HIV-1 antiretroviral resistance: scientific principles and clinical applications

Abstract

The efficacy of an antiretroviral (ARV) treatment regimen depends on the activity of the regimen's individual ARV drugs and the number of HIV-1 mutations required for the development of resistance to each ARV - the genetic barrier to resistance. ARV resistance impairs the response to therapy in patients with transmitted resistance, unsuccessful initial ARV therapy and multiple virological failures. Genotypic resistance testing is used to identify transmitted drug resistance, provide insight into the reasons for virological failure in treated patients, and help guide second-line and salvage therapies. In patients with transmitted drug resistance, the virological response to a regimen selected on the basis of standard genotypic testing approaches the responses observed in patients with wild-type viruses. However, because such patients are at a higher risk of harbouring minority drug-resistant variants, initial ARV therapy in this population should contain a boosted protease inhibitor (PI) - the drug class with the highest genetic barrier to resistance. In patients receiving an initial ARV regimen with a high genetic barrier to resistance, the most common reasons for virological failure are nonadherence and, potentially, pharmacokinetic factors or minority transmitted drug-resistant variants. Among patients in whom first-line ARVs have failed, the patterns of drug-resistance mutations and cross-resistance are often predictable. However, the extent of drug resistance correlates with the duration of uncontrolled virological replication. Second-line therapy should include the continued use of a dual nucleoside/nucleotide reverse transcriptase inhibitor (NRTI)-containing backbone, together with a change in the non-NRTI component, most often to an ARV belonging to a new drug class. The number of available fully active ARVs is often diminished with each successive treatment failure. Therefore, a salvage regimen is likely to be more complicated in that it may require multiple ARVs with partial residual activity and compromised genetic barriers of resistance to attain complete virological suppression. A thorough examination of the patient's ARV history and prior resistance tests should be performed because genotypic and/or phenotypic susceptibility testing is often not sufficient to identify drug-resistant variants that emerged during past therapies and may still pose a threat to a new regimen. Phenotypic testing is also often helpful in this subset of patients. ARVs used for salvage therapy can be placed into the following hierarchy: (i) ARVs belonging to a previously unused drug class; (ii) ARVs belonging to a previously used drug class that maintain significant residual antiviral activity; (iii) NRTI combinations, as these often appear to retain in vivo virological activity, even in the presence of reduced in vitro NRTI susceptibility; and rarely (iv) ARVs associated with previous virological failure and drug resistance that appear to have possibly regained their activity as a result of viral reversion to wild type. Understanding the basic principles of HIV drug resistance is helpful in guiding individual clinical decisions and the development of ARV treatment guidelines.

Table I

List of currently available US FDA-approved antiretroviral drugs

Fig. 1

Schematic of genetic barrier to resistance and potency of selected antiretrovirals. The genetic barrier to resistance and potency (antiviral activity) of an antiretroviral determine in large part how susceptible that antiretroviral is to development of HIV-1 resistance. This figure illustrates relative genetic barriers and potencies of commonly used antiretrovirals. Nucleoside/nucleotide reverse transcriptase inhibitors are depicted in black, non-nucleoside reverse transcriptase inhibitors are green, protease inhibitors are red, integrase inhibitors are blue, maraviroc is purple and enfuvirtide is orange.[–21] Refer to table I for a full list of drug name abbreviations and definitions. VL = viral load.

Fig. 2

Summary of nucleoside/nucleotide reverse transcriptase inhibitor drug-resistance mutations. Mutations are represented by their numeric position and amino acid letter code. The amino acid of the consensus wild-type sequence is represented by letters in the top row, while the amino acids of the mutations are below. Bold and underlining indicates mutations with high-level phenotypic and/or clinical resistance; bold indicates moderate phenotypic and/or clinical resistance; plain text indicates low-level resistance. Asterisks (***) represent increased susceptibility to the drug if the mutation is present. Refer to table I for a full list of drug name abbreviations and definitions. Adapted from the Stanford University HIV Drug Resistance Database.[40] Cons = consensus wild-type; Ins = insertion; MDR = multi-drug resistance.

