Avaliação da densidade mineral óssea em crianças e adolescentes que vivem com HIV e em tratamento com tenofovir disoproxil fumarato: uma revisão sistemática

Gusmão, Maria Brennda Ferreira de; Oliveira, Vinícius Vital de; Santos, Natália Maria da Silva; Melo, Luciana Costa

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Brasil

Revista Paulista de Pediatria

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Brasil

Español English

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Sumário

REVIEW ARTICLE • Rev. paul. pediatr. 42 • 2024 • https://doi.org/10.1590/1984-0462/2024/42/2023042 copiar

Avaliação da densidade mineral óssea em crianças e adolescentes que vivem com HIV e em tratamento com tenofovir disoproxil fumarato: uma revisão sistemática

Autoria SCIMAGO INSTITUTIONS RANKINGS

RESUMO

Objetivo:

Investigar o impacto do tenofovir disoproxil fumarato sobre a densidade mineral óssea e o conteúdo mineral ósseo em crianças e adolescentes infectados pelo vírus da imunodeficiência humana.

Fontes de dados:

O procedimento de busca foi executado de acordo com o Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement. A busca foi realizada até abril de 2022 nas seguintes bases de dados: Medical Literature Analysis and Retrieval System Online (Medline), Embase, Cochrane Central, Literatura Latino-Americana e do Caribe em Ciências da Saúde (Lilacs), Web of Science, Scopus, and MedRxiv. A combinação de termos utilizada foi: (Children OR Youth OR Teenagers) AND HIV AND (Tenofovir OR “Antiretroviral therapy”) AND (“Bone density” OR Osteoporosis OR Osteopenia). O protocolo foi registrado na base International Prospective Register of Systematic Reviews — PROSPERO (CRD42022312851).

Síntese dos dados:

As pesquisas iniciais resultaram em 1.156 artigos. Após a exclusão dos estudos duplicados, três revisores cegos analisaram título e resumo de 563 estudos, dos quais 57 permaneceram para leitura na íntegra. Somente nove artigos atenderam aos critérios de elegibilidade e foram incluídos para análises descritivas e de risco de viés. Com relação ao desenho dos estudos, quatro foram transversais, três foram estudos longitudinais antes-depois sem grupo controle e dois foram coortes prospectivas. Dos nove artigos, sete não mostraram associação significativa entre uso de TDF e redução de massa óssea em pessoas jovens. Entretanto, esses estudos não tiveram alta qualidade metodológica.

Conclusões:

Embora a maioria dos estudos selecionados não tenha encontrado efeito prejudicial do TDF sobre massa óssea, novas pesquisas primárias com maior qualidade metodológica são necessárias para que sejam obtidas evidências científicas robustas.

