Systematic Literature Review and Meta-Analysis of Renal Function in Human Immunodeficiency Virus (HIV)-Infected Patients Treated with Atazanavir (ATV)-Based Regimens

<div><p>Some HIV antiretroviral therapies (ART) have been associated with renal toxicities, which become of increasing concern as HIV-infected patients age and develop comorbidities. The objective of this study was to evaluate the relative impact of atazanavir (ATV)-based regimens on the renal function of adult patients with HIV. We conducted a systematic literature review by searching PubMed, EMBASE, Cochrane library, and the CRD from 2000 until March 2013. Major HIV-related conferences occurring in the past two years were also searched. All randomized clinical trials and large cohort studies assessing renal function in treatment-naïve and/or treatment-experienced HIV patients on ATV-based regimens were included. Fixed-effect mixed-treatment network analyses were carried out on the most frequently reported renal outcomes. 23 studies met the inclusion criteria, and change in estimated glomerular filtration rate (eGFR) from baseline to 48 weeks was identified as the main outcome. Two networks including, respectively, six studies (using the Cockcroft-Gault method) and four studies (using MDRD and CKD-EPI) were analysed. With CG network, ATV/r + TDF/FTC was associated with lower impact on the decline of eGFR than ATV/cobicistat + TDF/FTC but with higher decrease in eGFR than ATV/r + ABC/3TC (difference in mean change from baseline in eGFR repectively +3.67 and –3.89). The use of ATV/cobicistat + TDF/FTC led to a similar decline in eGFR as EVG/cobicistat/TDF/FTC. With respect to third agents combined with TDF/FTC, ATV/r had a lower increase in eGFR in comparison to EFV, and no difference was shown when compared to SQV/r and DRV/r. The effect of ATV-based regimens on renal function at 48 weeks appears similar to other ART regimens and appears to be modest regardless of boosting agent or backbone, although TDF containing backbones consistently leads to greater decline in eGFR.</p></div

48-week safety ranking on the mean change in eGFR from baseline (assessed with the MDRD and CKD-EPI methods).

<p>CKD-EPI: Chronic Kidney Disease-Epidemiology; eGFR: estimated Glomerular Filtration Rate; MDRD: Modification Diet Renal Disease. The values of this double entry table were computed using the rank function in WinBugs 1.4. Each row represents the probability of a treatment occupying different rankings (the blue one being the highest one) and each column represents the probability of different treatments occupying a specific rank (the blue one being the highest one).The table is organised so that the treatment with the highest probability of being ranked first (safest) is placed at the top row and the treatment with the highest probability of begin ranked last (most harmful) is at the bottom.</p

PICOS methodology.

<p>ATV: Atazanavir; CKD: Chronic Kidney Disease; eGFR: estimated Glomerular Filtration Rate; TDF: Tenofovir</p><p>PICOS methodology.</p

Network diagram—change in eGFR from baseline using the CG method.

<p>CG: Cockcroft–Gault; eGFR: estimated Glomerular Filtration Rate. The number on the arrowed line represents the number of studies reported pairwise comparison.</p

Results from the MTC: Difference in mean change in eGFR from baseline at 48 weeks (using CG method).

<p>CG: Cockcroft–Gault; eGFR: estimated Glomerular Filtration Rate; MTC: Mixed-Treatment Comparison.</p

Network diagram—change in eGFR from baseline using the pooled MDRD and CKD-EPI methods.

<p>CKD-EPI: Chronic Kidney Disease-Epidemiology; eGFR: estimated Glomerular Filtration Rate; MDRD: Modification Diet Renal Disease. The number on the arrowed line represents the number of studies reported pairwise comparison.</p

MTC results providing the difference in mean change in eGFR from baseline compared with ATV/r + TDF/FTC (CG method).

<p>95%CrIs: 95% Credible Intervals; CG: Cockcroft–Gault; eGFR: estimated Glomerular Filtration Rate; MTC: Mixed-Treatment Comparison</p><p>MTC results providing the difference in mean change in eGFR from baseline compared with ATV/r + TDF/FTC (CG method).</p

MTC results providing the difference in mean change in eGFR from baseline compared with ATV/r + TDF/FTC (pooled MDRD and CKD-EPI methods).

<p>95%CrIs: 95% Credible Intervals; CKD-EPI: Chronic Kidney Disease-Epidemiology; eGFR: estimated Glomerular Filtration Rate; MDRD: Modification Diet Renal Disease; MTC: Mixed-Treatment Comparison</p><p>MTC results providing the difference in mean change in eGFR from baseline compared with ATV/r + TDF/FTC (pooled MDRD and CKD-EPI methods).</p

Study design and patients’ demographic characteristics.

<p>Q1-Q3: Quartile 1-Quartile 3; NR: Non Reported; RCT: Randomized Clinical Trial; SD: Standard Deviation</p><p>^a Weighted average between the treatment arms</p><p>^b SD was calculated assuming the samples were independent and normally distributed</p><p>Study design and patients’ demographic characteristics.</p

Flow-chart of systematic literature search.

<p>^*One congress abstract (Gallant et al. 2012) [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0124666#pone.0124666.ref050" target="_blank">50</a>] which was presented during the XIX international AIDS conference was replaced by a complete communication that became available at the data-extraction stage (Gallant et al. 2013) [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0124666#pone.0124666.ref012" target="_blank">12</a>].</p