The BOKITO-2B Study: Tenofovir DF Bone and Kidney Toxicity.;Incidence and reversibility in HBV-monoinfected patients.

For extensive information regarding background, see also study protocol text,
page 10-14.

After its recent approval for use in the treatment of chronic hepatitis B virus
(HBV)-infection (cHBV) tenofovir disoproxil fumarate (TDF), a nucleotide
reverse transcriptase inhibitor, has become a preferred first line drug in this
pathology. TDF is a first line drug in HIV treatment as well. The last few
years increasing evidence has emerged relating TDF use to the development of
kidney proximal tubular dysfunction (KPTD), renal insufficiency and
osteomalacia in HIV-infected individuals. KPTD, with renal losses of phosphate,
small proteins, amino acids, glucose and uric acid, is found in up to 22-53% of
asymptomatic HIV-infected patients on TDF containing ART. The pathophysiology
behind its development has not been elucidated and may be multifactorial. Risk
factors for its development in HIV identified from studies performed to date
include increased age, low body weight, pre-existing decrease in kidney
function, and concomitant use of nephrotoxic drugs. As recently shown in
HIV-infected persons, the intracellular tenofovir-diphosphate (TFV-DP, its
active metabolite) increases 8% with every 10 mL/min decrease in glomerular
filtration rate and with every 1-L/h decline in TFV renal clearance. Currently,
in the TDF package insert TDF dose adjustment is recommended in patients with
renal clearances < 50 mL/min but not in patients with mild renal impairment
(CCl 50-80 mL/min). This advice however has to be taken with caution as it is
based on pharmacokinetic studies with single dose TDF monotherapy in non-HIV
infected volunteers.
There are no data on the occurrence of KPTD in HBV-monoinfected individuals on
TDF. Furthermore no data exist on drug levels of TDF and its metabolites in
cHBV treatment. Also, there are few data on the reversibility of tenofovir
associated KPTD and no prospective studies on the effect of TDF dose reduction
in patients with KPTD.

The main objective of this study is to assess incidence of, clinical
determinants for, dose reduction in and reversibility of tenofovir associated
renal insufficiency and KPTD.
Secondary objectives are to assess kidney tubular function in patients with
cHBV on entecavir and without treatment, to relate plasma and intracellular
levels of tenofovir (diphosphate) to the occurrence of renal insufficiency and
KPTD, to report on plasma and intracellular levels of tenofovir (diphosphate)
in cHBV.

Cross-sectional and prospective, observational study.

Dose reduction:

Subjects in group 1 meeting the following criteria at inclusion (weeks 0 and
4), will have TDF dose reduction from TDF 300 mg qd to TDF 300 mg eod
(Monday-Wednesday-Friday):
Patients with:
• tenofovir plasma levels above the upper limit of normal (normal range
0.05-0.30 mg/L) at weeks 0 and 4.
• KPTD at weeks 0 and 4.
• Renal insufficiency: a confirmed renal clearance of < 80 mL/min, or a
confirmed >25% decrease in renal clearance since initiation of TDF.

Definition of baseline renal clearance: estimated GFR (eGFR) at TDF initiation,
or at least within 6 months before as determined by CG formula.

Definition of confirmed renal clearance: best of two values for eGFR as
determined by the CG formula at weeks 0 and 4.

After TDF dose reduction urine and laboratory tests will be performed at 4, 8,
12, 24, 36 and 48 weeks (at week 8 HBV-DNA only).
If renal dysfunction/KPTD in a patient is not fully reversible after 24 weeks
(reversible is GFR within 10% of baseline eGFR/no KPTD criteria) we will leave
it to the treating physician to decide whether to switch from TDF to another
antiviral drug or to continue TDF.

Definition of and course of action in case of viral blip and virologic failure
in patients on reduced TDF-dose:
1. In patients with an undetectable HBV-viral load before dose reduction on at
least two consecutive occasions virologic failure is defined as an HBV-viral
load > 1000 IU/mL. In these patients this finding will be confirmed in a second
sample. If confirmed genotypic testing will be performed to search for
resistant viral genetic variants. Patients then will be excluded from the study
and we leave it to the treating physician to decide whether to switch from TDF
to another antiviral drug, to add another antiviral drug or to increase the TDF
dose.

2. In patients with an undetectable HBV-viral load before dose reduction on at
least two consecutive occasions a viral blip is defined as an HBV-viral load
>50 and <1000 IU/mL. In patients with a viral blip a repeat HBV-viral load test
will be done 4 weeks after the last measurement. If undetectable (< 50 IU/mL)
the patient will continue the reduced TDF dose. If >50 IU/mL, genotypic
testing will be performed to search for resistant viral genetic variants.
Patients then will be excluded from the study and we leave it to the treating
physician to decide whether to switch from TDF to another antiviral drug, to
add another antiviral drug or to raise the TDF dose.

3. In patients with detectable HBV-viral load previous to dose reduction,
virologic failure is defined as an increase in HBV-viral load of at least 1
log. In these patients this finding will be confirmed in a second sample. If
confirmed genotypic testing will be performed to search for resistant viral
genetic variants. Patients then will be excluded from the study and we leave it
to the treating physician to decide whether to switch from TDF to another
antiviral drug, to add another antiviral drug or to raise the TDF dose.

NOTE: In the aforementioned inclusion period for selection of patients meeting
the criteria for dose reduction (week 0 and 4), we expect to find adequate
numbers. However, if the number of patients meeting these criteria is below 20
the authors aim to extend the inclusion period. The medical ethical commission
of the Erasmus MC (METc) will be notified if this should be the case.

People already receive standard of care (physical examination, blood and urine
testing and treatment). During 52-96 weeks they are observed, using blood
parameters of routinely taken samples in the frequency used in daily practice.
Urine samples are taken each visit (6 times in the first 48 weeks and twice in
the second 48 weeks), where in daily clinical practice twice yearly would be
advised.

The extra 'burden' of this research consists of
- a questionnaire each visit (2 minutes extra)
- urine sample each visit (3 minutes extra)
- 3 extra blood tubes each visit (no extra vena puncture required)
- 1 extra blood tube once (pharmacogenetic research, additional informed
consent) (no extra vena puncture required)

Benefit:
close monitoring and intervention (dose reduction) in case of meeting criteria
for dose reduction, with the potential benefit of early detection of renal side
effect and reversibility upon dose reduction.

Group relatedness: because it involves monitoring for adverse events, this
study can only be performed on patients with chronic hepatitis B.