SUMMARY: HIV positive participants in the large EuroSIDA study who used antiretroviral therapy (ART) regimens that included tenofovir (Viread, also in the Truvada and Atripla coformulations) were at higher risk for developing chronic kidney disease, researchers reported at the 17th Conference on Retroviruses & Opportunistic Infections (CROI 2010) last month in San Francisco. In addition, weaker associations were seen for the protease inhibitors indinavir (Crixivan) and atazanavir (Reyataz).

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; Charles Univ Hosp, Plzen, Czech Republic; Specialistic Hosp, Chorzow, Poland; Hosp Clin, Barcelona, Spain; Univ Hosp Zurich, Switzerland; Rigshospitalet, Copenhagen, Denmark

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Reference
O Kirk, A Mocroft, P Reiss, and others. Chronic Kidney Disease and Exposure to ART in a Large Cohort with Long-term Follow-up: The EuroSIDA Study. 17th Conference on Retroviruses & Opportunistic Infections (CROI 2010). San Francisco. February 16-19, 2010. Abstract 107LB.