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Genotypic Testing for HIV-1 Drug Resistance
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Rationale for HIV-1 Drug Resistance Testing
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Evolution of HIV-1 Drug Resistance
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Identifying and Characterizing Drug Resistance Mutations
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transparent imageDefinition of Antiviral Drug Resistance
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transparent imageDrug Susceptibility Testing
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transparent imageCharacterizing Drug Resistance Mutations
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transparent imageConventions for Describing Drug Resistance Mutations
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transparent imageReproducibility of Genotypic Testing by Dideoxynucleoside Sequencing
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Protease Inhibitor (PI) Resistance
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transparent imageHIV-1 Protease
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transparent imageProtease Inhibitors (PIs)
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transparent imageProtease Substrate Cleft Mutations
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transparent imageProtease Flap Mutations
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transparent imageProtease Mutations at Other Conserved Residues
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transparent imagePolymorphic Sites Contributing to Resistance
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transparent imageAdditional Treatment-Associated Mutations
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transparent imagePI Cross-Resistance Patterns and Salvage Therapy
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transparent imageInvestigational PIs
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Nucleoside/Nucleotide RT Inhibitor (NRTI) Resistance
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transparent imageHIV-1 RT
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transparent imageNRTIs
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transparent imageMechanisms of NRTI Resistance
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transparent imageMutations at Positions 41, 67, 70, 210, 215, and 219 ("TAMs")
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transparent imageM184V
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transparent imageMutations at Positions 65, 69, 74, and 75
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transparent imageMultinucleoside Resistance Due to Q151M
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transparent imageOther NRTI Resistance Mutations
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transparent imageNRTI Cross-Resistance Patterns
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Nonnucleoside RT Inhibitor (NNRTI) Resistance Mutations
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transparent imageNNRTIs
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transparent imageNNRTI Mutations Between Codons 98 and 108
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transparent imageNNRTI Mutations Between Codons 179 and 190
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transparent imageNNRTI Mutations Between Codons 225 and 238
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transparent imageOther NNRTI Resistance Mutations
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transparent imageNNRTI Cross-Resistance
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transparent imageNNRTI and NRTI Mutation Interactions
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transparent imageInvestigational NNRTIs
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HIV-1 Fusion Inhibitors
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Intersubtype Variability
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Interpretation of Genotypic Resistance Tests
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transparent imageRules-Based Algorithms
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transparent imageMachine-Learning Algorithms
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transparent imageInteralgorithm Comparisons and Algorithm Validation
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Genotype-Phenotype Discordances
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transparent imageHIV-1 Mixtures
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transparent imageTransitional Mutations
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transparent imageAntagonistic Mutations
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transparent imageThymidine Analog Mutations
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transparent imageAtypical Mutations
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transparent imageNew Drugs and Complex Patterns of Mutations
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Limitations of Drug Resistance Testing
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transparent imageComplex Relationship Between Drug Resistance and Clinical Progression
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transparent imageArchived Drug-Resistant Variants of HIV-1
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transparent imageCross-Resistance
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Acknowledgements
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References
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Tables
Table 1.Expert Panel Recommendations on HIV Drug Resistance Testing
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Table 2.Sources of Knowledge on HIV Drug Resistance Mutations
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Table 3.Correlations Between HIV-1 Protease Inhibitor (PI) Resistance Mutations and Response to a New PI-Containing Regimen
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Table 4.Discordance Between In Vitro and In Vivo Potency of Nucleoside RT Inhibitors
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Table 5.Drug Susceptibility Data on Isolates with Common Combinations of Thymidine Analog Mutations
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Table 6.Correlations Between HIV-1 NRTI Resistance Mutations and Response to a Treatment Regimen
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Table 7.Common Causes of Discordance Between Genotypic and Phenotypic Test Results
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Figures
Figure 1.Structural Model of HIV-1 Protease Homodimer Labeled with Protease Inhibitor Resistance Mutations
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Figure 2.Schematic Representation of How the Protease Recognizes Nine Cleavage Sites to Create the Structural Proteins from the gag Gene and Enzymes from the pol Gene
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Figure 3.Protease Inhibitors (PIs) and PI-Resistance Mutations
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Figure 4.Structural Model of HIV-1 Reverse Transcriptase (RT) Labeled with Nucleoside RT Inhibitor (NRTI) Resistance Mutations
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Figure 5.Nucleoside and Nucleotide RT Inhibitors (NRTIs) and NRTI Resistance Mutations
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Figure 6.A Model for Interactions Between HIV-1 RT and the Chain-Terminated Primer/Template
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Figure 7.Structural Model of HIV-1 Reverse Transcriptase (RT) Labeled with Non-Nucleoside RT Inhibitor (NNRTI) Resistance Mutations
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Figure 8.Non-Nucleoside RT Inhibitors (NNRTIs) and NNRTI Resistance Mutations
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Figure 9.Nature of Discordances Between Four HIV Genotypic Resistance Interpretation Algorithms According to Drug
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Rationale for HIV-1 Drug Resistance Testing
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Nineteen antiretroviral drugs have been approved for the treatment of HIV-1 infection: one nucleotide and seven nucleoside reverse transcriptase inhibitors (NRTIs), seven protease inhibitors (PIs), three nonnucleoside RT inhibitors (NNRTIs), and one fusion inhibitor. In previously untreated individuals with drug-susceptible HIV-1 strains, combinations of three or more drugs from two drug classes can lead to prolonged virus suppression and immunologic reconstitution.

Even where effective antiretroviral therapy (ART) is available, drug resistance remains a crucial issue. First, tens of thousands of individuals who began therapy in the early and mid-1990s already harbor multidrug-resistant viruses. Second, a significant proportion of new HIV infections result from the transmission of strains that are already resistant to one or more antiretroviral drugs. Third, as the epidemic continues to grow worldwide, increasing numbers of individuals are being treated. The margin of success for achieving and maintaining virus suppression is narrow. Extraordinary patient effort is required to adhere to drug regimens that are expensive, inconvenient, and often associated with dose-limiting side effects. Incomplete virus suppression due to these factors predisposes to the development of drug resistance, which threatens the success of future treatment regimens.

The presence of drug-resistant virus before starting a new drug regimen is an independent predictor of virologic response to that regimen.(1-4) Several prospective controlled studies have also shown that patients whose physicians have access to drug resistance data, particularly genotypic resistance data, respond better to therapy than control patients whose physicians do not have access to these assays.(5-11) The accumulation of such retrospective and prospective data has led several expert panels to recommend the use of resistance testing in the treatment of HIV-1-infected patients.(12-15) (Table 1). The purpose of this review is to summarize the genetic basis of HIV-1 drug resistance and the implications of genotypic resistance data for choosing antiretroviral therapies.

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Evolution of HIV-1 Drug Resistance
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The evolution of HIV-1 drug resistance within an individual depends on the generation of genetic variation in the virus and on the selection of drug-resistant variants during therapy. HIV-1 genetic variability is a result of the inability of HIV-1 reverse transcriptase (RT) to proofread nucleotide sequences during replication.(16) This variability is compounded by the high rate of HIV-1 replication, the accumulation of archived proviral variants during the course of HIV-1 infection, and genetic recombination when viruses of different sequence infect the same cell. As a result, innumerable genetically distinct variants (quasispecies) evolve within an individual in the months following primary infection.(17)

Development of drug resistance depends on the extent to which virus replication continues during drug therapy, the ease of acquisition of a particular mutation (or set of mutations), and the effect of drug resistance mutations on drug susceptibility and viral fitness. Some mutations selected during drug therapy confer measurable phenotypic resistance by themselves, whereas other mutations compensate for the diminished replicative activity that can be associated with drug resistance or cause resistance only when present in combination with other mutations.

It is estimated that every possible single point mutation occurs between 104 and 105 times per day in an untreated HIV-1-infected individual and that double mutants also occur commonly.(17) Therefore, most drug resistance mutations are probably present prior to the start of therapy. However, viruses containing sufficient drug resistance mutations to replicate in the presence of multiple drugs do not appear to exist in previously untreated persons infected with wild-type viruses. Indeed, once potent HIV-1 suppression is achieved in previously untreated persons, it usually persists indefinitely if therapy is not interrupted.(18)

Resistant virus strains can also be transmitted between individuals. In the United States and Europe about 10 to 20% of new infections are with HIV-1 strains harboring resistance to at least one of three classes of antiretroviral drugs.(19-35) These studies show a gradual increase in resistance to PIs and NNRTIs and a gradual increase in isolates with resistance to drugs in more than one drug class. In persons found to be newly diagnosed with HIV-1 in whom the year of infection is not known, rates of resistance are lower but still clinically significant, ranging between 5 and 10%.(32,33,35-37)

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Identifying and Characterizing Drug Resistance Mutations
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Definition of Antiviral Drug Resistance
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Antiviral drug resistance is defined by the presence of viral mutations that reduce drug susceptibility compared with the susceptibility of wild-type viruses. Antiviral resistance can be mediated either by changes in the molecular target of therapy (the primary mechanism observed in HIV-1) or in other viral proteins that indirectly interfere with a drug,s activity. HIV-1 drug resistance should be distinguished from other causes of drug failure such as nonadherence, insufficient drug levels, and drug regimens with intrinsically weak antiviral activity.

The terms "drug resistance" and "reduced drug susceptibility" have similar meanings, provided that each term is viewed as representing a continuum between susceptible and highly resistant. Because antiretroviral drugs differ in their potencies, reductions in susceptibility must be related to the activity of the drug against wild-type viruses. Pre-existing resistant variants are often present in a small subset of wild-type virus populations. Although many group O isolates are intrinsically resistant to NNRTIs, naturally occurring resistance in group M HIV-1 is uncommon for currently approved antiretroviral drugs.

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Drug Susceptibility Testing
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Drug susceptibility testing involves culturing a fixed inoculum of HIV-1 in the presence of serial dilutions of an inhibitory drug. The concentrations of drug required to inhibit virus replication by 50% (IC50) or 90% (IC90) are the most commonly used measures of drug susceptibility. Drug susceptibility results depend on the inoculum size of virus tested, the cells used for virus replication, and the means of assessing virus replication. Drug susceptibility assays are not designed to determine the exact amount of drug required to inhibit virus replication in vivo but rather to identify differences in the drug concentration required to inhibit a fixed inoculum of a virus relative to the concentrations required to inhibit wild-type viruses. Virus susceptibility to a drug can be characterized by the range in susceptibility obtained testing wild-type virus isolates (wild-type susceptibility range) and the range in susceptibility obtained testing resistant virus isolates (dynamic susceptibility range).

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Characterizing Drug Resistance Mutations
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Drug-resistant viruses are often first identified by in vitro passage experiments in which HIV-1 isolates are cultured in the presence of increasing concentrations of an antiviral compound. Isolates identified in this manner are sequenced to identify genetic changes arising during selective drug pressure and tested for drug susceptibility to confirm the development of resistance. In some cases, the specific mutations observed during in vitro passage experiments are placed in a wild-type HIV-1 construct to confirm their role in causing drug resistance and to quantify their effect.

However, the spectrum of mutations developing during in vitro passage experiments is narrower than the spectrum of mutations developing in virus isolates from treated patients, especially those receiving drugs in combination or in sequence. Therefore, mutations should also be linked to drug resistance by showing that they are selected in persons receiving an antiretroviral drug, that they reduce drug susceptibility in clinical isolates, or that they interfere with the virologic response to a new drug treatment (Table 2).

HIV-1 isolates from persons experiencing virologic failure provide insight into which mutations the virus uses to escape from drug suppression in vivo and are particularly important for elucidating the genetic mechanisms of resistance to drugs that are difficult to test in vitro. Drug susceptibility results quantify the impact of a mutation or combination of mutations in vitro. Finally, correlations between genotype and virologic response to a new regimen are essential for demonstrating the clinical significance of drug resistance mutations. Many drug resistance mutations compromise enzymatic function. Although the fitness of these variants can be tested in vitro, such tests cannot distinguish defects for which other genetic changes in the virus may readily compensate from defects that may be more crippling. How a mutant virus responds to a new drug regimen in vivo therefore provides the most meaningful test of virus fitness.

