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Infobiomed Consortium Meeting, Barcelona, 26th-27th Jan, 2006

Infobiomed – WP4 Proposal of a BMI demonstrator focused on the integration of viral genomics with clinical data in HIV infection. Infobiomed Consortium Meeting, Barcelona, 26th-27th Jan, 2006. Roberto Ricci - Informa. New infections far from declining even in developed countries!

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Infobiomed Consortium Meeting, Barcelona, 26th-27th Jan, 2006

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  1. Infobiomed – WP4Proposal of a BMI demonstrator focused on the integration of viralgenomics with clinical data in HIV infection Infobiomed Consortium Meeting, Barcelona, 26th-27th Jan, 2006 Roberto Ricci - Informa

  2. New infections far from declining even in developed countries! 4.9 million new infections and 3.1 million deaths in 2004 Infobiomed Consortium Meeting, Barcelona, 26th-27th Jan, 2006 Roberto Ricci - Informa

  3. Licensed anti-HIV compounds First anti-HIV compound available in 1987 but treatment poorly effective till 1995 Effective treatment available since 1996 HAART = “Highly Active Antiretroviral Therapy” (combined use of 3-4 anti-HIV drugs) 19 anti-HIV drugs available, belonging to 4 different classes (i. e. different targets in HIV life cycle) And more to come... Infobiomed Consortium Meeting, Barcelona, 26th-27th Jan, 2006 Roberto Ricci - Informa

  4. Treatment and resistance Anti-HIV drugs work but the virus is not eradicated Treatment is a lifelong perspective Many long-term issues (e. g. adherence, toxicity) The virus replicates itself and eventually generates variants with reduced susceptibility to anti-HIV drugs DRUG RESISTANCE Infobiomed Consortium Meeting, Barcelona, 26th-27th Jan, 2006 Roberto Ricci - Informa

  5. BEST WORST Antiretroviral treatment coverage Infobiomed Consortium Meeting, Barcelona, 26th-27th Jan, 2006 Roberto Ricci - Informa

  6. Cumbersome • Lengthy • Costly • Direct interpretation • Quantitative result • Insensitive to minority species • Less technically demanding • Faster turnaround time • Less expensive • Inferred interpretation • Result not truly quantitative • Insensitive to minority species Antiretroviral resistance testing Virus replication in the presence of drug PHENOTYPE Direct sequencing of the relevant parts of HIV genome GENOTYPE Infobiomed Consortium Meeting, Barcelona, 26th-27th Jan, 2006 Roberto Ricci - Informa

  7. Where known drug resistance mutations are located in HIV genome gp41 200 bases (?) PR RT 1,300 bases Infobiomed Consortium Meeting, Barcelona, 26th-27th Jan, 2006 Roberto Ricci - Informa

  8. How to interpret HIV genotype • Correlations between genotype and phenotype. We can observe the behavior of mutant virus in the presence of drug in vitro • Correlations between genotype and treatment history. We can find that certain mutations are more frequent in vivo following exposure to certain drugs • Correlations between genotype and response to treatment. We can find that certain mutations decrease the effectiveness of certain drugs in vivo Most experts favor the observed correlation between genotype and response to treatment as the most important data to develop a genotype interpretation system Infobiomed Consortium Meeting, Barcelona, 26th-27th Jan, 2006 Roberto Ricci - Informa

  9. How to measure response to treatment in vivo ‘Viral load’ (plasma HIV RNA) CD4/mm3 600 500 400 300 200 100 HIV RNA levels (amount of virus) and CD4 counts (size of the residual target cell population) are the reference ‘surrogate markers’ for monitoring response to treatment HAART can stop the train (halt disease progression) and push it back (restore immune function) Infobiomed Consortium Meeting, Barcelona, 26th-27th Jan, 2006 Roberto Ricci - Informa

  10. Antiretroviral Resistance Cohort Analysis https://www.hivarca.net Current Pending Infobiomed Consortium Meeting, Barcelona, 26th-27th Jan, 2006 Roberto Ricci - Informa

  11. Antiretroviral Resistance Cohort Analysis https://www.hivarca.net 15/08/2005 THERAPY(N = 12.054) PatientID Treatment regimen Date of start Date of stop Reason for change/stop GENOTYPE(n = 8595) PatientID Date Sequence Method Subtype Resistance mutations Other mutations PATIENTS(n = 4161) PatientID Gender Year of birth Country of origin HCV status HBV status HIV RNA(n = 30407) PatientID Date Copies/ml <LLD (undetectable) Method CD4(n = 37361) PatientID Date CD4/mmc CD4% Infobiomed Consortium Meeting, Barcelona, 26th-27th Jan, 2006 Roberto Ricci - Informa

