Chronic Kidney Disease Linked to Tenofovir (Viread) in EuroSIDA Study

March 14, 2011

By Liz Highleyman

People with HIV have an elevated risk for kidney impairment compared with the

general population, likely attributable to a combination of chronic viral

infection and its resulting inflammation, traditional risk factors, and possibly

certain antiretroviral drugs. EuroSIDA is an ongoing observational study that

now includes more than 16,500 HIV positive participants at 103 centres in

Europe. In the present study, investigators analyzed data from 6843 participants

who had at least 3 available serum creatinine measurements. Most participants

(75%) were men, 85% were white, and the median age was 43 years. About 23% were

coinfected with hepatitis C virus (HCV), 22% had high blood pressure, and 5% had

diabetes all known risk factors for kidney disease. The current median CD4 cell

count was relatively high at 450 cells/mm3, but about one-third had a prior AIDS

diagnosis. Participants were followed for an average of about 4 years,

accumulating a total 21,482 person-years of data. The researchers looked at

rates and risk factors for chronic kidney disease. Confirmed chronic kidney

disease was defined as persistent (2 assessments at least 3 months apart)

estimated GFR (eGFR) 60 ml/min/1.73m2 if the baseline level was above 60, or a

25% decline if it started lower (Cockcroft-Gault formula). GFR is a measure of

how efficiently capillary bundles in the kidney (glomeruli) can filter the

blood; creatinine levels are used in the estimation equation. To asses the

influence of antiretroviral agents, drug exposure duration was divided into 4

categories: never used, used 0-1 years, use 1-2 years, used 2-3 years, and used

more than 3 years. The analysis did not include the mostly recently approved

drugs due to insufficient data.

Results: 225 participants (3.3%) progressed to chronic kidney disease during

follow-up, for an incidence rate of 1.1 per 100 person-years. Kidney disease

incidence increased over time, from less than 0.5% after the 1 year, to 1.5%

after 2 years, to about 4.5% after 4 years of follow-up. Cumulative exposure to

4 drugs was linked to higher likelihood of developing chronic kidney disease:

Tenofovir; Indinavir; Atazanavir; Lopinavir/ritonavir (Kaletra).

People never exposed to tenofovir had a chronic kidney disease incidence rate

of 0.7 per 100 person-years, while those with 3 or more years of exposure had an

incidence rate of 2.4 per 100 person-years. Considering drug exposure alone, the

incident rate ratio (IRR) for tenofovir was 1.32, or about 32% higher; after

adjusting for other factors, it fell to 1.16, which remained statistically

significant. Looking at participants who stopped taking tenofovir during

follow-up, the risk of chronic kidney disease was 4-fold higher compared with

never-exposed patients during the first 12 months (IRR 4.05), but then became

similar (IRR 1.12). For indinavir, the incidence rate was 0.6 per 100

person-years for no exposure versus 1.9 per 100 person-years with the longest

exposure. The IRR for indinavir was 1.18 in isolation and 1.12 after adjustment

(significant). For atazanavir, the incidence rate was 0.8 per 100 person-years

without exposure versus 3.9 per 100 person-years with the longest exposure. The

unadjusted IRR for atazanavir was 1.48 and the adjusted IRR was 1.21

(significant). Lopinavir/ritonavir showed the weakest association. The rate of

kidney disease was higher after 3 years compared with baseline, but there was

not a consistent increase in risk with longer duration of exposure, as was seen

with the other 3 drugs. The unadjusted IRR for lopinavir/ritonavir was 1.15 and

the adjusted IRR was 1.08 (significant). General patterns for these 4 drugs were

similar when 2 other methods (MDRD and CKD-EPI) were used to calculate eGFR

instead of Cockcroft-Gault, and when using alternate definitions of chronic

kidney disease. No other antiretroviral drugs or regimen types were

significantly associated with a higher risk of chronic kidney disease. Other

independent risk factors were male sex, older age, lower baseline eGFR, AIDS

during follow-up, higher viral load, high blood pressure, diabetes, hepatitis C,

and non-AIDS malignancies. Based on these findings, the researchers summarized,

" Increasing exposure to tenofovir [was] associated with a higher risk of chronic

kidney disease. Association with chronic kidney disease [was] also identified

for indinavir and atazanavir. Results for lopinavir/ritonavir [were] less

clear. " The researchers noted that long-term kidney impairment may be due to

differing mechanisms including glomerular and tubular dysfunction for tenofovir

and build-up of drug crystals or kidney stones for the protease inhibitors. " We

have identified several [antiretrovirals] associated with progressive, long-term

renal impairment/chronic kidney disease, " they included. " Although biologically

plausible, the exact pathogenesis behind these findings remains to be

elucidated...Studies on the clinical implications of the findings and the

long-term consequences are warranted. " Copenhagen HIV Prgm, Univ of Copenhagen,

Denmark; Royal Free and Univ Coll London Med Sch, UK; Academic Med Ctr, Univ of

Amsterdam, Netherlands; Ctr Hosp Univ Saint-Pierre, Brussels, Belgium;

Univ Hosp, Plzen, Czech Republic; Specialistic Hosp, Chorzow, Poland; Hosp Clin,

Barcelona, Spain; Univ Hosp Zurich, Switzerland; Rigshospitalet, Copenhagen,

Denmark 3/5/10

March 14, 2011