Tenofovir toxicity: association with Inosine Triphosphate Pyrophosphohydrolase activity and ITPA genotype

Anti-retroviral therapy (ART) for patients infected with the human
immunodeficiency virus (HIV) has improved substantially over the last years.
However, adverse events (AE) are common and can be severe. Measuring HLA-B*5701
can predict which patient will develop hypersensitivity for abacavir, a potent
HIV-1-nucleoside-analogue reverse-transcriptase inhibitor (NRTI). However, no
other genetic susceptibility traits are known to help guide the choice of ART
regimen.
The enzyme Inosine 5*-triphosphate pyrophosphohydrolase (ITPase) is encoded by
the ITPA gene and prevents intracellular accumulation of the inosine
nucleotides ITP (Inosine 5*-triphosphate) and dITP (deoxy-Inosine 5*-
triphosphate). A substantial part of Western population carries one of the
single nucleotide polymorphisms (SNPs) ITPA c.94 C>A and ITPA c.124+21 A>C.
These polymorphisms result in a decreased ITPase activity compared to the wild
type ITPA gene. ITPA population genetics were evenly distributed between
HIV-infected and control populations. However, the majority of HIV-infected
patients had decreased erythrocyte ITPase activity compared to healthy controls
with the same ITPase genotype. Decreased ITPase activity is associated with a
reduced risk to develop ribavirin-induced haemolytic anemia in patients on
treatment for hepatitis, but with an increased risk of AEs in patients treated
with thiopurines.
In the treatment of HIV-infected patients with ART the nucleoside analogues
abacavir and didanosine and the nucleotide analogue tenofovir are purine
analogues. Purine analogues are potential substrates for ITPase. To develop
more tailor-made treatment for the patients with HIV, further investigation is
warranted to the role of ITPase activity and ITPA genotype in the occurrence of
adverse events during therapy with tenofovir.

To investigate the association of ITPA genotype and ITPase activity with
nephrotoxicity, bone toxicity and recovery of nephrotoxicity and bone toxicity
during and after anti-retroviral treatment with a tenofovir containing regimen
for HIV.

In a case-control study of HIV-infected patients who are using or have been
using tenofovir in the antiretroviral treatment regimen, who had signs for
nephrotoxicity during this treatment regimen, will be matched to control
patients who are using or have been using tenofovir without nephrotoxicity.
ITPA genotype and ITPase activity and the association of these parameters with
adverse events will be determined.
Further, for the patients in which these data are available, the association
between bone toxicity, determined by bone mineral density measurement, ITPA
genotype and ITPase activity will be determined.

The burden of the patients participating will be minimal, while only two extra
tubes of blood will be retrieved during venapuncture that is performed for
their regular visit to the outpatient clinic. If the patients had already had
his/her blood drawn for the regular outpatient visit, he will be asked if the
two extra tubes of blood may be obtained by an extra vena puncture. Further
cooperation will not be needed. The results of this investigation will possibly
affect the prescription of antiretroviral therapy to them and other
HIV-infected patients, when an association will be found between ITPA genotype,
ITPase activity and the occurrence of adverse events. In this way future
adverse events caused by certain antiretroviral medication might reduced.