Tenofovir treatment impairs kidney function, but clinical significance limited

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 1^st 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 drug.

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 time.

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 sources.

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:

• More sensitive testing of kidney function was used to diagnose the cases seen in “real world” settings.

• 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 trials.

“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.

Cooper RD et al. Systematic review and meta-analysis: renal safety of tenofovir disoproxil fumarate in HIV-infected patients. Clin Infect Dis 51: 496-505, 2010.