Assessment and Monitoring of Renal Proximal Tubular Tolerance of Nucleoside and Nucleotide Analogues Using Early Screening Tools in Patients Chronically Mono-infected With Hepatitis B Virus (HBVSECURE)

Assessment and Monitoring of Renal Proximal Tubular Tolerance of Nucleoside and Nucleotide Analogues Using Early Screening Tools in Patients Chronically Mono-infected With Hepatitis B Virus.

Nucleotide analogues are associated in the long term with a risk of proximal tubular nephropathy (PT) with loss of phosphate, and, when compensatory mechanisms are overwhelmed, with osteopenia or osteoporosis. This toxicity has been particularly documented for tenofovir (TDF) in HIV disease, but its prevalence varies widely in the literature and is mainly associated with comorbidities: on average this prevalence is 0.39% after 48 weeks with exceptional cases of Fanconi syndrome described. In HBV monoinfection after 60 months of treatment with TDF, an 11% decrease of creatinine clearance (CreatCl) is observed. A single study showed a significant increase in creatinine level with entecavir (ETV) therapy, a second-generation nucleoside, hitherto not described as nephrotoxic. Furthermore, if the direct renal toxic effect characteristic of HIV in the kidney is well known, the role of HBV is less clear. Thus, HBV treatment appears to have a renal protective effect. The monitoring tools recommended by the SPC, CreatCl and plasma phosphorus level are late markers of tubular damage. The threshold of phosphate tubular reabsorption (TmPi/GFR) and the fractional excretion of uric acid (FEUA) are unexpensive early screening tools. However, the long-term evolution of this subclinical tubular involvement in HBV monoinfection is not known.

Study Overview

• Status: Completed
• Conditions: Hepatitis B; Renal Failure With Tubular Necrosis
• Intervention / Treatment: Biological: plasma and urine samples, sample with ADN

Detailed Description

260 naive untreated patients, 220 patients treated with TDF and 220 patients treated with ETV and consecutively recruited in this interventional study, will have at baseline and every three months, a determination of phosphorus, creatinine, uric acid in plasma and urine samples for determination of TMPi / GFR and FEUA, and an evaluation of urinary calcium level. Depending on local opportunities, every six months, a urine sample will be stored in a declared biological collection to perform β2-microglobuline and cystatin dosage. A 25-OHD3 and PTH dosage will be conducted annually. A sample of genomic DNA will be collected after informed consent of the patient from a saliva sample (Saliva autocollection kits) in order to investigate genetic polymorphism in transporters responsible for the renal elimination of TDF and ETV. A serum sample will be stored at baseline, at one year and at endpoint for the retrospective dosage of bone markers (bone PAlk, PINP and CTX).

• Study Type: Observational
• Enrollment (Actual): 216

Contacts and Locations

Study Locations

• France
  • Amiens, France, 80054
    • CHU d'AMIENS
  • Angers, France, 49933
    • CHU d'Angers
  • Besancon, France, 25000
    • CHU de Besançon
  • Bordeaux, France, 33000
    • CHU de Bordeaux - Hôpital Saint André
  • Brest, France, 29609
    • CHU de Brest
  • Caen, France, 14033
    • CHU de Caen
  • Clermont Ferrand, France, 63003
    • CHU de Clermont Ferrand
  • Clichy, France, 92110
    • AP-HP - Hôpital Beaujon
  • Creil, France, 60109
    • Centre Hospitalier Laennec de Creil
  • Hyères, France, 83407
    • Centre Hospitalier d'Hyères
  • La Roche sur Yon, France, 85925
    • Centre Hospitalier de La Roche sur Yon
  • Le Kremlin Bicêtre, France, 94275
    • AP-HP - Hôpital Kremlin Bicêtre
  • Lille, France, 59037
    • CHU de Lille - Hôpital Huriet
  • Limoges, France, 87042
    • CHU de Limoges - Fédération Hépatologie
  • Lyon, France, 69317
    • Hospices Civils de Lyon - Hôpital Croix Rousse
  • Montpellier, France, 34295
    • CHU De Montpellier - Hopital Saint Eloi
  • Nice, France, 06202
    • CHU de Nice
  • Paris, France, 75651
    • AP-HP - Hôpital La Pitié Salpétrière
  • Paris, France, 75877
    • AP-HP - Hôpital Bichat
  • Pessac, France, 33604
    • CHU de Bordeaux - Hopital Haut Leveque
  • Point à Pitre, France, 97159
    • CHU de Point à Pitre
  • Poitiers, France, 86021
    • CHU de Poitiers
  • Strasbourg, France, 67091
    • CHU de Strasbourg - Hôpital Civil
  • Tours, France, 37044
    • CHU de Tours - Hopital Trousseau
  • Vandoeuvre les Nancy, France, 54511
    • CHU de Nancy - Hôpital Brabois

