1. The 8 th Southern African HIV Drug Resistance and Treatment Monitoring Workshop Summary Thursday 21 Nov Raph Hamers

2. Opening session South Africa largest HIV epidemic and ART program (2.1M) “The best way to prevent HIV resistance is to prevent infection” (Cloete van Vuuren) Science translated into national policy and clinical practice Broad variety of HIV topics  “ geeky” mutations to adherence to clinical cases SATuRN 4 pillars (Tulio de Oliveira): – advanced diagnostics – PHC clinics – Surveillance & research – Collaboration and capacity building Donor perspective RNE: to stimulate collaboration and research translating into policy

3. If you want to go fast, go alone. If you want to go far, go together. We need to go very far, very fast. “A modified African proverb applicable to the African HIV treatment expansion...” Tulio de Oliveira

6. Keynote 1: Is understanding HIVDR still relevant? Mark Wainberg Dolutegravir data

8. Results were confirmed in per protocol analysis: 91% DTG versus 84% DRV/r, ∆ (CI): 7.4 (1.4 - 13.3) Proportion (95% CI) of Individuals With HIV-1 RNA <50 c/mL Over Time – Snapshot (Flamingo) Clotet et al. EACS 2013; Brussels, Belgium. Abstract LBPS4/6. DTG: 90% DRV/r: 83% Week BL481216362448 Proportion (%) 95% CI for difference a Favours DRV/r Favours DTG -20%020% 7.10.913.2 -12% Test for superiority: P=0.025

9. Dolutegravir resistance Resistance mutations selected in vitro with dolutegravir are: R263K or G118R plus H51Y (low-level resistance) – Addition of H51Y increases resistance against DTG but also further decreases viral fitness No compensatory mutations in regard to restoring viral fitness have developed over more than two years in culture. – These findings help to explain why resistance against dolutegravir in INSTI-naïve patients has not been observed “DTG monotherapy in ARV-naive patients?”

10. Keynote 2: Addressing adherence challenges – what does the evidence say? Catherine Orrell

11. Barriers to Adherence in sub-Saharan Africa – ETOH/substance use – Depression – Memory – Side effects – Pill burden/dosing frequency – Adolescence – Transportation to clinic – Food security – Stigma – Stock-outs and substitutions – Unfriendly service Mill PLoS 2006, Oyugyi AIDS 2007, Tuller AIDS Beh 2010, Weiser JAIDS 2003; McCurdy CROI 2010, Nachega AIDS 2008, JAIDS 20090

12. What works in RLS? Review of recent literature - 27 studies from resource-limited settings identified by early 2012. studies with comparator arms (case-control or randomised) and an adherence or biological marker as an outcome. Bärnighausen, Lancet ID 2011 Thompson, Annals Int Med 2012 Peer-driven group pre-treatment education (BIII). Peer support (BIII) DOTS – benefit in terms of adherence, but not biological outcomes Monthly food supplementation packages (BII) Electronic adherence reminder devices (AI) Task-shifting no negative impact (3 RCTs)

13. Adherence interventions are successful StudyYearnInterventionOutcome Berki- Benhaddad 200615Personal adh supportAve decrease VL by 2.3 log Calmy200723 2 Counseling, pill boxes, support group, treatment partner 77% achieved VL<400 DeFino200445Counseling, pill boxes, alarm reminders, repeat education… Ave decrease VL by 0.6 log Khan201340Structured adh counseling, including families 78% achieved resuppression Orrell200743Pill box, dosing diaries, counseling, home visit 54% achieved resuppression Parker201320 0 Intensive adh counseling48% achieved resuppression Pirkle2009561 month mDAART, weekly f/u visits36% decreased VL by >1 log Wilson200940Counseling and education90% resuppression Bonner, JAIDs 2013

14. Develop your adherence toolkit: Medication factors - – OD, FDC, simplify Service / provider factors – – Education, peer support – Measure adherence: SR and pharmacy refill – Interactive communication devices Patient factors - – Use VL – Be friendly and flexible

15. Panel discussion 1: Clinical Case Review. Ava Avalos

16. Successful with good retention, viral success and low levels of resistance Financial challenges: – International donor funding ending, clinical training & mentorship programme are now experiencing setbacks – Efforts to more effective and cost-efficient ways to ensure the long-term financial sustainability Botswana National Program

17. The long-term sustainability of the Botswana ART Program will depend largely on our ability to prevent HIV-DR through the capacity to detect and promptly address virological failure and sub-optimal adherence. Failure Management is the KEY – Routine VL monitoring – ART Failure Management Team & Protocols – Good retention, viral success and low levels of resistance Clinical cases: holistic view – psychosocial, hypertension, diabetes, neoplasma, etc.

18. Keynote 3: HIVDR impact and significance in context of generalized epidemics. Deenan Pillay

19. ART works, with or without resistance testing Resistance is relative not absolute: – Residual activity of the drug – Fitness cost (Consensus statement Pillay-Wainberg) Resistance is a function of roll-out of treatment The utility of resistance testing is determined by Optimal use of VL tests Availability of therapies Health systems and costs

20. “Better alive with drug-resistant virus, than dead with drug-susceptible virus” (Kevin de Cock, WHO)

21. Outcome of ART after 24 months of ART in PASER-M Pascale Ondoa

22. First (n=2755) and second-line ART (n=253) good retention and viral suppression up to 24 months – Early mortality first-line Limited accumulation of DRMs between 12 and 24 months of ART Limited bPI mutations on 2 nd line VL results may not be adequately used for clinical decision- making  Causes to be further explored

23. Pediatric HIVDR: the case of Uganda Cissy Kityo

24. MARCH – Study: only pediatric cohort in Uganda currently assessing HIVDR Important barriers to care remain for children: – Late presentation (median age 4 yrs) Extensive resistance at switch (46% multiple TAMs) due to delayed switching  fear of exhausting treatment options in children? Risk factors for baseline HIVDR: – PMTCT exposure, maternal ART use and breastfeeding HIV drug resistance among children is underreported, surveillance data necessary to inform pediatric guidelines

25. Pretherapy HIVDR: what’s next? Raph Hamers

26. Pre-ART resistance and TDR are on the rise, particularly in southern and East Africa, mostly confined to NNRTI, associated with duration and coverage of national ART programs Currently, measured levels are of concern, but not at unexpected levels and rates, far majority of patients receive effective regimens – Lack of routine HIVDR surveillance data  not up-to-date Strengthening of program functioning, retention and adherence, VL monitoring, access to 2nd line ART Modelling suggests that risk of TDR may be outweighed by HIV prevention – Implementation of novel TasP strategies (Option B+) will need to be closely monitored to assess the consequences for retention- adherence-HIVDR

27. Panel discussion 2: Clinical Case Review. Jan Loot Pretorius

28. First-line failure and resistance due to GI malabsorption, biopsy: MAC Single-drug substitutions in patient with detectable VL burn drug options bPI plus residual activity of NRTI backbone can effectively resuppress VL – Sigaloff JID2012; Houseinipour HIVMed2011

29. Sponsors: We would like to thank to our sponsors: Organized by: Public Drug Resistance and Clinical Management databases: