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Study sheds light on how tenofovir is processed in different body tissues
Liz Highleyman, 2015-08-13 07:50:00
Tenofovir, which is widely used for HIV
treatment and prevention, is activated in a tissue-specific manner, being
processed by different enzymes in immune cells, the vagina and the colon,
according to a study published in the July 19 advance edition of EBioMedicine. These findings have
implications for the effectiveness of tenofovir for pre-exposure prophylaxis
Tenofovir disoproxil fumarate or TDF (Viread, also in the Truvada,
Atripla, Eviplera and Stribild
coformulations) is among the most widely used antiretroviral drugs for HIV
treatment. A new formulation under development, tenofovir alafenamide or TAF,
reaches higher levels in HIV-susceptible immune cells when taken at lower doses
that are easier on the kidneys and bones.
Oral Truvada is the only agent currently approved for HIV PrEP in the US.
Other tenofovir formulations are under study including gels and vaginal rings.
The iPrEx trial of mostly gay and bisexual men showed that once-daily Truvada reduced the risk of HIV
infection by 44% overall, rising to 92% among participants with blood drug
levels indicating consistent use.
Truvada PrEP also performed well in the Partners PrEP and TDF2 studies
of heterosexual couples in Africa. But the FEM-PrEP and VOICE trials of
young women were unable to show a protective effect for Truvada
or tenofovir vaginal gel. This has primarily been attributed to poor adherence,
but animal and human studies suggest there are also physiological reasons why
tenofovir may be less effective against vaginal compared to rectal HIV
Julie Lade and colleagues of Johns Hopkins University School of Medicine performed a laboratory
study to analyse the chemical processing required to convert tenofovir to its
pharmacologically active form in the body.
Tenofovir requires two phosphorylation steps (addition
of phosphate groups), being converted first to tenofovir monophosphate then to
the active form tenofovir diphosphate. But the specific kinase enzymes that
activate tenofovir in cells and tissues susceptible to HIV infection have not
yet been identified, the study authors noted as background.
In this study, the researchers examined peripheral
blood mononuclear cells (PBMCs) and vaginal and colon-rectal tissue samples
that were transfected with siRNA targeting nucleotide kinases and incubated
with tenofovir in the laboratory. As explained in a Johns Hopkins press release, this had the effect of "knock[ing] out
genes for phosphate-adding enzymes one by one."
They also genetically sequenced clinical samples from
142 women who participated in Microbicide Trials Network study MTN-001, which
tested oral tenofovir and 1% tenofovir vaginal gel.
The investigators found that adenylate
kinase 2 (AK2) performed the first phosphorylation step – converting tenofovir to tenofovir monophosphate – in
PBMCs, vaginal tissue and colon tissue. Both of the pyruvate kinase isoenzymes –
muscle (PKM) and liver/red blood cell (PKLR) versions – were able to
phosphorylate tenofovir monophosphate to tenofovir
diphosphate in PBMCs and vaginal tissue. However,
the creatine kinase muscle isoenzyme (CKM) performed this conversion in colon
Sequencing of the MTN-001 clinical samples detected 71
previously unreported variants in the genes encoding these kinases, several of
which could make the enzymes ineffective. Overall, 8% of the women had genetic
variants that would likely make them unable to convert tenofovir to its
"[O]ur results demonstrate that tenofovir is
activated in a compartment-specific manner," the authors concluded.
"Further, genetic variants have been identified that could negatively
impact tenofovir activation, thereby compromising tenofovir efficacy in HIV
treatment and prevention."
"Because these enzymes are polymorphic and may be
dysfunctional in some individuals, these findings suggest that tenofovir-based
HIV PrEP may not be protective for all individuals," they added.
"Tenofovir has been shown in trials to be very
effective, so when it doesn’t work, researchers and clinicians tend to assume
the individual just wasn’t taking the drug as directed," coauthor Namandje
Bumpus explained in the Johns Hopkins press release. "That is probably
true in most cases, but in others, it’s possible that genetic variation is
actually at fault."
"If confirmed by further studies, our results suggest that in the
future, before prescribing tenofovir to a patient, a doctor could order genetic
testing and know in advance if it works, and prescribe a different drug if it
won’t," she added.