Treatment with tenofovir has an adverse
impact on kidney function, but the clinical significance of this is modest,
according to the results of a systematic review and meta-analysis conducted by
an international team of investigators and published in the September 1st
edition of Clinical Infectious Diseases.
The investigators looked at the results of
17 studies involving a total of 11,000 patients. All the studies compared
outcomes in patients taking tenofovir-containing regimens to those seen in
patients whose HIV treatment did not include this drug. Loss of kidney function
was significantly greater amongst patients who took a combination of drugs that
included tenofovir. In addition, those taking tenofovir were more likely to
develop kidney disease.
However, the investigators comment: “Although
our review identified a significant loss of renal function associated with TDF
[tenofovir] use, the clinical magnitude of this effect was modest.”
Tenofovir (Viread, also in the combination pills Truvada and Atripla) is a
widely-used antiretroviral drug in both industrialised and resource-limited
settings. The clinical trials that formed the basis of the drug’s formal
approval showed that it was very safe.
Nevertheless, after its licensing, case
reports were published showing that some patients treated with the drug had
developed kidney dysfunction or disease. Moreover, several observational cohort
studies have founded that approximately 1% of tenofovir-treated patients per
year develop such severe kidney dysfunction that they cease therapy with the
Patients who are taking antiretroviral
drugs in the UK and similar countries are recommended to have their kidney
function monitored at regular intervals. However, such monitoring is
impractical and unaffordable in many poorer countries.
Therefore, to gain a better understanding of
the safety of treatment with tenofovir investigators performed a systematic
review and meta-analysis of studies reporting on kidney function in patients
taking the drug. They also monitored the effect of the drug on bone metabolism,
as there is some evidence that therapy with tenofovir may reduce bone mineral
density and increase the risk of fractures.
A total of 17 studies were identified by
the investigators. The design of these studies varied. Nine were randomised
controlled trials, five of which were double-blinded. Seven studies gathered
prospective, observational data, and one study used prospectively collected
information from an adverse events register.
A total of 10,889 patients were recruited to these studies. The individual sample
sizes ranged from 49 to 3439. The median duration of follow-up was 48 weeks.
The treatment histories of patients varied
between the studies. Eleven studies only included patients who were
antiretroviral-experienced; three included therapy-naive people, and
three included both naive and experienced patients.
The mean age of patients ranged from 34 to
45 years. Women were under-represented, the percentage of men recruited to the studies ranging from 59% to 100%.
Information on creatinine clearance
(CG-GFR) was reported in eleven studies. There was a significantly greater loss
of this measure of kidney function amongst patients taking tenofovir compared
with the control arms (mean difference, 3.92 ml/min; 95% CI: 2.13 to
5.70). However, the results were highly
inconsistent between the studies.
Six studies reported on the estimated glomerular
filtration rate (MDRD-GFR), another important measure of kidney function. This
showed that this was poorer amongst patients taking tenofovir, but the
difference with those in the control arm was not significant (mean difference,
2.56 ml/min; 95% CI: 0.57 to 5.69). Once again, the results of the individual
studies differed considerably.
Randomised controlled trials were more
likely to find that tenofovir had an adverse impact on kidney function. There
was some evidence that patients who had experience of antiretroviral therapy
were more likely to experience a loss of kidney function due to tenofovir
treatment, compared to patients starting antiretroviral drugs for the first
Studies that were sponsored by drug
companies were slightly less likely to find an association between tenofovir
treatment and loss of kidney function than was research funded from other
Eight studies reported on the incidence of
kidney disease. There was a small, but significant, increase in the risk of
acute renal failure for patients taking tenofovir (difference with patients
taking an alternative antiretroviral = 0.7%).
However, treatment with tenofovir was not
associated with any increase in the risk of chronic kidney disease, or of
end-stage kidney failure requiring long-term dialysis. Nor were patients taking
tenofovir more likely to have protein in their urine.
Only two studies reported on fracture
rates, and these showed that the proportion of patients experiencing fractures
was comparable between the tenofovir and the control arms. Changes in bone
mineral density were also similar between the patients taking tenofovir and
individuals in the control arms.
“Our systematic review suggests that the
risk of clinically relevant renal toxicity due to TDF is relatively low, at
least during the short-term,” comment the investigators.
Nevertheless, they note that “dozens” of
cases of tenofovir-associated kidney dysfunction have been reported. The
researchers provide a number of explanations for the differences between the
findings of their meta-analysis and the outcomes seen in routine practice:
- Many of the cases seen in
clinical practice involved individuals who were also taking ddI (didanosine, Videx, Videx EC) or a
ritonavir-boosted protease inhibitor. By contrast, most of the patients in the
studies were taking an NNRTI and the use of ddI was scrupulously avoided.
- Many case reports involve older
patients, those with advanced HIV disease, and individuals with mild kidney
dysfunction at baseline. Such individuals would be excluded from clinical
“Our findings do not support the need to
restrict TDF use in jurisdictions where regular monitoring of renal function… is
difficult or impractical,” conclude the investigators.