HIV Acquired drug resistance: Causes, patterns, and implications for sub-saharan Africa

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Sénégal 10 th International Workshop on HIV treatment Pathogenesis and

1 HIV Acquired drug resistance: Causes, patterns, and implications for sub-saharan Africa Pr Coumba Touré Kane Cheikh Anta Diop University Dakar Sénégal 10 th International Workshop on HIV treatment Pathogenesis and Prevention Research in < resource-limited settings INTEREST Yaoundé 3-6 May 2016

2 Outline 1. Introduction 2. Progress on HIV global response 3. Causes of Acquired drug resistance 4. Data on Acquired drug resistance in Adults 5. Data on Acquired drug resistance in children 6. HIV-2 drug resistance 7. Implications TDR 8. Summary 2

3 Introduction 2015 : Almost 16 million people are receiving HIV treatment, including 11.4 million in Africa. Despite benefits that rapid scale-up has had on AIDS-related morbidity and mortality Emergence of HIV DR +++

4 Progress in the global HIV response

5 Antiretroviral treatment ART Improves the health and well-being of people living with HIV Stops further HIV transmission but Needs good laboratories in the Health System to monitor the efficacy Avoid potential for widespread emergence and transmission of HIV drug resistance to antiretrovirals (ARVs)

6 Causes of HIV ART Acquired Resistance

ART failure Errors RT High genetic diversity Need for

7 7 Causes: Emergence of HIVDR ART for life ++Factors Viral replication +++ Sélection of Résistant virus ART failure Errors RT High genetic diversity Need for Resistance surveillance During treatment Before treatment

8 Drug pressure Treatment failure failure could be cause/consequences of DR HIV DR is major ongoing concern in public Health

9 Causes: ART monitoring in RLS WHO : Recommandations CD4+/-VL - CD4 + VL +/- TF : copies/ml VL 6 months if possible VL for Failure confirmation TF copies VL : need for early TF detection TF : copies CD4 at 500 for initiation Treatment for ALL TF detection TF : copies 9

10 Evaluation of WHO criteria for antiretroviral treatment failure 16 in SSA Rutherford et al. AIDS 2014

11 WHO criteria for antiretroviral treatment failure in Adult Immunological criteria in adults : 16 studies Virologic failure (VF) / plasma viral load (VL) definition 11 VL > 50 to > 1000 copies/ml in adults 3 VL > 5000 copies/ml, 2 VL > copies/ml Sensitivity ranged from 16.8 to 54.9% Specificity from 82.9 to 95.5%, PPV from 15.0 to 38.8% and NPV from 90.9 to 98.6% Rutherford et al. AIDS 2014

12 WHO criteria for antiretroviral treatment failure in Adult Clinical criteria to predict VF> 50 to >1000 copies/ml : 7 studies Sensitivity was 11.0% Specificity 90.5% PPV 44.9%, and NPV 90.2% Clinical or immunologic criteria to predict VF > 50 to > 1000 copies/ml : 7 studies Sensitivity was 26.6% Specificity 85.9% PPV 49.4%, and NPV 91.1% Rutherford et al. AIDS 2014

13 Evaluation of WHO criteria for antiretroviral treatment failurein Children Immunologic criteria in children : 4 studies 3 defined VF as VL at least 5000 copies/ml 1 as VL at least 400 copies/ml. Sensitivity ranged from 4.5 to 6.3% Specificity from 97.7 to 99.3%, PPV from 20.0 to 54.9%, and NPV from 85.5 to 91.8% Rutherford et al. AIDS 2014

14 ART recommendations Treat all Actual context Scale-up of pre-exposure prophylaxis could increase levels of HIVDR To minimize the emergence and spread of HIVDR WHO recommends HIV treatment scale-up be accompanied by measures to monitor and improve the quality of ART delivery and surveillance of HIVDR

15 Actual context At country level, the strategy endorses: country ownership through Formation of a national HIVDR working group; integration of the national HIVDR strategy into the National Strategic HIV Plan integration of HVDR activities into routine Monitoring and Evaluation function

16 Actual context Country level : HIVDR assessments including Surveillance of HIVDR Annual monitoring of early warning indicators (EWI) Leveraging of enablers use of WHO-designated laboratory for HIVDR testing and identification and allocation of resources use of all available information to minimize the emergence and transmission of drug-resistant HIV and timely dissemination of information

17 Acquired Resistance in Adults and children Pattern

Acquired Resistance on 1First line Southern and Eastern Part on SSA A) nucleoside reverse transcriptase inhibitor agents Wallis et al, Katzenstein D7; A5230 team Clin Infect Dis. 2014.

