Abstract
The use of highly active antiretroviral therapy (HAART) involves combinations of drugs to achieve maximal virological response and reduce the potential for the emergence of antiviral resistance. There are two broad classes of reverse transcriptase inhibitors, the nucleoside reverse transcriptase inhibitors (NRTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs). Since the first classes of such compounds were developed, viral resistance against them has necessitated the continuous development of novel compounds within each class. This paper considers the NRTIs and NNRTIs currently in both preclinical and clinical development or approved for second line therapy and describes the patterns of resistance associated with their use, as well as the underlying mechanisms that have been described. Due to reasons of both affordability and availability, some reverse transcriptase inhibitors with low genetic barrier are more commonly used in resource-limited settings. Their use results to the emergence of specific patterns of antiviral resistance and so may require specific actions to preserve therapeutic options for patients in such settings. More recently, the advent of integrase strand transfer inhibitors represents another major step forward toward control of HIV infection, but these compounds are also susceptible to problems of HIV drug resistance.
Highlights
Infection by the human immunode ciency virus (HIV) is a major problem and the treatment for this condition is commonly referred to as highly active antiretroviral therapy (HAART). e latter consists of three or more HIV drugs, most commonly two nucleoside reverse transcriptase inhibitors (NRTIs) in combination with either a nonnucleoside reverse transcriptase inhibitor (NNRTI), a protease inhibitor (PI) or, more recently, an integrase inhibitor (INI) [1]. e goal of HAART is to optimally suppress HIV replication during long-term therapy and to maintain immune function [2]
Other in vitro EVG selections resulted in several high resistance mutations that have yet to be clinically validated such as P145S, Q146P, and V151A/L [139]. e V151L mutation confers ≈8-fold cross-resistance to RAL and has been identi ed in a single patient treated with this drug [142]. e use of EVG has recently been approved by the Food and Drug Administration of the US as part of a coformulation that includes FTC, TDF, and a pharmalogic enhancer of EVG termed cobicistat
Alternative strategies that target integration but that are not based on the catalytic triad, Scienti ca for example, allosteric integrase inhibitors (ALLINIs), are promising and such compounds retain full activity against viruses that are resistant to INSTIs
Summary
Infection by the human immunode ciency virus (HIV) is a major problem and the treatment for this condition is commonly referred to as highly active antiretroviral therapy (HAART). e latter consists of three or more HIV drugs, most commonly two nucleoside reverse transcriptase inhibitors (NRTIs) in combination with either a nonnucleoside reverse transcriptase inhibitor (NNRTI), a protease inhibitor (PI) or, more recently, an integrase inhibitor (INI) [1]. e goal of HAART is to optimally suppress HIV replication during long-term therapy and to maintain immune function [2]. Ese mutations are located on the genes that encode antiretroviral targets such as RT, resulting in the production of RT that is different than its wild-type (wt) counterpart in both structure and function This protein is still able to play its role in HIV replication, it is not inhibited as effectively as wt protein by the antiretroviral (ARV) compounds. E prevalence rate of transmitted antiretroviral drug resistance in treatment-naïve patients with HIV-1 has been estimated to be 5–15% for resistance mutations to at least one antiretroviral class [23]. In this US drug resistance survey, the NNRTI class showed the highest prevalence at a rate of 6.9% compared to NRTIs and PIs at 3.6% and 2.4%, respectively. Some resistance mutations can affect the binding of NNRTIs through several mechanisms [25]
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