Antiretroviral Therapy, Especially Efavirenz, Is Associated with Low Bone Mineral Density in HIV-Infected South Africans

Dave, Joel A.; Cohen, Karen; Micklesfield, Lisa K.; Maartens, Gary; Levitt, Naomi

doi:10.1371/journal.pone.0144286

Cited by 39 publications

(37 citation statements)

References 23 publications

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“…Some of these studies are also limited by retrospective design and lack of an HIV-negative control group. The effects of HIV and ART on bone health and vitamin D status in Sub-Saharan Africa, where the burden of HIV infection lies, and where osteoporotic fracture rates are predicted to rise, (13) are largely unstudied, (14) and, although data are emerging, (15)(16)(17) there are important gaps and an urgent need for targeted research. (14) We have shown, in a cross-sectional study of urban South African premenopausal women which compared those who were HIV-infected but ART-naive with those who were HIV-negative, that there were no significant differences in aBMD or vitamin D status related to HIV status, despite HIV-positive women with low CD4 counts having less body fat than both HIV-positive women with preserved CD4 counts and HIV-negative women.…”

Section: H Uman Immunodeficiency Virus (Hiv) Infection Is Associatedmentioning

confidence: 99%

“…Some of these studies are also limited by retrospective design and lack of an HIV‐negative control group. The effects of HIV and ART on bone health and vitamin D status in Sub‐Saharan Africa, where the burden of HIV infection lies, and where osteoporotic fracture rates are predicted to rise, are largely unstudied, and, although data are emerging, there are important gaps and an urgent need for targeted research …”

Section: Introductionmentioning

confidence: 99%

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Changes in Bone Mineral Density, Body Composition, Vitamin D Status, and Mineral Metabolism in Urban HIV-Positive South African Women Over 12 Months

Hamill

Pettifor

Ward

et al. 2017

Journal of Bone and Mineral Research

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HIV infection and antiretroviral therapy (ART) are associated with bone loss and poor vitamin D status in Caucasian populations, though their relative roles are not known. No previous studies have examined longitudinal changes in areal bone mineral density (aBMD), measured by DXA, or in vitamin D status in HIV-positive African women. Of 247 premenopausal, urban, black African women from Soweto, South Africa, initially recruited, 187 underwent anthropometry, DXA scanning and blood and urine collections at both baseline and 12 months. Of these, 67 were HIVnegative throughout (Nref), 60 were HIV-positive with preserved CD 4 counts at baseline (Ppres) and 60 were HIV-positive with low CD 4 counts at baseline, eligible for ART by South African standards of care at the time (Plow). No participant had been exposed to ART at baseline. By 12 months, 51 Plow women had initiated ART, >85% of whom took combined tenofovir disoproxil fumarate (TDF), lamivudine and efavirenz. By 12 months, Plow and Nref, but not Ppres, increased in body weight and fat mass (group-by-timepoint p ≤0.001, p=0.002 respectively). Plow had significant decreases in aBMD of 2-3%, before and after size adjustment, at the femoral neck (p ≤0.002) and lumbar spine (p ≤0.001), despite significant weight gain. These decreases were associated with increased bone turnover but there were no significant differences or changes over time in vitamin D status, serum phosphate concentrations or renal phosphate handling. Excluding data from 9 Plow women unexposed to ART and 11 Ppres women who had initiated ART accentuated these findings, suggesting the bone loss in Plow was related to ART exposure. This is the first study describing DXA-defined bone loss in HIV-positive Sub-Saharan African women in Authors responsibilities: MMH, AP and JMP designed the study; MMH conducted the study; JMP and SAN provided senior oversight of the study in South Africa; KW provided senior oversight and interpretation of the DXA data; AP provided senior oversight and interpretation of the biochemical data; MMH and AP jointly conducted the statistical analysis and drafted the paper; all authors had full access to the data and contributed to interpretation of the findings. MMH and AP have responsibility for data integrity. All authors approved the manuscript for publication.The authors state that they have no conflicts of interest. Europe PMC Funders Group

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Section: H Uman Immunodeficiency Virus (Hiv) Infection Is Associatedmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Changes in Bone Mineral Density, Body Composition, Vitamin D Status, and Mineral Metabolism in Urban HIV-Positive South African Women Over 12 Months

Hamill

Pettifor

Ward

et al. 2017

Journal of Bone and Mineral Research

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“…A recent study in South African premenopausal women, all of whom were treatment naïve, did not demonstrate any significant differences in BMD between infected and noninfected women . However, in 444 HIV‐infected South African individuals with a mean age of 35 years, hip BMD was significantly lower in those treated with ART compared to treatment‐naïve individuals, with low vitamin D status and use of efavirenz being significant determinants of lower BMD .…”

Section: Bone Mineral Densitymentioning

confidence: 99%

HIV infection and bone disease

Compston

2016

J Intern Med

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The success of antiretroviral therapy in treating HIV infection has greatly prolonged life expectancy in affected individuals, transforming the disease into a chronic condition. A number of HIV-associated non-AIDS comorbidities have emerged in the ageing HIV-infected population, including osteoporosis and increased risk of fracture. The pathogenesis of fracture is multifactorial with contributions from both traditional and HIV-specific risk factors. Significant bone loss occurs on initiation of antiretroviral therapy but stabilizes on long-term therapy. Fracture risk assessment should be performed in HIV-infected individuals and bone mineral density measured when indicated. Lifestyle measures to optimize bone health should be advised and, in individuals at high risk of fracture, treatment with bisphosphonates considered.

