Art, P

Arts, E

Avino, M

Gibson, R

Kityo, C

Kyeyune, F

Mugyenyi, P

Nankya, I

Ndashimye, Emmanuel

Quhinones-Mateu, M E

English

Scholarship@Western

Western University Scholarship@Western Community, Equity, Gender Western Heads East 11-15-2017 Time to Consider Dolutegravir for Treatment in Uganda: HIV Drug Resistance Profiles of Virologic Failures on First-,Second-, or Third Line/Raltegravir Containing Combined Antiretroviral Treatments Emmanuel Ndashimye P Art M Avino R Gibson M E. Quhinones-Mateu See next page for additional authors Follow this and additional works at: https://ir.lib.uwo.ca/wheceg Authors Emmanuel Ndashimye, P Art, M Avino, R Gibson, M E. Quhinones-Mateu, F Kyeyune, I Nankya, P Mugyenyi, C Kityo, and E Arts WesternSchulichMEDICINE & DENTISTRYTime to consider Dolutegravir for treatment in Uganda: HIV drug resistance profiles of virologic failures on first-,second-, or third line/Raltegravir containing combined antiretroviral treatments Emmanuel Ndashimye 1, Art P1, Avino M1, Gibson R2,3, Quinones-Mateu2, Kyeyune F1, Nankya I1, Mugyenyi P1, Kityo C1, and Arts E2• Resistance to at least one ART, 97.8%, 81.9% and 56.6% in FF, SF and RF. Any NNRTI resistance, 38.5%, 96.4%, 75.5%, and 53.8% in N, FF, SF, and RF. Any PI resistance, 30.8% and 23% in second line and RAL failuresrespectively. Any INSTIs resistant mutation in 38.2% RF. MethodsAcknowledgementResultsConclusionIntroduction• Uganda is among the countries with the highest burden of HIV-1 infections, with approximately 1.4 million (6.5%) people livingwith HIV/AIDS and 67% of them receiving combinedantiretroviral therapy.• Like other Low income countries (LICs), it is facing dilemma ofincreasing rates of HIV transmitted drug resistance andacquired drug resistance (DR).• Despite increasing access to generic Dolutegravir (DTG) in LICs,data on DTG associated DR in this setting is lacking.• We evaluated DTG associated DR in (n=400) patients who areART naïve (N), and those failing on first line(FF), second line (SF)and RAL based third line (RF) treatments in Uganda.• Deep sequencing using Illumina (Miseq) was done in (n=68) ofthese patients.• Patients with virological failure ( viral load of ≥ 1000 copies/ml)were selected for the study• HIV-1 integrase enzyme was amplified from extracted RNA andsequenced using Sanger and Miseq platforms.• Drug susceptibility was interpreted using HIV-1 genotypingresistance interpretation of Stanford HIV database(https://hivdb.stanford.edu) and Scueal program was used forHIV-1 subtype classifications.• Joint Clinical Research Centre, Kampala, Uganda• Dr Eric J Arts laboratory, department of Microbiology andImmunology, Schulich School of Medicine & Dentistry Universityof Western Ontario, London, Ontario, Canada1Department of Microbiology and Immunology, Schulich School of Medicine & Dentistry University of Western Ontario, London, Ontario, Canada2Joint Clinical Research Centre, Kampala, UgandaHIVdb drug susceptibility for all patient groupsHIV subtype distribution in study patientsA. Integrase          D    C * F1 H   F2    K   A2   * G   J *    ** * ** *     *  *   *   0.01 s/nt  *   *       100 HIV-1 Subtype Distribution (%) 80 60 40 20    * * * *  * *    * A1  *   B      B. RT   D        * *  *    0.01 s/nt  * *          * * * A2 *      *                  * * *            *          *    * * A1        B       J  G    C      H F2     F1     K                 0  Naive 1st Line 2nd Line RAL Failure Failure Failure   A D C AD  Others      100 HIV-1Subtype Distribution(%) 80 60     40   20   0  Naive 1st Line 2nd Line RAL Failure Failure Failure    HIV-1 infected patients failing on RAL-based regimen with primary and/or secondary (compensatory) INSTI mutationsPrimary/secondary mutations n (%) DTG RAL EVGM50I/L/MR 1(3.0) S S SM50I,L74I 1(3.0) S S ST97A 1(3.0) S P PT97A,G163R,L74M 3(8.8) S L LN155H 2(6.0) P H HN155H,T97A 1(3.0) P H HN155H,T97AT 1(3.0) P H HN155H,T97A,E157Q,L74I 1(3.0) P H HN155H,E157Q,G163R,M50L,L74I 1(3.0) P H HY143R,T97A 2(6.0) S H LY143R,T97AT,G163R 1(3.0) P H IY143R,T97A,M50I,L74LM 1(3.0) P H IE138A,T97A,V151A 1(3.0) P I IE138K,G140A,S147G,Q148K 1(3.0) H H HT66A,T97A,G163R,L74M 1(3.0) S I HThe work flow chart of the patient numbers and their respective groupsHIV-1 genotypic resistance interpretation based on Sanger sequencingIllumina SangerS147G, G140A, E138K, Q148K, S230N, M50L S147G, G140A, E138K, Q148KN155H, Y143H, M50I N155HY143R, T97A, G163R Y143R, T97A, T97A, L74M, M50I T97A, L74LMT97A, N155H, L74I T97A, N155H, L74IT97A, L74M, V151I, G163R T97AT97A, M50I, N155H T97AT, N155HN155H, V151I N155HE157K, R263G, M50I M50IM50L M50LM50L M50LG118V, M50I NONET66K NONET97A, L74M, V151I, G163R G163R, T97A, L74LM, V151IM50L M50LM50L, L74M, T97A, V151I, G163R L74M, T97A, V151I, G163RM50I NONESubtype No. (%)Group of patients a cART regimen (No. patients)bMean HIV-1 RNAlog10 c/ml cA D C A/D Other dcART naïve (n = 87) None 4.64 42(47.1) 17(19.5) 3(3.4) 9(10.3) 17(19.5)Failing First-line cART (n = 158) AZT, 3TC, NVP (38) 0.54 14(36.9) 11(28.9) 4(10.5) 2(5.3) 7(18.4)TDF, 3TC, EFV (34) 1.21 14(41.2) 10(29.4) 2(5.9) 1(2.9) 7(20.6)AZT, 3TC, EFV (18) 1.31 18(44.4) 6(33.3) 1(5.6) 1(5.6) 2(11.1)TDF, 3TC, FTC (15) 0.43 1(20) 1(20) 1(20) 0(0.0) 2(40)Other (14) 7.5 5(35.7) 5(35.7) 2(14.3) 2(14.3) 0(0.0)3TC, D4T, NVP (13) 2.2 8(61.5) 1(7.7) 0(0.0) 1(7.7) 3(23.1)ABC, 3TC, NVP (10) 2.56 4(40) 1(10) 1(10) 1(10) 3(30)ABC, 3TC, EFV (7) 0.64 7(100) 0(0.0) 0(0.0) 0(0.0) 0(0.0)TDF, 3TC, NVP (6) 0.97 0(0.0) 3(50) 0(0.0) 1(16.7) 2(33.3)3TC, AZT, NVP (4) 2.22 0(0.0) 1(25) 1(25) 1(25) 1(25)d4T, 3TC, NVP (3) 0.97 0(0.0) 3(100) 0(0.0) 0(0.0) 0(0.0)AZT, 3TC, ABC (2) ND 0(0.0) 1(50) 0(0.0) 0(0.0) 1(50)FTC, TDF, EFV (2) 0.7 1(50) 0(0.0) 0(0.0) 0(0.0) 1(50)TDF, ABC, AZT (n = 2) ND 1(50) 0(0.0) 0(0.0) 0(0.0) 1(50)Failing Second-line cART (n = 121) TDF, 3TC, LPVr (30) 1.22 13(43.3) 4(13.3) 2(6.7) 2(6.7) 9(30)TDF, 3TC, ATVr (30) 2.2 14(46.7) 7(23.3) 1(3.3) 2(6.7) 6(20)ABC, 3TC, LPVr (25) 2.13 12(48) 8(32) 1(4) 0(0.0) 4(16)ABC, 3TC, ATVr (25) 3.64 3(60) 0(0.0) 0(0.0) 0(0.0) 2(40)AZT, 3TC, LPVr (13) 7.82 4(30.7) 3(23.1) 0(0.0) 3(23.1) 3(23.1)LPVr (7) 0.05 3(42.9) 4(57.1) 0(0.0) 0(0.0) 0(0.0)AZT, 3TC, ATVr (6) 2.53 4(66.7) 2(33.3) 0(0.0) 0(0.0) 0(0.0)Other (5) 0.7 1(20) 1(20) 0(0.0) 1(20) 2(40)Failing RAL-based cART (n =34) RAL, LPVr (16) 2.2 7(43.75) 4(25) 0(0.0) 3(18.75) 2(12.5)Other (6) 0.3 4(66.6) 1(16.7) 0(0.0) 0(0.0) 1(16.7)RAL, DRVr (5) 9.5 4(80) 1(20) 0(0.0) 0(0.0) 0(0.0)RAL, ATVr (2) 8.5 1(50) 1(50) 0(0.0) 0(0.0) 0(0.0)RAL, TDF, 3TC, LPVr (2) 2.7 