KU Leuven
Rega Institute for Medical Research and University Hospitals Leuven
Microbiology and Immunology
Clinical and Epidemiological Virology
Ricardo Camacho 1,3, Kristel Van Laethem1, 2, Anna Maria Geretti4, Jens Verheyen5, Roger Paredes6 and Anne-Mieke Vandamme1
1 Rega Institute for Medical Research, KU Leuven, Leuven, Belgium
2 AIDS Reference Laboratory, University Hospitals Leuven, Leuven, Belgium
3 Centro de Malária e outras Doenças Tropicais, Instituto de Higiene e Medicina Tropical, Lisboa, Portugal
4 Royal Free Hospital and RF&UC Medical School, London, United Kingdom
5 Universitätsklinikum Essen, Institut für Virologie, Essen, Germany
6 HIV Unit and irsiCaixa AIDS Research Institute, Hospital Universitari Germans Trias i Pujol, Badalona, Catalonia, Spain

www.kuleuven.ac.be/rega/cev/links
kristel.vanlaethem@uzleuven.be

Algorithm for the use of genotypic HIV-1 resistance data
Rega v9.1.0 ©, Leuven, 29 October 2013
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
PI
PI/r
EI
INI
dolutegravir

resistant
0
0
0
0
0
0
0
0

intermediate resistant
0.5
0.25
0.5
0.5
0.75
0.25
0.25
0.5

susceptible
1
1
1
1
1.5
1
1
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 options

Target GSS
≥3.5
≥3
≥2

Criteria to consider an isolate resistant a,b,c

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

NRTI
zidovudine[at least 1 mutation of (69X-XX,151M)]
or [at least 4 mutations of (41L,67GN,69AN,70R,210W,215ACDEGHILNSVFY,219EHNQR)]
or [3 mutations of (41L,210W,215Y) and not 184IV and not 74V]or [at least 3 mutations of (67GN,70R,215F,219EQ)][2 or 3 mutations of (41L,67GN,69AN,70R,210W,215ACDEGHILNSVFY,219EHNQR)]
or [215ACDEGHILNSVFY and not 184IV]

didanosine

at least 1 mutation of (69DGN,69X-XX,151M)
or [184IV and at least 1 mutation of (65RN,74IV)]or [at least 5 mutations of (41L,67N,70R,74IV,210W,215ACDEGHILNSVFY,219EHNQR)]

at least 1 mutation of (65NR,70EG,74IV,75T)or [2 mutations of (41L,215FY)]or [at least 3 mutations of (41L,67N,70R,210W,215ACDEGHILNSVFY,219EHNQR)]
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stavudine[at least 1 mutation of (∆67,69X-XX,75AMST,151M)]
or [at least 4 mutations of (41L,67N,69ADGN,70R,210W,215ACDEGHILNSVFY,219EHNQR)]
or [3 mutations of (41L,210W,215Y)][2 or 3 mutations of (41L,67N,69ADGN,70R,210W,215ACDEGHILNSVFY,219EHNQR)]
or [215ACDEGHILNSVFY and not 184IV]

lamivudine

184IVor (65NR and 151M)[at least 1 mutation of (65NR,∆67,69X-XX,70EG)]or {[at least 1 mutation of (44AD,118I)]
and [at least 3 mutations of (41L,67N,69AN,70R,210W,215ACDEGHILNSVFY,219EHNQR)]}or [151M and at least 3 mutations of (75I,77L,116Y)]

abacavir[at least 1 mutation of (∆67,69G)]or [at least 2 mutations of (65NR,69X-XX,74IV,115F,151M,184IV)]or {(69X-XX) and [at least 3 mutations of (41L,67N,70R,210W,215ACDEGHILNSVFY,219EHNQR)]}or {[at least 1 mutation of (65NR,74IV,115F,184IV)]
and [at least 4 mutations of (41L,67N,70R,210W,215ACDEGHILNSVFY,219EHNQR]}
or [151M and at least 2 mutations of (75I,77L,116Y)][1 mutation of (69X-XX,70EG,151M)]
or {[1 mutation of (65NR,74IV,115F,184IV)]
and [2 or 3 mutations of (41L,67N,70R,210W,215ACDEGHILNSVFY,219EHNQR]}
or [at least 3 mutations of (41L,67N,70R,210W,215ACDEGHILNSVFY,219EHNQR)]

emtricitabine184IVor (65NR and 151M)[at least 1 mutation of (65NR,∆67,69X-XX,70EG)]or {[at least 1 mutation of (44AD,118I)]
and [at least 3 mutations of (41L,67N,69AN,70R,210W,215ACDEGHILNSVFY,219EHNQR)]}or [151M and at least 3 mutations of (75I,77L,116Y)]

