The risks of concurrent treatment with tenofovir and aminoglycosides in patients with HIV-associated tuberculosis.
We recently admitted a 47-year-old man with a background of hypertension who had a serum creatinine level of 131 [micro]mol/l prior to ART. He was diagnosed with pulmonary tuberculosis (Mycobacterium tuberculosis was cultured from his sputum). Because he had had a fully treated episode of pulmonary tuberculosis in 2007, he was commenced on regimen 2 Tb treatment (including streptomycin during the intensive phase) in March 2010. At this time he tested HIV positive, and because he had a CD4 count of 61 cells/[micro]l he was commenced on tenofovir, lamivudine and efavirenz in May 2010, while still receiving streptomycin. He was referred to our hospital 3 weeks later with a 1-week history of weakness, vomiting and confusion. The creatinine level was now 1 902 [micro]mol/l and the urea level 59 mmol/l. He was admitted, tenofovir was switched to stavudine, streptomycin was stopped, and he received intravenous rehydration and a broad-spectrum antibiotic. His blood culture was negative and urine microscopy showed no evidence of urinary tract infection. His creatinine level steadily decreased and within 3 weeks was 160 [micro]mol/l.
A 28-year-old HIV-infected man was on a tenofovir-based ART regimen when he was diagnosed with MDR TB. He was started on MDR TB treatment including kanamycin and remained on tenofovir. His creatinine level rose from 64 [micro]mol/l to 180 [micro]mol/l within 1 month of starting MDR treatment. He was then referred to our hospital. Tenofovir was changed to stavudine and the kanamycin was stopped, yet his creatinine remained elevated 3 months later (125 [micro]mol/l), suggesting that chronic renal damage may have resulted. He will continue to be followed up.
The aminoglycosides are potent nephrotoxins, in part because of the high concentrations they attain in the proximal tubular cells (PTCs)--up to 10% of the total parenteral dose may be concentrated in these cells. (2) Here they undergo retrograde transport through the endoplasmic reticulum, where they can interfere with protein sorting and synthesis, (3) and are then transported into the nucleus and mitochondria where they can inhibit mitochondrial ribosomes (4) (in a way that is analogous to their bactericidal effect on the small ribosomal unit of bacteria). It is thought that one mechanism through which they cause acute tubular necrosis (and Fanconi's syndrome) is tubular mitochondrial toxicity.
Like the aminoglycosides, tenofovir attains high concentrations in the PTCs as a result of active uptake into these cells. A substantial proportion of patients taking tenofovir may develop certain of the features of Fanconi's syndrome (a proximal tubular wasting syndrome) as a result of PTC dysfunction. One study reported that 22% of patients on tenofovir developed at least 2 out of 6 features of proximal tubular dysfunction such as hyperaminoaciduria, glycosuria in the presence of normoglycaemia, and hyperphosphaturia. (5) Tenofovir may also cause renal failure. There is evidence to suggest that tenofovir's nephrotoxicity is related to tubular mitochondrial toxicity with abnormal mitochondria having been observed on electron microscopy of tubular cells in renal biopsies of patients on tenofovir. (6) Acute tubular necrosis has been observed in patients who have had a renal biopsy after developing tenofovir-related acute renal failure. (7)
When tenofovir was developed there were concerns that it would be nephrotoxic because other nucleotide reverse transcriptase inhibitors (adefovir used to treat hepatitis B and cidofovir used to treat herpes virus infections) are nephrotoxic. (7) However, early clinical trials failed to demonstrate any excess risk of renal adverse events in participants receiving tenofovir. (8,9,10) These clinical trials did, however, exclude patients with impaired renal function and those on other nephrotoxic drugs. Subsequent reports from HIV treatment cohorts showed that tenofovir is associated with mild decreases in glomerular filtration rate when compared with patients on other antiretrovirals. (11,12) More importantly, a minority of patients on tenofovir develop acute or chronic renal failure. In a review of studies from developed world settings it was estimated that <1% will develop clinically significant renal impairment. (7) In 2006, Zimmermann et al. published 5 cases of acute renal failure related to tenofovir and reviewed a further 22 cases that had been reported in the literature to that date. (13) In 5 of these 27 patients the renal impairment did not fully resolve after stopping tenofovir. In a recent analysis of the EuroSIDA cohort, increasing exposure to tenofovir was associated with a higher incidence of chronic kidney disease. (14) A recently published systematic review and meta-analysis found that there was a modest but statistically significant increase in the risk of acute renal failure in patients on tenofovir compared with other antiretrovirals (risk difference 0.7%, 95% confidence interval (CI) 0.2-1.2). Importantly, in 11 of the 17 studies in the meta-analysis patients with abnormal renal function at baseline were excluded, and the majority of the studies reviewed were clinical trials from which patients on other nephrotoxic medications were likely to have been excluded. (15) These studies may therefore have underestimated the risk of tenofovir nephrotoxicity by excluding patients at higher risk.
