JAC Advance Access originally published online on March 21, 2007
Journal of Antimicrobial Chemotherapy 2007 59(5):1034-1037; doi:10.1093/jac/dkm064
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No change in calculated creatinine clearance after tenofovir initiation among Thai patients
1 University Hospital of Geneva, Geneva, Switzerland 2 The HIV Netherlands Australia Thailand Research Collaboration (HIV-NAT), Bangkok, Thailand 3 Khon Kaen University, Srinagarind Hospital, Khon Kaen, Thailand 4 Bamrasnaradura Institute, Nonthaburi, Thailand 5 Chulalongkorn University, Bangkok, Thailand 6 Gilead Sciences, Foster City, CA, USA
* Correspondence address. Division of Infectious Diseases, Geneva University Hospital, CH-1211 Geneva 14, Switzerland. Tel: +41-22-372-9812; E-mail: angele.gayet-ageron{at}hcuge.ch
Received 9 October 2006; returned 18 December 2006; revised 23 January 2007; accepted 13 February 2007
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Abstract |
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Objectives: Thai patients have a lower average body weight than patients from western Europe or the USA. Tenofovir is largely prescribed at the standard dosage of 300 mg once daily: therefore, the per kilogram dose is higher in Thailand than in the USA. We asked the question whether this higher per kilogram dose was associated with more nephrotoxicity.
Methods: Thai patients from the Staccato trial were treated with tenofovir/lamivudine combined with ritonavir-boosted saquinavir. Creatinine values were measured before the start of tenofovir and then every 12 weeks. Renal function was assessed using the Cockcroft–Gault formula and the MDRD formula. To compare CLCR before and after tenofovir, the t-paired or Wilcoxon signed rank tests were used. One-way analysis of variance and Spearman's correlation coefficient were used to study CLCR longitudinally.
Results: CLCR remained stable after a median of 21 weeks on tenofovir (difference of +1.06 mL/min; 95% CI –2.7–4.8, P = 0.58), even among patients with underlying diseases. The mean CLCR remained stable across time (P = 0.17).
Conclusions: We did not find renal dysfunction on tenofovir among Thai patients included in the Staccato trial. Tenofovir could be safely prescribed at a standard dosage of 300 mg once daily in the Thai population.
Keywords: antivirals , HIV/AIDS , safety , tolerance , nucleotide analogues , combination treatment , toxicity
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Introduction |
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Tenofovir disoproxil fumarate (Viread®; Gilead Sciences), a nucleotide reverse transcriptase inhibitor, has demonstrated an excellent safety profile in several controlled clinical trials1 evaluating its use for the treatment of HIV infection in previously untreated patients. However, rare cases of nephrotoxicity have been reported, especially in patients with a past history of renal complications or other risk factors for the development of renal disease.2 Small reductions in estimated CLCR without clinical sequelae have been reported in some studies,3–5 but not in others.6,7 The safety and efficacy of tenofovir disoproxil fumarate have not been evaluated in Asian patients. A previous study showed that saquinavir concentration was significantly higher in Thai patients compared with UK patients, perhaps due to their lower body weight (BW) and genetic factors.8 Here we evaluated the impact of standard tenofovir disoproxil fumarate therapy on renal function among Thai patients treated within the Staccato trial.9
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Methods |
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Staccato is a randomized trial of intermittent versus continuous antiretroviral treatment (HAART) in Thailand, Switzerland and Australia.9 Patients with CD4 >350 cells/mm3 and viral load (VL) <50 copies/mL were randomized 1:2 to either continuous HAART or scheduled treatment interruptions (STIs) (with treatment stops as long as CD4 counts exceeded 350 cells/mm3). During Staccato, Thai patients received ritonavir-boosted saquinavir; in addition, stavudine/didanosine was administered early during the trial and then switched to tenofovir/lamivudine in 2003. CLCR was used as a proxy of glomerular filtration ratio and was calculated using the Cockcroft–Gault formula and the Levey modification of diet in renal disease formula (MDRD).8 Creatinine values (in mg/dL), BW (in kg) and age were available before tenofovir and then measured every 12 weeks after. In the ‘before–after group’, we compared CLCR before and after tenofovir using t-paired tests (
= 5%) or the Wilcoxon signed rank test, when appropriate. Some patients only had creatinine values after tenofovir (‘after-only group’) and were thus compared with those in the before period using Student's t-test for independent samples ( = 5%). Finally, in order to study CLCR distribution longitudinally, we restricted our analyses to patients from the continuous treatment arm with several creatinine values (77.1% had at least three creatinine values after tenofovir initiation) after 12–84 weeks on tenofovir (n = 109) and used Spearman's correlation coefficient. We compared the mean CLCR between different time periods (12–36, 36–60, 60–84 and 84–108 weeks) using one-way analysis of variance and tested the effect of gender on CLCR over time using two-way analysis of variance. The Staccato protocol has been accepted by the local Ethics Committees from the different participating centres, and written informed consent was obtained from each participant. The Staccato study is registered at ClinicalTrials.gov with the identifier NCT00113126 [ClinicalTrials.gov] .
