarashi T , et al. Seroconversion of hepatitis B envelope antigen by entecavir in a child with hepatitis B virus related membranous nephropathy . J Nippon Med Sch 2013 ; 80 : 387 – 95 . Google Scholar CrossRef Search ADS PubMed 6 Lin CY , Lin CC , Chang GJ , et al. Defect of cell-mediated immune response against hepatitis B virus: an indication of pathogenesis of hepatitis B virus-associated membranous nephropathy . Nephron 1997 ; 76 : 176 – 85 . Google Scholar CrossRef Search ADS PubMed 7 Shepherd J , Jones J , Takeda A , et al. Adefovir dipivoxil and pegylated interferon alfa-2a for the treatment of chronic hepatitis B: a systematic review and economic evaluation . Health Technol Assess 2006 ; 10 :iii–iv, xi–xiv, 1 – 183 . Google Scholar CrossRef Search ADS 8 Chang TT , Gish RG , de Man R , et al. A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B . N Engl J Med 2006 ; 354 : 1001 – 10 . Google Scholar CrossRef Search ADS PubMed 9 Lai CL , Shouval D , Lok AS , et al. Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B . N Engl J Med 2006 ; 354 : 1011 – 20 . Google Scholar CrossRef Search ADS PubMed 10 Wang YC , Yang SS , Su CW , et al. Predictors of response to pegylated interferon in chronic hepatitis B: a real world hospital based analysis . Sci Rep 2016 ; 6 : 29605 . doi: 10.1038/srep29605. Google Scholar CrossRef Search ADS PubMed © The Author [2017]. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Tropical Pediatrics Oxford University Press