There is concern that in sub-Saharan Africa the risks of tenofovir nephrotoxicity may be greater because of the high background prevalence of renal disease, including HIV-associated nephropathy, and lack of capacity to monitor renal function regularly. An analysis of renal outcomes of the DART study, conducted in Uganda and Zimbabwe, showed no difference in the incidence of severe reductions in estimated glomerular filtration rate in patients started on tenofovir-based regimens compared with other regimens, but all the patients who died of renal failure (N=11) were on tenofovir. Contributing co-morbidities were identified in most of these 11 patients. In one of these patients it was thought that the combination of gentamicin and tenofovir was responsible. (16) An additional issue to consider in our setting is that if patients do develop severe renal failure, access to dialysis facilities, especially in rural areas, is limited.
It is biologically plausible that the toxicities of aminoglycosides and tenofovir may be additive in the mitochondria of PTCs. Analysis of data from the tenofovir expanded-access programme revealed that being on concomitant nephrotoxic medications was an independent risk factor for elevations in serum creatinine during follow-up. (17) In a case-control study conducted in a US HIV clinic, concurrent nephrotoxic medication (such as high-dose or chronic non-steroidal anti-inflammatory drugs (NSAIDs), amphotericin B and aminoglycosides) was shown to independently increase the risk of tenofovir-associated nephrotoxicity (odds ratio 6.4, 95% CI 2.2-18.4). (18) Indeed, the package insert for tenofovir states that it 'should be avoided with concurrent or recent use of a nephrotoxic agent'. (19)
A particular concern is that aminoglycosides for treating TB are prescribed for between 2 and 6 months. It is likely that the risk of nephrotoxicity with tenofovir and aminoglycoside will be greater if co-administered for this long duration. One approach that has been suggested is that the combination could be used, but with close monitoring of serum creatinine. However, given that drug-induced nephrotoxicity may result in acute renal failure within 1-2 weeks this would necessitate a frequency of monitoring and follow-up of results that is not practical in busy HIV and TB programmes.
While the new national ART guidelines do not address the risks of co-administration of tenofovir and aminoglycosides, (1) we think that there is sufficient evidence to concur with a recent recommendation to avoid the co-administration of tenofovir and aminoglycosides whenever possible. (20) When considering what to do in the light of this co-toxicity, it is important to recall that the aminoglycosides (kanamycin or amikacin) used in the treatment of MDR TB and the cyclic polypeptide, capreomycin, used in the treatment of extensively drug-resistant (XDR) TB, are essential components of these treatment regimens. On the other hand, streptomycin is not a critical component of regimen 2 TB treatment, particularly now that rapid drug susceptibility testing is available to appropriately direct therapy in patients being retreated for TB. We therefore recommend the following:
* During the intensive phase of MDR TB treatment (while the patient is on amikacin or kanamycin), do not prescribe tenofovir. In place of tenofovir use zidovudine, stavudine or abacavir. After completing the aminoglycoside component of MDR TB treatment, patients could be switched to tenofovir provided the estimated creatinine clearance is >50 ml/min. This switch to tenofovir is particularly important in patients with hepatitis B co-infection.
* The same approach should be used in patients on capreomycin during the intensive phase of XDR TB treatment. Capreomycin is also nephrotoxic.
* In patients on tenofovir who require regimen 2 TB treatment, omit streptomycin from regimen 2. In
How to calculate creatinine clearance (modified Cockroft and Gault formula)
eGFR = (140 - age) x weight (kg) / serum creatinine ([micro]mol/l)
For females multiply the GFR by 0.85. eGFR = estimated glomerular filtration rate.
patients starting tenofovir-containing ART while on regimen 2 TB treatment, omit the streptomycin from regimen 2 from when they start the tenofovir. In all other respects regimen 2 TB treatment should remain unchanged.
Our first case highlights another important point: that it is critically important to calculate the estimated creatinine clearance in patients before starting tenofovir, and if it is <50 ml/min, tenofovir should not be used. (1) This patient had an estimated clearance of 32 ml/min prior to ART (this was probably related to HIV-associated nephropathy and/or hypertensive nephropathy). This patient should therefore not have received tenofovir or streptomycin. It is likely that in this case underlying renal impairment and treatment with two nephrotoxins all contributed to the development of severe acute renal failure.
Acknowledgements. Graeme Meintjes is supported by the Wellcome Trust and received SATBAT research training funded by the Fogarty International Center and the NIH (NIH/FIC 1U2RTW007373 and 5U2RTW007370).
(1.) Clinical Guidelines for the Management of HIV & AIDS in Adults and Adolescents. Pretoria: National Department of Health, Republic of South Africa, 2010.
(2.) Galloe AM, Graudal N, Christensen HR, Kampmann JP. Aminoglycosides: single or multiple daily dosing? A meta-analysis on efficacy and safety. Eur J Clin Pharmacol 1995;48(1):39-43.
(3.) Sandavol RM, Molitoris BA. Gentamicin traffics through the secretory pathway and is released in the cytosol via the endoplasmic reticulum. Am J Physiol Renal Physiol 2004;286(4):617-624.
