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Progressive Decline of the Glomerular

Progressive Decline of the Glomerular Filtration Rate in HIV-infected Children Treated With Tenofovir Disoproxil Fumarate-based Regimens in West and Central Africa Aminata Diack, MD,* Caroline Yonaba, MD,† Aba Coulibaly, MD,‡ Sylvie Ouedraogo, MD,§ Ida Penda, MD,¶ Hélène Bukuru, MD,║ Madeleine Folquet, MD,** François Tanoh Eboua, MD,†† Mariam Sylla, MD,‡ Stéphane Blanche, MD,‡‡ and Mathurin Tejiokem, MD, PhD,§§ on behalf of the Enfants VIH Afrique network

Abstract: A cross-sectional study of 358 HIV-1-infected children and adolescents living in Sub-Saharan Africa treated with tenofovir disoproxil fumarate-based regimens for a median of 1.5 interquartile range [0.6–3.1 years] showed a loss of glomerular filtration rate estimated to be 0.41mL/ min/1.73 m2 per month of treatment. In contrast, there was no decrease depending on the duration of the previous antiretroviral treatment. Key Words: HIV, children, tenofovir, renal disease, toxicity (Pediatr Infect Dis J 2020;XX:00–00) Tenofovir disoproxil fumarate (TDF) is a common molecule used in anti-HIV and hepatitis B virus (HBV) treatment. The renal toxicity of TDF is well established in adults (reviewed in Tourret et al1 ), consisting mostly of acute or chronic tubular toxicity and a mild, gradual, time-dependent degradation of the estimated glomerular filtration rate (eGFR), sometimes leading to chronic renal failure. The pathophysiology is possibly linked to alteration of the mitochondria of renal tubular cells. The incidence of such toxicity is difficult to establish and depends on the choice of biological marker used and the dependence of environmental and genetic factors, which are difficult to match between studies. Certain drug combinations, notably those with boosted protease inhibitors (PIs), are associated with a greater risk of toxicity by interacting with TDF entry or exit receptors on renal tubular cells. Certain polymorphisms of the genes encoding these receptors may contribute to the risk of toxicity, although the data are still contradictory. Finally, the duration of treatment is a major determinant of toxicity, although early acute tubular toxicity can be observed. Although it is now gradually being replaced by the less nephrotoxic derivate tenofovir alafenamide fumarate,2 TDF is still largely prescribed in countries with limited medical resources. In 2020, TDF is still a first-line antiretroviral drug in association with 2 others in the World Health Organization recommendations for HIVinfected children >30 kg.3 Its prescription for pediatric HBV infection is also increasing.4 The first uses of TDF in children date back to 2004 and several observational studies on its renal tolerance have been published.5 Acute, symptomatic, or silent chronic tubulopathy have been described, similar to that observed in adults. However, alterations of the GFR is less clear than in adults, and the data are still contradictory (data summary and updated references in Table 1, Supplemental Digital Content 1, http://links.lww.com/ INF/D950). Of note, these data all come from the United States, Europe, Brazil and Thailand but not yet from Sub-Saharan Africa, where the vast majority of TDF-treated children and adolescents live. Here, we present an analysis of the eGFR as a function of time in a large observational cohort of children infected with HIV-1 treated with TDF and followed in 7 healthcare centers in West and Central Africa.

PATIENTS AND METHODS

Seven pediatric centers from 6 West and Central African countries (Burkina Faso, Côte d’Ivoire, Burundi, Senegal, Mali and Cameroon) participated in this cross-sectional field study. These centers participate in a project-sharing network (EVA Enfants VIH Afrique). After agreement of the ethics committees of each country, the study consisted of collecting the creatinine values (measured at inclusion or no more than 3 months before inclusion) of all children and adolescents receiving TDF and visiting a center for their usual follow-up during the study period. Children and adolescents were included after parental written consent (and the children’s assent when appropriate), regardless of the number of previous treatment lines and the type of antiretrovirals associated with TDF. Creatinine was measured by an enzymatic method in 5 centers and by colorimetry in 2. The eGFR was calculated using the 2009 Schwartz formula: eGFR = 0.413 × (height in cm/serum creatinine).6 Because of the nonrandom use of TDF in clinical practice, no control group was considered to be satisfactory in such an observational cohort study. We therefore assessed the relationship of the duration of TDF exposure on eGFR and that of the previous phase of antiretroviral treatment in the same group of patients. The effect of the collected variables on eGFR was studied as dependent variables using both univariate and backward stepwise multivariate linear regression analysis. A significance of P <0.10 was selected for inclusion in the multivariate analysis. A P value of <0.05 was considered statistically significant. Analysis was performed using RStudio software (Boston MA)-Version 1.1.463.

