Multiple Genetic Pathways Involving Amino Acid Position 143 of HIV-1 Integrase Are Preferentially Associated with Specific Secondary Amino Acid Substitutions and Confer Resistance to Raltegravir and Cross-Resistance to Elvitegravir

Huang, Wei; Frantzell, Arne; Fransen, Signe; Petropoulos, Christos J.

doi:10.1128/aac.00204-13

Cited by 27 publications

(26 citation statements)

References 33 publications

(46 reference statements)

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“…The Y143R single mutant in our panel has no effect on susceptibility to BIC or DTG (17) and is mildly resistant to EVG but has a higher resistance to RAL (55). BIC maintained activity against all of the single mutants at positions E92, Y143, Q148, N155, and R263, similar to DTG (17, 24, 26).…”

Section: Discussionmentioning

confidence: 99%

Antiviral Activity of Bictegravir (GS-9883), a Novel Potent HIV-1 Integrase Strand Transfer Inhibitor with an Improved Resistance Profile

Tsiang

Jones

Goldsmith

et al. 2016

Antimicrob Agents Chemother

235

183

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Bictegravir (BIC; GS-9883), a novel, potent, once-daily, unboosted inhibitor of HIV-1 integrase (IN), specifically targets IN strand transfer activity (50% inhibitory concentration [IC50] of 7.5 ± 0.3 nM) and HIV-1 integration in cells. BIC exhibits potent and selective in vitro antiretroviral activity in both T-cell lines and primary human T lymphocytes, with 50% effective concentrations ranging from 1.5 to 2.4 nM and selectivity indices up to 8,700 relative to cytotoxicity. BIC exhibits synergistic in vitro antiviral effects in pairwise combinations with tenofovir alafenamide, emtricitabine, or darunavir and maintains potent antiviral activity against HIV-1 variants resistant to other classes of antiretrovirals. BIC displayed an in vitro resistance profile that was markedly improved compared to the integrase strand transfer inhibitors (INSTIs) raltegravir (RAL) and elvitegravir (EVG), and comparable to that of dolutegravir (DTG), against nine INSTI-resistant site-directed HIV-1 mutants. BIC displayed statistically improved antiviral activity relative to EVG, RAL, and DTG against a panel of 47 patient-derived HIV-1 isolates with high-level INSTI resistance; 13 of 47 tested isolates exhibited >2-fold lower resistance to BIC than DTG. In dose-escalation experiments conducted in vitro, BIC and DTG exhibited higher barriers to resistance than EVG, selecting for HIV-1 variants with reduced phenotypic susceptibility at days 71, 87, and 20, respectively. A recombinant virus with the BIC-selected M50I/R263K dual mutations in IN exhibited only 2.8-fold reduced susceptibility to BIC compared to wild-type virus. All BIC-selected variants exhibited low to intermediate levels of cross-resistance to RAL, DTG, and EVG (<8-fold) but remained susceptible to other classes of antiretrovirals. A high barrier to in vitro resistance emergence for both BIC and DTG was also observed in viral breakthrough studies in the presence of constant clinically relevant drug concentrations. The overall virologic profile of BIC supports its ongoing clinical investigation in combination with other antiretroviral agents for both treatment-naive and -experienced HIV-infected patients.

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Section: Discussionmentioning

confidence: 99%

Antiviral Activity of Bictegravir (GS-9883), a Novel Potent HIV-1 Integrase Strand Transfer Inhibitor with an Improved Resistance Profile

Tsiang

Jones

Goldsmith

et al. 2016

Antimicrob Agents Chemother

235

183

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“…Whereas elvitegravir and raltegravir share similar genetic mechanisms of resistance [49,57], elvitegravir is now available in a one-daily pill coformulation with tenofovir and emtricitabine that may optimize adherence to a daily regimen. An NPEP tolerability trial evaluating the fixed-dose combination of tenofovir–emtricitabine–elvitegravir–cobicistat is underway, the results of which may help guide potential future use of this medication for NPEP.…”

Section: New Hiv Nonoccupational Postexposure Prophylaxis Regimensmentioning

confidence: 99%

Practical guidance for nonoccupational postexposure prophylaxis to prevent HIV infection

Jain

Mayer

2014

Aids

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Postexposure prophylaxis (PEP) with antiretroviral medication has been used as an HIV-prevention strategy for nearly 20 years. The fact that approximately 50 000 new HIV infections occur in the United States each year reflects marked underutilization of nonoccupational PEP (NPEP). There have been several advances in NPEP in the past 10 years. Clinical trials from different countries have demonstrated better tolerability, completion rates, and fewer drug–drug interactions with newer antiretroviral agents. Notably, there has been a shift from zidovudine-based to tenofovir-based regimens. Three-drug therapy is now favored for all potential HIV exposures. More recently, the US Public Health Service and the New York State Department of Health recommended tenofovir/emtricitabine and raltegravir as the first-line regimen universally for PEP. Advances in HIV testing technology may also allow shorter duration of follow-up HIV testing after a high-risk exposure. This review will discuss challenges with previously recommended regimens, newer potential candidate agents and the rationale for using them, intervals for laboratory monitoring, and cost considerations for NPEP. NPEP can be viewed as an educable moment and a potential bridge to preexposure prophylaxis, as part of a combination prevention package, for those who are likely to have recurrent higher-risk exposures. Thus, risk-reduction counseling should be an integral aspect of NPEP.

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“…INSTIs are now recognized as a safe and highly effective class of anti-HIV drugs (6). However, clinical resistance to RAL and EVG has been observed, and a high degree of cross-resistance between these two agents has been demonstrated (7,8,9,10,11,12). Furthermore, dosing of RAL is done twice daily, while once-daily administration of EVG requires a pharmacokinetic (PK) booster, such as ritonavir or cobicistat.…”

mentioning

confidence: 99%

Antiviral Characteristics of GSK1265744, an HIV Integrase Inhibitor Dosed Orally or by Long-Acting Injection

Yoshinaga

Kobayashi

Seki

et al. 2015

Antimicrob Agents Chemother

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GSK1265744 is a new HIV integrase strand transfer inhibitor (INSTI) engineered to deliver efficient antiviral activity with a once-daily, low-milligram dose that does not require a pharmacokinetic booster. The in vitro antiviral profile and mechanism of action of GSK1265744 were established through integrase enzyme assays, resistance passage experiments, and cellular assays with site-directed molecular (SDM) HIV clones resistant to other classes of anti-HIV-1 agents and earlier INSTIs. GSK1265744 inhibited HIV replication with low or subnanomolar efficacy and with a selectivity index of at least 22,000 under the same culture conditions. The protein-adjusted half-maximal inhibitory concentration (PA-EC 50 ) extrapolated to 100% human serum was 102 nM. When the virus was passaged in the presence of GSK1265744, highly resistant mutants with more than a 10-fold change (FC) in EC 50 relative to that of the wild-type were not observed for up to 112 days of culture. GSK1265744 demonstrated activity against SDM clones containing the raltegravir (RAL)-resistant Y143R, Q148K, N155H, and G140S/Q148H signature variants (FC less than 6.1), while these mutants had a high FC in the EC 50 for RAL (11 to >130). Either additive or synergistic effects were observed when GSK1265744 was tested in combination with representative anti-HIV agents, and no antagonistic effects were seen. These findings demonstrate that, similar to dolutegravir, GSK1265744 is differentiated as a new INSTI, having a markedly distinct resistance profile compared with earlier INSTIs, RAL, and elvitegravir (EVG). The collective data set supports further clinical development of GSK1265744.

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Multiple Genetic Pathways Involving Amino Acid Position 143 of HIV-1 Integrase Are Preferentially Associated with Specific Secondary Amino Acid Substitutions and Confer Resistance to Raltegravir and Cross-Resistance to Elvitegravir

Cited by 27 publications

References 33 publications

Antiviral Activity of Bictegravir (GS-9883), a Novel Potent HIV-1 Integrase Strand Transfer Inhibitor with an Improved Resistance Profile

Antiviral Activity of Bictegravir (GS-9883), a Novel Potent HIV-1 Integrase Strand Transfer Inhibitor with an Improved Resistance Profile

Practical guidance for nonoccupational postexposure prophylaxis to prevent HIV infection

Antiviral Characteristics of GSK1265744, an HIV Integrase Inhibitor Dosed Orally or by Long-Acting Injection

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