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.
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).
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 .
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 . 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. 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 , which was supported by the EuroSIDA study . 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 .
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.
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.
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.
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.
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.
atazanavir; chronic renal impairment; estimated glomerular filtration rate; HIV; reversibility; tenofovir
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