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Predictors of estimated glomerular filtration rate progression, stabilization or improvement after chronic renal impairment in HIV-positive individuals

Ryom, Lenea; Mocroft, Amandab; Kirk, Olea; Reiss, Peterc,d; Ross, Michaele; Smith, Coletteb; Moranne, Olivierf; Morlat, Philippeg; Fux, Christoph A.h; Sabin, Carolineb; Phillips, Andrewb; Law, Matthewi; Lundgren, Jens D.aon behalf of the D:A:D study group

doi: 10.1097/QAD.0000000000001464
CLINICAL SCIENCE
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Objectives: The objectives of this analysis were to investigate predictors of progression, stabilization or improvement in estimated glomerular filtration rate (eGFR) after development of chronic renal impairment (CRI) in HIV-positive individuals.

Design: Prospective observational study.

Methods: The Data Collection on Adverse events of Anti-HIV Drugs (D:A:D) study participants progressing to CRI defined as confirmed, at least 3 months apart, and eGFR 70 ml/min per 1.73 m2 or less were included in the analysis. The median of all eGFRs measured 24–36 months post-CRI was compared with the median eGFR defining CRI, and changes were grouped into improvement (>+10 ml/min per 1.73 m2), stabilization (−10 to +10 ml/min per 1.73 m2) and progression (<−10 ml/min per 1.73 m2). Adjusted polynomial regression models assessed odds of better eGFR outcomes after CRI, assuming that eGFR improvement is better than stabilization which in turn is better than progression.

Results: Of 2006 individuals developing CRI, 21% subsequently improved eGFR, 67% stabilized and 12% progressed. Individuals remaining on tenofovir (TDF) or atazanavir boosted with ritonavir (ATV/r) 24 months post-CRI had worse eGFR outcomes compared with those unexposed [TDF: 0.47 (0.35–0.63) and ATV/r: 0.63 (0.48–0.82)]. Individuals off TDF for 12–24 months [0.75 (0.50–1.13)] or off ATV/r for more than 12 months [1.17 (0.87–1.57)] had similar eGFR outcomes as those unexposed to these antiretrovirals. Older age, hypertension, later date of CRI and diabetes were associated with worse eGFR outcomes.

Conclusion: Current TDF and ATV/r use after a diagnosis of CRI was associated with worse eGFR outcomes. In contrast, TDF and ATV/r discontinuation lead to similar longer term eGFR outcomes as in those unexposed, suggesting that these drug-associated eGFR declines may be halted or reversed after their cessation.

Supplemental Digital Content is available in the text

aRigshospitalet, University of Copenhagen, CHIP, Department of Infectious Diseases, Copenhagen, Denmark

bResearch Department of Infection and Population Health, UCL, London, United Kingdom

cAcademic Medical Center, Division of Infectious Diseases and Department of Global Health, University of Amsterdam

dHIV Monitoring Foundation, Amsterdam, The Netherlands

eDivision of Nephrology, Mount Sinai School of Medicine, New York, New York, USA

fDepartment of Nephrology, Public Health Department, CHU Nice, Nice

gUniversité Bordeaux, INSERM U 897, CHU de Bordeaux, Bordeaux, France

hClinic for Infectious Diseases and Hospital Hygiene, Kantonsspital Aarau, Aarau, Switzerland

iThe Kirby Institute, University of New South Wales, Sydney, New South Wales, Australia.

Correspondence to Lene Ryom, MD, PhD, Rigshospitalet, University of Copenhagen, CHIP, Department of Infectious Diseases, Section 2100, Finsencentret, Blegdamsvej 9, DK-2100 Copenhagen O, Denmark. Tel: + 45 35 45 57 65; fax: +45 35 45 57 57; e-mail: lene.ryom.nielsen@regionh.dk

Received 17 November, 2016

Revised 22 February, 2017

Accepted 2 March, 2017

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (http://www.AIDSonline.com).

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Introduction

Currently, limited knowledge exists of the longer term outcomes of renal function after the development of chronic renal impairment (CRI) in HIV-positive persons and the relationship with use of antiretroviral drugs and other risk factors [1–5]. Although several commonly used antiretrovirals have been associated with development of moderate levels of CRI [6–9], the possibility that antiretroviral-associated CRI may be reversible after drug cessation has not yet been fully investigated.

