25 October 2000

Rega v4: Algorithm for the use of genotypic resistance data
Anne-Mieke Vandamme
Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium

Criteria to consider an isolate resistant or in the process of developing resistance resulting inthe advise against a particular drug: whenever the following mutations are found either asindicated or in combination with still other mutations

NRTI

NNRTI

PIdrugAmino acid substitutions

AZT

T215Y/F in absence of M184V; or (Q151M or T69S-SS); or 2 of (M41L,D67N,
K70R,L210W,T215Y/F,K219Q) in absence of M184V or in presence of(M184V+G333D/E); or 3 of (M41L,D67N,K70R,L210W,T215Y/F,K219Q) inpresence of M184V

DDC

K65R; or D67G; or T69D/G; or L74V; or V75T; or Q151M

DDI

K65R; or T69S-SS; or L74V; or Q151M

3TC

M184V/I; or (K65R and Q151M)

d4T

T69S-SS; or V75A/M/S/T; or Q151M; or [4 of(M41L,D67N,T69D/N,K70R,L210W,T215Y/F,K219Q)]

ABC[2 of (K65R,T69S-SS,L74V,Y115F, Q151M, M184V/I,T215Y/F)]; or [1 of(K65R,T69S-SS,L74V,Y115F, Q151M, M184V/I) and 3 of(M41L,D67N,K70R,V75T, V118I, L210W,T215Y/F,K219Q)]

PMEA

K65R; or K70E

NVP,DLV

L100I; or K103N; or V106A/I; or V108I; or Y181C/I; or Y188L; or Y188C/H (forNVP) or G190S/A (for NVP); or P236L (for DLV)EFVK103N; or Y188L; or G190S; or [2 of (L100I, K101E/Q, V106A, V108I, V179D,Y181C/I, Y188C/H, G190A)]

RTV orIND[(M46I/L or V82A/F/T/S or I84V)+1 of (L10F/I/R/V,K20M/R,L24I,L33F,M36I,M46I/L,G48V,I54V/L,A71I/T/V,G73S,V82A/F/T/S,I84V,L90M)]; or [4 of(L10I/R/V,K20M/R,L24I,L33F,M36I,G48V,I54V/L,A71I/T/V,G73S,L90M)]

SQV[(G48V or L90M) + 1 of (L10F/I/R/V, K20M/R,M46I/L,G48V, I54V/L,G73S,
V82A/F/T/S,I84V,L90M)]; or [4 of(L10F/I/R/V,K20M/R,M46I/L,I54V/L,G73S,V82A/F/T/S,I84V)]

NLF[(D30N or L90M) + 1 of (D30N,M36I,M46I/L,I54V/L,A71I/T/V,V77I,V82A/F/T/S,I84V,N88D,L90M)]; or [4 of (M36I,M46I/L,I54V/L,A71I/T/V,V77I,V82A/F/T/S,I84V,N88D)]

APV[I50V + 1 of (L10F/I/R/V,K20M/R, M46I/L,I47V,V82A/F/T/S,I84V,L90M)]; or [4 of(L10F/I/R/V,K20M/R,M46I/L,I47V,V82A/F/T/S,I84V,L90M)]

LPV/
RTV

More than 6 of (L10F/I/R/V,K20M/R,L24I,M46I/L,F53L,I54V/L,
A71I/T/V,V82A/F/T/S,I84V,L90M)

BMS23
2632

More than 6 of (L10F/I/Y, K20I/R/T, L24I, V32I, L33F/V/M/I, M36V/I/L,M46L/I/V, G48V, I50V/L, I54V, L63A/P/T, A71V/T, G73C/A/T, V77I,V82A/M/T, I84V, N88D/S, L89M, L90M)

Primary or key mutations are indicated in bold, secondary or accessory mutations are in plain text

Criteria to consider an isolate sensitive
resulting in no restraint on the use of a particular drug
No mutations or only 1 non-essential PI mutation; for ZDV 1 of
(M41L,D67N,K70R,L210W,T215Y/F,K219Q) in presence of M184V/I; for d4T up to 2 of
(M41L,D67N,T69D/N,K70R,L210W, T215Y/F,K219Q); for ABC up to 3 of(M41L,D67N,K70R,V75T,V118I,L210W,T215Y/F,K219Q); for LPV/RTV up to 4 of(L10F/I/R/V,K20M/R,L24I,M46I/L,F53L,I54V/L,A71I/T/V,V82A/F/T/S,I84V,L90M); for BMS232632 up
to 3 of (L10Y, V32I, L33F, M46I, G48V, I50L, L63P, A71V, I84V, N88S, L89M)

Criteria to advise against a particular drug when other options are still available
Any number of drug-related mutations as listed in the upper panel which is inbetween sensitive (middlepanel) and resistant (drug-related mutations in upper panel). In addition: for ABC, DDI, and DDC 4 of(M41L, D67N, T69D, K70R, V75T, L210W, T215Y/F, K219Q); for DDI and DDC the presence ofM184V/I; for ABC T215Y/F+M41L; for 3TC the presence of E44A/D and/or V118I in combination withseveral AZT resistance mutations, or the presence of T69S-SS; for d4T 3 of (M41L, D67N, T69D/N, K70R,L210W, T215Y/F, K219Q); for DDI the presence of V75T; for NNRTIs also A98G; for NVP and DLV
K101E/Q; for DLV Y188C/H

Patients carrying virus with combinations of mutations scored as resistant in the upper panel, may stillbe partially responding to MegaHAART (>4 drugs). Patients carrying virus with combinations ofmutations scored as intermediate in the lower panel, may still be temporarily responding to this drug ina HAART combination.

This algorithm was based on personal experience, on the references described in the legend toFigure 1, and on Anton et al., 1999; Bacheler et al., 1999, Bloor et al., 1999; Condra et al.,
1999; Danner et al., 1995; Davey et al., 1996; De Noon, 1998; Gulick et al., 1996; Hammer etal., 1999; Havlir et al., 1995,1996; Hertogs et al., 2000; Katzenstein et al., 1996; Kemp et al.,
1999; Kleim et al., 1997; Staszewski et al., 1997; Lanier et al., 1999; Larder et al., 1991,
1998; Lea et al., 1996; Lin et al., 1999; Markowitz et al., 1995; Patick et al., 1998; Schinazi etal., 1999; Schmidt et al., 2000; Schuurman et al., 1995; Shafer et al., 1999a; Staszewski et al.,
1998; Sun et al., 2000; Tisdale et al., 1999; Vandamme et al., 2000b, Winters et al., 1998;Colonno et al. Fourth International Workshop on HIV Drug Resistance and Treatment
Strategies, 12-16 June 2000, Sitges, Spain. (Abstract 8); B. Clotet, L. Menénendez-Arias, L.
Ruiz, C. Tural, A.-M. Vandamme, D. Burger, J.M. Shapiro, C.A. Boucher, R. D’Aquila, D.D.
Richman, eds. Guide to management of HIV resistance and pharmacokinetics of drug therapy.
Editorial TAISA, S.L., Barcelona, Spain, 2000.