18 Acquired Resistance on 1First line Southern and Eastern Part on SSA A) nucleoside reverse transcriptase inhibitor agents Wallis et al, Katzenstein D7; A5230 team Clin Infect Dis Chiang Mai, Thailand (Chiang Mai University ACTG CRS); KCMC, Tanzania (Kilimanjaro Christian Medical Centre CRS); Kumuza, Malawi (Kamuzu Central Hospital, University of North Carolina Lilongwe CRS); Wits, South Africa (University of the Witwatersrand HIV CRS); YRG CARE, India (Y.R. Gaitonde Centre for AIDS Research and Education, VHS CRS).

19 Acquired Resistance on 1First line Southern and Eastern Part on SSA B) nonnucleoside reverse transcriptase inhibitor agents the 148 individuals, 93% (n = 138) and 96% (n = 142) had at least 1 reverse transcriptase (RT) mutation associated with NRTI and NNRTI resistance, respectively

20 Acquired Resistance on 1First Country Locatio n ART durati on (mont hs) Design line Southern and Eastern Part on SSA VL (Th) (copies/ ml) Failur e rate (%) HIVDR (%) Author Date Malwi Urban Women 12 Option B Malwi /- 40 of VF Mancinelli, 2016 Uganda Urban 12 WHO-M , Pontiano, 2015 Namibia Urban 12 WHO-M Hong 2015 Rwanda Mixt 12 WHO-M Ndahimana, 2016

21 Tenofovir Resisistance Prevalence of nucleoside reverse transcriptase inhibitor mutations and thymidine analogue mutations (TAMs) in tenofovir (TDF; black) and stavudine (d4t, white) treatment groups. Skhosana L, 2015

22 Tenofovir Resisistance TenoRes 2016

23 Acquired Resistance on 1First Country Locatio n ART duration (months) line Central and Western Part on SSA Desig n VL (Th) (copies/ ml) Failure rate (%) HIVDR (%) Author Date Cameroon Urban 12 CS Kouanfack, 2009 Cameroon Urban 12 WHO-M Billong, 2013 Cote d Ivoire Urban 12 Cohort Messou, 2013 Nigeria Urban 12 WHO-M Ugbena, 2012 Togo Urban 12 CS Dagnra, 2011 Senegal Urban 12, 24, 60 Cohort /- 3, 11, 18 DeBaudrap, 2013 Mauritania Urban 32 CS 100 +/- 73 (VF) Fall, 2014

24 Acquired Resistance on 1First line Central and Western Part on SSA Country Locati on ART dura tion (mo nths ) Desi gn VL (Th) (copie s/ml) Failu re rate (%) HIVDR (%) Author Date Liberia Urban 42 CS Loube, 2015 CAR Urban 24 CS /- Pere, 2012 DRC Urban 25 CS Guinea Bissau HIV1 and dual Urban 6-12 CS (VF) Muwonga, 2011 Jespersen, 2016

25 Acquired Resistance on 1First line Projet ANRS 12186: First line ART treatment Western and Central Part on SSA

Virological outcome in countries using the WHO public health approach - ANRS 12186

- Low frequency of K65R for non-tdf regimen were found.

26 Virological outcome in countries using the WHO public health approach - ANRS Drug Resistance - Majority of resistance profiles and mutations were expected. - Low frequency of K65R for non-tdf regimen were found. - Significant accumulation of DRM in M24 patients, leading to unexpected resistance mutations/profiles (ABC, TDF, ETR and RPV).