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Conventions for Describing Drug Resistance Mutations
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There is a standard numbering system for HIV-1 protease and RT based on their amino acid sequences. The most commonly used wild-type reference sequence is the subtype B consensus sequence. This sequence was originally derived from alignments in the HIV Sequence Database at Los Alamos National Laboratory (38) and can also be found on the HIV RT and Protease Sequence Database (39) Mutations are typically described using a shorthand notation in which a letter indicating the consensus B wild-type amino acid is followed by the amino acid residue number, followed by a letter indicating the mutation (eg, T215Y). If there is a mixture of more than one amino acid at a position, the components of the mixture are written after the position, often separated by a slash (eg, K103K/N denotes that the sequence has a mixture of the wild-type residue lysine (K) and the mutant residue asparagine (N) at position 103).

Because so many mutations in both the protease and RT have been associated with drug resistance, it has become customary to label some drug resistance mutations as either "primary" or "major" and other mutations as "secondary" or "minor". Primary mutations are those that reduce drug susceptibility by themselves whereas secondary mutations reduce drug susceptibility in combination with primary mutations or improve the replicative fitness of virus isolates with a primary mutation. However, which mutations are considered primary and which are considered secondary are not strictly defined and some mutations might be considered to be primary for one drug but secondary for another drug.

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Reproducibility of Genotypic Testing by Dideoxynucleoside Sequencing
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The results of genotypic sequencing have become highly reproducible. In a study in which two laboratories compared the reproducibility of RT and protease sequencing using cryopreserved plasma aliquots from 46 heavily treated HIV-1-infected persons, the rates of complete sequence concordance between the two laboratories was 99.1%.(40) Approximately 90% of the discordances were partial, defined as one laboratory detecting a mixture and the second laboratory detecting only one of the mixture,s components. Therefore, only 0.1% of the nucleotides were discordant and these were significantly more likely to occur in plasma samples with lower plasma HIV-1 RNA levels. In every case in which one laboratory detected a mixture, the second laboratory detected the same mixture or detected one of the mixture,s components. The high rate of concordance in detecting mixtures and the fact that most discordances were partial suggest that most discordances were caused by variation in sampling of the HIV-1 quasispecies, rather than by sequencing errors.

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Protease Inhibitor (PI) Resistance
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HIV-1 Protease
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The HIV-1 protease enzyme is responsible for the post-translational processing of the viral Gag and Gag-Pol polyproteins to yield the structural proteins and enzymes of the virus. The enzyme is an aspartic protease composed of two noncovalently associated, structurally identical monomers 99 amino acids in length (Figure 1). Its active site resembles that of other aspartic proteases and contains the conserved triad, Asp-Thr-Gly, at positions 25-27. The hydrophobic substrate cleft recognizes and cleaves nine different peptide sequences to produce the matrix, capsid, nucleocapsid, and p6 proteins from the Gag polyprotein and the protease, RT, and integrase proteins from the Gag-Pol polyprotein (Figure 2). The enzyme contains a flexible flap region that closes down on the active site upon substrate binding.

The three-dimensional structures of wild-type HIV-1 protease and several drug-resistant mutant forms bound to various inhibitors (41-46) and to the enzymes, natural polypeptide substrates (47) have been determined by crystallography. Mutations in the substrate cleft cause resistance by reducing the binding affinity between the inhibitor and the mutant protease enzyme. Mutations elsewhere in the enzyme either compensate for the decreased kinetics of enzymes with active site mutations or also cause resistance by altering enzyme catalysis, dimer stability, inhibitor binding kinetics, or by re-shaping the active site through long-range structural perturbations.(48-50) Most substrate cleft mutations cause a two- to fivefold reduction in susceptibility in vitro to one or more PIs. However, additional mutations in the enzyme flap and in other parts of the molecule are usually required for resistance to emerge in vivo. This requirement for multiple mutations to overcome the activity of PI has been referred to as a "genetic barrier" to drug resistance.(51-53)

Mutations at several of the protease cleavage sites are also selected during treatment with protease inhibitors.(54-61) Protease cleavage site mutations improve the kinetics of protease enzymes containing PI-resistance mutations. Cleavage site mutations are compensatory rather than primary and there have been no reports of changes at cleavage sites alone causing PI resistance. Most of the reported cleavage site mutations occur at the cleavage sites in the 3, part of the gag gene, the p7/p1 and p1/p6 cleavage sites. It is not known whether these are the most commonly mutated cleavage sites or whether mutations at these sites are just detected most commonly because they are convenient to sequence, being just 5, to the protease gene.

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Protease Inhibitors (PIs)
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There are seven FDA-approved PIs: amprenavir, indinavir, lopinavir (manufactured in combination with ritonavir), nelfinavir, ritonavir, saquinavir, and the recently approved compound atazanavir. The dynamic susceptibility range for each of the PIs is about 100-fold.(53,62-65) The spectrum of mutations developing during therapy with indinavir, nelfinavir, saquinavir, ritonavir, and amprenavir have been well characterized,(51,52,66-72) but fewer data are available for lopinavir (73,74) and atazanavir.(75) Fosamprenavir (GW433908) is a prodrug of amprenavir with improved bioavailability that was approved by the FDA in October 2003. Preliminary data suggest that the spectrum of mutations developing during therapy with fosamprenavir is similar to that developing with amprenavir.(76)

Pharmacologic factors influence the clinical efficacy of PIs more than that of the other classes of antiretroviral drugs.(68,77-84) Virologic response is highly correlated with the inhibitory quotient (IQ), defined as the trough concentration divided by the inhibitory concentration of the drug (eg, the IC50 in a standardized assay).(83,85,86) Drug levels achieved during PI monotherapy can vary greatly among individuals, often resulting in low IQs.(84) This has led to the practice of administering subtherapeutic doses of ritonavir (a cytochrome P450 enzyme inhibitor) in combination with other PIs to increase, or "boost" their drug levels.(84) Lopinavir is formulated in a fixed combination with ritonavir (87); and saquinavir, indinavir, and amprenavir are now usually administered with low-dose ritonavir.(84) Boosted PIs require higher levels of resistance than PIs given as monotherapy before significant loss of antiviral activity and virologic rebound occur.(85,86,88)

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Protease Substrate Cleft Mutations
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(Refer to Figure 1 and Figure 3)

V82A/T/F/S occur predominantly in HIV-1 isolates from patients receiving treatment with indinavir or ritonavir.(51,52) V82A also occurs in isolates from patients receiving prolonged therapy with saquinavir following the development of the mutation G48V.(89,90) By themselves, mutations at codon 82 confer reduced susceptibility in vitro to indinavir, ritonavir, and lopinavir (51-53,91) but not to nelfinavir, saquinavir, or amprenavir. However, when present with other PI mutations, V82A/T/F/S contribute phenotypic and clinical resistance to each of the PIs (53,86,89,91-93) (Table 3). V82A is the most common mutation at this position; V82S, the least common. The phenotypic and clinical significance of the differences between each of these mutations has not been studied. V82I occurs in about 1% of untreated individuals with subtype B HIV-1 and in 5-10% of untreated individuals with non-B isolates.(94) Although V82I occasionally emerges during PI therapy,(72) preliminary data suggest that V82I confers minimal or no resistance to the available PIs.(39,95-97)

I84V has been reported in patients receiving indinavir, ritonavir, saquinavir, and amprenavir as their sole PI (51,52,63,69,72,90) and causes phenotypic (51,53,60,93,98-102) and/or clinical (86,88,103,104) resistance to each of the PIs. I84V is rarely the first major PI-resistance mutation to develop, usually developing in isolates that already have the mutation L90M.(105,106) I84A and I84C are extremely rare mutations that are also associated with resistance to multiple PIs when present in combination with other PI-resistance mutations.(107)

G48V occurs primarily in patients receiving saquinavir and rarely in patients receiving indinavir. This mutation causes 10-fold resistance to saquinavir and about threefold resistance to indinavir, ritonavir, and nelfinavir.(62,89,98,108) G48V has been reported to cause low-level biochemical resistance to amprenavir when present in site-directed mutants, but to interfere with amprenavir resistance when present together with more typical amprenavir-resistance mutations such as M46I, I47V, and I50V.(109) Its effect on lopinavir and atazanavir is not known. G48V usually occurs with mutations at positions 54 and 82.(92,101,106,110)

D30N occurs solely in patients receiving nelfinavir and confers no in vitro or clinical cross-resistance to the other PIs.(89,98,111,112) D30N reduces nelfinavir susceptibility by five- to 20-fold. D30N is often followed by the development of N88D, and the combination reduces nelfinavir susceptibility by about 50-fold.(39) D30N usually does not develop in isolates containing other primary PI-resistance mutations.(105,106,113)

I50V has been reported only in patients receiving amprenavir as their first PI.(72) In addition to causing reduced amprenavir susceptibility, it causes reduced susceptibility to ritonavir and lopinavir.(60,65,99,100,114,115) The development of I50V usually requires a specific compensatory cleavage site mutation.(60,72) I50L occurs in patients receiving atazanavir as their first PI.(75) It reduces atazanavir susceptibility by five- to 10-fold and causes hypersusceptibility to each of the remaining PIs.(75)

V32I occurs in patients receiving indinavir, ritonavir, or amprenavir. It usually occurs in association with other PI resistance mutations in the substrate cleft or flap and by itself appears to cause minimal resistance to any one drug. However, in combination with other mutations such as M46I/L, I47V, V82A, and I84V, high levels of resistance to multiple PIs, including lopinavir, have been reported.(65)

R8K and R8Q are substrate cleft mutations that cause high-level resistance to one of the precursors of ritonavir (A-77003) (116,117) but they have not been reported with the current PIs.

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Protease Flap Mutations
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(Refer to Figure 1 and Figure 3)

The protease flaps (residues 33-62) extend over the substrate-binding cleft and must be flexible to allow entry and exit of the polypeptide substrates and products.(118,119) The flap tips (residues 46-54) are particularly mobile and are the site of many drug resistance mutations. In addition to mutations at positions 48 and 50, which extend into the substrate cleft, mutations at positions 46, 47, 53, and 54 make important contributions to drug resistance.

Mutations at position 54 (generally I54V, less commonly I54T/L/M/S) contribute resistance to each of the approved PIs (51-53,72,93) and have been frequently reported during primary therapy with indinavir, ritonavir, amprenavir, and saquinavir, (51,52,68,70,72) and salvage therapy with lopinavir.(73,74,120) I54L and I54M are particularly common in persons receiving amprenavir and have a greater effect on amprenavir than does I54V.(72)

Mutations at position 46 (usually M46I/L, rarely M46V) contribute to resistance to each of the PIs except possibly saquinavir (51-53,72,93) and have been frequently reported during primary therapy with indinavir, ritonavir, amprenavir, and nelfinavir (52,68,70,72,121) and during salvage therapy with lopinavir.(73,74)

I47V has been reported in patients receiving amprenavir, indinavir, and ritonavir, and often occurs in conjunction with the nearby substrate cleft mutation V32I.(65) I47A is an uncommon mutation that is associated with high-level resistance to lopinavir and intermediate resistance to amprenavir.(122)

F53L has been reported rarely in patients receiving PI monotherapy, but it occurs in >10% of patients treated with multiple PIs.(106) In a multivariate analysis it has been associated with phenotypic resistance to lopinavir.(53) F53Y is a less commonly occurring substitution at this position that occurs only in treated persons and probably has a similar role as F53L.(106)

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Protease Mutations at Other Conserved Residues
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(Refer to Figure 1 and Figure 3)

L90M has been reported in isolates from patients treated with saquinavir, nelfinavir, indinavir, and ritonavir. L90M either contributes to or directly confers in vitro and in vivo resistance to each of the seven approved PIs (51,53,63,70,88,93,104,123-125) (Table 3). Crystal structures with and without the mutation have shown that the Leu90 side chain lies next to Leu24 and Thr26 on either side of the catalytic Asp25 (45,46,126), but the mechanism by which L90M causes PI resistance is not known.

Mutations at codon 73, including G73C/S/T, have been reported in 10% of patients receiving indinavir or saquinavir as their only PI and less commonly in patients receiving nelfinavir as their only PI.(67,106) However, this mutation occurs most commonly in patients failing multiple PIs, usually in conjunction with L90M.(105,106)

Mutations at position 88 (N88D and N88S) commonly occur in patients receiving nelfinavir and occasionally in patients receiving indinavir. By itself, a mutation at this position causes low-level resistance to nelfinavir, atazanavir, and indinavir. However, mutations at this position cause high-level nelfinavir resistance in the presence of D30N or M46I.(64,127,128) N88S (but not N88D) has been shown to hypersensitize isolates to amprenavir.(127)

L24I has been reported primarily in HIV-1 isolates from patients receiving indinavir (121) and has not been shown to confer cross-resistance to other PIs, except possibly lopinavir.(53)

L33F has been reported primarily in persons treated with ritonavir, amprenavir, or lopinavir.(52,72) Its effect on PI susceptibility levels has not been studied. However, it has gained attention recently because of its association with lack of response to the experimental PI tipranavir.(129) In contrast, L33I/V are polymorphisms in untreated persons and their effect, if any, on drug resistance is not known.

