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  19th Conference on Retroviruses and
Opportunistic Infections
Seattle, WA March 5 - 8, 2012
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Kidney Function in D:A:D With TDF, ATV, and LPV
  19th Conference on Retroviruses and Opportunistic Infections, March 5-8, 2012, Seattle
Mark Mascolini
The D:A:D cohort researchers reported on renal function related to several ARTs. Of 22,603 persons included with a normal baseline renal function 2.1% progressed to ceGFR≤70 and 0.6%) to CKD during a median follow-up of 4.5 years (IQR 2.7-6.1). This eGFR decline of at least 20 ml/min (from eGFR>90 to ≤70) during 4.5 years equals an annual decline of at least 4-5 ml/min. Baseline characteristics and all the other graphs & tables of included persons are shown below.
Renal toxicity associated with tenofovir, atazanavir, and other antiretrovirals is a familiar concern for clinicians. To determine how antiretrovirals affect kidney function in people with normal pretreatment function, D:A:D investigators undertook this study of 22,603 HIV-positive people. Everyone began follow-up with a Cockroft-Gault-determined eGFR above 90 mL/min/1.73m(2). Follow-up continued until a person's last eGFR or until eGFRs at least 3 months apart were at or below 70 (when antiretrovirals may be switched) or at or below 60 (indicating chronic kidney disease [CKD]).
During a median follow-up of 4.5 years, 468 people (2.1%) had a confirmed eGFR at or below 70 to yield an incidence of 4.78 per 1000 person-years (95% confidence interval [CI] 4.35 to 5.22). There were 131 people (0.6%) who reached the CKD endpoint for an incidence of 1.33 per 1000 person-years (95% CI 1.10 to 1.56).
Of the 22,603 D:A:D members assessed, 73% were men, 44% men who have sex with men, and 47% white. Median age stood at 39 (interquartile range 33 to 44). Median CD4 count and viral load were 440 and 2.1 log10 copies/mL (just over 100 copies). These people had been infected with HIV for a median of 5.2 years.
Compared with the overall group, people who had a confirmed eGFR at or below 70 or CKD were older (median 46 years in both groups), had a lower median CD4 count (380 in both groups), and had been infected with HIV longer (10.0 years in the under-70 eGFR group and 10.8 years in the CKD group). Diabetes prevalence was higher in the under-70 eGFR group (9%) and the CKD group (11%) than in the entire group (3%). The authors said: Other predictors of ceGFR≤70 from eGFR>90 in adjusted models included age, diabetes, current CD4 count and prior AIDS. They also said: Adjustment for variables at baseline did not alter the results. There were no significant interactions between ARV use (per year) and main predictors.
People whose eGFR fell to between 60 and 70 had a 72% higher rate of stopping tenofovir than people who maintained an eGFR above 90 (adjusted incidence rate ratio 1.72, 95% CI 1.38 to 2.14). But eGFR declines to this range were not associated with a higher risk of stopping other antiretrovirals.
In this analysis, cumulative tenofovir, atazanavir, and lopinavir were each independently associated with renal deterioration to a confirmed eGFR at or below 70, and cumulative lopinavir was also associated with progression to CKD, at the following adjusted incidence rate ratios (aIRR) (and 95% CIs):
Progression to eGFR
-- Cumulative tenofovir: aIRR 1.18 (1.12 to 1.25)
-- Cumulative atazanavir/ritonavir: aIRR 1.19 (1.09 to 1.32)
-- Cumulative lopinavir/ritonavir: aIRR 1.11 (1.05 to 1.17)
Progression to CKD:
-- Cumulative lopinavir/ritonavir: aIRR 1.22 (1.16 to 1.28)
The poster said: These findings remained consistent when the analysis excluded concomitant use of each antiretroviral and after statistical adjustment for prior antiretroviral use.
Every 10 years of age more than doubled the risk of progression to a confirmed eGFR at or below 70 (aIRR 2.60, 95% CI 2.31 to 2.93). Diabetes raised that risk more than 50% (aIRR 1.52, 95% CI 1.05 to 2.21), and prior AIDS raised the risk almost 40% (aIRR 1.39, 95% CI 1.13 to 1.70). Every 2 times higher current CD4 count cut the risk of progression to this endpoint by 25% (aIRR 0.75, 95% CI 0.69 to 0.82).
The D:A:D investigators noted that their analysis is limited by lack of data on proteinuria, family history of kidney disease, and use of other potentially kidney-toxic drugs. With these limitations in mind, the researchers cautioned that the eGFR changes they recorded "may represent significant issues for lifelong use should the rates remain constant or even increase with age."
CROI 2010: Chronic kidney disease and exposure to ARTs in a large cohrt with long-term follow-up: EuroSida - (02/20/10).
1. Ryom L, and the D:A:D Study Group. Exposure to ARV and the risk of renal impairment among HIV+ persons with normal baseline renal function: the D:A:D study. 19th Conference on Retroviruses and Opportunistic Infections. March 5-8, 2012. Seattle. Abstract 865. http://www.cphiv.dk/portals/0/files/CROI_2012_LR.pdfM.
Exposure to Antiretrovirals (ARVs) and the Risk of Renal Impairment among HIV+ Persons with Normal Baseline Renal Function: the D:A:D Study
Reported by Jules Levin
L Ryom1, A Mocroft2, SW Worm1,, DA Kamara2, P Reiss3, M Ross4, C Fux5, P Morlat6, O Moranne7, C Smith2, O Kirk1,8 and JD Lundgren1,8 on behalf of the D:A:D study group 1Copenhagen HIV Programme, University of Copenhagen, Denmark; 2Research Dept. of Infection and Population Health, UCL, London, United Kingdom; 3Academic Medical Center, Div. of Infectious Diseases and Dept. of Global Health, University of Amsterdam, The Netherlands; 4Division of Nephrology, Mount Sinai School of Medicine, New York, USA; 5Clinic for Infectious Diseases and Hospital Hygiene, Kantonsspital Aarau, Switzerland; 6Service de medecine interne et maladies infectieuses, Hopital Saint-Andre, CHU de Bordeaux, France; 7Nephrology department, Public Health department, CHU Nice, France; 8Epidemiklinikken M5132, Rigshospitalet, Copenhagen, Denmark
Tenofovir (TDF), atazanavir (ATV) and other ARVs have been associated with renal impairment (ref. 1-5), but the extent of such adverse drugs reactions in HIV+ persons with normal baseline renal function is unknown.