Clinical Cases: Integrase Inhibitor use in Africa. Dr Julia Turner Medical Advisor Right to Care NGO

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1 Clinical Cases: Integrase Inhibitor use in frica Dr Julia Turner Medical dvisor Right to Care NGO

2 Disclosure Receipt of grants/ research supports Right to Care NGO is funded by USID PEPFR, ealth Systems Strengthening Grant Receipt of honoraria Mylan, bbvie and Jansen Pharmaceutical companies have paid me honoraria to conduct IV Training for doctors and nurses Conference Sponsorship Viral Education has sponsored attendance of the Global IV Clinical Forum Jansen Pharmaceuticals has sponsored registration to IS IDS2018 Participation in a company sponsored speaker s bureau Member of a Young frican IV Researchers Forum organised by Viiv Pharmaceuticals however I have not benefited financially

3 Ethics REC Ethics waiver through Wits uman Research Ethics Committee No patient identifying data has been used TLRT uthorisation from National Third Line RV Database holder RTC uthorisation from the database holder of Right to Care IV Clinical elpline

4 Source: South frica

5 1 st World Cities Source: Source:

6 Peri-urban Townships Source:

7 Rural areas Source :

8 ealth System 7.1 Million IV + Prevalence: 12.5% (90% subtype C) Massive Residual Inequality Private Sector Public Sector % of Population 16% 84% Number of IV+ patients Minority Majority % of Doctors 70% 30% Regulation of prescriptions Genotype Testing INSTI Prescription None / Medical Insurance When medical insurer allows/ privately funded. No regulation Sources: (Statistics South frica, 2017) (Maartens et al., 2012) (Rensburg, 2018) Essential Drug Lists and National Guidelines Test after 2 nd line failure Future Guidelines National 3rd Line RV Committee when genotype test proves PI resistance.

9 Third Line lgorithm If Low Level to either LPV or TV DRV/r + 3TC or FTC + TDF or ZT (BC) If intermediate resistance to TDF/ZT OR low level resistance to DRV dd RL (now DTG) If intermediate resistance to TDF/ZT ND low level resistance to DRV dd ETR (unless there is intermediate resistance to ETR)

10 Number of Patients INSTI use in South frican Public Sector > 1500 Third Line RV Patients 1415 recorded regimens Number of Patients on Third Line RVs DRV RL and DTG ETR ntiretroviral Drugs Source :South frican National Third Line RV Database, from Ruth Lancaster, Secretariat of S Third Line Committee

11 Number of Patients Number of Patients INSTI use in South frican Public Sector > 1500 Third Line RV Patients 1415 recorded regimens Number of Number patients of on Patients First, Second Third and Line Third RVsLine RVs mill First 0Line RVs Second Line DRV RL and DRVRVs RL and DTG DTG ETR ntiretroviral Drugs Drugs <0.05% of public IV+ patients are currently on an INSTI ETR Source :South frican National Third Line RV Database, from Ruth Lancaster, Secretariat of S Third Line Committee

12 INSTI Mutations Dolutegravir F E G Q N R Y S R Elvitegravir T 66 E 92 T 97 F S Q N R I Q G Y G R Raltegravir L 74 E 92 T 97 F E G Y Q N R M Q G Y S R C R IS-US dapted From: Wensing et al. Top ntivir Med. 2017;24(4). Updates, user notes, and references available at

13 Cases Right to Care Clinical elpline South frica Zimbabwe INSTI

14 Cases Right to Care Clinical elpline South frica Zimbabwe INSTI

15 Case 1: 11 yr old boy General Information Diagnosis Born in 2006 Mother was not on RVs during pregnancy or breastfeeding Received stat NVP at birth Diagnosed with TB and IV at 6 months Treatment 6/12 TB treatment (RZ) 3 months later started RVs: d4t + 3TC + LPV/r With ritonavir super boosting

16 Years on RVs Baseline Initiation d4t, 3TC, LPV/r Drugs VL (copies/ml) CD4 CD4 Count 300,000 1,487 (9.8%) 6/ (4.2%) 1 1,200 4,213 (35%) 3 4,600 2,038 (36%) 3 4,900 2,346 (35%) 3 Transferred out to local clinic. Incomplete records from this time

17 Years on RVs 6 (Unsure) assumed d4t, 3TC, LPV/r Drugs VL CD4 CD4 Count 3,328, BC, ZT, EFV, LPV/r 7 45, ,323 8 First resistance test performed

18 9 yrs old Genotype 1 Mutations and Drug Susceptibility NNRTI NRTI PI INSTI Mutations L100I/L, 103/N D67N, 70/R, L74L/V, M184V, T215FIST, 219E/ M46I, I54V, L76V, V82 Not tested igh Level EFV NVP RPV ZT FTC 3TC BC LPV/r Intermediate Level ETR TDF TV/r Low Level Susceptible DRV/r RL

