Katholieke Universiteit Leuven
Rega Institute for Medical Research and University Hospitals Leuven
Microbiology and Immunology
Clinical and Epidemiological Virology
Kristel Van Laethem1, 2, Koen Deforche1, Anna Maria Geretti4, Ricardo Camacho3 and Anne-Mieke Vandamme1
1 Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium
2 AIDS Reference Laboratory, University Hospitals Leuven, Leuven, Belgium

3 Molecular Biology Laboratory, Centro Hospitalar de Liboa Ocidental, Lisbon, Portugal
4 Royal Free Hospital and RF&UC Medical School, London, United Kingdom

www.kuleuven.ac.be/rega/cev/linkskristel.vanlaethem @uz.kuleuven.ac.be

Algorithm for the use of genotypic HIV-1 resistance data
Rega v7.1.1 ©, Leuven, 5 July 2007
The rules include and score mutations for which in vitro phenotypic drug resistance or in vivo therapy response data have been reported, or for which retrospective associations with drug experience have been described. Some of the mutations do not necessarily
result in high-level phenotypic resistance. Instead, they have been identified as key mutations along a pathway leading to high-level resistance (e.g., T215 revertants) or have proved to be predictive of therapy failure. Where supported by reliable evidence, theantagonistic or synergistic interaction effects of combinations of mutations are also incorporated (e.g., M184IV and TAMs). Three levels of interpretation criteria are applied: for HIV-1, criteria to consider an isolate as resistant, intermediately resistant or susceptible.
Genotypic susceptibility scores (GSS) are assigned to the three susceptibility levels for each drug class or individual drug. Although the same rules apply to each PI and its respective PI/r, different GSS are assigned to the boosted and un-boosted drug.
GSS
NRTI - NtRTI
NNRTI
Etravirine
PIPI/r
EI

resistant
000000intermediate resistant
0.5
0.25
0.5
0.5
0.75
0.25

susceptible
1111
1.5
1

Target GSS for the entire treatment combination regimen are proposed. Resistance development is expected when therapy changes with GSS below the target are installed.
Clinical situation
Therapy-naive persons with indications of transmitted drug resistance
Therapy-naive and therapy-experienced persons
Therapy-experienced persons with limited treatment optionsTarget GSS≥3.5≥3≥2Criteria to consider an isolate resistant a,b,c

Criteria to consider an isolate intermediately resistant a,b,c

NRTIzidovudine[at least 1 mutation of (T69X-XX,Q151M)]
or [at least 4 mutations of (M41L,D67GN,T69AN,K70R,L210W,T215ACDEGHILNSVFY,K219EHNQR)]
or [3 mutations of (M41L,L210W,T215Y) and not M184IV and not L74V]or [at least 3 mutations of (D67GN,K70R,T215F, K219EQ)][2 or 3 mutations of (M41L,D67GN,T69AN,K70R,L210W,T215ACDEGHILNSVFY,K219EHNQR)]
or [T215FY and not M184IV]

didanosine

at least 1 mutation of (T69DGN,T69X-XX,Q151M)
or [M184IV and at least 1 mutation of (K65RN,L74IV)]or [at least 5 mutations of (M41L,D67N,K70R,L210W,T215ACDEGHILNSVFY,K219EHNQR)]

at least 1 mutation of (K65NR,L74IV,V75T)or [3 or 4 mutations of (M41L,D67N,K70R,L210W,T215ACDEGHILNSVFY,K219EHNQR)]

stavudine[at least 1 mutation of (∆67,T69X-XX,V75AMST,Q151M)]
or [at least 4 mutations of (M41L,D67N,T69ADGN,K70R,L210W,T215ACDEGHILNSVFY,K219EHNQR)]
or [3 mutations of (M41L,L210W,T215Y)][2 or 3 mutations of (M41L,D67N,T69ADGN,K70R,L210W,T215ACDEGHILNSVFY,K219EHNQR)]
or [T215FY and not M184IV]

