Short communication Tenofovir disoproxil fumarate and bone mineral density: a 60-month longitudinal study in a cohort of

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1 Antiviral Therapy : (doi: /IMP1650) Short communication Tenofovir disoproxil fumarate and bone mineral density: a 60-month longitudinal study in a cohort of HIV-infected youths Alessandra Viganò 1, Gian V Zuccotti 2, Maria Puzzovio 3, Valentina Pivetti 2, Ilaria Zamproni 3, Chiara Cerini 2, Valentina Fabiano 2, Vania Giacomet 1, Stefano Mora 3 * 1 Pediatric Infectious Diseases Unit, Department of Pediatrics, L Sacco Hospital, University of Milan, Milan, Italy 2 Department of Pediatrics, L Sacco Hospital, University of Milan, Milan, Italy 3 Laboratory of Pediatric Endocrinology, Division of Metabolic and Cardiovascular Sciences, San Raffaele Scientific Institute, Milan, Italy *Corresponding author mora.stefano@hsr.it Background: Decreased bone mineral density (BMD) has been associated with the use of tenofovir disoproxil fumarate (TDF) in HIV-infected adults. The data in HIVinfected children are conflicting. The aim of this study was to assess the safety of a TDF-containing antiretroviral (ARV) regimen on BMD in paediatric patients. We report the results of a longitudinal 60-month follow-up study. Methods: A total of 21 vertically HIV-infected Caucasian youths (10 male and 11 female) on ARV treatment containing lamivudine, efavirenz and TDF were enrolled (age range years at baseline). BMD was measured at the lumbar spine and in the whole skeleton by DXA. Bonespecific alkaline phosphatase (BAP) was measured as a bone formation marker and urinary N-telopeptide of type-i collagen (NTx) was measured as a bone resorption index. Results: Baseline mean (±sd) BMD measurements of HIVinfected patients expressed as z-scores were -0.7 (±0.9) for lumbar spine and (±1.0) for the whole skeleton. BMD measurements did not change significantly during the 60-month observation period. Both BAP and NTx concentrations were higher than a reference group of controls at baseline and remained unchanged throughout the study. Conclusions: Our data indicate that a TDF-containing regimen does not decrease the BMD of HIV-infected youths. Introduction The use of highly active antiretroviral treatment (HAART) has significantly improved the survival of HIV-infected patients [1]; however, it has been associated with several side effects, mainly affecting lipid and insulin metabolism and fat tissue distribution [2 4]. Bone mass reduction and bone mineral metabolism alterations have been reported both in adults and in children with HIV infection [5]. The effect of antiretroviral treatment on bone metabolism derangements is still being debated. Nevertheless, there is evidence that a tenofovir disoproxil fumarate (TDF)-based therapeutic regimen is associated with bone mass decrement during the first few months of treatment in adult patients [6,7]. Studies in children are conflicting: there are both reports confirming the finding of a reduction of bone mass measurements during TDF-containing HAART [8,9] and studies demonstrating the safety of a TDF-containing regimen on bone mass and metabolism [10]. The aim of the present study was to assess the change in bone mineral density (BMD) and bone metabolism markers during TDF-containing HAART in a cohort of HIV-infected children. In particular, we were interested in assessing whether a TDF-containing regimen could decrease BMD. Methods Vertically HIV-infected children and adolescents who had switched from a TDF-sparing to a TDF-containing HAART were eligible for this study. A total of 21 patients (10 male and 11 female) were enrolled. Of them, 15 patients were part of a previous report on short-term effect of TDF treatment [10]. All patients enrolled in this study were also part of another study of TDF on renal safety [11]. The characteristics of the study cohort are presented in Table 1. Prior to the current study, all patients were 2010 International Medical Press (print) (online) 1053

