Raltegravir: Its use in the Treatment of HIV Infection

2009 ◽  
Vol 1 ◽  
pp. CMT.S32
Author(s):  
Marianne Harris
Keyword(s):  
Hiv Infection ◽  
Safety Data ◽  
Resistance Testing ◽  
Strand Transfer ◽  
Antiretroviral Agents ◽  
First Line Therapy ◽  
Effective Option ◽  
Treatment Naïve ◽  
Transfer Inhibitor ◽  
Integrase Strand Transfer Inhibitor

Raltegravir is the first integrase strand transfer inhibitor to be approved for the treatment of HIV infection. Administered orally in doses of 400 mg twice daily, it is well-tolerated and has minimal drug-drug interactions with coadministered antiretrovirals and other agents. In clinical trials including treatment-experienced and treatment-naïve HIV-infected adults, raltegravir in combination with other antiretroviral agents has demonstrated a rapid and potent virologic effect and a generally benign safety profile. Like other antiretrovirals, raltegravir should ideally be given with two additional agents to which the patient's virus is susceptible based on results of resistance testing. In this context, raltegravir offers a safe and effective option as a component of combination therapy in treatment-experienced patients who are infected with HIV-1 strains showing evidence of resistance to other antiretroviral agents. Pending the availability of longer-term efficacy and safety data, raltegravir cannot currently be recommended as part of first-line therapy for treatment-naïve patients.

scholarly journals HIV-1 Integrase Inhibitors That Are Active against Drug-Resistant Integrase Mutants

2020 ◽  
Vol 64 (9) ◽  
Author(s):  
Steven J. Smith ◽  
Xue Zhi Zhao ◽  
Dario Oliveira Passos ◽  
Dmitry Lyumkis ◽  
Terrence R. Burke ◽  
...  
Keyword(s):  
Strand Transfer ◽  
First Line ◽  
Preclinical Development ◽  
First Line Therapy ◽  
Line Therapy ◽  
Treatment Naïve ◽  
Transfer Inhibitor ◽  
Resistant Mutants ◽  
Hiv 1

ABSTRACT The currently recommended first-line therapy for HIV-1-infected patients is an integrase (IN) strand transfer inhibitor (INSTI), either dolutegravir (DTG) or bictegravir (BIC), in combination with two nucleoside reverse transcriptase inhibitors (NRTIs). Both DTG and BIC potently inhibit most INSTI-resistant IN mutants selected by the INSTIs raltegravir (RAL) and elvitegravir (EVG). BIC has not been reported to select for resistance in treatment-naive patients, and DTG has selected for a small number of resistant viruses in treatment-naive patients. However, some patients who had viruses with substitutions selected by RAL and EVG responded poorly when switched to DTG-based therapies, and there are mutants that cause a considerable decrease in the potencies of DTG and BIC in in vitro assays. The new INSTI cabotegravir (CAB), which is in late-stage clinical trials, has been shown to select for novel resistant mutants in vitro. Thus, it is important to develop new and improved INSTIs that are effective against all the known resistant mutants. This led us to test our best inhibitors, in parallel with DTG, BIC, and CAB, in a single-round infection assay against a panel of the new CAB-resistant mutants. Of the INSTIs we tested, BIC and our compound 4d had the broadest efficacy. Both were superior to DTG, as evidenced by the data obtained with the IN mutant T66I/L74M/E138K/S147G/Q148R/S230N, which was selected by CAB using an EVG-resistant lab strain. These results support the preclinical development of compound 4d and provide information that can be used in the design of additional INSTIs that will be effective against a broad spectrum of resistant mutants.

scholarly journals Might dolutegravir be part of a functional cure for HIV?