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Polymorphic Sites Contributing to Resistance
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(Refer to Figure 1 and Figure 3)

Amino acid variants at several polymorphic positions also make frequent contributions to drug resistance but only in combination with drug resistance mutations at nonpolymorphic positions. Mutations at positions 10, 20, 36, and 71 each occur in up to 5 to 10% of untreated persons infected with subtype B viruses. However, in heavily treated patients harboring isolates with multiple other PI-resistance mutations, the prevalence of mutations at these positions increases dramatically. Mutations at positions 10 and 71 increase to 60 to 80%, whereas mutations at positions 20 and 36 increase to 30 to 40%.(63,106) Position 63 is the most polymorphic protease position. In untreated persons, about 45% of isolates have 63L (considered the subtype B consensus), about 45% have 63P, and about 10% have other residues at this position. However, the prevalence of amino acids other than L increases to 90% in heavily treated patients.(106,130) Mutations at positions 77 and 93 increase in prevalence from about 25% in untreated persons to about 40% in heavily treated persons.(106) I93L is statistically associated with multiple PIs, whereas V77I is statistically associated only with nelfinavir.

In some HIV-1 subtypes, mutations at codons 20, 36, and 93 occur at higher rates than they do in subtype B isolates.(94,131,132) In contrast, mutations at positions 63 and 77 usually occur more commonly in subtype B than in non-B isolates. It has been hypothesized that individuals harboring isolates containing multiple accessory mutations may be at a greater risk of virologic failure during PI therapy.(133,134) However, most studies have not supported this hypothesis.(133-140)

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Additional Treatment-Associated Mutations
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In a recent analysis of 2,244 protease isolates from 1,919 persons, 45 protease positions were more likely to be mutant in isolates from treated compared with untreated persons, 17 positions exhibited polymorphisms that were unrelated to treatment, and 37 positions rarely, if ever, varied.(106) The 45 treatment-associated positions included 23 positions previously associated with drug resistance that are described above and 22 positions that had not previously been associated with drug resistance. Twelve of the 22 newly described treatment-associated positions (positions 11, 22, 23, 45, 58, 66, 74, 75, 76, 79, 83, 85) were highly conserved in untreated persons. Several of these mutations have also been described in other recent publications containing analyses of large databases.(65,141) The phenotypic and clinical impact of these mutations is not yet known because they rarely occur in the absence of other known drug resistance mutations and have not been studied in vitro.(106)

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PI Cross-Resistance Patterns and Salvage Therapy
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In a study of over 6,000 HIV-1 isolates tested for susceptibility to indinavir, nelfinavir, ritonavir, and saquinavir, 59 to 80% of isolates with a 10-fold decrease in susceptibility to one PI also had a 10-fold decrease in susceptibility to at least one other PI.(63) In a study of 3,000 HIV-1 isolates, resistance to indinavir, ritonavir, and lopinavir were highly correlated.(142) Isolates that were resistant to these drugs were generally also resistant to nelfinavir; however, isolates resistant to nelfinavir due to D30N were not resistant to other drugs.

Susceptibilities to saquinavir and amprenavir are somewhat less well correlated with one another and with susceptibilities to the other PIs,(142-145) although isolates that are highly resistant to amprenavir are often cross-resistant to lopinavir.(65) Atazanavir selects for a unique protease mutation in previously untreated persons, I50L, but most of the mutations that confer resistance to other PIs appear also to confer atazanavir resistance.(93)

Patients in whom nelfinavir-resistant isolates arise after nelfinavir treatment often respond to a regimen containing a different PI because D30N confers little cross-resistance to other PIs (103,144) (Table 3). But because >20% of nelfinavir failures may be associated with mutations at positions 46 and/or 90, virologic failure during nelfinavir does not guarantee susceptibility to other PIs.(70,71,146) Nelfinavir is usually unsuccessful as salvage therapy because most of the mutations that confer resistance to other PIs confer cross-resistance to nelfinavir.(63,123,147,148)

In a study of ritonavir/saquinavir salvage therapy using the hard gel capsule formulation of saquinavir (400-600 mg two times per day), the number of mutations at positions 46, 48, 54, 82, 84, and 90 predicted the virologic response at 4, 12, and 24 weeks (Table 3). Patients with three or more of these mutations had no virologic response to salvage therapy.(103) Decreased phenotypic susceptibility also predicted a reduced virologic response in this cohort.(103) However, 9 patients with isolates having mutations at positions 82 and 90 and at either or both positions 46 and 54 had no virologic response to ritonavir/saquinavir salvage despite the fact that their isolates were found to be phenotypically susceptible to saquinavir or to have only low-level reductions of saquinavir susceptibility.(103,149)

There are few data on the genotypic predictors of response to indinavir/ritonavir salvage therapy. In 2 small published studies, adherence, indinavir levels, and the number of PI-resistance mutations at positions 46, 48, 54, 82, 84, and 90 were predictive of virologic response.(85,150)

In vitro susceptibility studies suggest that patients experiencing treatment failure with other PIs often have isolates that retain susceptibility to amprenavir.(143,145) Data on the utility of amprenavir for salvage therapy are shown in Table 3.(151-154) In the NARVAL ANRS 088 trial, the presence of fewer than four of the following mutations--L10I, V32I, M46IL, I47V, I54V, G73S, V82A/T/F/S, I84V, L90M--was associated with a 1.6 log10 RNA reduction 12 weeks after the institution of an amprenavir-containing regimen.(153) The presence of exactly four mutations was associated with a 0.6 log10 RNA reduction. In another study, suppression of plasma HIV-1 RNA levels to <400 copies/ml during treatment with amprenavir/ritonavir was associated with having fewer than six of the following mutations (L10F/I/V, K20M/R, E35D, R41K, I54V, L63P, V82A/F/T/S, I84V).(86) Of note, the mutations at positions 35 and 41 are common polymorphisms and have not been associated with PI resistance in any previous analyses.

In a study of salvage therapy with a regimen containing lopinavir and efavirenz, the number of mutations at positions 10, 20, 24, 46, 53, 54, 63, 71, 82, 84, and 90 predicted the level of phenotypic resistance and the virologic response after 24 weeks of therapy (53,88) (Table 3). A decreased response to therapy was observed only in those patients whose viral isolates had six or more of the listed mutations. Subsequent analyses have suggested that mutations at positions 10, 20, 46, 54, and 82 may be more predictive than the other mutations listed (114,155) and that other mutations, including V32I, I47V/A, I50V, and G73S, may contribute to resistance in patient cohorts with different antiretroviral treatment experience.(60,65,156,157) Lopinavir has also proven highly effective as salvage therapy when combined with nevirapine in NNRTI-naive patients experiencing failure of their first PI regimen.(158)

During in vitro passage experiments, atazanavir-resistant isolates develop mutations at positions 32, 50, 84, and/or 88, a pattern of mutations that differs from but overlaps with the mutations developing in patients treated with other PIs.(159) In patients receiving atazanavir as their first PI, the most common drug-resistance mutation to develop, I50L, causes resistance to atazanavir alone, while hypersensitizing to other PIs. However, two of eight isolates in the setting of atazanavir failure had mutations at positions 46 and/or 82 in addition to I50L,(75) suggesting that susceptibility to other PIs may not be guaranteed. The usefulness of atazanavir in salvage therapy is currently being studied in Phase III clinical trials.(160)

Because of the high cross-resistance among the approved PIs, the choice of a PI for salvage therapy depends primarily on the drug levels that are likely to be achieved. The presence of mutations known to affect the activity of one specific drug (eg, G48V and saquinavir, I50V and amprenavir), will occasionally also influence the choice of salvage therapy. However, many combinations of mutations produce only subtle differences in susceptibility between available drugs. Clinical studies are needed to determine the usefulness of the protease genotype or phenotype for guiding selection of a particular boosted PI for treatment of individuals experiencing failure of a protease inhibitor-containing regimen.

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Investigational PIs
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Tipranavir and TMC114 are the investigational PIs at the most advanced stage of clinical development. The relative potency of tipranavir compared to other PIs either in vitro or in vivo has not been well described because this drug has been studied entirely in salvage therapy settings.(161-163) However, tipranavir has a remarkably high genetic barrier to resistance. After prolonged in vitro passage, mutations at positions 32, 33, 45, 82, and 84 have been selected leading to a virus with 14-fold reduced susceptibility.(164) Most PI-resistant clinical isolates, even those with >10-fold resistance to the original four PIs (saquinavir, indinavir, ritonavir, and nelfinavir) rarely have more than twofold resistance to tipranavir.(165)

Reduced tipranavir susceptibility of clinical isolates obtained from persons treated with other PIs appears to require three of the following four mutations: L33I/V/F, V82A/F/L/T, I84V, L90M.(162) Phase II salvage therapy studies have shown that the optimal response to tipranavir occurs when 500 mg of tipranavir is administered with 200 mg of ritonavir two times per day.(166) In heavily treated persons harboring viruses resistant to most other PIs, 14 days of boosted tipranavir reduced plasma HIV-1 RNA levels by 1.2 log10, provided baseline tipranavir resistance was less than twofold.(166) No virologic suppression was observed with viruses having greater than twofold reduction in susceptibility.

TMC114 and its precursor compound TMC126 are highly potent in vitro.(167,168) Like tipranavir, it has also been shown to have a high genetic barrier to resistance (169,170) and to be active, at least in the short term (14 days), as part of a salvage therapy regimen when boosted with ritonavir.(171) Published data on the mechanisms of resistance to TMC114 in vivo are not yet available.

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Nucleoside/Nucleotide RT Inhibitor (NRTI) Resistance
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HIV-1 RT
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The RT enzyme is responsible for RNA-dependent DNA polymerization and DNA-dependent DNA polymerization. RT is a heterodimer consisting of p66 and p51 subunits. The p51 subunit is composed of the first 440 amino acids of the pol gene. The p66 subunit is composed of all 560 amino acids of the pol gene. Although the p51 and p66 subunits share 440 amino acids, their relative arrangements are significantly different. The p66 subunit contains the DNA-binding groove and the active site; the p51 subunit displays no enzymatic activity and functions as a scaffold for the enzymatically active p66 subunit. The general shape of the polymerase domain of the p66 subunit can be likened to a human hand with subdomains referred to as fingers, palm, and thumb. The remainder of the p66 subunit contains an RNaseH subdomain and a connection subdomain.(172,173)

Most RT inhibitor resistance mutations are in the 5, polymerase coding regions, particularly in the "fingers" and "palm" subdomains (Figure 4). Structural information for RT is available from X-ray crystallographic studies of unliganded RT,(174) RT bound to an NNRTI,(175) RT bound to double-stranded DNA,(176) RT bound to double-stranded DNA and the incoming dNTP (ternary complex),(177) and RT bound to double-stranded DNA containing an AZT-terminated DNA primer pre- and post-translocation.(178) There have been fewer structural determinations of mutant RT enzymes than of mutant protease enzymes.(179-182)

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NRTIs
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The NRTIs are chain terminators that block further extension of the proviral DNA during reverse transcription. The FDA has approved seven nucleoside and one nucleotide analog. The nucleoside analogs are zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, and emtricitabine. Tenofovir disoproxil fumarate (tenofovir DF) is the only approved nucleotide analog. It is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate, which is converted by diester hydrolysis to tenofovir. Both nucleoside and nucleotide analogs are prodrugs that must be phosphorylated by host cellular enzymes. Nucleosides must be tri-phosphorylated; nucleotides, because they already have one phosphate moiety, must be di-phosphorylated. Phosphorylated NRTIs compete with natural deoxynucleoside triphosphates (dNTPs) for incorporation into the newly synthesized DNA chains and thereby cause chain termination.

