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Impaired creatinine-based estimated glomerular filtration rate in Thai individuals switching to dolutegravir: illustrating the role of cystatin C testing to aid clinical decision making

AIDS Research and Therapy volume 22, Article number: 15 (2025) Cite this article

Abstract

Introduction

Data about impact of switch to dolutegravir (DTG)-based antiretroviral therapy (ART) on estimated glomerular filtration rate (eGFR) in Asians are scarce. RV254/SEARCH010 is a prospective observational cohort in Bangkok, Thailand with ART initiation during acute HIV infection (AHI) where participants switched to DTG-based ART.

Methods

Participants started Efavirenz (EFV)-based ART during AHI (n = 214) and switched to DTG-based ART after a median of 97 weeks (IQR 61–145). GFR was estimated by serum creatinine (eGFRcre) every 24 weeks before and after switch. Estimated GFR by cystatin C (eGFRcystC) was ordered at clinician’s discretion for decreased eGFRcre after switch. Random-effect linear regression model was used to assess changes in eGFRcre over 96 weeks from starting ART, and from switching to DTG.

Results

At study entry, 20 participants (9.3%) had eGFRcre < 90 ml/min/1.73 m2. During EFV-based ART, an additional 17 (8%) developed eGFRcre < 90 ml/min/1.73 m2, nearly all transient, while mean eGFRcre remained stable and within normal range. At switch to DTG, 21 (9.8%) had eGFRcre < 90 ml/min/1.73 m2 but an additional 116 (54%) developed eGFRcre < 90 ml/min/1.73 m2 during follow-up with eGFRcre decrease being mostly persistent. Mean eGFRcre decreased 20.8% from 117.0 to 92.4 ml/min/1.73 m2 (p < 0.001). Among 20 post-switch participants with eGFRcystC measured within 4 weeks of eGFRcre < 90 mL/min/1.73 m2, 13 (65%) had normal kidney function by eGFRcystC.

Conclusions

Persistent eGFRcre decrease to < 90 ml/min/1.73 m2 after switch to DTG was common in this Thai population. eGFRcystC was helpful to identify individuals with clinically significant decrease in kidney function and obviate unnecessary ART modifications.

Trial registration Clinical Trials Registry Number: ClininicalTrials.gov NCT00796146.

Introduction

Monitoring kidney function is standard of care for people living with HIV (PLWH) due to increased risk of kidney disorders, including drug nephrotoxicity, HIV-associated nephropathy and chronic kidney disease (CKD) [1].

Glomerular filtration rate (GFR) is most commonly used to measure kidney function and to screen for asymptomatic kidney impairment [2], measured directly or estimated by a substance filtered but not actively secreted or reabsorbed by the kidney tubules. Assessing plasma clearance of inulin is the gold standard for direct GFR measurement but is expensive and is not available in most clinical settings. Moreover, inulin or other exogenous markers (e.g. iothalamate, iohexol, DTPA or EDTA), require peripheral administration and 24-h urine collection [2].

Clinically, GFR is usually estimated using serum creatinine level (eGFRcre). Creatinine is freely filtered across the glomerulus and neither reabsorbed or metabolized, but undergoes further secretion by an organic cation transporter (OCT2) on the basolateral side of proximal kidney tubule cells [3]. This tubular secretion affects creatinine clearance (CrCl) by contributing approximately 10% to 40% to urinary creatinine. OCT2 is inhibited by certain drugs, causing a decrease in creatinine clearance (CrCl) without affecting true GFR [4]. Other well-known serum creatinine related eGFR confounders are race and muscle mass, with equations estimating GFR evolving over time to best account for such confounders [5].

Cystatin C estimated GFR (eGFRcystC) is an alternative measure of kidney function [6, 7] as cystatin C is also freely filtered at the glomerulus and not reabsorbed. It is affected by some other factors than serum creatinine but its metabolism is not affected by OCT2 [8] and it is reported to be more precise and accurate for GFR estimation in Thai PLWH [9].