2016 ◽  
Vol 62 (5) ◽  
pp. 375-382 ◽  
Author(s):  
Mark A. Wainberg ◽  
Ying-Shan Han ◽  
Thibault Mesplède
Keyword(s):  
First Generation ◽  
Strand Transfer ◽  
Resistance Mutations ◽  
Functional Cure ◽  
Viral Reservoirs ◽  
Genetic Barrier ◽  
Clinical Resistance ◽  
Treatment Naïve ◽  
Transfer Inhibitor ◽  
Integrase Strand Transfer Inhibitor

Antiretroviral therapy (ART) has greatly decreased HIV-related morbidity and mortality. However, HIV can establish viral reservoirs that evade both the immune system and ART. Dolutegravir (DTG) is a second-generation integrase strand transfer inhibitor (INSTI) related to the first-generation INSTIs raltegravir (RAL) and elvitegravir (EVG). DTG shows a higher genetic barrier to the development of HIV-1 resistance than RAL and EVG. More interestingly, clinical resistance mutations to DTG in treatment-naïve patients have not been observed to date. This review summarizes recent studies on strategies toward a cure for HIV, explores resistance profiles of DTG, and discusses how DTG might help in finding a functional cure for HIV.

scholarly journals Canary in the Coal Mine? Transmitted Mutations Conferring Resistance to All Integrase Strand Transfer Inhibitors in a Treatment-Naive Patient

2018 ◽  
Vol 5 (11) ◽  
Author(s):  
Kara S McGee ◽  
Nwora Lance Okeke ◽  
Christopher B Hurt ◽  
Mehri S McKellar
Keyword(s):  
Human Immunodeficiency Virus ◽  
Drug Resistance ◽  
Transmitted Drug Resistance ◽  
Strand Transfer ◽  
Naive Patient ◽  
Immunodeficiency Virus ◽  
Integrase Strand Transfer Inhibitors ◽  
Treatment Naïve ◽  
Transfer Inhibitor ◽  
Integrase Strand Transfer Inhibitor

Abstract Transmitted drug resistance to the integrase strand transfer inhibitor (INSTI) class of antiretrovirals is very rare. We present a case of a treatment-naive female patient with human immunodeficiency virus harboring resistance to all INSTIs, including bictegravir and dolutegravir.

scholarly journals A systematic review of the genetic mechanisms of dolutegravir resistance

2019 ◽  
Vol 74 (11) ◽  
pp. 3135-3149 ◽  
Author(s):  
Soo-Yon Rhee ◽  
Philip M Grant ◽  
Philip L Tzou ◽  
Geoffrey Barrow ◽  
P Richard Harrigan ◽  
...  
Keyword(s):  
Strand Transfer ◽  
Resistance Mutations ◽  
First Line Therapy ◽  
Highly Effective ◽  
Active Viral Replication ◽  
Drug Regimens ◽  
Genetic Mechanisms ◽  
Transfer Inhibitor ◽  
Integrase Strand Transfer Inhibitor

Abstract Background Characterizing the mutations selected by the integrase strand transfer inhibitor (INSTI) dolutegravir and their effects on susceptibility is essential for identifying viruses less likely to respond to dolutegravir therapy and for monitoring persons with virological failure (VF) on dolutegravir therapy. Methods We systematically reviewed dolutegravir resistance studies to identify mutations emerging under dolutegravir selection pressure, the effect of INSTI resistance mutations on in vitro dolutegravir susceptibility, and the virological efficacy of dolutegravir in antiretroviral-experienced persons. Results and conclusions We analysed 14 studies describing 84 in vitro passage experiments, 26 studies describing 63 persons developing VF plus INSTI resistance mutations on a dolutegravir-containing regimen, 41 studies describing dolutegravir susceptibility results, and 22 clinical trials and 16 cohort studies of dolutegravir-containing regimens. The most common INSTI resistance mutations in persons with VF on a dolutegravir-containing regimen were R263K, G118R, N155H and Q148H/R, with R263K and G118R predominating in previously INSTI-naive persons. R263K reduced dolutegravir susceptibility ∼2-fold. G118R generally reduced dolutegravir susceptibility >5-fold. The highest levels of reduced susceptibility occurred in viruses containing Q148 mutations in combination with G140 and/or E138 mutations. Dolutegravir two-drug regimens were highly effective for first-line therapy and for virologically suppressed persons provided dolutegravir’s companion drug was fully active. Dolutegravir three-drug regimens were highly effective for salvage therapy in INSTI-naive persons provided one or more of dolutegravir’s companion drugs was fully active. However, dolutegravir monotherapy in virologically suppressed persons and functional dolutegravir monotherapy in persons with active viral replication were associated with a non-trivial risk of VF plus INSTI resistance mutations.