The requirement for triphosphorylation complicates the in vitro assessment of both NRTI activity and phenotypic resistance testing. Table 4 shows that there are significant differences between the relative in vitro and in vivo potency of the NRTIs. Zidovudine appears to be the most potent NRTI in vitro because the concentration of zidovudine that inhibits HIV-1 replication by 50% (IC50) is 10- to 100-fold lower than that of the other NRTIs. Yet, in patients, lamivudine, emtricitabine, abacavir, tenofovir, and didanosine are more potent than zidovudine at lowering plasma HIV-1 RNA levels. The basis for this discordance has been known since the early 1990s. In vitro susceptibility tests use activated lymphocytes because it is difficult to culture HIV-1 using resting lymphocytes. Activated lymphocytes triphosphorylate zidovudine at a higher rate than other NRTIs, making zidovudine appear more active. In contrast, didanosine, for example, is converted to its active form, ddA-triphosphate, at much lower rates in activated lymphocytes, making it appear much weaker in vitro.(183)

Differences in NRTI triphosphorylation rates between the cells used for susceptibility testing and the wider variety of cells infected by HIV-1 in vivo also appear to explain why resistance to some drugs is difficult to detect by in vitro susceptibility testing. Mutant isolates from patients failing therapy with zidovudine and lamivudine usually have high-level (often >100-fold) phenotypic drug resistance. In contrast, mutant isolates from patients failing therapy with each of the other NRTIs have much lower levels of phenotypic resistance. As explained in the next section, one of the two main mechanisms of NRTI resistance--primer unblocking--also depends on intracellular dNTP concentrations, which are highly dependent on the state of cell activation. Difficulty in detecting resistance to NRTIs such as didanosine, zalcitabine, stavudine, and tenofovir appears to be related to the high dNTP concentrations present in the activated cells used for in vitro susceptibility testing.(184,185)

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Mechanisms of NRTI Resistance
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There are two biochemical mechanisms of NRTI drug resistance. The first mechanism is mediated by mutations that allow the RT enzyme to discriminate against NRTIs during polymerization, thereby preventing their addition to the growing DNA chain relative to the natural dNTP substrates.(172,173,177) The second mechanism is mediated by mutations that promote the hydrolytic removal of the chain-terminating NRTI and thus enable continued DNA synthesis (186-189) (Figure 6). This mechanism of resistance has also been referred to as pyrophosphorolysis, nucleotide excision, and primer unblocking. The hydrolytic removal requires a pyrophosphate donor, which in most cells is usually ATP.(186,187,190-192) Mutations that discriminate against NRTIs are generally associated with decreased enzymatic polymerase activity in vitro. Primer unblocking mutations are associated with lesser enzymatic impairment.

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Mutations at Positions 41, 67, 70, 210, 215, and 219 ("TAMs")
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(Refer to Figure 4 and Figure 5)

The most common mutations in HIV-1 samples obtained from patients receiving NRTIs were originally identified for their role in zidovudine resistance. During the past few years, many studies have shown that these mutations are associated with phenotypic (Table 5) (193) and clinical (Table 6) resistance to each of the other NRTIs. The six mutations reviewed in this section are also referred to as thymidine analog mutations (TAMs) because they are most often selected by zidovudine and stavudine-containing regimens.

Various combinations of these mutations at positions 41, 67, 70, 210, 215, and 219 (194-197) have been shown to promote ATP-dependent hydrolytic removal of a dideoxynucleotide monophosphate (ddNMP) from a terminated cDNA chain.(184,186-188) Early biochemical studies suggested that D67N and K70R are the mutations most responsible for rescue of chain-terminated primers (186,188) and that the main effect of T215Y/F might be to cause a compensatory increase in RT processivity.(188,198,199) More recent structural and modeling studies have shown that codons 70 and 215 are close to the incoming dNTP (177,182) and that T215Y/F are in a position that would increase the affinity of RT for ATP so that, at physiologic ATP concentrations, excision is reasonably efficient.(178,190,200) Mutations at positions 41 and 210 appear to stabilize the interaction of 215Y/F with the dNTP binding pocket.(177,178)

In an NRTI-terminated primer, the presence of the dNTP that would have been incorporated next--had the primer been free for elongation--results in the formation of a stable "dead-end" catalytic complex between RT, primer, template, and dNTP (178,185,190,200-202) (Figure 6). The formation of such a dead-end complex interferes with the ability of even a mutant RT to facilitate the resumption of viral DNA chain elongation. Several studies have suggested that the bulky azido group of zidovudine interferes with the formation of a dead-end catalytic complex by preventing translocation and the addition of the next dNTP.(178,185,190) Therefore ATP-dependent rescue of zidovudine-terminated primers is more likely to occur than rescue of other NRTI-terminated primers at the dNTP concentrations present in activated cells.(184) This observation helps explain why the primer unblocking mutations cause the highest levels of phenotypic resistance to zidovudine, but it also suggests that these mutations can cause cross-resistance to other NRTIs in cells where dNTP pools are low.(184,185)

TAMSs represent primer unblocking mutations that are selected primarily in patients treated with zidovudine or stavudine either alone or in combination with other NRTIs.(203-215) They also occur in about 10% of patients treated with didanosine monotherapy (216-218) but do not appear to occur during abacavir monotherapy (219) or with combination regimens lacking zidovudine or stavudine.

T215Y/F results from a two base-pair mutation and causes intermediate (10- to 15-fold) zidovudine resistance. It arises in patients receiving dual NRTI therapy, as well as in those receiving zidovudine monotherapy.(206,220,221) T215S/C/D are transitional mutations between wild-type and Y or F that do not cause reduced drug susceptibility but rather indicate the presence of previous selective drug pressure.(222-224) They are also referred to as T215 revertants because they are commonly observed in persons who once had viruses containing T215Y/F but who discontinued therapy and in persons who have been infected with a drug-resistant virus. In a study of 603 recently infected, untreated individuals, 2 had isolates with T215Y, 1 had T215F, and 20 (3.3% of total) had other mutations at this position including T215D (8), T215C (6), T215S (4), and T215E (1).(225) T215I/V are additional treatment-associated mutations at this position.(39)

K70R causes low-level (about fourfold) zidovudine resistance and is usually the first drug resistance mutation to develop in patients receiving zidovudine monotherapy.(204,226) Mutations at positions 70 and 215 are antagonistic in their effect on zidovudine resistance and these two mutations rarely occur together unless additional TAMs are also present.(204,227) Mutations at positions 67 and 219 may occur with mutations at position 70 or with mutations at position 215. Mutations at positions 41 and 210 occur only with mutations at position 215.(196,197,227,228) In patients experiencing failure of multiple dual-NRTI regimens it is not unusual for isolates to have four or five TAMs.

Clinical studies have shown that primer unblocking mutations, particularly mutations at position 215, interfere with the clinical response to zidovudine,(205,229) stavudine,(213,230) abacavir,(151,231-233) didanosine,(234-236) and most dual-NRTI regimens.(206,208,214,230,235,237) Complete loss of response to abacavir appears to require the combination of three or more TAMs together with the mutation M184V.(231,233,238) The presence of one or two TAMs has little effect on the virologic response to the addition of didanosine to a stable regimen; three TAMs causes a reduction in response; complete loss of response appears to require four TAMs.(236) In the presence of M41L, L210W, and T215Y, there is little virologic response to tenofovir.(239-241) In contrast, mutations at positions 67, 70, and 219, and the T215F substitution, have less impact on tenofovir susceptibility and virologic response.(239-241)

Both K70R and T215Y cause reproducible reductions in zidovudine susceptibility regardless of the susceptibility assay used. Phenotypic resistance to other NRTIs generally requires multiple TAMs. The presence of four or more TAMs will typically cause >100-fold decreased susceptibility to zidovudine, five- to sevenfold decreased susceptibility to abacavir, and two- to fivefold decreased susceptibility to stavudine, didanosine, zalcitabine, and tenofovir.(185,202,242-249) The TAMs cause low-level phenotypic lamivudine resistance but do not appear to compromise lamivudine activity. Regimens containing zidovudine, lamivudine, and a potent third drug are often highly effective even in the presence of multiple TAMs.(250,251)

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M184V
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(Refer to Figure 4 and Figure 5)

M184V emerges rapidly in patients receiving lamivudine monotherapy.(252-256) This mutation is also usually the first to develop in isolates from patients receiving incompletely suppressive lamivudine-containing regimens.(257-263) M184V is also selected during therapy with emtricitabine,(264) abacavir,(219,243,265) and less commonly with didanosine.(217,266,267)

M184I results from a G-to-A mutation (ATG [methionine] to ATA [isoleucine]) and usually develops before M184V in patients receiving lamivudine because HIV-1 RT is more prone to G-to-A substitutions than to A-to-G substitutions (ATG to GTG [valine]).(268-270) Although M184I also causes high-level resistance to lamivudine, the enzymatic efficiency of M184I is less than that of M184V, and nearly all patients with mutations at this position eventually develop M184V.(271) Steric conflict between the oxathiolone ring of lamivudine and the side chain of beta-branched amino acids such as valine and isoleucine at position 184 perturbs inhibitor binding, leading to a reduction in lamivudine incorporation.(179)

M184V by itself causes high-level (>100-fold) resistance to lamivudine and emtricitabine.(193,252,253,272) In the absence of other drug resistance mutations, M184V causes a median 1.5-fold reduction in didanosine susceptibility and threefold reduction in abacavir susceptibility in the PhenoSense assay (ViroLogic, South San Francisco, CA, U.S.A.).(39) In the presence of TAMs, M184V decreases susceptibility to didanosine, zalcitabine, and abacavir and increases susceptibility to zidovudine, stavudine, and tenofovir.(101,193,273-276) Resensitization may be due to the ability of M184V to impair the rescue of chain-terminated DNA synthesis (191,277) and probably explains the slow evolution of phenotypic zidovudine resistance in patients receiving the combination of lamivudine with either zidovudine or stavudine.(272,278,279) Resensitization, however, can be overcome by the presence of four or more zidovudine resistance mutations.(193,253)

Position 184 is in a conserved part of the RT close to the active site. The possibility that isolates containing M184V are compromised was suggested by the initial lamivudine monotherapy studies showing that plasma HIV-1 RNA levels remained about 0.5 log10 copies below their starting value in patients receiving lamivudine for 6 to 12 months despite the development of M184V and lamivudine resistance.(280-282) Data from multiple lamivudine-containing dual NRTI regimens also suggest that lamivudine continues to exert a beneficial effect even in patients whose virus isolates contain M184V.(11,283,284) The role of lamivudine in these situations may be to maintain selective pressure on the virus to retain M184V, which increases HIV-1 susceptibility to zidovudine, stavudine, and tenofovir.

M184V by itself does not significantly compromise virologic response to treatment with abacavir.(231,238,285,286) However, M184V in combination with multiple zidovudine-resistance mutations or in combination with mutations at positions 65, 74, or 115 leads to both in vitro and in vivo abacavir resistance.(101,231,238,243,287) Although M184V may also be selected by didanosine monotherapy (in viruses that also have L74V), M184V by itself has little, if any, effect on the virologic response to didanosine. Two studies have shown that in heavily treated patients infected with isolates containing multiple TAMs and M184V, a change from lamivudine to didanosine was usually associated with an improved virologic response.(288,289) Adding didanosine to a treatment regimen in the setting of genotypic evidence of M184V (and varying numbers of TAMs) led to a median plasma HIV-1 RNA reduction of 0.6 log10 copies/ml.(236) Moreover, M184V is frequently observed to revert to wild-type in persons changing therapy from lamivudine to didanosine.(289)

Several studies have shown that RT enzymes with M184V have increased fidelity in vitro (290-292), and other studies have shown decreased processivity.(293-296) The clinical significance of these biochemical studies is not known, and the increased fidelity does not appear to limit the ability of HIV to develop new mutations under continued selective drug pressure.(297,298)

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Mutations at Positions 65, 69, 74, and 75
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Positions 64-72 form a loop between the ß2 and ß3 strands in the "fingers" region of the RT, which makes important contacts with the incoming dNTP during polymerization.(172,177) In addition to the TAMs at positions 67 and 70, this region contains several important NRTI resistance mutations.

Substitutions at position 69 are the most commonly occurring NRTI resistance mutations other than the TAMs and M184V. T69D was initially identified as causing resistance to zalcitabine (299) but substitutions at this position have since been reported after treatment with each of the available NRTIs. In site-directed mutagenesis studies, other mutations at this position including T69N/S/A have been shown to confer resistance to zidovudine, didanosine, zalcitabine, and stavudine.(300) Mutations at position 69 when they occur together with TAMs may contribute to resistance to each of the NRTIs.(62,273,300-302) In a group of 23 zidovudine-treated children, each with multiple TAMs (including T215Y/F), the development of T69D/N was associated with a poor response to subsequent didanosine monotherapy.(303) In this study, mutations at position 69 were more likely to develop than mutations at position 74, the mutation that usually develops in isolates without TAMs during didanosine treatment.

