Restricted accessResearch articleFirst published online 2014-3
An investigation of the pattern of kidney injury in HIV-positive persons exposed to tenofovir disoproxil fumarate: an examination of a large population database (MHRA database)
The potential for tenofovir to cause a range of kidney syndromes has been established from mechanistic and randomised clinical trials. However, the exact pattern of kidney involvement is still uncertain. We undertook a descriptive analysis of Yellow Card records of 407 HIV-positive persons taking tenofovir disoproxil fumarate (TDF) as part of their antiretroviral therapy regimen and submitted to the Medicines and Healthcare Products Regulatory Agency (MHRA) with suspected kidney adverse effects. Reports that satisfy defined criteria were classified as acute kidney injury, kidney tubular dysfunction and Fanconi syndrome. Of the 407 Yellow Card records analysed, 106 satisfied criteria for TDF-related kidney disease, of which 53 (50%) had features of kidney tubular dysfunction, 35 (33%) were found to have features of glomerular dysfunction and 18 (17%) had Fanconi syndrome. The median TDF exposure was 316 days (interquartile range 120–740). The incidence of hospitalisation for TDF kidney adverse effects was high, particularly amongst patients with features of Fanconi syndrome. The pattern of kidney syndromes in this population series mirrors that reported in randomised clinical trials. Cessation of TDF was associated with complete restoration of kidney function in up half of the patients in this report.
BHIVA. Guidelines for the treatment of HIV-1 infected adults with antiretroviral therapy. HIV MED 2012; 9: 1–85.
2.
BucherHCWolbersMPorterK. Guidelines for antiretroviral treatment of HIV from the International AIDS Society-USA Panel. JAMA2010; 304: 1897–1898.
3.
MayMGompelsMDelpechV. The impact of late diagnosis impact of late diagnosis and treatment on life expectancy in people with HIV-1: UK Collaborative HIV Cohort (UK CHIC) study. BMJ2011; 343: d61016–d61016.
4.
HerbstAJCookeGSBärnighausenT. Adult mortality and antiretroviral treatment roll-out in rural KwaZulu-Natal, South Africa. Bull World Health Organ2009; 87: 754–762.
5.
JustmanJEBenningLDanoffA. Protease inhibitor use and the incidence of diabetes mellitus in a large cohort of HIV-infected women. J Acquir Immune Defic Syndr2003; 32: 298–302.
6.
BrownTTColeSRLiX. Antiretroviral therapy and the prevalence and incidence of diabetes mellitus in the multicenter AIDS cohort study. Arch Intern Med2005; 165: 1179–1184.
7.
GlassTRUngsedhapandCWolbersM. Prevalence of risk factors for cardiovascular disease in HIV-infected patients over time: the Swiss HIV cohort study. HIV Med2006; 7: 404–410.
8.
PadillaSGutiérrezFMasiáM. Low frequency of renal function impairment during one-year of therapy with tenofovir-containing regimens in the real-world: a case-control study. AIDS Patient Care STDS2005; 19: 421–424.
9.
IzzedineHSebastien HulotJVittecoqD. Long-term renal safety of tenofovir disoproxil fumarate in antiretroviral-naive HIV-1-infected patients. Data from a double blind randomized active-controlled multicentre study. Nephrol Dial Transplant2005; 20: 743–746.
10.
ScherzerREstrellaMLiY. Association of tenofovir exposure with kidney disease risk in HIV infection. AIDS2012; 26: 867–875.
11.
GallantJEStaszewskiSPozniakAL. Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviral-naive patients: a 3-year randomized trial. JAMA2004; 292: 191–201.
12.
GallantJEParishMAKerulyJC. Changes in renal function associated with tenofovir disoproxil fumarate treatment, compared with nucleoside reverse-transcriptase inhibitor treatment. Clin Infect Dis2005; 40: 1194–1198.
13.
