2. Introduction
• India has the second highest population of HIV positive patients in
the world which stands at 2.1 million out of which 600,000 patients
are on antiretroviral therapy.
• Tenofovir based antiretroviral therapy is increasingly used for
treatment naïve and treatment experienced patients in India over
the last 5 years as per recommendation by national guidelines
• It has coincided with availability of generic fixed dose combinations
of Tenofovir/emtricitabine(TE),
Tenofovir/Emtricitabine/Efavirenz(TEE) and
Tenofovir/Lamivudine/Efavirenz(TLE).
• Tenofovir was considered safe and well tolerated due to rarity of
side-effects observed in phase 3 clinical registrational trials.
• Structural similarity to adefovir and cidofovir
• However the experience in “real world” clinical settings is different
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4. Spectrum of kidney injury
• Proximal renal tubular injury - Fanconi
syndrome
• Isolated hypophosphatemia
• Reduced bone mineral density
• Acute kidney injury
• Chronic kidney disease
5. Fanconi syndrome
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With or without reduced GFR
Tubular dysfunction is seen in 17-20% of TDF treated patients
Normal anion gap renal tubular acidosis
Normoglycemic glycosuria
Aminoaciduria
Hypokalemia
Hypophosphatemia
Nephrogenic diabetes insipidus
Calcitriol deficiency
Hypouricemia
Tubular proteinuria : Beta 2 microglobinuria
6. Diagnosis of Fanconi syndrome
• Dipstick test for spot proteinuria, spot
glycosuria
• Protein creatinine ratio > 200 mg/g
• Urinary Beta 2 microglobulin estimation
• Urinary Retinol binding protein or Cystatin C
estimation
7. Tenofovir and Acute kidney injury
(AKI)
• Tenofovir is associated with small but significant risk of AKI
(incidence 1-2.5%)
• Inhibition of mitochondrial DNA polymerase in proximal
tubular epithelial cells leads to acute tubular necrosis and
tubulointerstitial scarring.
• May be observed even a few months after TDF initiation
• Non oliguric renal failure
• Incidence of AKI is higher in observational cohort studies as
compared to randomized controlled trials
• Renal function recovers on discontinuation atleast partially
8. Acute kidney injury : Definition
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AKIN criteria :
Rapid time course (less than 48 hours)
Absolute increase in serum creatinine > 0.3 mg/dl
Percentage increase in serum creatinine > 50 %
Decrease in urine output < 0.5 ml/kg/hr for 6 hours
Rifle criteria :
Injury : GFR decrease > 50 %, doubling of serum creatinine or
urine output < 0.5 ml/kg/hr for 12 hours
• Failure : GFR decrease > 75 %, tripling of serum creatinine or
urine output < 0.3 ml/kg/hr for 24 hours
9. Predictors of renal function decline
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Pre-existing renal impairment
Older age
Low body weight
Low CD4 count
Hepatitis C co-infection
Diabetes mellitus
Concomitant use of nephrotoxic drugs
Use of protease inhibitors with Tenofovir
11. Tenofovir nephrotoxicity in resource limited setting
of Western India : Higher rate of renal function
decline, acute kidney injury and progression to
chronic kidney disease compared to Western data
A.Dravid1,A.Sadre2,S.Dhande1, A.Borkar1,M.Kulkarni1,M.Dravid3
IAS 2013, Kualalumpur, Malaysia
12. Study overview
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Retrospective observational cohort design
Tenofovir was initiated in patients with Creatinine Clearance (Cr Cl) > 50 ml/min.
Patients started on Tenofovir at baseline Cr Cl < 50 ml/min were excluded.
Annual decline in GFR was calculated by CG formula and MDRD equation for
Tenofovir containing and Tenofovir sparing regimens.
Acute Kidney Injury was defined as Serum creatinine > 2 mg/dl, Cr Cl decrease to
< 50 ml/min or Cr Cl decrease > 50% of baseline (Rifle criteria 2002).
