Antiviral Activity, Pharmacokinetics, and Dose Response of the HIV-1 Integrase Inhibitor GS-9137 (JTK-303) in Treatment-Naive and Treatment-Experienced Patients

DeJesus, Edwin; Berger, Daniel; Markowitz, Martin; Cohen, Calvin; Hawkins, Trevor; Ruane, Peter; Elion, Richard; Farthing, Charles; Zhong, Lijie; Cheng, Andrew; McColl, Damian J.; Kearney, Brian P.

doi:10.1097/01.qai.0000233308.82860.2f

Cited by 244 publications

(201 citation statements)

References 15 publications

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“…First, monotherapy resulted in an extensive monophasic decay that was comparable in all dosage groups, with a median decrease of 2.2 log 10 HIV RNA copies/ml over 10 days (20,40,42). Monotherapy with other INIs (L-870,810, elvitegravir, and GSK364735) has shown similar overall viral-load declines (11,12). Second, in a combination study of antiretroviral therapynaïve patients receiving tenofovir and lamivudine as background therapy, individuals also taking raltegravir had a more rapid decline in HIV-1 viremia than those taking the potent nonnucleoside reverse transcriptase inhibitor (RTI) efavirenz (40,42), although both arms reached the same ultimate decrease in the viral load.…”

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confidence: 98%

Pharmacovirological Impact of an Integrase Inhibitor on Human Immunodeficiency Virus Type 1 cDNA Species In Vivo

Goffinet

Allespach

Oberbremer

et al. 2009

J Virol

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Clinical trials of the first approved integrase inhibitor (INI), raltegravir, have demonstrated a drop in the human immunodeficiency virus type 1 (HIV-1) RNA loads of infected patients that was unexpectedly more rapid than that with a potent reverse transcriptase inhibitor, and apparently dose independent. These clinical outcomes are not understood. In tissue culture, although their inhibition of integration is well documented, the effects of INIs on levels of unintegrated HIV-1 cDNAs have been variable. Furthermore, there has been no report to date on an INI's effect on these episomal species in vivo. Here, we show that prophylactic treatment of transgenic rats with the strand transfer INI GSK501015 reduced levels of viral integrants in the spleen by up to 99.7%. Episomal two-long-terminal-repeat (LTR) circles accumulated up to sevenfold in this secondary lymphoid organ, and this inversely correlated with the impact on the proviral burden. Contrasting raltegravir's dose-ranging study with HIV patients, titration of GSK501015 in HIV-infected animals demonstrated dependence of the INI's antiviral effect on its serum concentration. Furthermore, the in vivo 50% effective concentration calculated from these data best matched GSK501015's in vitro potency when serum protein binding was accounted for. Collectively, this study demonstrates a titratable, antipodal impact of an INI on integrated and episomal HIV-1 cDNAs in vivo. Based on these findings and known biological characteristics of viral episomes, we discuss how integrase inhibition may result in additional indirect antiviral effects that contribute to more rapid HIV-1 decay in HIV/AIDS patients.

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confidence: 98%

Pharmacovirological Impact of an Integrase Inhibitor on Human Immunodeficiency Virus Type 1 cDNA Species In Vivo

Goffinet

Allespach

Oberbremer

et al. 2009

J Virol

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“…This is consistent with the clinical observation that the pharmacoenhancement effect of RTV results from inhibition of CYP3A and that it persists beyond the time that the plasma concentrations of RTV are adequately above or close to K i values conferring direct inhibition of the enzymes. [13][14][15] Besides affecting the PKs of HIV PI drugs, RTV has been shown in clinical studies to enhance the PKs of important antiviral drugs that are CYP3A substrates, including the HIV-1 integrase inhibitor elvitegravir, 16 the CCR5 antagonist maraviroc, 17,18 and the HCV PI narlaprevir. 19 Elvitegravir is metabolized primarily by CYP3A4 in the liver and intestine.…”

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confidence: 99%

Cobicistat (GS-9350): A Potent and Selective Inhibitor of Human CYP3A as a Novel Pharmacoenhancer

Xu¹,

Liu²,

Murray³

et al. 2010

ACS Med. Chem. Lett.

169

165

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Cobicistat (3, GS-9350) is a newly discovered, potent, and selective inhibitor of human cytochrome P450 3A (CYP3A) enzymes. In contrast to ritonavir, 3 is devoid of anti-HIV activity and is thus more suitable for use in boosting anti-HIV drugs without risking selection of potential drug-resistant HIV variants. Compound 3 shows reduced liability for drug interactions and may have potential improvements in tolerability over ritonavir. In addition, 3 has high aqueous solubility and can be readily coformulated with other agents.

