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

Hepatitis B Clinical Trial

— HBVSECURE  

Official title:

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.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01500265
• Other study ID #: I10006 HBVSECURE
• Status: Completed
• Phase: N/A
• First received: December 22, 2011
• Last updated: February 23, 2016
• Start date: December 2011
• Est. completion date: December 2015

Study information

• Verified date: February 2016
• Source: University Hospital, Limoges
• Contact: n/a
• Is FDA regulated: No
• Health authority: France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
• Study type: Observational

Clinical Trial Summary

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.

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 216
• Est. completion date: December 2015
• Est. primary completion date: December 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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 Design

Observational Model: Case Control, Time Perspective: Prospective

Related Conditions & MeSH terms

• Hepatitis
• Hepatitis A
• Hepatitis B
• Renal Failure With Tubular Necrosis

Intervention

Biological:
• plasma and urine samples, sample with ADN
plasma and urine samples every three months Sample with ADN at baseline

Locations

Country	Name	City	State
France	CHU d'Amiens	Amiens
France	CHU d'Angers	Angers
France	CHU de Besancon	Besancon
France	CHU de Bordeaux - Hôpital Saint André	Bordeaux
France	CHU de Brest	Brest
France	CHU de CAEN	Caen
France	CHU de Clermont Ferrand	Clermont Ferrand
France	AP-HP - Hôpital Beaujon	Clichy
France	Centre Hospitalier Laennec de Creil	Creil
France	Centre Hospitalier d'Hyères	Hyères
France	Centre Hospitalier de La Roche sur Yon	La Roche sur Yon
France	AP-HP - Hôpital Kremlin Bicêtre	Le Kremlin Bicêtre
France	CHU de Lille - Hôpital Huriet	Lille
France	CHU de Limoges - Fédération Hépatologie	Limoges
France	Hospices Civils de Lyon - Hôpital Croix Rousse	Lyon
France	CHU de Montpellier - Hôpital Saint Eloi	Montpellier
France	CHU de Nice	Nice
France	AP-HP - Hôpital Bichat	Paris
France	AP-HP - Hôpital La Pitié Salpétrière	Paris
France	CHU de Bordeaux - Hôpital Haut Levêque	Pessac
France	CHU de Point à Pitre	Point à Pitre
France	CHU de Poitiers	Poitiers
France	CHU de Strasbourg - Hôpital Civil	Strasbourg
France	CHU de Tours - Hôpital Trousseau	Tours
France	CHU de Nancy - Hôpital Brabois	Vandoeuvre les Nancy

Sponsors (1)

Lead Sponsor	Collaborator
University Hospital, Limoges

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Secondary	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	No