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CAPITULO 01.Indd DRUG RESISTANCE: 1. DEFINITIONS AND CONCEPTS • José Ramón Santos • Marc Noguera-Julian • Maria Casadellà • Josep Maria Llibre • Bonaventura Clotet • Roger Paredes 1.1. INTRODUCTION Definition Antiretroviral drug resistance is the ability of HIV to replicate in the presence of antiretroviral drug concentrations that suppress viral replication of non-resistant virus. Most antiretroviral drugs are competitive inhibitors, i.e. they inhibit a viral enzyme (protease, PR; reverse transcriptase, RT; integrase, IN) by competing with its natural substrate for attachment to the enzyme’s catalytic site. Resistance to competitive inhibitors is a function of viral susceptibility and the drug levels achieved in the target cells. Higher drug levels can suppress partially resistant viruses, with resistance occurring in a continuum. Viral susceptibility to competitive inhibitors is expressed as the drug concentration able to inhibit virus growth in vitro to 50% (50% inhibitory concentration, 1 IC50) or 90% (IC90), relative to a wildtype reference virus. The small-molecule CCR5 antagonists, are allosteric inhibitors of the human CCR5 transmembrane protein, one of the two co-receptors required for HIV entry into target cells. Due to their allosteric inhibition, decrease in viral susceptibility to CCR5 antagonists is reflected by progressive decreases in the percent of maximal inhibition rather than by shifts in IC50. Further increases in drug concentrations once drug resistance is established do not achieve further virological suppression. Pathogenesis HIV has a quasispecies distribution.1 Soon after infection with a relatively homogeneous viral population, viral replication ensues at an extraordinary rate: 109-12 new virions are generated every day. Because HIV’s RT lacks proofreading ability, 10-3 to 10-4 mutations (one or two per genome) are spontaneously generated per replication cycle.2, 3 Given HIV’s high replication rate, any single mutant and some dual mutants could be generated per day. Most mutations are deleterious and drive mutant viruses to extinction. Others, have neutral or beneficial effects on HIV’s replicative capacity and remain incorporated in the quasispecies. Variants in the virus quasispecies may have different fitness in different environments.4 The variant with better ability to replicate in the absence of therapy, the wildtype (WT) variant, predominates before therapy initiation. Mutants with a fitness advantage in the presence of therapy remain at very low levels in the absence of treatment. However, they can outcompete the WT within days after therapy initiation if viral replication is not averted. Secondary mutations often accumulate in the presence of continued viral replication; they compensate the potential fitness losses derived from primary resistance mutations and increase cross-class resistance. 1 ❖ Factors involved in the emergence and evolution of drug-resistance • Rapid turnover of HIV-1 (half-life free virus <2 hours). • Large amounts of daily virus production (1010) • High error rate of the reverse transcriptase (RT) (~1:104). • Recombination (1 recombination event per every 3-8 mutations) • Incomplete suppression of viral replication in subjects under therapy (suboptimal therapies, low adherence, malabsorption, etc…). • Genetic barrier of antiretroviral agents contained in a regimen. • Magnitude of resistance conferred by mutations • Viral Fitness • Interaction between resistance mutations and pathways • Adherence in the context of different treatments Risk of resistance by antiviral activity of therapy The likelihood of developing antiretroviral resistance depends on the relative potency of the antiretroviral regimen and the degree of ongoing replication in the presence of therapy.5,6,7 (Figure 1) A regimen with small antiviral potency creates minimal selective pressure on the virus and leads to slow resistance evolution, even if replication persists. A more potent regimen that is unable to suppress viral replication leads to increased selective pressure over the virus, which rapidly accumulates resistance. Finally, a highly potent regimen that decreases viral replication to minimal levels is associated with slow resistance accumulation, despite the potent selective pressure exerted on the virus. Figure 1. Relation between antiviral drug activity and emergence of resistance. ✕ 2 ❖ Adherence and antiretroviral resistance • Each antiretroviral therapeutic class has a unique adherence-resistance relationship (Figure 2)8. • NNRTI-treated individuals rarely develop resistance at high levels of adherence due to the virological effectiveness of these regimens. NNRTI resistance develops rapidly at moderate to low levels of resistance due to the low ‘fitness’ costs associated with single mutations. • Unboosted PI-treated individuals may develop resistance at high levels of adherence because residual viral replication is often seen in such patients. PI resistance is uncommon at low levels of adherence because of the significant fitness costs associated with these mutations. • Resistance to a ritonavir-boosted PI is only possible in a narrow range of adherence where there is sufficient drug around to present for mutations that reduce fitness while still allowing residual viral replication. 