Palavras-chave:
Criança; Adolescente; HIV; Densidade óssea; Tenofovir

Author	1. Study population 2. Sample (n)	Objectives	1. Study design 2. Statistical analysis	Outcomes^* * The outcomes are presented according to the control for confounding variables if the study used group pairing or regression analysis. HIV: Human Immunodeficiency Virus; TDF: tenofovir disoproxil fumarate; BMDz: bone mineral density z score; ART: antiretroviral therapy; BMD: bone mineral density; LS: lumbar spine.
Hazra et al.³⁷37. Hazra R, Gafni RI, Maldarelli F, Balis FM, Tullio AN, DeCarlo E, et al. Tenofovir disoproxil fumarate and an optimized background regimen of antiretroviral agents as salvage therapy for pediatric HIV infection. Pediatrics. 2005;116:e846-54. https://doi.org/10.1542/peds.2005-0975 https://doi.org/10.1542/peds.2005-0975...	1. HIV-infected children and adolescents who had progressive disease even after using 2 antiretroviral regimens. 2. n=18.	Provide preliminary TDF safety data.	1. Longitudinal before-after. 2. Wilcoxon Test and Spearman Correlation.	The median decrease in LS BMDz was statistically significant at week 24 (p=0.007) and at week 48 (p=0.02). However, reductions in BMDz at week 48 were not correlated with TDF pharmacokinetic parameters.
Negra et al.³⁵35. Negra DM, Carvalho AP, Aquino MZ, Pinto JA, Silva MT, Andreatta KN, et al. Long-term efficacy and safety of tenofovir disoproxil fumarate in HIV-1-infected adolescents failing antiretroviral therapy: the final results of study GS-US-104-0321. Pediatr Infect Dis J. 2015;34:398-405. https://doi.org/10.1097/INF.0000000000000649 https://doi.org/10.1097/INF.000000000000...	1. Adolescents infected with HIV-1, with previous ART failure and with a viral load greater than 1000 copies/mL. 2. n=81.	To evaluate the efficacy and safety of TDF in adolescents.	1. Longitudinal before-after. 2. Wilcoxon Test and Mann-Whitney Test.	Median LS BMD increased at weeks 144 (p<0.001), 192 (p<0.001), 240 (p<0.002) from baseline. The median reduction in LS BMDz adjusted for chronological age was -0.265 (p=0.001) at week 96. However, after 288 weeks there as an increase in LS BMDz.
Giacomet et al.³⁰30. Giacomet V, Maruca K, Ambrosi A, Zuccotti GV, Mora S. A 10-year follow-up of bone mineral density in HIV-infected youths receiving tenofovir disoproxil fumarate. Int J Antimicrobial Agents. 2017;50:365-70. https://doi.org/10.1016/j.ijantimicag.2017.03.026 https://doi.org/10.1016/j.ijantimicag.20...	1. Children and adolescents vertically infected with HIV with previous long-term ART without TDF. 2. n=26.	Evaluate the effect of TDF on bone mass in young people with HIV	1. Longitudinal before-after. 2. Linear mixed effects model.	BMD changes observed over the years in HIV-infected patients did not differ from those expected in healthy children and adolescents, indicating that the TDF-containing regimen did not impair skeletal mineralization. After 12 months, mean LS BMDz increased by 0.2 in the total sample.
Bunders et al.³²32. Bunders MJ, Frinking O, Scherpbier HJ, van Arnhem LA, van Eck-Smit BL, Kuijpers TW, et al. Bone mineral density increases in HIV-Infected children treated with long-term combination antiretroviral therapy. Clin Infect Dis. 2013;56:583-6. https://doi.org/10.1093/cid/cis917 https://doi.org/10.1093/cid/cis917...	1. Children with HIV treated at Emma Children’s Hospital between 2002 and 2010. Exposed to TDF (n=13) and controls (n=53). 2. n=66.	To determine the impact of ART on the BMD of HIV-infected children.	1. Longitudinal. 2. Univariate and multivariate linear regressions.	Despite the negative trend observed between femoral BMDz-score and TDF treatment, femoral (p=0.244) and lumbar spine (p=0.584) BMDz-scores were not significantly lower among children treated with TDF in univariate regression.
Aurpibul et al.³⁴34. Aurpibul L, Cressey TR, Sricharoenchai S, Wittawatmongkol O, Sirisanthana V, Phongsamart W, et al. Efficacy, safety and pharmacology of tenofovir disoproxil fumarate in virologic-suppressed HIV-infected children using weight-band dosing. Pediatr Infect Dis J. 2015;34:392-7. https://doi.org/10.1097/INF.0000000000000633 https://doi.org/10.1097/INF.000000000000...	1. HIV-infected children with viral suppression after regimen without TDF. Intervention (n=40) and controls (n=40). 2. n= 80.	Evaluate the efficacy, safety and pharmacokinetics of TDF.	1. Longitudinal with control group. 2. Analysis of variance for repeated measures.	Significant reduction in LS BMDz occurred in children receiving TDF in the first 24 weeks of treatment (p=0.011), however there were no significant changes after 96 weeks of follow-up. No correlation was seen between tenofovir and absolute change in LS BMD (p=0.086).

