In this article, we will discuss HIV-1 Drug Resistance (Mechanism). So, let’s get started.
HIV-1 Drug Resistance (Mechanism)
Mechanisms of HIV-1 drug resistance
HIV-1 genetic variability results from the high rate of HIV-1 reverse transcriptase (RT) processing errors, recombination when more than one viral variants infect the same cell, and the accumulation of proviral variants during the course of infection (Abram et al., 2010; Coffin, 1995: Levy et al., 2004; Mansky, 1996). Although most HIV-1 infections are initiated by a single viral variant (Keele et al., 2008), innumerable variants (or quasispecies) related to the initial transmitted virus emerge within weeks following infection (Coffin, 1995: Perelson and Ribeiro,
The selection of drug-resistant variants depends on the extent to which viral replication continues during incompletely suppressive therapy, the ease of acquisition of a particular drug resistance mutation (DRM), and the effect of DRMs on drug susceptibility and virus replica-
tion. Although naturally occurring drug-resistant viruses arise every day
in untreated patients (Perelson and Ribeiro, 2013), these variants rarely
rise to detectable levels because they are less fit than drug-susceptible viruses in the absence of selective drug pressure. Indeed, nearly all clinically significant DRMs arise only as a result of selective drug pressure band are otherwise non-polymorphic.
For some ARVs, multiple DRMs are required to reduce susceptibility.
while for others a single DRM is sufficient. The number of DRMs required and the effect of each DRM on virus fitness contribute to the ARV’s genetic barrier to resistance. DRMs can be categorized as primary DRMs that directly reduce drug susceptibility and accessory DRMs that enhance fitness of variants containing primary DRMs or that contribute further reductions in susceptibility. The extent to which an ARV reduces plasma HIV-1 RNA levels is known as its antiviral potency. An ARV’s intrinsic antiviral potency combined with its genetic barrier to resistance influences its ability to protect an ART regimen from VF (Fig 1.0).
There is essentially no cross-resistance between drug classes. Viruses that are highly-resistant to drugs in one ARV class are completely susceptible to ARVs from unused classes (Larder, 1994). In contrast,
significant cross-resistance within a drug class is common because most DRMs reduce susceptibility to multiple ARVs of the same class (Melikian et al., 2012; Melikian et al., 2014; Rhee et al., 2010; Tang and Shafer, 2012; Whitcomb et al., 2003). However, there are important exceptions in that several DRMs increase susceptibility to other ARVs of the same class (Whitcomb et al., 2002). Knowledge of ARV cross-resistance profiles is therefore essential when using more than one drug from the same ARV class either in combination or in sequence.
Most ART regimens used for first-line therapy are sufficiently potent to completely block HIV-1 replication and have a genetic barrier to resistance high enough to maintain long-term virological suppression. As a result, most cases of VF and drug-resistance arise from incomplete
adherence, which exposes a patient’s virus to the incompletely suppressive ARV levels capable of exerting drug selective pressure. Accordingly, HIVDR appears to be less common in patients receiving FDCs containing ARVs that have similar half-lives because incomplete adherence to these combinations is less likely to expose a virus to selective drug pressure (Chi et al., 2007: Geretti et al. 2013: Panel on Antiretroviral Guidelines for Adults and Adolescents, 2016). Lower rates of HIVDR have also been associated with routine viral load monitoring programs in which early detection of virological rebound provides the opportunity for adherence counseling or regimen modification as necessary, prior to the evolution of multiple DRMs (Charest et al., 2014: Gupta et al., 2009: Tenores Study. 2016).