27 Sylla and al, Antivir Ther 2008 Late First line failure in Mali and Burkina Faso 40% of TAMs, the others NRTIs use is not possible most of theses patients

28 Acquired resistance in decentralized settings

29 Improving access to virological monitoring in RLC using alternative tools ANRS12235 (DBS) M24 M24 M24 Sénégal Burkina-Faso Togo Côte d Ivoire Cameroun Vietnam Thaïlande M24 M36 M24 On field validation of dried blood spot (DBS) approach for HIV viral load and drug resistance testing. M24 Group Res ANRS 29

30 number of samples DBS ANRS12235 Number of samples with nucleotide (nt) difference <1% nt difference % nt difference % nt difference % difference >4% nt difference lab A Lab B Lab C Lab D Lab E Lab F Total N=11 N=20 N=11 N=3 N=38 N=15 N=98 Group Res ANRS 30

DBS ANRS12235 Number of samples with DRM missed at VL detection and/or genotyping for the different sites study site Plasma VL >1,000 DBS VL <1,000 DRM in FN* DBS samples Discordant DRM Plasma/DBS

all) Main outcome DBS can reliably replace plasma specimen for 1.

31 DBS ANRS12235 Number of samples with DRM missed at VL detection and/or genotyping for the different sites study site Plasma VL >1,000 DBS VL <1,000 DRM in FN* DBS samples Discordant DRM Plasma/DBS Lab A 16/60 1/16 0/1 1/11 Lab B 24/60 0/24-4/20 Lab C 13/53 0/13-3/11 (1 no DRM at all) Lab D 12/60 3/12 2/3 1/3 Lab E 67/91 10/67 10/10 5/38 (1 no DRM at all) Lab F 23/58 2/23 2/2 9/15 (8 no DRM at all) Main outcome DBS can reliably replace plasma specimen for 1. VL 90% and (139/155) HIVDR in of settings VF were where correctly plasma collection, processing and transportation is identified challenging. using DBS. Selection of adequate technique according to the local context (eg: genetic diversity) is essential. Quality monitoring is also important % (77/96) of HIVDR interpretations were correct. Service R&PED 31 Monleau, 2014

32 HIVDR using DBS A B C D HIVDR on DBS 231 patients under First line ART from 10 régions in Sénégal AZT-3TC-NVP/EFV 80.9%; 187/231) Diouara et al 2013

33 HIVDR using DBS Median follow-up 18-month (6-68 months) Virological failure 23.8% (55/231) Global resistance rate 17.7% (41/231 Diouara et al 2013

34 HIVDR using DBS Diouara et al 2013

35 Resistance using DBS: WAHO projet Multicentric study Guinée, Mali, Sénégal Diouara et al 20134

36 Resistance using DBS Countries Senegal Mali Guinea Total Samples collection sites Number of patients enrolled Female (Percent) 94 (78.9%) 102 (67.1%) 83 (61%) 279 (68.5%) Median age (Years) 42 [IQR: 18-65] 41 [IQR: 18-66] 38 [IQR: 18-61] 40 [IQR: 18-66] Fist line therapy (2 NRTI+ 1 NNRTI) 114 (95.7%) 136 (89.4%) 129 (94.8%) 379 (93.1%) AZT+3TC+NVP/EFV D4T+3TC+NVP/EFV Other fist-line combinations Second line therapy (2 NRTI+ 1 PI) Median time on ART 32 [IQR: 6-112] 39 [IQR: 6-136] 35 [IQR: 6-108] 36 [IQR: 6-136] VL technical cut off (800 Copies/mL) Median of Viral load 3.63 [IQR: ] 3.94 [IQR: ] 3.64 [IQR: ] 3.68 [IQR: ] Virological failure (VL 3Log 10 Copies/mL) 31 (26%) 16 (10.5%) 33 (24.2%) 80 (19.6%) Genotyped 27 (87%) 15 (93.7%) 28 (84.8%) 70 (87.5%) Any DRM DRM in patients with virological failure 70.3% (n=19/27) 93.3% (n=14/15) 67.8% (n=19/28) 74.2% (n=52/70) Global DRM 15.9% (n=19/119) 9.2% (n=14/152) 13.9% (n=19/136) 12.7% (n=52/407) Diouara et al 2014

37 Resistance using DBS NNRTI mutations 12 Number of mutations Senegal Mali Guinea Diouara et al 2014

38 Acquired resistance in children

39 Children under first line ART Kebe et al 2013

40 Children under first line ART K219Q/E K70R D67N M41L DRM to NRTIs TAMs = 40% L210W T215Y/F Q151M 2% M184V/I 95% High rate DRM P225H 6% Y188L K101E 13% 21% DRM to NNRTis G190A 23% Y181C 32% Kebe et al 2013 K103N 34%