Author	1. Study population 2. Sample (n)	Objectives	1. Study design 2. Statistical analysis	Outcomes^* * The outcomes are presented according to the control for confounding variables if the study used group pairing or regression analysis. HIV: Human Immunodeficiency Virus; ART: antiretroviral therapy; TDF: tenofovir disoproxil fumarate; PI: protease inhibitors; LS: lumbar spine; BMDz: bone mineral density Z-score; BMC: bone mineral content; BMCz: bone mineral content z score; BMADz: bone mineral apparent density; TBLH: total body less-head.
Zuccotti et al.³¹31. Zuccotti G, Viganò A, Gabiano C, Giacomet V, Mignone F, Stucchi S, et al. Antiretroviral therapy and bone mineral measurements in HIV-infected youths. Bone. 2010;46:1633-9. https://doi.org/10.1016/j.bone.2010.02.029 https://doi.org/10.1016/j.bone.2010.02.0...	1. HIV-infected children and adolescents on long-term ART or naïve to ART. Exposed to TDF (n=28). 2. n=86.	To evaluate the role of different antiretroviral regimens on bone mass measurements.	1. Cross-sectional. 2. Multiple linear regression.	Only stavudine (p=0.001) and PI (p=0.03) significantly interfered in reduction of LS BMDz. There was no correlation between the use of TDF and changes in LS BMDz (p>0.05). The LS BMC values of patients using TDF did not differ from healthy or ART naïve subjects (p>0.05).
Macdonald et al.³³33. Macdonald HM, Chu J, Nettlefold L, Maan EJ, Forbes JC, Côté H, et al. Bone geometry and strength are adapted to muscle force in children and adolescents perinatally infected with HIV. J Musculoskelet Neuronal Interact. 2013;13:53-65. PMID: 23445915	1. Children and adolescents vertically infected with HIV. Exposed to TDF (n=11). 2. n=31.	To investigate the association of bone mass measurements with the use of ART.	1. Cross-sectional. 2. Univariate regression analysis.	There was no significant association between use of TDF and changes in LS BMCz (p>0.05) and TB BMCz (p>0.05) despite the positive trend.
Sudjaritruk et al.³⁶36. Sudjaritruk T, Bunupuradah T, Aurpibul L, Kosalaraksa P, Kurniati N, Sophonphan J, et al. Impact of tenofovir disoproxil fumarate on bone metabolism and bone mass among perinatally HIV-infected Asian adolescents. Antivir Ther. 2017;22:471-9. https://doi.org/10.3851/IMP3103 https://doi.org/10.3851/IMP3103...	1. Vertically HIV-infected adolescents with long-term viral suppression on ART. Exposed to TDF (n=136). 2. n=394.	Determine the effect of TDF on metabolism and bone mass.	1. Cross-sectional. 2. Mann-Whitney test and multiple linear regression.	There was no significant difference in median BMDz between TDF users and non-users (p=0.27). The use of TDF had no significant association with changes in LS BMDz (p=0.09). There was no significant relationship between BMDz and duration of TDF treatment (p=0.34).
Rukuni et al.¹³13. Rukuni R, Rehman AM, Mukwasi-Kahari C, Madanhire T, Kowo-Nyakoko F, McHugh G, et al. Effect of HIV infection on growth and bone density in peripubertal children in the era of antiretroviral therapy: a cross-sectional study in Zimbabwe. Lancet Child Adolesc Health. 2021;5:569-81. https://doi.org/10.1016/S2352-4642(21)00133-4 https://doi.org/10.1016/S2352-4642(21)00...	1. Children and adolescents using ART for at least 2 years. Exposed to TDF (n=95). 2. n=279.	Identify the prevalence of low bone density and investigate associated risk factors.	1. Cross-sectional. 2. Chi-square, Fisher’s exact test; Univariate and multiple linear regressions.	TDF use was significantly associated with lower TBLH BMCz (p=0.015) and LS BMADz (p=0.012) relative to non-TDF users. TDF was associated with decreased LS-BMADz in univariate (p<0.0001) but not multivariate analysis (p=0.25). Regarding TBLH-BMCz, there was also this association in both the univariate (p=0.037) and multivariate (p=0.046) analysis. TDF use for more than 4 years was correlated with more pronounced TBLH-BMCz deficits in multivariate analysis (p=0.046).