scholarly journals Cost-Efficacy of Antiretroviral Regimens Recommended in Treatment-Naive HIV-Infected Adults. A Single Center Experience

Processes ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 956
Author(s):  
Raluca Jipa ◽  
Iulia Nedelcu ◽  
Eliza Manea ◽  
Anca Damalan ◽  
Adriana Hristea
Keyword(s):  
Similar Efficacy ◽  
Strand Transfer ◽  
Software Application ◽  
Single Center Experience ◽  
Combined Antiretroviral Therapy ◽  
Treatment Naïve ◽  
Cost Efficacy ◽  
Transfer Inhibitor ◽  
The Cost ◽  
Integrase Strand Transfer Inhibitor

We aimed to assess the prescription trends of combined antiretroviral therapy (cART) in one infectious diseases department and the cost-efficacy (C/E) of different regimens used in treatment-naïve patients. The C/E was assessed with a software application developed by a group of researchers in Spain. The efficacy was already calculated in the application. The costs included the local cost of antiretrovirals and other direct costs specific to our institution. In the software application, the C/E reference regimen was ABC/3TC/DTG. In total, 181 HIV-infected patients were diagnosed and initiated cART during 2015–2019. The proportion of patients treated with integrase-strand transfer inhibitor (INSTI)-based regimens increased from 2015–2018 (54%) to the end of 2019 (81%). The relative C/E ranged from 0.90 to 1.28 for the evaluated INSTI-based regimens. Among INSTI-based regimens, ABC/3TC/DTG and TAF/FTC/EVG/c are the regimens with similar efficacy and relative C/E.

scholarly journals E157Q integrase strand-transfer inhibitor substitution in patients with acute/recent HIV infection

AIDS ◽  
2019 ◽  
Vol 33 (10) ◽  
pp. 1613-1617 ◽  
Author(s):  
Juan Ambrosioni ◽  
José Ángel Fernández-Caballero Rico ◽  
David Nicolás ◽  
María Mar Mosquera ◽  
Elisa de Lazzari ◽  
...  
Keyword(s):  
Hiv Infection ◽  
Strand Transfer ◽  
Transfer Inhibitor ◽  
Recent Hiv Infection ◽  
Integrase Strand Transfer Inhibitor

scholarly journals Emergent Resistance to Dolutegravir Among INSTI-Naïve Patients on First-line or Second-line Antiretroviral Therapy: A Review of Published Cases

2020 ◽  
Vol 7 (6) ◽  
Author(s):  
Muge Cevik ◽  
Chloe Orkin ◽  
Paul E Sax
Keyword(s):  
Virological Failure ◽  
Clinical Decision Making ◽  
Clinical Decision ◽  
Poor Adherence ◽  
Clinical Aspects ◽  
Strand Transfer ◽  
Treatment Naïve ◽  
Transfer Inhibitor ◽  
Integrase Strand Transfer Inhibitor

Abstract None of the licensing studies of dolutegravir (DTG) reported any treatment-emergent resistance among DTG-treated individuals, though virological failure in treatment-naïve and treatment-experienced, integrase strand transfer inhibitor (INSTI)–naïve individuals has been reported in clinical practice. While the spectrum of dolutegravir-selected mutations and their effects on clinical outcome have been described, the clinical characteristics of these rare but important virological failure cases are often overlooked. In this perspective piece, we focus on key clinical aspects of emergent resistance to DTG among treatment-naïve and treatment-experienced INSTI-naïve patients, with an aim to inform clinical decision-making. Poor adherence and HIV disease factors contribute to emergent drug resistance, even in regimens with high resistance barriers. Patients with severe immunosuppression or poor adherence are under-represented in licensing studies, and these patients may be at higher risk of treatment failure with DTG resistance, which requires close clinical and laboratory follow-up.

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