HIV drug resistance against strand transfer integrase inhibitors
| Autor: | Thibault Mesplède, Kaitlin Anstett, Mark A. Wainberg, Bluma G. Brenner |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
lcsh:Immunologic diseases. Allergy
0301 basic medicine INSTIs Anti-HIV Agents Resistance 030106 microbiology Integrase inhibitor HIV Infections HIV Integrase Review Pharmacology Elvitegravir 03 medical and health sciences chemistry.chemical_compound Cabotegravir Virology Drug Resistance Viral medicine Humans HIV Integrase Inhibitors Selection Genetic Clinic biology Bictegravir HIV Raltegravir 3. Good health Integrase Enzyme Activation Infectious Diseases Selections chemistry Dolutegravir Mutation HIV-1 biology.protein lcsh:RC581-607 HIV drug resistance medicine.drug |
| Zdroj: | Retrovirology Retrovirology, Vol 14, Iss 1, Pp 1-16 (2017) |
| ISSN: | 1742-4690 |
| Popis: | Integrase strand transfer inhibitors (INSTIs) are the newest class of antiretroviral drugs to be approved for treatment and act by inhibiting the essential HIV protein integrase from inserting the viral DNA genome into the host cell’s chromatin. Three drugs of this class are currently approved for use in HIV-positive individuals: raltegravir (RAL), elvitegravir (EVG), and dolutegravir (DTG), while cabotegravir (CAB) and bictegravir (BIC) are currently in clinical trials. RAL and EVG have been successful in clinical settings but have relatively low genetic barriers to resistance. Furthermore, they share a high degree of cross-resistance, which necessitated the development of so-called second-generation drugs of this class (DTG, CAB, and BIC) that could retain activity against these resistant variants. In vitro selection experiments have been instrumental to the clinical development of INSTIs, however they cannot completely recapitulate the situation in an HIV-positive individual. This review summarizes and compares all the currently available information as it pertains to both in vitro and in vivo selections with all five INSTIs, and the measured fold-changes in resistance of resistant variants in in vitro assays. While the selection of resistance substitutions in response to RAL and EVG bears high similarity in patients as compared to laboratory studies, there is less concurrence regarding the “second-generation” drugs of this class. This highlights the unpredictability of HIV resistance to these inhibitors, which is of concern as CAB and BIC proceed in their clinical development. |
| Databáze: | OpenAIRE |
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