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TABLE 2-10:

Resistance Mutations (Continued)

Drug	Major mutations	Minor mutations	Comments
Integrase Inhibitors: Integrase gene mutations
RAL		148 H/K/R, 155 H	Distinct resistance pathways: Major mutations are 148H/K/R or 155 H and ≥ one minor mutation: 148H/K/R + 74M + 138A, 138K or 140S. 148H + 140S is most common and causes the greatest resistance. 155H typically is combined with 74M, 92Q, 97A, 143 H; 92Q + 97A, 163 K/R, 151 I or 232N (Antivir Theryr? 12:510)

* The distinction between primary and secondary mutations has been eliminated for NRTIs and NNRTIs by the IAS-USA Expert Committee; this distinction has been retained for PIs, but with the terms have been replaced by “major” or “minor”muations

^† Major mutations emerge first or are associated with decreased drug binding or reduced viral activity; these effect phenotype resistance.

^‡ Minor mutations appear later and, by themselves, do not significantly change phenotypic resistance, but they may further decrease susceptibility in combination with major mutations, or help to compensate for loss of fitness caused by major mutations..

TABLE 2-11:

Nucleoside and Nucleotide Analog Resistance Mutations by Category

Mutation Category	Mutation	Comments
Thymidine analog mutations (TAMs)	M41L, D67N/G, K70R, L210W, T215F/Y, K219E/Q/ N	Selected by thymidine analogs (AZT, d4T) but cause resistance to all NRTIs. 41L/210W/215Y pattern more common in subtype B virus and causes higher-level NRTI resistance than 67N/70R/219. T215C/D/ E/S/I/V are “revertants” that typically indicate “back mutations” after initial infection with NRTI-resistant virus. Revertants do not cause resistance themselves, but may indicate presence of archived resistant virus.
Accessory mutations	E44D, VI118I	Contribute to NRTI resistance when accompanied by multiple TAMs.
Non-TAM nucleoside analog mutation	K65R	Selected by TDF, ABC, ddI. Causes variable decrease in susceptibility to those drugs and to d4T, 3TC, and FTC, but hypersusceptibility to AZT. Rarely occurs in patients on AZTcontaining regimens or in setting of TAMs. Can also be selected by d4T. Selection appears less common with TDF/FTC than with TDF/3TC.
Non-TAM nucleoside analog mutation	L74V	Selected by ABC, ddI. (More common than K65R with ABC/3TC- containing regimens). Causes variable decrease in susceptibility to ABC and ddI, but hypersusceptibility to AZT, TDF. Rarely occurs in patients on AZT-containing regimens or in setting of TAMs.
3TC/FTC resistance mutation	M184V/I	Selected by 3TC, FTC. Causes high-level resistance to both drugs and modest decrease in susceptibility to ABC and ddI (not clinically significant when present alone). Increases susceptibility to AZT, d4T, TDF. Delays emergence of TAMs in thymidine analog-containing regimens.

(continued)

Chapter 2: Laboratory Tests

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Chapter 1

Chapter 2

Chapter 3

Chapter 4

Chapter 5

Chapter 6

Chapter 7

Chapter 2: Laboratory Tests