Research in context
Evidence before this study
Some antiretrovirals that are used to treat HIV infection might be associated with an increased risk of chronic kidney disease or a decline in estimated glomerular filtration rate (eGFR). We did a review of the available literature on PubMed, in which we searched for clinical trials and observational (cohort) studies published from 2004 up to the search date (April 20, 2015) that reported changes in eGFR or chronic kidney disease and individual antiretroviral drugs. Our search terms were “gfr”, “chronic kidney disease”, “HIV”, and “antiretrovirals”, and we searched for articles published in English language only. Evidence from clinical trials, especially for tenofovir, suggests that any decreases in eGFR occur within the first few months of treatment, with little further change after this point. Evidence from observational studies has suggested a cumulative effect of antiretrovirals, including ritonavir-boosted atazanavir or lopinavir, and tenofovir, on chronic kidney disease. Clinical trials in HIV-positive individuals tend to be short in duration and might exclude those at a raised risk of chronic kidney disease, and therefore do not follow participants for long enough to record the occurrence of chronic kidney disease, whereas observational studies have not focused on people with an initially normal eGFR higher than 90 mL/min per 1·73 m2, or have not used a confirmed eGFR lower than 60 mL/min per 1·73 m2 to define chronic kidney disease.
Added value of this study
23 905 study participants with first eGFR higher than 90 mL/min per 1·73 m2 were included, of who 285 developed chronic kidney disease. After adjustment for potential confounding variables (both HIV-associated and traditional risk factors for chronic kidney disease), we recorded a 14%, 20%, and 11% increase in chronic kidney disease associated with each additional year of exposure to tenofovir disoproxil fumarate, ritonavir-boosted atazanavir, and ritonavir-boosted lopinavir, respectively, but no increased incidence of chronic kidney disease associated with either abacavir or other ritonavir-boosted protease inhibitors.
Implications of all the available evidence
Our findings suggest that the annual incidence of chronic kidney disease was increasing for up to 6 years of follow-up after starting tenofovir disoproxil fumarate, ritonavir-boosted atazanavir, or ritonavir-boosted lopinavir treatment in HIV-positive individuals with an initially normal eGFR. Although the absolute number of chronic kidney disease events was modest, the incidence of the disease continued to increase with up to 5 or more years of exposure to the antiretrovirals; after 5 years, it was equivalent to an increased incidence of chronic kidney disease of 1·94-fold for tenofovir, 2·44-fold for ritonavir-boosted atazanavir, and 1·66-fold ritonavir-boosted lopinavir. The continued increase in risk of chronic kidney disease that we recorded with exposure suggests a cumulative toxic effect of these drugs. The benefits of potentially nephrotoxic antiretrovirals, even in individuals with an initially normal renal function, should be weighed against the risks in those patients at highest risk of chronic kidney disease.