19 Years on RVs Started BC, 3TC, DRV/r, RL Drugs VL CD4 CD4 Count 8, ,066 1,170,690 9 Second resistance test performed, including IN

20 10 yrs old Genotype 2 Mutations and Drug Susceptibility NNRTI NRTI PI INSTI Mutations L100I/L, 103/N D67N, 70/R, L74LV, M184V, T215F/I/S/T, 219/E M46I, I54V, L76V, V82, 43T, L23I, L10L/F, T74S/T None igh Level EFV NVP RPV ZT FTC 3TC BC LPV/r Intermediate Level ETR TDF TV/r Low Level Susceptible DRV/r DTG EVG RL

21 Years on RVs 9 Drugs VL CD4 CD4 Count Left on same regimen and counselled on adherence BC, 3TC, DRV/r, RL 1, ,600 Failing Third Line 3 rd resistance test done

22 Genotype 3 Mutations and Drug Susceptibility NNRTI NRTI PI INSTI Mutations L100IL, 103/N, V179D/V, F227F/L 62V, D67N, 70E//R, 65R/, V75I/T L74L/V, M184V, T215F/I/S/T, 219/E V32I, M46I, I54V, L76V, V82, L90M 43I/T, L23I, L10L/F, T74S/T, L33F/L Y143R, T97, G163R igh Level EFV NVP RPV ZT FTC TDF 3TC BC LPV/r TV/r For discussion Intermediate Level ETR DRV/r TV/r Low Level Susceptible

23 INSTI Mutations Dolutegravir F E G Q N R Y S R Elvitegravir T 66 E 92 T 97 F S Q N G R I Q G Y G R R Raltegravir L 74 E 92 T 97 F E G Y Q N G R M Q G Y S R C R R IS-US dapted From: Wensing et al. Top ntivir Med. 2017;24(4). Updates, user notes, and references available at

24 Genotype 3 Maraviroc Tropism Test: CXCR4 Tropic Mutations and Drug Susceptibility NNRTI NRTI PI INSTI Mutations L100IL, 103/N, V179D/V, F227F/L 62V, D67N, 70E//R, 65R/, V75I/T L74L/V, M184V, T215F/I/S/T, 219/E V32I, M46I, I54V, L76V, V82, L90M 43I/T, L23I, L10L/F, T74S/T, L33F/L Y143R, T97, G163R igh Level EFV NVP RPV ZT FTC TDF 3TC BC LPV/r TV/r RL Intermediate Level ETR DRV/r EVG Low Level DTG Susceptible

25 11 yrs old 26kg Genotype 3 Maraviroc Tropism Test: CXCR4 Tropic Mutations and Drug Susceptibility NNRTI NRTI PI INSTI Mutations L100IL, 103/N, V179D/V, F227F/L 62V, D67N, 70E//R, 65R/, V75I/T L74L/V, M184V, T215F/I/S/T, 219/E V32I, M46I, I54V, L76V, V82, L90M 43I/T, L23I, L10L/F, T74S/T, L33F/L Y143R, T97, G163R igh Level EFV NVP RPV ZT FTC TDF 3TC BC LPV/r TV/r RL Intermediate Level ETR DRV/r EVG Low Level DTG Susceptible

26 Chosen Regimen DTG TDF/FTC DRV Ritonavir 50mg bd po 2/3 (200mg/300mg) tab dly po 400mg bd po 100mg bd po Started 2 weeks ago Due for VL in 3 months

27 Cases South frica Zimbabwe INSTI 2

28 Case 2: 21 yr old female General Information Born in 1997 Diagnosis Treatment Diagnosed with IV at 8 years old Initiated on d4t + 3TC + EFV Changed to 2 nd line after 3 years due to virologic failure ZT + DDI + LPV/r 1 st resistance test after 3 years due to virologic failure

29 15 yrs old Genotype 1 Mutations and Drug Susceptibility NNRTI NRTI PI INSTI Mutations 103N D67N, T69D 70R, T215FY, 219Q M46I, I54V, L76V, V82, L10F, T74S Not tested igh Level EFV NVP ZT DDI d4t LPV/r TV/r Intermediate Level TDF BC Low Level FTC 3TC DRV/r Susceptible ETR RPV RL

30 Years on RVs 7 TDF, FTC, DRV/r, RL, ETR Drugs VL (copies/ml) CD4 CD4 Count 7 ½ 29, , ½ 49, , nd Test

31 Genotype 2 Mutations and Drug Susceptibility NNRTI NRTI PI INSTI Mutations 103N, Y181C, E138Q, V179I/N/D/V D67N, T69D 70R, M184V, T215FY, 219Q M46I, I54V, L76V, V82, L10F, L33F, L24I, 43T, T74S N155, T97, E157E/Q, V151I igh Level EFV RPV NVP ZT DDI FTC d4t 3TC BC LPV/r TV/r For discussion Intermediate Level ETR TDF DRV/r Low Level Susceptible

