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1 - Laboratório de AIDS e Imunologia Molecular – IOC – FIOCRUZ , Rio de Janeiro, Brazil.

Brazilian Ministry of Health Oswaldo Cruz Foundation Oswaldo Cruz Institute. Monitoring the emergence of resistance mutations in patients under salvage therapy with Raltegravir in Rio de Janeiro, Brazil: a six month follow-up .

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1 - Laboratório de AIDS e Imunologia Molecular – IOC – FIOCRUZ , Rio de Janeiro, Brazil.

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  1. Brazilian Ministry of Health Oswaldo Cruz Foundation Oswaldo Cruz Institute Monitoring the emergence of resistance mutations in patients under salvage therapy with Raltegravir in Rio de Janeiro, Brazil: a six month follow-up Caroline Passaes1, Monick Guimarães1, Sandra Wagner 2, Valdiléa Veloso 2, Beatriz Grinsztejn 2, Mariza Morgado1 1 - Laboratório de AIDS e Imunologia Molecular – IOC – FIOCRUZ , Rio de Janeiro, Brazil. 2 - Instituto de Pesquisa Clínica Evandro Chagas – IPEC – FIOCRUZ, Rio de Janeiro, Brazil.

  2. Background • Raltegravir (RAL) was approved for salvage therapy in Brazil in 2009. • Resistance pathways: N155H + L74M, E92Q, T97A, V151I, and/or G163R; Q148K/R/H + E138K/A and/or G140S/A; Y143R/C + L74A/I, E92Q, T97A, I203M, and/or S230R. • Since Raltegravirwas approved, several efforts have been made in order to describe the emergence of resistance mutations in patients taking HAART under a Raltegravir-containing regimen.

  3. Question • How long will it take to the integrase resistance mutations emerge in multi-experienced patients under RAL-containing regimens?

  4. Methods Start treatment with RAL 12 months Baseline 2 months • Samples: • The EvandroChagas Clinical Research Institute (IPEC) is the clinical Unit of the Oswaldo Cruz Foundation (FIOCRUZ) that is responsible for the treatment and follow-up of more than 2000 HIV positive patients in the Rio de Janeiro State, Brazil. • Prospective and longitudinal study. • Study design: • CD4 (FACS Calibur Cytometer) • Viral load (bDNA) • Genotyping of HIV-1 integrase (home brew method developed in our laboratory) 4 months 9 months 6 months

  5. Methods • Samples: • Four patients receiving a Raltegravir-containing regimen (HAART) at IPEC, Rio de Janeiro, Brazil 6 months follow-up. • All patients have more than 10 years of infection and ARV use. All of them have used at least 3 classes of ARVs (NRTI, NNRTI and PI).

  6. Results • Sustained Virologic Response HIV+ since 1995 Previous therapeutic scheme: 3TC/DDI/TDF/LPV/r Actual therapeutic scheme: 3TC/TDF/DRV/r/Raltegravir Subtype B HIV+ since 1993 Previous therapeutic scheme: 3TC/TDF/DRV/r/T20 Actual therapeutic scheme: 3TC/TDF/DRV/r/Raltegravir Subtype F

  7. Results • Virologic Failure HIV+ since 1986 Previous therapeutic scheme: AZT/3TC/TDF/DRV/r/T20 Actual therapeutic scheme: AZT/3TC/ TDF/DRV/r/Raltegravir Subtype B HIV+ since 1991 Previous therapeutic scheme: 3TC/TDF/DRV/r/ETR Actual therapeutic scheme: 3TC/TDF/fAPV/r/Raltegravir Subtype B Q148H/G140S

  8. Questions • Is it possible to detect the integrase resistance mutations in the proviral compartment before its detection in the plasma samples? • Can this approach be used as a predictor of the emergence of integrase resistance mutations?

  9. Methods Start treatment with RAL 12 months Baseline 2 months • Samples: • Provirus: Amplification by PCR (limit dilution) 10 clones for each visit of all patients 150 sequences analyzed 4 months 9 months 6 months

  10. Results • Major resistance mutations were detected in proviral clones only in that sample presenting major resistance mutations in the plasma. However, these mutations were detected in the provirus after their emergence in the plasma. 140 148 G140S Q148H • Some minor resistance mutations were observed in the DNA analysis: L74M; Q146H; Q95K; E138Q; M154I; G163R; S230N and R263K.

  11. Conclusions • In spite of being a good option for the clinical management of patients presenting highly resistance to multiple antiretroviral drugs, in our study 2 out of 4 individuals showed early virologicfailure to a RAL-containing regimen. For one of these cases integrase resistance mutations could be detected. • Similar cases of early failure to RAL have been recently described (Baldanti et al., J Med Virol, 2010; da Silva et al., J Antimicrob Chemother, 2010; Tommasi et al., Scand J Infect Dis, 2010). • The DNA provirus analysis did not antecipate the emergence of integrase resistance mutations. • Close follow-up of multi-drug experienced patients should be warranted.

  12. Acknowledgments • AIDS 2010 Organizers • International Scholarship Program/Sidaction • Laboratory of AIDS and Molecular Immunology team – IOC/FIOCRUZ • EvandroChagas Clinical Research Institute team –IPEC/FIOCRUZ • All patients enrolled in the study • PAPES V/FIOCRUZ, CNPq and FAPERJ grants cpassaes@ioc.fiocruz.br

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