Anna Maria Geretti on behalf of co-authors Professor of Virology & Infectious Diseases, University of Liverpool Expert Scientist, Roche Pharma

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1 Anna Maria Geretti on behalf of co-authors Professor of Virology & Infectious Diseases, University of Liverpool Expert Scientist, Roche Pharma Research & Early Discovery

2 Funding: Wellcome Trust, National Institutes of Health Research Governance: University of Liverpool (UoL) Employment: AMG is employed by the UoL and by Roche Pharma Research & Early Discovery (pred) the work presented is independent of and not endorsed by Roche pred

3 Alexander Stockdale a,b Matthew Saunders c Mark Boyd d,e Laura Bonnett a Victoria Johnston f Gilles Wandeler g Annelot Schoffelen h Laura Ciaffi i Kristen Stafford j Ann Collier k Nicholas Paton l a University of Liverpool, UK; b Malawi- Liverpool-Wellcome Trust CRP, Malawi; c Imperial College London, UK; d University of New South Wales and e University of Adelaide, Australia; f London School of Hygiene & Tropical Medicine, UK; g University of Bern, Switzerland; h University Medical Centre Utrecht, Netherlands; i University of Montpellier, France; j University of Maryland School of Medicine, USA; k University of Washington School of Medicine, USA; l National University of Singapore, Singapore

4 The number of people receiving ART in SSA increased from 7.5 million in 2010 to 17 million in ,2 Virological suppression rates with 1 st -line ART in LMICs: 67% at 12 months, 65% at 24 months, 62% at 48 months (meta-analysis of 93 studies, ITT) 3 The need for 2 nd -line ART projected to increase to >4M by 2030, in keeping with the expansion of treatment provision 2,4,5 Outcome data required to inform policy ART= Antiretroviral Therapy; SSA= Sub-Saharan Africa LMICs= Low-Middle-Income Countries; ITT= Intention-To-Treat 1. UNAIDS. Joint United Nations Programme on HIV/AIDS, 2016; 2.UNAIDS An ambitious treatment target to help end the AIDS epidemic, 2014; 3. Boender et al. Long-term virological outcomes of first-line antiretroviral therapy for HIV-1 in low- and middle-income countries: A systematic review and meta-analysis. Clin Infect Dis 2015; 4. WHO. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection, 2016; 5. Estill et al. The need for second-line antiretroviral therapy in adults in sub-saharan Africa up to 2030: a mathematical modelling study. Lancet HIV 2016

5 Systematic review and meta-analysis of studies reporting the virological outcomes of PI-based 2 nd -line ART in SSA PRIMARY OUTCOME Virological suppression* after 48 and 96 weeks of treatment SECONDARY OUTCOMES 1. Impact of NRTI resistance 2. Proportion with PI RAMs at 2 nd -line failure *Virological suppression: Plasma HIV-1 RNA <400 cps/ml PI= Protease Inhibitor; RAMs= Resistance-Associated Mutations

6 PubMed, EMBASE, Cochrane Central Register of Controlled Trials, Scopus, Web of Science Terms: HIV, sub-saharan Africa (and countries therein), second-line, protease inhibitor, generic and proprietary names of drugs included in 2 nd -line ART Articles published from 1 Jan 1996 to 10 Jul 2016 One previous systematic review of the effectiveness of 2 nd - line ART in LMIC (2012); new RCTs (e.g., SECOND-LINE, EARNEST, 2- LADY, SELECT) and cohort studies published since References cited in the articles and abstracts from IAS ( ) and CROI ( ) conferences Authors contacted to obtain and clarify data RCTs= Randomised Clinical Trials

7 RCTs (n=5) and observational cohort studies reporting virological outcomes of PI-based 2 nd -line ART in SSA INCLUSIONS HIV-1 positive subjects aged >10 years 1 st -line ART (2 NRTIs + NNRTI) for 6 months prior to starting 2 nd -line ART Clinical, immunological or virological criteria for starting 2 nd -line ART Viral load measured at least annually EXCLUSIONS Studies with <20 participants Participants outside SSA in multi-centre trials PIs or non-standard regimens used as 1 st -line ART No clearly defined criteria for switching from 1 st - to 2 nd -line ART

8 Data from South Africa, Nigeria, Uganda, Zimbabwe, Kenya, Malawi, Zambia, Burkina Faso, Cameroon, Senegal, Tanzania Most patients received LPV/r; one RCT randomised one third of patients to DRV/r (800mg od) WEEK 48: 13 studies 3408 participants Virological suppression 70.0%*[95% CI 56.7, 81.7] WEEK 96: 8 studies 2145 participants Virological suppression 61.5%* [95% CI 47.2, 74.9] *ITT analysis Virological failure by WHO definition (>1000 cps/ml): % at wk 48, % at wk 96 CI= Confidence Interval