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Results |
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One hundred and forty-three patients were included in the before–after group and 121 patients in the after-only group. The mean BW at baseline in Thai patients was significantly lower than that in Swiss and Australian patients (57.1 ± 10.4 versus 70.2 ± 12.1 kg, P < 10–3) (in women: mean weight 52.4 ± 7.7 kg and in men: 63.5 ± 10.3 kg). Patient characteristics are presented in Table 1.
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In the before–after group, 11.2% of patients were antiretroviral-naive at tenofovir initiation, whereas the others were receiving stavudine/didanosine/ritonavir-boosted saquinavir. The mean creatinine at baseline was 0.92 ± 0.36 mg/dL; it was 0.87 ± 0.23 mg/dL after a median of 21.4 weeks on tenofovir [interquartile range (IQR) 15–36.3] (P = 0.04). After tenofovir, the mean CLCR was 89.5 mL/min (
+1.06 mL/min, 95% confidence interval –2.71 to +4.83, t-paired test P = 0.58). Among patients with underlying disease (n = 15 with chronic hepatitis B/C, high blood pressure or diabetes), the mean CLCR remained stable (92.0 ± 24.9 mL/min before versus 87.5 ± 18.9 mL/min after tenofovir, Wilcoxon signed ranks test P = 0.30). Four patients with baseline CLCR <50 mL/min did not worsen their renal function and even tended to improve it, after a median of 23.4 weeks on tenofovir (IQR 14.7–51.7) (median of 34.1 mL/min, IQR 23.5–40.9, before and 60.6 mL/min, IQR 31.1–79.2, after tenofovir, P = 0.15). Demographical and infection-related characteristics were similar in both subgroups, which allow us to compare them (Table 1). In the after-only group, tenofovir was used for a median of 23.4 weeks (IQR 16–36). The mean creatinine was 0.91 ± 0.17 mg/dL, not statistically different from creatinine values before tenofovir in the before–after group (P = 0.79). The mean CLCR was also not statistically different at 83.8 ± 21.5 mL/min (P = 0.13).
Using the MDRD formula in the before–after group, we found a mean CLCR of 91.2 ± 28.8 mL/min before tenofovir and 92.8 ± 21.6 mL/min after tenofovir, which were not significantly different (t-paired test P = 0.46). In patients with underlying conditions (n = 15), the mean MDRD did not change between both periods (92.3 ± 24.9 mL/min before tenofovir and 88.2 ± 16.3 mL/min after tenofovir P = 0.40). In the after-only group, the mean CLCR using the MDRD formula was 87.7 ± 17.2 mL/min and was also not significantly different from the CLCR before tenofovir in the before–after group (P = 0.23).
In a subset of 109 continuous arm patients with creatinine values on tenofovir at different time points (from 12 to 108 weeks), there was no correlation between CLCR and time spent on tenofovir (Spearman's 
= 0.064, P = 0.18). The mean CLCR remained stable across time (P = 0.17 in ANOVA). We found an interaction between gender and time spent on tenofovir, with a significantly lower CLCR after 36 weeks on tenofovir in women (CLCR 94.5 ± 25.5 mL/min in men and 80.3 ± 19.3 mL/min in women), which tended to disappear after 60 weeks on tenofovir (92.3 ± 25.1 and 84.5 ± 18.7 mL/min in the 60–84 week period and 83.6 ± 16.2 and 77.1 ± 21.2 mL/min in the 84–108 week period, in men and women, respectively). No patient discontinued Staccato because of renal adverse events.
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Discussion |
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We did not find renal dysfunction on tenofovir among Thai patients included in the Staccato trial. CLCR remained stable when time spent on tenofovir increased. The transient dip in CLCR, observed only at 36 weeks, and only in women, may be a statistical artefact due to multiple measurements, without clinical significance, as CLCR at tenofovir initiation was significantly higher among women. Nonetheless, this transient dip could also be real in light of some other observational data, suggesting an initial drop in CLCR on tenofovir, which does not progress with time.5,10,11 We postulated that due to a lower BW on average, Thai patients should have a higher exposure to tenofovir and might be more likely to develop nephrotoxicity on the standard 300 mg daily dose. However, tenofovir disoproxil fumarate was well tolerated, and significant renal toxicity was not observed.