ArribasJRPozniakALGallantJE. Tenofovir disoproxil fumarate, emtricitabine, and efavirenz compared with zidovudine/lamivudine and efavirenz in treatment-naive patients: 144-week analysis. J Acquir Immune Defic Syndr2008; 47: 74–78.
14.
Medicines and Healthcare Products Regulatory Agency/Commission on Human Medicines, United Kingdom, http://www.mhra.gov.uk/ (accessed 29 August 2013).
15.
Rodriguez-NovoaSLabargaPSorianoV. Predictors of kidney tubular dysfunction in HIV-infected patients treated with tenofovir: a pharmacogenetic study. Clin Infect Dis2009; 48: 108–116.
16.
IzzedineHHulotJSVillardE. Association between ABCC2 gene haplotypes and tenofovir-induced proximal tubulopathy. J Infect Dis2006; 194: 1481–1491.
17.
NishijimaTKomatsuHHigasaK. Single nucleotide polymorphisms in ABCC2 associate with tenofovir-induced kidney tubular dysfunction in Japanese patients with HIV-1 infection: a pharmacogenetic study. Clin Infect Dis2012; 55: 12–12.
18.
PushpakomSPLiptrottNJRodríguez-NóvoaS. Genetic variants of ABCC10, a novel tenofovir transporter, are associated with kidney tubular dysfunction. J Infect Dis2011; 204: 145–153.
19.
CaoYHanYXieJ. Impact of a tenofovir disoproxil fumarate plus ritonavir-boosted protease inhibitor-based regimen on renal function in HIV-infected individuals: a prospective, multicenter study. BMC Infect Dis2013; 13: 301–301.
20.
CihlarTRayASLaflammeG. Molecular assessment of the potential for renal drug interactions between tenofovir and HIV protease inhibitors. Antivir Ther2007; 12: 267–272.
21.
KiserJJCartenMLAquilanteCL. The effect of lopinavir/ritonavir on the renal clearance of tenofovir in HIV-infected patients. Clin Pharmacol Ther2008; 83: 265–272.
22.
RayASWrightMRRhodesGR. Lack of evidence for an effect of lopinavir/ritonavir on tenofovir renal clearance. Clin Pharmacol Ther2008; 84: 660–660.
23.
GoicoecheaMLiuSBestB. Greater tenofovir-associated renal function decline with protease inhibitor-based versus non-nucleoside reverse-transcriptase inhibitor-based therapy. J Infect Dis2008; 197: 102–108.
24.
GallantJEMooreRD. Renal function with use of a tenofovir containing initial antiretroviral regimen. AIDS2009; 23: 1971–1971.
25.
FuxCASimcockMWolbersM. Tenofovir use is associated with a reduction in calculated glomerular filtration rates in the Swiss HIV Cohort Study. Antivir Ther2007; 12: 1165–1173.
26.
BuchaczKYoungBBakerRK. Renal function in patients receiving tenofovir with ritonavir/lopinavir or ritonavir/atazanavir in the HIV Outpatient Study (HOPS) cohort. J Acquir Immune Defic Syndr2006; 43: 626–628.
27.
YoungJSchäferJFuxC. Renal function in patients with HIV starting therapy with tenofovir and either efavirenz, lopinavir or Atazanavir. AIDS2012; 26: 567–575.
28.
KearneyBPMathiasAMittanA. Pharmacokinetics and safety of tenofovir disoproxil fumarate on co-administration with lopinavir/ritonavir. J Acquir Immune Defic Syndr2006; 43: 278–283.
29.
WeverKvan AgtmaelMACarrA. Incomplete reversibility of tenofovir-related renal toxicity in HIV-infected men. J Acquir Immune Defic Syndr2010; 55: 78–81.
30.
PostFAMoyleGJStellbrinkHJ. Randomized comparison of renal effects, efficacy, and safety with once-daily abacavir/lamivudine versus tenofovir/emtricitabine, administered with efavirenz, in antiretroviral-naive, HIV-1-infected adults: 48-week results from the ASSERT study. J Acquir Immune Defic Syndr2010; 55: 49–57.