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lamivudine

M184IVor (K65NR and Q151M)[at least 1 mutation of (∆67,T69X-XX,K65NR,Q151M)]
or {[at least 1 mutation of (E44AD,V118I)]
and [at least 3 mutations of (M41L,D67N,T69AN,K70R,L210W,T215FY,K219EHNQR)]}

abacavir[at least 1 mutation of (∆67,T69G)]or [at least 2 mutations of (K65NR,T69X-XX,L74IV,Y115F,Q151M,M184IV)]or {(T69X-XX or Q151M) and [at least 3 mutations of (M41L,D67N,K70R,L210W,T215ACDEGHILNSVFY,K219EHNQR)]}or {[at least 1 mutation of (K65NR,L74IV,Y115F,M184IV)]
and [at least 4 mutations of (M41L,D67N,K70R,L210W,T215ACDEGHILNSVFY,K219EHNQR]}[1 mutation of (T69X-XX,Q151M)]
or [1 mutation of (K65NR,L74IV,Y115F,M184IV)]
and [2 or 3 mutations of (M41L,D67N,K70R,L210W,T215ACDEGHILNSVFY,K219EHNQR]}
or [at least 3 mutations of (M41L,D67N,K70R,L210W,T215ACDEGHILNSVFY,K219EHNQR)]

emtricitabine

M184IVor (K65NR and Q151M)[at least 1 mutation of (∆67,T69X-XX,K65NR,Q151M)]
or {[at least 1 mutation of (E44AD,V118I)]
and [at least 3 mutations of (M41L,D67N,T69AN,K70R,L210W,T215FY,K219EHNQR)]}[at least 1 mutation of (K65NR,T69X-XX)]or [at least 5 mutations of (M41L,D67N,K70R,L210W,T215ACDEGHILNSVYF,K219EHNQR)][at least 1 mutation of (70EG,Q151M)]
or [K65NR and M184IV]or [3 mutations of (M41L,L210W,T215Y)]
or [at least 4 mutations of (M41L,D67N,K70R,L210W,T215ACDEGHILNSVYF,K219EHNQR)]

nevirapine[at least 1 mutation of (L100I,K101P,K103HNST,V106AM,Y181CIV,Y188CHL,G190ACEQSTV,M230L)]or [at least 4 mutations of (A98G,K101EQ,K103R,V106I,V108I,V179D,H221Y,F227L,K238T,Y318F)][2 or 3 mutations of (A98G,K101EQ,V106I,V108I,V179D,H221Y,F227L,K238T,Y318F)]or (K103R and V179D)

delavirdine[at least 1 mutation of (L100I,K103HNT,V106AM,Y181CIV,Y188L,G190E,M230L,P236L)]or [at least 2 mutations of (K101P,K103S,Y188CH,G190Q,Y318F)]or [1 mutation of (K101P,K103S,Y188CH,G190Q,Y318F) and at least 2 mutations of(A98G,K101EQ,K103R,V106I,V108I,V179D,F227L)]or [at least 4 mutations of (A98G,K101EQ,K103R,V106I,V108I,V179D,F227L)][1 mutation of (K101P,K103S,Y188CH,G190Q,Y318F)]or [2 or 3 mutations of (A98G,K101EQ,V106I,V108I,V179D,F227L)]or (K103R and V179D)

efavirenz[at least 1 mutation of (K103HN,V106M,Y181C,Y188L,G190CEQSTV,M230L)]or [at least 2 mutations of (L100I,K101P,K103ST,V106A,Y181IV,Y188CHF,G190A,P225H)]or [1 mutation of (L100I,K101P,K103ST,V106A,Y181IV,Y188CHF,G190A,P225H)
and at least 2 mutations of (A98G,K101EQ,K103R,V106I,V108I,V179D,H221Y,F227L,K238T,Y318F)]or [at least 4 mutations of (A98G,K101EQ,K103R,V106I,V108I,V179D,H221Y,F227L,K238T,Y318F)][1 mutation of (L100I,K101P,K103ST,V106A,Y181IV,Y188CHF,G190A,P225H)]or [2 or 3 mutations of (A98G,K101EQ,V106I,V108I,V179D,H221Y,F227L,K238T,Y318F)]or (K103R and V179D)

