Treatment with tenofovir disoproxil
fumarate (TDF) does not increase the risk of fractures, according to French
research published in the online edition of the Journal of Acquired Immune Deficiency Syndromes. Findings of the
case-controlled study showed there was no association between TDF and
fractures in any of the statistical models designed by the authors.
This is the most thorough research
to date assessing the relationship between TDF and fracture risk. The lack of
any clear associations between the drug and fracture risk calls into question
of value of prescribing patented tenofovir alafenamide (TAF) over TDF which is now available in much cheaper generic formulations.
TDF is a component of Truvada and Atripla and their generic equivalents, as well as Eviplera and Stribild. TAF is a component of Odefsey, Genvoya, Symtuza, Descovy and Biktarvy.
Protease inhibitor (PI) therapy has
also been associated with an increased risk of fracture but the authors were
unable to establish a robust link between any antiretroviral, PIs included, and elevated fracture rates.
“We found no evidence of an excess
risk of fracture after exposure to TDF and PIs,” comment the authors. “This has
important implications for the debate concerning tenofovir alafenamide versus
generic TDF.”
People with HIV have lower bone
mineral density (BMD) and an increased risk of fractures compared to age- and
sex-matched HIV-negative controls. BMD drops after starting antiretroviral
therapy (ART), especially with TDF-containing regimens and treatment based on a
PI.
Ten studies have examined the links
between specific antiretroviral drugs and the risk of fracture. Their
methodology differed considerably, including the definition of fracture.
Moreover, few of the studies took into account the full range of traditional
risk factors for low BMD and fractures.
Investigators used data from the
French Hospital Database on HIV to design a study in order to more thoroughly
examine the potential link between individual antiretroviral drugs and fracture
risk.
Their study population consisted of
254 people who experienced a low-impact fracture between 2000 and 2010 who
were enrolled in the database before starting antiretroviral treatment. These people were matched with 376
age- and sex-matched HIV-positive fracture-free controls who were likewise
recruited while antiretroviral naïve.
The association between ART
exposure and individual drugs was studied using various models that took into
account any exposure and cumulative use.
The investigators considered a
range of potential confounders. The following traditional risk factors were
explored: region of geographical origin, body mass index (BMI), smoking,
alcohol consumption, use of systemic glucocorticoids, and menopausal status for
women. Numerous HIV-related factors were also included in the investigators’
modelling, including year of HIV diagnosis,
HIV transmission group, year of ART initiation, AIDS status, nadir and current CD4 cell count, viral load and
hepatitis C virus antibody status. Information was also gathered on
kidney function, a possible pathway for the posited link between TDF therapy
and increased fracture risk.
Median age was 49 years and 67% of participants were men. Almost three-quarters of the cases were diagnosed with HIV
before 1997. Median and nadir CD4 cell
counts for the cases were 436 cell/mm3 and 172 cells/mm3,
respectively. Two-thirds of cases had an undetectable viral load.
All fractures were low impact and
at sites potentially associated with osteoporosis. Over three-quarters of cases
(79%) experienced only one fracture, 14% had two fractures, 4% had three
fractures and 2% had four fractures. The most common fracture sites were the vertebrae, hip and wrist.
At the time of fracture diagnosis,
49% of cases had ever been treated with TDF and 82% with a PI. The median duration of exposure was 2.5 years for TDF and 4.3 years for PIs.
In both the univariate nor
multivariate models, and regardless of how ART use was defined, no association
was found between TDF use and risk of fracture. After adjustment for
confounders, there was no association in the “ever-exposed” model (OR = 1.21;
95% CI, 0.61-2.39) or the cumulative exposure model (OR = 1.04; 95% CI,
0.86-1.27).
Therapy with the protease inhibitor
atazanavir was associated with increased fracture risk in some models, but this
finding was far from robust and ceased to be significant in a sensitivity
analysis that took into account other risk factors. Nor did the investigators
find any evidence of an interaction between TDF and atazanavir to increase
fracture risk.
The authors were also unable to
establish a clear and robust relationship between any other individual
antiretroviral and an increased risk of fractures.
“We found no robust association
between the risk of fracture in HIV-infected patients and exposure to ARV drugs
including exposure to TDF and PIs,” comment the authors. “Some drugs,
particularly efavirenz associated with a lower risk and atazanavir associated
with a higher risk, were significantly associated with fracture risk in some
models we constructed; however, sensitivity analyses showed that these
associations were not robust.”
TAF is being presented as a safer
alternative to TDF, with a lower risk of osteoporosis, fractures and kidney dysfunction. But
the results of this research call into question the potential safety benefits of
branded TAF over much cheaper generic TDF, in relation to fractures specifically. The investigators conclude: “these
results have important implications for the use of tenofovir alafenamide versus
generic TDF.”