Bictegravir versus dolutegravir, each with emtricitabine and tenofovir alafenamide, for initial treatment of HIV-1 infection: a randomised, double-blind, phase 2 trial

Sax, Paul E.; DeJesus, Edwin; Crofoot, Gordon; Ward, Douglas J.; Benson, Paul M.; Dretler, Robin; Mills, Anthony; Brinson, Cynthia; Péloquin, Julie; Wei, Xuelian; White, Kirsten; Cheng, Andrew; Martin, Hal; Quirk, Erin

doi:10.1016/s2352-3018(17)30016-4

Cited by 73 publications

(49 citation statements)

References 22 publications

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“…Raltegravir (RAL) and elvitegravir (EVG) were the first INSTIs to be approved in 2007 and 2012, respectively [4,5]. However, the emergence of resistance to RAL and EVG (thereby cross-resistance to each other) has been a challenge [1,6], and subsequently second-generation INSTIs were developed: dolutegravir (DTG) was approved in 2013; bictegravir (BIC), formerly GS-9883, approved in the USA in February 2018; and cabotegravir (CAB), also known as GSK744, now in phase III of clinical development with an anticipated release in 2019 [7][8][9]. CAB, a structural analog of DTG, displays unique physicochemical and pharmacokinetic properties allowing the formulation to be used as a single oral tablet for daily dosing or as a long-acting nanosuspension for monthly to quarterly intramuscular injection.…”

Section: Introductionmentioning

confidence: 99%

Update on Adverse Effects of HIV Integrase Inhibitors

Kołakowska

Maresca

Collins

et al. 2019

Curr Treat Options Infect Dis

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Keywords HIV integrase inhibitors I Drug-related side effects and adverse reactions I Raltegravir I Elvitegravir I Dolutegravir Abstract Purpose of review The goal of this paper is to provide an up-to-date review of adverse events related to the class of integrase strand transfer inhibitors (INSTIs), which became the class of choice in few years. We sought answers specifically to issues pertaining to neuropsychiatric adverse events, as well as weight gain, which were the two most important categories of adverse events raised in recent studies based on real-life experience. The primary focus of this paper is on adults with a brief summary on pregnant women and children/adolescents. Recent findings Dolutegravir (DTG) bears the heaviest burden of neuropsychiatric side effects. Weight gain was reported with all INSTIs, although there are methodological caveats in the analyses and the findings need to be interpreted with caution. Moreover, due to recent findings on neural tube defects in infants exposed to dolutegravir during their peri-conception period, its use is not recommended for women of childbearing age without proper birth control method, while raltegravir remains the only drug which may be prescribed without caution. Given the importance of cognitive and metabolic comorbidities in people living with HIV in regard to their quality of life, future research needs to focus on long-term effects of INSTIs in relation to these adverse events. Pharmacogenetics seems to be a promising tool. Safety during pregnancy is also another important issue to further clarify. Summary INSTIs are a generally well-tolerated class of antiretrovirals (ARV), and has a

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Section: Introductionmentioning

confidence: 99%

Update on Adverse Effects of HIV Integrase Inhibitors

Kołakowska

Maresca

Collins

et al. 2019

Curr Treat Options Infect Dis

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“…MK-2048 showed potent activity against most RAL/EVG resistant variants and did not select for the same substitutions in tissue culture studies but its clinical development was halted due to poor pharmacokinetics. Both CAB and BIC are promising and both are currently in advanced clinical trials [15, 19, 50, 80]. …”

Section: Second-generation Instismentioning

confidence: 99%

“…The fact that BIC selected for R263K may be related to structural similarities between this drug and DTG. So far, the results of a phase II trial of BIC at 48 weeks in HIV infected individuals have been reported and, as yet, there has been no detection of resistance-associated changes in IN [19]. …”

Section: Second-generation Instismentioning

confidence: 99%

“…Specifically, initial TDF/FTC/DTG treatment was supplemented with ritonavir-boosted darunavir following failure; the latter drug was subsequently substituted with RPV for reason of diffuse erythoderma. The second case reported transient emergence of a T97A substitution that did not confer any resistance on its own against DTG in vitro and was not observed at subsequent time points [19]. Although it cannot be excluded that unambiguously documented cases of emergent resistance mutations against first-line DTG will eventually be reported, it is expected that this will be rare.…”

Section: Introductionmentioning

confidence: 99%

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HIV drug resistance against strand transfer integrase inhibitors

et al. 2017

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Integrase strand transfer inhibitors (INSTIs) are the newest class of antiretroviral drugs to be approved for treatment and act by inhibiting the essential HIV protein integrase from inserting the viral DNA genome into the host cell’s chromatin. Three drugs of this class are currently approved for use in HIV-positive individuals: raltegravir (RAL), elvitegravir (EVG), and dolutegravir (DTG), while cabotegravir (CAB) and bictegravir (BIC) are currently in clinical trials. RAL and EVG have been successful in clinical settings but have relatively low genetic barriers to resistance. Furthermore, they share a high degree of cross-resistance, which necessitated the development of so-called second-generation drugs of this class (DTG, CAB, and BIC) that could retain activity against these resistant variants. In vitro selection experiments have been instrumental to the clinical development of INSTIs, however they cannot completely recapitulate the situation in an HIV-positive individual. This review summarizes and compares all the currently available information as it pertains to both in vitro and in vivo selections with all five INSTIs, and the measured fold-changes in resistance of resistant variants in in vitro assays. While the selection of resistance substitutions in response to RAL and EVG bears high similarity in patients as compared to laboratory studies, there is less concurrence regarding the “second-generation” drugs of this class. This highlights the unpredictability of HIV resistance to these inhibitors, which is of concern as CAB and BIC proceed in their clinical development.

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“…The next potential advance in this class will be the availability of another INSTI called bictegravir that does not require pharmacologic boosting and will be combined with FTC/TAF as a single-tablet regimen. Recent phase II data show promise for safety and efficacy 25 , with several large randomized controlled trials underway for both first-line and switch therapy in virologically suppressed patients.…”

Section: Evolution Of Third Drugs To Be Combined With Nucleoside Revementioning

confidence: 99%

Novel approaches to HIV therapy

Daar

2017

F1000Res

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There are approximately 35 million people infected by human immunodeficiency virus (HIV), with an estimated 2 million incident infections annually across the globe. While HIV infection was initially associated with high rates of morbidity and mortality, advances in therapy have transformed it into a chronic and manageable disease. In addition, there is very strong evidence that those on antiretroviral therapy are much less likely to transmit infection to their partners. The success rates for maintaining viral suppression in treated patients has dramatically increased owing to the development of agents that are potent and well tolerated and can often be co-formulated into single pills for simplification. This review will outline advances in treatment over the last several years as well as new strategies that may shift the existing treatment paradigm in the near future.

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Bictegravir versus dolutegravir, each with emtricitabine and tenofovir alafenamide, for initial treatment of HIV-1 infection: a randomised, double-blind, phase 2 trial

Cited by 73 publications

References 22 publications

Update on Adverse Effects of HIV Integrase Inhibitors

Update on Adverse Effects of HIV Integrase Inhibitors

HIV drug resistance against strand transfer integrase inhibitors

Novel approaches to HIV therapy

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