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Extended use of raltegravir in the treatment of HIV-1 infection: optimizing therapy.

Charpentier C, Weiss L - Infect Drug Resist (2010)

Bottom Line: Raltegravir is the first licensed compound in 2007 of the new integrase inhibitor drug class.At the dose of 400 mg twice daily, raltegravir showed a potent antiviral action in antiretroviral-naïve patients when associated with tenofovir and emtricitabine.In conclusion, raltegravir improved the clinical management of HIV-1 infection both in antiretroviral-naïve and in antiretroviral-experienced patients.

View Article: PubMed Central - PubMed

Affiliation: Assistance Publique-Hôpitaux de Paris, Hôpital Bichat-Claude Bernard, Laboratoire de Virologie, Université Paris-Diderot, Paris, France;

ABSTRACT
Raltegravir is the first licensed compound in 2007 of the new integrase inhibitor drug class. At the dose of 400 mg twice daily, raltegravir showed a potent antiviral action in antiretroviral-naïve patients when associated with tenofovir and emtricitabine. Raltegravir was also found to be highly active in antiretroviral-experienced patients with virological failure and displaying multiresistant virus, as shown with the BENCHMRK and ANRS 139 TRIO trials. Finally, the use of raltegravir was assessed in the context of a switch strategy in antiretroviral-experienced patients with virological success [human immunodeficiency virus type 1 (HIV-1) RNA below detection limit], highlighting the following mandatory criteria in this strategy: the nucleoside reverse transcriptase inhibitors associated with raltegravir have to be fully active. In the different studies, raltegravir had a favorable safety and tolerability profile. In the clinical situation a switch in virologically suppressed patients receiving a protease inhibitor, an improvement of the lipid profile was observed. Overall, when analyzing the Phase II and III trials together, only a few patients on raltegravir discontinued for adverse events. The development of resistance to raltegravir mainly involved three resistance mutations in integrase gene: Q148H/K/R, N155H, and Y143C/H/R. In conclusion, raltegravir improved the clinical management of HIV-1 infection both in antiretroviral-naïve and in antiretroviral-experienced patients.

No MeSH data available.


Related in: MedlinePlus

Steps of viral integration. Copyright © 2002. Reproduced with permission from NCBI DNA Replication, Repair, and Recombination. In: “Basic Genetic Mechanisms”, Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P, editors. Molecular Biology of the Cell. New York, NY: Garland Science; 2002.
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f1-idr-3-103: Steps of viral integration. Copyright © 2002. Reproduced with permission from NCBI DNA Replication, Repair, and Recombination. In: “Basic Genetic Mechanisms”, Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P, editors. Molecular Biology of the Cell. New York, NY: Garland Science; 2002.

Mentions: The complete viral life cycle requires integration of HIV-1 viral DNA into the host cell genome. It occurs in three steps (Figure 1).5,7,8 The double-stranded DNA copy generated by reverse transcription of the HIV-1 viral RNA genome is a part of the “preintegration complex”, containing both cellular and viral proteins, including integrase. In a first step, termed “3′ processing”, two nucleotides are removed from the 3′ ends of the viral DNA. In a second step, termed “strand transfer”, the proviral DNA is inserted into the host DNA and joined with it. Then, gaps in DNA are repaired by cellular enzymes by removing the two unpaired nucleotides at the 5′ end of the proviral DNA. The HIV integrase catalyses all steps of integration process except the last one, ie, DNA repair and ligation. A large series of selective inhibitors of strand transfer, β-diketo acid derivates, were tried to be developed as orally bioavailable agents.6,9–12 Mechanistic studies showed that L-731,988, a β-diketo acid derivate, recognizes and selectively binds the integrase donor substrate complex exclusively in the context of catalytically active protein assembled on the viral DNA end. Thus, L-731,988 binds within the integraseactive site and inhibits strand transfer by competing with the target DNA substrate.13


Extended use of raltegravir in the treatment of HIV-1 infection: optimizing therapy.