Successful Use of Entecavir in Hepatitis B-associated Membranous Nephropathy

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Abstract

Abstract We report the case of a 7-year-old unimmunized boy who presented with generalized anasarca for the first time, along with nephrotic-range proteinuria, hypoalbuminemia, microscopic hematuria and hypertension. Special investigations revealed ELISA test to be positive for hepatitis B surface antigen (HBsAg) and hepatitis B envelope antigen (HBeAg); hepatitis B viral DNA load (HBV DNA) level (real-time polymerase chain reaction) was 54 360 903 IU/ml. For hepatitis B virus (HBV)-related glomerulopathy, he was started on enalapril and lasilactone, and percutaneous renal biopsy was performed, which revealed membranous nephropathy (MN). A diagnosis of MN secondary to HBV infection contracted via horizontal transmission was made. The patient was started on peginterferon alfa-2b (50 μg/week) for 24 weeks. He failed to attain remission and seroconversion after interferon (IFN) therapy. Then, oral therapy with entecavir was started, and he attained remission as well as seroconversion after 3 months of therapy. He maintained his seroconversion status at his 6-month and the recent 12-month (quantitative HBV DNA level was 373 IU/ml) follow-up visit. Entecavir seems a promising drug for HBV-related glomerulopathy, especially in IFN-resistant cases. secondary nephrotic syndrome, membranous glomerulonephritis, hepatitis B virus-related glomerulopathy, antivirals, interferon resistance INTRODUCTION Membranous nephropathy (MN) is caused by subepithelial deposition of immune complexes in the glomerular basement membrane. MN is classified as primary and secondary, caused by infections like hepatitis B virus (HBV) infection or autoimmune diseases like systemic lupus erythematosus [1]. The overall prevalence of MN in children is 8% [2]. Secondary MN accounts for 75% of total MN cases seen in children. Global pediatric prevalence of MN closely follows the prevalence of HBV infection [3]. HBV infects 2 billion people worldwide. Renal involvement is among its common extrahepatic manifestations. Most common clinical presentation of HBV-related nephropathy is nephrotic syndrome. MN is the most characteristic glomerular lesion seen in (>85%) children with chronic HBV infection [3, 4]. Spontaneous remission is known in secondary MN because of HBV infection in children. However, treatment with interferon (IFN) or nucleoside analogs is warranted in presence of high hepatitis B viral DNA load (HBV DNA) levels. This aids in removing immune complexes causing MN and lowering raised HBV DNA titers, which otherwise put the patient at a high risk for hepatocellular carcinoma [4, 5]. We report the case of a patient with HBV-associated MN, resistant to IFN, treated successfully with entecavir, a nucleoside analog. PATIENT’S MEDICAL REPORTS A 7-year-old boy, unimmunized for HBV, presented to our outpatient department with generalized anasarca for the first time for 2 weeks. However, he also had hypertension (blood pressure = 120/70 mm Hg); the rest of his systemic examinations, including fundal examination, was normal. Family history was noncontributory. There was no history of blood transfusions. His laboratory investigations revealed nephrotic-range proteinuria (2.55 g protein/24 h), hypoalbuminemia (serum albumin 1.8 g/dl) and microscopic hematuria. Blood investigations revealed hemoglobin level to be 9.8 mg/dl, white blood cell count to be 10 500/µl and platelet count to be 2.2 lac/µl; dimorphic anemia on peripheral blood film; serum cholesterol level was 385 mg/dl; renal and liver function tests were normal; antinuclear and anti-neutrophilic cytoplasmic antibodies were negative; and C3 levels were normal. We also performed specific investigations for secondary causes of nephrotic syndrome, which revealed hepatitis B surface antigen (HBsAg) to be positive by ELISA, hepatitis B envelope antigen (HBeAg) to be positive by ELISA and negative serology for hepatitis C virus and HIV. Further workup including quantitative HBsAg was done and antigen level was found to be 27 906.7 IU/ml (normal < 0.05); quantitative HBV DNA level by real-time polymerase chain reaction (RT-PCR) using TaqMan technology was 54 360 903 IU/ml (linear range of assay ≥20–<1.7 × 108; 1 IU/ml = 5.82 copies/ml); anti-HBeAb was negative; and anti-HBc IgM (hepatitis B core antibodies) was negative, confirming chronic HBV infection (Table 1). Renal ultrasound was normal. Table 1. Laboratory investigations Serial number Test Baseline; pretreatment After IFN alfa-2b; 24 weeks posttreatment After entecavir till date 1 HBsAg (ELISA) Positive Positive Positive 2 HBeAg (ELISA) Positive Positive Negative 3 Anti-HBeAb (ELISA) Negative Negative Positive 4 Anti-HBc IgM Negative 5 Quantitative HBV