Protease Inhibitor Resistance at 2nd-line HIV Treatment Failure in Sub-Saharan Africa

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Berenice Banks
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1 Protease Inhibitor Resistance at 2nd-line HIV Treatment Failure in Sub-Saharan Africa T. Sonia Boender; Raph L. Hamers; Pascale Ondoa; Maureen Wellington; Cleophas Chimbetete; Margaret Siwale; Eman E F Labib Maksimos; Sheila N. Balinda; Cissy M. Kityo; Titilope A. Adeyemo; Alani Sulaimon Akanmu; Kishor Mandaliya; Mariette E. Botes; Wendy S. Stevens; Tobias F. Rinke de Wit; Kim C.E. Sigaloff. XXV International HIV Drug Resistance Workshop Clinical Implications of Resistance for Treatment and Prevention Strategies Sunday February 21, 2016, Boston, MA, USA. Abstract 38

2 Background: Antiretroviral therapy in sub-saharan Africa Public health approach: standard, empirical ART regimen First line NNRTI 2NRTI Second line PI 2NRTI? Third line

3 Objectives What are the risk factors for virological failure on protease inhibitor based second-line antiretroviral therapy? Adherence? NRTI or PI resistance? How many patients will need third-line antiretroviral therapy because of protease inhibitor resistance? >1 year?

Methods Prospective cohort study 6 countries, 13 clinical sites PASER-M enrollment 2007-2008 With and without on-site VL testing >180 days of

4 Methods Prospective cohort study 6 countries, 13 clinical sites PASER-M enrollment With and without on-site VL testing >180 days of second-line PI based ART Monitoring of routine care 2-3 years Retrospective testing VL and genotyping if VL>1,000 cps/ml at ART switch and after 12, 24, 36 months

5 Results: virological outcomes 12 months 24 months 36 months VL<400 cps/ml 175/205 (85%) 150/177 (85%) 80/90 (89%) 25% had VL>400 cps/ml at least once PI mutation 2/17 (12%) 6/21 (29%) 2/3 (67%)

6 Results: risk factors for virological failure First-line regimen; compared to ZDV/3TC/NNRTI o non-standard NNRTI-based HR 7.1 (95%CI: ) p<0.001 o PI-based regimen HR 7.6 (95%CI: ) p=0.001 PI-resistance at switch HR 6.7 (95%CI: ) p<0.001 <95% adherence, time updated HR 3.1 (95%CI: ) p=0.025 Not: sex, age, CD4+ cell count at switch, duration of first-line ART, HIV RNA load at switch, NRTI resistance at switch

7 Results: susceptibility to PIs after second-line failure % LPV/r ATV/r NFV FPV/r IDV/r SQV/r TPV/r DRV/r High-level resistance Intermediate resistance Low-level resistance Potential low-level resistance Susceptible 7/32 (22%) had 1 protease mutation: M46I, V82A, L76V, I50V, L90M

8 Conclusions While over 85% had viral suppression, 22% had major PI resistance after failing second-line ART 3% of people on second-line ART in sub-saharan Africa Future treatment of these individuals require third-line drugs, which are currently unavailable in sub-saharan Africa. To ensure long-term ART success: intensified adherence support through virological monitoring if failing, resistance testing & availability of third-line drug options

AIGHD Amsterdam & Kampala Tobias Rinke de Wit, Kim Sigaloff, Raph Hamers, Pascale Ondoa, Corry Manting, Bram Prins, Nadine Pakker, Frank

9 Acknowledgements Special thanks to all study participants, study doctors, laboratory staff, study coordinators and data team The PASER network Maureen Wellington, Margaret Siwale, Mariette Botes, Cissy Kityo, Sulaimon Akanmu, Kishor Mandaliya, Nicaise Ndembi, Kim Steegen AIGHD Amsterdam & Kampala Tobias Rinke de Wit, Kim Sigaloff, Raph Hamers, Pascale Ondoa, Corry Manting, Bram Prins, Nadine Pakker, Frank van Leth, Cathy Nalubwama, Miriam Nakitto, Martin Omello PharmAccess Foundation Academic Medical Centre, Amsterdam Sonia Boender

11 Participant characteristics at switch N % Sex Female Age Years (median, IQR) Median duration of first-line regimen Months (median, IQR) ART regimen at failure ZDV/3TC/NNRTI d4t/3tc/ NNRTI TDF/ FTC/NNRTI NNRTI-based, other a Triple NRTI b PI-based c Second-line ART regimen LPV/r + 2NRTI, incl 3TC/FTC LPV/r + 2NRTI, other LPV/r + 3NRTI Non preferred PI, double PI d Criteria used for switch Clinico-immunological only Targeted viral load testing Drug resistance (G) 1 mutation Resistance to prescribed NRTI Resistance to prescribed PI 5 2.9

12 Virological outcome 12 months 24 months 36 months Total follow up N % N % N % N % Viral load Results available <1,000 cps/ml <400 cps/ml Drug resistance Genotypic test results available Any mutation c NRTI-resistance PI-resistance PI- & NRTI-resistance

13 Risk factors for virological failure (VL>400 cps/ml) Not associated: sex, age, CD4+ cell count at switch, duration of first-line ART, HIV RNA load at switch, NRTI resistance at switch First-line ART regimen ZDV, 3TC, NNRTI 1.00 HR 95% CI P D4T, 3TC, NNRTI TDF, FTC, NNRTI Non-standard NNRTI-based <0.001 Triple NRTI PI-based Protease inhibitor resistance at switch GSS GSS < <0.001 Adherence to second-line ART (time-updated) 95% 1.00 <95%

14 Within months: 7/32 (22%) have major PI-mutations 100% 80% 60% 40% 20% 0% Any NRTI M41L K65R D67N K70R mutat /E ion K74V V75I Q151 M M184 V T215 Y/F/I K219 Q Any TAM Any PI M46I I50V L76V V82A L90M mutat ion 12 months 41% 24% 12% 12% 12% 0% 6% 6% 29% 24% 6% 29% 12% 12% 0% 6% 12% 6% 24 months 57% 10% 5% 19% 19% 5% 0% 0% 43% 24% 14% 38% 29% 24% 0% 10% 19% 0% 36 months 100% 0% 0% 33% 33% 0% 0% 0% 1 0% 0% 33% 67% 67% 33% 0% 33% 0%

15 Antiretroviral resistance after second-line failure % TC FTC AZT d4t ddi TDF ABC EFV NVP ETR RPV LPV/rATV/r NFV FPV/rIDV/rSQV/rTPV/rDRV/r reverse transcriptase inhibitors protease inhibitors High-level resistance Intermediate resistance Low-level resistance Potential low-level resistance Susceptible

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