  12. CD4 Treatment switch HIV RNA Baseline GENOTYPE, viral load, CD4 Follow-up viral load, CD4 Model training What ARCA helps develop A treatment response predictive model derived from experience Infobiomed Consortium Meeting, Barcelona, 26th-27th Jan, 2006 Roberto Ricci - Informa

  13. INPUT OUTPUT What ARCA helps develop A ‘virtual response’ provider on the web Input data RT GENOTYPE 41L 210W 215Y PR GENOTYPE 10I 63P 77I 90M HIV RNA4.3 log CD4330 Treatment AZT, D4T+DDI+EFV Predicted response at 3-6 months Regimen 1 - 1.5 log HIV RNA +126 CD4 Regimen 2 - 1.3 log HIV RNA +102 CD4 ..….. ..….. Computation Public Server Remote user Infobiomed Consortium Meeting, Barcelona, 26th-27th Jan, 2006 Roberto Ricci - Informa

  14. Proposal of a BMI demonstrator • Create a new public DB by integrating ARCA with other genotype-response DBs • (Integrate the new DB with host data) • Integrate the new DB with other publicly available resources (coreceptors, subtyping, T and B cell epitopes, …) Infobiomed Consortium Meeting, Barcelona, 26th-27th Jan, 2006 Roberto Ricci - Informa

  15. ARCA KI AREVIR A possible extra-network synergy EURESIST (IST-2004-2.4.11: Biomedical information for better health) The system schema Infobiomed Consortium Meeting, Barcelona, 26th-27th Jan, 2006 Roberto Ricci - Informa

  16. Integrating genotype-response DBs with host data • HLA type • Chemokine receptors and chemokine polymorphisms (e.g. CCR5 Δ32, SDF-1 3’ α) • Polymorphisms in genes impacting drug metabolism (e.g. MDR1, MRP1, P450 cytochrome) • Other polymorphisms impacting immune response (e.g. KIR) • .... Infobiomed Consortium Meeting, Barcelona, 26th-27th Jan, 2006 Roberto Ricci - Informa

  17. Integrating the HIV cohort DB with other publicly available resources Obtaining expected HIV drug susceptibility in vitro http://www.geno2pheno.org/cgi-bin/geno2pheno.pl Infobiomed Consortium Meeting, Barcelona, 26th-27th Jan, 2006 Roberto Ricci - Informa

  18. Integrating the HIV cohort DB with other publicly available resources Obtaining expected coreceptor use (CCR5 vs. CXCR4) http://coreceptor.bioinf.mpi-sb.mpg.de/cgi-bin/coreceptor.pl Infobiomed Consortium Meeting, Barcelona, 26th-27th Jan, 2006 Roberto Ricci - Informa

  19. Integrating the HIV cohort DB with other publicly available resources Obtaining information on HIV subtype http://bioafrica.mrc.ac.za/subtypetool/html/subtyping.html Infobiomed Consortium Meeting, Barcelona, 26th-27th Jan, 2006 Roberto Ricci - Informa

  20. Integrating the HIV cohort DB with other publicly available resources Mapping T and B cell epitopes in patient virus sequence data http://hiv-web.lanl.gov/content/immunology/index.html Infobiomed Consortium Meeting, Barcelona, 26th-27th Jan, 2006 Roberto Ricci - Informa

  21. PREDICTIONS Drug susceptibility & metabolism Coreceptor use Virus subtype B and T cell epitopes Optimal treatment strategy Virus-host interactions in HIV infection(possible design for a clinically oriented tool) VIRUS HOST Reverse transcriptase Protease Env LTR Accessory genes HLA Chemokine receptors Drug transporters Drug toxicities Other traits Infobiomed Consortium Meeting, Barcelona, 26th-27th Jan, 2006 Roberto Ricci - Informa

  22. Implied activities • Contact the people legally and technically responsible for the public DBs/tools considered (usually different persons), asking for permission and willingness to contribute/cooperate to the project • Develop all the necessary platforms for data flow or linking • Develop a dedicated web site • Test everything carefully before releasing it to the public • Disseminate the initiative • Care for maintenance and the necessarily frequent updates of the engines Infobiomed Consortium Meeting, Barcelona, 26th-27th Jan, 2006 Roberto Ricci - Informa

  23. Intra-network collaborations • UPM: integration tools and methods • (Custodix: in case of possible privacy and confidentiality issues) • (All other partners: as data providers or facilitators in HIV cohort data procurement) Infobiomed Consortium Meeting, Barcelona, 26th-27th Jan, 2006 Roberto Ricci - Informa

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