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Patient with hepatitis B virus

Description

Inclusion Criteria:

• Age ≥ 18 years
• Patients with chronic HBV virus monoinfected
• For groups of patients treated: Patients with an indication of ETV or TDF
• For the group of naive patients: treatment-naive patients who have no indication of treatment (or do not want) for the duration of the study
• globular filtration rate (GFR) ≥ 50 ml / min / 1.73 m2 with no known cause of renal disease
• Patients who have given their informed and written informed consent
• Women of childbearing potential with an effective method of contraception without interruption for the duration of the research and during the 4 months after stopping treatment

Exclusion Criteria:

• Patients co-infected with HIV, hepatitis C or hepatitis Delta
• Patients who have already received the TDF in the group to receive the TDF and having already received ETV in the group to receive ETV
• Patient with a GFR <50 ml / min / 1.73 m2 or with known causes of renal disease
• Patient with hypophosphatemia <0.48 mmol / l
• Patients with hepatocellular carcinoma (diagnosed or suspected)

Study Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Patient naive; Patient with hepatitis B virus naive untreated	Biological: plasma and urine samples, sample with ADN; plasma and urine samples every three months Sample with ADN at baseline
Patient with TDF; Patient with hepatits B treated with Tenofovir	Biological: plasma and urine samples, sample with ADN; plasma and urine samples every three months Sample with ADN at baseline
Patient with ETV; Patient with hepatitis B virus treated with Entecavir	Biological: plasma and urine samples, sample with ADN; plasma and urine samples every three months Sample with ADN at baseline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
the prevalence of "subclinical" proximal tubular abnormalities	to compare at 2 years the prevalence of "subclinical" proximal tubular abnormalities (TmPi/GFR and FEUA) in 3 groups of HBV monoinfected patients treated with TDF, ETV or untreated.	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
the prevalence at baseline of "subclinical" proximal tubular abnormalities	to describe the prevalence at baseline, and the cumulative incidence of these abnormalities during the follow-up and determine the proportion of patients who present at 2 years an impaired CreatCl, an hypophosphatemia and an hypercalciuria (suggesting a bone impact), according to the presence or absence of "subclinical" proximal tubular abnormalities.	1 day

Collaborators and Investigators

• Sponsor: University Hospital, Limoges

Study record dates

Study Major Dates

• Study Start: December 1, 2011
• Primary Completion (Actual): December 1, 2013
• Study Completion (Actual): December 1, 2015

Study Registration Dates

• First Submitted: December 22, 2011
• First Submitted That Met QC Criteria: December 27, 2011
• First Posted (Estimate): December 28, 2011

Study Record Updates

• Last Update Posted (Estimate): February 24, 2016
• Last Update Submitted That Met QC Criteria: February 23, 2016
• Last Verified: February 1, 2016

More Information

Terms related to this study

• Keywords: hepatitis B virus; early screening tools; renal proximal tubular tolerance
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Liver Diseases; Hepatitis, Viral, Human; Hepadnaviridae Infections; DNA Virus Infections; Enterovirus Infections; Picornaviridae Infections; Hepatitis B; Hepatitis; Hepatitis A; Necrosis
• Other Study ID Numbers: I10006 HBVSECURE