In 2018, the World Health Organization (WHO) recommended dolutegravir (DTG)-based antiretroviral therapy (ART) as the preferred first-line treatment for PLWH and subsequently, in 2019, as the preferred second-line treatment for those without prior exposure [10]. DTG inhibits OCT2, resulting in elevated serum creatinine and a decreased eGFRcre [11]. In mostly white, healthy volunteers an average decrease in eGFRcre of 10% with DTG 50 mg once daily and 14% with DTG 50 mg twice daily was seen [12]. Virologically controlled PLWH (n = 108, 95% men) in Japan had a median eGFRcre decrease from 74 to 66.5 ml/min/1.73 m2 (p < 0.001) 48 weeks after switching to DTG [13]. Both studies are among multiple reports showing unchanged cystatin C levels after starting DTG and the general utility of cystatin C monitoring for patients receving DTG [14,15,16,17,18,19]. In the SPRING-1 study, 51 treatment naïve HIV-positive participants (75% white males) receiving DTG 50 mg once daily had mean (SD) decrease in serum creatinine at week 96 of 10.1 (11.07) μmol/L from a baseline of 82.2 μmol/L [20]. In the Spring-2 study 349 treatment naïve HIV-positive participants (majority white males) receiving DTG 50 mg once daily had mean decrease in estimated CrCl at week 96 of 19.6 mL/min [21]. The Spring-2 study did not report on eGFR changes, but only 16/342 participants were reported to have a creatinine increase meeting Division of AIDS (DAIDS) adverse event criteria, with 14 out of 16 being grade 1 (creatinine 1.1–1.3 × upper limit of normal) [22].

We describe incidence and magnitude of decrease in eGFRcre in a Thai cohort for up to 96 weeks after efavirenz (EFV)-based ART initiated during acute HIV infection (AHI), and in the same participants up to 96 weeks after switch to DTG. In a subset of participants on DTG we compare with eGFRcystC. This analysis was initiated after more significant decreases in eGFRcre were observed in the study cohort after switch than anticipated from prior studies and the dolutegravir package insert.

Methods

RV254/SEARCH010 cohort participants in Bangkok, Thailand (ClinicalTrial.gov: NCT00796146) started EFV-based ART between March 2010 and November 2016 and switched to DTG-based ART between February 2017 and June 2018 after a median of 97 weeks (IQR 61–145) on EFV. We analyzed eGFRcre levels of this cohort for up to 96 weeks (Median, IQR: 96, 48–96 weeks) pre-switch and up to an additional 96 weeks (Median, IQR: 96, 72–96 weeks) after switch to DTG. The 214 participants included in the analysis are Thai who were stable on EFV-based ART (all but one in combination with tenofovir [TDF] + lamivudine [3TC] OR tenofovir [TDF] + emtricitabine [FTC]), had plasma HIV RNA < 20 copies/mL at time of switch to DTG, and did not use any OCT2 inhibitors (e.g. ritonavir, rilpivirine, cimetidine, or trimethoprim). eGFRcre was calculated at least every 24 weeks before and after switch to DTG. Based on guidelines and terminology of the National Kidney Foundation and DAIDS, kidney function was defined as decreased at eGFR below 90 ml/min/1.73 m2 and as normal at ≥ 90 ml/min/1.73 m2 [22, 23]. Decreased eGFR was defined as being persistent if present at at least three time-points over 96 weeks, including the last available measurement. eGFR baseline was considered to be the value upon first starting ART for the period on EFV, and the value upon the day of switch to DTG for the period on DTG. As hepatitis B and C are known predictors of progressive kidney disease in PLWH on ART, sensitivity analysis was done for participants with hepatitis B and/or C to assess whether eGFRcre and eGFRcre changes differed from the overall cohort [24]. At discretion of treating clinicians, a decline in eGFRcre after switch to DTG was eligible for evaluation with eGFRcystC at any timepoint, using the same blood sample or a repeat blood draw.

The re-expressed Modification of Diet in Renal Disease (MDRD) eGFR formula adjusted for Thai racial factor was used to calculate eGFRcre while eGFRcystC was calculated using the eGFR cystatin C equation. These formulas were selected for reportedly providing values closest to direct kidney function measurement in a Thai cohort of PLWH [9].

