Elsevier

The Lancet HIV

Volume 3, Issue 1, January 2016, Pages e23-e32
The Lancet HIV

Articles
Cumulative and current exposure to potentially nephrotoxic antiretrovirals and development of chronic kidney disease in HIV-positive individuals with a normal baseline estimated glomerular filtration rate: a prospective international cohort study

https://doi.org/10.1016/S2352-3018(15)00211-8Get rights and content

Summary

Background

Whether or not the association between some antiretrovirals used in HIV infection and chronic kidney disease is cumulative is a controversial topic, especially in patients with initially normal renal function. In this study, we aimed to investigate the association between duration of exposure to antiretrovirals and the development of chronic kidney disease in people with initially normal renal function, as measured by estimated glomerular filtration rate (eGFR).

Methods

In this prospective international cohort study, HIV-positive adult participants (aged ≥16 years) from the D:A:D study (based in Europe, the USA, and Australia) with first eGFR greater than 90 mL/min per 1·73 m2 were followed from baseline (first eGFR measurement after Jan 1, 2004) until the occurrence of one of the following: chronic kidney disease; last eGFR measurement; Feb 1, 2014; or final visit plus 6 months (whichever occurred first). Chronic kidney disease was defined as confirmed (>3 months apart) eGFR lower than 60 mL/min per 1·73 m2. The primary outcome was the occurrence of chronic kidney disease. Poisson regression was used to estimate the incidence rate of chronic kidney disease associated with cumulative exposure to tenofovir disoproxil fumarate, ritonavir-boosted atazanavir, ritonavir-boosted lopinavir, other ritonavir-boosted protease inhibitors, or abacavir.

Findings

Between Jan 1, 2004, and July 26, 2013, 23 905 eligible individuals from the D:A:D study were included. Participants had a median baseline eGFR of 110 mL/min per 1·73 m2 (IQR 100–125), a median age of 39 years (33–45), and median CD4 cell count of 441 cells per mm3 (294–628). During a median follow-up of 7·2 years (IQR 5·1–8·9), 285 (1%) of 23 905 people developed chronic kidney disease (incidence 1·76 per 1000 person-years of follow-up [95% CI 1·56–1·97]). After adjustment, we recorded a significant increase in chronic kidney disease associated with each additional year of exposure to tenofovir disoproxil fumarate (adjusted incidence rate ratio 1·14 [95% CI 1·10–1·19], p<0·0001), ritonavir-boosted atazanavir (1·20 [1·13–1·26], p<0·0001), and ritonavir-boosted lopinavir (1·11 [1·06–1·16], p<0·0001), but not other ritonavir-boosted protease inhibitors or abacavir.

Interpretation

In people with normal renal function, the annual incidence of chronic kidney disease increased for up to 6 years of exposure to tenofovir disoproxil fumarate, ritonavir-boosted atazanavir, or ritonavir-boosted lopinavir therapy. Although the absolute number of new cases of chronic kidney disease was modest, treatment with these antiretrovirals might result in an increasing and cumulative risk of chronic kidney disease. Patients on potentially nephrotoxic antiretrovirals or at high risk of chronic kidney disease should be closely monitored.

Funding

The Highly Active Antiretroviral Therapy Oversight Committee.

Introduction

Following the widespread introduction of combination antiretroviral therapy (ART) and the rapid decline in mortality associated with HIV infection,1 the focus of patient care has shifted to chronic diseases such as cardiovascular, liver, and renal disease, for which a complex association exists between immunodeficiency, chronic inflammation, ageing, and the long-term toxicities of antiretrovirals.2 The prevalence of chronic kidney disease in HIV-positive individuals treated with combination ART varies greatly, ranging from 2% to more than 30%,3 depending on the prevalence of other risk factors, including both HIV-related factors and more traditional risk factors for chronic kidney disease (eg, hypertension or diabetes).4, 5 Several studies have focused on the role of antiretrovirals, including the D:A:D study.6 Tenofovir disoproxil fumarate has been widely shown to be associated with decreases in estimated glomerular filtration rate (eGFR) and progression to chronic kidney disease,7 and some studies have suggested similar associations with ritonavir-boosted atazanavir or lopinavir,6, 8 together with reports of crystalluria, urolithiasis, and interstitial nephritis.9, 10 Additionally, several antiretrovirals, including dolutegravir, ritonavir, and rilpivirine, can reduce creatinine clearance (thereby decreasing eGFR) without changing the actual glomerular filtration rate.11

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.

Results from some large cohort studies have shown that some antiretrovirals have nephrotoxic effects in people with both a normal and impaired eGFR at start of follow-up.6, 8, 12 Some clinical trials, mostly with short follow-up, have suggested that exposure to tenofovir disoproxil fumarate is associated with an initial decline in eGFR that does not continue with increasing exposure,13, 14 whereas others have reported no initial decline in renal function.15, 16 Despite the many studies of renal function in HIV, none so far has been adequately powered to formally assess the exact nature of the association between exposure to antiretrovirals and chronic kidney disease in people with an initially normal eGFR. Therefore, whether or not the so-called early-hit phenomenon remains true after extended exposure to antiretrovirals is unknown, especially in people with an initially normal renal function. Because treatment with combination ART can last for many years, to ascertain whether or not the risks of chronic kidney disease will be self-limiting is crucial, to help clinical decision making and monitoring of HIV-positive patients.

In this study, we aimed to investigate the association between duration of exposure to antiretrovirals and the development of chronic kidney disease in people with an initially normal eGFR.

Section snippets

Study design and participants

The Data Collection on Adverse events of Anti-HIV Drugs Study (D:A:D) is a prospective cohort collaboration established in 1999 with more than 49 000 HIV-1-positive people in Europe, the USA, and Australia; full details of the study have been published previously.17 Data for routine clinical care, including demographic factors, ART, laboratory values, cardiovascular risk factors, and AIDS events, are collected electronically at enrolment and annually thereafter. Serum creatinine measurements

Results

Between Jan 1, 2004, and July 26, 2013, eligible individuals from the D:A:D study were enrolled. Of 37 022 individuals in the D:A:D study with at least one eGFR measurement since Jan 1, 2004, 25 933 had a baseline eGFR greater than 90 mL/min per 1·73 m2. 1792 individuals were excluded because they did not have two additional eGFR measurements more than 3 months apart during follow-up, and 236 were excluded because of missing viral load or CD4 cell counts. These 2028 patients had a later

Discussion

This large study of almost 24 000 HIV-positive individuals with an initially normal eGFR clearly shows, for the first time, that the association between tenofovir disoproxil fumarate, ritonavir-boosted atazanavir, and ritonavir-boosted lopinavir and chronic kidney disease is cumulative in nature. This finding suggests that people starting treatment with these antiretrovirals have a small, but significantly rising, incidence of chronic kidney disease with increasing exposure to these drugs. The

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    D:A:D study investigators and participating cohorts are listed in the appendix

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