etravirine(V179DEFI and Y181CV)or [at least 1 mutation of (Y181I,F227C,M230L) and at least 1 mutation of (L100I,K101ENP,E138K,V179DEFI,Y181CV,Y188L,G190ES)]or [at least 1 mutation of (Y181I,F227C,M230L) and at least 2 mutations of (A98G,K101QR,K103N,V106AM,V108I,Y188CFH,G190ACQTV,H221Y,P225H,F227L,L234I,P236L,K238T,Y318T)]or [at least 3 mutations of (L100I,K101ENP,E138K,V179DEFI,Y181CV, Y188L,G190ES)]or [at least 2 mutations of (L100I,K101ENP,E138K,V179DEFI,Y181CV,Y188L,G190ES) and at least 2 mutations of(A98G,K101QR,K103N,V106AM,V108I,Y188CFH,G190ACQTV,H221Y,P225H,F227L,L234I,P236L,K238T, Y318T)]or [at least 1 mutation of (L100I,K101ENP,E138K,V179DEFI,Y181CV,Y188L,G190ES) and at least 4 mutations of(A98G,K101QR,K103N,V106AM,V108I,Y188CFH,G190ACQSTV,H221Y,P225H,F227L,L234I,P236L,K238T, Y318T)]or [at least 6 mutations of (A98G,K101QR,K103N,V106AM,V108I,Y188CFH,G190ACQTV,H221Y,P225H,F227L,L234I,P236L,K238T,Y318T)][1 mutation of (Y181I,F227C,M230L)]or [2 mutations of (L100I,K101ENP,E138K,V179DEFI,Y181CV, Y188L,G190ES)]or [1 mutation of (L100I,K101ENP,E138K,V179DEFI,Y181CV,Y188L,G190ES) and at least 2 mutations of(A98G,K101QR,K103N,V106AM,V108I,Y188CFH,G190ACQTV,H221Y,P225H,F227L,L234I,P236L,K238T,Y318T)]or [4 or 5 mutations of (A98G,K101QR,K103N,V106AM,V108I,Y188CFH,G190ACQTV,H221Y,P225H,F227L,L234I,P236L,K238T,Y318T)]

NtRTI
tenofovir

NNRTI

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PIdsaquinavir/rscore is at least 3.5[add 1.5 to the score for every mutation in the following list: 48MV,54AST,84AC,90M;
add 1 to the score for every mutation in the following list: 24I,53L,54V,71V,84V,88DS,89V;
add 0.5 to the score for every mutation in the following list: 10F,20T,46IL,48A,50V,54LM,58E,71I,73STC, 74SP,89T;
add 0.25 to the score for every mutation in the following list: score 0.25: 10IV,11I,20IMRV,62V,71T,74A,82AIFLMST,89I;
distract 0.5 from the score for every mutation in the following list: 50L]

score is at least 2[add 1.5 to the score for every mutation in the following list: 48MV,54AST,84AC,90M;
add 1 to the score for every mutation in the following list: 24I,53L,54V,71V,84V,88DS,89V;
add 0.5 to the score for every mutation in the following list: 10F,20T,46IL,48A,50V,54LM,58E,71I,73STC, 74SP,89T;
add 0.25 to the score for every mutation in the following list: score 0.25: 10IV,11I,20IMRV,62V,71T,74A,82AIFLMST,89I;
distract 0.5 from the score for every mutation in the following list: 50L]

indinavir/rscore is at least 3[add 1.5 to the score for every mutation in the following list: 46IL,54AST,82AT,84A;
add 1 to the score for every mutation in the following list: 10F,24I,32I,48MV,54V,76V,82FMS,88S,90M;
add 0.5 to the score for every mutation in the following list: 20T,32X-X,43T,48A,54LM,66F,71I, 73STC,74P,84CV,88D,89TV,95F;
add 0.25 to the score for every mutation in the following list: score 0.25: 10IV,20IMRV,35DGN,43R,62V,71TV,74AS,82I,89I;
distract 0.5 from the score for every mutation in the following list: 50L]

score is at least 2[add 1.5 to the score for every mutation in the following list: 46IL,54AST,82AT,84A;
add 1 to the score for every mutation in the following list: 10F,24I,32I,48MV,54V,76V,82FMS,88S,90M;
add 0.5 to the score for every mutation in the following list: 20T,32X-X,43T,48A,54LM,66F,71I, 73STC,74P,84CV,88D,89TV,95F;
add 0.25 to the score for every mutation in the following list: score 0.25: 10IV,20IMRV,35DGN,43R,62V,71TV,74AS,
82I,89I;
distract 0.5 from the score for every mutation in the following list: 50L]