41 Togo Salou M et al. Journal of the International AIDS Society 2016, 19:20683

42 Kityo et al 2016

43 Kityo et al 2016

44 Acquired resistance in 2 nd and 3th line

45 2 nd line regime in SSA * Afrique du Sud (n= 1648)* 46% VF > 6 months Associated factors Pujades-rodriguez M, Jama 2010 CD4 low suboptimal Treatment * EARNEST (n=1277) (Malawi, Uganda, Zimbabwe, Kenya, Zambia) Success: 2 INTI + LPV/r (74%), LPVr + RAL (73%) IAS, Kuala Lampur LPV/r (44%) Meta Analyse 19 studies 2nd-line failure rates (n=2035 ) VF 21.8, 23.1, 26.7 and 38.0% at 6, 12, 24 and 36 months Rates VF on 2 nd -. Ajose O, AIDS Poor adherence appeared to be the main driver of virological failure 45

46 * Mutations to NRTI: Resistance to 2 nd line regimen N=106, médian ART 4 years M184 (61%), T215 Y (32%), Q151M (5%) K65 R (2%); Maiga Al. J Antimicrob Chemother 2012 R: 3TC/FTC (66%), ABC (48%), d4t (42%), ddi (42%), AZT (40%), TDF(33%) * Mutations to NNRTI: Y181C/I/V (22%), K103N (16%), V90I (12%), G190S/A (10%); R: NVP (56%), EFV (52%),ETV (38%) * Mutations to PI: M46IL(16%), L76V (12%), I54M/L (10%) I47V (6%), R: LPV (25%), DRV (12%) 8,6% résistances to 3 classes Van Zyl G, Plos One 2013, (n=1416, 490 LPV/r), 1.3% R to 3 Classes (South Africa)

47 Resistance to 2 nd line regimen N=106, médian ART 5 years *patients second-line treatment. success 81% ANRS 1215 SENEGAL VF 27% at 24 months, multiple resistances. DeBeaudrap. J AIDS 2013

48 Third-line antiretroviral therapy in Africa third-line regimens for patients failing second-line ART with multidrug resistant HIV in Africa effective with INI.

Prediction of INI efficacy in 3th line 52 patients sous 2 ème ligne de TARV Femmes 53,8% (n=28), Age médian : 41 ans [IQR, 18-78] Données sous 2 ème ligne : TDF + 3TC/FTC + LPV/r (69,2%) Médiane 32

49 Prediction of INI efficacy in 3th line 52 patients sous 2 ème ligne de TARV Femmes 53,8% (n=28), Age médian : 41 ans [IQR, 18-78] Données sous 2 ème ligne : TDF + 3TC/FTC + LPV/r (69,2%) Médiane 32 mois (IQR, 3 71) Situation virologique CV disponible : 52 (100%) Echec virologique : 25% (13/52) Génotypes réussis : pol : 13/13 (100%) Intégrase : 12/13 Résistance : 92,3% (12/13) Données antérieurs (1 ère ligne) : D4T/AZT + 3TC + EFV/NVP (71,2%) Médiane 55 mois (IQR, ) Situation virologique CV disponible : 49/52 6 patients avec CV < 1000 cp/ml Echec virologique : 87,7% (43/49) Génotypes disponibles : 29/43 Résistance : 100% (29/29) Tchiakpe et al

50 Prediction of INI efficacy in 3th line Profils de résistance en 1 ère et 2 eme ligne Pourcentage(%) 40,0 35,0 30,0 25,0 20,0 15,0 10,0 5,0 0,0 86,2% vs 29,4%!!!!! INTI TAMs: 65,5% vs 61,7% Première ligne Deuxième ligne Pourcentage(%) 35,0 30,0 25,0 20,0 15,0 10,0 5,0 0,0 26,2% vs 33,3% INNTI Première ligne Deuxième ligne Mutations Mutations Pourcentage(%) 60,0 50,0 40,0 30,0 20,0 10,0 IP Première ligne Deuxième ligne INI Seul 2 mutations (L74I, H114Y) polymorphisme au niveau de l Intégrase 0,0 Mutations Tchiakpe et al

Prediction of INI efficacy in 3th line Echantillons TARV 2ème Ligne Analyse et interprétation des mutations et molécules efficaces selon l'algorithme de l'anrs (version Septembre 2014) IP INRT INNRT

