Dr Marta Boffito Chelsea and Westminster Hospital, London

Dr Marta Boffito Chelsea and Westminster Hospital, London Speaker Name Statement Dr Marta Boffito has received travel and research grants from and has been an advisor for Janssen, Roche, Pfizer, ViiV, Bristol- Myers Squibb, Merck Sharp & Dohme, Teva, Mylan, Cipla and Gilead Date : 8 September 2016

20th Annual Antiviral Therapy & Drug Resistance Meeting Thursday 15 September 2016 Wellcome Collection, London Emerging evidence and knowledge gaps to inform treatment guidelines Marta Boffito MD, PhD Head of Clinical Trials, St. Stephen s Centre (SSAT) Consultant Physician, Chelsea and Westminster Hospital Reader, Imperial College

Introduction Studies have shown significant rates of baseline drug resistant mutations to any ARV in PLWH, with rates up to 19.3% START: 4.4% in the UK to 13% in USA CW (x 3 clinics) rates are approx 15% Treatment guidelines recommend inclusion of a PI/b when initiating cart in patients with baseline transmitted drug resistance (TDR) Baxter et al HIV Med 2015; McFaul et al AIDS 2015

True or false?

http://www.eacsociety.org/guidelines EACS 2016 No statement on starting cart in PLWH with TDR

EACS update on PHI (confidential) Treatment selection preferably be recruited into a clinical trial curative strategies use PrEP or PEP taken into account A drug resistance test is recommended in all cases as soon as possible after diagnosis Where there are indications for immediate treatment (Table 1), therapy may have to start before the results of resistance testing become available. Whilst evidence is evolving, current guidance remains that in such cases preference should be given to starting a PI/r in order to increase the barrier to resistance of the overall regimen InSTI should also be included in order to induce rapid viral load suppression plus TDF/FTC or TAF/FTC adjusted once the resistance test becomes available and viral load suppression is achieved patterns of TDR may assist with treatment selection

www.bhiva.org BHIVA 2015 No statement on starting cart PLWH with TDR

www.bhiva.org ART should be started only when the individual feels ready to do so there are certain clinical presentations of PHI where expedited ART initiation recommended Neurological involvement (1D) Any AIDS-defining illness (1A) CD4 cell count <350 cells/µl (1C) PHI diagnosed within 12 weeks of a previous negative test (1C) BHIVA 2016 - PHI

www.bhiva.org ART should be started only when the individual feels ready to do so there are certain clinical presentations of PHI where expedited ART initiation recommended Neurological involvement (1D) Any AIDS-defining illness (1A) CD4 cell count <350 cells/µl (1C) PHI diagnosed within 12 weeks of a previous negative test (1C) BHIVA 2016 - PHI NO statement on what to start with

https://aidsinfo.nih.gov/guidelines DHHS 2016 Determining initial treatment transmission of drug-resistant HIV strains is well documented and associated with suboptimal virologic response to initial ART The risk of acquiring drug-resistant virus is related to the prevalence of drug resistance in HIV-infected persons engaging in high-risk behaviors in a given community In high-income countries approx 10% to 17% of ART-naive patients have resistance mutations to at least 1 ARV drug. Up to 8%, but generally less than 5%, of transmitted viruses will exhibit resistance to drugs from more than class Transmitted resistant HIV is generally either NRTI- or NNRTI-resistant. PI resistance is much less common, and to date, transmitted INSTI resistance is rare

IAS 2016 Baseline resistance testing is recommended for all patients, but initiating therapy prior to availability of the results may be appropriate in some cases Recent data suggest little transmitted drug resistance to InSTIs and PIs but not NNRTIs https://www.iasusa.org/guidelines

Growing evidence on how to treat PLWH with TDR

TAMs = Thymidine analogue mutations (RT codons 41, 67, 70, 210, 215, 219) *T215rev: any T215 change other than T215Y/F Geretti et al CROI 2016 Impact of transmitted TAMs on responses to first-line ART Why TAMs: in Europe and North America, TAMs continue to be a frequently reported form of TDR Study objective: to investigate the virological outcomes of first-line ART in HIV-1 positive adults harbouring 1 TAMs* as the sole form of TDR compared with subjects who started ART in the absence of detectable resistance

Time to virological suppression 1 - No resistance, NNRTI 2 - No resistance, bpi 3 Isolated TAMs, NNRTI 4 - Isolated TAMs, bpi a= Virological suppression defined as 2 consecutive VL 50 cps/ml

Time to virological failure 1 - No resistance, NNRTI 2 - No resistance, bpi 3 - Isolated TAMs, NNRTI 4 - Isolated TAMs, bpi b= Virological failure defined as 2 consecutive VL >50 cps/ml or a single VL >50 cps/ml followed by a significant treatment change

Time to virological failure by singleton vs. multiple TAMs 1 - Singleton TAM, NNRTI 2 - Singleton TAM, bpi 3 - Multiple TAMs, NNRTI 4 - Multiple TAMs, bpi

