The efficacy and safety of tenofovir alafenamide versus tenofovir disoproxil fumarate in antiretroviral regimens for HIV-1 therapy

Wang, Huilian; Lu, Xi; Yang, Xudong; Xu, Nan

doi:10.1097/md.0000000000005146

Cited by 80 publications

(78 citation statements)

References 34 publications

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“…Moreover, a meta‐analysis of 2210 patients suggested that changing the HIV regimen to TDF is associated with a reduction in BMD, and switching from TDF to tenofovir alafenamide (TAF) led to an improvement in BMD . A recent double‐blind phase 3 trial of 1733 ART‐naïve HIV‐infected individuals found that a TAF‐based regimen had better virologic efficacy and less impact on BMD compared with a TDF‐based regimen formulated with similar antiretroviral agents . For the moment, it is clear that TAF users had fewer signals of kidney injury compared with TDF users, and decreases in BMD were generally milder, although there is still a significant effect on BMD.…”

Section: Discussionmentioning

confidence: 99%

Tenofovir Causes Bone Loss via Decreased Bone Formation and Increased Bone Resorption, Which Can Be Counteracted by Dipyridamole in Mice

Conesa-Buendía

Llamas-Granda

Larrañaga-Vera

et al. 2019

Journal of Bone and Mineral Research

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Osteopenia and fragility fractures have been associated with human immunodeficiency virus (HIV) infection. Tenofovir, a common antiviral in HIV treatment, also leads to increases in bone catabolism markers and decreased BMD in children and young adults. In murine models and human cell lines, tenofovir inhibits adenosine triphosphate release and decreases extracellular adenosine levels. Adenosine and adenosine A2A receptor inhibit osteoclast formation, and increase local adenosine concentration with dipyridamole, an agent that blocks adenosine cellular uptake and stimulates new bone formation as well as bone morphogenic protein 2. We hypothesized that tenofovir regulates bone resorption by diminishing endogenous adenosine levels and questioned whether dipyridamole may be a useful treatment to counteract the deleterous bone effects of tenofovir. Primary murine osteoclasts were induced by M‐CSF/RANKL, and the number of TRAP‐positive‐cells was studied after challenge with tenofovir alone or in combination with dipyridamole. Differentiation markers were studied by RT‐PCR and MAPK/NFkB expression by Western blot. Male C57Bl/6 mice were treated as follows: saline 0.9% (control), tenofovir 75 mg/kg/day, dipyridamole 25 mg/kg/day, combination tenofovir/dipyridamole (n = 10, 4 weeks). Calcein/Alizarin Red‐labeling of newly formed bone was used, and long bones were prepared for micro‐computed tomography (μCT)/histology. Tenofovir produced a dose‐dependent increase in osteoclast differentiation (EC50 = 44.5nM) that was reversed by dipyridamole (IC50 = 0.3 μM). Tenofovir increased cathepsin K and NFATc1 mRNA levels and dipyridamole reversed the effect. Dipyridamole reversed the effect of tenofovir on pERK1/2, pp38, and NFkB nuclear translocation. Mice treated with tenofovir lost nearly 10% of their body weight (p < 0.001). μCT revealed decreased BMD and altered trabecular bone in tenofovir‐treated mice, reversed by dipyridamole. TRAP‐staining showed increased osteoclasts in tenofovir‐treated mice (p < 0.005), an effect reversed by dipyridamole. Similar results were obtained for cathepsin K and CD68. RANKL‐positive cells were increased in tenofovir‐treated mice, whereas osteoprotegerin‐positive cells were decreased; both effects were reversed by dipyridamole. These results suggest that treatment with agents that increase local adenosine concentrations, like dipyridamole, might prevent bone loss following tenofovir treatment. © 2019 American Society for Bone and Mineral Research.

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Section: Discussionmentioning

confidence: 99%

Tenofovir Causes Bone Loss via Decreased Bone Formation and Increased Bone Resorption, Which Can Be Counteracted by Dipyridamole in Mice

Conesa-Buendía

Llamas-Granda

Larrañaga-Vera

et al. 2019

Journal of Bone and Mineral Research

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“…These results are consistent with findings of clinical studies assessing TAF-based and NRTI-sparing regimens. E/C/F/TAF was found to be comparable in efficacy to other recommended TDF-or-ABC-based regimens [5,25], while NRTI-sparing regimens were associated with a trend for lower efficacy in most clinical trials compared with other recommended TDFor ABC-based regimens [11,16,18,19,26,27]. Results in patients with viral load < 100 000 copies/mL were consistent with the full analysis and showed similar mean RR with 95% CrI including 1, probably as a consequence of the smaller number of studies which increases the uncertainty and the corresponding 95% CrI.…”

Section: Discussionmentioning

confidence: 92%

Comparison of 48‐week efficacies of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide and nucleoside/nucleotide reverse transcriptase inhibitor‐sparing regimens: a systematic review and network meta‐analysis

Gallien

Massetti²,

Flandre

et al. 2018

HIV Medicine

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The NMA results suggest that E/C/F/TAF represents a more effective option than NRTI-sparing regimens in terms of 48-week efficacy in treatment-naïve patients. Furthermore, TAF pharmacological properties, as well as tolerability results in clinical studies, suggest a safety profile similar to that of NRTI-sparing regimens. Thus, the E/C/F/TAF combination might represent a more appropriate option than NRTI-sparing regimens for initiation of antiretroviral therapy in treatment-naïve HIV-infected patients.

