Abstract
Drug resistance prevents the successful treatment of HIV-positive individuals by decreasing viral sensitivity to a drug or a class of drugs. In addition to transmitted resistant viruses, treatment-naïve individuals can be confronted with the problem of drug resistance through de novo emergence of such variants. Resistant viruses have been reported for every antiretroviral drug tested so far, including the integrase strand transfer inhibitors raltegravir, elvitegravir and dolutegravir. However, de novo resistant variants against dolutegravir have been found in treatment-experienced but not in treatment-naïve individuals, a characteristic that is unique amongst antiretroviral drugs. We review here the issue of drug resistance against integrase strand transfer inhibitors as well as both pre-clinical and clinical studies that have led to the identification of the R263K mutation in integrase as a signature resistance substitution for dolutegravir. We also discuss how the topic of drug resistance against integrase strand transfer inhibitors may have relevance in regard to the nature of the HIV reservoir and possible HIV curative strategies.
Highlights
The rapid emergence of HIV drug resistance was first observed in individuals treated with a singleThe rapid molecule emergence of HIV drugandresistance first observedof inhighly individuals treated with antiretroviral led to thewas implementation active antiretroviral a single(HAART)antiretroviral molecule combines and led to drugs the implementation active therapy that classically three antiretroviral for the treatmentofof highlyHIV-positive antiretroviral[1]. therapy (HAART)that the classically combines three antiretroviral drugs for the treatment of individualsHAART precludes emergence of drug resistance in most individuals.HIV-positiveHAART who precludes the emergence drug resistance in mostcan individuals.viral strains individuals from some [1].individuals are not successfullyoftreated with HAART develop
These inhibitors include raltegravir (RAL), elvitegravir (EVG) and dolutegravir (DTG), each of which has been shown to be well-tolerated with relatively few side effects: this is perhaps due to the fact that there is no human enzyme that is functionally homologous to HIV integrase, in contrast to reverse transcriptase (RT) and PR
N155H resistance mutation in integrase was found, in the absence of any mutation in PR [21]. This observation is in agreement with the fact that DRV possesses a higher genetic barrier for resistance than nucleos(t)ides RT inhibitors (NRTIs) that were used in the Protocol 004 and NEAT studies
Summary
The rapid molecule emergence of HIV drugandresistance first observedof inhighly individuals treated with antiretroviral (monotherapy) led to thewas implementation active antiretroviral a single(HAART). The most recent antiretroviral drugs to have been approved for therapy are integrase strand transfer inhibitors (INSTIs) These inhibitors include raltegravir (RAL), elvitegravir (EVG) and dolutegravir (DTG), each of which has been shown to be well-tolerated with relatively few side effects: this is perhaps due to the fact that there is no human enzyme that is functionally homologous to HIV integrase, in contrast to RT and PR. In addition to their low toxicity, INSTI-based antiretroviral regimens are highly efficacious at suppression of HIV replication in vivo and are recommended for initiation of HIV therapy in adults [5,6,7,8,9]. The object of the current review is to discuss the emergence of HIV resistant viruses in individuals treated with INSTIs and how data obtained with DTG may relate to HIV reservoirs and the potential to achieve viral eradication
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