Impact of Tenofovir Disoproxil Fumarate on Bone Metabolism and Bone Mass among Perinatally HIV-Infected Asian Adolescents

Sudjaritruk, Tavitiya; Bunupuradah, Torsak; Aurpibul, Linda; Kosalaraksa, Pope; Kurniati, Nia; Sophonphan, Jiratchaya; Ananworanich, Jintanat; Puthanakit, Thanyawee

doi:10.3851/imp3103

Cited by 9 publications

(16 citation statements)

References 34 publications

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“…For example, among 74 Brazilian adolescents (mean age 17•3 years [SD 1 •8]), increased duration of TDF use was associated with lower (albeit non size-adjusted) lumbar spine and total body bone density; 35 whereas a larger study of 394 Thai adolescents of a similar age (median 16•1 years [IQR 14•7-17•4) found no such association for (non-size adjusted) total body bone density or (size-adjusted) LS-BMAD. 36 Our study supports the hypothesis that TDF use has a detrimental effect on bone health in children. Notably, we observed a dose response, with increased TDF exposure associated with pronounced bone deficits.…”

Section: Discussionsupporting

confidence: 88%

“…For example, among 74 Brazilian adolescents (mean age 17·3 years [SD 1·8]), increased duration of TDF use was associated with lower (albeit non size-adjusted) lumbar spine and total body bone density; 35 whereas a larger study of 394 Thai adolescents of a similar age (median 16·1 years [IQR 14·7–17·4) found no such association for (non-size adjusted) total body bone density or (size-adjusted) LS-BMAD. 36 …”

Section: Discussionmentioning

confidence: 99%

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Effect of HIV infection on growth and bone density in peripubertal children in the era of antiretroviral therapy: a cross-sectional study in Zimbabwe

Rukuni

Rehman

Mukwasi-Kahari

et al. 2021

The Lancet Child & Adolescent Health

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Background Faltered linear growth and pubertal delay, which are both common in children with HIV in sub-Saharan Africa, might affect adolescent bone accrual and future fragility fracture risk. We investigated the association of HIV with bone density adjusted for skeletal size in peripubertal children in Zimbabwe. MethodsWe did a cross-sectional study of baseline data from the IMVASK cohort, which enrolled children aged 8-16 years with HIV who had been taking antiretroviral therapy (ART) for at least 2 years, and children of the same age without HIV. Children with HIV were recruited from public sector HIV clinics at Parirenyatwa General Hospital and Harare Central Hospital (Harare, Zimbabwe), and children without HIV were recruited from six schools in the same suburbs that the hospitals serve. Sociodemographic, clinical, and anthropometric data were collected. Dual-energy X-ray absorptiometry (DXA) was used to measure the bone outcomes of total-body less-head bone mineral content for lean mass adjusted for height (TBLH-BMC LBM ), and lumbar spine bone mineral apparent density (LS-BMAD), and we assessed the prevalence of low TBLH-BMC LBM and low LS-BMAD (defined by Z-scores of less than -2•0). Size adjustment techniques were used to overcome the size dependence of DXA measurement. We used linear regression models, with multiple imputation for missing data, to assess relationships between risk factors and TBLH-BMC LBM and LS-BMAD Z-scores in children with and without HIV. Findings We recruited 303 children with HIV (mean age 12•4 years [SD 2•5]; 151 [50%] girls) and 306 children without HIV (mean age 12•5 years [SD 2•5]; 155 [51%] girls). In children with HIV, median age of HIV diagnosis was 3•0 years (IQR 1•2-5•8), and median ART duration was 8•1 years (6•2-9•5); for 102 (34%) children, ART included tenofovir disoproxil fumarate (TDF). Children with HIV had a higher prevalence of low TBLH-BMC LBM Z-score than children without HIV (29 [10%] of 279 children with available data vs 18 [6%] of 292 with available data; p=0•066) and a higher prevalence of low LS-BMAD Z-score (40 [14%] of 279 vs 17 [6%] of 293 with available data; p=0•0007). HIV and male sex were associated with earlier pubertal (Tanner) stage. The negative associations between HIV and Z-scores for TBLH-BMC LBM and LS-BMAD were more pronounced with pubertal maturation, particularly in girls. Among children with HIV, TDF exposure and orphanhood were associated with lower TBLH-BMC LBM Z-score in confounder-adjusted analysis. Current TDF use (vs non-TDF-based ART) was associated with a reduction in TBLH-BMC LBM Z-score of 0•41 (95% CI 0•08-0•74; p=0•015) and in LS-BMAD Z-score of 0•31 (0•08-0•69; p=0•12). Interpretation Despite ART, HIV is associated with substantial skeletal deficits towards the end of puberty. The extent of bone deficits associated with TDF and its widespread use in children in sub-Saharan Africa are a concern for future adult fracture risk. Funding Wellcome Trust.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Effect of HIV infection on growth and bone density in peripubertal children in the era of antiretroviral therapy: a cross-sectional study in Zimbabwe

Rukuni

Rehman

Mukwasi-Kahari

et al. 2021

The Lancet Child & Adolescent Health

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“…However, there are few data regarding these effects in HBV‐HIV co‐infected populations. Bone mineral turnover (BMT) markers may mediate the BMD decline observed with TDF‐containing regimens as evidenced by high BMT markers associated with bone resorption markers, PTH levels and negatively associated with bone formation markers [ 57 ].…”