Insertions at position 69 occur in about 2% of heavily treated HIV-1-infected patients.(304) By themselves, these insertions cause low-level resistance to each of the NRTIs, but isolates containing insertions together with T215Y/F and other TAMs have high-level resistance to each of the NRTIs.(305-309) Insertions at this position are associated with up to 20-fold resistance to tenofovir, which is the highest reported level of resistance to this drug.(246) Insertions at this position act in a manner similar to the TAMs by causing ATP-mediated primer unblocking but they also destabilize the dead-end complex described above and thus cause more phenotypic resistance to the whole NRTI class than observed with the TAMs alone.(185,192,310,311) Single amino acid deletions between codons 67-70 occur in <1% of heavily treated patients.(312-315) These deletions also contribute to resistance to each of the NRTIs in patients with viruses containing multiple NRTI mutations.

L74V occurs commonly during didanosine and abacavir monotherapy (217,219,243,316,317) and confers two- to fivefold resistance to didanosine and zalcitabine (217,318) and two- to threefold resistance to abacavir.(265) L74V is sufficient to cause virologic failure in patients receiving didanosine monotherapy (317) and appears to prevent antiviral activity when didanosine is used for intensification,(236) but additional mutations may be required to cause virologic failure of abacavir monotherapy.(219) L74V causes hypersusceptibility to zidovudine and is consequently rarely observed in patients receiving dual nucleoside therapy with didanosine plus zidovudine.(202,206,316,318,319) L74V is also rarely observed with didanosine plus stavudine (209,210) but it is unclear whether this mutation also increases susceptibility to stavudine or tenofovir.(276) L74V has also been shown to cause decreased RT processivity in enzymatic studies and decreased replication in cell culture.(296,320,321) L74I is a less commonly occurring mutation at this position; it is also associated with a two- to fivefold reduction in didanosine susceptibility.(39)

Position 65 interacts with the gamma-phosphate of the bound dNTP. K65R improves discrimination between dNTPs and most NRTIs leading to intermediate levels of resistance to didanosine, abacavir, zalcitabine, lamivudine, emtricitabine, and tenofovir, and low-level resistance to stavudine.(64,219,246,265,302,322-329) K65R is selected in vitro by abacavir,(265) tenofovir,(302) and stavudine (330). It has been reported during monotherapy with didanosine,(217) zalcitabine,(322) and abacavir,(219) and during tenofovir intensification.(331) K65R hypersensitizes HIV-1 to zidovudine (173,193,328) and does not develop in patients receiving zidovudine-containing regimens.(39)

Although once rare, the prevalence of K65R in clinical settings has been increasing from about 1 to 4% of treated persons.(332) In previously untreated persons, it occurred in 2.7% of individuals receiving tenofovir, lamivudine, and efavirenz, and in 0.6% receiving stavudine, lamivudine, and efavirenz.(333) It occurs even more commonly and appears to be associated with a much larger proportion of virologic failures in persons receiving triple nucleoside regimens lacking zidovudine, such as stavudine, didanosine, and abacavir;(334) tenofovir, abacavir, and lamivudine; (335,336) and tenofovir, didanosine, and lamivudine.

K65R generally occurs in association with other mutations such as M184V and Q151M that discriminate NRTIs from the natural dNTP substrates rather than causing primer unblocking.(227) Like other discriminatory mutations, K65R is associated with a decrease in replication capacity.(333) It also appears to increase the replication fidelity of HIV-1 RT.(337,338)

V75T develops in isolates cultured in the presence of increasing concentrations of stavudine and causes about fivefold resistance to stavudine, didanosine, and zalcitabine.(339) Biochemical and structural modeling data suggest that mutations at this position cause drug resistance through nucleotide discrimination and possibly also through a non-ATP-mediated mechanism of primer unblocking.(185,340) V75T occurs rarely in vivo, even in patients receiving stavudine. V75I generally occurs in isolates that also have the multinucleoside resistance mutation, Q151M. V75M/A are other NRTI-selected mutations that occur in 2.1% (M) and 0.6% (A) of persons receiving NRTIs and also appear to contribute to stavudine resistance.(39,301)

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Multinucleoside Resistance Due to Q151M
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Q151M is a two-base pair change in a conserved RT region that is close to the first nucleotide of the single-stranded nucleotide template.(177,341,342) Q151M causes resistance by decreasing the rate of incorporation of NRTIs relative to the natural dNTP substrates.(343) This mutation develops in up to 5% of patients who receive dual NRTI therapy with didanosine in combination with zidovudine or stavudine (206,209,210,304,316,344,345) but rarely with lamivudine-containing NRTI regimens. Q151M alone causes intermediate levels of resistance to zidovudine, didanosine, zalcitabine, stavudine, and abacavir.(342,346-348) It is nearly always followed by mutations at positions 62, 75, 77, and 116. Isolates with V75I, F77L, F116Y, and Q151M have high-level resistance to each of these NRTIs, and low-level resistance to lamivudine and tenofovir.(101,246) HIV-1 isolates with Q151M usually contain few, if any, primer unblocking mutations.(227) Q151M is a common genetic mechanism of NRTI resistance in HIV-2-infected persons.(349,350)

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Other NRTI Resistance Mutations
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E44D/A and V118I each occur in about 1% of untreated individuals and in 10-15% of those receiving NRTIs.(39) The prevalence of these two mutations is much higher in isolates obtained from patients receiving dual NRTI combinations, particularly in isolates containing multiple TAMs.(39,227,351,352) Although these mutations were first shown to contribute low-level resistance to lamivudine,(353) they have since been shown to be selected by and to contribute low-level resistance to most of the other NRTIs.(287,352,354,355) E44D and V118I cause NRTI resistance by different mechanisms. E44D increases primer unblocking; V118I interacts with the incoming nucleotide to decrease NRTI incorporation.(356) By themselves, these mutations do not appear to limit the virologic activity of lamivudine-containing regimens.(357)

Y115F is an uncommon mutation that occurs predominantly in patients receiving abacavir.(219) It has also been reported in combination with Q151M, in patients receiving other NRTI combinations.(39) Position 115 is in close proximity to F116 and V118, two other residues that interact with the incoming dNTP.

In a recent analysis of RT sequences from 267 untreated persons and 857 persons treated with NRTIs, mutations at nine additional positions were significantly associated with NRTI treatment: K20R, T39A, K43E/Q/N, E203D/K, H208Y, D218E, H221Y, D223E/Q, and L228H/R.(227) The first three mutations are also found as polymorphisms in untreated persons, occurring in 4%, 4%, and 1% of untreated persons, respectively. The remaining six mutations occur only in treated persons and are particularly common in persons receiving multiple courses of NRTI therapy, perhaps explaining their delayed recognition. These newly identified mutations nearly always occur in combination with other previously characterized NRTI resistance mutations suggesting that they act primarily as accessories to increase NRTI resistance or to compensate for the decreased replication capacity associated with other NRTI resistance mutations. The precise phenotypic effect of these mutations alone and in combination with other mutations has not yet been studied.

G333E is a polymorphism that has been reported in 4 of 70 (6%) untreated persons and in 26 of 212 (12%) persons receiving NRTIs.(358) G333E has been reported to facilitate zidovudine resistance in isolates from patients receiving zidovudine and lamivudine who also have multiple TAMs.(359) However, dual resistance to zidovudine and lamivudine usually emerges without this change.(92,279,360) There are no data suggesting that this mutation by itself reduces susceptibility to zidovudine or any other NRTI.

Two reports have suggested that, in some isolates, the common polymorphisms R211K and L214F may facilitate dual zidovudine and lamivudine resistance in the presence of mutations at positions 41 and 215 or dipeptide insertions at position 69.(202,311,361)

P157A/S is a rare mutation associated with lamivudine resistance. This mutation was first identified in a feline immunodeficiency virus isolate cultured in the presence of lamivudine and has subsequently been shown to be associated with high-level lamivudine resistance even in isolates lacking M184V.(212,362,363) There is only one published clinical HIV-1 isolate with this mutation.(212) Q145M is another rare mutation (also reported in a single isolate) that has been reported to cause resistance to each of the NRTIs.(364)

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NRTI Cross-Resistance Patterns
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There are four patterns of mutations associated with resistance to either all or nearly all of the approved NRTIs:

  1. The most common pattern includes multiple TAMs and M184V often in combination with substitutions at positions 44, 69, 75, and 118.

  2. Occasionally, there is a dipeptide insertion rather than a substitution at position 69. This is often described as a separate mechanism of resistance; however, the dipeptide insertion usually occurs in the same mutational context as the first mechanism.

  3. Q151M and its associated mutations V75I, F77L, and F116Y usually occur in the absence of TAMs. M184V, which is required for high-level lamivudine resistance, may also be present.

  4. K65R by itself causes some degree of resistance to each of the NRTIs except zidovudine. As noted above, K65R has been emerging with increased frequency as a cause of virologic failure in triple NRTI regimens lacking zidovudine and occurs in association with M184V and occasionally Q151M but not TAMs.

The extent of clinical cross-resistance between different NRTIs has been determined largely from the retrospective analysis of studies in which a single NRTI was substituted for a second NRTI or added to a failing regimen. (Table 6) The main conclusions of these studies have been that the TAMs compromise the activity of each of the NRTIs except lamivudine and that M184V interferes with the activity of lamivudine but has much less impact on abacavir and didanosine. Unless three or more TAMs are present, abacavir, tenofovir, and didanosine each lead to reductions in plasma HIV-1 RNA when they are added to a failing regimen. The extent to which each of these drugs is acting alone as opposed to producing synergistic effects with the NRTIs that were already being used is not known.

The antagonism between the TAMs and discriminatory mutations such as M184V and L74V probably explains the clinical synergism observed with several of the dual-NRTI combinations such as zidovudine/lamivudine, stavudine/lamivudine, zidovudine/didanosine, and stavudine/didanosine. Patients switching from one dual-NRTI combination to a second dual-NRTI combination will generally have some response as long as high-level resistance to the first combination has not yet emerged. High-level resistance to both drugs in these dual-NRTI combinations usually requires multiple TAMs and M184V. In contrast, combinations of NRTIs such as tenofovir, lamivudine, and abacavir that select only for discriminatory mutations--although consisting of drugs that are individually highly potent (365,366)--have a lower genetic barrier to resistance because a single point mutation such as K65R can cause resistance to all three drugs.

The most recently approved NRTI, emtricitabine, is structurally highly similar to lamivudine, which is also an oxathialone-cytosine analog. Preliminary data suggest that it is more potent than lamivudine in vitro (367) but that the cross-resistance profiles between the two drugs are likely to be the same. M184V is the most common mutation selected in vitro (253,368) and in vivo (369) by emtricitabine. Biochemical data suggest K65R also modestly reduces susceptibility to both drugs.(370)

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Nonnucleoside RT Inhibitor (NNRTI) Resistance Mutations
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The NNRTIs bind to a hydrophobic pocket in the RT located between the ß6-ß10-ß9 and ß2-ß13-ß14 sheets of the p66 subunit.(371) (Figure 7) A small portion of the pocket is also formed by residues from the p51 subunit. The NNRTI-binding pocket is close to but not contiguous with the active site. The NNRTIs inhibit HIV-1 replication allosterically by displacing the catalytic aspartate residues relative to the polymerase-binding site.(175,372,373) The hydrophobic NNRTI-binding pocket is less well conserved than the dNTP-binding site. Indeed, HIV-1 Group O and HIV-2 (374-377) are intrinsically resistant to most NNRTIs.