Author	Defined goal	Specified population	Participation rate of eligible persons equal to 100%	Representative sample	Adequate sample size	Weel-defined intervention/exposure	Reliable measurement of outcome	Blinding of evaluators	Follow-up loss ≤ 20%	Appropriate statistical analysis	Dependent variable measured multiple times before and after the intervention	Statistical analysis for intervention at the group level	Quality rating
Hazra et al.³⁷37. Hazra R, Gafni RI, Maldarelli F, Balis FM, Tullio AN, DeCarlo E, et al. Tenofovir disoproxil fumarate and an optimized background regimen of antiretroviral agents as salvage therapy for pediatric HIV infection. Pediatrics. 2005;116:e846-54. https://doi.org/10.1542/peds.2005-0975 https://doi.org/10.1542/peds.2005-0975...	●	●	●	●	●	●	●	●	●	●	●	●	Fair
Negra et al.³⁵35. Negra DM, Carvalho AP, Aquino MZ, Pinto JA, Silva MT, Andreatta KN, et al. Long-term efficacy and safety of tenofovir disoproxil fumarate in HIV-1-infected adolescents failing antiretroviral therapy: the final results of study GS-US-104-0321. Pediatr Infect Dis J. 2015;34:398-405. https://doi.org/10.1097/INF.0000000000000649 https://doi.org/10.1097/INF.000000000000...	●	●	●	●	●	●	●	●	●	●	●	●	Fair
Giacomet et al.³⁰30. Giacomet V, Maruca K, Ambrosi A, Zuccotti GV, Mora S. A 10-year follow-up of bone mineral density in HIV-infected youths receiving tenofovir disoproxil fumarate. Int J Antimicrobial Agents. 2017;50:365-70. https://doi.org/10.1016/j.ijantimicag.2017.03.026 https://doi.org/10.1016/j.ijantimicag.20...	●	●	●	●	●	●	●	●	●	●	●	●	Poor

Author, year	Defined goal	Specified population	Participation rate of eligible persons >50%	Pre-specified and uniform eligibility criteria	Representative sample size	Exposure measured before the outcome	Adequate follow-up time	Weel-defined intervention/exposure	Reassessment of intervention/exposure	Weel-defined outcome	Evaluators blinding	Follow-up loss ≤ 20%	Statistical adjustment for confounding factors	Quality
Rukuni et al.¹³13. Rukuni R, Rehman AM, Mukwasi-Kahari C, Madanhire T, Kowo-Nyakoko F, McHugh G, et al. Effect of HIV infection on growth and bone density in peripubertal children in the era of antiretroviral therapy: a cross-sectional study in Zimbabwe. Lancet Child Adolesc Health. 2021;5:569-81. https://doi.org/10.1016/S2352-4642(21)00133-4 https://doi.org/10.1016/S2352-4642(21)00...	●	●	●	●	●	●	●	●	●	●	●	●	●	Fair
Sudjaritruk et al.³⁶36. Sudjaritruk T, Bunupuradah T, Aurpibul L, Kosalaraksa P, Kurniati N, Sophonphan J, et al. Impact of tenofovir disoproxil fumarate on bone metabolism and bone mass among perinatally HIV-infected Asian adolescents. Antivir Ther. 2017;22:471-9. https://doi.org/10.3851/IMP3103 https://doi.org/10.3851/IMP3103...	●	●	●	●	●	●	●	●	●	●	●	●	●	Poor
Zuccotti et al.³¹31. Zuccotti G, Viganò A, Gabiano C, Giacomet V, Mignone F, Stucchi S, et al. Antiretroviral therapy and bone mineral measurements in HIV-infected youths. Bone. 2010;46:1633-9. https://doi.org/10.1016/j.bone.2010.02.029 https://doi.org/10.1016/j.bone.2010.02.0...	●	●	●	●	●	●	●	●	●	●	●	●	●	Poor
Macdonald et al.³³33. Macdonald HM, Chu J, Nettlefold L, Maan EJ, Forbes JC, Côté H, et al. Bone geometry and strength are adapted to muscle force in children and adolescents perinatally infected with HIV. J Musculoskelet Neuronal Interact. 2013;13:53-65. PMID: 23445915	●	●	●	●	●	●	●	●	●	●	●	●	●	Fair

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[1] *Corresponding author. E-mail: luciana.melo@icbs.ufal.br (L.C. Melo)