Important note: Information in this article was accurate in May 2009. The state of the art may have changed since the publication date.
Tenofovir and renal safety
HIV Treat Bull - 2009 Sep/Oct;10(9/10): 06
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 occured in a small minority of patients.[1]
DART randomised over 3,300 treatment-naïve 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.[2]
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 (>360µmol/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 | ||||
| TDF | NVP | ABC | p | |
| 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.
References:
Carr A et al. Reversibility of tenofovir-related renal toxicity. IAS Conf HIV Pathog Treat 2009 Jul 19-22;5th: Poster abstract TUPEB177.
2009-09-10
IB2009-09-06
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