69X-XXor (65NR and not 184IV)
or [at least 5 mutations of (41L,67N,70R,210W,215ACDEGHILNSVYF,219EHNQR)]

70EG
or [65NR and 184IV]
or [at least 3 mutations of (41L,210W,215Y)]
or [at least 4 mutations of (41L,67N,70R,210W,215ACDEGHILNSVYF,219EHNQR)]
or [151M and at least 3 mutations of (75I,77L,116Y)]

nevirapinescore is at least 2[add 2 to the score for every mutation in the following list: 100I,101P,103HNST,106AM,181CIV,188CHL,190ACEQSTV,
230IL;
add 1 to the score for every mutation in the following list: 138KQ,227CL,238NT,318F;
add 0.5 to the score for every mutation in the following list: 98G,101EHNQ,103R,106I,108I,179DE,221Y]

score is at least 1[add 1 to the score for every mutation in the following list: 138KQ,227CL,238NT,318F;
add 0.5 to the score for every mutation in the following list: 98G,101EHNQ,103R,106I,108I,179DE,221Y]

efavirenz

score is at least 2[add 2 to the score for every mutation in the following list: 100I,101P,103HNST,106M,181CIV,188CHFL,190ACEQSTV,
230IL;
add 1.5 to the score for every mutation in the following list: 106A,138Q,225H;
add 0.5 to the score for every mutation in the following list: 90I,98G,101EHNQ,103R,106I,108I,138K,179DE,221Y,
227CL,238NT,318F]

score is at least 1[add 1.5 to the score for every mutation in the following list: 106A,138Q,225H;
add 0.5 to the score for every mutation in the following list:
90I,98G,101EHNQ,103R,106I,108I,138K,179DE,221Y,227CL,238NT,318F]

NtRTI
tenofovir

NNRTI

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etravirinescore is at least 3[add 1.5 to the score for every mutation in the following list: 100I,101P,181CIV,227C,230IL;
add 0.75 to the score for every mutation in the following list:138KQ,179F,190CEQSTV;
add 0.5 to the score for every mutation in the following list: 101EHNQ,106I,138A,190A;
add 0.25 to the score for every mutation in the following list: 90I,98G,101R,103HNST,106AM,108I,179DET,188CHFL,
221Y,225H,227L,234I,236L,238NT,318F]

score is at least 1.5[add 1.5 to the score for every mutation in the following list: 100I,101P,181CIV,227C,230IL;
add 0.75 to the score for every mutation in the following list:138KQ,179F,190CEQSTV;
add 0.5 to the score for every mutation in the following list: 101EHNQ,106I,138A,190A;
add 0.25 to the score for every mutation in the following list: 90I,98G,101R,103HNST,106AM,108I,179DET,188CHFL,
221Y,225H,227L,234I,236L,238NT,318F]

rilpivirinescore is at least 2.5[add 2.5 to the score for every mutation or combination of mutations in the following list:
101P,(101E+184IV),(100I+103N),(138K+184IV),181IV,188L;
add 1.5 to the score for every mutation in the following list: 101E,138AGKQRS,179L,181C,221Y,227C,230IL;
add 0.5 to the score for every mutation in the following list: 90I,101QT,103S,106AI,108I,179DIT,189I,190E]

score is at least 1.5[add 1.5 to the score for every mutation in the following list: 101E,138AGKQSR,179L,181C,221Y,227C,230IL;
add 0.5 to the score for every mutation in the following list: 90I,101QT,103S,106AI,108I,179DIT,189I,190E]

saquinavir/rscore is at least 3.5[add 2 to the score for every mutation in the following list: 48MV,90M;
add 1.5 to the score for every mutation in the following list: 54AST,84AC;
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: 10IV,11I,20IMRV,62V,71T,74A,82AFLMST,89I;
subtract 0.25 from the score for every mutation in the following list: 50L]

score is at least 2[add 2 to the score for every mutation in the following list: 48MV,90M;
add 1.5 to the score for every mutation in the following list: 54AST,84AC;
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: 10IV,11I,20IMRV,62V,71T,74A,82AFLMST,89I;
subtract 0.25 from the score for every mutation in the following list: 50L]

indinavir/rscore is at least 3[add 2 to the score for every mutation in the following list: 82AFST,84AV;
add 1.5 to the score for every mutation in the following list: 46IL,54AST;
add 1 to the score for every mutation in the following list: 10F,24I,32I,48MV,54V,76V,82M,88S,90M;
add 0.5 to the score for every mutation in the following list: 20T,43T,48A,54LM,66F,71I, 73STC,74P,84C,88D,89TV,95F;
add 0.25 to the score for every mutation in the following list: 10IV,20IMRV,35GN,43R,62V,71TV,74AS,89I;
subtract 0.25 from the score for every mutation in the following list: 50L]