Studies of non-antiretroviral drugs with nephrotoxic properties such as aminoglycosides and amphotericin B have shown that iatrogenic-induced tubular or interstitial renal damage is reversible if the damage is recognized early, the causative drug is discontinued, low cumulative doses are administered and the treated patient has few other comorbidities that increase the risk of nephrotoxicity [3,10–14]. However, in contrast to most other potentially nephrotoxic drugs, treatment with antiretrovirals is lifelong. As a consequence, high cumulative doses are delivered to the kidneys with a potential for accumulating damage to the renal tissue and risk of more permanent renal impairment. Other factors that induce chronic nephron injury leading to renal fibrosis (i.e. diabetes and hypertension) are often irreversible, despite initiation of appropriate treatment [15]. However, it is plausible that reduced renal function due to antiretroviral-related CRI, depending on the specific effects and duration of the antiretroviral used, may improve or stabilize, whereas CRI associated with traditional renal risk factors may be more likely to progress.

Others have investigated associations between the use (and discontinuation) of several antiretrovirals, particularly tenofovir (TDF), and the possible reversibility of renal function deterioration. However, the lack of a common definition of reversibility of renal function, the small number of cases, limited follow-up and a focus primarily on mild and acute renal failure have meant that these studies have provided limited insight into this question [1–4,15–19]. Reversibility of renal impairment is a difficult endpoint to define as estimated glomerular filtration rate (eGFR) is known to decline with advancing age [20]. Therefore, when assessing longitudinal data on renal function stretching over long follow-up periods, one cannot expect to see a complete return of eGFR to levels of earlier time periods regardless of the intervention. Likewise, other comorbidities such as diabetes may be progressive in nature making resolution of any antiretroviral-associated eGFR decline unlikely despite timely discontinuation [18]. For these reasons, assessments of reversibility of renal function should be interpreted with caution, and a focus on eGFR improvement, stabilization or progression may be more informative.

Prior studies from the Data Collection on Adverse events of Anti-HIV Drugs study (D:A:D) have shown increased TDF discontinuation rates already at eGFR 70 ml/min per 1.73 m2 or less, thus potentially limiting the value of confirmed eGFR 60 ml/min per 1.73 m2 or less as a CRI threshold for addressing the question of reversibility of antiretroviral-associated renal impairment [8]. This analysis is an extension of earlier work from D:A:D, suggesting an association between use of certain antiretrovirals and CRI, but in which follow-up was too limited to assess eGFR changes after CRI.

If switching away from antiretrovirals associated with renal impairment results in stabilization or even improvement in eGFR after CRI has developed, this will have major clinical implications for future risk stratification in relation to antiretroviral treatment (ART) initiation and switches.

The aim of this analysis was therefore to investigate predictors of progression, stabilization or improvement in eGFR after development of CRI in HIV-positive individuals.

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Methods

The D:A:D study is a prospective cohort collaboration established in 1999 following more than 49 000 HIV-1-positive persons in Europe, Australia and the United States of America; details have been published previously [21]. Information on clinical events including end-stage renal disease and death is collected during routine clinical care, validated centrally and regularly monitored. Data on demographic factors, ART, laboratory values, cardiovascular risk factors and AIDS events are collected electronically at enrollment and every 6 months thereafter.

Participants with an eGFR greater than 80 ml/min per 1.73 m2 after 1 January 2004 (date of systematic creatinine collection) actively progressing to CRI (confirmed, ≥3 months apart, eGFR ≤ 70 ml/min per 1.73 m2) with at least two eGFRs in the follow-up period 24–36 months after CRI were included in the analysis. Follow-up ended at the earliest of last visit and 6 months and 1 February 2016. The requirement of a baseline eGFR greater than 80 ml/min per 1.73 m2 ensures an active eGFR decline of at least 10 ml/min per 1.73 m2 before CRI and aimed at preventing inclusion of individuals with long-standing CRI with limited potential for subsequent eGFR improvement. A 24–36-month follow-up period was included to allow sufficient time to establish the subsequent trajectory of renal function.