Statistical methods

eGFRcre before and changes after switch to DTG were described by mean. Paired t-test was used to compare eGFRcre and eGFRcystC. Difference in prevalence of decreased eGFR before and after DTG switch was assessed by McNemar’s test. Change in eGFR from baseline was assessed by random-effect linear regression model. A p-value < 0.05 was deemed significant for all calculations. Analyses were performed using StataCorp 2019. Stata Statistical Software: Release 16, StataCorp LLC, College Station, Texas, USA. Figures were generated with GraphPad Prism version 8.2.0 for Windows, GraphPad Software, San Diego, California, USA.

Results

Study population characteristics

Participants’ characteristics at ART initiation and at switch to DTG are listed in Table 1. The cohort consists primarily of men who have sex with men (MSM). At time of switch to DTG, participants meeting analysis inclusion criteria were on EFV-based ART for a median (IQR) duration of 97 (61–145) weeks with median CD4+ T-cell count of 637 cells/mm3. Out of 214 participants, 166 (77.6%) switched from TDF to abacavir (ABC) at time of switch to DTG, while 48 (22.4%) remained on TDF and 45 (21%) had a diagnosis of hepatitis B and/or C.

Table 1 Study population characteristics at ART initiation and at time of switch to DTG
Full size table

Mean eGFRcre reduced after switch to DTG

Over the initial 96 weeks on EFV-based ART, mean (SD) eGFRcre did not change significantly from 115.1 (19.0) to 115.4 (18.5) ml/min/1.73 m2 (p = 0.10). At switch to DTG, mean (SD) eGFRcre was 117.0 (19.4), also not significantly different from when the cohort first started ART (p = 0.08). However, at the first available measurement on DTG, 12 weeks after switch, serum creatinine had increased and mean (SD) eGFRcre had decreased significantly by 18.8% (8.0) to 92.8 (15.9) ml/min/1.73 m2 (both p < 0.001), with the eGFRcre decrease persisting at all time points thereafter compared to baseline (Fig. 1, p < 0.001 for all time points after switch). By week 96 on DTG, mean (SD) eGFRcre had decreased by 20.8% (10.9) or 25.6 (14.3) ml/min/1.73 m2 (both p < 0.001).

Fig. 1
figure 1

Creatinine and eGFRcre pre and post switch. Mean creatinine (A, B) and eGFRcre (C, D) during 96 weeks on initial ART (A, C) and during 96 weeks after switch to DTG (B, D)

Full size image

More decreased eGFRcre events after switch to DTG

Upon EFV-based ART initiation 20/214 (9.3%) volunteers had decreased eGFRcre, while after a median of 97 (IQR 61–145) weeks on EFV-based ART, at switch to DTG, 21/214 (9.8%) had decreased eGFRcre (p = 0.81). An additional 17/194 (7.9%) participants developed decreased eGFRcre at any time point while on EFV-based ART vs. 116/193 (54.2%) while on DTG-based ART after the switch (p < 0.001). New onset decreases in eGFR were transient whilst on EFV-based ART in 87% but were persistent in a majority of 59% after switch to DTG. eGFRcre (mean, SD) did not differ at week 96 after switch to DTG between those who continued TDF and those who switched to ABC in addition to switching to DTG at 90.4 (13.9) ml/min/1.73 m2 vs. 93.17 (18.0) ml/min/1.73 m2 (p = 0.433). No difference was seen between participants with or without hepatitis B and/or C in terms of total creatine, eGFRcre, or change in eGFRcre.

eGFRcystC is of clinical utility in those with eGFRcre decrease

Twenty eight participants with a decline in eGFRcre after switch to DTG had eGFRcystC measurement within 4 weeks of the decline. The mean (SD) calculated eGFRcystC in these participants was 98.4 (14.6) ml/min/1.73 m2, significantly higher than mean (SD) eGFRcre at 80.4 (13.0) ml/min/1.73 m2 (p < 0.001) (Fig. 2). Of these 28, 20 had decreased eGFRcre at < 90 ml/min/1.73 m2, but when cystatin C was used for GFR estimation, 13/20 (65%) had eGFRcystC ≥ 90 ml/min/1.73 m2.

