What is the Virologic Support for Two-Drug Regimens?

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1 What is the Virologic Support for Two-Drug Regimens? Daniel R. Kuritzkes, M.D. Division of Infectious Diseases Brigham and Women s Hospital Harvard Medical School

2 Disclosures The speaker has received consulting honoraria, speaker fees or research grants from the following companies: Gilead GlaxoSmithKline Janssen Merck ViiV

3 Rapid turnover of HIV quasispecies Approximately half of the virus population in plasma is cleared and replaced each day. High turnover allows rapid emergence of drugresistant variants under selective pressure. Resistant variants replaced by residual wild-type virus if selective pressure is removed. Resting latently infected cells continue to harbor drug-resistant provirus. DRK

4 Why three drugs? Historically, 3-drug regimens provided more durable virologic suppression Models suggested 3-drug regimens necessary to prevent emergence of resistance Earlier 2-drug regimens that included NNRTIs or PIs with low barriers to resistance failed Even some 3-drug regimens were vulnerable to pre-existing resistance to a single component

5 Time to virologic failure (ITT) Kuritzkes et al J Infect Dis 2008 DRK

6 Preventing HIV-1 drug resistance Use potent, fully suppressive regimens to avoid selecting resistant virus Resistance testing prior to starting antiretroviral therapy (and at time of virologic failure) Avoid virtual monotherapy when adding newer drugs to a failing regimen DRK

7 Effect of transmitted TAMs on virologic response to modern ART Geretti et al CROI 2016 DRK

8 No major resistance in setting of LPV/r monotherapy for maintenance Arribas J et al JAIDS 2005

9 ACTG A5142: Lopinavir/ritonavir plus efavirenz Riddler SA et al N Engl J Med 2008

10 Resistance in A5142 Riddler SA et al N Engl J Med 2008

11 OLE study: Switch to LPV/r + 3TC Resistance testing showed K103N and M184V at VF in one of two participants from dual group Retrospective testing showed these were pre-existing Arribas JR et al Lancet Infect Dis 2015

12 GARDEL: LPV/r + 3TC as initial ART Resistance testing: 2 of 5 in dual therapy arm developed M184V versus 0 of 7 in triple arm Cahn P et al Lancet Infect Dis 2014

13 ACTG A5262: DRV/r + RAL pilot Taiwo B et al AIDS 2011 PID Baseline VL IN mutations 1 230,627 Q148Q/R, N155H/N 9 147,076 N155H/N ,212 Q148K/Q, N155H/N ,043 N155H ,729 N155H/N 23 others WT (20) or amplification failure (3)

14 NEAT001: Phase 3 DRV/r + RAL Raffi F et al Lancet 2014

15 SWORD studies: DTG + RPV switch Resistance testing in one participant with nonadherence showed K101K/E 1.2-fold shift in RPV susceptibility; no DTG resistance Llibre JM et al Lancet 2018

16 ACTG A5353: DTG/3TC dual therapy Taiwo B et al Clin Infect Dis 2018 (epub ahead of print)

17 Cabotegravir and Rilpivirine as Two-Drug Oral Maintenance Therapy: LATTE Week 96 results Margolis DA et al Lancet Infect Dis 2015

18 Resistance in LATTE VF in one participant in the RPV + 10 mg CAB arm at week 48 Subtherapeutic levels of RPV and CAB Developed resistance to both drugs IN Q148R mutation (3.1-fold resistance to CAB; 30-fold resistance to raltegravir) RT E138Q Two other participants with VF developed RPV resistance but INSTI resistance not present (1) or not tested (1) Margolis et al Lancet Infect Dis 2015

19 LATTE-2: 96 week results Margolis DA et al Lancet 2017

20 LATTE-2: Resistance data 3 participants met protocol-defined criteria for virological failure 1 in oral dosing arm: no PR, RT or IN resistance mutations 2 in Q8W injection arm: One with R269R/G mixture in IN (no fold-change) One with K103N, E138G, K238T in RT and Q148R in IN (resistant to NNRTIs, RAL, EVG, CAB but DTG sens) Margolis DA et al Lancet 2017

21 Emergence of DTG resistance in monotherapy studies Study name N Efficacy VF (N) GRM/n GRM/VFs Mutations ITALY 20 95% DONOMO 86 88% 8 3/86 (3.5%) 3/8 (37.5%) DOLAM % 2 2/31 (65%) 2/2 (100%) REDOMO % 11 9/122 (7.4%) 9/11 (82%) DOLUFRENCH 28 89% 3 3/28 (11%) 3/3 (100%) 263K (1) 155H (1) 230R (1) 155H, 147G, 148R (1) 138K, 155H, 140S (1) (next slide) 138K, 140A, 148R (1), 74I, 92Q (1), 155H (1) Adapted from Blanco JL et al Curr Opin Infect Dis 2018

22 DTG resistance in REDOMO Adapted from Blanco JL et al Curr Opin Infect Dis 2018

23 Time to VF in DONOMO Wijting et al J Infect Dis 2018 (epub ahead of print)

24 Resistance in GEMINI 1 & 2 Data to be presented at IAS 2018

25 Conclusions 2-drug ART can be effective as initial or maintenance therapy, but regimen matters! At least one drug in the regimen must have a high barrier to resistance Impact of pre-existing XTC or NNRTI resistance on efficacy of DTG/3TC or DTG/RPV is unknown Given risk of DTG resistance emergence with monotherapy, best to avoid dual therapy when XTC or RPV resistance is present