Tenofovir Alafenamide Versus Tenofovir Disoproxil Fumarate in the First Protease Inhibitor–Based Single-Tablet Regimen for Initial HIV-1 Therapy

Mills, Anthony; Crofoot, Gordon; McDonald, Cheryl; Shalit, Peter; Flamm, Jason; Gathe, Joseph; Scribner, Anita; Shamblaw, David; Saag, Michael S.; Cao, Huyen; Martin, Hal; Das, Moupali; Thomas, Anne; Liu, Hui C.; Yan, Mingjin; Callebaut, Christian; Custodio, Joseph M.; Cheng, Andrew; McCallister, Scott

doi:10.1097/qai.0000000000000618

Cited by 136 publications

(128 citation statements)

References 42 publications

(59 reference statements)

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“…But, supporting our data, in a large study, Scherzer et al found an independent association between TDF and increased risk of proteinuria, rapid decline in kidney function, and CKD [25], and Shlipak et al recently described a strong and independent association of the high tertiles of biomarkers of tubular damage with a faster rate of annual kidney function decline among HIV-infected women [26]. As an indirect confirmation, a significant lower incidence of tubular abnormalities and eGFR decline has been observed in preliminary studies by using tenofovir alafenamide (TAF), a novel prodrug of TDF reaching lower concentrations in tubular cells [27].…”

Section: Discussionmentioning

confidence: 90%

Prevalence and significance of proximal renal tubular abnormalities in HIV-infected patients receiving tenofovir

Casado

Bañón

Santiuste

et al. 2016

Aids

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Section: Discussionmentioning

confidence: 90%

Prevalence and significance of proximal renal tubular abnormalities in HIV-infected patients receiving tenofovir

Casado

Bañón

Santiuste

et al. 2016

Aids

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“…Tenofovir alafenamide (TAF) is a novel prodrug of tenofovir (TFV) that has demonstrated a high degree of efficacy when administered as a part of an antiretroviral regimen and a safety profile differentiated from that of TDF, in particular, improved bone and renal safety, in HIV-infected patients (2)(3)(4)(5). The prodrug TDF is better able to permeate enterocytes than the parent nucleotide, TFV; TDF is rapidly converted into TFV systemically after intestinal absorption, and circulating TFV exhibits an exposure-response relationship for antiviral activity.…”

mentioning

confidence: 99%

Pharmacokinetics and Safety of Tenofovir Alafenamide in HIV-Uninfected Subjects with Severe Renal Impairment

Custodio

Fordyce

Garner

et al. 2016

Antimicrob Agents Chemother

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Tenofovir alafenamide (TAF) is an oral prodrug of tenofovir (TFV) that has greater stability in plasma than TFV disoproxil fumarate (TDF) and circulates as intact TAF, resulting in the direct and higher lymphatic loading of and exposure to TFV diphosphate, the active moiety. Unlike TFV, TAF is minimally eliminated in urine. The pharmacokinetics (PK) of TAF and TFV in HIVuninfected subjects with severe renal impairment and matched healthy controls were evaluated. Subjects with severe renal impairment (RI; estimated glomerular filtration rate [eGFR], 15 to 29 ml/min) and controls (eGFR, >90 ml/min) matched for age, gender, and body mass index received a single dose of TAF at 25 mg. Blood and urine samples for TAF and TFV PK determinations were collected over 7 days postdosing, and subjects were followed up at 14 days. A total of 14 renally impaired subjects and 13 control subjects enrolled and completed the study. The TAF maximum observed concentration in plasma (C max ) and the area under the concentration-versus-time curve (AUC) extrapolated to infinite time (AUC inf ) were 79% and 92% higher, respectively, in subjects with severe RI than the controls, primarily due to higher absorption. The TFV C max and AUC inf were 2.8-fold and 5.7-fold higher, respectively, in subjects with severe RI than the controls. In subjects with severe RI, TAF at 25 mg provided a TFV AUC 10 to 40% lower than that from historical TDF-based TFV exposures in subjects with normal renal function. There were no discontinuations due to adverse events. In subjects with severe RI receiving TAF at 25 mg, TAF exposures were higher than those for the controls; these differences are unlikely to be clinically meaningful. TFV exposures were higher than those for the controls but lower than the exposures in nonrenally impaired subjects on TDF-based regimens.T he availability of efficacious and well-tolerated antiretroviral agents and their coformulation into a single-tablet regimen (STR) for convenient dosing have transformed the treatment landscape and rendered HIV into a manageable disease (1). Indeed, several STRs have been approved for HIV treatment, including efavirenz (EFV)-emtricitabine (FTC)-tenofovir disoproxil fumarate (TDF), rilpivirine (RPV)-FTC-TDF, elvitegravir (EVG)-cobicistat (COBI)-FTC-TDF, and, recently, abacavir (ABC)-dolutegravir (DTG)-lamivudine (3TC). Although STRs have been beneficial to a large number of HIV-infected patients, their use in special populations, such as those with end-organ dysfunction, has been limited due to the inability to alter the dose and the discordance in the doses of the various components with the different routes of elimination needed. Specifically, one or more components of the STRs mentioned above are predominantly if not exclusively renally eliminated [i.e., the nucleos(t)ide reverse transcriptase inhibitors TDF, FTC, and 3TC], necessitating dose reductions in patients with certain levels of renal impairment that is incompatible with fixed-dose-strength STR dosage forms. Therefore, patients with m...

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“…Phase II and III trials comparing the new formulation tenofovir alafenamide fumarate (TAF) with TDF have found significantly higher declines in the eGFR in the TDF group after short drug exposure periods (median < 70 weeks) [29][30][31]. Further data will be needed about the renal safety profile of TAF in the long term.…”

Section: Discussionmentioning

confidence: 99%

Long-term comparative and prospective cohort study of renal function in patients with HIV infection treated with tenofovir disoproxil fumarate

Calle¹,

Pulido²,

Sánchez-Conde³

et al. 2017

HIV & AIDS Review

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Tenofovir Alafenamide Versus Tenofovir Disoproxil Fumarate in the First Protease Inhibitor–Based Single-Tablet Regimen for Initial HIV-1 Therapy

Cited by 136 publications

References 42 publications

Prevalence and significance of proximal renal tubular abnormalities in HIV-infected patients receiving tenofovir

Prevalence and significance of proximal renal tubular abnormalities in HIV-infected patients receiving tenofovir

Pharmacokinetics and Safety of Tenofovir Alafenamide in HIV-Uninfected Subjects with Severe Renal Impairment

Long-term comparative and prospective cohort study of renal function in patients with HIV infection treated with tenofovir disoproxil fumarate

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