Fig. 2
figure 2

Creatinine compared to Cystatin C in those with matching samples. Comparison of eGFRcre with eGFRcystC (n = 28)

Full size image

Discussion

Dolutegravir administration is associated with an increase in serum creatinine as early as 2 weeks after initiation and a consequent decrease in eGFRcre which persists over time [12, 21]. The Thai participants described here had a mean (SD) eGFRcre decrease of 21.8 (10.2) ml/min/1.73 m2 or 18.8% (8.0) at 12 weeks after switching to DTG which persisted for the remainder of the 96 weeks observation period.

Koteff et al. reported a phase I study with a decrease in estimated CrCl in healthy, predominantly white volunteers without HIV of 10% on DTG 50 mg once daily and 14% on DTG 50 mg twice daily but with no effect on GFR as measured by iohexol plasma clearance. The SPRING-2 study meanwhile reported a mean decrease in estimated CrCl at week 96 of 19.6 mL/min among 349 participants. Meanwhile, Yukawa et al. reported a median decrease in eGFRcre from 74 to 66.5 ml/min/1.73 m2 at 48 weeks in an Asian (Japanese) population switching to DTG. Since estimated CrCl tends to be higher than estimated GFR and the Cockcroft-Gault equation estimates CrCl in mL/min while the MDRD equation estimates GFR in mL/min/1.73 m2, our findings stand out for magnitude and frequency of eGFRcre decrease [25, 26]. Just over 9% of the participants with acute HIV had decreased eGFRcre at study baseline, which is no different from the overall rate in the Thai population [27]. After a median of 97 weeks on EFV-based ART, this proportion was nearly unchanged, still consistent with the overall decreased eGFRcre rate in the Thai population and suggesting no significant ARV drug toxicity.

It is reassuring that among volunteers for whom eGFRcystC was ordered, 65% had no clinically significant decrease in actual kidney function. However, the fact that 35% also had decreased eGFR using cystatin C seems to contrast with prior studies that reported that eGFRcystC did not change after switch to DTG [13,14,15, 17, 18].

Further study is necessary about the differences observed among these populations and if they can be attributed to race, weight, co-morbidities, or ART history, including protracted tenofovir use in our population.

Our study has several limitations. Cystatin C within 4 weeks of eGFRcre decrease on DTG was only available in 20 of 116 participants with a decrease in eGFRcre below 90 ml/min/1.73 m2 and selection bias cannot be excluded. Second, our study was performed in predominantly Thai MSM who started ART soon after HIV infection. Further studies are needed to confirm our findings in other Thai and Southeast Asian PLWH.

Conclusions

In our cohort of predominantly young Thai MSM, switch to DTG was associated with more frequent and greater decrease in eGFRcre than expected based on earlier reports [12, 13, 20, 21]. Decreased eGFR after switching to DTG was common when calculated by serum creatinine but not confirmed in 65% of 20 participants for whom cystatin C was available.

As low- and middle-income countries transition to the use of DTG based ART, access to cystatin C measurement or other alternative measurements of GFR for those with marked eGFRcre decrease seems of clinical importance to avoid unnecessary ART modifications.

Data availability

The data that support the findings of this study are available on request from the corresponding author on reasonable request.

Abbreviations

3TC:

Lamivudine

ABC:

Abacavir

AHI:

Acute HIV infection

ART:

Antiretroviral therapy

AZT:

Zidovudine

CKD:

Chronic kidney disease

CrCl:

Creatinine clearance

DAIDS:

Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health

DTG:

Dolutegravir

DTPA:

Diethylenetriaminepentaacetic acid

EDTA:

Ethylenediaminetetraacetic acid

EFV:

Efavirenz

FTC:

Emtricitabine

GFR:

Glomerular filtration rate

eGFR:

Estimated glomerular filtration rate

eGFRcre :

Creatinine based estimated glomerular filtration rate

eGFRcystC :

Cystatin C based estimated glomerular filtration rate

HBsAg:

Hepatitis B surface antigen

HCV:

Hepatitis C virus

IQR:

Interquartile range

MDRD:

Modification of diet in renal disease

MSM:

Men who have sex with men

OCT2:

Organic cation transporter 2

PLWH:

People living with HIV

RNA:

Ribonucleic acid

SD:

Standard deviation

TDF:

Tenofovir

WHO:

World Health Organization

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Acknowledgements

We thank the participants in the RV254/SEARCH010 cohort and the members of the study group. We thank the staff at the Thai Red Cross AIDS Research Centre, Institute of HIV Research and Innovation, the Armed Forces Research Institute of Medical Sciences in Bangkok, Thailand, and the Military HIV Research Program in Maryland, USA.