Patients with GFR value < 60 ml/min(MDRD equation), 3 months after Tenofovir
discontinuation were classified as having Chronic kidney disease (CKD).
Presence of co morbidities which increase incidence of renal toxicity like diabetes
mellitus, hypertension, use of concomitant nephrotoxic drugs, obstructive
uropathy and urinary tract infecton were recorded.
Angiotensin converting enzyme inhibitors(ACEI), Non steroidal anti-inflammatory
drugs(NSAID’s), Amino glycosides and Amphotericin B were the nephrotoxic drugs
studied.
Obstructive uropathy included conditions like renal calculus disease, urethral
stricture and benign prostatic hypertrophy.
13. Baseline characteristics
TDF containing regimens
TDF sparing regimens
Total number
743
340
Age (Mean yrs)
43 yrs
39.5 yrs
Sex (M: F)
68 : 32
62 : 38
Median Baseline CD4 count
168 cells/mm3
121 cells/mm3
Weight (kg)
55.45 kg
52.2 kg
Serum Creatinine
0.85 mg/dl
0.8 mg/dl
GFR (CG) mean
87.7 ml/min
84.51 ml/min
GFR (MDRD equation) mean
96.04 ml/min
100.04 ml/min
Baseline OI
36.6 %
23.2 %
Mean duration of F/U
21 months
33 months
14. Baseline GFR values
GFR by CG formula
No of patients
GFR by MDRD
equation
No of patients
50-70 ml/min
214
30-60 ml/min
22
71-90 ml/min
233
61-90 ml/min
266
91-120 ml/min
218
91-120 ml/min
328
>120 ml/min
78
>120 ml/min
127
16. Tenofovir and Acute kidney injury
• Number of patients who developed AKI : 36/743
(4.8%)
• Time to developing AKI
• < 6 months : 16
• 6 – 12 months : 5
• 12 -24 months : 8
• > 24 months : 7
• Median time to developing AKI : 8.5 months.
• Number of patients requiring haemodialysis : 3/36
(8.33 %)
• Number of patients who died : 4/36 (11.11 %)
17. Analysis of risk factors which increase Tenofovir toxicity
by multiple logistic regression
Risk factor
Number of patients
Number of patients
developing AKI
P value by multiple
logistic regression
Creatinine clearance
50-70 ml/min
214
22
P = 0.01
CD 4 count < 100
cells/mm3
258
22
P = 0.002
Tenofovir with PI
155
17
P = 0.042
Diabetes mellitus
48
9
P = 0.69
Hypertension
65
5
P = 0.105
Concomitant
nephrotoxic drugs
56
12
P = 0.031
Obstructive uropathy
37
11
P = 0.001
18. Tenofovir associated renal dysfunction in clinical
practice : an observational cohort from Western India
• Ketan Patel, Atul Patel et al. Indian Journal of
Sexually transmitted diseases (IJSTD) 2010.
• Incidence of renal dysfunction in patients on
Tenofovir containing ART 6.53 %
• Renal dysfunction more common with TDF +
Protease inhibitor (9.44%) as compared to TDF +
NNRTI (5.01 %).
• Serum Creatinine normalized in all patients after
discontinuing Tenofovir
19. Tenofovir and chronic kidney disease/ESRD
• In randomised controlled trials , increased risk of chronic
kidney disease or end stage renal disease (ESRD) requiring
dialysis in patients exposed to Tenofovir as compared to other
antiretroviral drugs is not observed.
• However in observational cohort studies Tenofovir is strongly
associated with adverse renal outcomes including CKD (eGFR
< 60 ml/min/1.73 m2 BSA,MDRD formula)
• Decline in GFR of 7-10 ml/min/year has been described in
patients on Tenofovir
• Age related GFR loss is 1 ml/min/year
• So in effect, eGFR decline seen in patients taking Tenofovir
based ART cohort studies is similar to that seen in patients
suffering from diabetic nephropathy.