nelfinavirscore is at least 2.5[add 1.5 to the score for every mutation in the following list: 30N,54AST,84AC,88S,90M;
add 1 to the score for every mutation in the following list: 54V,82ATF,88D;
add 0.5 to the score for every mutation in the following list: 10F,20T,23I,24I,32I,43T,46IL,48AV,
54LM,58E,66F,71I,73STC,74P,82LMS,84V,89TV,93M;
add 0.25 to the score for every mutation in the following list:
10IV,20IMRV,33FI,35DGN,43R,62V,64V,71TV,74AS,82I,89I;
distract 0.5 from the score for every mutation in the following list: 50L;
distract 0.25 from the score for every mutation in the following list: 70R]

score is at least 1.5[add 1.5 to the score for every mutation in the following list: 30N,54AST,84AC,88S,90M;
add 1 to the score for every mutation in the following list: 54V,82ATF,88D;
add 0.5 to the score for every mutation in the following list: 10F,20T,23I,24I,32I,43T,46IL,48AV,
54LM,58E,66F,71I,73STC,74P,82LMS,84V,89TV,93M;
add 0.25 to the score for every mutation in the following list:
10IV,20IMRV,33FI,35DGN,43R,62V,64V,71TV,74AS,82I,89I;
distract 0.5 from the score for every mutation in the following list: 50L;distract 0.25 from the score for every mutation in the following list: 70R]

fosamprenavir(/r)

score is at least 3.5[add 1.5 to the score for every mutation in the following list: 32X-X,50V,84AC;
add 1 to the score for every mutation in the following list: 47AV,48M,54MTV,76V,82F,84V;
add 0.5 to the score for every mutation in the following list: 10F,20T,24I,32I,33F,43T,46IL,48A,54AL,58E,82AMST,89TV;
add 0.25 to the score for every mutation in the following list: 10IV,20IRMV,33I,43R,48V,82I,89I,90M;
distract 0.5 from the score for every mutation in the following list: 50L]

score is at least 2[add 1.5 to the score for every mutation in the following list: 32X-X,50V,84AC;
add 1 to the score for every mutation in the following list: 47AV,48M,54MTV,76V,82F,84V;
add 0.5 to the score for every mutation in the following list: 10F,20T,24I,32I,33F,43T,46IL,48A,54AL,58E,82AMST,89TV;
add 0.25 to the score for every mutation in the following list: 10IV,20IRMV,33I,43R,48V,82I,89I,90M;
distract 0.5 from the score for every mutation in the following list: 50L]lopinavir/rscore is at least 4[add 1.5 to the score for every mutation in the following list: 32X-X,47A,54AT;
add 1 to the score for every mutation in the following list: 47V,48M,50V,54SV,76V,82FS,84A;
add 0.5 to the score for every mutation in the following list: 10F,20T,24FI,32I,33F,43T,46IL,48AV,53L,54LM, 71I,73STC,
82ALMT,84V,88D,90M;
add 0.25 to the score for every mutation in the following list: 10IV,20IMRV,33I,43R,64MV,71TV,77ATV,82I;
distract 0.5 from the score for every mutation in the following list: 50L]score is at least 2.5[add 1.5 to the score for every mutation in the following list: 32X-X,47A,54AT;
add 1 to the score for every mutation in the following list: 47V,48M,50V,54SV,76V,82FS,84A;
add 0.5 to the score for every mutation in the following list: 10F,20T,24FI,32I,33F,43T,46IL,48AV,53L,54LM, 71I,73STC,82ALMT,84V,88D,90M;
add 0.25 to the score for every mutation in the following list: 10IV,20IMRV,33I,43R,64MV,71TV,77ATV,82I;
distract 0.5 from the score for every mutation in the following list: 50L]

atazanavir(/r)