A single mutation in the NNRTI-binding pocket may result in high-level resistance to one or more of the NNRTIs. Resistance usually emerges rapidly when NNRTIs are administered as monotherapy or in the presence of incomplete virus suppression, suggesting that resistance is caused by the selection of a pre-existing population of mutant viruses within an individual.(378-381) Several studies have shown that a single dose of nevirapine used to prevent mother-to-child HIV transmission can select for NNRTI-resistant mutants that are detectable for at least 2 months.(380,382,383) As with many of the PI and NRTI resistance mutations, some of the NNRTI resistance mutations may also compromise viral replication capacity in the absence of NNRTIs. Two mechanisms of impaired replication have been proposed: changes in the conformation of the dNTP binding pocket (348,384) and changes in RNaseH activity.(385,386)

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NNRTIs
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There are three FDA-approved NNRTIs: nevirapine, delavirdine, and efavirenz. The dynamic susceptibility range for each of the NNRTIs is >100-fold. Wild-type HIV-1 Group M isolates tend to have greater inter-isolate variability in their susceptibility to NNRTIs than to NRTIs and PIs.(387) However, preliminary data suggest that the moderate (greater than fivefold) decreases in NNRTI susceptibility that have been reported in the absence of previous NNRTI therapy or known NNRTI resistance mutations do not interfere with the virologic response to an NNRTI-containing regimen.(388,389)

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NNRTI Mutations Between Codons 98 and 108
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(Refer to Figure 7 and Figure 8)

K103N occurs more commonly than any other mutation in patients receiving NNRTIs (381,390-395) and causes 20- to 50-fold resistance to each of the available NNRTIs.(64,396-398) Although this degree of resistance is less than the highest levels of resistance observed with these drugs, K103N by itself appears sufficient to cause virologic failure with each of the NNRTIs.(392,399-401) K103S occurs in about 1% of NNRTI-treated persons and causes about 10-fold resistance to efavirenz and delavirdine, and 30-fold resistance to nevirapine.(402) K103R occurs in about 1% of untreated persons.(39) By itself it does not cause NNRTI resistance, but in combination with V179D it is associated with about 10-fold resistance to each of the NNRTIs.(403)

Residue 103 is located on the outer rim of the NNRTI-binding pocket and in the vicinity of the entrance to the pocket. Structural studies of HIV-1 RT with K103N in both unliganded and NNRTI-bound conformations have shown that this mutation only minimally changes the enzyme structure but that, unliganded, it forms a network of hydrogen bonds that are not present in the wild-type enzyme.(371) These changes appear to stabilize the closed pocket form of the enzyme and interfere with the ability of inhibitors to bind to the enzyme.(371)

V106A causes more than 30-fold resistance to nevirapine, and two- to fivefold resistance to delavirdine and efavirenz.(64,396-398,404-408) V106M, although rare in subtype B isolates, occurs commonly in subtype C isolates from persons failing NNRTIs.(409,410) This mutation causes about 20-fold resistance to nevirapine and 10-fold resistance to efavirenz in subtype B isolates,(39) although higher levels of resistance have been reported in subtype C isolates.(409) V106I is a polymorphism that occurs in 1% of treated and untreated persons and is not associated with NNRTI resistance.(39)

L100I causes intermediate resistance to efavirenz and delavirdine and low-level resistance to nevirapine.(64,396,404,405,411,412) L100I usually occurs with K103N in patients receiving efavirenz and significantly increases efavirenz resistance in these isolates.(393) L100I also partially reverses T215Y-mediated zidovudine and tenofovir resistance.(276,411,413)

K101E causes about 10-fold resistance to nevirapine and fivefold resistance to efavirenz and delavirdine but the clinical significance of this reduction in susceptibility is not known.(64,398) K101Q is a common mutation at this position that causes twofold resistance to each of the NNRTIs.(39) K101P occurs in heavily treated persons failing NNRTIs. It is a 2-base-pair mutation that confers >20-fold resistance to each of the NNRTIs.(403)

A98G and V108I each cause about twofold resistance to each of the NNRTIs.(64,396-398,411) A98S is a common polymorphism that does not cause NNRTI resistance.(39)

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NNRTI Mutations Between Codons 179 and 190
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(Refer to Figure 7 and Figure 8)

Y181C/I causes more than 30-fold resistance to nevirapine and delavirdine and two- to threefold resistance to efavirenz.(64,396,405,411) Nonetheless, nevirapine-treated patients with isolates containing Y181C generally have only transient virologic responses to efavirenz-containing salvage regimens.(395,400,414) It is suspected that virologic failure in this setting is due not to low-level Y181C-mediated efavirenz resistance but rather to the more likely possibility that the virus population within patients developing isolates with Y181C is also enriched for other NNRTI-associated mutations, including K103N, at levels below the detectable range.

G190A causes high-level resistance to nevirapine and intermediate levels of resistance to efavirenz.(64,404,415) G190S causes high-level resistance to both nevirapine and efavirenz. Isolates containing G190A or G190S are hypersusceptible to delavirdine.(415) Other mutations at position 190 such as G190E occur uncommonly.(393,400) These mutations generally cause high-level resistance to efavirenz and nevirapine and low-level resistance to delavirdine and cause markedly reduced replication capacity.(384,415)

Y188L causes high-level resistance to nevirapine and efavirenz and intermediate resistance to delavirdine.(64,396,398,404,405) Y188C and Y188H are uncommon mutations at this position that cause intermediate-to-high levels of nevirapine resistance and low levels of resistance to efavirenz and delavirdine.

V179D causes low-level (about twofold) resistance to each of the NNRTIs.(396,405,412,416) V179I is a common polymorphism that occurs in 2% of untreated persons and in 12% of persons receiving NNRTIs but does not cause resistance to any of the approved NNRTIs.(39)

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NNRTI Mutations Between Codons 225 and 238
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(Refer to Figure 7 and Figure 8)

Mutations in this region occur less commonly than those in the 98-108 and 179-190 regions. P225H occurs with K103N in patients receiving efavirenz.(393,397,417) K103N + P225H causes about 100-fold resistance to efavirenz and nevirapine and about 10-fold resistance to delavirdine because P225H confers hypersusceptibility to delavirdine. M230L is an uncommon mutation that causes about 20-, 40-, and 60-fold decreased susceptibility to efavirenz, nevirapine, and delavirdine, respectively.(418) P236L is an even rarer mutation that causes high-level resistance to delavirdine and hypersusceptibility to nevirapine.(392,397,419) P236L causes slowing of both DNA 3,-end- and RNA 5,-end-directed RNaseH cleavage, possibly explaining the markedly decreased replication capacity of isolates with this mutation.(385) F227L augments nevirapine resistance when present with V106A but does not cause resistance on its own or affect sensitivity to other NNRTIs.(39,407) L234I causes resistance to the experimental NNRTI capravirine but its effect on other NNRTIs is not known.(404) K238N/T occur in 1-2% of NNRTI-treated isolates. K238N causes intermediate resistance to nevirapine and delavirdine and low-level resistance to efavirenz. K238R is a polymorphism that is the consensus amino acid at this position in subtype E (CRF01_AE) viruses.

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Other NNRTI Resistance Mutations
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Y318F is a mutation in the NNRTI-binding pocket which causes high-level resistance (about 40-fold) to delavirdine and low-level resistance (less than threefold) to nevirapine and efavirenz.(420) This mutation rarely occurs in the absence of other NNRTI resistance mutations. Mutations at codon 138 (eg, E138K) have been shown to confer resistance to an experimental group of NNRTIs called TSAO inhibitors (421) but do not cause resistance to the currently approved NNRTIs.(422) This mutation exerts its effect via the part of the p51 subunit that contributes to the NNRTI-binding pocket.(421) Mutations at position 135 and 283 have been shown to cause low-level resistance to NNRTIs, particularly when present in combination, but do not appear to influence the virologic response to NNRTI-containing regimens.(387)

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NNRTI Cross-Resistance
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High levels of cross-resistance to the NNRTIs have been reported in clinical HIV-1 isolates from patients experiencing failure of therapy with an NNRTI.(395,400,401,414,423-425) Part of this cross-resistance results from the fact that most NNRTI resistance mutations confer resistance to multiple drugs (Figure 8). Cross-resistance may also result from the fact that a single drug may select for multiple different NNRTI resistance mutations even if only one or two predominant mutations are detected during genotyping. Although some NNRTI mutations cause hypersusceptibility to at least one NNRTI (eg, G190A/S and delavirdine), the rarity of hypersusceptibility in the absence of cross-resistance mutations suggests that hypersusceptibility to NNRTIs is unlikely to be clinically significant, and no benefit of using NNRTIs either in combination or in sequence has been demonstrated.(426)

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NNRTI and NRTI Mutation Interactions
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There are two favorable interactions between NNRTI- and NRTI-resistance mutations that may explain the synergy observed when drugs from these classes are used in combination. In the early 1990s, it was shown that Y181C and L100I hypersensitize HIV-1 to zidovudine.(405,427) This has been confirmed more recently and appears to also apply to tenofovir.(276) This phenomenon has not been exhaustively studied and conceivably other NNRTI mutations may have a similar effect on NRTI susceptibility. The mechanism of action appears to be interference with primer unblocking.(428) The clinical significance of these interactions is not known.

The second favorable interaction was reported more recently. HIV-1 isolates containing multiple NRTI resistance mutations are consistently more susceptible (hypersusceptible) to the currently approved NNRTIs than are isolates lacking NRTI resistance mutations.(429) In the case of isolates without NNRTI resistance mutations, this phenomenon results in an IC50 that in the PhenoSense assay is defined as being <0.4-fold the IC50 of wild-type virus.(429) In the case of isolates containing NNRTI resistance mutations, this phenomenon results in an IC50 that is usually about three to five times lower than that of an isolate with the same NNRTI resistance mutations but lacking NRTI resistance mutations (resensitization).(430)

The biophysical basis for NNRTI hypersusceptibility is not known. However, two statistical analyses have provided some insight into the genetic basis for this phenomenon.(429,431) Several primer unblocking mutations, including M41L, D67N, L210W, and T215Y, and substitutions and insertions at position 69 have been associated with hypersusceptibility, whereas the role of other mutations, such as M184V, has not yet been clarified.(429,431)

In two studies, NNRTI hypersusceptibility was reported to be associated with improved clinical outcome when NNRTIs were used for salvage therapy.(432,433) It is important that this finding be independently verified to exclude the possibility that the benefit of NNRTI hypersusceptibility in these studies reflects some confounding factor. For example, in patients experiencing failure of an NRTI-containing regimen, the absence of any NRTI resistance (and associated lack of NNRTI hypersusceptibility) may be a marker for nonadherence to therapy. Moreover, the phenomenon of NNRTI resensitization (ie, the presence of low levels of phenotypic NNRTI resistance despite the presence of a major NNRTI-resistance mutation such as K103N) has been shown not to be of clinical benefit.(430)

In addition to these two common favorable interactions between NNRTI- and NRTI-resistance mutations, there are two rare unfavorable interactions. In one of these, an NNRTI mutation--Y181C--leads to a subtle reduction in susceptibility to an NRTI (stavudine).(276,434,435) In a different scenario, an NRTI resistance mutation--L74V or V75I/L--facilitates the emergence of NNRTI-associated mutations at position 190.

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Investigational NNRTIs
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Capravirine and TMC125 are the investigational NNRTIs in the most advanced stages of clinical development. Capravirine (also known as AG1549 and formerly S-1153) appears to be about as potent as other NNRTIs, by itself reducing plasma HIV-1 RNA levels 1.7 log10 over 10 days.(436) Capravirine has been shown to retain nearly full in vitro activity against HIV-1 isolates containing the RT mutation K103N.(404,437) However, other known NNRTI resistance mutations such as Y181C and combinations of NNRTI resistance mutations such as L100I + K103N or V106A + F227L have led to >10-fold reductions in capravirine susceptibility.(404,437) Moreover, a new NNRTI resistance mutation, L234I, has been observed during in vitro passage experiments.(404) Preliminary data suggest that capravirine may have residual activity in a subset of persons who have failed a previous NNRTI-containing regimen.(438)

TMC125 is a highly potent compound that retains activity against HIV-1 isolates containing all single NNRTI resistance mutations, possibly by possessing more than one conformation capable of blocking the NNRTI-binding pocket.(439,440) In a randomized, double-blind, placebo-controlled study, 12 previously untreated HIV-1-infected patients receiving TMC125 had a mean plasma HIV-1 RNA reduction of 2.0 log10 within 7 days.(441) This rate of plasma HIV-1 RNA reduction is similar to what had previously been observed with a 7-day course of therapy using five antiretroviral drugs belonging to three drug classes.(442) In patients who failed previous nevirapine- or efavirenz-containing regimens and had documented NNRTI resistance mutations, a 7-day course of TMC125 reduced plasma HIV-1 RNA levels by >0.5 log10 in 12 of 16 patients and by >1.0 log10 copies/ml in 7 of 16 patients. Neither the genetic mechanisms of resistance to TMC125 nor the long-term activity of this drug when treating patients experiencing failure of other NNRTIs has yet been described.