Section: Discussionmentioning

confidence: 99%

A prospective cohort study of renal function and bone turnover in adults with hepatitis B virus (HBV)‐HIV co‐infection with high prevalence of tenofovir‐based antiretroviral therapy use

et al. 2022

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Objective Tenofovir disoproxil fumarate (TDF) is a common component of antiretroviral therapy in hepatitis B virus (HBV)‐HIV co‐infected adults but few studies have evaluated worsening renal function and bone turnover, known effects of TDF. Methods Adults from eight North American sites were enrolled in this cohort study. Research assessments were conducted at entry and every 24 weeks for ≤192 weeks. Bone markers were tested at baseline, week 96 and week 192 from stored serum. We evaluated changes in markers of renal function and bone turnover over time and potential contributing factors. Results A total of 115 patients were prospectively followed; median age 49 years, 91% male and 52% non‐Hispanic Black. Duration of HIV was 20.5 years. TDF use ranged from 80% to 92% throughout follow‐up. Estimated glomerular filtration rate (eGFR) (ml/min/1.73m2) decreased from 87.1 to 79.9 over 192 weeks (p < 0.001); however, the prevalence of eGFR <60 ml/min/1.73m2 did not appear to differ over time (always <16%; p = 0.43). From baseline to week 192, procollagen type I N‐terminal propeptide (P1NP) (146.7 to 130.5 ng/ml; p = 0.001), osteocalcin (14.4 to 10.2 ng/ml; p < 0.001) and C‐terminal telopeptides of type I collagen (CTX‐1) (373 to 273 pg/ml; p < 0.001) decreased. Younger age, male sex and overweight/obesity versus normal weight predicted a decrease in eGRF. Black race, healthy weight versus underweight, advanced fibrosis, undetectable HBV DNA, and lower parathyroid hormone level predicted worsening bone turnover. Conclusion In this HBV‐HIV cohort with high prevalence of TDF use, several biomarkers of renal function and bone turnover indicated worsening status over approximately 4 years, highlighting the importance of clinical awareness in co‐infected adults.

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“…It is thought that tenofovir may cause renal proximal tubule toxicity, resulting in phosphate wasting and increased bone turnover 18. Although tenofovir and protease inhibitors have been associated with low BMD in adults,19 20 studies in children have shown inconsistent findings 21–23. Malnutrition, opportunistic infections and social deprivation may also impede musculoskeletal development.…”

Section: Introductionmentioning

confidence: 99%

The IMpact of Vertical HIV infection on child and Adolescent SKeletal development in Harare, Zimbabwe (IMVASK Study): a protocol for a prospective cohort study

et al. 2020

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IntroductionThe scale-up of antiretroviral therapy (ART) across sub-Saharan Africa (SSA) has reduced mortality so that increasing numbers of children with HIV (CWH) are surviving to adolescence. However, they experience a range of morbidities due to chronic HIV infection and its treatment. Impaired linear growth (stunting) is a common manifestation, affecting up to 50% of children. However, the effect of HIV on bone and muscle development during adolescent growth is not well characterised. Given the close link between pubertal timing and musculoskeletal development, any impairments in adolescence are likely to impact on future adult musculoskeletal health. We hypothesise that bone and muscle mass accrual in CWH is reduced, putting them at risk of reduced bone mineral density (BMD) and muscle function and increasing fracture risk. This study aims to determine the impact of HIV on BMD and muscle function in peripubertal children on ART in Zimbabwe.Methods and analysisChildren with (n=300) and without HIV (n=300), aged 8–16 years, established on ART, will be recruited into a frequency-matched prospective cohort study and compared. Musculoskeletal assessments including dual-energy X-ray absorptiometry, peripheral quantitative computed tomography, grip strength and standing long jump will be conducted at baseline and after 1 year. Linear regression will be used to estimate mean size-adjusted bone density and Z-scores by HIV status (ie, total-body less-head bone mineral content for lean mass adjusted for height and lumbar spine bone mineral apparent density. The prevalence of low size-adjusted BMD (ie, Z-scores <−2) will also be determined.Ethics and disseminationEthical approval for this study has been granted by the Medical Research Council of Zimbabwe and the London School of Hygiene and Tropical Medicine Ethics Committee. Baseline and longitudinal analyses will be published in peer-reviewed journals and disseminated to research communities.

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Impact of Tenofovir Disoproxil Fumarate on Bone Metabolism and Bone Mass among Perinatally HIV-Infected Asian Adolescents

Abstract: Recent TDF administration was correlated with PTH elevation and bone turnover dysregulation but not with bone mass reduction in our cohort. A study with extended follow-up to ascertain TDF-associated bone mass deterioration is warranted.

Cited by 9 publications

References 34 publications

Effect of HIV infection on growth and bone density in peripubertal children in the era of antiretroviral therapy: a cross-sectional study in Zimbabwe

Effect of HIV infection on growth and bone density in peripubertal children in the era of antiretroviral therapy: a cross-sectional study in Zimbabwe

A prospective cohort study of renal function and bone turnover in adults with hepatitis B virus (HBV)‐HIV co‐infection with high prevalence of tenofovir‐based antiretroviral therapy use

The IMpact of Vertical HIV infection on child and Adolescent SKeletal development in Harare, Zimbabwe (IMVASK Study): a protocol for a prospective cohort study

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