6 Figure 2. Relationship between medication adherence and the risk of developing PI or NNRTI drug resistance.8 Cross-resistance, hypersusceptibility and replication capacity Given the molecular structure similarities within compounds of the same antiretroviral family and their interaction with similar target sites, the emergence of resistance to one drug may extend to the other drugs of the same family. On the other hand, some mutations conferring high-level resistance to one agent may increase viral susceptibility to another compound, resulting in a so-called “hypersusceptible” virus to the second agent. 3 In addition, resistance-conferring mutations may decrease replication capacity in com- parison with the WT virus. The clinical correlates of replication capacity measurements, however, remain unclear. Minority drug-resistant variants Resistant HIV can be transmitted from person-to-person. In addition, the high turnover and production of genetic variants ensure that every possible variant containing one resistance mutation and many variants with two resistance mutations can be spontaneously generated in treatment-naïve individuals. Resistant variants present at a frequency of less than 15-20% of the viral population unlikely to be detected by standard drug resistance assays. Several studies suggest that pre-existing minority NNRTI-resistant variants increase the risk of virological failure to first-line NNRTI-including regimens 3 to 6-fold.9-11 In addition, its detection by means of ultrasensitive HIV-1 genotyping tests has demonstrated to be a useful tool to improve the GSS-based prediction of virological response in treatment-experienced patients.12 Studies are ongoing to establish clinically meaningful thresholds that discriminate outcomes with high sensitivity and specificity. The clinical role of minority resistant variants in antiretroviral regimens with higher genetic barrier is also under evaluation. ❖ Two major mechanisms are involved in HIV resistance to NRTI and NNRTI: 1) impairment of the incorporation of the analogue into DNA and 2) removal of the prematurely terminated DNA chain.13, 14 • Steric exclusion of the analogue incorporation: Mutations M184V, K65R and the Q151M complex promote resistance by selectively impairing the ability of reverse transcriptase to incorporate an analogue into DNA. • Removal of the analogue from the terminated DNA chain: This mechanism is associated with the thymidine analogue mutations. TAMs induce removal of the nucleoside analogue from the 3’ end of the terminated DNA chain. This process involves an ATP- or pyrophosphate-mediated attack to the phosphodiester bond linking the nucleoside analogue to the DNA chain. Entry of ATP and pyrophosphate, a by- product of DNA polymerization, is facilitated by the structure of a reverse transcriptase expressing TAMs. However, such entry is significantly decreased in the presence of the M184V mutation, what explains the difficulty for TAMs to emerge in the presence of M184V. 4 ❖ Implications of drug resistance • Loss of treatment efficacy • Increase in complexity and decrease in tolerability of therapy • Increased risk of virological failure to subsequent ART • Increased cost of HIV management • Increase in susceptibility to some drugs • Some authors have suggested increased mortality, but that is uncertain ❖ Drug resistance can be inferred from genotypic or phenotypic assays. • Genotypic resistance: presence of mutations in the HIV genome, which are known to be associated with phenotypic resistance to one or more drugs. • Phenotypic resistance: Increased ability of a virus to replicate in the presence of drugs, relative to a wild type reference strain. ❖ There are two ways of measuring drug resistance: Genotypic testing: Comparison of the genomic nucleotide composition of a patient’s virus with that of a wild-type reference strain. Mutations are coded as: “wildtype aminoacid” -gene codon where the mutation occurs – “mutant aminoacid”. 5 Phenotypic testing: Assessment of the susceptibility of a virus to antiretroviral drugs in a virus replication assay. Results can be expressed as: * Competitive inhibitors IC50, IC90, IC95: Concentration (in µ g/ml or µ M) of drug needed to inhibit the virus growth in vitro by 50%, 90% or 95%, respectively.
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