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

nelfinavirscore is at least 2[add 2 to the score for every mutation in the following list: 30N,90M;
add 1.5 to the score for every mutation in the following list: 54AST,84AC,88S;
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,76V,82LMS,84V,89TV,93M;
add 0.25 to the score for every mutation in the following list: 10IV,20IMRV,33FI,35GN,43R,62V,64V,71TV,74AS,89I;
subtract 0.25 from the score for every mutation in the following list: 50L]

score is at least 1.25
[add 2 to the score for every mutation in the following list: 30N,90M;
add 1.5 to the score for every mutation in the following list: 54AST,84AC,88S;
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,76V,82LMS,84V,89TV,93M;
add 0.25 to the score for every mutation in the following list: 10IV,20IMRV,33FI,35GN,43R,62V,64V,71TV,74AS,89I;
subtract 0.25 from the score for every mutation in the following list: 50L]

fosamprenavir/rscore is at least 3.5[add 2 to the score for every mutation in the following list: 50V;
add 1.5 to the score for every mutation in the following list: 76V,84ACV;
add 1 to the score for every mutation in the following list: 47AV,48M,54MTV,82F;
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,89I,90M;
subtract 0.25 from the score for every mutation in the following list: 50L,88S]

score is at least 2[add 2 to the score for every mutation in the following list: 50V;
add 1.5 to the score for every mutation in the following list: 76V,84ACV;
add 1 to the score for every mutation in the following list: 47AV,48M,54MTV,82F;
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,89I,90M;
subtract 0.25 from the score for every mutation in the following list: 50L,88S]

PId

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lopinavir/rscore is at least 3.5[add 2 to the score for every mutation in the following list: 47A;
add 1.5 to the score for every mutation in the following list: 32X-X,50V,54AT,76V;
add 1 to the score for every mutation in the following list: 47V,48M,54SV,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;
subtract 0.25 from the score for every mutation in the following list: 50L]

score is at least 2[add 2 to the score for every mutation in the following list: 47A;
add 1.5 to the score for every mutation in the following list: 32X-X,50V,54AT,76V;
add 1 to the score for every mutation in the following list: 47V,48M,54SV,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;
subtract 0.25 from the score for every mutation in the following list: 50L]

atazanavir(/r)

score is at least 3.5[add 2 to the score for every mutation in the following list: 48MV,50L;
add 1.5 to the score for every mutation in the following list: 54AST,88S;
add 1 to the score for every mutation in the following list: 10Y,20T,47V,54V,74P,82LT,84V,88D,90M;
add 0.5 to the score for every mutation in the following list: 10F,24I,32I,46IL,54LM,58E,71IL,73ACFST,82AMSF,85V;
add 0.25 to the score for every mutation in the following list: 10IV,20IMRV,33FI,71TV,74AS;
subtract 0.25 from the score for every mutation in the following list: 76V]

score is at least 2[add 2 to the score for every mutation in the following list: 48MV,50L;
add 1.5 to the score for every mutation in the following list: 54AST,88S;
add 1 to the score for every mutation in the following list: 10Y,20T,47V,54V,74P,82LT,84V,88D,90M;
add 0.5 to the score for every mutation in the following list: 10F,24I,32I,46IL,54LM,58E,71IL,73ACFST,82AMSF,85V;
add 0.25 to the score for every mutation in the following list: 10IV,20IMRV,33FI,71TV,74AS;
subtract 0.25 from the score for every mutation in the following list: 76V]

tipranavir/rscore is at least 3.5[add 2 to the score for every mutation in the following list: 47V, 74P,82T;
add 1.5 to the score for every mutation in the following list: 58E,82LS,83D;
add 1 to the score for every mutation in the following list:: 41T,43T,54AMV,84ACV;
add 0.5 to the score for every mutation in the following list: 33F,47A,46L,54ST;
add 0.25 to the score for every mutation in the following list: 11L,32I,38W,45I,71L,73T,82AFM,89TV,90M;
subtract 0.25 from the score for every mutation in the following list: 50L]