For each individual, the difference in eGFR between the median of all eGFRs measured at 24–36 months after CRI and the median of the two eGFR values defining CRI were categorized as eGFR improvement (>+10 ml/min per 1.73 m2), stabilization (−10 to +10 ml/min per 1.73 m2) or progression (<−10 ml/min per 1.73 m2), Supplementary Fig. 1, http://links.lww.com/QAD/B69.

The Cockcroft–Gault equation [22], standardized for body surface area [23], was used to estimate creatinine clearance used as a surrogate for eGFR in this analysis [24]. As several specific cohorts were prohibited from collecting ethnicity information, the Cockcroft–Gault was used rather than an equation including ethnicity.

Baseline was defined as the date of CRI (median date of the two eGFRs defining CRI), and characteristics at baseline were compared between the improvement, stabilization and progression groups using the chi-squared test or the Wilcoxon sign rank test.

A polynomial ordinal logistic regression model was used to assess odds of better eGFR outcomes after CRI, assuming that eGFR improvement is better than stabilization, which, in turn, is better than progression. The method assumes that any change in odds comparing stable with progressive eGFR is the same as the change in odds comparing improved with stable eGFR.

A multivariable model included the following non-antiretroviral variables, selected a priori and measured at baseline: sex, age, hypertension (>150/>100 mmHg or use of antihypertensive drugs), prior cardiovascular disease (CVD, case report verified myocardial infarction, invasive cardiovascular procedure or stroke, details at www.cphiv.dk), diabetes (antidiabetic treatment or case report verified), viral hepatitis C (HCV, anti-HCV positive and HCV-RNA positive/unknown), CD4+ cell count, nadir CD4+ cell count, CRI date, eGFR at CRI and eGFR slope prior to CRI. The eGFR slope was calculated as the annual eGFR change between the first eGFR greater than 80 ml/min per 1.73 m2 and the eGFR at CRI using least squares regression (using all eGFRs available). An eGFR slope of −10 ml/min per 1.73 m2 or less defined a faster and more than −10 ml/min/1.73 m2, a slower eGFR decline prior to CRI.

The model was further adjusted for use of antiretrovirals with a reported association with renal impairment: TDF, atazanavir boosted with ritonavir (ATV/r) or atazanavir (ATV) without ritonavir, lopinavir boosted with ritonavir (LPV/r), other boosted protease inhibitors (PI/r) and abacavir (ABC) [6–9,25–27]. Indinavir (IDV) use after 2004 was limited and was only included to adjust for potential unmeasured confounding. In all analyses, antiretroviral drug use was fitted at time of CRI diagnosis and 24 months to allow for assessment of drug switches at and around the time of CRI, Supplementary Fig. 1, http://links.lww.com/QAD/B69. Antiretroviral use was further categorized as never exposed, currently on and currently off for ATV/r; as never exposed, currently on and currently off (≤12, 12–24 and >24 months) for TDF; and never exposed, currently on and currently off (≤12 and >12 months) for all other antiretrovirals. These categories were mutually exclusive and chosen to allow sufficient numbers within each category for meaningful analysis. Those currently off an individual antiretroviral less than 12–24 months will, by definition, have discontinued use between the CRI diagnosis and the time of CRI and 24 months, whereas those off the antiretroviral for more than 24 months, by definition, will have discontinued use before development of CRI.

All statistical analyses were carried out using SAS version 9.3 (Cary, North Carolina, USA).

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Results

A total of 33 151 persons had an eGFR greater than 80 ml/min per 1.73 m2 and at least three eGFR measurements after 1 January 2004 (Fig. 1). Of these, 4456 (13.4%) progressed to CRI during prospective follow-up, and 2006 persons had at least two eGFR measurements 24–36 months after CRI.

Fig. 1

Fig. 1

Those included in analyses were predominantly white (49.4%) male (76.2%), having acquired HIV homosexually (51.2%). The CD4+ cell count closest to baseline (time of CRI) was 520 cells/μl, and median eGFR was 65 ml/min per 1.73 m2. A total of 93.8% were on ART. 16.8% had hypertension, 6.3% diabetes for more than 5 years and 9.2% previous CVD. Baseline characteristics are shown in Table 1.

