Dynamics i in the Short-Term rm E Evol olution on of of HIV D - - PowerPoint PPT Presentation

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HIV D Drug g Res esistance e – Prelim limin inary Data ta

Arevir 2019 Jennifer Brown Molecular Virology, Department of Biomedicine, University of Basel

Higher levels of drug resistance upon viremia in patients from Lesotho than Uganda or Switzerland 1

< 1000 c/mL ≥ 1000 c/mL Standard of Care (WHO guidelines) Patient on ART with viral load ≥ 1000 c/mL 2-3x adherence counselling Repeat viral load test after 3 months

Does the counselling process select for additional drug resistance? Some patients (31%) resuppress to < 1000 c/mL Patients with some resistance at the 1st high viral load may acquire additional drug resistance during the 3-month counselling process

Rationale

Time point Switzerland, Uganda Time point Lesotho

• 1. Bachmann et al., JAC. 74(2):468-472 (2018). doi: 10.1093/jac/dky436.

Samples from CART trial (NCT02126696) in Lesotho 1 NGS analysis of samples before and after adherence counselling (3 month interval) Patients with 1st and 2nd VL ≥ 1000 c/mL (n=64; t1 available for n=48; t2 available for n=63) Patients with 1st VL ≥ 1000 c/mL and 2nd VL 80-999 c/mL (n=12; t1 available for n=11; t2 available for n=11) Characteristics: % regimens containing following ARVs (2 NRTIs + 1 NNRTI for all) TDF 50% AZT 50% 3TC or FTC 100% EFV 60.34% NVP 39.66%

Methods / Patient Characteristics

• 1. N. D. Labhardt et al., Medicine (Baltimore). 95(28):e3985 (2016). doi: 10.1097/MD.0000000000003985.

Preliminary Results – High Resistance at 1st VL

• 59 samples: 48 with sustained VL ≥ 1000 c/mL; 11 with partial resuppression to 80-999 c/mL
• Cut-off 5%

Number of major DRMs Number (%) among sustained VL ≥ 1000 c/mL Number (%) among partial resuppression to 80-999 c/mL Total (%) 4 (8.3) 2 (18.2) 6 (10.2) 1 2 (4.2) 0 (0.0) 2 (3.4) 2 4 (8.3) 5 (45.5) 9 (15.3) 3 6 (12.5) 1 (9.1) 7 (11.9) > 3 32 (66.7) 3 (27.3) 35 (59.3)

4

K103N: high resistance to NVP and EFV; nonpolymorphic V106M: high resistance to NVP and EFV; nonpolymorphic; particularly common in subtype C Y181C: high resistance to NVP; resistance also to other NNRTIs; nonpolymorphic G190A: high resistance to NVP; resistance also to other NNRTIs; nonpolymorphic

Preliminary Results – Changes in NNRTI Resistance

K103N  K103S (high resistance to NVP and EFV) G190A  G190S (62%), G190T (10%) (high resistance to NVP and EFV)

M41L: Moderate resistance to AZT and TDF; thymidine analog mutation (TAM) K65R: High resistance TDF, moderate resistance to 3TC/FTC, increased susceptibility to AZT (except in combination with Q151M); more likely to emerge in subtype C D67N: Moderate resistance to AZT; TAM K70R: Moderate resistance to AZT and low resistance to TDF; TAM L74I: May have compensatory effects on viral fitness, especially in the presence of NNRTI DRMs M184V: High resistance to 3TC/FTC, increased susceptibility to AZT and TDF and slows emergence of AZT and TDF resistance; associated with reduced viral replication K219Q: Moderate resistance to AZT when present with other TAMs; TAM

Preliminary Results – Changes in NRTI Resistance

Exeptionally high rates of resistance at 1st high VL... ... probably since VL testing had only just been introduced (2014), and patients may had high VLs for many months/years. Trend towards an acquisition of additional drug resistance in patients who already have drug resistance starting EAC (majority in Lesotho)... ... calls into question the WHO-recommended policy of enhanced adherence counselling. More work to be done to assess the extent of potential harm (through selection for resistance) vs. benefit (no regimen change for those without resistance) of the adherence counselling approach in settings without access to resistance testing.

Preliminary Interpretation

Thank you

Molecular Virology Research Group: Thomas Klimkait Nina Marty Fabian Otte Lorena Urda Ulrike Seeburger Siro Ellenberger Olga Burger Niklaus Labhardt Karin Metzner Roger Kouyos Nadine Bachmann Herbert Mbunkah Christine Leemann