20. Tenofovir nephrotoxicity in resource limited setting
of Western India : Higher rate of renal function
decline, acute kidney injury and progression to
chronic kidney disease compared to Western data
A.Dravid1,A.Sadre2,S.Dhande1, A.Borkar1,M.Kulkarni1,M.Dravid3
IAS 2013, Kualalumpur, Malaysia
21. eGFR decline on follow up for entire cohort
Baseline
12
months
24 months
36 months
48 months
Number of patients
completing F/U
743
553
274
132
56
Mean GFR by CG
formula
87.7 ml/min
91.04
ml/min
91.70
ml/min
92.36
ml/min
92.12
ml/min
Mean GFR by MDRD
equation
96.04
ml/min
89.14
ml/min
84.92
ml/min
82.87
ml/min
84.52
ml/min
6.4
ml/min
5.82
ml/min
4.23
ml/min
-0.22 ml/min
GFR baseline – GFR
F/U by MDRD
equation
22. eGFR decline on follow up (TDF + NNRTI vs TDF + PI)
12 months
24 months
36 months
48 months
Number of patients
404
196
90
38
GFR decline in TDF +
NNRTI by MDRD equation
(ml/min)
5.5 ml/min
6.3 ml/min
4.19 ml/min
0.9 ml/min
Number of patients
93
55
28
9
GFR decline in TDF + PI by
MDRD equation (ml/min)
11.75 ml/min
7.04 ml/min
7.33 ml/min
- 2.7 ml/min
23. Follow up GFR decline
• Mean decline in GFR in Tenofovir exposed
cohort : 5.29 ml/min/year
• Mean decline in GFR in patients exposed to
TDF + NNRTI only : 4.18 ml/min/year
• Mean decline in GFR in patients exposed to
TDF + PI only : 9.19 ml/min/year
• Mean decline in GFR in patients exposed to
Tenofovir sparing regimens : 2 ml/min/year
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25. Recovery of renal function post Tenofovir withdrawal
and progression to grade 3-5 chronic kidney disease
• Out of 36 patients who developed AKI, 18 patients completed
6 months of follow up post Tenofovir cessation.
• 4 patients died and 2 were lost to follow up.
• Only 2 patients had Serum creatinine >2 mg/dl, 6 months
after Tenofovir withdrawal.
• None of the patients have required long term renal
replacement therapy as of now.
26.
27. Increased Risk and Faster Progression of Renal Impairment With TDFcontaining Regimens amongst Indian HIV Patients: A Comparative Cohort
Analysis Between Western India and the United Kingdom.
Sanjay Pujari et al CROI 2013
28. Prevention and treatment of Nephrotoxicity
• HIVMA/IDSA guidelines : serum creatinine,creatinine
clearance, eGFR, serum phosphorus, proteinuria and
glycosuria every 4 months in patients on Tenofovir.
• Urine dipstick assays to identify early tubular damage
• Tenofovir withdrawal leads to reversal of toxicity in
majority of patients
• Modify the Tenofovir molecule : Tenofovir alefamide
fumarate (TAF)
29. Conclusions
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There is higher incidence of acute kidney injury and amongst our Tenofovir
exposed population compared to that seen in Western resource rich
settings.
This could be attributable to lower baseline creatinine clearance, lower
eGFR, lower baseline CD4 count and higher incidence of co-morbidities in
our population
Recovery of eGFR after withdrawal of Tenofovir is incomplete in significant
proportion of patients. GFR decline in patients on Tenofovir is higher than
those on Tenofovir sparing regimens. This leads to increased risk of
progression to stage 3-5 Chronic kidney disease.
Regular monitoring of all patients exposed to Tenofovir to assess
glomerular or tubular dysfunction can help us identify toxicity early and
take corrective action
Finally, management of Tenofovir nephrotoxicity in resource limited
settings like India is tough due to limited access to routine laboratory
monitoring, renal replacement therapy and alternate antiretroviral drugs
like Abacavir.