51 Prediction of INI efficacy in 3th line Echantillons TARV 2ème Ligne Analyse et interprétation des mutations et molécules efficaces selon l'algorithme de l'anrs (version Septembre 2014) IP INRT INNRT INI Molécules encore éfficaces 101HALD TDF+3TC+LPV/r IDV, SQV, NFV, FPV, LPV, ATV,TPV, DRV 3TC/FTC, AZT, DDI, D4T, ABC, TDF EFV, NVP, ETV, RPV RAL, EVG, DTG SQV, FPV, LPV, ATV,TPV, DRV, DDI, ABC, TDF, ETV 1523HALD TDF+3TC+LPV/r IDV, SQV, NFV, FPV, LPV, ATV,TPV, DRV 3TC/FTC, AZT, DDI, D4T, ABC, TDF EFV, NVP, ETV, RPV RAL, EVG, DTG IDV, SQV, NFV, FPV, LPV, ATV,TPV, DRV, DDI, ABC, D4T, AZT, TDF, ETV 1837HALD 2401HALD 2931HALD TDF+3TC+LPV/r TDF+FTC+LPV/r TDF+FTC+LPV/r IDV, SQV, NFV, FPV, LPV, ATV,TPV, DRV IDV, SQV, NFV, FPV, LPV, ATV,TPV, DRV 3TC/FTC, AZT, DDI, D4T, ABC, TDF 3TC/FTC, AZT, DDI, D4T, ABC, TDF EFV, NVP, ETV, RPV RAL, EVG, DTG 2 NRTI + 1 NNRTI IDV, SQV, NFV, FPV, AZT, 3TC/FTC, D4T, LPV, ATV,TPV, DRV DDI, ABC, TDF (AZT/TDF + 3TC/FTC + ETV) EFV, NVP, ETV, RPV RAL, EVG, DTG EFV, NVP, ETV, RPV RAL, EVG, DTG FPV,TPV, DRV, DDI, EFV, NVP, ETV, RPV IDV, SQV, NFV, FPV, LPV, ATV,TPV, DRV, ETV, RPV IDV, SQV, NFV, FPV, LPV, ATV,TPV, DRV, AZT, DDI, D4T, ABC, TDF, ETV, RPV 3259HALD TDF+FTC+LPV/r IDV, SQV, NFV, FPV, LPV, ATV,TPV, DRV Aucune molécule efficace EFV, NVP, ETV, RPV RAL, EVG, DTG SQV,TPV, DRV,EFV,NVP, ETV, RPV 4039HALD 478HALD 8253HALD TDF+3TC+LPV/r TDF+3TC+LPV/r TDF+3TC+ATV IDV, SQV, NFV, FPV, LPV, ATV,TPV, DRV IDV, SQV, NFV, FPV, LPV, ATV,TPV, DRV IDV, SQV, NFV, FPV, LPV, ATV,TPV, DRV 3TC/FTC, AZT, DDI, D4T, ABC, TDF 3TC/FTC, AZT, DDI, D4T, ABC, TDF 3TC/FTC, AZT, DDI, D4T, ABC, TDF EFV, NVP, ETV, RPV EFV, NVP, ETV, RPV EFV, NVP, ETV, RPV RAL, EVG, DTG RAL, EVG, DTG RAL, EVG, DTG IDV, SQV, NFV, FPV, LPV, ATV,TPV, DRV, 3TC/FTC, AZT, DDI, D4T, ABC, TDF, ETV SQV, NFV, FPV, LPV, ATV,TPV, DRV, AZT, DDI, D4T, ABC, TDF, ETV, RPV IDV, SQV, NFV, FPV, LPV, ATV,TPV, DRV, AZT, DDI, D4T, ABC, TDF, ETV, RPV 929HALD LPV/r IDV, SQV, NFV, FPV, LPV, ATV,TPV, DRV Aucune molécule efficace Aucune molécule efficace RAL, EVG, DTG FPV, TPV, DRV, DDI 2698HALD TDF+3TC+LPV/r IDV, SQV, NFV, FPV, LPV, ATV,TPV, DRV 3TC/FTC, AZT, DDI, D4T, ABC, TDF Aucune molécule efficace RAL, EVG, DTG IDV, SQV, NFV, FPV, LPV, ATV,TPV, DRV, AZT, DDI, D4T, ABC, TDF 2107HALD TDF+3TC+LPV/r IDV, SQV, NFV, FPV, LPV, ATV,TPV, DRV 3TC/FTC, AZT, DDI, D4T, ABC, TDF EFV, NVP, ETV, RPV RAL, EVG, DTG Tchiakpe et al 2014 IDV, SQV, NFV, FPV, LPV, ATV,TPV, DRV, DDI, TDF, ETV, RPV 51