9 48 weeks, ITT Observed: 83.3% [76.7, 89.0] Proportion <400 cps/ml

10 B: 96 weeks 96 weeks, ITT Study Year Total VL <400 Proportion (95% CI) Weight (%) Randomised trials Paton (72.27, 80.30) Boyd/Amin ( 66.77, 83.31) (72. 75, ) Observational study Osinusi Adekanmbi (44.76, 66.95) Schoffelen (35.44, 50.79) Wandeler (34.19, 40.26) Boender/ Sigaloff (55.48, 67.61) Murphy (46.03, 62.55) Castelnuovo (70.93, 92.94) Subtotal (I^2 = 94 45%, p < 0 001) (43.14, 67.82) Heterogeneity between groups: p < Overall (I^2 = %, p < 0 001); Proportion <400 cps/ml Proportion with viral load <400 copies/ml (%) (47 15, 74 87). Observed 84.8% [78.8, 89.9]

11 48 weeks, ITT RCTs vs. Observational studies 85.9% [80.8, 90.3] vs. 58.1% [46.0, 69.7] p<0 001 Proportion <400 cps/ml

12 B: 96 weeks 96 weeks, ITT Study Year Total VL <400 Proportion (95% CI) Weight (%) Randomised trials Paton Boyd/Amin Observational study RCTs vs. Observational studies 76.5% [72.8, 80.4] vs. 55.7% [43.1, 67.8] p< (72.27, 80.30) ( 66.77, 83.31) (72. 75, ) Osinusi Adekanmbi (44.76, 66.95) Schoffelen (35.44, 50.79) Wandeler (34.19, 40.26) Boender/ Sigaloff (55.48, 67.61) Murphy (46.03, 62.55) Castelnuovo (70.93, 92.94) Subtotal (I^2 = 94 45%, p < 0 001) (43.14, 67.82) Heterogeneity between groups: p < Overall (I^2 = %, p < 0 001); Proportion <400 cps/ml Proportion with viral load <400 copies/ml (%) (47 15, 74 87).

13 IMPACT OF NRTI RESISTANCE Resistance test results at start of 2 nd -line ART available in 6 studies Fully active Partially active Study VL<400 Total (%) VL<400 Total (%) OR (95% CI) Weight (%) Sigaloff (86 3) (84.8) 1 12 (0 49, 2 55) Boyd 4 10 (40 0) (87 7) 0 09 (0 02, 0 39) Castelnouvo (91 7) 4 4 (100) 0 85 (0 03, 25 05) 4 75 Hosseinipour 3 5 (60 0) (94 4) 0 09 (0 01, 0 66) Johnston (51 4) (78 5) 0 29 (0 12, 0 68) Paton (66 6) (86 6) 0 31 (0 14, 0 68) Overall (I squared = 62 8%, p = 0 020) 0 31 (0 14, 0 70) NOTE: Weights are from random effects analysis Lower odds of virological suppression with fully active regimen Odds Ratio Odds ratio Higher odds of virological suppression with fully active regimen

14 Unbiased selection method for resistance testing required: either all patients meeting a defined viral load threshold, or a random selection of the total failure population 11 studies Threshold for resistance testing cps/ml Duration of 2 nd -line ART at resistance testing: 6-31 months

15 0-7% of at-risk population, 0-25% of failure population 0-7% at 6-12 months; 0-29% at months Proportion with PI RAMs Proportion with major PI mutation(%) Reynolds Sigaloff Johnston Boyd Ciaffi Court Wallis Levison Maigi Paton Ndahimana Median duration of 2 nd -line ART at time of failure

16 PI-based 2 nd -line ART (with continued NRTI use) results in virological suppression in most patients in SSA and carries a relatively low risk of PI resistance

17 PI-based 2 nd -line ART (with continued NRTI use) results in virological suppression in most patients in SSA and carries a relatively low risk of PI resistance Substantial heterogeneity across observational studies ØOne source: variable proportion of missing viral load data not explained by death or loss to follow-up Virological outcomes significantly better (and loss to follow-up lower) among RCT participants vs. observational studies NRTI resistance predicted higher odds of virological suppression ØResistance as a proxy for higher adherence ØZDV and TDF retain significant residual activity despite TAMs, enhanced by continuation of 3TC

18 Long-term data Standardised reporting ØE.g., size of 1 st -line ART population, rate of 1 st -line ART failure, rate of switching to 2 nd -line ART, NRTIs used in 1 st - and 2 nd -line regimens, rate of adverse events, contribution of tolerability to treatment discontinuation One third of patients did not achieve virological suppression ØRisk of disease progression and onward HIV transmission Optimal strategies for preventing, defining, and managing 2 nd -line ART failure, both with and without PI resistance, represent a research priority for SSA

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