DNA (RT-PCR) 54 360 903 IU/ml 11 524 620 IU/ml 373 IU/ml 6 24-h urine protein 2.55 g/TV 1.89 g/TV 0.2 g/TV 7 Serum albumin 1.8 g/dl 2.2 g/dl 4.2 g/dl 8 Serum cholesterol 385 mg/dl 315 mg/dl 280 mg/dl Serial number Test Baseline; pretreatment After IFN alfa-2b; 24 weeks posttreatment After entecavir till date 1 HBsAg (ELISA) Positive Positive Positive 2 HBeAg (ELISA) Positive Positive Negative 3 Anti-HBeAb (ELISA) Negative Negative Positive 4 Anti-HBc IgM Negative 5 Quantitative HBV DNA (RT-PCR) 54 360 903 IU/ml 11 524 620 IU/ml 373 IU/ml 6 24-h urine protein 2.55 g/TV 1.89 g/TV 0.2 g/TV 7 Serum albumin 1.8 g/dl 2.2 g/dl 4.2 g/dl 8 Serum cholesterol 385 mg/dl 315 mg/dl 280 mg/dl Table 1. Laboratory investigations Serial number Test Baseline; pretreatment After IFN alfa-2b; 24 weeks posttreatment After entecavir till date 1 HBsAg (ELISA) Positive Positive Positive 2 HBeAg (ELISA) Positive Positive Negative 3 Anti-HBeAb (ELISA) Negative Negative Positive 4 Anti-HBc IgM Negative 5 Quantitative HBV DNA (RT-PCR) 54 360 903 IU/ml 11 524 620 IU/ml 373 IU/ml 6 24-h urine protein 2.55 g/TV 1.89 g/TV 0.2 g/TV 7 Serum albumin 1.8 g/dl 2.2 g/dl 4.2 g/dl 8 Serum cholesterol 385 mg/dl 315 mg/dl 280 mg/dl Serial number Test Baseline; pretreatment After IFN alfa-2b; 24 weeks posttreatment After entecavir till date 1 HBsAg (ELISA) Positive Positive Positive 2 HBeAg (ELISA) Positive Positive Negative 3 Anti-HBeAb (ELISA) Negative Negative Positive 4 Anti-HBc IgM Negative 5 Quantitative HBV DNA (RT-PCR) 54 360 903 IU/ml 11 524 620 IU/ml 373 IU/ml 6 24-h urine protein 2.55 g/TV 1.89 g/TV 0.2 g/TV 7 Serum albumin 1.8 g/dl 2.2 g/dl 4.2 g/dl 8 Serum cholesterol 385 mg/dl 315 mg/dl 280 mg/dl A clinical possibility of HBV-related glomerulopathy was considered. The patient was initially started on enalapril and lasilactone. Percutaneous renal biopsy was performed. Light microscopy (PAS and H&E staining) showed diffuse global basement membrane thickening with focal increase in mesangial matrix and cellularity, capillary loop stiffening and lifting up of podocytes at places. Extensive vacuolization was seen in the tubules, indicating proteinuria. Direct immunofluorescence (DIF) showed capillary loop positivity for IgG, C3, kappa and lambda (2–3+) consistent with a membranous pattern. DIF for IgA, IgM and C1q was negative. Electron microscopy showed presence of transmembranous and epimembranous immune complex deposits with laying down of basement membrane between deposits. Effacement of the foot processes was seen (Fig. 1). Hence, a diagnosis of MN secondary to HBV infection was made. Fig. 1. View largeDownload slide (A and B) Light microscopy (PAS and H&E stain) showing enlarged glomerulus with eosinophilic refractile thickening of the glomerular capillary walls (black arrows), mild neutrophilic infiltration and a cellular crescent. (C) Electronmicroscopy showing highly osmiophilic, dense deposits present in the lamina densa of the glomerular capillary basement membrane (white arrows) in a segmental pattern. (D) Immunofluorescence showing 3+ positivity for IgG (D1), C3 (D2), kappa (D3) and lambda (D4) in the glomerular capillary walls in an interrupted fashion with mesangial staining and presence of staining in the Bowman’s capsule. Fig. 1. View largeDownload slide (A and B) Light microscopy (PAS and H&E stain) showing enlarged glomerulus with eosinophilic refractile thickening of the glomerular capillary walls (black arrows), mild neutrophilic infiltration and a cellular crescent. (C) Electronmicroscopy showing highly osmiophilic, dense deposits present in the lamina densa of the glomerular capillary basement membrane (white arrows) in a segmental pattern. (D) Immunofluorescence showing 3+ positivity for IgG (D1), C3 (D2), kappa (D3) and lambda (D4) in the glomerular capillary walls in an interrupted fashion with mesangial staining and presence of staining in the Bowman’s capsule. The patient was started on peginterferon alfa-2b (50 µg subcutaneously/week) for 24 weeks. He failed to attain remission (nephrosis persisted; 24-h urine protein was 1.89 g after completion of IFN therapy) as well as seroconversion after IFN therapy (repeat HBsAg and HBeAg were positive; anti-HBeAb was negative; quantitative HBV DNA level by RT-PCR was 11 524 620 IU/ml) (Table 1). Therefore, oral entecavir (0.5 mg daily) was started. After 3 months of therapy, the patient attained remission (24-h urine protein =0.2 g) as well as seroconversion (HBeAg-negative). He maintained his seroconversion status at 12 months of follow-up (HBeAg-negative; anti-HBeAb-positive; quantitative HBV DNA level by RT-PCR was 373 IU/ml at the 12-month follow-up visit) (Table 1). No adverse reaction was observed during IFN/entecavir therapy. DISCUSSION MN is the most common form of HBV-related glomerulopathy, especially in children. It