Tenofovir and renal safety
Simon Collins, HIV i-Base
A couple of posters presented interesting data relating to renal safety associated with tenofovir.
Firstly, and encouragingly, a sub-study from the international DART study suggested that while tenofovir may have a slightly greater renal toxicity compared to either abacavir or nevirapine, this still occurred in a small minority of patients. 
DART randomised over 3,300 treatment-naive patients in Uganda and Zimbabwe to routine CD4 and labaoratory monitoring or to clinical monitoring (with only grade 4 laboratory results reported in real time). Virological results were reported in the last issue of HTB. 
Patients used one of three treatment arms: tenofovir (n=2469, 74%), nevirapine (n=547, 16%) or abacavir (n=300, 9%), each used in combination with AZT/3TC), allowing safety and efficacy to be compared by drug class.
Elevated creatine (>360umol/L(4.1mg/dL) was an exclusion criteria. GFR was estimated by Cockcroft-Gault, and was adjusted for body surface area.
For this renal sub-study, glomerular filtration rate (GFR) severity was defined as mild, moderate and severe if 60-<90, 30-60 and <30 ml/min/1.73m2 respectively. Chronic kidney disease (CKD) was defined as GFR <60 on two tests for > 3 months or a 25% reduction in patients with eGFR <60 at baseline. An analysis also looked at 25% reduction rates in all patients.
Baseline demographics included 65% women; median age 37 years; CD4 86 cells/mm3; and weight 57 kg. Median eGFR was 89: with 48% >90; 45% 60-90; 7% 60 – 30 and 0.2% <30.
By week 216, patients in all three groups had small mean increases in GFR (lowest in the tenofovir group, and a slightly higher incidence of GFR decreases to <30 and <60, and in the percentages of patients with more than a 25% reduction, see Table 1. Renal disease contributed to death in 0.4% (n=13) patients on tenofovir-based therapy.
The incidence of severe reductions (GFR<30) was higher in the clinically monitored group [3.4% (2.7-4.5%) vs 2.3% (1.7-3.1%), p=0.05]. However, the study emphasised that rates were low in all arms.
The main DART study, showed an almost 90% 5-year survival rate without routine laboratory monitoring, and contrasted with <10% survival rates pre-HAART. In this context, the researcher are right to concluded that the study showed supportive safety data for wider use of tenofovir in reseource-limited settings. This is particularly important given the toxicities associated with d4T and AZT.
Table 1: Changes in renal function in DART study
|B/line GFR; median (IQR)||90 (75-107)||89 (76-103)||80 (70-98)|
|Adj GFR change; mean (95%CI)||+2 (+1, +3)||+7 (+5, +9)||+6 (+3, +9)||<0.001|
|Renal-associated death||0.7% (0.4-1.1%)||0||0||0.07|
|Severe GFR decrease (<30)||3.1% (2.5-3.9%)||1.9% (1.0-3.4%)||2.4% (1.2-5.0%)||0.26|
|CKD (GFR<60)||5.9% (5.0-6.9%)||2.1% (1.2-3.7%)||3.1% (1.6-5.8%)||0.0004|
|CKD >25% (all pts)||3.4% (2.7-4.2%)||1.1% (0.5-2.5%)||2.1% (0.9-4.5%)||0.01|
The second study resented results on the reversibilty of kidney damage associated with tenofovir in 26 adult male patients who either switched from tenofovir (n=24) or dose-reduced (n=2) due to renal impairment.
Median eGFR (using MDRD) was 72 (IQR 60, 88) before starting tenofovir, and fell to 49 (IQR 37, 54) mL/min/1.73m2 prior to the change in regimen. After a median of 15 months, his increased to 56 (IQR 45, 70) mL/min/1.73m2. Howverer, although the changes were only slight and developed slowly, with only 10 (38%) patients reached their pre-treatment level.
Although in small patient numbers, this is one of the first studies to show a potential reversal of reduced kidney function after switching from tenofovir, though the improvements were very modest in clinical terms.
- Reid A et al. Glomerular dysfunction and associated risk factors through four years following initiation of ART in adults with HIV infections in Africa in the DART trial. 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention, 19-22 July 2009, Cape Town. Poster abstract TUPEB184.
- Carr A et al. Reversibility of tenofovir-related renal toxicity. 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention, 19-22 July 2009, Cape Town. Poster abstract TUPEB177.