To the Editors:
We read with interest the article by Bygrave et al,1 entitled “Implementing a tenofovir (TDF)-based first-line regimen in rural Lesotho: clinical outcomes and toxicities after two years”. Given the recent guideline of the World Health Organization (WHO) to roll-out TDF-based first-line treatment in resource-constrained settings, this study provides important operational data. In this antiretroviral treatment (ART) program, renal function was assessed before ART initiation. TDF was systematically withheld from patients with kidney dysfunction, defined as a creatinine clearance of <50 mL/minute. In contrast to this study, current WHO guidelines recommend TDF for patients with moderate kidney dysfunction, but at reduced dose.2 Importantly, with any strategy chosen (systematic avoidance or dose reduction), adequate determination of kidney function will be needed for safe and effective use of TDF in resource-constrained settings. Relating to this, we would like to raise a concern with important practical implications for ART programs starting to implement TDF-based first-line treatment.
Although complicated tests exist to measure the glomerular filtration rate (GFR) directly, equations to estimate kidney function have been developed for routine clinical practice.3 Traditionally, the Cockroft-Gault equation, requiring patient age, sex, weight and serum creatinine, has been most often used. More recently, the modification of diet in renal disease (MDRD) Study equation, requiring age, sex and race—for the abbreviated version—has gained importance.3 Current WHO guidelines recommend to use the Cockroft-Gault equation and to increase TDF dosing interval to 48 hours for those with a creatinine clearance of 30-50 mL/minute, and to 72-96 hours in case of clearance of 10-30 mL/minute.2 In case of severe dysfunction (clearance <10 mL/min), TDF use should be avoided. Both of the equation methods were developed based on Western populations. Data on its validity in resource-constrained settings, and specifically in HIV-patients, are lacking. We compared the prevalence of kidney dysfunction and the proportion of patients needing TDF dose reduction using these 2 equations in a large ART cohort in Cambodia.
In 2003, we started providing ART in a tertiary hospital in Phnom Penh, Cambodia.4 From the onset, clinical and laboratory data were prospectively captured, after obtaining informed consent. Treatment was initiated in line with WHO guidelines. Baseline investigations included creatinine determination. We conducted a retrospective analysis of all antiretroviral-naive adult patients initiating ART between March 2003 and December 2010.
A total of 2625 patients were included, with a median age of 35 [interquartile range (IQR) 30-41] years. Fifty-two percent were female, the median baseline CD4 cell count was 87 (IQR 25-206) cells per microliter. At baseline, a median creatinine of 71 (IQR 60-82) μmol/L and 87 (IQR 71-107) μmol/L was documented for females and males, respectively (normal range <80 and 97 μmol/L for females and males). The estimated median baseline GFR was 74 mL/min with the Cockcroft-Gault equation and clearly higher (90 mL/min/1.73 m2) using the MDRD Study equation (Table 1). Whereas TDF dose reduction was indicated for 10.1% of patients based on the Cockcroft-Gault equation, this was only 2.3% using the MDRD calculation. Severe kidney dysfunction, with TDF contraindicated, was rare (0.04% with both methods). To take into account differences in body habitus between individuals or populations, some have recommended to use Cockroft-Gault estimates standardized for body surface area (BSA), as is done for the MDRD Study equation.5 Median BSA in our patient population was 1.47 (IQR 1.36-1.48) m2, clearly lower than the “standard” of 1.73 m2. Compared with the unadjusted equation, the BSA-adjusted Cockroft-Gault version provided clearly higher GFR estimates that were very similar to the MDRD Study equation.
Depending on the method used, a 4-fold difference in need of TDF dose reduction was observed when applying WHO dosing recommendations. This could lead to either overdosing—with potentially increased toxicity—or underdosing—facilitating the emergence of drug resistance—in a substantial proportion of patients. Future research is needed to determine the preferential method to be used for safe and effective use of this pivotal drug in resource-constrained settings. Standardisation of the Cockcroft-Gault equation for BSA should be explored. Meanwhile, avoidance of TDF for those with kidney dysfunction, as in the study by Bygrave et al,1 might be an alternative careful strategy.
Johan van Griensven, MD, PhD*
Thai Sopheak, MD†
Olivier Koole, MD, MPH*
Gert A. Verpooten, MD, PhD‡
Lutgarde Lynen, MD, PhD*
*Department of Clinical Sciences, Institute of Tropical Medicine, Antwerp, Belgium † Infectious Diseases Department, Sihanouk Hospital Center of Hope, Phnom Penh, Cambodia ‡Department of Nephrology-Hypertension, Antwerp University Hospital, Antwerp, Belgium
1. Bygrave H, Ford N, van Cutsem G, et al. Implementing a tenofovir-based first-line regimen in rural lesotho: clinical outcomes and toxicities after two years. J Acquir Immune Defic Syndr
2. World Health Organization.Antiretroviral Therapy for HIV Infection in Adults and Adolescents: Recommendations for a Public Health Approach: 2010 Revision
. Geneva, Switserland: World Health Organization; 2010.
3. Stevens LA, Coresh J, Greene T, et al. Assessing kidney function-measured and estimated glomerular filtration rate. N Engl J Med
4. Thai S, Koole O, Un P, et al.Five-year experience with scaling-up access to antiretroviral treatment in an HIV care programme in Cambodia. 2009;14:1048-1058.
5. Rostoker G, Andrivet P, Pham I, et al. A modified Cockcroft-Gault formula taking into account the body surface area gives a more accurate estimation of the glomerular filtration rate. J Nephrol