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“…Raltegravir (RAL) was the first INSTI to be approved for therapy in 2007 (64) and is safe and efficient in both treatment-naïve and treatment-experienced subjects (11,17,23,35,49,62,63). Elvitegravir (EVG) is another INSTI currently in advanced clinical trials (10,12,77).…”

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confidence: 99%

Characterization of the R263K Mutation in HIV-1 Integrase That Confers Low-Level Resistance to the Second-Generation Integrase Strand Transfer Inhibitor Dolutegravir

Quashie

Mésplède

Han

et al. 2012

J Virol

214

306

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Integrase (IN) strand transfer inhibitors (INSTIs) have been developed to inhibit the ability of HIV-1 integrase to irreversibly link the reverse-transcribed viral DNA to the host genome. INSTIs have proven their high efficiency in inhibiting viral replication in vitro and in patients. However, first-generation INSTIs have only a modest genetic barrier to resistance, allowing the virus to escape these powerful drugs through several resistance pathways. Second-generation INSTIs, such as dolutegravir (DTG, S/GSK1349572), have been reported to have a higher resistance barrier, and no novel drug resistance mutation has yet been described for this drug. Therefore, we performed in vitro selection experiments with DTG using viruses of subtypes B, C, and A/G and showed that the most common mutation to emerge was R263K. Further analysis by site-directed mutagenesis showed that R263K does confer low-level resistance to DTG and decreased integration in cell culture without altering reverse transcription. Biochemical cell-free assays performed with purified IN enzyme containing R263K confirmed the absence of major resistance against DTG and showed a slight decrease in 3= processing and strand transfer activities compared to the wild type. Structural modeling suggested and in vitro IN-DNA binding assays show that the R263K mutation affects IN-DNA interactions.T he high mutation rate of HIV-1 reverse transcriptase (RT) allows the virus to escape pressure through adaptive mutations that include drug resistance mutations that limit the effectiveness of antiretroviral drugs (5,31,66,69,70). The use of multiple drugs in combination can hamper this process by restraining viral replication, limiting the emergence of resistant strains. The addition of integrase inhibitors to the arsenal of drugs against HIV-1 is important since these inhibitors are active against viruses resistant to other drug classes (16,49,63).The HIV-1 integrase enzyme catalyzes two reactions. The first is 3= processing, which consists of cleavage of a dinucleotide at both 3= ends of the reverse-transcribed linear viral DNA and results in the exposure of reactive hydroxyl groups. The second step termed "strand transfer" is carried out through a nucleophilic attack by exposed 3= hydroxyl groups on host genomic DNA (26, 47). Even though 3= processing may be a suitable therapeutic target, the integrase inhibitors developed so far are integrase strand transfer inhibitors (INSTIs) that preferentially inhibit strand transfer while only modestly affecting 3= processing (18,24,26). Raltegravir (RAL) was the first INSTI to be approved for therapy in 2007 (64) and is safe and efficient in both treatment-naïve and treatment-experienced subjects (11,17,23,35,49,62,63). Elvitegravir (EVG) is another INSTI currently in advanced clinical trials (10,12,77).Although first-generation INSTIs strongly inhibit HIV-1 replication, they possess only a modest genetic barrier to resistance. Three main resistance pathways have been identified for RAL, involving initial mutations of the N1...

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Antiviral Activity, Pharmacokinetics, and Dose Response of the HIV-1 Integrase Inhibitor GS-9137 (JTK-303) in Treatment-Naive and Treatment-Experienced Patients

Abstract: GS-9137 demonstrated substantial short-term antiviral activity and was well tolerated as monotherapy, thus warranting further study.

Cited by 244 publications

References 15 publications

Pharmacovirological Impact of an Integrase Inhibitor on Human Immunodeficiency Virus Type 1 cDNA Species In Vivo

Pharmacovirological Impact of an Integrase Inhibitor on Human Immunodeficiency Virus Type 1 cDNA Species In Vivo

Cobicistat (GS-9350): A Potent and Selective Inhibitor of Human CYP3A as a Novel Pharmacoenhancer

Characterization of the R263K Mutation in HIV-1 Integrase That Confers Low-Level Resistance to the Second-Generation Integrase Strand Transfer Inhibitor Dolutegravir

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