2 A Viganò et al. Table 1. Characteristics of 21 HIV-infected children and adolescents at baseline and during 60 months of follow-up a Characteristic Baseline 12 months 24 months 36 months 48 months 60 months Age, years ( ) ( ) ( ) ( ) ( ) ( ) Weight, kg ( ) ( ) ( ) ( ) ( ) ( ) Weight, z-score ( ) ( ) ( ) ( ) ( ) ( ) Height, cm ( ) ( ) ( ) ( ) ( ) ( ) Height, z-score ( ) ( ) ( ) ( ) ( ) ( ) BMI, kg/m ( ) ( ) ( ) ( ) ( ) ( ) BMI, z-score ( ) ( ) ( ) ( ) ( ) ( ) Duration of 69.5 HAART prior to ( ) the switch, months Patients with HIV RNA <50 copies/ml, n CD4 + T-cell count, cells/µl (236 1,518) (264 1,436) (300 1,466) (339 1,211) (283 1,526) (314 1,526) CD4 + T-cell percentage ( ) ( ) ( ) ( ) ( ) ( ) All data are presented as median (range) unless indicated otherwise. a After replacing protease inhibitor treatment with efavirenz and stavudine with tenofovir disoproxil fumarate. BMI, body mass index; HAART, highly active antiretroviral treatment. on HAART that included lamivudine, stavudine and a protease inhibitor. All patients were maintained on lamivudine (4 mg/kg twice daily) throughout the duration of the study. The protease inhibitor was replaced with efavirenz and stavudine was replaced with TDF. The switch of antiretroviral therapy was done to reduce toxicity and to maintain adherence. Efavirenz was administered once daily, at weight-dependent doses, as recommended by the manufacturer. TDF was administrated once daily at a body-surface-area-dependent dose: 150 mg for m 2, 225 mg for m 2 and 300 mg for 1.30 m 2. Participants did not receive calcium or vitamin D supplements. Informed consent was obtained from the parents or legal guardians of each patient and from the patients when appropriate. This study was approved by the ethics committee of the L Sacco Hospital (Milan, Italy) and it was performed according to the principles of the Declaration of Helsinki. Measurements were obtained before treatment, at baseline and at 12, 24, 36, 48 and 60 months after switching antiretroviral regimen. Anthropometric measurements were obtained at each time point. Body mass index (BMI) was calculated as the ratio of weight to height in kg/m 2. Standard deviation scores of anthropometric measurements were calculated using specific Italian standards [12]. Pubertal development was assessed according to the criteria reported by Tanner and Whitehouse [13]. BMD was measured at the L2 L4 vertebrae level and in the whole skeleton. The data were acquired and analysed using paediatric software (encore version 13; GE Medical Systems, Madison, WI, USA) and by using DXA (Lunar Prodigy Advance, GE Medical Systems). Blood was drawn between 08:00 and 10:00 AM after an overnight fast for the determination of serum bone-specific alkaline phosphatase (BAP) concentration. BAP is a specific marker of bone formation, and its concentration was measured using a commercial immunoassay (Metra BAP EIA kit; Quidel Corp., San Diego, CA, USA). Intraassay reproducibility was <4% and interassay variation was <7%. The sensitivity of the assay was 0.7 U/l. Bone resorption rate was assessed by measuring N-terminal telopeptide of type-i collagen (NTx) in urine samples. Urine samples were collected between 10:00 AM and 12:00 PM as the second voiding of the day [14]. NTx was measured using ELISA (Osteomark NTx Urine; Wampole Laboratories, Princeton, NJ, USA). Assay values were normalized for International Medical Press

