Kidney Risk Climbs With Increasing Time on Tenofovir, Atazanavir or Lopinavir

February 21, 2016

In people with initially normal kidney function, each additional year taking tenofovir disoproxil fumarate (TDF, Viread), ritonavir (Norvir)-boosted atazanavir (Reyataz) or lopinavir/ritonavir (Kaletra) raised the risk of chronic kidney disease (CKD) in a 23,905-person study. Cumulative use of abacavir (Ziagen) or other boosted protease inhibitors (PIs) did not affect CKD risk in this D:A:D study analysis.

D:A:D investigators who conducted this study note that reported prevalence of CKD in people with HIV ranges from 2% to 30%, depending on prevalence of classic risk factors and HIV-related factors, including antiretroviral therapy (ART). Much research has linked TDF and ritonavir-boosted PIs to development of CKD, but whether the impact is only short-term or also cumulative remains controversial, especially in people with normal kidney function when they start treatment.

To address that question, the researchers conducted this analysis of adults in their European-US-Australian cohort who initially had normal kidney function, defined as estimated glomerular filtration rate (eGFR) >90 mL/min. Participants in this analysis were at least 16 years old, had a baseline eGFR after January 1, 2004 >90 mL/min and had at least two additional eGFRs more than three months apart. Follow-up of individual participants continued until (1) development of CKD (two eGFRs <60 mL/min >3 months apart), (2) last study visit plus six months, (3) last eGFR plus six months or (4) February 1, 2014, whichever came first. The researchers used Poisson regression to model incidence of CKD according to cumulative exposure to individual antiretrovirals after adjustment for potentially confounding variables.

The analysis included 23,905 individuals, 73% of them men, 46% white, 8% black and 44% of unknown race. Most participants became infected with HIV during sex between men (45%) or between men and women (36%), while 13% became infected while injecting drugs. Median age stood at 39 years and median baseline CD4+ count at 441 cells/mm3. About one-quarter of cohort members (27%) never took ART.

Through a median 7.2 years of follow-up, CKD developed in 285 people (1%) for an incidence of 1.76 per 1000 person-years. The proportion of participants with CKD rose from 0.11% after two years of ART to 0.49% after five years and to 1.46% after eight years. People in whom CKD developed were more likely to be older, to have a lower baseline eGFR, to have more cardiovascular risk factors and to have started ART.

After adjustment for confounders, increasing exposure to TDF, boosted atazanavir or boosted lopinavir (but not other boosted PIs or abacavir) was associated with higher incidence of CKD: for each year of TDF incidence rate ratio (IRR) 1.14, 95% confidence interval (CI) 1.10 to 1.19; for every five years of TDF IRR 1.94, 95% CI 1.57 to 2.39; for each year of boosted atazanavir IRR 1.20, 95% CI 1.13 to 1.26; for every five years of boosted atazanavir IRR 2.44, 95% CI 1.86 to 3.21; for each year of boosted lopinavir IRR 1.11, 95% CI 1.06 to 1.16; for every five years of boosted lopinavir IRR 1.66, 95% CI 1.32 to 2.09 (P < .0001 for all associations). These associations were attenuated but still significant in a model excluding people who never started ART. The associations of the boosted PIs to higher CKD incidence were independent of exposure to TDF.

The D:A:D team repeated the analysis with development of chronic renal impairment (confirmed eGFR <70 mL/min) as the endpoint. Each single year or five years of TDF, boosted atazanavir, or boosted lopinavir (but not other antiretrovirals assessed) remained independently associated with development of chronic renal impairment.

The researchers believe their findings show for the first time that the association between TDF, boosted atazanavir, or boosted lopinavir and CKD is cumulative in people with initially normal kidney function. In other words, the impact of these antiretrovirals on CKD risk is not limited to the first few months of therapy and does not plateau after six or more years of follow-up. The authors recommend close kidney monitoring for people taking these antiretrovirals or for those at high risk of CKD. A CKD risk score proposed by D:A:D investigators could help clinicians decide whether the benefits of certain antiretrovirals outweigh renal risk.

Mark Mascolini writes about HIV infection.

Copyright © 2016 Remedy Health Media, LLC. All rights reserved.

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