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  International HIV and Hepatitis Drug Resistance Workshop
June 8-12, 2010,
Dubrovnik Croatia
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HIV Integrase Resistance Profiles and S/GSK1349572 Baseline Phenotypic Susceptibility for Subjects Experiencing Virologic Failure on Raltegravir (RAL) in the VIKING Study (ING112961)
  Reported by Jules Levin
International Drug Resistance Workshop, 8-12 June 2010, Dubrovnik, Croatia
B Clotet1, C Katlama2, J Lalezari3, B Young4, J Huang5, MR Underwood6, M Ait-Khaled7, and WG Nichols61Hospital Germans Trias i Pujol, Barcelona, Spain, 2Hopital de la Pitie-Salpetriere, Paris, France, 3Quest Clinical Research, San Francisco, CA, 4Denver Infectious Disease Consultants, PLLC, Denver, CO, 5GlaxoSmithKline Canada, Mississauga, Canada, 6GlaxoSmithKline, Inc., RTP, NC, United States, 7GlaxoSmithKline, Stockley Park, London, UK

Background: S/GSK1349572, a next generation integrase inhibitor in Phase IIb clinical development, has low fold change in IC50 (FC) against HIV with RAL-associated mutations of the Y143C/H/R and N155H pathways and against Q148H/K/R single mutants. However, S/GSK1349572 FC increases against Q148H/K/R virus with increasing number of Q148H/K/R-associated mutations.
Methods: Subjects with current or historical RAL virologic failure were screened. Prior antiretroviral therapy, time on RAL, and genotypic and phenotypic resistance data were obtained.
Results: Fifty-three subjects were screened and 27 enrolled. Forty-three of 53 screening isolates had RAL-associated mutations: 7 in N155H, 13 in Y143C(n=3)/H(n=0)/R(n=10), 18 in Q148H(n=13)/K(n=0)/R(n=5) pathways, 2 with mixture of Q148H and Y143H pathways, and 3 Others (non-signature substitutions T97A, V151I, E138D/V151I/E157Q). This population had lower proportions of N155H and higher proportions of Y143C/H/R or Q148H/K/R+≥2 mutations viruses than described for early virologic failure populations from raltegravir P005 and Benchmrk studies. All 7(100%) enrolled subjects harboring virus with Q148H/K/R + ≥1 associated mutations had failing regimen phenotypic susceptibility scores of 0, vs. 11/20 (55%) for all others.
Median(range) prior RAL treatment duration in months for enrolled subjects was longest for viruses with Q148H/K/R +≥2 mutations (n=3) [31(25-41)], shortest for Q148H/K/R +1 mutation (n=4) [23(19-25)] and Q148H/Y143H mixture (n=2) [24(24-24.4)], and intermediate for N155H (n=4) [27(12-38.6)], Y143C/H/R viruses (n=12) [27(3.4-41)], and Others (n=2) [26.14(16.9-35.4)].
S/GSK1349572 baseline FC median (range) varied by RAL-associated mutation (type and number): Y143 FC = 1.12(0.55-1.42), N155 FC = 1.84(1.46-5.08), while Q148/Y143 mixture FC = 7.8(6.5-9.1), Q148+1 mutations FC = 5.47(3.29-25) and Q148+≥2 mutations FC= 21(14-35), demonstrating increasing FC with increasing number of 148-associated substitutions.
Discussion: Viruses from subjects screened into VIKING demonstrated more evolved raltegravir resistance profiles than described for subjects experiencing early virologic failure in published RAL clinical studies. Different prior RAL therapy duration observed for the distinct genotypic pathways is consistent with ordered evolution of RAL resistance, as previously described for the Q148H/K/R pathway. Isolates with the highest FC to S/GSK1349572 (Q148+≥2 mutations) were associated with the longest median duration of RAL therapy. Prompt genotypic testing upon RAL virologic failure and rapid regimen switch may preserve patients' treatment options within the integrase inhibitor class.
·VIKING is a phase IIb pilot study designed to investigate S/GSK1349572 dosed 50mg once daily in ART-experienced subjects with either current or past virologic failure to raltegravir (RAL).
·Subjects with virologic failure and reduced integrase susceptibility from clinical studies of RAL typically harbor virus with one of 3 RAL signature mutational pathways, Q148, N155 or Y143.
·In vitro studies1have shown S/GSK1349572 has limited cross-resistance to RAL and ELV, good in vitroactivity against Q148 single mutant viruses, and against site-directed mutant viruses with Y143 or N155 signature mutations (regardless of RAL-associated secondary mutations). However, S/GSK1349572 activity against viruses with Q148 plus additional RAL resistance-associated substitutions has been shown to display a broader range and more reduced activity, particularly as the number of RAL-associated mutations increases.2This S/GSK1349572 resistance profile was also demonstrated in viruses with RAL resistance mutations from subjects in the SCOPE cohort experiencing virologic failure.3
·Enrollment criteria for VIKING required evidence of genotypic INI resistance mutations at Screen.
·An Integrase screening genotype was used to assign up to 15 subjects into one of two groups.
-- Group A -integrase mutational pathway Q148H/K/R plus one or more Q148-associated integrase resistance mutations (at L74 and/or E138 and/or G140).
-- Group B -all alternative genotypes (from the N155H and Y143H pathways or Q148H/K/R single mutants).
-- to examine HIV integrase genotypes and S/GSK1349572 baseline phenotypic susceptibility in subjects experiencing virologic failure while on RAL.



Genotypes from subject viruses with signature mutations at Y143 or N155 have low FC versus 572, while genotypes with Q148 mutation plus additional 148-associated mutations have broader range and higher median FC .

Genotypes from subject viruses with signature mutations at Y143 or N155 have low FC versus 572, while genotypes with Q148 mutation plus additional 148-associated mutations have broader range and higher median FC .

More ongoing evolution of RAL resistance genotypes were observed in the VIKING screening population (e.g., Y143 and Q148+2 shownabove) compared with early RAL virologic failure virus isolates observed during Phase2b/3 ART-experienced studies with RAL4.
Figure 2. VIKING Enrollment Groups to IN Mutational Pathway Analysis Groups

Virus with the 148 pathway genotypes were most frequently associated with PSS scores of zero

Time of RAL therapy was consistent with ordered evolution of RAL resistance

Median FC was > for RAL than S/GSK1349572 in all cases. Note that asterixes indicate data points and/or median FCs which were greater than max concentration testedS
1.Seki et al. CROI 2010, Poster 555
2.Sato A et al. ICAAC 2009, Poster H-932
3.Underwood M et al. IAS 2009, Cape Town, Poster WEPEA098.
4.FDA DAVP Advisory Committee Meeting, September 5, 2007. URL