New antiretroviral drugs: a review of the efficacy, safety, pharmacokinetics, and resistance profile of tipranavir, darunavir, etravirine, rilpivirine, maraviroc, and raltegravir

Hughes, Christine; Robinson, Linda; Tseng, Alice; MacArthur, Rodger D.

doi:10.1517/14656560903176446

Cited by 74 publications

(59 citation statements)

References 60 publications

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“…Additional ARVs are needed and are continuously introduced, including novel agents from known drug classes, as well as novel drug classes. 47,48 The methodology incorporated into SQUAT can be expanded to include the examination of additional HIV genes as more HIV-infected patients are exposed to more novel ARVs and respective sequencing for resistance testing is mandated. Additionally, as more microbes are being sequenced and as genomic medicine becomes more widespread, this methodology can also be implemented in non-HIV sequences.…”

Section: Discussionmentioning

confidence: 99%

Sequence Quality Analysis Tool for HIV Type 1 Protease and Reverse Transcriptase

DeLong

Bennett

et al. 2012

AIDS Research and Human Retroviruses

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Access to antiretroviral therapy is increasing globally and drug resistance evolution is anticipated. Currently, protease (PR) and reverse transcriptase (RT) sequence generation is increasing, including the use of in-house sequencing assays, and quality assessment prior to sequence analysis is essential. We created a computational HIV PR/RT Sequence Quality Analysis Tool (SQUAT) that runs in the R statistical environment. Sequence quality thresholds are calculated from a large dataset (46,802 PR and 44,432 RT sequences) from the published literature (http://hivdb.Stanford.edu). Nucleic acid sequences are read into SQUAT, identified, aligned, and translated. Nucleic acid sequences are flagged if with > five 1-2-base insertions; > one 3-base insertion; > one deletion; > six PR or > 18 RT ambiguous bases; > three consecutive PR or > four RT nucleic acid mutations; > zero stop codons; > three PR or > six RT ambiguous amino acids; > three consecutive PR or > four RT amino acid mutations; > zero unique amino acids; or < 0.5% or > 15% genetic distance from another submitted sequence. Thresholds are user modifiable. SQUAT output includes a summary report with detailed comments for troubleshooting of flagged sequences, histograms of pairwise genetic distances, neighbor joining phylogenetic trees, and aligned nucleic and amino acid sequences. SQUAT is a stand-alone, free, web-independent tool to ensure use of high-quality HIV PR/RT sequences in interpretation and reporting of drug resistance, while increasing awareness and expertise and facilitating troubleshooting of potentially problematic sequences.

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Section: Discussionmentioning

confidence: 99%

Sequence Quality Analysis Tool for HIV Type 1 Protease and Reverse Transcriptase

DeLong

Bennett

et al. 2012

AIDS Research and Human Retroviruses

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“…Raltegravir is the first agent in a new class of antiretrovirals, HIV integrase inhibitors. It has a demonstrated potent efficacy against multidrug-resistant HIV-1 and was initially approved by Food and Drug Administration in 2007 to treat treatment-experienced HIV-1-infected patients (Cocohoba and Dong, 2008;Steigbigel et al, 2008;Elbasha et al, 2009;Hughes et al, 2009). Based on the most recent guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents released by the United States Department of Health and Human Services in December 2009, raltegravir also has been listed as one of the preferred regimens recommended for treatment-naive HIV-1-infected patients.…”

Section: Discussionmentioning

confidence: 99%

“…Based on the most recent guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents released by the United States Department of Health and Human Services in December 2009, raltegravir also has been listed as one of the preferred regimens recommended for treatment-naive HIV-1-infected patients. Clinical studies have shown that raltegravir was well tolerated and had fewer side effects compared with other classes of antiretrovirals, such as HIV PIs and reverse transcriptase inhibitors (Hughes et al, 2009). The peak plasma concentration ranges from 10.63 to 24.67 M with 400-to 800-mg/day doses (Iwamoto et al, 2008c).…”

Section: Discussionmentioning

confidence: 99%

“…Raltegravir is primarily metabolized in the liver by uridine diphosphate glucuronosyltransferase 1A1-mediated glucuronidation (Kassahun et al, 2007). Ritonavir is an inhibitor of CYP3A, which is recommended to be used as a boosting agent to increase the plasma levels of other HIV PIs (Hughes et al, 2009). Several studies have reported that there are no significant drug-drug interactions between HIV PIs and raltegravir (Iwamoto et al, 2008a,b;Imaz et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

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Prevention of HIV Protease Inhibitor-Induced Dysregulation of Hepatic Lipid Metabolism by Raltegravir via Endoplasmic Reticulum Stress Signaling Pathways