has a male preponderance and presents as nephrotic syndrome with preserved renal function, as seen in the index case. The pathogenesis is attributed to deposition of immune complexes of viral antigen and host antibody [2, 6]. The diagnosis is based on detection of HBV in blood and exclusion of other causes of glomerular disease. The index patient had HBV-associated MN with high HBV DNA titers, which was resistant to IFN therapy. Cytokine therapy like IFN alfa-2b monotherapy is often the first choice in HBV-related glomerulopathy because of its defined course and ability for HBV DNA suppression. IFN accelerates clearance of virus and improves proteinuria through its action on cytokine and T-cell pathways [7]. However, in most controlled studies on children, IFN therapy was effective only in 20–50% of treated patients [3, 7]. Other options available are nucleoside and nucleotide analogs. Their advantages include enteral administration and more profound HBV DNA suppression as compared with IFN. Furthermore, they are efficacious even in cases nonresponsive to IFN therapy [4]. Entecavir is a guanosine analog. Compared with lamivudine, it results in more potent viral suppression and better histologic improvement, in both HBeAg-positive and HBeAg-negative patients [8, 9]. Its dual action inhibits HBV DNA polymerase at the priming and elongating steps of DNA synthesis. Entecavir was found to be safe in adult patients with kidney diseases, but the dose needs to be adjusted in renal failure. A virological response (defined as serum HBV DNA level of <2000 IU/ml) as well as a combined response (defined as virological response plus serological response for HBeAg-positive hepatitis B) were achieved in the index case [10]. Unfortunately, resurgence of HBV DNA levels can occur if the drug is discontinued prematurely or if resistance develops. CONCLUSION Entecavir seems a promising drug therapy for HBV-related glomerulopathy, especially in IFN-resistant cases in children. However, prospective studies are needed to validate this and identify the best target patients. What is known Secondary MN, caused by HBV, requires treatment with IFN or nucleoside analogs in presence of high HBV DNA levels. What is new Entecavir seems a promising drug for HBV-related glomerulopathy, especially in IFN-resistant cases. Compliance with ethical standards Ethical approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors. Informed consent: Informed consent was obtained from all individual participants included in the study. REFERENCES 1 Kidney Disease Improving Global Outcomes (KDIGO) Glomerulonephritis Work Group . KDIGO clinical practice guideline for glomerulonephritis . Kidney Int Suppl 2012 ; 2 : 139 – 274 . CrossRef Search ADS 2 Ayalon R , Beck LH Jr . Membranous nephropathy: not just a disease for adults . Pediatr Nephrol 2015 ; 30 : 31 – 9 . Google Scholar CrossRef Search ADS PubMed 3 Bhimma R , Coovadia HM. Hepatitis B virus-associated nephropathy . Am J Nephrol 2004 ; 24 : 198 – 211 . Google Scholar CrossRef Search ADS PubMed 4 Elewa U , Sandri AM , Kim WR , et al. Treatment of hepatitis B virus-associated nephropathy . Nephron Clin Pract 2011 ; 119 : c41 – 9 . Google Scholar CrossRef Search ADS PubMed 5 Igarashi T , Shimizu A , Igarashi T , et al. Seroconversion of hepatitis B envelope antigen by entecavir in a child with hepatitis B virus related membranous nephropathy . J Nippon Med Sch 2013 ; 80 : 387 – 95 . Google Scholar CrossRef Search ADS PubMed 6 Lin CY , Lin CC , Chang GJ , et al. Defect of cell-mediated immune response against hepatitis B virus: an indication of pathogenesis of hepatitis B virus-associated membranous nephropathy . Nephron 1997 ; 76 : 176 – 85 . Google Scholar CrossRef Search ADS PubMed 7 Shepherd J , Jones J , Takeda A , et al. Adefovir dipivoxil and pegylated interferon alfa-2a for the treatment of chronic hepatitis B: a systematic review and economic evaluation . Health Technol Assess 2006 ; 10 :iii–iv, xi–xiv, 1 – 183 . Google Scholar CrossRef Search ADS 8 Chang TT , Gish RG , de Man R , et al. A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B . N Engl J Med 2006 ; 354 : 1001 – 10 . Google Scholar CrossRef Search ADS PubMed 9 Lai CL , Shouval D , Lok AS , et al. Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B . N Engl J Med 2006 ; 354 : 1011 – 20 . Google Scholar CrossRef Search ADS PubMed 10 Wang YC , Yang SS , Su CW , et al. Predictors of response to pegylated interferon in chronic hepatitis B: a real world hospital based analysis . Sci Rep 2016 ; 6 : 29605 . doi: 10.1038/srep29605. Google Scholar CrossRef Search ADS PubMed © The Author [2017]. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

Journal

Journal of Tropical PediatricsOxford University Press

Published: Jul 27, 2017

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