Efficacy and safety of tenofovir alafenamide versus tenofovir disoproxil fumarate given as fixed-dose combinations containing emtricitabine as backbones for treatment of HIV-1 infection in virologically suppressed adults: a randomised, double-blind, active-controlled phase 3 trial

Gallant, Joel E.; Daar, Eric S.; Raffi, François; Brinson, Cynthia; Ruane, Peter; DeJesus, Edwin; Johnson, Margaret; Clumeck, Nathan; Osiyemi, Olayemi; Ward, Doug; Morales-Ramirez, Javier O; Yan, Mingjin; Abram, Michael E.; Plummer, Andrew; Cheng, Andrew; Rhee, Martin S

doi:10.1016/s2352-3018(16)00024-2

Cited by 153 publications

(143 citation statements)

References 15 publications

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“…0.1-1μg/ml TAF reduced HIV replication ~40-98% in medium alone, but reduced HIV replication ~1-64% in the presence of adipocytes (p<0.05, n=4). Additionally, the more potent activity of TAF at lower doses relative to tenofovir and TDF in these in vitro experiments is consistent with patient studies reporting equivalent efficacy and less toxicity of TAF compared to TDF (Sax et al, 2014; Sax et al, 2015; Wohl et al, 2016; Gallant et al, 2016). The attenuation of tenofovir antiviral activity was also confirmed by measuring extracellular p24 by ELISA in which 0.1-1μg/ml TDF reduced HIV replication ~57-85% in medium alone, but reduced HIV replication ~4-41% in the presence of adipocytes (p<0.01, n=5).…”

Section: Resultssupporting

confidence: 84%

Adipocytes impair efficacy of antiretroviral therapy

et al. 2018

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Adequate distribution of antiretroviral drugs to infected cells in HIV patients is critical for viral suppression. In humans and primates, HIV- and SIV-infected CD4 T cells in adipose tissues have recently been identified as reservoirs for infectious virus. To better characterize adipose tissue as a pharmacological sanctuary for HIV-infected cells, in vitro experiments were conducted to assess antiretroviral drug efficacy in the presence of adipocytes, and drug penetration in adipose tissue cells (stromal-vascular-fraction cells and mature adipocytes) was examined in treated humans and monkeys. Co-culture experiments between HIV-1-infected CD4 T cells and primary human adipocytes showed that adipocytes consistently reduced the antiviral efficacy of the nucleotide reverse transcriptase inhibitor tenofovir and its prodrug forms tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF). In HIV-infected persons, LC-MS/MS analysis of intracellular lysates derived from adipose tissue stromal-vascular-fraction cells or mature adipocytes suggested that integrase inhibitors penetrate adipose tissue, whereas penetration of nucleoside/nucleotide reverse transcriptase inhibitors such as TDF, emtricitabine, abacavir, and lamivudine is restricted. The limited distribution and functions of key antiretroviral drugs within fat depots may contribute to viral persistence in adipose tissue.

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Section: Resultssupporting

confidence: 84%

Adipocytes impair efficacy of antiretroviral therapy

et al. 2018

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“…In switch studies of patients on TDF-containing regimens, slight increases in hip and spine bone mineral density were seen at 48 weeks in those who changed to TAF-containing regimens, while slight decreases in bone mineral density at those sites occurred in patients who continued to receive TDF. Similar differences in the effects on bone mineral density between TAF and TDF have been described in other studies 19 20…”

Section: Current Therapy and Recent Advancessupporting

confidence: 83%

Hepatitis B: changing epidemiology and interventions

Nannini

Sokal

2016

Arch Dis Child

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Hepatitis B virus infection is still a major public health problem worldwide, since more than 350 million people have chronic, lifelong infection and nearly 1 million deaths occur each year owing to complications. Most infections are acquired at birth or during early childhood. Nowadays, low- and middle-income countries bear the majority of the burden of hepatitis B-related liver cancer deaths despite the availability of an effective vaccine and antiviral treatments. In this review the epidemiology, strategies of prevention and the recent advances in therapy, genotype diversity and resistance are discussed.

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“…60–62 Lamivudine and emtricitabine each have substantial antiviral activity against HBV. However, there is a high risk of HBV resistance and viral breakthrough if these drugs are used without TDF or TAF, and neither is recommended alone for HBV in coinfection.…”

Section: Recommended Initial Regimensmentioning

confidence: 99%

“…98 Data also support a switch from suppressive TDF/emtricitabine–based regimens to TAF/emtricitabine–based regimens. 60 The lack of randomized clinical trial data does not preclude the possibility of a switch, provided certain caveats are considered.…”

Section: When and How To Switchmentioning

confidence: 99%