Table 1

Table 1

Persons with CRI excluded from the analysis due to lack of eGFR measurements in the follow-up period (n = 832) or inadequate length of follow-up (n = 1618, of whom 144 persons died) were generally older, had a later baseline date, were less likely to be on ART and have a lower baseline eGFR. Prior exposure to antiretrovirals was similar in those excluded to those included (data not shown). Among the 144 persons dying in the follow-up period after CRI, the most common individual causes of death were non-AIDS-defining malignancies (n = 40; 27.8%), AIDS-defining illness (n = 19; 13.2%), chronic viral hepatitis (n = 17; 11.8%) and unknown causes (n = 16; 11.1%). Only two individuals (1.4%) died of renal-related causes.

During follow-up after CRI, 20.7% of included individuals experienced improvement in eGFR, 67.0% stabilization and 12.3% progression.

After adjustment, individuals remaining on TDF at the time of CRI plus 24 months follow-up had lower odds of better eGFR outcomes [adjusted odds ratio, 0.47 (95% confidence interval (CI), 0.35–0.63)] compared with individuals who had never started TDF (Fig. 2). Likewise, individuals who had been off TDF less than 12 months at CRI plus 24 months had lower odds of better eGFR outcomes [0.26 (0.17–0.40)]. In contrast, individuals off TDF for 12–24 months [0.75 (0.50–1.13)] or more than 24 months [0.89 (0.61–1.31)] had similar odds of better outcomes compared with individuals never exposed to TDF. Similar trends were seen for ATV/r except the odds of better eGFR outcomes returned to the levels of those who had never started ATV/r less than 12 months of ATV/r discontinuation (Fig. 3). Data for unboosted ATV were limited and showed similar results to those seen for LPV/r (although not statistically significant) (Fig. 3). In contrast, there was no clear association between use of, or time since discontinuation of ABC and other PI/r and outcomes after CRI (Fig. 3).

Fig. 2

Fig. 2

Fig. 3

Fig. 3

The results were consistent after follow-up for each of the antiretrovirals was censored for any follow-up with concomitant use of the other included antiretrovirals (i.e. follow-up on ATV/r use was censored for any TDF use, data not shown).

Older persons had significantly lower odds of better eGFR outcomes [0.58 (0.52–0.65) per 10 years], but there was no suggestion of a given age at which odds of better outcomes started to decrease (Fig. 4). Other predictors of worse eGFR outcomes were diabetes for more than 5 years [0.47 (0.32–0.71)], hypertension [0.73 (0.56–0.95)] and a later date of CRI [0.93 (0.89–0.97)]. HIV viremia and HCV positivity did not significantly impact on eGFR outcomes. Although there was no interaction between hypertension, diabetes and antiretroviral use (all P > 0.05), a significant interaction between TDF, age and eGFR outcomes (P = 0.0009) was observed, suggesting that the higher odds of better outcomes associated with discontinuing TDF were decreased for individuals aged more than 50 years compared with those aged less than 50 years.

Fig. 4

Fig. 4

A large number of sensitivity analyses were carried out to test the robustness of the antiretroviral drug associations with eGFR outcomes, including looking at outcomes at time of CRI, at 12–24 months after CRI or at more than 36 months after CRI. Results were further unchanged by adjustment for calendar time. Further stratification of exposure to antiretrovirals was also investigated, but the CIs became too wide to draw clinically relevant conclusions.

Additional sensitivity analyses tested if the proportional odds assumption was reasonable (i.e. that changes in odds comparing eGFR improvement with stabilization was similar to changes comparing eGFR stabilization to progression). Results were tested using a nominal logistic regression model, which showed highly consistent results (data not shown). Consistent results were also seen using only two eGFR outcomes; improvement/stabilization versus progression (data not shown).