Cao¹,

Hu²,

Wang³

et al. 2010

J Pharmacol Exp Ther

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Hyperlipidemia associated with the HIV protease inhibitor (PI), the major component of highly active antiretroviral treatment (HAART) for HIV infection, has stimulated interest in developing new agents that minimize these side effects in the clinic. HIV integrase inhibitor is a new class of anti-HIV agents. Raltegravir is a first-in-its-class oral integrase inhibitor and has potent inhibitory activity against HIV-1 strains that are resistant to other antiretroviral regimens. Our previous studies have demonstrated that HIV PI-induced endoplasmic reticulum (ER) stress links to dysregulation of lipid metabolism. However, little information is available as to whether raltegravir would have similar effects as the HIV PIs. In this study, we examined the effect of raltegravir on lipid metabolism both in primary rat hepatocytes and in in vivo mouse models, and we further determined whether the combination of raltegravir with existing HIV PIs would potentially exacerbate or prevent the previously observed development of dyslipidemia. The results indicated that raltegravir did not induce ER stress or disrupt lipid metabolism either in vitro or in vivo. However, HIV PI-induced ER stress and lipid accumulation were significantly inhibited by raltegravir both in in vitro primary rat hepatocytes and in in vivo mouse liver. High-performance liquid chromatography analysis further demonstrated that raltegravir did not affect the uptake and metabolism of HIV PIs in hepatocytes. Thus, raltegravir has less hepatic toxicity and could prevent HIV PI-induced dysregulation of lipid metabolism by inhibiting ER stress. These results suggest that incorporation of this HIV integrase inhibitor may reduce the side effects associated with current HAART.

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“…Although recent clinical trials did not report any serious side effects associated with ETR (21), its safety in longterm usage is yet to be determined. A disadvantage of ETR is that it is administered twice a day, and this contributes to the inconvenience for patients, whereas EFV requires only a single dose per day (19). Therefore, the discovery of new NNRTIs remains an ongoing priority to ensure that effective treatment is available for HIV/AIDS patients.…”

mentioning

confidence: 99%

F18, a Novel Small-Molecule Nonnucleoside Reverse Transcriptase Inhibitor, Inhibits HIV-1 Replication Using Distinct Binding Motifs as Demonstrated by Resistance Selection and Docking Analysis

Liu

Zhang

et al. 2012

Antimicrob Agents Chemother

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Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are one of the key components of antiretroviral therapy drug regimen against human immunodeficiency virus type 1 (HIV-1) replication. We previously described a newly synthesized small molecule, 10-chloromethyl-11-demethyl-12-oxo-calanolide A (F18), a (؉)-calanolide A analog, as a novel anti-HIV-1 NNRTI (H. Xue et al., J. Med. Chem. 53:1397-1401, 2010). Here, we further investigated its antiviral range, drug resistance profile, and underlying mechanism of action. F18 consistently displayed potent activity against primary HIV-1 isolates, including various subtypes of group M, circulating recombinant form (CRF) 01_AE, and laboratory-adapted drug-resistant viruses. Moreover, F18 displayed distinct profiles against 17 NNRTI-resistant pseudoviruses, with an excellent potency especially against one of the most prevalent strains with the Y181C mutation (50% effective concentration, 1.0 nM), which was in stark contrast to the extensively used NNRTIs nevirapine and efavirenz. Moreover, we induced F18-resistant viruses by in vitro serial passages and found that the mutation L100I appeared to be the dominant contributor to F18 resistance, further suggesting a binding motif different from that of nevirapine and efavirenz. F18 was nonantagonistic when used in combination with other antiretrovirals against both wild-type and drug-resistant viruses in infected peripheral blood mononuclear cells. Interestingly, F18 displayed a highly synergistic antiviral effect with nevirapine against nevirapine-resistant virus (Y181C). Furthermore, in silico docking analysis suggested that F18 may bind to the HIV-1 reverse transcriptase differently from other NNRTIs. This study presents F18 as a new potential drug for clinical use and also presents a new mechanism-based design for future NNRTI.

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New antiretroviral drugs: a review of the efficacy, safety, pharmacokinetics, and resistance profile of tipranavir, darunavir, etravirine, rilpivirine, maraviroc, and raltegravir

Abstract: These six new agents have resulted in marked progress towards the goal of being able to provide HIV-infected individuals with the drugs necessary to achieve decades of durable suppression of HIV without substantial toxicity.

Cited by 74 publications

References 60 publications

Sequence Quality Analysis Tool for HIV Type 1 Protease and Reverse Transcriptase

Sequence Quality Analysis Tool for HIV Type 1 Protease and Reverse Transcriptase

Prevention of HIV Protease Inhibitor-Induced Dysregulation of Hepatic Lipid Metabolism by Raltegravir via Endoplasmic Reticulum Stress Signaling Pathways

F18, a Novel Small-Molecule Nonnucleoside Reverse Transcriptase Inhibitor, Inhibits HIV-1 Replication Using Distinct Binding Motifs as Demonstrated by Resistance Selection and Docking Analysis

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