Disclaimer

The views expressed are those of the authors and should not be construed to represent the positions of the U.S. Army, the Department of Defense, the National Institutes of Health, the Department of Health and Human Services, or the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. The investigators have adhered to the policies for protection of human subjects as prescribed in AR-70–25. Preliminary data were presented as a poster at the 22nd International AIDS Conference, 23–27 July 2018, Amsterdam, the Netherlands.

Funding

Cohort study RV254/SEARCH010 is supported by cooperative agreements (W81XWH-18-2-0040) between the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., and the U.S. Department of Defense (DOD) and in part by the National Institutes of Health (DAIDS, NIAID, NIH grant AAI21058-001-01000). Additional funding was given through NIH R01MH130197 grant. ART for RV254/SEARCH 010 participants was supported by the Thai Government Pharmaceutical Organization, Gilead Sciences, Merck, and ViiV Healthcare.

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Authors and Affiliations

  1. SEARCH Research Foundation, Block 28, 926 Tower C, Room C114-C115, Soi Chula 7, Wang Mai, Pathum Wan, Bangkok, 10330, Thailand

    Carlo Sacdalan, Eugène Kroon, Orlanda Goh, Krittaporn Pornpaisakul, Jintana Intasan, Tassanee Luekasemsuk & Nitiya Chomchey

  2. Research Affairs, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand

    Carlo Sacdalan & Krittaporn Pornpaisakul

  3. Washington University School of Medicine in St. Louis, St. Louis, MO, USA

    Curtis Austin

  4. Medicine and Surgery, University of Milan, Milan, Italy

    Aswathy Varma

  5. United States Military HIV Research Program; Walter Reed Army Institute of Research, Silver Spring, MD, USA

    Suteeraporn Pinyakorn, Donn J. Colby, Merlin L. Robb, Sandhya Vasan & Denise Hsu

  6. The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, USA

    Suteeraporn Pinyakorn, Donn J. Colby, Merlin L. Robb, Sandhya Vasan & Denise Hsu

  7. Institute of HIV Research and Innovation, Bangkok, Thailand

    Eugène Kroon, Orlanda Goh & Nittaya Phanuphak

  8. Department of Neurology, Yale University, New Haven, CT, USA

    Phillip Chan

  9. Amsterdam UMC, Department of Global Health, Amsterdam Institute for Global Health and Development, Amsterdam, The Netherlands

    Jintanat Ananworanich

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Consortia

the SEARCH 010/RV254 study group

Contributions

Conceptualization by CS, DJC, MLR, NP, JA and DH; methodology and analysis by CA, AV and SP; literature search by OG, KP; design and conduct of the clinical trial by CS, EK, DJC, PC, OG, KP, JI, TL, NC, MLR, JA, NP and SV; writing, review and editing by CS, EK, DJC, OG, KP, SP, and DH; all authors have read and approved the final manuscript.

Corresponding author

Correspondence to Carlo Sacdalan.

Ethics declarations

Ethics approval and consent to participate

All participants signed written informed consent and participated in protocols approved by Thai (Chulalongkorn University, Faculty of Medicine, OHRP IRB00001607) and US (Walter Reed Army Institute of Research, OHRP IRB00000794) Institute Review Boards.

Competing interests

The authors declare no competing interests.

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Sacdalan, C., Austin, C., Varma, A. et al. Impaired creatinine-based estimated glomerular filtration rate in Thai individuals switching to dolutegravir: illustrating the role of cystatin C testing to aid clinical decision making. AIDS Res Ther 22, 15 (2025). https://doi.org/10.1186/s12981-025-00712-0

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Keywords

AIDS Research and Therapy

ISSN: 1742-6405

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