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HIV-1 Fusion Inhibitors
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The HIV-1 envelope glycoprotein consists of two noncovalently associated subunits: a surface glycoprotein (gp120) and a transmembrane glycoprotein (gp41). Portions of gp120 bind to the CD4 protein and to one of the chemokine receptors on target cells. After gp120-CD4-coreceptor binding, the gp41 subunit undergoes a conformational change that promotes fusion of viral and cellular membranes, resulting in entry of the viral core into the cell. This conformational change results in a transient species, termed the pre-hairpin intermediate, in which gp41 exists simultaneously as a membrane protein in both the viral and cellular membranes.(443)

Crystallographic studies of gp41 fragments show that in the process of fusion, two heptad repeat domains (HR1 and HR2) form a helical bundle containing trimers of each domain.(444) The first successful inhibitors of viral entry were synthetic peptides designed to inhibit the interaction of HR1 and HR2 by mimicking either HR1 or HR2. The entry inhibitor enfuvirtide (T-20) is one of these peptides, corresponding to part of HR2 (residues 127 to 162 of gp41). When this drug was administered intravenously over a 2-week period, the median plasma HIV-1 RNA levels of subjects receiving the higher dose levels (100 mg two times per day) declined by 2.0 log10.(445) In two Phase III studies that led to its FDA approval, the addition of enfuvirtide to an optimized antiretroviral regimen reduced plasma HIV-1 RNA levels by about 1.5 log10 in persons who had previously experienced failure of therapy with each of the three original drug classes.(446,447) In contrast, a reduction in HIV-1 RNA levels of only 0.7 log10 occurred in the control patients receiving an optimized antiretroviral regimen in the absence of enfuvirtide.

The extraviral portion of gp41 is the most conserved region in the HIV-1 envelope glycoprotein.(448-451) Nonetheless, there is about 10-fold variation in enfuvirtide susceptibility among isolates from untreated persons, with an IC50 that is generally between 0.1 and 1.0 uM.(452,453) This naturally occurring variation is due to gp41 polymorphisms (454) and to other parts of the envelope or genome that influence cell fusion. Enfuvirtide can target gp41 during a kinetic window that appears to be opened by CD4 binding and closed by coreceptor engagement; factors that influence these two processes logically affect enfuvirtide sensitivity.(455) One group reported that the IC50 of HIV-1 isolates tropic for the coreceptor CCR5 are about 0.3 to 0.6 log10 higher than those of CXCR4-tropic isolates,(456,457) but this finding has not been replicated.(458) Moreover, variation in baseline enfuvirtide susceptibility did not appear to affect virologic response.(452)

HIV-1 isolates resistant to enfuvirtide have been identified in persons receiving the inhibitor, and by culturing HIV-1 in the presence of increasing enfuvirtide concentrations. . Sequences of resistant isolates developing during in vitro passage experiments have demonstrated mutations in positions 36 to 38 of gp41,(459) whereas sequences from patients receiving enfuvirtide have demonstrated either single or double mutations between positions 36 and 45.(460-462) In site-directed mutagenesis experiments, isolates with a single mutation display one- to 21-fold reductions in susceptibility, whereas isolates with two mutations display 15- to 500-fold reductions in susceptibility.(462) In patients discontinuing enfuvirtide for 4 months, drug-resistant mutants in plasma were replaced by wild-type isolates, suggesting that drug-resistance mutations compromise virus replication in the absence of therapy.

T-1249 is a fusion inhibitor currently in development that has a longer half-life and retains activity against enfuvirtide-resistant isolates. (463) T-1249 is a 39 amino acid peptide that overlaps with enfuvirtide but includes a region of HR2 that binds into a deep pocket of HR1.(464) Virologic responses have been observed in patients harboring enfuvirtide-resistant viruses who have been treated with T-1249 for 10 days.(465)

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Intersubtype Variability
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During its spread among humans, group M HIV-1 has evolved into multiple subtypes that differ from one another by 10 to 30% along their genomes.(466,467) The antiretroviral drugs used to treat HIV-1 were developed using biophysical and biochemical studies targeting subtype B isolates--the predominant subtype in North America and Western Europe--and the vast majority of data on the genetic mechanisms of HIV-1 drug resistance have been generated from observations on subtype B viruses. However, HIV-1 subtype B viruses account for only about 12% of the global HIV pandemic, (468) and as therapy is introduced into developing countries the numbers of persons with non-B virus starting therapy will increase dramatically.

HIV-1 subtypes differ from one another by 10 to 12% of their nucleotides and 5 to 6% of their amino acids in the protease and RT.(94) Although most inter-subtype variation is caused by synonymous nucleotide substitutions, there are subtype-specific amino acid patterns. Naturally occurring polymorphisms in the protease of different subtypes often occur at sites that have been identified as accessory mutations in subtype B isolates. However, as noted above, these mutations at positions 20, 36, 93--as well as V82I--do not appear to interfere with the response to protease inhibitor therapy. Naturally occurring polymorphisms in RT of different subtypes generally do not occur at sites associated with drug resistance.

An increasing number of observational studies, both in vitro and in vivo, suggest that the currently available protease and RT inhibitors are probably as active against wild-type non-B viruses as they are against wild-type subtype B viruses.(469-486) However, some in vitro and in vivo observations suggest that there may be differences in susceptibility among the different subtypes.(96,487-492)

Preliminary data have shown that all drug resistance mutations that have been described in subtype B have also been observed in at least one non-B subtype.(493) However, it is not known whether drug resistance mutations that have not been recognized in subtype B may occur in other subtypes. Moreover, the patterns of mutations in non-B viruses from persons experiencing failure of therapy occasionally differ from the pattern observed in subtype B viruses. For example, several groups have reported that, although both protease mutations D30N and L90M occur in non-B viruses during nelfinavir therapy, D30N occurs more commonly in subtype B viruses, whereas L90M occurs more commonly in subtypes C, G, and CRF01_AE.(113,479,494,495) Two groups also reported that the NNRTI resistance mutation V106M occurs more commonly in subtype C than subtype B viruses in the setting of treatment with anNNRTI.(409,496)

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Interpretation of Genotypic Resistance Tests
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The interpretation of HIV-1 genotypic resistance tests is complicated for several reasons. First, there are many HIV-1 drug resistance mutations and they emerge in complex patterns. Second, HIV-1 drug resistance is rarely an all-or-none phenomenon. Clinicians treating infected patients usually need the answers to two separate questions: 1) Does the result suggest that the patient will respond to a drug in a manner comparable to a patient with a wild-type isolate? 2) Does the result suggest that the patient will obtain any antiviral benefit from the drug? Third, the results of resistance testing must be integrated with a sound understanding of the principles of antiretroviral therapy as outlined in the frequently updated published treatment guidelines.(15)

Because few clinicians can be expected to remember all that is known about the biological and clinical significance of these mutations, genotypic test results generally include not only a list of mutations but also an accompanying interpretation. The fact that genotypic interpretation is independent of the process of genotyping makes genotypic interpretation an ideal application for a computerized expert system that accepts either a nucleotide sequence or a list of mutations and returns a predicted level of resistance to different antiretroviral drugs, a list of comments about the mutations in the sequence, or both. However, genotypic reports are not yet capable of recommending specific drugs because they do not take into account potential resistance to drugs that a person received in the past but to which drug resistance is not evident from the submitted sequence; they do not take into account individual risk facotors for drug toxicity, and they do not incorporate the logic of which drugs should and should not be used in combination.

There are two basic approaches to genotypic interpretation: rules-based algorithms and machine-learning algorithms. Rules-based algorithms are developed by experts based upon distillation of large amounts of published data on the phenotypic impact and clinical significance of drug resistance mutations. Machine-learning algorithms contain rules developed by a computer program that analyzes data linking genotype to phenotype or clinical outcome.

Most algorithms in current clinical use are based on rules. These algorithms have three advantages relative to machine-learning algorithms. First, most machine-learning algorithms can operate only on a homogeneous data set such as correlations between genotype and phenotype, but not one that considers each of the three types of data summarized in Table 2. Second, most data sets contain insufficient data linking genotype to other forms of data to fully exploit the learning ability of those algorithms with the most predictive power. In contrast, experts can extrapolate based upon a wide variety of knowledge to create rules for mutations that are represented at low frequency in a database. Finally, whereas the logic of rules-based algorithms is transparent and can be examined by the clinician, the logic of machine-learning algorithms is often not transparent.

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Rules-Based Algorithms
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Bayer Diagnostics (Trugene) and Celera Diagnostics (ViroSeq) have each developed FDA-approved kits for HIV-1 genotypic testing and interpretation. The Bayer Diagnostics algorithm is based on a set of more than 70 rules.(497) The Celera Diagnostics is based on assigning scores to drugs based on the presence of specific drug resistance mutations.

The online Stanford HIVdb (http://hivdb.stanford.edu/) algorithm accepts either a user-submitted sequence or list of mutations and returns inferred levels of resistance to 17 FDA-approved RT and protease inhibitors.(39,498,499) The program assigns a drug penalty score to each drug resistance mutation and, adding the scores associated with each mutation, derives the total score for a drug. Using the total drug score, the program reports one of the following levels of inferred drug resistance: susceptible, potential low-level resistance, low-level resistance, intermediate resistance, and high-level resistance. The HIV reverse transcriptase and protease sequence database (39) contains a detailed explanation of the rules as well as each of the drug penalty scores and comments used by the algorithm.

The Agence Nationale de Recherche sur le SIDA (ANRS) algorithm is updated on a regular basis by a panel of expert researchers on the basis of published studies as well as ANRS clinical trials. It has been used in several clinical trials and retrospective studies (500,501) and can be found at http://www.hivfrenchresistance.org/tab2003.html. An algorithm created by researchers at the Rega Institute in Leuven, Belgium, has been evaluated using a data set of 240 HIV-1-infected persons and was found to be a significant predictor of virologic response to therapy at 3 months after starting a new regimen.(502) The Retrogram algorithm was shown to be useful to clinicians in a clinical trial.(9) Finally, many large commercial laboratories in the United States typically develop their own algorithms for HIV-1 genotypic interpretation.

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Machine-Learning Algorithms
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Machine-learning algorithms learn from a training data set and then test their performance using a test data set. This process is necessary to prevent these algorithms from learning concepts that are too specific to the training set and thus not applicable to other sets of data. Of the well-known learning algorithms, decision trees are the fastest to construct. Decision trees are robust to missing data, outliers, and irrelevant data, and they produce interpretable data. However, they rarely can provide predictive accuracy comparable to the best that can be achieved with the available data.(503,504) Categorical analysis and regression trees (CART) is a statistical method that is somewhat similar to decision trees. CART has been applied to genotypic data to predict phenotype (90) and virologic response to therapy.(505) Neural networks are especially effective in problems with a high signal-to-noise ratio and in settings in which prediction without interpretation is the goal. However, they are particularly vulnerable to missing values, outliers, and overfitting. There is one published report of using a neural network to predict lopinavir resistance.(506)

The VirtualPhenotype (Virco; Cambridge UK, and Mechelin, Belgium) is a proprietary algorithm that uses correlations between genotypes and phenotypes in the Virco database. The exact procedure has not been published but the basic concept is as follows. A list of mutations or differences from a consensus reference sequence is submitted to the program. The program then identifies sequences in the database that have a match to the submitted mutations. The phenotypes of the matching sequences are then analyzed to determine the median and range in the levels of fold-resistance. If the median is above the drug resistance cutoff for a drug, the virus is considered to be resistant. In one prospective study, the VirtualPhenotype was shown to be as useful as the Virco phenotypic assay, the Antivirogram, for guiding salvage therapy.(507)

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Interalgorithm Comparisons and Algorithm Validation
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Two types of studies have been designed to examine the performance of algorithms for interpreting protease and RT genotypes: studies of interalgorithm concordance and studies comparing the performance of one or more algorithms on a data set in which genotype has been linked to the virologic response to a new treatment regimen.(508,509) For these types of studies, it has been necessary to normalize the results of algorithms that report more than three levels of susceptibility with those algorithms that report just three levels of susceptibility (susceptible, intermediate, resistant).

A study of the first type applied four rules-based algorithms to sequences from 2,045 individuals.(498) Drug resistance interpretations were classified as S for susceptible, I for intermediate, and R for resistant. The results of 30,675 interpretations (2,045 sequences x 15 drugs) were as follows: 4.4% were completely discordant, with at least one algorithm assigning an S and another an R; 29.2% were partially discordant, with at least one algorithm assigning an S and another an I, or at least one algorithm assigning an I and another an R; and 66.4% displayed complete concordance, with all four algorithms assigning the same interpretation (Figure 9). Discordances between NRTI interpretations usually resulted from several simple, frequently occurring mutation patterns. Discordances between PI interpretations resulted from a larger number of more complex mutation patterns. Discordances between NNRTI interpretations were uncommon and resulted from a small number of individual drug resistance mutations.