32 INSTI Mutations Dolutegravir F E G Q N R Y S R Elvitegravir T 66 E 92 T 97 F S Q N R I Q G Y G R Raltegravir L 74 E 92 T 97 F E G Y Q V N E R M Q G Y S R C R I Q IS-US dapted From: Wensing et al. Top ntivir Med. 2017;24(4). Updates, user notes, and references available at

33 17 yrs old Genotype 2 Maraviroc Tropism Test: CCR5 Tropic Mutations and Drug Susceptibility NNRTI NRTI PI INSTI Mutations 103N, Y181C, E138Q, V179I/N/D/V D67N, T69D 70R, M184V, T215FY, 219Q M46I, I54V, L76V, V82, L10F, L33F, L24I, 43T, T74S N155, T97, E157E/Q, V151I igh Level EFV RPV NVP ZT DDI FTC d4t 3TC BC LPV/r TV/r RL EVG Intermediate Level ETR TDF DRV/r Low Level DTG Susceptible

34 Years on RVs 9 10 TDF, FTC, ZT, BC Drugs VL (copies/ml) CD4 CD4 Count DTG not available yet 10 <80 11 TDF, FTC, DTG, DRV/r, MVC She remains virologically suppressed and was counselled on possible teratogenicity

35 Cases South frica Zimbabwe INSTI 3

36 Case 3 General Information Details have been removed as case will be published Diagnosis Treatment

37 INSTI Mutations Dolutegravir F E G Q N R Y S R Elvitegravir T 66 E 92 T 97 F S Q N R I Q G Y G R Raltegravir L 74 E 92 T 97 F E G Y Q N R M Q G Y S R C R IS-US dapted From: Wensing et al. Top ntivir Med. 2017;24(4). Updates, user notes, and references available at

38 ll Three Cases Dolutegravir F E G Q N R Y Y S R Elvitegravir T 66 E 92 T 97 F S Q N R I Q G Y G R Raltegravir L 74 E 92 T 97 F E G Y Q N R M Q G Y S R C R IS-US dapted From: Wensing et al. Top ntivir Med. 2017;24(4). Updates, user notes, 1 and references 3 available 2 at

39 Conclusion lthough we have very few patients on INSTI s in the public sector, we are starting to see resistance with Raltegravir The resistance patterns follow the three common pathways 143, 148 and 155 These resistance mutations (especially 148 and 155 pathway) can lead to DTG resistance INSTI resistance is possibly under identified because IN genotyping is not done routinely and needs to be requested There is likely more INSTI resistance in our private sector We should try to avoid using Raltegravir in cases where future Dolutegravir use may be compromised

40 The Future of Integrase Inhibitors in South frica Patients currently on RVs Current Regimen New Regimen First line TDF + FTC + EFV TDF + 3TC + DTG Second line ZT + 3TC + LPV/r ZT + 3TC + DTG Third line Based on genotyping Based on genotyping First line Second line Treatment naïve patients TDF/TF + XTC + DTG TDF/ZT + XTC + DRV/r Females at reproductive age??? Third line Based on genotyping from first and second line

41 Important spects of Role Out Cost RVs Viral load testing Genotype Tests CW Capacitation INSTI Records VL monitoring before switching Drug interactions (Rifampicin) Genotype Testing after DTG failure Risks in pregnancy Monitor patterns dapt Guidelines

42 Can Integrase Inhibitors help us to achieve the last 90? Source:

43 References Maartens, G., Cotton, M., Wilson, D., Venter, F., Meyers, T., & Bekker, L.-G. (2012). andbook of IV Medicine. (G. Maartens, M. Cotton, D. Wilson, F. Venter, T. Meyers, & L.-G. Bekker, Eds.) (Third). Cape Town: Oxford University Press. Rensburg, R. (2018). NI Bill - So near yet so far. Retrieved July 10, 2018, from Statistics South frica. (2017). Statistical Release: Mid year Population Estimates. Pretoria. Retrieved from Venter, F., Moorhouse, M., Serenata, C., South frican IV Clinicians Society, Wits Reproductive ealth and IV Institute, & Clinton ealth ccess Initiative. (2018). Dolutegravir and New RVs. Johannesburg. Wensing, nnemarie Calvez, V., Günthard,. F., Paredes, R., Johnson, V.., Pillay, D., & Richman, R. W. S. D. D. (2017) Update in the Drug Mutations in IV-1. Topics in ntiviral Medicine, 24(4),

44 cknowledgements Patients Treating clinicians Jonathan Shapiro Leon Levin Francois Venter Lisa orak Theresa Rossouw Ruth Lancaster Caroline Makura nthony Wilson Wits uman Research Ethics Committee Virology Education

45 Thank You

46 Disclaimer: This presentation is made possible by the support of the merican people through the United States gency for International Development (USID). The contents are the sole responsibility of Right to Care and do not necessarily reflect the views of USID or the United States Government.