52 Prediction of INI efficacy in 3th line Ech TARV 2ème Ligne Molécules encore éfficaces selon ANRS AC11 (September 2014) Molécules encore éfficaces selon Sandford Version HALD TDF+3TC+LPV/r SQV, FPV, LPV, ATV,TPV, DRV, DDI, ABC, TDF, ETV DRV, TPV, TDF 1523HALD TDF+3TC+LPV/r IDV, SQV, NFV, FPV, LPV, ATV,TPV, DRV, DDI, ABC, D4T, AZT, TDF, ETV ATV, DRV, FPV, LPV, IDV, SQV, TPV 1837HALD TDF+3TC+LPV/r FPV,TPV, DRV, DDI, EFV, NVP, ETV, RPV Aucune molécule efficace 2401HALD TDF+FTC+LPV/r IDV, SQV, NFV, FPV, LPV, ATV,TPV, DRV, ETV, RPV ATV, DRV, FPV, IDV, LPV, SQV, TPV 2931HALD TDF+FTC+LPV/r IDV, SQV, NFV, FPV, LPV, ATV,TPV, DRV, AZT, DDI, D4T, ABC, TDF, ETV, RPV ATV, DRV, FPV, IDV, LPV, NFV, SQV, TPV, AZT, D4T, ETV, RPV 3259HALD TDF+FTC+LPV/r SQV,TPV, DRV,EFV,NVP, ETV, RPV NVP, EFV, ETV, RPV 4039HALD TDF+3TC+LPV/r IDV, SQV, NFV, FPV, LPV, ATV,TPV, DRV, 3TC/FTC, AZT, DDI, D4T, ABC, TDF, ETV ATV, DRV, FPV, IDV, LPV, NFV, SQV, TPV, 3TC, ABC, AZT, D4T, FTC, TDF 478HALD TDF+3TC+LPV/r SQV, NFV, FPV, LPV, ATV,TPV, DRV, AZT, DDI, D4T, ABC, TDF, ETV, RPV DRV, AZT, D4T, TDF 8253HALD TDF+3TC+ATV IDV, SQV, NFV, FPV, LPV, ATV,TPV, DRV, AZT, DDI, D4T, ABC, TDF, ETV, RPV ATV, DRV, FPV, IDV, LPV, SQV, TPV,TDF, ETV, RPV 929HALD LPV/r FPV, TPV, DRV, DDI Aucune molécule efficace 2698HALD TDF+3TC+LPV/r IDV, SQV, NFV, FPV, LPV, ATV,TPV, DRV, AZT, DDI, D4T, ABC, TDF ATV, DRV, FPV, IDV, LPV, SQV, TPV, AZT, D4T, TDF 2107HALD TDF+3TC+LPV/r IDV, SQV, NFV, FPV, LPV, ATV,TPV, DRV, DDI, TDF, ETV, RPV ATV, DRV, FPV, IDV, LPV, SQV, TPV Tchiakpe et al

53 Prediction of INI efficacy in 3th line ANRS 3 th ligne with RAL : possible 10/12 patients 1/10 susceptible ETR / RPV 9/10 susceptible ETV / RPV and INTI Stanford 3 th ligne with RAL : possible 6/12 patients 2/6 susceptible ETR / RPV 4/6 susceptible to NRTI 2/4 to AZT/D4T and TDF, 1/4 to TDF, 1/4 to all NRTI Tchiakpe et al

54 Lessons learned ARV resistance not very different from the northern countries Possibility of reducing the emergence of resistance mutations to ARVs if correct monitoring is undertaking Results => scaling and decentralizing ART Level of HIVDR through public health approach Accumaluation compromized efficacy 2 nd, 3th line MDR associated to TDF increasing TDR increasing First line sub optimal

55 Consequences TDR A snapshot of an interactive map plotting the prevalence of transmitted drug resistance in 111 countries from 287 studies between 2000 and 2013

