Slow But Steady Increase in Kidney Risk Observed With TDF, Atazanavir, Lopinavir

Each additional year of tenofovir disoproxil fumarate (TDF, Viread), ritonavir (Norvir)-boosted atazanavir (Reyataz) or lopinavir (part of lopinavir/ritonavir, or Kaletra) was independently linked to higher incidence of chronic kidney disease (CKD) in a 23,905-person cohort with initially normal renal function. By contrast, CKD incidence was not affected either by other ritonavir-boosted protease inhibitors (PIs) or by abacavir (Ziagen) in this seven-year D:A:D study analysis, which was published earlier this year in The Lancet HIV.

Previous research has identified associations between TDF, boosted atazanavir or boosted lopinavir and declining estimated glomerular filtration rate (eGFR). But studies disagree on whether antiretrovirals have only an initial impact on kidney function or a cumulative impact as long as treatment continues. To address that question in HIV-positive people with normal kidney function, D:A:D investigators conducted this long-term analysis of their large cohort.

D:A:D is an ongoing prospective study of HIV-positive people in Europe, the United States and Australia. This analysis focused on D:A:D participants at least 16 years old who had at least one eGFR measurement since January 2004 above 90 mL/min (the cutoff for normal renal function) and two or more subsequent eGFRs more than three months apart. The investigators defined CKD as a confirmed eGFR below 60 mL/min. Follow-up of each D:A:D participant continued until (1) development of CKD, (2) last 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 CKD incidence after adjustment for numerous potential confounders including race, sex, nadir CD4 count and baseline eGFR.

The study group included 23,905 people of whom 73% were men, with a median age of 39 and a median CD4 count of 441 cells/mm3. Race or ethnicity was not known for 44% of the group, while 46% were known to be white and 8% to be black. One-quarter of the group (27%) had never taken antiretrovirals, and 56% had a viral load below 400 copies/mL. Median baseline eGFR stood at 110 mL/min (interquartile range [IQR] 100 to 125).

Through a median follow-up of 7.2 years (IQR 5.1 to 8.9), CKD developed in 285 people (1%) for an incidence of 1.76 per 1000 person-years. The CKD rate rose steadily from 0.11% after two years of follow-up, to 0.49% after five years and to 1.46% after eight years. CKD developed more often in cohort members who were older (median 47 versus 39 years), had a lower baseline eGFR (median 102 versus 110 mL/min), had started antiretroviral therapy (87% versus 72%) and had more cardiovascular risk factors such as smoking, hypertension and diabetes.

Multivariate regression analysis found a higher CKD incidence rate ratio (IRR) with each year of TDF (IRR 1.14, 95% confidence interval [CI] 1.10 to 1.19), ritonavir-boosted atazanavir (IRR 1.20, 95% CI 1.13 to 1.26) and ritonavir-boosted lopinavir (IRR 1.11, 95% CI 1.06 to 1.16) (P < .0001 for all), but not with other boosted PIs or with abacavir. The association held true for boosted atazanavir and ritonavir when the researchers censored the analyses when a person started TDF. The CKD association also held for TDF and the two boosted PIs when the researchers eliminated people who had never started antiretroviral therapy Finally, TDF and the two boosted PIs were independently associated with a higher incidence of chronic renal impairment (eGFR below 70 mL/min).

"Although the absolute number of new cases of chronic kidney disease was modest," the D:A:D team concludes, "treatment with [TDF or ritonavir-boosted atazanavir or lopinavir] might result in an increasing and cumulative risk of chronic kidney disease." They recommend close monitoring of people taking potentially nephrotoxic antiretrovirals or with an otherwise high risk of CKD.

Mark Mascolini writes about HIV infection.