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“…Nei pazienti HIV-positivi i dettagli eziopatogenetici di tale processo non sono ancora del tutto chiariti (16). Alcuni dati dimostrano come il passaggio a TAF può migliorare la densità minerale ossea rispetto alla prosecuzione di un regime con TDF (17). Miglioramenti nella funzionalità renale e nel metabolismo osseo sono stati riscontrati anche in uno studio relativo allo switch a E/C/F/TAF in pazienti coinfetti HIV/HBV senza alterazioni della funzionalità renale e in un recente lavoro relativo a sicurezza ed efficacia a 48 settimane dello switch a E/C/F/TAF in pazienti monoinfetti HIV con insufficienza renale da lieve a caso clinico Figura 1.…”

Section: Discussioneunclassified

Sindrome di Fanconi Tenofovir-correlata in paziente con coinfezione HIV/HBV: un problema di gestione clinica

Tebini¹,

Zeroli²,

Pizzi³

et al. 2017

JHA

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RiassuntoLa sindrome di Fanconi è un raro evento avverso di tenofovir disoproxil fumarato (TDF). L'osteonecrosi è una condizione multifattoriale descritta nei pazienti HIV-positivi, il cui meccanismo eziologico è dibattuto. Riportiamo il primo caso di un paziente coinfetto HIV-1/HBV trattato con successo con elvitegravir/cobicistat/emtricitabina/tenofovir alafenamide dopo una sindrome di Fanconi TDF-correlata, con miglioramento della funzionalità renale e completa regressione di una precoce osteonecrosi della testa del femore, con un follow-up di 1 anno. Abstract Introduzione L'utilizzo di tenofovir (TVF) è tutt'oggi fondamentale nella terapia antiretrovirale; nei pazienti coinfetti HIV/ HBV costituisce molto spesso una scelta obbligata (1). Tenofovir Alafenamide (TAF) è un nuovo profarmaco di TFV che, rispetto a tenofovir-disoproxil-fumarato (TDF) consente di ottenere adeguate concentrazioni intracellulari del metabolita attivo tenofovir-difosfato (TFV-DP) a fronte di concentrazioni plasmatiche significativamente ridotte (2-3). Anche a livello epatico, TAF consente il raggiungimento di concentrazioni più elevate di TFV-DP, con una emivita superiore alle 24 ore (4). Tenofovir alafenamide ha un minore impatto sulla funzionalità renale e sul metabolismo osseo rispetto a TDF, grazie alle minori concentrazioni plasmatiche di TFV, come ampiamente dimostrato da studi clinici relativi alla co-formulazione di TAF 10 mg con elvitegravir 150 mg, cobicistat 150 mg, emtricitabina 200 mg (E/C/F/TAF) (5-6). L'esposizione prolungata ad alti livelli plasmatici di TFV è associata a disfunzione tubulare e circa lo 0,3% dei pazienti in terapia con TDF può sviluppare una sindrome di Fanconi (7), una condizioni rara caratterizzata da una disfunzione del tubulo renale prossimale che altera il trasporto di aminoacidi, glucosio, fosfato, acido urico, sodio, potassio, bicarbonato e proteine (8). L'utilizzo di TDF è notoriamente correlato anche a riduzione della densità minerale ossea nell'anca e nella colonna, tramite un aumentato turnover osseo, correlato anche alla perdita di fosfati dovuta alla tossicità tubulare (9-12). Descriviamo di seguito il caso di un paziente coinfetto HIV-1/HBV in esiti di sindrome di Fanconi TDF-correlata e affetto da un'iniziale osteonecrosi della testa del femore sinistro, trattato con E/C/F/TAF con miglioramento della funzionalità renale e completa regressione dell'osteonecrosi femorale, con un anno di follow-up. Case report

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The efficacy and safety of tenofovir alafenamide versus tenofovir disoproxil fumarate in antiretroviral regimens for HIV-1 therapy

Abstract: Supplemental Digital Content is available in the text

Cited by 80 publications

References 34 publications

Tenofovir Causes Bone Loss via Decreased Bone Formation and Increased Bone Resorption, Which Can Be Counteracted by Dipyridamole in Mice

Tenofovir Causes Bone Loss via Decreased Bone Formation and Increased Bone Resorption, Which Can Be Counteracted by Dipyridamole in Mice

Comparison of 48‐week efficacies of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide and nucleoside/nucleotide reverse transcriptase inhibitor‐sparing regimens: a systematic review and network meta‐analysis

Sindrome di Fanconi Tenofovir-correlata in paziente con coinfezione HIV/HBV: un problema di gestione clinica

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