Fig. 3

Summary of non-nucleoside reverse transcriptase inhibitor drug-resistance mutations. Mutations are represented by their numeric position and amino acid letter code. The amino acid of the consensus wild-type sequence is represented by letters in the top row, while the amino acids of the mutations are below. Bold and underlining indicates high-level phenotypic and clinical resistance (probable contraindication); bold text indicates moderate phenotypic or clinical resistance; plain text indicates contributes to resistance. Additional mutations: nonpolymorphic, usually accessory: V179F (NVP, ETR), P225H (EFV), F227L (NVP), E138QG (ETR, RPV), K238TN (EFV, NVP), Y318F (NVP), N348I (NVP); nonpolymorphic, rare: K101HN, K103HT, G190QTCV, F227C; polymorphic accessory: V90I, A98G, V108I, E138A, V179DE, H221Y. Genotypic susceptibility scores: ETR (Tibotec): 181IV (3.0); 100I, 101P, 181C, 230L (2.5); 90I, 138A, 179F, 190S (1.5); 98G, 101EH, 179DT, 190A (1.0); <2.5 susceptible; 2.5–3.0 intermediate; >3.0 high-level. Refer to table I for a full list of drug name abbreviations and definitions. Adapted from the Stanford University HIV Drug Resistance Database.[40] Cons = consensus wild-type.

Fig. 4

Summary of protease inhibitor (PI) drug-resistance mutations. Mutations are represented by their numeric position and amino acid letter code. The amino acid of the consensus wild-type sequence is represented by letters in the top row, while the amino acids of the mutations are below. Bold and underlining indicates significant phenotypic or clinical resistance (probable contraindication); bold indicates significant contribution to resistance; plain text indicates primarily accessory contribution to resistance. Common accessory mutations: L10IVF, V11I, K20TVI, L23I, L24IF, L33F, K43T, F53L, Q58E, A71VTIL, G73STCA, T74PS, N83D, L89V. Hypersusceptibility mutations: I50L increases susceptibility to all PIs except ATV. I50V and I54L to TPV. L76V to ATV, SQV and TPV. N88S to FPV. Genotypic susceptibility scores: DRV (Tibotec):11I, 32I, 33F, 47V, 50V, 54LM, 74P, 76V, 84V, 89V; <3 susceptible; 3–4 low/intermediate; >4 high level. TPV (Boehringer): 47V (+4), 74P (+4), 82LT(+4), 83D (4), 58E (3), 84V (3), 36I (2), 43T (2), 54AMV (2), 10V (1), 33F (1), 46L (1), 24I (−2), 76V (−2), 50L/V (−4), 54L (−6); <4 susceptible; 5–10 intermediate; >10 high level. Refer to table I for a full list of drug name abbreviations and definitions. Adapted from the Stanford University HIV Drug Resistance Database.[40] Cons = consensus wild-type.

Fig. 5

Summary of integrase inhibitor drug-resistance mutations. Mutations are represented by their numeric position and amino acid letter code. The amino acid of the consensus wild-type sequence is represented by letters in the top row, while the amino acids of the mutations are below. Bold and underlining indicates >10- to 20-fold decreased susceptibility (probable contraindication); bold text indicates significant contribution to phenotypic and/or clinical resistance; plain text indicates <5- to 10-fold decreased susceptibility. Refer to table I for a full list of drug name abbreviations and definitions. Adapted from the Stanford University HIV Drug Resistance Database.[40] Cons = consensus wild-type.

Table II

Genotypic resistance profiles associated with dual NRTIs used for initial ART: implications for choice of NRTIs for second-line ART^a

Table III

Genotypic resistance profiles associated with initial antiretroviral therapy^a failure: implications for choice of second-line antiretroviral therapy