Meta-analysis Finds Tenofovir Linked to Modest Kidney Impairment, No Increase in Bone Fractures

		SUMMARY: Use of tenofovir (Viread, also in the Truvada and Atripla combination pills) was found to be associated with statistically significant loss of kidney function in a systematic review and meta-analysis, but this was considered to have only a modest clinical impact, researchers reported in the September 15, 2010 issue of Clinical Infectious Diseases. This review also found no link between tenofovir and bone fractures. Researchers concluded that tenofovir use does not need to be limited in areas where kidney function cannot be adequately monitored.

By Liz Highleyman

Tenofovir and related drugs have the potential to cause kidney toxicity, specifically damage to the tubules that filter blood and reabsorb water, minerals and other substances. Kidney dysfunction was not seen in the pivotal clinical trials leading to the drug's approval, but these studies excluded people with known pre-existing kidney problems. Several case reports and more recent studies have shown a link between tenofovir use and impaired kidney function, but others have not seen this association.

Individuals receiving tenofovir-containing antiretroviral therapy (ART) regimens in high-income countries like the U.S. are advised to receive regular kidney function monitoring, but this may not be available in resource-limited regions, raising questions about whether tenofovir is safe to use in such settings.

In the present study, Ryan Cooper from the University of Alberta and colleagues aimed to determine the renal (kidney) safety of tenofovir-containing antiretroviral regimens. They also looked at bone fractures, since bone loss is another side effect associated with tenofovir in some but not all studies.

The study authors performed a systematic medical literature review, searching the MEDLINE, EMBASE, Global Health, Scopus, Biosis Previews, Cochrane Library, and Web of Science databases, as well as previous systematic reviews. They selected prospective studies comparing tenofovir-containing versus non-tenofovir-containing ART regimens.

A total of 17 studies, including 9 randomized controlled trials, met the selection criteria. The total number of participants was 10,889, with a median study sample size of 517 (range 49 to 3439). The researchers collected data on study design, participant characteristics, therapeutic interventions, kidney function, bone density, and fracture rates. The median follow-up duration was 48 weeks.

Selected studies included both treatment-naive and treatment-experienced participants. A majority were men (60%-100%) and the average age ranged from about 35 to 45 years. 11 studies used Cockcroft-Gault creatinine clearance (CG) and 6 used the MDRD equation to calculate glomerular filtration rate (GFR), an indicator of kidney function; the CG method is better able to detect mild kidney impairment.

Results

	Overall, tenofovir recipients showed significantly greater loss of kidney function compared with patients taking other antiretroviral drugs.
	Kidney impairment was more likely to occur among treatment-experienced patients compared with those just starting ART.
	Tenofovir use was associated with significantly greater kidney impairment using the Cockcroft-Gault GFR method (average difference of 3.92 mL/min).
	Tenofovir was associated with slightly worse MDRD GFR, but the difference did not reach statistical significance (average difference of 2.56 mL/min).
	Patients taking tenofovir also had a higher rate of acute kidney failure, but the overall risk was small (risk difference 0.7%).
	However, there was no evidence that tenofovir use led to increased risk of chronic kidney disease, end-stage kidney disease requiring dialysis, severe proteinuria (protein in the urine), or hypophosphatemia (low blood phosphate level).
	In the 2 studies that reported bone fracture rates, tenofovir recipients did not have a higher risk of fractures.
	Loss of bone mineral density was also similar among tenofovir recipients and people taking other antiretroviral drugs.

"Although [tenofovir] use was associated with a statistically significant loss of renal function, the clinical magnitude of this effect was modest," the study authors concluded. "Our findings do not support the need to restrict [tenofovir] use in jurisdictions where regular monitoring of renal function and serum phosphate levels is impractical."

In their discussion, the investigators suggested that this review may have found less kidney impairment than some prior studies and case reports because participants in this analysis were generally younger, did not have advanced HIV disease, were less likely to have pre-existing kidney problems (such patients are typically excluded from clinical trials), and were less likely to be taking didanosine (ddI, Videx) or ritonavir (Norvir), which can also contribute to kidney toxicity.

Investigator affiliations: Department of Medicine, Public Health Sciences, and Division of Critical Care Medicine, University of Alberta, Edmonton, Alberta, Canada; Center for Public Health Practice, Arkansas Department of Health, Little Rock, AR; University of Texas, Medical Branch, Galveston, TX; Department of Internal Medicine, University of Witwatersrand, Johannesburg, South Africa.

9/14/10

Reference
RD Cooper, N Wiebe, N Smith, and others. Systematic review and meta-analysis: renal safety of tenofovir disoproxil fumarate in HIV-infected patients. Clinical Infectious Diseases 51(5): 496-505 (Abstract). September 15, 2010.