The Effects of Vitamin D and Calcium Supplementation to Parathyroid Hormone in CHB Patients Treated With Tenofovir Disoproxil Fumarate

Study Overview
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Brief Summary
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Nucleot(s)ide is an antiviral drug that can reduce the number of viruses, reduce the risk of HCC, regress hepatic fibrosis and reduce death from Hepatitis B viral infection. Tenofovir disoproxil fumarate (TDF) is one of nucleotide analogue that is recommended to treated patients with Hepatitis B viral infection. However, long-term TDF therapy may have side effects especially nephrotoxicity and bone toxicity. Previous studies in human immunodeficiency virus (HIV) infected patients who treated with TDF containing regimen antiretroviral therapy, in vitamin D supplement group had a statistic significance of low parathyroid hormone level and better in bone mineral density regardless of initial vitamin D level. Therefore, the main objective of this study is to evaluate the vitamin D and calcium supplement to patients with hepatitis B who have taken TDF, in parathyroid hormone level, bone mineral density, renal function and renal phosphate loss compared to patients who have no vitamin D and calcium supplement.

Detailed Description
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Hepatitis B virus is a global public health problem. This infection leads to chronic hepatitis, cirrhosis and liver cancer. According to past statistics, infection with hepatitis B virus is a common cause of hepatocellular carcinoma about 60% in East-Asia and Africa and about 20% in Western countries. About 350-400 million people are infected worldwide. Infection with hepatitis B virus is also an important factor of death in 1million patients per year. Nucleot(s)ide is an antiviral drug that can reduce the number of viruses, reduce the risk of HCC, regress hepatic fibrosis and reduce death from Hepatitis B viral infection. Nowadays, the recommendation of nucleot(s)ide prefers Tenofovir disoproxil fumarate (TDF), Tenofovir Alafenamide (TAF) and Entecavir (ETV) than Lamivudine, Adefovir and Telbivudine due to high potency and low resistance rate Tenofovir disoproxil fumarate (TDF) is one of nucleotide analogue that inhibits reverse transcriptase in HBV replication process. However, long-term TDF therapy may have side effects especially nephrotoxicity. The proposed mechanisms of nephrotoxicity of TDF are cumulative of TDF at proximal tubule of kidney leads to mitochondrial toxicity, downregulation of sodium-phosphorus cotransporter, sodium/ hydrogen exchanger 3 and aquaporin 2, decreased endothelial nitric oxide-synthase (eNOS) and renal vasoconstriction results in tubulopathy in renal proximal tubule, increase of phosphate loss in urine and increase od serum creatinine. Moreover, TDF also affects to decrease bone mineral density (BMD) that related with renal phosphate loss, loss of osteoblast function, high parathyroid hormone level regardless of vitamin D level and high fibroblast growth factor 23 (FGF23) leads to worsen in bone mineralization Vitamin D has a protective effect and indicate for osteoporosis treatment. The chronic hepatitis B infected patients with vitamin D deficiency may have a poor prognosis in hepatic fibrosis and high HBV DNA level. Previous studies in human immunodeficiency virus (HIV) infected patients who treated with TDF containing regimen antiretroviral therapy, in vitamin D supplement group had a statistic significance of low parathyroid hormone level and better in bone mineral density regardless of initial vitamin D level. Therefore, the main objective of this study is to evaluate the vitamin D and calcium supplement to patients with hepatitis B who have taken TDF, in parathyroid hormone level, bone mineral density, renal function and renal phosphate loss compared to patients who have no vitamin D and calcium supplement.

Official Title
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The Effects of Vitamin D and Calcium Supplementation to Parathyroid Hormone in CHB Patients Treated With Tenofovir Disoproxil Fumarate

Conditions
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Parathyroid Hormone, Tenofovir Disoproxil Fumarate, Chronic Hepatitis, B Virus Without Hepatitis Delta (Diagnosis), Vitamin D

Intervention / Treatment
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* Drug: Ergocalciferol Capsules
* Drug: Calcium carbonate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age between 18 - 75 years old Chronic hepatitis B infected patients treated with TDF monotherapy eGFR ≥ 60 mL/ min/ 1.73 m2 HBV viral load <10 IU/ mL Exclusion Criteria: HIV infection or hepatitis C co-infection Decompensated cirrhosis, including variceal bleeding, ascites, hepatic encephalopathy History of Hepatocellular carcinoma Active malignancy of cancer in other organs Pregnancy or lactation Primary hyperparathyroidism History of thyroid or parathyroid surgery History of radiation at neck area Any osteoporosis treatment or history of osteoporosis diagnosis Chronic kidney disease Current use of Vitamin D Adverse event or allergy to TDF Chronic hepatitis B patients with TDF resistance

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Supplement group<br>Vitamin D2 supplement based on initial vitamin D level ≥ 20ng/mL -> vitamin D2 20,000unit/week 10-19.9ng/mL -> vitamin D2 40,000unit/week <10ng/mL -> vitamin D2 60,000unit/week Calcium carbonate 1000mg/day | Drug: Ergocalciferol Capsules<br>* Depend on initial 25(OH) vitamin D level If <10ng/mL, 60000U of Ergocalciferol capsules per week If 10-19.9ng/mL, 40000U of Ergocalciferol capsules per week If >20 ng/mL, 20000U of Ergocalciferol capsule per week<br>Drug: Calcium carbonate<br>* 1000mg of Calcium carbonate daily<br>|
| No Intervention: No supplement group<br>no medication supplement | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in serum parathyroid hormone | Change from the baseline in serum parathyroid hormone as assessed by Electrochemiluminescent immunoassay (ECLIA) | 48weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in bone mineral density | Change from the baseline in bone mineral density as assessed by Dual-energy X-ray absorptiometry (DXA) | 48weeks | 
| Renal function changes | Change from the baseline in renal function (eGFR) based on creatinine as assessed by Enzymatic method | 48weeks | 
| Change in renal phosphate loss | Change from the baseline in the tubular reabsorption of phosphate (TRP) as renal phosphate loss depended on serum creatinine, urine creatine (assessed by enzymatic method) and serum phosphate, urine phosphate (assessed by modification of the classical phosphomolybdate method by Fiske and Subbarow) | 48weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tenofovir disoproxil fumarate, Tenofovir, Chronic hepatitis B, Parathyroid hormone, Bone mineral density, Renal phosphate loss, Vitamin D, Calcium, PTH, CHB, HBV, TDF