56 TDR A snapshot of an interactive map plotting the prevalence of transmitted drug resistance in 111 countries from 287 studies between 2000 and 2013

57 Survey in Dakar Low level of HIVDR at ART initiation after > 10 years of ARV circulation

58 HIV TDR in children

59 HIV TDR in children Country Zimbab we patient s Median Age m 1-9 m Senegal m 1-12 m Sex M% TDR % RTI Prot Authors NRTI % NNRTI % 51.7 > na Chakany uka, na Kebe, 2014 Kenya ans na Lei, 2014 Togo 237 5m 1-18 m na Salou 2016

60 HIV-1 Group 0 HIV-2

Résistance Sélection de mutation sous Raltegravir 146 CD4, 4 Log, cancer utérus cart : TDF/FTC/RAL Séquençage résistance non réalisable -> suspicion HIV-1/O Séquençage spécifique avant l initiation =

61 Résistance Sélection de mutation sous Raltegravir 146 CD4, 4 Log, cancer utérus cart : TDF/FTC/RAL Séquençage résistance non réalisable -> suspicion HIV-1/O Séquençage spécifique avant l initiation = HIV-1/O - Polymorphisme ++ HIV-1/O - + K65R, M184V, G190A -> monotherapie RAL = sélection de Q148R Séquençage systématique de tout nouveau diagnostic Vigilance en cas de discordance dans l algorithme de dépistage confirmation - suivi Plantier Communication 2015

62 HIV-2 HIV-2 resistant to the nonnucleoside reversetranscriptase inhibitors and to less susceptible than HIV-1 to some protease inhibitors (PIs). Senegal HIV-2 and HIV1/2 2NRTIs and PI

63 HIV-2 23 patients Multiclass DRM (NRTI and PI) 30% of patients 52% to at least 1 ARV class. M184V 43% K65R, 9% Q151M 9% TAMS (M41L, D67N, K70R, L210W, and T215Y/F) not observed exception of K70R, together with K65R and Q151M in 1 patient. 8 PI mutations associated with indinavir resistance, including K7R, I54M, V62A, I82F, L90M, L99F 4 patients had strains with multiple PI resistance associated mutations. The duration of ARV associated with the development of drug resistance (P =.02). 9 (82%) of 11 patients detectable ARV resistance had undetectable plasma HIV-2 RNA loads (<1.4 log10 copies/ml) Goetlieb et al 2013

64 Summary ART more efficient Gain Optimal lab monitoring ( Diagnostic and monitoring) Resources ( financial, human and hardware) Need of innovative approaches Good Procurement System Quality Assurance Program HIVDR Genotyping national or South-South cooperation and North-South (Networking +++)

65 WHO Recommandations Great success of HIV treatment scale-up is not threatened by HIV drug resistance (HIVDR) Preventing HIVDR is an important part of meeting the targets by the year 2020 Commitment at country level From MoH to community

66 Summary Senegal : HIVDR Surveillance: 3 priority surveys Survey Frequency Cost (K USD) Pre-treatment HIVDR (PDR) Every 3 years 238 K Acquired HIVDR (ADR) (Adult and paediatric) Every 3 years 336 K EWI Yearly Integrated in M&E 2 additional surveys Survey Pediatric < 18 months Transmitted HIVDR (TDR) Cost (K USD) 135 K 182 K

WHO Essential Package of HIVDR Surveillance of HIVDR in populations initiating ART and populations failing ART Cross sectional surveys Surveillance of Transmitted HIVDR Transmitted HIVDR Surveys

67 WHO Essential Package of HIVDR Surveillance of HIVDR in populations initiating ART and populations failing ART Cross sectional surveys Surveillance of Transmitted HIVDR Transmitted HIVDR Surveys Estimate HIVDR in children < 18 months of age Pediatric Surveys National HIVDR evidence base Monitor program factors associated with emergence of HIVDR Early Warning Indicators Results lead to programmatic action to: Minimize emergence and transmission of HIVDR Optimize quality of patient care Select population-based ART regimens

Dr Carole Wallis, PhD Medical Director, BARC-SA Head of the Specialty Molecular Division, Lancet Laboratories, South Africa

Dr Carole Wallis, PhD Medical Director, BARC-SA Head of the Specialty Molecular Division, Lancet Laboratories, South Africa Transmitted drug resistance Resistance patterns in first-line failures in adults