Use of confirmed eGFR of 60 ml/min per 1.73 m2 or less [moderate chronic kidney disease (CKD)] as an alternative CRI definition (with progression from an initial eGFR greater than 70 ml/min per 1.73 m2) did not significantly alter the proportions in the eGFR improvement, stabilization or progression groups (Fig. 1). The predictors of better eGFR outcomes were likewise largely similar to the primary analysis with the exception of women having better odds of improvement than men [1.59 (1.15–2.20)] and being currently on TDF at time of CKD plus 24 months, which was no longer significantly associated with a worse eGFR outcome [0.77 (0.50–1.19)] as compared with TDF unexposed. Those off TDF for less than 12 months had similar odds of a better eGFR outcome [0.88 (0.52–1.50)], whereas those off 12–24 months had higher odds [1.96 (1.20–3.20)] compared with TDF unexposed.

Finally, a CRI resolution endpoint was investigated; a return to confirmed eGFR greater than 70 ml/min per 1.73 m2 at 24–36 months after CRI. Of the 2006 persons included 470 [23.4% (21.5–25.3)] experienced CRI resolution, and younger age and earlier date of CRI diagnosis were significant predictors (data not shown). The relation between TDF use and discontinuation and resolution confirmed the findings of the primary analysis [currently on TDF at CRI plus 24 months 0.43 (0.31–0.60), off ≤12 months 0.32 (0.19–0.53), off 12–24 months 0.98 (0.63–1.56) and off >24 months 0.90 (0.59–1.39)], all compared with TDF unexposed. The relation with the other nephrotoxic antiretrovirals did not reach statistical significance, but showed similar findings to those shown in Fig. 3 (data not shown).

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Discussion

The current study is the first one to investigate longer term confirmed eGFR outcomes after progression to CRI in HIV-positive persons. Our results suggest that continued use of TDF and ATV/r after a CRI diagnosis is associated with worse renal outcomes and that discontinuation of these drugs may in time halt or improve eGFR in particular in individuals younger than 50 years. These analyses extend previous work from D:A:D, demonstrating the association between use of TDF, ATV/r and LPV/r and progression to CRI from an initial normal eGFR [8].

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Antiretroviral drug use and discontinuation as predictors of eGFR outcomes

The observation that current use of primarily TDF and ATV/r after CRI is associated with worse eGFR outcomes after CRI is consistent with previous, primarily observational, studies linking use of these antiretrovirals with a CRI diagnosis [6–9]. The associations with LPV/r and ATV were less clear, possibly due to lack of power, but trended toward a worse eGFR outcome, after stopping these antiretrovirals. In contrast, there was no suggestion of an association between eGFR outcomes and use of ABC or other PI/r. These results suggest that TDF-associated and ATV/r-associated eGFR declines may not represent irreversible renal tissue damage, and timely discontinuation may independently be beneficial for HIV-positive individuals with declining eGFR. The observation that eGFR outcomes were similar in those off ATV/r less than 12 months and those never exposed to ATV/r, but that this first occurred at more than 12 months after stopping TDF may suggest different underlying biological mechanisms of antiretroviral-related renal impairment. As such, ATV/r crystaluria/interstitial nephritis may be easier to resolve than TDF-related tubulopathy, but additional mechanistic studies are warranted.

It is, of some concern, that the potential to improve/stabilize eGFR seems less strong in individuals aged more than 50 years, and focus should hence be put on older individual on TDF with declining eGFR. Using confirmed eGFR of 60 ml/min per 1.73 m2 or less to define CRI did not reach statistical significance for current TDF use, but showed similar trends of increasing odds of better eGFR outcomes with time since TDF discontinuation as in the primary analysis. These findings must be interpreted with some caution as they are affected by the common nephrotoxic antiretroviral switches in this eGFR range [8]. The eGFR outcomes after ATV/r discontinuation in this exploratory analysis were similar to those observed in the primary analysis, with higher odds of better renal outcomes after discontinuation, although not reaching statistically significance and limited by reduced power and shorter follow-up periods.