2(100) 0(0.0) 0(0.0) 0(0.0) 0(0.0)TDF, 3TC, RAL, DRVr (2) 0.03 1(50) 1(50) 0(0.0) 0(0.0) 0(0.0)RAL, ETR, DRVr (2) 1.1 2(100) 0(0.0) 0(0.0) 0(0.0) 0(0.0)Clinical and virological characteristics of the patientsOn average, subtype A, 45.7%, subtype D, 25.2%, subtype C, 4.75%and recombinant AD, 7.5%.In all 400 patients; Y143R (0.75%), Q148K (0.25%), N155H (1.5%),E138A/K (0.5%), G140A (0.25%), S147G (0.25%). Accessory mutations;T97A (8.75%), M50I 6.5%), L74M/I (3%), E157Q (1.25%), V151I/A (2%),G163R (1.5%). In bold, are integrase major resistance mutations.INSTIs DRMs detected by Population and Illumina in RAL failures01234561 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17Number of mutationsPatientssanger illumina00.511.522.533.54Y143R/H Q148K/R N155H E138K/A S147G G140A/E T66KNumber of mutations (n)Resistance mutationssanger IlluminaY143R/H, Q148K/R, G140A/E, 1.47%, 3.0%, S147G, 1.47%, 1.47% , T66K,0.0%, 1.47% Sanger and Illumina respectively.051015202530354045Number of mutations (n)Resistance mutationssanger IlluminaComparison of INSTIs accessory DRMs detected by Sanger and IlluminaR263G, 0.0%, 4.4%, S230N, 0.0%, 1.47%, G118V, 0.0%, 1.47%,T97A/S, 20.5%, 22.0%, M50I/L, 30.8%, 63.2%, L74M/I, 16.17%,20.5%, G163R/E/T, 2.94%, 7.35%, V151I, 1.47%, 5.88%, Q95A/R,1.47%, 3.0%, F121L, 0.0%, 1.47% by sanger and Illuminarespectively.HIVdb program Genotypic resistance interpretation algorithm fromStanford university HIV drug resistance database was used to predictthe levels of susceptibility. A susceptible genotype is shown in green,intermediate and high level resistance is shown in yellow and redrespectively.Genotypic resistance interpretation and scueal HIV subtypeclassifications from deep sequencing data.Number of mutationsART naïve First line failures Second line failures RAL failuresNumber of mutationsA='A', A1='A', A2='A', A3='A', 'A,A1 recombinant'='A', 'A1,A2recombinant'='A', D='D', 'A,D recombinant'='A,D rec.', 'A3,Drecombinant'='A,D rec.', 'A1,D recombinant'='A,D rec.', 'A2,Drecombinant'='A,D rec.', C=‘C’Dark green =susceptible [0-10); light green = potential low-level resistance [10,15); yellow = low-level resistance [15,30);orange = intermediate resistance [30,60); red = high-levelresistance [60, inf).No primary DTG DRMs were found in 366 INSTIs naïve patients, and only one patient was found to have DTG resistance genotype in RAL failures. The very high NNRTIs resistance across all patient groups call for introduction of DTG or Bictegravir in treatment naïve patients in UgandaThe HIV subtype was predicted using SCUEAL subtype classificationalgorithm. Viral loads were assayed using Abbott m2000sp/rt orRoche COBAS Amplicor Monitor ultrasensitive tests, v1.5.Comparison of INSTIs major DRMs detected by Sanger and Illumina

Time to Consider Dolutegravir for Treatment in Uganda: HIV Drug Resistance Profiles of Virologic Failures on First-,Second-, or Third Line/Raltegravir Containing Combined Antiretroviral Treatments

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Time to Consider Dolutegravir for Treatment in Uganda: HIV Drug Resistance Profiles of Virologic Failures on First-,Second-, or Third Line/Raltegravir Containing Combined Antiretroviral Treatments

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