Our study had some limitations, including its retrospective nature, the lack of a control group and incomplete data on creatinine values at tenofovir initiation. We did not consider the relative short follow-up time of patients as a limitation. Most of the published works had shown early changes in renal function on tenofovir.10,11 In addition, in the primary analysis, estimates of CLR were made using the Cockcroft–Gault formula. The MDRD formula is considered by some to be more accurate, as the Cockcroft–Gault formula may overestimate renal function by as much as 16%,8 but others considered that both formulas lacked precision.12 Moreover, MDRD has not been validated in HIV-infected patients with normal renal function, but it was developed as an estimate of glomerular filtration ratio in patients with impaired renal function. The additional analyses using the MDRD formula showed consistent results using both estimations of glomerular filtration ratio.10 Finally, our results might differ from those of other observational studies due to the specificity of our study population, which was younger, with a higher CD4 count, mostly treatment-naive, with a normal renal function at baseline and the absence of underlying diseases.9
In conclusion, Thai patients from our study treated with a tenofovir-containing regimen were safely treated at the 300 mg once daily standard dosage, despite their lower weight.
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J. A. has received travel grants and speakers' honoraria from Roche. P. C. has received travel grants from Abbott. K. R. has received travel grants, consultancy fees and speakers' honoraria from Roche, Abbott and Bristol-Myer-Squibb. B. H. has received travel grants and speakers' honoraria from Roche, Abbott and Gilead. All the others have not accepted financial contribution, which may affect the conclusion of this article. No authors own stocks from companies involved in this work.
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Footnotes |
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Members are listed in the Acknowledgements section. 
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Acknowledgements |
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The Staccato study was funded by grants from Swiss National Science Foundation through the Swiss HIV Cohort Study, the Wilsdorf, Sidaide and de Brocard Foundations, Geneva, from the Department of Social Affairs and Economics, Geneva, and Roche. Roche, Abbott and Gilead donated antiretrovirals used in Staccato. Bristol-Myer-Squibb sold antiretrovirals at a reduced price to Staccato.
The Staccato Study Group: Protocol committee: Bernard Hirschel, Jintanat Ananworanich, Praphan Phanuphak, Kiat Ruxrungtham, David Cooper. Study nurses, monitors and laboratory technicians in Thailand: Bangkok: Sukontha Saenawat, Saijai Wicharuk, Siriporn Nonenoy, Natnipa Wannachai, Sineenart Chautrakarn, Theshinee Chuenyam, Thantip Nuchapong, Apicha Mahanontharit, Jongkol Sankote, Wiphawee Kiatatchasai, Vantanit Pairoj, Napawan Seekaow, Wipawan Karakate. Nonthaburi: Suchittra Putthawong, Wattana Sanchiem, Sirirat Liganonsakul, Pongpan Boonchoo, Malee Suannum. Khon Kaen: Parichat Bunyaprawit, Ratthanant Kaewmarg. Chiang Mai: Yaowaluk Penglimoon. Phitsanulok: Sopha Khongsawad. Study nurses in Switzerland: Michelle Le Braz, Susan Hochstrasser, Tina Wylie, Susan Niepmann, Jacqueline Voggensperger, Susanne Stölz, Helen Weyermann, Anna Christen, Rachel Spycher, Marina Russoti. Laboratory measures in Switzerland: Sabine Yerly, Chantal Gaille. Investigators in Thailand: Sasisopin Kiertiburanakul (Ramathibodi Hospital, Mahidol University, Bangkok, Thailand), Warangkana Munsakul (Bangkok Metropolitan Administration Medical College and Vajira Hospital, Bangkok, Thailand), Phitsanu Raksakulkarn and Wirat Klinbuayam (Sanpatong Hospital, Chiang Mai, Thailand), Somboon Tansuphasawadikul (Buddhachinnaraj Hospital, Phitsanulok, Thailand). Recruitment and care of patients in Switzerland: Bernard Hirschel, Angele Gayet-Ageron, Veronique Schiffer, Laurent Kaiser, Catherine Fagard (Geneva), Hansjakob Furrer (Bern), Reto Nuesch (Basel), Daniel Genné (La-Chaux-de-Fonds), Urs Karrer (Zürich), Matthias Cavassini (Lausanne), Pietro Vernazza (St Gallen), Enos Bernasconi, Lorenzo Magenta (Lugano). Recruitment and care of patients in Australia: Nicholas Doong, John Dyer, Fraser Drummond (Australia).
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1 Gallant JE, DeJesus E, Arribas JR, et al. (2006) Tenofovir DF, emtricitabine, and efavirenz vs. zidovudine, lamivudine, and efavirenz for HIV. N Engl J Med 354:251–60.
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Froissart M, Rossert J, Jacquot C, et al. (2005) Predictive performance of the modification of diet in renal disease and Cockcroft–Gault equations for estimating renal function. J Am Soc Nephrol 16:763–73.
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