(4.) Hobbie SN, Akshay S, Kalapala SK, Bruell CM, Scherbakov D, Bottger EC. Genetic analysis of interactions with eukaryotic rRNA identify the mitoribosome as target in aminoglycoside ototoxicity. Proc Natl Acad Sci USA 2008;105(52):20888-20893.
(5.) Labarga P, Barreiro P, Martin-Carbonero L, et al. Kidney tubular abnormalities in the absence of impaired glomerular function in HIV patients treated with tenofovir. AIDS 2009;23:689-696.
(6.) Cote HC, Magil AB, Harris M, et al. Exploring mitochondrial nephrotoxicity as a potential mechanism of kidney dysfunction among HIV-infected patients on highly active antiretroviral therapy. Antivir Ther 2006;11(1):79-86.
(7.) Gitman MD, Hirschwerk D, Baskin CH, Singhal PC. Tenofovir-induced kidney injury. Expert Opin Drug Saf 2007;6(2):155-164.
(8.) Schooley RT, Ruane P, Myers RA, et al.; Study 902 Team. Tenofovir DF in antiretroviral-experienced patients: results from a 48-week, randomized, double-blind study. AIDS 2002;16(9):1257-1263.
(9.) Gallant JE, Staszewski S, Pozniak AL, et al.; 903 Study Group. Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviral-naive patients: a 3-year randomized trial. JAMA 2004;292(2):191-201.
(10.) Gallant JE, DeJesus E, Arribas JR, et al.; Study 934 Group. Tenofovir DF, emtricitabine, and efavirenz vs. zidovudine, lamivudine, and efavirenz for HIV. N Engl J Med 2006;354(3):251-260.
(11.) Gallant JE, Parish MA, Keruly JC, Moore RD. Changes in renal function associated with tenofovir disoproxil fumarate treatment, compared with nucleoside reverse-transcriptase inhibitor treatment. Clin Infect Dis 2005;40(8):1194-1198.
(12.) Winston A, Amin J, Mallon P, et al. Minor changes in calculated creatinine clearance and anion-gap are associated with tenofovir disoproxil fumarate-containing highly active antiretroviral therapy. HIV Med 2006;7(2):105-111.
(13.) Zimmermann AE, Pizzoferrato T, Bedford J, Morris A, Hoffman R, Braden G. Tenofovir-associated acute and chronic kidney disease: a case of multiple drug
interactions. Clin Infect Dis 2006;42(2):283-290.
(14.) Mocroft A, Kirk O, Reiss P, et al. EuroSIDA Study Group. Estimated glomerular filtration rate, chronic kidney disease and antiretroviral drug use in HIV-positive patients. AIDS 2010;24(11):1667-1678.
(15.) Cooper RD, Wiebe N, Smith N, Keiser P, Naiker S, Tonelli M. Systematic review and meta-analysis: Renal safety of tenofovir disoproxil fumarate in HIV-infected patients. Clin Infect Dis 2010;51(5):496-505.
(16.) Reid A, Stohr W, Walker S, et al. Severe renal dysfunction and risk factors associated with renal impairment in HIV-infected adults in Africa initiating antiretroviral therapy. Clin Infect Dis 2008;46:1271-1281.
(17.) Nelson MR, Katlama C, Montaner JS, et al. The safety of tenofovir disoproxil fumarate for the treatment of HIV infection in adults: the first 4 years. AIDS 2007;21:1273-1281.
(18.) Castellano C, Williams W, Kepler T, et al. Clinical predictors of tenofovir-associated nephrotoxicity in HIV-1 infected patients. Presented at the 17th International AIDS Conference, Mexico City, 3-8 August 2008. Abstract WEAB0104.
(19.) Viread (Tablets) Package Insert, 23 February 2007.
(20.) Coyne KM, Pozniak AL, Lamorde M, Boffito M. Pharmacology of second-line antituberculosis drugs and potential for interactions with antiretroviral agents. AIDS 2009; 23:437-446.
Chris Kenyon [1,2], MB ChB, FCP (SA), Cert ID (SA) Nicci Wearne , MB ChB, FCP (SA) Rosie Burton [1,2], MB ChB, FCP (SA), Cert ID (SA) Graeme Meintjes [1,2,4,5], MB ChB, FCP (SA), MRCP, Dip HIV Man (SA)
 Department of Medicine, G F Jooste Hospital, Cape Town
 Division of Infectious Diseases and HIV Medicine, Department of Medicine, University of Cape Town
 Division of Nephrology, Department of Medicine, University of Cape Town
 Institute of Infectious Diseases and Molecular Medicine, University of Cape Town
 Department of Medicine, Imperial College London
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|Title Annotation:||CASE STUDIES--HIV AND THE KIDNEYS|
|Author:||Kenyon, Chris; Wearne, Nicci; Burton, Rosie; Meintjes, Graeme|
|Publication:||Southern African Journal of HIV Medicine|
|Article Type:||Case study|
|Date:||Apr 1, 2011|
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