icon-folder.gif   Conference Reports for NATAP  
 
  18th HIV Drug Resistance Workshop
June 9-12 2009
Ft Myers Florida
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The HIV-1 RT Mutant Q151L Shows Decreased Replication Capacity, Selective High-Level Resistance to GS-9148 and Hypersusceptibility to Tenofovir and Zidovudine
 
 
  XVIII International HIV Drug Resistance Workshop
June 9-13, 2009
Fort Myers, Florida
 
Rima Kulkarni, Nicolas Margot, Florence Myrick, Jenny Svarovskaia, James Chen, Eric Lansdon, Adrian Ray, Tomas Cihlar, S Swaminathan, Michael Miller, and Kirsten White
 
Gilead Sciences, Inc., Foster City, CA, and Durham, NC, USA
 
"The investigational nucleotide reverse transcriptase inhibitor (NRTI) GS-9148 (GS-9131 is prodrug) maintains potent activity against a majority of clinically observed resistance mutations". "The hyperssusceptibility of Q151L to tenofovir and AZT suggest potential utility of combination therapy of GS-9131 with these agents". From Jules: it appears the drug is potentially active against tenofovir resistance, is more potent than tenofovir, has less if any renal side effects, and tenofovir might be active against GS-9148 resistance. This drug has potential use for patients. Gilead has placed development of this drug on hold.
 
AUTHOR CONCLUSIONS
 

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Introduction
 
GS-9148 (Fig. 1) is a novel nucleotide HIV RT inhibitor (NtRTI) that maintains potent activity against a majority of clinically observed resistance mutations including M184V, K65R, L74V, and ≥ 4 TAMs1
 
GS-9148 has low-level cross-resistance to Q151M + complex
 
GS-9131 (Fig. 1), an orally bioavailable phosphonoamidate prodrug of GS-9148, was designed to effi ciently enter PBMCs in vivo and then release GS-9148 intracellularly2
 
GS-9131 has completed initial phase I evaluation in HIV-1 infected patients
 
A GS-9148 resistance selection with HIV-1 IIIB previously resulted in K70E+D123N+T165I RT mutations and low-level reduced susceptibility to GS-91487
 
OBJECTIVES
 
To further characterize the resistance that develops to GS-9148 in vitro
 
To evaluate the cross-resistance of the selected mutations to other N(t)RTIs
 
To characterize the developing resistance mutations for their impact on viral replication capacity

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References
 
1. Cihlar, et al., Antimicrobial Agents and Chemotherapy (2008) 52(2):655-665.
2. Ray, et al., Antimicrobial Agents and Chemotherapy (2008) 52(2):648-654.
3. Petropoulos, et al., Antimicrobial Agents and Chemotherapy (2000) 44(4):920-928.
4. Lansdon, et al., CROI (2009) Abstract # 66LB.
5. Huang, et al., Science (1998) 282:1669-1675.
6. Stanford HIV database: http://hivdb.stanford.edu/index.html. Database accessed on May 1, 2009.
7. Lafl amme, et al., ICAAC (2007) Poster # H-1037.
8. Kosalaraksa, et al., Journal of Virology (1999) 73(7): 5356-5663.
 
We would like to thank Eric Lam and Monogram Biosciences for their contributions. We would also like to thank Bob Shafer and the Stanford HIV Database.