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WHO Updates List of Transmitted Mutations for Surveillance Studies
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3rd International Workshop on HIV Transmission:
Principles of Intervention
July 31-August 2, 2008, Mexico City
Mark Mascolini
Experts enlisted by the World Health Organization (WHO) updated a published list [1] of resistance mutations most likely to be transmitted from an infected person already harboring those mutations [2]. This list is proving valuable in understanding transmitted resistance because it eliminates mutations that may arise without drug pressure and tries to exclude other mutations with a low likelihood of transmission.
Resistance transmission leaders first proposed such a list in 2007 based on several rules:
- Mutations must occur on at least three of five mutation lists: IAS-USA, Los Alamos National Laboratory Sequence Database, the Stanford HIV Database interpretation program, the French Agence Nationale Reserche sur le SIDA (ANRS), and the Rega Institute.
- Mutations must not arise without more than 0.5% drug pressure in any HIV-1 subtype with more than 1000 sequences analyzed and without more than 1% drug pressure in any subtype with fewer sequences analyzed.
- Mutations are excluded if they occur in fewer than 1% of treated patients.
- Mutations must be applicable to all HIV-1 subtypes.
Excluding viral sequences from any untreated person with two or more antiretroviral-associated mutations, Diane Bennett (Centers for Disease Control) and coworkers analyzed 6669 subytpe B and 6733 non-B viruses from people naive to protease inhibitors (PIs), 6620 subtype B and 1168 non-B viruses from PI-treated people, 5087 subtype B and 5698 non-B viruses from reverse transcriptase inhibitor-naive people, 3499 subtype B and 829 non-B viruses from nucleoside-treated people, and 2094 subtype B and 1677 non-B viruses from nonnucleoside-treated people. The most frequent non-B viral samples were A (1125), AE (1008), AG (1481), C (2011), D (412), F (355), and G (341).
This analysis yielded the following list, with newly added mutations in bold italics:
PI mutations
L23I, L24I, T74P, D30N, V32I, I47V/M, G48M/V, I50V/L, F53L/Y, I54V/M/L/T/S/A, Q58E, G73S/T/C/A, L76V, V82A/F/L/T/ S/M/C, N83D, I84V, 85V, N88D/S, L89V, L90M
Nucleoside mutations
M41L, K65R, D67N/G, T69D/N/ins, K70E/R, L74I/V, V75T/M/S, Y115F, Q151M, M184V/I, L210W, T215C/D/E/F/V/Y/S/I, K219E/Q
Nonnucleoside mutations
L100I, K101E/P, K103N, V106A/M, E138K, V179F, Y181C/I/V, Y188L/C, G190A/S, P225H, M230L, 318F
Bennett and colleagues dropped the M46I PI mutation from the list because in the new analysis it appeared in 0.9% of 1008 subtype AE viral samples of untreated people.
These findings appeared in the workshop proceedings but were not presented during the meeting. The complete updated list is online at
http://hivdb.stanford.edu/pages/WHOResistanceList.html.
References
1. Shafer RW, Rhee SY, Pillay D, et al. HIV-1 protease and reverse transcriptase mutations for drug resistance surveillance. AIDS. 2007;21:215-223.
2. Bennett D, Kiuchi M, Rhee SY, et al. The World Health Organization 2008 list of mutations for surveillance of transmitted drug resistant HIV strains. 3rd International Workshop on HIV Transmission: Principles of Intervention. July 31-August 2, 2008, Mexico City. Abstract 38.
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