Abstract
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.
Highlights
Since the beginning of the pandemic, HIV/AIDS has claimed the lives of over 35 million people, and approximately 35 million individuals are currently infected [1]
For the first-generation Integrase strand transfer inhibitors (INSTIs) RAL and EVG, the resistance pathways that were selected in vitro were generally predictive of the mutations that would arise in patients failing therapy with these drugs, the frequencies of primary and/or secondary mutations selected may vary depending on whether in vitro or in vivo results are considered
Since CAB has selected for the Q148 pathway in vivo, it is possible that the clinical resistance profile of this INSTI will resemble that of the first-generation INSTIs
Summary
Since the beginning of the pandemic, HIV/AIDS has claimed the lives of over 35 million people, and approximately 35 million individuals are currently infected [1].
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