score is at least 2[add 2 to the score for every mutation in the following list: 47V, 74P,82T;
add 1.5 to the score for every mutation in the following list: 58E,82LS,83D;
add 1 to the score for every mutation in the following list:: 41T,43T,54AMV,84ACV;
add 0.5 to the score for every mutation in the following list: 33F,47A,46L,54ST;
add 0.25 to the score for every mutation in the following list: 11L,32I,38W,45I,71L,73T,82AFM,89TV,90M;
subtract 0.25 from the score for every mutation in the following list: 50L]

darunavir/rscore is at least 3.5[add 1.5 to the score for every mutation in the following list: 50V,54M,76V,84ACV;
add 1 to the score for every mutation in the following list: 11I,32I,33F,41T,47AV,54L,70E,74P,89V;
add 0.5 to the score for every mutation in the following list: 32L,33MV,34V,35G,41I,46IL,48M,54STV,73ACFSTV,
74E,82FL,85V,89T;
add 0.25 to the score for every mutation in the following list: 33I,35N,89I;
subtract 0.25 from the score for every mutation in the following list: 50L,88S]

score is at least 2[add 1.5 to the score for every mutation in the following list: 50V,54M,76V,84ACV;
add 1 to the score for every mutation in the following list: 11I,32I,33F,41T,47AV,54L,70E,74P,89V;
add 0.5 to the score for every mutation in the following list: 32L,33MV,34V,35G,41I,46IL,48M,54STV,73ACFSTV,
74E,82FL,85V,89T;
add 0.25 to the score for every mutation in the following list: 33I,35N,89I;
subtract 0.25 from the score for every mutation in the following list: 50L,88S]

enfuvirtide

score is at least 2[add 1 to the score for every mutation in the following list: 36DESV,38AEM,40H,41R,42DEHKQT,43DKQS,44MV,
45MPQ]

score is at least 1[add 1 to the score for every mutation in the following list: 36DESV,38AEM,40H,41R,42DEHKQT,43DKQS,44MV,
45MPQ]

maraviroc e[(CXCR4-tropic or D/M tropic) by ES TrofileTM]or [(X4 or R5X4) by the clonal interpretation of geno2pheno with false positive rate of 10% using V3 loop triplicate
population sequences or 20% using V3 loop single population sequence]

EI

INI

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raltegravir

score is at least 20[add 20 to the score for every mutation in the following list: 143R,148HKR,155HS]

score is at least 1[add 1 to the score for every mutation in the following list: 74M,92Q,138A,140AS,143CH,163K,232N;
add 0.25 to the score for every mutation in the following list: 97A,138K,151I,156N,163R,206S,230N]

elvitegravir

score is at least 2[add 2 to the score for every mutation in the following list: 66AIK,92QG,145S,146ILPR,147G,148HKR,155HST;
add 1 to the score for every mutation in the following list: 121Y,140ACS;
add 0.5 to the score for every mutation in the following list: 51Y,97A,114Y,146K,153FY,263K]

score at least 1[add 1 to the score for every mutation in the following list: 121Y,140ACS;
Add 0.5 to the score for every mutation in the following list: 51Y,97A,114Y,146K,153FY,263K]

dolutegravir

score at least 2[add 1.5 to the score for every mutation in the following list: 118R,263K;
add 1 to the score for every mutation in the following list: 148HKR;
add 0.5 to the score for every mutation in the following list: 51Y,74M,92Q,97A,124A,138K,140ACS,143CHR,
153F,155H]

score at least 1.5[add 1.5 to the score for every mutation in the following list: 118R,263K;
add 1 to the score for every mutation in the following list: 148HKR;
add 0.5 to the score for every mutation in the following list: 51Y,74M,92Q,97A,124A,138K,140ACS,
143CHR,153F,155H]

a 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 and the maximum score at that particular position is considered.
c If none of the criteria to consider an isolate resistant towards a particular 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, nucleoside reverse transcriptase inhibitor; NtRTI, nucleotide reverse transcriptase inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibitor; PI, protease inhibitor; EI, entry inhibitor; INI, integrase inhibitor. e For
genotypic prediction of co-receptor usage we refer to http://coreceptor.bioinf.mpi-inf.mpg.de/index.php (Sing T. et al. Predicting HIV co-receptor usage based on genetic and clinical covariates. Antiviral Therapy, 2007). For phenotypic prediction of co-receptor usage
we refer to the Enhanced TrofileTM assay (Monogram Biosciences) http://trofileassay.com.

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