score is at least 3.5[add 1.5 to the score for every mutation in the following list: 48V,50L,54AT;
add 1 to the score for every mutation in the following list: 20T,47V,54V,74P,82T,84V,88DS,90M;
add 0.5 to the score for every mutation in the following list: 10F,24I,32I,46IL,54LM,58E,71IL,73ACFST,82ALMSF,85V;
add 0.25 to the score for every mutation in the following list: 10IV,20IMRV,33FI,71TV,74AS,82I]score is at least 2[add 1.5 to the score for every mutation in the following list: 48V,50L,54AT;
add 1 to the score for every mutation in the following list: 20T,47V,54V,74P,82T,84V,88DS,90M;
add 0.5 to the score for every mutation in the following list: 10F,24I,32I,46IL,54LM,58E,71IL,73ACFST,82ALMSF,85V;
add 0.25 to the score for every mutation in the following list: 10IV,20IMRV,33FI,71TV,74AS,82I]

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tipranavir/rscore is at least 5[add 1.5 to the score for every mutation in the following list: 47V,54A,82T,84V;
add 1 to the score for every mutation in the following list: 11L,32I,33FM,38W,41T,54S,73T,82L;
add 0.5 to the score for every mutation in the following list: 10F,20T,43T,45I,46IL,54MVT,58E, 71ILF,73SC,82ACSFM,88DS,89VT,90M;
add 0.25 to the score for every mutation in the following list:
10IV,13V,20IMRV,33IV,35DGN,36I,41K,43R,69K,71TV,82I,89I;
distract 0.5 from the score for every mutation in the following list: 50L;
distract 0.25 from the score for every mutation in the following list: 57R]

score is at least 3[add 1.5 to the score for every mutation in the following list: 47V,54A,82T,84V;
add 1 to the score for every mutation in the following list: 11L,32I,33FM,38W,41T,54S,73T,82L;
add 0.5 to the score for every mutation in the following list: 10F,20T,43T,45I,46IL,54MVT,58E, 71ILF,73SC,82ACSFM,88DS,89VT,90M;
add 0.25 to the score for every mutation in the following list:
10IV,13V,20IMRV,33IV,35DGN,36I,41K,43R,69K,71TV,82I,89I;
distract 0.5 from the score for every mutation in the following list: 50L;
distract 0.25 from the score for every mutation in the following list: 57R]

darunavir/rscore is at least 5[add 1.5 to the score for every mutation in the following list: 50V;
add 1 to the score for every mutation in the following list: 76V,84ACV;
add 0.5 to the score for every mutation in the following list: 32I,33F,47AV;
add 0.25 to the score for every mutation in the following list: 11I,32L,33IMV,34V,35GN,41IT,46IL,54LM,70E,73ACFSTV,
74E,82L,85V,89ITV]

score is at least 3[add 1.5 to the score for every mutation in the following list: 50V;
add 1 to the score for every mutation in the following list: 76V,84ACV;
add 0.5 to the score for every mutation in the following list: 32I,33F,47AV;
add 0.25 to the score for every mutation in the following list: 11I,32L,33IMV,34V,35GN,41IT,46IL,54LM,70E,73ACFSTV,
74E,82L,85V,89ITV]

at least 2 mutations of (G36DESV,V38AEM,Q40H,Q41R,N42DEHKQT,N43DKQS,L44MV,L45MPQ)

1 mutation of (G36DESV,V38AEM,Q40H,Q41R,N42DEHKQT,N43DKQS,L44MV,L45MPQ)

EI
enfuvirtidea T69X-XX, X whatever amino acid. ∆67, deletion of amino acid 67. A, alanine; R, arginine; N, asparagine; D, aspartic acid; C, cysteine; Q, glutamine; E, glutamic acid; G, glycine; H, histidine; I, isoleucine; L, leucine; K, lysine; M, methionine; F, phenylalanine; P,proline; S, serine; T, threonine; W, tryptophan; Y, tyrosine and V, valine. b If more mutations are present at a certain position (e.g. T215Y and T215F), they are only counted as one mutation in the rules. c If none of the criteria to consider an isolate resistant towards aparticular drug are full-filled, proceed to the criteria to consider an isolate intermediately resistant. If none of the latter criteria are full-filled, the isolate can be scored susceptible to that particular drug. d r, PI boosted with baby dose of ritonavir. NRTI, nucleosidereverse transcriptase inhibitor; NtRTI, nucleotide reverse transcriptase inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibitor; PI, protease inhibitor; EI, entry inhibitor.

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