Three additional studies compared the VirtualPhenotype to one or more rules-based algorithms and have generally reported high levels of concordance except for the nucleoside RT inhibitors didanosine, stavudine, and zalcitabine, which were more likely to be called susceptible by the VirtualPhenotype.(510-512)

The validation of algorithms using a virologic outcome data set is not straightforward. First, because multiple drugs are typically used for salvage therapy, it is necessary to create a predicted level of activity for each drug that takes into account both the intrinsic activity of the drug as well as the predicted loss of activity due to drug resistance. Second, the predictive ability of different algorithms will depend heavily on the precise definition of success: whether success is treated as a binary or continuous variable, and whether success is defined as plasma HIV-1 RNA levels becoming undetectable or decreasing by at least a certain amount at a specific point in time after the initiation of salvage therapy.

Two published studies have retrospectively compared the performance of one or more algorithms on the ability to predict virologic response to a new treatment regimen. In one study, the genotypes of 261 individuals were examined for their ability to predict plasma HIV-1 RNA levels at 12 and 24 weeks of treatment. (513) All analyzed interpretation systems were significantly predictive of the virologic response, with odds ratios ranging from 1.35 to 2.04 at 12 weeks and 1.44 to 2.10 at 24 weeks. However, only three of 10 interpretation systems showed significant independent prediction of the 12- or 24-week response in a multivariable model that included characteristics of patient history, baseline features such as HIV-1 RNA levels and number of resistance mutations, and characteristics of the salvage regimen (number of new and total number of antiretroviral drugs and use of a new drug class). Not surprisingly, the algorithms were significantly more predictive in adherent than in nonadherent patients. In the other study, the Trugene and Retrogram algorithms were more predictive than the VirtualPhenotype.(512)

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Genotype-Phenotype Discordances
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Physicians ordering simultaneous genotype and phenotype tests often get back interpretations that appear to be discordant. This section reviews six causes for these apparent discordances: 1) genotypic mixtures, 2) transitional mutations, 3) antagonistic mutations, 4) the effect of TAMS on didanosine, stavudine, and tenofovir susceptibility, 5) atypical mutations, and 6) complex patterns of mutations. The first three causes of discordance are intrinsic limitations of testing the susceptibility of a virus quasispecies and reflect the fact that phenotypic tests measure the average susceptibility of a population of viruses whereas genotypic tests provide a panoramic assessment of resistance within the virus population. The fourth reflects an artifact of NRTI susceptibility testing caused by the fact that the NRTIs are prodrugs that are triphosphorylated at different rates in vivo and in the cells used for phenotypic susceptibility testing. The fifth and sixth reflect limitations of genotypic assays that can only be overcome by studies linking genotypic and phenotypic results.

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HIV-1 Mixtures
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About 1% of all nucleotide positions in the RT and protease isolates from persons receiving antiretroviral therapy have detectable mixtures by population-based sequencing.(40) However, in persons receiving antiretroviral therapy, that proportion of mixtures at codons associated with drug resistance is considerably higher (>5%) because these positions are under selective drug pressure. If an isolate contains a mixture of a mutation and a wild-type residue at a position associated with drug resistance, genotypic algorithms will consider the mutation to be present and will infer the presence of resistance. Phenotypic assays, however, will not detect resistance if the mutation is present in a minority of the virus quasispecies.(514)

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Transitional Mutations
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The canonical transitional mutations have been referred to as T215 revertants. These are mutations at RT position 215 such as T215S/C/E/D that are found as HIV-1 transitions from wild-type to mutant (222) or as HIV-1 reverts from mutant to wild-type in the absence of drug pressure.(223,224,515) According to phenotypic assays, isolates containing T215 revertants will be fully drug susceptible. In contrast, most genotypic interpretations assign an intermediate level of resistance to isolates containing T215 revertants.

The concept of a transitional mutation can be generalized to mean any mutation that by itself does not cause resistance but that indicates evolving resistance. This is particularly common for protease drug resistance mutations. For example, protease mutations at position 82 and 90 are generally considered by genotypic algorithms to reduce responsiveness to indinavir and saquinavir, respectively. However, these mutations alone often do not reduce susceptibility in phenotypic assays because accessory mutations (often at highly polymorphic sites) may be required.(514) However, the presence of these mutations indicates that the genetic barrier to resistance has been greatly lowered and that, with the development of the accessory mutations, phenotypic resistance will also be detectable.

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Antagonistic Mutations
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As noted in the sections above on interactions among mutations, mutations causing resistance to one drug commonly hypersensitize HIV-1 to a second drug. The two best studied examples are the antagonistic effect of the RT mutations M184V, L74V, L100I, and Y181C on resistance to zidovudine and tenofovir (and stavudine in the case of M184V) and of the NRTI resistance mutations on resistance to the NNRTIs. When antagonistic mutations are present, phenotypic assays may not detect resistance to the drug to which susceptibility is increased. Genotypic assays will usually provide an interpretation that indicates the presence of drug resistance mutations indicative of either active or latent drug resistance, and may report reduced resistance to the "resensitized" drug or provide a comment about the potential for resensitization.

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Thymidine Analog Mutations
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As noted in the NRTI section, differences in NRTI triphosphorylation rates between the cells used for susceptibility testing and the wider variety of cells infected by HIV-1 in vivo appear to explain why resistance to some drugs is difficult to detect in vitro. The primer unblocking mutations, particularly the thymidine analog mutations (TAMs), are known to compromise the clinical response to all NRTIs, but the effect of these mutations on susceptibility to didanosine, stavudine, zalcitabine, and tenofovir is often minimal in phenotypic assays and is below the level of technical reproducibility of probably all assays except for the highly reproducible PhenoSense assay.

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Atypical Mutations
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Most genotypic resistance interpretation algorithms classify a mutation as a drug resistance mutation if the mutation has been shown to reduce susceptibility in site-directed mutants or in large numbers of clinical isolates. Mutations at about 55 positions in protease and RT are classified as drug resistance mutations. However, many additional mutations at these 55 positions that occur commonly in persons receiving antiretroviral drugs have not been studied. The phenotypic effect of these mutations will be detected by phenotypic assays but some genotypic algorithms may not even report these mutations.

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New Drugs and Complex Patterns of Mutations
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The genetic mechanisms of resistance to a new antiretroviral drug are initially developed on the basis of data from in vitro passage experiments and early clinical studies. For example, the initial genotypic predictors of lopinavir resistance were based on data from an early cohort of about 100 patients.(53,88) A subsequent study containing data on about 1,000 HIV-1 isolates, however, showed that the genotypic predictors of lopinavir resistance could be further improved by studying the correlation between genotype and phenotype on a larger number of isolates from additional patients with a wider range of prior treatments and protease mutation patterns.(65)

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Limitations of Drug Resistance Testing
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The clinical usefulness of both genotypic and phenotypic drug resistance testing is limited by the following factors:

  1. The relationship between drug resistance and clinical failure is complex. Drug resistance is not the only cause of treatment failure. Nonadherence, the use of insufficiently potent treatment regimens, pharmacokinetic factors that decrease the levels of one or more drugs in a treatment regimen, and possibly even host genomic factors, also contribute to treatment failure. Conversely, a drug may have some benefit even in the setting of resistance, because many drug-resistant variants are less fit than drug-susceptible variants. In addition, all antiretroviral drugs are used in combinations, many of which are synergistic. Reduced susceptibility to a drug may not interfere with the drug,s beneficial effect on the antiretroviral activity of another drug used in the same regimen.

  2. HIV-1 exists in each infected individual as a complex quasispecies in which many different subpopulations of drug-resistant variants may be archived in latently infected cells. The complexity of this quasispecies may influence the success of therapy in ways that cannot be predicted by any single drug resistance test.

  3. Cross-resistance within each of the three commonly used drug classes is common and often limits treatment options even if the information conveyed by a resistance test is accurate and predictive.

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Complex Relationship Between Drug Resistance and Clinical Progression
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The natural history of HIV-1 infection is highly variable and dependent on a complex set of host-virus interactions.(516,517) In the absence of therapy, some patients progress to advanced immunodeficiency within 3 years following infection, whereas other patients remain healthy for more than 15 years. It is likely that the same host-virus interactions that so greatly influence disease progression in the absence of drug therapy also influence the risk of virologic failure in patients receiving antiretroviral therapy.

Two consistent observations underscore the complexity of the relationship between drug resistance and disease progression. Patients developing virologic failure on their first treatment regimen are often found to have HIV-1 isolates with resistance to only one of the drugs in the regimen.(257,258,260,263,333,518,519) The drugs to which resistance most commonly develops in this situation are lamivudine and the NNRTIs; resistance to PIs and NRTIs other than lamivudine is less common in patients with initial virologic failure. The observation that virus becomes detectable and replication ensues despite the fact that the replicating virus remains sensitive to at least two drugs in the treatment regimen suggests that virologic failure is multifactorial, with factors in addition to drug resistance contributing to failure. Possibly, the remaining drugs in the regimen are not potent enough to fully suppress virus even though they remain active. Alternatively, one of the presumably effective drugs in the regimen may have been present at insufficient levels because of nonadherence or pharmacokinetic factors.

In vitro experiments have consistently shown that isolates containing protease and/or RT drug resistance mutations replicate less well in cell culture and that purified enzymes with these mutations usually have less activity than wild-type enzymes.(520,521) Drug resistance mutations are also often replaced in vivo by wild-type variants within weeks to months after removal of selective drug pressure.(515,522-525) A potential clinical corollary is that virologic failure in patients receiving antiretroviral therapy is not always followed by immunologic and clinical deterioration.(526-529) This may be because the immunologic benefits of virus suppression persist beyond the period of virus suppression or because multidrug-resistant viruses may be less virulent, particularly when they first emerge and are associated with fewer compensatory mutations.(525,530) Indeed, two randomized controlled clinical trials have confirmed that there is often a benefit of continuing antiretroviral therapy even in the face of persistent viremia and drug resistance because discontinuation of therapy is often accompanied by higher levels of viremia and loss of CD4 cells.(527,531)

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Archived Drug-Resistant Variants of HIV-1
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A recognized limitation of HIV-1 drug susceptibility testing by either genotypic or phenotypic methods is the unreliability of these tests in detecting minority HIV-1 variants in the virus population of the patient tested. This limitation is particularly troublesome in patients with complicated treatment histories or those who have discontinued one or more antiretroviral drugs.(523,524,532) In some patients, the treatment history can be used to infer the presence of archived drug resistance mutations. For example, if a patient previously received lamivudine as part of an incompletely suppressive treatment regimen, it is likely that M184V exists within the virus population of that patient even if it is not detected at the time of genotyping. The same principle would apply to patients who received NNRTIs as part of an incompletely suppressive treatment regimen. In contrast, patients receiving lamivudine and NNRTIs as part of completely suppressive treatment regimens are not expected to harbor variants resistant to these drugs.

If a patient once harbored drug-resistant variants, these variants may persist at low levels in latently infected cells even if a subsequent treatment regimen brings about complete virus suppression.(532-539) In patients in whom previous resistance tests have documented extensive drug resistance, the clinical usefulness of repeated resistance testing is likely to be minimal because many resistant variants selected by previous treatment regimens will go undetected in subsequent tests, yet are likely to emerge during attempts at therapy.

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Cross-Resistance
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Most mutations arising during drug therapy contribute resistance to multiple drugs within the same drug class. Because only four drug classes are available, and because combinations of drugs from at least two classes are usually required to achieve durable HIV-1 suppression, cross-resistance significantly limits treatment options. Resistance assays frequently do not identify enough fully active non-cross-resistant drugs to completely block HIV-1 replication and many patients changing regimens because of virologic failure will have to use a regimen containing drugs that are partially compromised at the start of therapy. Although cross-resistance is not a direct limitation of resistance testing, it limits its utility, particularly in heavily treated patients.

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Acknowledgements
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Robert W. Shafer is supported by NIH grants AI-27666-12 and AI46148-01 and has received unrestricted educational grants from various pharmaceutical and diagnostic companies for maintenance of the HIV RT and Protease Sequence Database. A list of the companies who have supported the database can be found at http://hivdb.stanford.edu/pages/acknowledgements.html.

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