RESULTS Characteristics of the Children and Adolescents From May 2018 to July 2019, 363 children treated with a TDF-containing regimen were seen in outpatient clinics at the participating centers and included. They accounted for 48% of all children on TDF and 31% of all children treated with antiretrovirals in these centers. After excluding 5 children due to incomplete information, 358 (182 girls, 51%) were analyzed. The median age [interquartile range] was 15.5 years [14.0–16.8 years] and the median weight and height 45.6 kg [39.0–51.0 kg] and 156cm [150–164 cm], respectively, with a body mass index of 18.2 kg/m2 [16.8–20.0 kg/ m2 ]. The median age at antiretroviral initiation was 6.7 years [4.0– 10.6 years]. Fifty-four children (15.1%) initiated combination therapy with TDF as a first-line treatment, whereas the others had been treated for a median of 7.3 years [4.3–10.0 years] before the introduction of TDF. The median duration of TDF treatment was 1.5 years [0.6–3.1 years]. All children received 300mg/d TDF, leading to a median dose/weight of 6.6mg/kg [5.9–7.7mg/kg]. In addition to lamivudine or emtricitabine, TDF was associated with efavirenz, n = 269 (75.1%) or atazanavir/r, n=31 (8.7%) or lopinavir/r, n = 58 (16.2%). EGFR and Associated Factors The median eGFR for the entire group was 88.8mL/min /1.73 m2 [76.8–105.9mL/min /1.73 m2 ]. Univariate analysis showed that female gender, age, TDF associated with a PI and duration of TDF exposure were negatively associated with eGFR. The decrease in the eGFR was estimated to be −0.41mL/min/1.73 m2 per month of TDF treatment. In contrast, the duration of the pre-TDF treatment in the 304 children for whom TDF was given as second-line treatment was not associated with the eGFR (Fig. 1). Multivariate analysis confirmed that age, coexposure to a PI and duration of TDF exposure had an independent role in lowering the eGFR (Table 2, Supplemental Digital Content 2, http://links.lww.com/INF/D951).

Fifteen children, consisting of 4 girls and 11 boys (2.2% vs. 6.3%; P = 0.06), had an eGFR between 30 and 60mL/min/1.73 m2 (moderate renal disease) range [39.2–59.6] after a median duration of TDF exposure of 2.9 years [1.6–3.1 years]. None of these children were symptomatic. DISCUSSION In this large observational field study, we observed a progressive decline in eGFR in children and adolescents treated with TDF as a function of the time of treatment. Conversely, the duration of the previous antiretroviral treatment for those who received TDF in the second line had no influence on creatinine clearance. Tolerance to TDF in children and adolescents has been thus far described in 14 studies from the United States, Europe, Brazil and Thailand (Table 1, Supplemental Digital Content 1, http://links.lww.com/INF/D950). This analysis is first performed in children and adolescents living in Sub-Saharan Africa. All but one available study was observational, retrospective, often noncomparative or based on multicentric cohorts of infected children treated with various antiretroviral regimens. Clinical or biological markers of tubulopathy were observed in all but one study, confirming, as expected, that children and adolescents have roughly the same tolerance profile as adults. The results concerning the eGFR are less clear than those in adults, but only 3 studies included more than 100 TDF-treated children, and the statistical power for such a parameter, with a large standard error, was limited. Five studies did not find modifications, whereas 4 observed a decline in the eGFR. In 1 large study, a composite criterion defining “chronic kidney disease” was clearly associated with TDF treatment >3 years.7 The magnitude of decline observed here was similar to that observed in adults. In a retrospective study including more than 15,000 adults treated with TDF in South Africa, the yearly decline evaluated by the Modification of Diet in Renal Disease method was −4.4mL/min, for a baseline eGFR >90mL/min.8 The main limitation of this study was the lack of a control group (as for all other published studies to date). Such a control group is impossible to correctly assign in an observational setting, because the prescription of TDF is not random and many biases could alter the comparison, with children receiving another treatment or nonHIV-infected children. Another limitation was the absence of data concerning the role of the disease itself, through the measurement of immunologic or virologic parameters (viral load, CD4+ cells). Two elements provide a solid indirect indication of a link between TDF and a decrease of eGFR: (1) the duration of previous antiretroviral treatment before TDF exposure was not associated with eGFR alterations and (2) the deleterious effect of the coprescription of TDF with a boosted PI, which is known to increase the renal toxicity of TDF via the intracellular concentration of TDF in tubular cells. This additive toxic effect is well established in adult patients.9 In addition, a recently published large-cohort study of more than 500 HIV-infected children followed in South Africa, treated with various antiretroviral regimens, but only 7 (1.4%) with TDF, did not show alteration of the eGFR.10 This confirms that the incidence of HIV-associated nephropathy has dramatically declined under antiretroviral treatment. Therefore, the decline of eGFR observed here cannot be solely attributed to possible HIV-related nephropathy. The overall decline was modest, but significant. Given the indefinite duration of anti-HIV and/or HBV treatments and the reduced antiviral armament in many countries, such progressive deterioration of renal function should not be neglected. In addition, the reduced monitoring capacity in primary healthcare centers could not identify the children with a marked decrease in GFR. It is hoped that tenofovir alafenamide fumarate, which has lower renal toxicity than TDF, will soon be available in low-resource countries.2 ACKNOWLEDGMENTS The authors thank the families who accepted to participate in the study. They also give special thanks to Cheikh Tidiane Tall and Karim Diop, respectively, the former and present executive director of the Enfants VIH Afrique network, and Mamadou Dieng and Soumeya Rahli from Expertise France, who actively supported the project.