To the Editors:
We read with interest the recent letter by van Griensven et al1 published in April 1, 2014, edition of JAIDS. Using routinely collected cross-sectional data from HIV-infected patients attending the Sihanouk Hospital Center of HOPE, Phnom Penh, Cambodia, the authors generated a clinical prediction tool (CPT) for targeted creatinine testing during pre-antiretroviral therapy (ART) evaluation. Such a tool may prevent superfluous renal function assessment before initiating the nephrotoxic antiretroviral drug, tenofovir. This will become increasingly important in coming years given the World Health Organization's (WHO) recommendation of tenofovir in first-line ART2,3 and expanding global use of tenofovir.4–7
Details on the generation of the CPT can be found in van Griensven et al1 and elsewhere.8–11 The primary outcome was kidney dysfunction (KD) at pre-ART evaluation, defined as an estimated creatinine clearance <50 mL per minute based on the Cockroft–Gault equation. The WHO recommends tenofovir avoidance or dose reduction at this level of renal impairment.2,3 A risk prediction score that included age, body weight, and hemoglobin, hereafter referred to as the primary CPT, achieved an area under the receiver operating characteristic (AUROC) of 0.81 [95% confidence interval (CI): 0.76 to 0.86] in their validation data set. The probability of KD ranged from 1.0% in those with a score of 0%–51.2% in those with a score of 5. With the cutoff score set at ≥2, sensitivity was 91.5%, specificity was 54.7%, and creatinine testing would have been avoided in 50.5% of patients. Replacing body weight with body mass index (BMI), hereafter referred to as the BMI CPT, achieved an AUROC of 0.77 (95% CI: 0.72 to 0.83); however, sensitivities and specificities were not described. With an alternative risk prediction score including age, body weight, sex, and WHO stage, hereafter referred to as the alternate CPT, AUROC was 0.81 (95% CI: 0.76 to 0.85). With a cutoff score of ≥2, sensitivity was 95.8%, specificity was 40.7%, and creatinine testing would have been avoided in 37.4% of patients.
We sought to provide further validation of van Griensven's CPT by evaluating its performance in the TREAT Asia HIV Observational Database (TAHOD) cohort. TAHOD and the TREAT Asia Studies to Evaluate Resistance-Monitoring (TASER-M) have been described previously.12,13 Briefly, TAHOD is an observational study of patients with HIV involving 21 adult treatment centers in 12 countries and territories of varying income levels in Asia, which aims to assess HIV disease natural history in treated and untreated patients in the region. Retrospective and prospective data are collected at each site. Recruitment started in September 2003. TASER-M was a multicenter cohort study monitoring development of HIV drug resistance in patients taking ART. Patients eligible for first- or second-line ART initiation were enrolled sequentially. Data on previous antiretroviral use were collected retrospectively. Patient recruitment commenced in March 2007 and ceased in 2011. Follow-up data continue to be collected as TASER-M was merged with TAHOD in 2012. Currently, each TAHOD site has contributed data from 100 to 450 patients. Data are transferred to the data management center at the Kirby Institute, Sydney, Australia, twice annually in March and September.
For this analysis, we used data from the September 2013 TAHOD transfer and included patients started on ART that had creatinine, body weight, and hemoglobin data recorded at the time of treatment initiation. A window period of 6 months before ART was allowed for creatinine and hemoglobin levels. The window period for body weight was within 3 months on either side of ART initiation. Patients with any history of a WHO stage III/IV illness leading up to the date of ART start were considered to be in WHO stage III/IV. Those with no such history were categorized as WHO stage I/II. BMI was calculated for those patients with height data available.
Of 7993 patients with a record of ART use, 3200 (40.0%) had sufficient data available for inclusion in this analysis. Most patients (68.5%) were male. Patients were receiving ART in Thailand (23.1%), Vietnam (12.5%), Malaysia (12.1%), Cambodia (11.7%), Hong Kong (11.5%), India (7.9%), Indonesia (7.6%), Singapore (3.7%), Taiwan (3.5%), China (3.0%), Japan (1.7%), Philippines (0.9%), and South Korea (0.9%). Median age was 35.8 years [interquartile range (IQR): 30.6–42.3], median CD4 cell count was 115 cells per cubic millimeter (IQR: 38–217), median body weight was 55 kg (IQR: 48.5–63.3), and median hemoglobin was 12.2 g/dL (IQR: 10.9–13.8). Height data were available for 2965 (92.7%) patients. KD, as defined by van Griensven et al1 (creatinine clearance <50 mL/min based on the Cockroft–Gault equation), was documented in 141 (4.4%) patients. Table 1 shows the performance of all 3 above-mentioned CPT versions when applied to the TAHOD cohort. For the primary CPT, an AUROC of 0.81 (95% CI: 0.77 to 0.84) was achieved. The probability of KD ranged from 0.8% in those with a score of 0%–50.0% in those with a score of 5. With the cutoff score set at ≥2, sensitivity was 85.1%, specificity was 59.3%, and creatinine testing would have been avoided in 57.3% of patients. For the BMI CPT, the AUROC was 0.80 (95% CI: 0.76 to 0.84). When the cutoff score was ≥2, sensitivity was 87.6%, specificity was 54.4%, and creatinine testing would have been avoided in 52.6% of patients. Applying the alternate CPT, AUROC was 0.79 (95% CI: 0.76 to 0.83). With the cutoff score at ≥2, sensitivity was 86.5%, specificity was 56.0%, and creatinine testing would have been avoided in 54.1% of patients. We also examined the alternate CPT with weight substituted for BMI. This yielded an AUROC of 0.79 (95% CI: 0.76 to 0.83). With a cutoff score of ≥2, sensitivity was 88.4% and specificity was 50.2%.