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“…This difference in results may be because of the fact that in the former study, 26 BMDs were not adjusted for confounding effects of smoking status and alcohol consumption unlike in our study. Dave et al 27 determined factors associated with low BMD in HIVinfected South Africans. They reported that exposure to efavirenz or lopinavir-based ART was associated with lower total hip BMD, whereas higher body weight and higher serum VitD concentration were associated with higher total hip BMD.…”

Section: Variable (Mean and Sd)mentioning

confidence: 99%

“…The use of efavirenz-based ART was also independently associated with lumbar spine BMD. 27 Bedimo et al 28 found that HIV-infection and hepatitis C virus infection were significantly associated with low BMD but when the statistical models were adjusted for TDF-use, it greatly diminished the association. Their findings suggested that the effect of HIV-infection on BMD was principally driven by TDF.…”

Section: Variable (Mean and Sd)mentioning

confidence: 99%

Bone turnover markers in HIV-infected women on tenofovir-based antiretroviral therapy

Mulubwa

Viljoen

Kruger

et al. 2017

South. Afr. j. HIV med.

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How to cite this article:Mulubwa M, Viljoen M, Kruger IM, Kruger HS, Rheeders M. Bone turnover markers in HIV-infected women on tenofovir-based antiretroviral therapy. S Afr J HIV Med. 2017;18(1), a739. https://doi.org/10.4102/ sajhivmed.v18i1.739 IntroductionLow bone mineral density (BMD) is common among persons infected with human immunodeficiency virus (HIV).1 In HIV-infected people, causes of osteoporosis, fractures and low BMD are multifactorial, involving traditional risk factors (smoking, alcohol use, low body weight and physical inactivity), but also genetics and HIV-infection per se.1,2 Exposure to antiretroviral treatment (ART), especially nucleoside reverse transcriptase inhibitors (NRTIs) and protease inhibitors (PIs) in HIV-infected people, is associated with low BMD.3 Osteomalacia was reported in patients on a tenofovir disoproxil fumarate (TDF)-based ART regimen that was characteristic of hypophosphataemia and increased serum alkaline phosphatase (ALP). 4In clinical studies, TDF-based ART regimens were reported to be associated with decreased BMD, characterised by increased serum concentrations of bone turnover markers (BTMs). These include bone resorption markers such as C-terminal telopeptide (CTx) and bone formation markers such as procollagen type 1 N-terminal propeptide (P1NP), bone-specific ALP (BALP) osteocalcin and ALP. 5,6,7,8 Furthermore, increased bone turnover, after initiation of TDF therapy, was characterised by elevated serum concentrations of parathyroid hormone (PTH).9 However, elevated serum concentrations of PTH were more profound in patients with vitamin D (VitD) deficiency. 10,11,12 Tenofovir disoproxil fumarate undergoes initial di-ester hydrolysis in plasma to tenofovir (TFV). A proposed bone loss mechanism associated with TFV, a phosphonate, is selective uptake by osteoclasts via a mechanism similar to that of bisphosphonates, which eventually cause cellular stress. 13 Resulting cellular stress perturbs deoxyribonucleic (DNA) synthesis by altering gene expression that is involved in signalling osteoblast activity resulting in decreased bone formation.13,14 Despite studies 3,5,7 performed on the relationship between TDF-use and bone Background: Tenofovir disoproxil fumarate (TDF) antiretroviral therapy is associated with disruption of the bone turnover process. Objectives:The objective of this study was to determine the association between tenofovir (TFV) plasma concentration and various bone turnover markers and compare these markers in HIV-infected women and HIV-uninfected controls. Method:A cross-sectional sub-study included 30 HIV-infected women on TDF and 30 HIVuninfected matched participants. Serum calcium (SrCa), serum phosphate (SrP), C-terminal telopeptide (CTx), parathyroid hormone (PTH), alkaline phosphatase (ALP), C-reactive protein (CRP), vitamin D (VitD) and bone mineral density (BMD) were measured. Plasma TFV was assayed on HPLC-MS/MS. The statistical tests applied were Mann-Whitney test, unpaired t-test, analysis of covariance, regression and correlation anal...

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Antiretroviral Therapy, Especially Efavirenz, Is Associated with Low Bone Mineral Density in HIV-Infected South Africans

Cited by 39 publications

References 23 publications

Changes in Bone Mineral Density, Body Composition, Vitamin D Status, and Mineral Metabolism in Urban HIV-Positive South African Women Over 12 Months

Changes in Bone Mineral Density, Body Composition, Vitamin D Status, and Mineral Metabolism in Urban HIV-Positive South African Women Over 12 Months

HIV infection and bone disease

Bone turnover markers in HIV-infected women on tenofovir-based antiretroviral therapy

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