3 TDF and BMD in HIV-infected youths urine dilution by urine creatinine concentration. The intraassay variation was <10% and the interassay precision was <9%; the sensitivity of the assay was 20 nmol bone collagen equivalent/l. Parameters of glomerular function (serum creatinine, estimated glomerular filtration rate and urinary protein/ creatinine ratio) and tubular function (serum phosphorus, glycosuria, urinary α-1-microglobulin/creatinine ratio and maximal tubular phosphate reabsorption) were assessed every 6 months. Data are expressed as median (range). All statistical analyses were conducted at the α=0.05 level and were two-tailed. The distribution of the variables was checked by the Shapiro Wilk W test using the statistical software JMP version 7.0 (SAS Institute, Inc., Cary, NC, USA). Standard deviation scores (z-scores) for BMD measurements were computed using the database of the GE-Lunar paediatric software. Changes of z-scores over time were assessed by analysis of variance (ANOVA) for repeated measures. Biochemical measurements obtained in the cohort of HIV-infected patients were compared with values calculated using data obtained from healthy children and adolescents previously reported [14,15]. Briefly, individual values of BAP and NTx were calculated by using age- and sex-specific regression equations, and comparisons between the observed and the calculated (expected) values were performed by Wilcoxon signedrank test for paired samples. Changes over time were assessed by ANOVA for repeated measures. Results Patients showed undetectable HIV RNA concentrations at entry of the study and maintained a good control of infection during the whole follow-up period. We found no evidence of impaired glomerular or tubular renal function during treatment with TDF [11]. None of the participants had delayed pubertal development or short stature. Seven participants were prepubertal at baseline. Individual BMD z-scores are shown in Table 2. BMD z-scores of the lumbar spine did not change significantly over time (F=2.3; P=0.09). Similarly, ANOVA for repeated measures showed that BMD z-scores of the whole skeleton did not change significantly over time (F=1.16; P=0.37). Lumbar spine BMD z-scores of prepubertal children did not decrease during the 60-month study period. Similarly, no significant changes were observed in total body BMD z-scores. The concentrations of the bone metabolism markers are shown in Table 3. BAP serum concentration was higher compared with a similar reference group at baseline and remained significantly higher during follow-up. Similarly, NTx urine concentration of HIV-infected patients was higher compared with values of a similar reference group at baseline and during the whole study period. ANOVA did not reveal significant changes in BAP serum concentration over time (F=0.87; P=0.34). Likewise, NTx urine measurements did not show significant changes over the study period (F=2.7; P=0.12). Discussion The recent introduction of new antiretroviral drugs has simplified the daily schedule of treatment in HIVinfected children and adolescents, and it might also have improved adherence to treatment among young patients. The effect of long-term TDF-containing HAART on BMD is still not clear. In a previous work on a cohort of HIV-infected children and adolescents, we showed that switching from TDF-sparing to TDFcontaining HAART did not affect BMD measurements during the first 12 months of treatment [10]. The current study reports and extends the results of BMD and bone metabolism markers over 60 months of treatment with TDF. To evaluate the changes occurring over time, with regards to the changes of BMD taking place during growth, we expressed BMD values as z-scores. The analyses for repeated measures failed to show any significant change during the 60-month follow-up period. Our data thus indicate that a TDFcontaining HAART regimen does not negatively affect bone health in young patients. These results contrast with previous reports [8,9]. There are some aspects that should be considered. In one study, the patients were included on the basis of high plasma HIV RNA copies and of a history of failing antiretroviral therapy at least twice [8]. A decrease of BMD z-scores was observed at 24 and 48 weeks after initiation of TDF treatment, and recovery of BMD was achieved after discontinuation of TDF. In another study, HIVinfected children showed decreased BMD measurements after 48 weeks of TDF treatment [9]. In both studies, the patients received therapy that included a combination of >3 antiretroviral drugs and, in all cases, patients were also receiving a protease inhibitor (ritonavir), which has been associated with low BMD measurements in young patients [16]. By contrast, our patients were in optimal control of viral infection and had received HAART with three drugs that did not include protease inhibitors. We could speculate that the combined use of several antiretroviral drugs that include TDF and ritonavir might be detrimental for bone health, whereas the use of TDF and efavirenz does not produce side effects on bone. One study [8] suggested that young HIV-infected patients might be at higher risk of decreased BMD measurements during treatment with TDF. By contast, we did not observe significant changes of BMD in prepubertal participants over a long follow-up period. Antiviral Therapy

4 A Viganò et al. Table 2. Individual BMD measurements expressed as z-scores of 21 HIV-infected patients treated with efavirenz and tenofovir disoproxil fumarate at baseline and during 60 months of follow-up Patient number Measurement site Baseline 12 months 24 months 36 months 48 months 60 months 1 LS TB LS TB LS TB LS TB LS TB LS TB LS TB LS TB LS TB LS TB LS TB LS TB LS TB LS TB LS TB LS TB LS TB LS TB LS TB LS TB LS TB BMD, bone mineral density; LS, lumbar spine; TB, total body. In the present study, we found high serum concentrations of BAP and high levels of urinary NTx at baseline and during the 60 months follow-up, as already reported in other studies [17 19]. The analyses for repeated measures did not show significant changes of both markers during the study period; thus, indicating that the TDF-containing ARV regimen does not alter the bone metabolism rate in children. The current study has some limitations. The cohort of HIV-infected children included a wide age range, which might have interfered with the bone measurements. For this reason, we expressed BMD measurements as z-scores, thus correcting for sex and age differences. Another possible bias could be generated by the small number of HIV-infected participants. However, the aim of our study was to assess whether a TDF International Medical Press