Conclusions - NNRTI-based ART: Detection of isolated TAMs did not affect virological responses - bpi-based ART: Virological responses were reduced overall but differed by VL cut-off and baseline resistance profile Subjects with no resistance had the highest risk of failure regardless of VL cut-off (50 or 200 cps/ml) Consistent with practice in our setting where (in the absence of TDR) bpi-based ART is started when there are concerns about adherence Subjects with TDR had an increased risk of low-level viraemia (50-200 cps/ml) but showed similar failure rates as with NNRTI-based ART when using >200 cps/ml for defining failure

Comparison of efavirenz- and protease inhibitorbased cart regimens in treatment-naive PLWH with baseline resistance We conducted this retrospective study to assess virological outcomes of treatment-naive patients with primary HIV drug resistance started on either a boosted PI/b or efavirenz-based regimen Lim et al AIDS 2016

Results I 2903 patients commencing cart between 2011 2014 276 patients met the inclusion criteria 181 (65.6%) were treated with a PI/r 95 (34.4%) with alternative regimens (81 (29.4%) with EFV; 9 (3.3%) with non-efv NNRTIs; 5 (1.8%) with InST) Most frequent reasons for non PI/r : patient preference, use of other medications (e.g. statins, PPIs), co-infection with HCV and presence of baseline PI TDR 262 patients treated with PI/b-based (n=181) or efavirenz-based (n=81) regimens were included for further analysis At cart initiation PI/b group mean viral load = 199,332.4/mL EFV group mean viral load = 334,888/mL Mean time to achieving an undetectable viral load PI/b group = 6.17 months (median 5.17, 95% CI 5.78-6.55) EFV group = 5.23 months (median 5.20, 95% CI 4.90-5.56) (p<0.0001)

Results II At 6 mo post-cart initiation 32.75% of PI/r group vs 32.39% of EFV group had detectable viral load At 12 mo post-cart initiation 9.26% of PI/b group vs 4.23% of EFV group had a detectable viral load Mainly TAMs but 20% with VL<50 on EFV had 103N (!) Proportion of patients with viral rebound, defined as 2 consecutive viral load measurements over 200/mL after successful suppression 4.08% of PI/b group vs 0% (0/67) of EFV group PI/r group: failed to achieve viral suppression within 6 months 49.29% (35/71) with NRTI mutations 43.85% (57/130) with NNRTI mutations 0% (0/6) with PI mutations EFV group: failed to achieve viral suppression within 6 months 38.10% (8/21) with NRTI mutations 38.78% (19/49) with NNRTI mutations 43.75% (7/16) with PI mutations

Treatment success TAF (n=865) All patients 749/865 (87%) Subtype B 644/743 (88%) Subtype non-b 105/122 (86%) NRTI-R 61/73 (84%) No NRTI-R 688/792 (87%) TAMs 17/21 (81%) No TAMs 732/844 (87%) NNRTI-R 134/155 (86%) No NNRTI-R 615/710 (87%) K103N/S 38/48 (79%) No K103N/S 711/817 (87%) PI-R 21/29 (72%) No PI-R 728/836 (87%) TDF (n=867) 739/867 (85%) 630/749 (84%) 109/118 (92%) 49/56 (88%) 690/811 (85%) 11/16 (69%) 728/851 (86%) 140/159 (88%) 599/708 (85%) 44/47 (94%) 695/820 (85%) 25/28 (89%) 714/839 (85%) Pre-Existing Drug Resistance Mutations in Treatment-Naïve Subjects Do Not Affect Response to Tenofovir Disoproxil Fumarate (TDF) or Tenofovir Alafenamide (TAF) Containing Regimens Prevalence of pre-existing TDR to tenofovir (K65R) or FTC/3TC (M184V/I) was rare Presence of other pre-existing resistance mutations, notably TAMs had no impact on treatment response to TDF or TAF-based regimens Margot et al International Resistance Workshop 2016

Implications for care What should current guidance on the management of subjects that by conventional sequencing show TAMs as the sole form of TDR? The observations must be placed into the context of TAMs being detected most commonly as singleton mutations, and T215rev variants accounting for most case Need of controlled studies? Only TAMs? What combinations should be studied? Development of novel ARVs has prompted interest in their use in patients with existing TDR

ABC/3TC/DTG use in PLWH with DTR Use of Triumeq in PLWH naïve to cart with Arm 1 = 1 TAM Arm 2 = 2 TAMS +/- 184V

Case 1 34 y.o. man HIV + > 6 mo ago CD4 660 VL 120,000 TasP with STR Baseline RT 103N

Case 1 34 y.o. man HIV + > 6 mo ago CD4 660 VL 120,000 TasP with STR Baseline RT 103N TDF/FTC plus InSTI ABC/3TC/DTG OR TDF/FTC plus PI/r?

54 y.o. man HIV + < 2 mo ago CD4 800 VL 380,000 PHI Baseline RT 41L, 215Y Case 2

Case 2 54 y.o. man HIV + < 2 mo ago CD4 800 VL 380,000 PHI Baseline RT 41L, 215Y TDF/FTC plus InSTI or ABC/3TC/DTG plus PI/r When VL < 40 TDF/FTC plus anything?? or plus PI/r?

Questions? Thank you to Prof AM Geretti for her help in putting together this talk!