We have shown that the utility of the CPT described by van Griensven et al1 extends beyond the Cambodian clinic within which it was developed. Opinion on the most suitable of the CPT versions evaluated will vary with the perceived importance of various factors. We believe it is crucial to minimize the number of patients with preexisting KD treated with tenofovir while avoiding unnecessary creatinine testing if possible. Therefore, a test with high sensitivity that does not substantially compromise specificity is most appropriate. Our results indicate that the primary CPT had the highest sensitivity when the specificity threshold was arbitrarily set at >50% (sensitivity 90.8%, specificity 52.9% with cutoff score at ≥1). A cutoff score of ≥2 for the primary CPT also performed well in the TAHOD cohort (sensitivity: 85.1% and specificity: 59.3%) and was the pick of the CPTs in van Griensven's validation cohort (sensitivity: 91.5% and specificity: 54.7%). Nevertheless, because the aim of the CPT is to avert unnecessary creatinine testing, the primary CPT, which requires a blood test result (hemoglobin), may not be entirely logical. The alternate CPT only needs basic patient data and a medical history. With a cutoff score of ≥2, it performed reasonably well in our independent validation. Sensitivity was 86.5% and specificity was 56.0%, which translates to 54.1% of patients avoiding creatinine testing during their pre-ART evaluation and 13.5% of patients with KD being considered fit to initiate tenofovir. We believe this may be a clinically acceptable tool; however, future investigation will need to confirm its cost-effectiveness. Serum creatinine testing is not particularly expensive in Asia (approximately $3 per test at one TAHOD center in Thailand), whereas the cost of managing a patient with chronic renal failure may be substantial.
Using data from a large multicenter cohort of HIV-infected patients in Asia, we have provided supportive evidence for a CPT that could limit unnecessary renal function testing before tenofovir initiation. Further validation and cost-effectiveness analysis is required and will need to consider the savings achievable with this tool as tenofovir use expands. Optimizing resources is of the utmost importance to the sustained global scale-up of ART.
TAHOD/TASER study members: A. Kamarulzaman, S. F. S. Omar, S. Vanar, I. Azwa, and L. Y. Ong, University Malaya Medical Center, Kuala Lumpur, Malaysia; B. L. H. Sim and R. David, Hospital Sungai Buloh, Sungai Buloh, Malaysia; C. V. Mean, V. Saphonn, and K. Vohith, National Center for HIV/AIDS, Dermatology, and STDs, Phnom Penh, Cambodia; E. Yunihastuti‡, D. Imran, and A. Widhani, Working Group on AIDS Faculty of Medicine, University of Indonesia/Cipto Mangunkusumo Hospital, Jakarta, Indonesia; F. J. Zhang, H. X. Zhao, and N. Han, Beijing Ditan Hospital, Capital Medical University, Beijing, China; J. Y. Choi, S. Na, and J. M. Kim, Division of Infectious Diseases, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea; M. Mustafa and N. Nordin, Hospital Raja Perempuan Zainab II, Kota Bharu, Malaysia; N. Kumarasamy, S. Saghayam, and C. Ezhilarasi, YRG Centre for AIDS Research and Education, Chennai, India; O. T. Ng, P. L. Lim, L. S. Lee, and M. T. Tan, Tan Tock Seng Hospital, Singapore; P. C. K. Li and M. P. Lee, Queen Elizabeth Hospital and KH Wong, Integrated Treatment Centre, Hong Kong, China; P. Kantipong and P. Kambua, Chiangrai Prachanukroh Hospital, Chiang Rai, Thailand; P. Phanuphak, K. Ruxrungtham, A. Avihingsanon, P. Chusut, and S. Sirivichayakul, HIV-NAT/Thai Red Cross AIDS Research Centre, Bangkok, Thailand; R. Ditangco‡, E. Uy, and R. Bantique, Research Institute for Tropical Medicine, Manila, Philippines; R. Kantor, Brown University, RI, USA; S. Oka, J. Tanuma, and T. Nishijima, National Center for Global Health and Medicine, Tokyo, Japan; S. Pujari, K. Joshi, and A. Makane, Institute of Infectious Diseases, Pune, India; S. Kiertiburanakul†, S. Sungkanuparph, L. Chumla, and N. Sanmeema, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand; T. P. Merati†, D. N. Wirawan, and F. Yuliana, Faculty of Medicine, Udayana University and Sanglah Hospital, Bali, Indonesia; R. Chaiwarith, T. Sirisanthana, W. Kotarathititum, and J. Praparattanapan, Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand; T. T. Pham, D. D. Cuong, and H. L. Ha, Bach Mai Hospital, Hanoi, Vietnam; V. K. Nguyen, V. H. Bui, and T. T. Cao, National Hospital for Tropical Diseases, Hanoi, Vietnam; W. Ratanasuwan and R. Sriondee, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand; W. W. Wong, W. W. Ku, and P. C. Wu, Taipei Veterans General Hospital, Taipei, Taiwan; Y. M. A. Chenand and Y. T. Lin, Kaohsiung Medical University, Kaohsiung City, Taiwan; A. H. Sohn, N. Durier, B. Petersen, and T. Singtoroj, TREAT Asia, amfAR—The Foundation for AIDS Research, Bangkok, Thailand; D. A. Cooper, M. G. Law, A. Jiamsakul, and D. C. Boettiger, The Kirby Institute, UNSW Australia, Sydney, Australia. †Current Steering Committee chairs and ‡co-chairs.
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