5 TDF and BMD in HIV-infected youths Table 3. Results of biochemical markers of bone formation and bone resorption Marker Time, months Actual value Expected value Paired analyses BAP, U/l Baseline ( ) ( ) P= ( ) ( ) P< ( ) 83.7 ( ) P< ( ) 63.9 ( ) P< ( ) 55.5 ( ) P< ( ) 38.5 ( ) P< NTx, nm BCE/mM Baseline (88.5 1,431.8) ( ) P=0.05 creatinine (72.1 1,029.7) ( ) P= (39.3 1,091.5) ( ) P= (45.6 1,171.1) ( ) P= (31.5 1,122.2) ( ) P= ( ) 85.1 ( ) P= Results of biochemical markers of bone formation (bone-specific alkaline phosphatase [BAP]) and bone resorption (N-terminal telopeptide of type-i collagen [NTx]) measurements in 21 HIV-infected patients at baseline and during 60-month treatment with efavirenz and tenofovir disoproxil fumarate, and expected values calculated using regression analyses from data of healthy controls [14,15]. All data are presented as median (range) unless indicated otherwise. BCE, bone collagen equivalent. containing ARV could adversely affect bone health and the longitudinal analyses were sufficiently robust to exclude any adverse effect in well-controlled patients. In conclusion, our data indicate that a TDFcontaining regimen does not impair bone health of HIV-infected children and adolescents with undetectable viral load. Moreover, the long-term survey also showed the safety of such a HAART regimen over time. Acknowledgements This work was supported, in part, by grant number 30G.31 from the Istituto Superiore di Sanità, VI Programma Nazionale di Ricerca sull AIDS Disclosure statement The authors declare no competing interests. References 1. Antiretroviral Therapy Cohort Collaboration. Life expectancy of individuals on combination antiretroviral therapy in high-income countries: a collaborative analysis of 14 cohort studies. Lancet 2008; 372: Obel N, Thomsen HF, Kronborg G, et al. Ischemic heart disease in HIV-infected and HIV-uninfected individuals: a population-based cohort study. Clin Infect Dis 2007; 44: Kotler DP. HIV and antiretroviral therapy: lipid abnormalities and associated cardiovascular risk in HIV-infected patients. J Acquir Immune Defic Syndr 2008; 49 Suppl 2:S79 S Mallewa JE, Wilkins E, Vilar J, et al. HIV-associated lipodystrophy: a review of underlying mechanisms and therapeutic options. J Antimicrob Chemother 2008; 62: Viganò A, Mora S. Adverse effects of antiretroviral therapy: focus on bone density. Expert Opin Drug Saf 2004; 3: Gallant JE, Staszewski S, Pozniak AL, et al. Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviral-naive patients: a 3-year randomized trial. JAMA 2004; 292: Jones S, Restrepo D, Kasowitz A, et al. Risk factors for decreased bone density and effects of HIV on bone in the elderly. Osteoporos Int 2008; 19: Gafni RI, Hazra R, Reynolds JC, et al. Tenofovir disoproxil fumarate and an optimized background regimen of antiretroviral agents as salvage therapy: impact on bone mineral density in HIV-infected children. Pediatrics 2006; 118:e711 e Purdy JB, Gafni RI, Reynolds JC, Zeichner S, Hazra R. Decreased bone mineral density with off-label use of tenofovir in children and adolescents infected with human immunodeficiency virus. J Pediatr 2008; 152: Giacomet V, Mora S, Martelli L, Merlo M, Sciannamblo M, Viganò A. A 12-month treatment with tenofovir does not impair bone mineral accrual in HIV-infected children. J Acquir Immune Defic Syndr 2005; 40: Giacomet V, Bedogni G, Manfredini V, et al. Renal safety of HAART including tenofovir in vertically HIV-infected youths: a 60-month longitudinal study. 17th Conference on Retroviruses and Opportunistic Infections February 2010, San Francisco, CA, USA. Abstract Cacciari E, Milani S, Balsamo A, et al. A Italian crosssectional growth charts for height, weight and BMI (2 to 20 yr). J Endocrinol Invest 2006; 29: Tanner JM, Whitehouse RH. Clinical longitudinal standards for height, weight, height velocity and weight velocity and stages of puberty. Arch Dis Child 1976; 51: Mora S, Prinster C, Proverbio MC, et al. Urinary markers of bone turnover in healthy children and adolescents: Age related changes and effect of puberty. Calcif Tissue Int 1998; 63: Mora S, Cafarelli L, Erba P, et al. Differential effect of age, gender and puberty on bone formation rate assessed by measurement of bone-specific alkaline phosphatase in healthy children and adolescents. J Bone Miner Metab 2009; 27: Zuccotti G, Viganò A, Gabiano C, et al. Antiretroviral therapy and bone mineral measurements in HIV-infected youths. Bone 2010; 46: Mora S, Sala N, Bricalli D, Zuin G, Chiumello G, Viganò A. Bone mineral loss through increased bone turnover in HIVinfected children treated with highly active antiretroviral therapy. AIDS 2001; 15: Antiviral Therapy

6 A Viganò et al. 18. Mora S, Zamproni I, Beccio S, Bianchi R, Giacomet V, Viganò A. Longitudinal changes of bone mineral density and metabolism in antiretroviral-treated human immunodeficiency virus-infected children. J Clin Endocrinol Metab 2004; 89: Mora S, Zamproni I, Cafarelli L, et al. Alterations in circulating osteoimmune factors may be responsible for high bone resorption rate in HIV-infected children and adolescents. AIDS 2007; 21: Accepted for publication 29 April International Medical Press

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