T H E  S O U T H E R N  A F R I C A N  J O U R N A L  O F  H I V  M E D I C I N E                                    A P R I L  2 0 1 1

The South African public sector antiretroviral treatment 
(ART) guidelines have recently been changed to include 
tenofovir in the first-line regimen.1 Injectable drugs 
from the aminoglycoside class are part of the intensive 
phase of regimen 2 tuberculosis (TB) treatment and 
the multidrug-resistant (MDR) TB treatment regimen 
in the South African TB programme. We wish to draw 
the attention of clinicians managing patients with HIV-
associated TB to the potential dangers of concurrent 
administration of these drugs. We present two illustrative 
cases.

CASE 1
We recently admitted a 47-year-old man with a 
background of hypertension who had a serum creatinine 
level of 131 µmol/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/µl 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 µmol/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 µmol/l. 

CASE 2
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 µmol/l to 180 µmol/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 µmol/l), suggesting that chronic 
renal damage may have resulted. He will continue to be 
followed up. 

DISCUSSION
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 ribosomes4 (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 

THE RISKS OF CONCURRENT TREATMENT 
WITH TENOFOVIR AND AMINOGLYCOSIDES 

IN PATIENTS WITH HIV-ASSOCIATED 
TUBERCULOSIS

Chris Kenyon1,2, MB ChB, FCP (SA), Cert ID (SA)
Nicci Wearne3, MB ChB, FCP (SA) 

Rosie Burton1,2, MB ChB, FCP (SA), Cert ID (SA)
Graeme Meintjes1,2,4,5, MB ChB, FCP (SA), MRCP, Dip HIV Man (SA)

1Department of Medicine, G F Jooste Hospital, Cape Town
2Division of Infectious Diseases and HIV Medicine, Department of Medicine, University of Cape Town

3Division of Nephrology, Department of Medicine, University of Cape Town
4Institute of Infectious Diseases and Molecular Medicine, University of Cape Town

5Department of Medicine, Imperial College London

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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:

n    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.

n    The same approach should be used in patients on 
capreomycin during the intensive phase of XDR TB 
treatment. Capreomycin is also nephrotoxic. 

n    In patients on tenofovir who require regimen 2 TB 
treatment, omit streptomycin from regimen 2. In 

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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.

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11.   Gallant JE, Parish MA, Keruly JC, Moore RD. Changes in renal function associated 
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12.   Winston A, Amin J, Mallon P, et al. Minor changes in calculated creatinine clearance 
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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 
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patients. AIDS 2010;24(11):1667-1678. 

15.   Cooper RD, Wiebe N, Smith N, Keiser P, Naiker S, Tonelli M. Systematic review and 
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16.   Reid A, Stohr W, Walker S, et al. Severe renal dysfunction and risk factors associated 
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17.   Nelson MR, Katlama C, Montaner JS, et al. The safety of tenofovir disoproxil 
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18.   Castellano C, Williams W, Kepler T, et al. Clinical predictors of tenofovir-associated 
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19.   Viread (Tablets) Package Insert, 23 February 2007.
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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).

How to calculate creatinine clearance (modified 
Cockroft and Gault formula)

eGFR = (140 – age) × weight (kg)
 serum creatinine (µmol/l)

For females multiply the GFR by 0.85.
eGFR = estimated glomerular filtration rate.

45