Among the other studies investigating associations between TDF discontinuation and renal function, Jose et al.[5] likewise showed an overall eGFR improvement using median piecewise slope evaluation after switching away from TDF. Two safety studies and a small US study found improvement/resolution of all TDF-associated renal impairment cases after TDF discontinuation, but suffered from several methodological challenges [16,17,19]. Other studies have found that only certain individuals discontinuing TDF reached their preexposure eGFR levels suggesting incomplete recovery [1,4,6,18], but the progressive age-related eGFR decline is difficult to account for in these analyses. For ATV, a 2007 US Food and Drug Administration (FDA) study found that all individuals with ATV-related urolithiasis regained renal function after stone removal and ATV discontinuation [28], which was supported by the EuroSIDA study [6]. Other PI-related urolithiasis are relatively rare, although asymptomatic crystalluria may be more prevalent and have, to date, not been assessed in safety trials.

From this and other studies, it seems increasingly compelling that a better renal outcome is possible after discontinuation of TDF and ATV/r, and possibly other nephrotoxic antiretrovirals after CRI development. We were unable to identify a threshold below which eGFR improvement or stabilization was no longer possible despite drug discontinuation. It is unknown if such a threshold exists, but it represents an essential question to address in the future to enhance identification of when antiretrovirals with nephrotoxic potential need to be discontinued to avoid irreversible damage [5].

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Non-antiretroviral drug predictors of eGFR outcomes

Age was, as expected, consistently one of the factors most strongly associated with a worse eGFR outcome after CRI in this analysis. As also expected, hypertension and longer term diabetes were associated with worse eGFR outcomes, underlining the importance of optimizing blood pressure levels, glycemic control and limiting diabetic-related proteinuria. Interestingly, a diagnosis of CRI in later years was also independently associated with a worse outcome, highlighting the need for a more proactive screening and management to prevent CRI.

We found no association between a fast or slowly declining eGFR slope prior to CRI and eGFR outcomes, contrasting a smaller study in which a slowly declining eGFR led to worse renal outcomes [1,29]. No HIV-related factors were associated with better eGFR outcomes despite other studies, including earlier D:A:D studies, have shown a strong association between eGFR and current CD4+ cell count [8,30,31]. This may be due, in part, to the majority of the persons included in this study having well controlled HIV and high CD4+ cell counts.

Our results suggest that eGFR improvement after CRI is relatively common, with one in five individuals experiencing significant eGFR improvement, and 23% experiencing complete resolution of CRI. Likewise, most HIV-positive individuals progressing to CRI subsequently stabilized eGFR at moderate levels of renal impairment rather than continued to decline. These observations offer reassurance for HIV-positive persons and their healthcare providers as it seems that at least some of the excess renal risk among HIV-positive persons can be modified with appropriate management [30,31]. Future studies are however needed to assess which renal interventions are the most effective for HIV-positive individuals and at which level of renal impairment they should be initiated.

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Limitations

There are some limitations to acknowledge in this analysis. We cannot exclude the possibility of selection bias as those excluded from the analysis were more likely to have several common renal risk factors, and as a result, we may have underestimated the proportion of individuals progressing to CRI. Further, a relatively large number of individuals were excluded due to insufficient number of eGFR measurements or follow-up after the CRI diagnosis, although only two of those excluded were known to have died of renal-related causes. As a consequence, the proportion of individuals with eGFR improvement or stabilization after CRI may be overestimated. Exposure to tenofovir alafenamide (TAF) and cobicistat in D:A:D is to date extremely limited and is unlikely to affect our findings. The integrase inhibitor dolutegravir inhibits renal creatinine secretion with artifactual eGFR declines, but this is unlikely to explain our findings as all individuals in this analysis had an eGFR decline more than 10 ml/min per 1.73 m2. Finally, unmeasured confounding cannot be ruled out due to the lack of urinary markers, biopsy findings, family history and the use of other nephrotoxic non-antiretroviral drugs. Our main conclusions were however tested in a number of sensitivity analyses with consistent results, including modifying the CRI and eGFR outcomes, fitting antiretroviral exposure at different time points and after censoring follow-up time for concomitantly used antiretrovirals.

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Conclusion

Even after progression to a diagnosis of CRI, subsequent longer term improvements in renal function are relatively common among HIV-positive persons, with the majority stabilizing and only few persons experiencing continued decline in eGFR over time. Older age, hypertension, longer term diabetes, later date of CRI diagnosis and use of TDF and ATV/r were associated with lower odds of better eGFR outcomes after CRI. Persons who stopped TDF and ATV/r had similar eGFR outcomes compared with those who had never started these antiretrovirals, suggesting that antiretroviral-associated eGFR decline may be halted or reversed with timely drug cessation.

