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HIV that Is Resistant to Dolutegravir May not be Transmissible. Mark A Wainberg McGill University AIDS Centre Jewish General Hospital. Disclosures. I have received honoraria from AbbVie, Bristol Myers Squib, Gilead, Janssen,Merck, ViiV. FLAMINGO (ING114915) Study Design.
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HIV that Is Resistant to Dolutegravir May not be Transmissible Mark A Wainberg McGill University AIDS Centre Jewish General Hospital
Disclosures I have received honoraria from AbbVie, Bristol Myers Squib, Gilead, Janssen,Merck, ViiV
FLAMINGO (ING114915) Study Design Open-label randomized phase Extension phase HIV+ ART-naiveVL ≥1,000 c/mL Stratified by screening plasma HIV-1 RNA (≤ vs >100,000 c/mL) and background dual NRTI (ABC/3TC or TDF/FTC*) DTG 50 mg QD + 2 NRTIs DTG + ART DRV/r 800 mg/100 mg QD + 2 NRTIs Randomization Week 48 analysis Week 96 analysis Primary endpoint: proportion with HIV-1 RNA <50 c/mL at Week 48, FDA Snapshot analysis, -12% non-inferiority (NI) margin Secondary endpoints: antiviral activity, safety, tolerability, health outcomes and viral resistance *Investigator selected backbone of choice Clotet et al. EACS 2013; Brussels, Belgium. Abstract LBPS4/6.
Proportion (95% CI) of Individuals With HIV-1 RNA <50 c/mL Over Time – Snapshot DTG: 90% DRV/r: 83% 95% CI for differencea FavoursDRV/r FavoursDTG Proportion (%) 0.9 7.1 13.2 -20% -12% 0 20% BL 4 8 12 16 24 36 48 Test for superiority: P=0.025 Week Results were confirmed in per protocol analysis: 91% DTG versus 84% DRV/r, ∆ (CI): 7.4 (1.4 - 13.3) Clotet et al. EACS 2013; Brussels, Belgium. Abstract LBPS4/6.
Resistance to INSTIs in clinical trials in treatment-naïve patients RALTEGRAVIR Cooper et al., NEJM, 2008 Sichtig et al, JAC, 2009 Canducci et al, AIDS, 2009 Hatano et al, JAIDS, 2010 ELVITEGRAVIR Sax et al, Lancet, 2012 DeJesus et al, Lancet, 2012 DOLUTEGRAVIR vanLunzen et al., Lancet Infect. Dis., 2012
Major resistance pathways against INSTIs(clinical and tissue culture data) Quashie et al., Curr. Opin. Infect. Diseases, in press
Secondary INSTI-resistance mutations often restore HIV replication capacity Mbisa et al., Infect. and drug resistance, 2011--Canducci et al., JAC, 2010--Reigadas et al., Plos One, 2010--Delelis et al., AAC, 2009
Dolutegravir activity on RAL-resistant clinical isolates (n=39)(median IC50 for wild-type=1.07 nM) Underwood et al., JAIDS, 2012
Subtype-specific mutations selected in vitro with dolutegravir Quashie, Mesplède et al., Journal of Virology, 2012
The R263K mutation confers low-level resistance to dolutegravir in cell culture *Methodological differences (EC50 for wild-type ≈1-6nM) Quashie, Mesplède et al., Journal of Virology, 2012
SAILING • CROI 2013. A study in which Dolutegravir was shown to be superior to Raltegravir in treatment-experienced integrase inhibitor-naïve subjects. • The R263K mutation was present in two individuals who either rebounded or did not achieve virologic suppression to <50 c/ml.
The R263K mutation decreases integrase activity in cell-free assays Quashie, Mesplède et al., Journal of Virology, 2012
The R263K mutation decreases dolutegravir residency time in an integrase-vDNA complex
The addition of H51Y to R263K further decreases IN strand transfer activity A B
The combination of H51Yand R263K negatively impacts viral fitness
Dolutegravir resistance associates with a decrease in viral replication capacity
The R263K Mutation Confers a Higher Level of Drug Resistance against DTG than INSTI Mutations Associated with RAL and EVG This explains why R263K is selected preferentially by DTG and why the R263K virus is then unable to proceed along any of the alternative INSTI resistance pathways that are associated with high level resistance against all members of the INSTI family of drugs
Replication Capacity of HIV Containing Various Combinations of INSTI Resistance Mutations
Conclusions • Resistance mutations selected in vitro with dolutegravir are: R263K or G118R plus H51Y • R263K and G118R confer low-level resistance against dolutegravir, e.g. 2.5-6 fold • The addition of H51Y to either R263K or G118R increases resistance against DTG but also further decreases viral fitness • These findings help to explain why resistance against dolutegravir in INSTI-naïve patients has not been observed
No compensatory mutations in regard to DTG resistance and viral fitness have developed over more than two years in culture.
Acknowledgements • Bluma Brenner • Hongtao Xu • Dimitri Coutsinos • Jerry Zaharatos • Maureen Oliveira • Thibault Mesplède • Peter Quashie
Long-Term Safety and Efficacy of Raltegravir-Based Versus Efavirenz-Based Combination Therapy in Treatment-Naïve HIV-1 Infected Patients: Final 5-Year Double-Blind Results From STARTMRK AIDS 2012 Poster #LBPE19
Proportion (%) of Patients Achieving HIV RNA <50 copies/mL (95% CI) Over Time 100 86 81 76 75 71% 80 82 79 60 69 67 61% HIV RNA Levels <50 Copies/mL Percent of Patients with 40 20 0 0 12 24 48 72 96 120 144 168 192 216 240 Weeks Number of Contributing Patients Raltegravir 400 mg bid. 281 278 279 280 281 281 277 280 281 281 277 279 Efavirenz 600 mg qHS. 282 282 282 281 282 282 281 281 282 282 282 279 Non-Completer = Failure Approach
Change From Baseline in CD4-Cell Count (95% CI) Over Time 374 361 400 331 350 300 240 312 301 295 250 189 200 225 CD4 Cell Count (cells/mm3) Change from Baseline 150 163 100 50 0 0 12 24 48 72 96 120 144 168 192 216 240 Weeks Number of Contributing Patients Raltegravir 400 mg bid. 281 272 266 258 255 250 240 235 231 235 227 222 Efavirenz 600 mg qHS. 281 268 266 251 252 243 234 228 224 220 218 212