Charpentier C, Weiss L - Infect Drug Resist (2010)

Steps of viral integration. Copyright © 2002. Reproduced with permission from NCBI DNA Replication, Repair, and Recombination. In: “Basic Genetic Mechanisms”, Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P, editors. Molecular Biology of the Cell. New York, NY: Garland Science; 2002.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3108740&req=5

f1-idr-3-103: Steps of viral integration. Copyright © 2002. Reproduced with permission from NCBI DNA Replication, Repair, and Recombination. In: “Basic Genetic Mechanisms”, Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P, editors. Molecular Biology of the Cell. New York, NY: Garland Science; 2002.
Mentions: The complete viral life cycle requires integration of HIV-1 viral DNA into the host cell genome. It occurs in three steps (Figure 1).5,7,8 The double-stranded DNA copy generated by reverse transcription of the HIV-1 viral RNA genome is a part of the “preintegration complex”, containing both cellular and viral proteins, including integrase. In a first step, termed “3′ processing”, two nucleotides are removed from the 3′ ends of the viral DNA. In a second step, termed “strand transfer”, the proviral DNA is inserted into the host DNA and joined with it. Then, gaps in DNA are repaired by cellular enzymes by removing the two unpaired nucleotides at the 5′ end of the proviral DNA. The HIV integrase catalyses all steps of integration process except the last one, ie, DNA repair and ligation. A large series of selective inhibitors of strand transfer, β-diketo acid derivates, were tried to be developed as orally bioavailable agents.6,9–12 Mechanistic studies showed that L-731,988, a β-diketo acid derivate, recognizes and selectively binds the integrase donor substrate complex exclusively in the context of catalytically active protein assembled on the viral DNA end. Thus, L-731,988 binds within the integraseactive site and inhibits strand transfer by competing with the target DNA substrate.13

Bottom Line: Raltegravir is the first licensed compound in 2007 of the new integrase inhibitor drug class.At the dose of 400 mg twice daily, raltegravir showed a potent antiviral action in antiretroviral-naïve patients when associated with tenofovir and emtricitabine.In conclusion, raltegravir improved the clinical management of HIV-1 infection both in antiretroviral-naïve and in antiretroviral-experienced patients.

View Article: PubMed Central - PubMed

Affiliation: Assistance Publique-Hôpitaux de Paris, Hôpital Bichat-Claude Bernard, Laboratoire de Virologie, Université Paris-Diderot, Paris, France;

ABSTRACT
Raltegravir is the first licensed compound in 2007 of the new integrase inhibitor drug class. At the dose of 400 mg twice daily, raltegravir showed a potent antiviral action in antiretroviral-naïve patients when associated with tenofovir and emtricitabine. Raltegravir was also found to be highly active in antiretroviral-experienced patients with virological failure and displaying multiresistant virus, as shown with the BENCHMRK and ANRS 139 TRIO trials. Finally, the use of raltegravir was assessed in the context of a switch strategy in antiretroviral-experienced patients with virological success [human immunodeficiency virus type 1 (HIV-1) RNA below detection limit], highlighting the following mandatory criteria in this strategy: the nucleoside reverse transcriptase inhibitors associated with raltegravir have to be fully active. In the different studies, raltegravir had a favorable safety and tolerability profile. In the clinical situation a switch in virologically suppressed patients receiving a protease inhibitor, an improvement of the lipid profile was observed. Overall, when analyzing the Phase II and III trials together, only a few patients on raltegravir discontinued for adverse events. The development of resistance to raltegravir mainly involved three resistance mutations in integrase gene: Q148H/K/R, N155H, and Y143C/H/R. In conclusion, raltegravir improved the clinical management of HIV-1 infection both in antiretroviral-naïve and in antiretroviral-experienced patients.

No MeSH data available.


Related in: MedlinePlus