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Acknowledgements

The work was supported by the HAART Oversight Committee (HAART-OC), a collaborative committee with representation from academic institutions, the European Agency for the Evaluation of Medicinal Products, the United States Food and Drug Administration, the patient community and pharmaceutical companies with licensed anti-HIV drugs in the European Union: AbbVie, Bristol-Myers Squibb, Gilead Sciences Inc., ViiV Healthcare, Merck & Co Inc. and Janssen Pharmaceuticals. Supported also by a grant (grant number DNRF126) from the Danish National Research Foundation (CHIP & PERSIMUNE); by a grant from the Dutch Ministry of Health, Welfare and Sport (ATHENA); by a grant from the Agence nationale de recherches sur le sida et les hépatites virales (ANRS, Action Coordonnée no.7, Cohortes) to the Aquitaine Cohort; The Australian HIV Observational Database (AHOD) is funded as part of the Asia Pacific HIV Observational Database, a program of The Foundation for AIDS Research, amfAR, and is supported in part by a grant from the U.S. National Institutes of Health's National Institute of Allergy and Infectious Diseases (NIAID) (grant number U01-AI069907) and by unconditional grants from Merck Sharp & Dohme; Gilead Sciences; Bristol-Myers Squibb; Boehringer Ingelheim Roche; Pfizer; GlaxoSmithKline and Janssen Pharmaceuticals. The Kirby Institute is funded by The Australian Government Department of Health and Ageing, and is affiliated with the Faculty of Medicine, The University of New South Wales. By grants from the Fondo de Investigación Sanitaria (grant number FIS 99/0887) and Fundación para la Investigación y la Prevención del SIDA en Espanã (grant number FIPSE 3171/00), to the Barcelona Antiretroviral Surveillance Study (BASS); by the National Institute of Allergy and Infectious Diseases, National Institutes of Health (grants numbers 5U01AI042170-10 and 5U01AI046362-03), to the Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA); by grants from the BIOMED 1 (grant number CT94-1637) and BIOMED 2 (grant number CT97-2713) programs and the 5th framework program (grant number QLK2-2000-00773), the 6th Framework (LSHP-CT-2006-018632), and the 7th Framework (FP7/2007-2013, EuroCoord no. 260694) programmes of the European Commission and unrestricted grants by Janssen R&D, Merck and Co. Inc., Pfizer Inc., GlaxoSmithKline LLC, [the participation of centers from Switzerland is supported by The Swiss National Science Foundation (grant 108787)] to the EuroSIDA study; by unrestricted educational grants of AbbVie, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Pfizer, Janssen Pharmaceuticals to the Italian Cohort Naive to Antiretrovirals (The ICONA Foundation); and by a grant from the Swiss National Science Foundation (grant no. 148522) to the Swiss HIV Cohort Study (SHCS). The content of this publication is solely the responsibility of the authors and does not necessarily represent the official views of any of the institutions mentioned above.

