<i>In Vitro</i>Antiviral Activity of Cabotegravir against HIV-2

Smith, Robert A.; Wu, Vincent H.; Zavala, Christopher G; Raugi, Dana N.; Ba, Selly; Seydi, Moussa; Gottlieb, Geoffrey S.

doi:10.1128/aac.01299-18

Cited by 16 publications

(11 citation statements)

References 70 publications

(82 reference statements)

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“…As previously reported for HIV-1, replacements G140S/Q148H in HIV-1 NL4-3 integrase conferred low-level (2.0-fold) resistance to bictegravir (33,39,51), whereas the T97A/ Y143C mutant did not show resistance to the drug (33) ( Table 3). In addition, the combination of E138K/G140S/Q148R in HIV-1 NL4-3 , which conferred 10-fold resistance to cabotegravir in our previous study (22), yielded a modest increase in the EC 50 for bictegravir (2.3-fold) ( Table 3).…”

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confidence: 76%

“…All drug susceptibility measurements were performed using our established MAGIC-5A indicator cell assay, which quantifies drug-dependent inhibition in a single round of HIV infection (35). We previously showed that the results obtained with this assay are concordant with those seen in spreading infections of immortalized T-cell lines, as demonstrated for the INIs raltegravir (17), dolutegravir (21), and cabotegravir (22). In addition, other groups have used similar single-cycle assays to quantify the activity of various INIs against HIV-1 and simian immunodeficiency virus (SIV) (33,(36)(37)(38)(39)(40).…”

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confidence: 98%

“…Bictegravir was purchased from Toronto Research Chemicals, Inc. (North York, ON, Canada). Master stocks and working dilutions of the drug were prepared as previously described for cabotegravir (22). MAGIC-5A indicator cells (HeLa-CD4-LTR-␤gal) and the pROD9 infectious molecular clone of HIV-2 were obtained from Michael Emerman, Fred Hutchinson Cancer Research Center, Seattle, WA.…”

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confidence: 99%

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Comparison of the Antiviral Activity of Bictegravir against HIV-1 and HIV-2 Isolates and Integrase Inhibitor-Resistant HIV-2 Mutants

Smith

Raugi

et al. 2019

Antimicrob Agents Chemother

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We compared the activity of the integrase inhibitor bictegravir against HIV-1 and HIV-2 using a culture-based, single-cycle assay. Values of 50% effective concentrations ranged from 1.2 to 2.5 nM for 9 HIV-1 isolates and 1.4 to 5.6 nM for 15 HIV-2 isolates. HIV-2 integrase mutants G140S/Q148R and G140S/Q148H were 34- and 110-fold resistant to bictegravir, respectively; other resistance-associated mutations conferred ≤5-fold changes in bictegravir susceptibility. Our findings indicate that bictegravir-based antiretroviral therapy should be evaluated in HIV-2-infected individuals.

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confidence: 76%

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confidence: 98%

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confidence: 99%

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Comparison of the Antiviral Activity of Bictegravir against HIV-1 and HIV-2 Isolates and Integrase Inhibitor-Resistant HIV-2 Mutants

Smith

Raugi

et al. 2019

Antimicrob Agents Chemother

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“…Particularly, in the absence of protective vaccines against HIV-1 46 , 47 , effective long-acting ART not only are the best approaches for PrEP 47 but also could serve as a vaccine-mimetic if dosing intervals are extended to yearly or longer. Moreover, CAB’s activities against HIV-2 provides real potential for dual treatment 48 , 49 . Altogether, we conclude that a major extension of the dosing interval could allow NM2CAB to be developed as a vaccine-mimetic.…”

Section: Discussionmentioning

confidence: 99%

A year-long extended release nanoformulated cabotegravir prodrug

et al. 2020

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Long-acting cabotegravir (CAB) extends antiretroviral drug (ARV) administration from daily to monthly. However, dosing volumes, injection site reactions, and health care oversight are obstacles towards broad usage. The creation of poloxamer-coated hydrophobic and lipophilic CAB prodrugs with controlled hydrolysis and tissue penetrance can overcome these obstacles. To such ends, fatty acid ester CAB nanocrystal prodrugs with 14, 18, and 22 added carbon chains were encased in biocompatible surfactants named NMCAB, NM2CAB, and NM3CAB and tested for drug release, activation, cytotoxicity, antiretroviral activities, pharmacokinetics (PK), and biodistribution. PK studies, performed in mice and rhesus macaques, with the lead 18-carbon ester chain NM2CAB, showed plasma CAB levels above the protein-adjusted 90% inhibitory concentration for up to a year. The NM2CAB, compared to NMCAB and NM3CAB, demonstrated prolonged drug release, plasma circulation time and tissue drug concentrations after a single 45 mg/kg intramuscular injection. These prodrug modifications could significantly improve CAB’s effectiveness.

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“…A study on integrase inhibitor‐naïve population was conducted to determine the antiviral activity of CAB against HIV‐2. The findings showed that HIV‐2 was sensitive to CAB and suggested that CAB could be a potential ART in PrEP for HIV‐2 …”

Section: Integrase Inhibitormentioning

confidence: 99%

Antiretroviral agents in pre-exposure prophylaxis: emerging and advanced trends in HIV prevention

Yap

Xin

Tan

et al. 2019

Journal of Pharmacy and Pharmacology

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Objectives Antiretroviral agents (ARVs) have been the most promising line of therapy in the management of human immunodeficiency virus (HIV) infections. Some of these ARVs are used in the pre-exposure prophylaxis (PrEP) to suppress the transmission of HIV. Prophylaxis is primarily used in uninfected people, before exposure, to effectively prevent HIV infection. Several studies have shown that ART PrEP prevents HIV acquisition from sexual, blood and mother-to-child transmissions. However, there are also several challenges and limitations to PrEP. This review focuses on the current antiretroviral therapies used in PrEP. Key findings Among ARVs, the most common drugs employed from the class of entry inhibitors are maraviroc (MVC), which is a CCR5 receptor antagonist. Other entry inhibitors like emtricitabine (FTC) and tenofovir (TFV) are also used. Rilpivirine (RPV) and dapivirine (DPV) are the most common drugs employed from the Non-nucleoside reverse transcriptase inhibitor (NNRTIs) class, whereas, tenofovir disoproxil fumarate (TDF) is primarily used in the Nucleoside Reverse Transcriptase Inhibitor (NRTIs) class. Cabotegravir (CAB) is an analog of dolutegravir, and it is an integrase inhibitor. Some of these drugs are also used in combination with other drugs from the same class. Summary Some of the most common pre-exposure prophylactic strategies employed currently are the use of inhibitors, namely entry inhibitors, non-nucleoside reverse transcriptase inhibitors, nucleoside reverse transcriptase inhibitors, integrase and protease inhibitors. In addition, we have also discussed on the adverse effects caused by ART in PrEP, pharmacoeconomics factors and the use of antiretroviral prophylaxis in serodiscordant couples.HIV and pre-exposure prophylaxis Pui Khee Yap et al.

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In VitroAntiviral Activity of Cabotegravir against HIV-2

Cited by 16 publications

References 70 publications

Comparison of the Antiviral Activity of Bictegravir against HIV-1 and HIV-2 Isolates and Integrase Inhibitor-Resistant HIV-2 Mutants

Comparison of the Antiviral Activity of Bictegravir against HIV-1 and HIV-2 Isolates and Integrase Inhibitor-Resistant HIV-2 Mutants

A year-long extended release nanoformulated cabotegravir prodrug

Antiretroviral agents in pre-exposure prophylaxis: emerging and advanced trends in HIV prevention

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