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Conflicts of interest

L.R., J.D.L. and M.R. have no conflicts of interest. A.M. has received consultancy fees/honoraria/speaker fees from BMS, Pfizer, Merck, BI and Gilead Sciences. O.K. had prior/present board membership at ViiV Healthcare, Gilead Sciences and Merck, received payment for lectures and/or for development of educational presentations from Abbott, Gilead Sciences and Tibotec and had travel/accommodations/meeting expenses paid by Abbott, BMS, Gilead Sciences, Merck and ViiV Healthcare. P.R. has served as a scientific advisor to Bristol-Myers Squibb, Gilead Sciences, Grupo Ferrer, GlaxoSmithKline, Janssen Pharmaceuticals, Merck & Co, Inc and ViiV Healthcare. He has served on data and safety monitoring boards and endpoint adjudication committees for Janssen Pharmaceuticals and his institution has received honoraria for speaking engagements at scientific conferences from Bristol-Myers Squibb, Gilead Sciences, Inc, GlaxoSmithKline. He has received research support from Gilead Sciences, ViiV Healthcare, Merck & Co, Inc, Janssen Pharmaceuticals, Bristol-Myers Squibb, Abbott and Boehringer Ingelheim Pharmaceuticals. C.A.F. is an advisory board member for Gilead Sciences and MSD, has pending grants from Gilead Sciences and Abbott and received payment for lectures by Gilead HIV and the body. P.M. is board member at ViiV Healthcare, MSD, Gilead Sciences and Boehringer Ingelheim Pharmaceuticals and had expenses paid for travel/accommodation/meetings by BMS, ViiV Healthcare, Abbott and MSD. O.M. has received honoraria speaker from Abbott and Gilead Sciences, is a board member for Roche and had expenses paid for travel/accommodation/meetings by Roche and Baxter companies. C.S. has a pending grant from Bristol-Myers Squibb and received payment for development of educational presentations by Gilead Sciences. A.P. received personal fees from Gilead Sciences, Abbvie, GlaxoSmithKline Vaccines and grants from BMS. C.S. received personal fees from Gilead Sciences, Bristol-Myers Squibb, Janssen-Cilag, Abbott Pharmaceuticals, and Viiv Healthcare. M.L. has received research grants from Boehringer Ingelheim, Bristol Myer Squibb, Gilead, GlaxoSmithKline, Janssen-Cilag Pty Ltd, Merck Sharp & Dohme, Pfizer and Roche.

D:A:D participating cohorts: AHOD (Australia), Aquitaine (France), Athena (The Netherlands), BASS (Spain), CPCRA (USA), EuroSIDA (multinational), HivBivus (Sweden), ICONA (Italy), Nice (France), SHCS (Switzerland) and St. Pierre (Belgium) D:A:D Steering Committee: Names marked with *, Chair with # Members of the D:A:D SC from the Oversight Committee: B. Powderly*, N. Shortman*, C. Moecklinghoff *, G. Reilly*, X. Franquet* D:A:D Central Coordination: C.I. Hatleberg, L. Ryom*, C.A. Sabin*, D. Kamara, C. Smith, A. Phillips*, A. Mocroft, A. Bojesen, J. Nielsen, C. Matthews, D. Raben, J.D. Lundgren# D:A:D data managers: R. Salbøl Brandt (coordinator), M. Rickenbach, I. Fanti, E. Krum, M. Hillebregt, S. Geffard, Jaohar Mourabi, A. Sundström, M. Delforge, E. Fontas, F. Torres, H. McManus, S. Wright, J. Kjær, Dennis Kristensen Verification of Endpoints: A. Sjøl (CVD primary endpoint), P. Meidahl (oncology, new endpoint), J. Helweg-Larsen (hematology, new endpoint), J. Schmidt Iversen (nephrology, new endpoint) Kidney working group: L. Ryom*, A. Mocroft, O. Kirk*, P. Reiss*, C. Smit, M. Ross, C.A. Fux, P. Morlat, O. Moranne, E. Fontas, D.A. Kamara, C. Smith, J.D. Lundgren# Mortality working group: C. Smith, L. Ryom*, A. Phillips*, R. Weber*, P. Morlat, C. Pradier*, P. Reiss*, N. Friis-Møller, J. Kowalska, J.D. Lundgren# Cancer working group: C. Sabin*, M. Law*, A. d’Arminio Monforte*, F. Dabis*, F. Bonnet, P. Reiss*, C. Smith, D.A. Kamara, M Bower, G. Fätkenheuer, A. Grulich, L. Ryom*, J.D. Lundgren

For a complete list of acknowledgements of the 11 cohorts providing data to D:A:D, please see Supplementary Document 2, http://links.lww.com/QAD/B69.

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* The D:A:D study is a collaboration among the following cohort studies: AHOD, Aquitaine, Athena, BASS, CPCRA, EuroSIDA, HivBivus, ICONA, Nice, SHCS and St. Pierre.

Keywords:

atazanavir; chronic renal impairment; estimated glomerular filtration rate; HIV; reversibility; tenofovir

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