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Antiretroviral Drug Resistance

Antiretroviral Drug Resistance. Basic Knowledge Global Impact Utility of Global Surveillance Anthony Amoroso, MD Assistant Professor of Medicine University of Maryland School of Medicine Institute of Human Virology Chief of Infectious Diseases, VA Maryland Health Care System.

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Antiretroviral Drug Resistance

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  1. Antiretroviral Drug Resistance • Basic Knowledge • Global Impact • Utility of Global Surveillance • Anthony Amoroso, MDAssistant Professor of MedicineUniversity of Maryland School of MedicineInstitute of Human VirologyChief of Infectious Diseases, VA Maryland Health Care System

  2. “ Living with HIV used to be like playing checkers and now it’s like playing chess.” Becky Trotter, POZ

  3. HIV-1 Viral Dynamics : Basis of resistance • In an HIV-1 infected individual, it is estimated that: • 10.3 x 109 virons are produced each day • Average life span of an HIV-1 viron in plasma is 5.6hours • Average HIV-1 generation time is 2.6 days

  4. HIV-1Viral Dynamics - Mutations • Genome Size - 104 base pairs • Mutation rate of HIV-1 is estimated to be 3.4 x 105 per base pair per replication cycle • If true, then every mutation at every position on the genome would occur numerous times each day

  5. How Quickly Resistance Can Occur Depends on the Viral Load Adapted from Siliciano, 2002

  6. Development of Viral Resistance Barrier to resistance mutations VIRUS • High replication rate • Error prone • Latent reservoir PATIENT • Non adherence • Side effects DRUG • Subtherapeutic concentrations • Selective pressure of less potent ARV therapy Ctrough Intrinsic activity

  7. Viral Resistance is the Outcome of Viral Replication, Mutation and Selection New Virus Quasispecies Original Virus Quasispecies Selection Pressure exerted by Drugs HIV RNA Level Minority Quasispecies with reduced susceptibility Resistant virus Time

  8. HIV-1 RNA Response in Subjects With M184V (M184V Present by Week 12) 300 mg BID (n=14) Kuritzkes D, et al. AIDS 1996;10:975-81.

  9. HIVNET-012: Prevalence of NVP Resistance Mutations at 6 to 8 Weeks Postpartum 60 46 40 % with resistance mutations 19 20 0 Mothers(n=111) Infected infants(n=24) Eshleman SH, et al. 8th CROI; February 4-8, 2001; Chicago, IL. Abstract 516.

  10. Case # 9 – Gulu, Uganda 16 year old female

  11. Pre-ARV HX • No previous ARV exposure • OIs prior to ARV – Diarrhea and wasting, Genital ulcerative disease • Baseline weight – 35 kg • WHO stage – III • Baseline CD4 – 37 c/mm3 (11/2004) • ARV start date – 22/12/04 • Baseline labs – Hb – 10.3g/dl, AST – 22, ALT –18, Cr – 0.7

  12. ARV therapy • 14 month duration of therapy • Start 22/12/04: TDF/3TC/EFV • Switch 21/07/0: TDF/FTC/EFV (current)

  13. OIs since ARV start • Herpes Simplex • Genital Ulcerative Disease • Tonsillitis – 22/02/05 • Anal sores – 16/11/05 • Perinatal viral warts – 14/03/06

  14. Adherence • Patient had treatment preparation, home visits and DOT • Dispensing frequency – Monthly • No subjective history of missed doses in the past 6 months • No history of missed refills in past 6 months • No history of missed appointments in past 6 months

  15. Viral Load? • >750,000 copies/ml

  16. Why? • Poor adherence to safe sexual practices is been closely linked to poor adherence to ARVs. • Adolescents are notoriously horrible at taking chronic medications

  17. What is major concern in this case? • This pt is at high risk for spreading resistance virus. • Is secondary prevention counseling going to have any effect on this patient’s behavior?

  18. Surveillance

  19. Rise in ARV Resistance Among Treatment-Naive Patients Patients With >10-Fold Resistance N = 408 >10-Fold Resistance 1 drug 1996-1998 10 2 drugs 1999-2000 8 P = .001 P = .05 6 Patients (%) 4 2 0 NNRTIs PIs 1999-2000 Little. 8th CROI; 2001; Chicago. Abstract 756

  20. Reduced Susceptibility (>10 Fold) of Transmitted HIV during Primary Infection 20 NRTI NNRTI PI 15 Percentage 10 5 0 1996 1997 1998 1999 2000 n 32 106 88 71 15 Year Little SJ. 8th CROI, Chicago, 2001. #756

  21. Prevalence of Drug Resistance1080/1906 patients Total Study Population* Population with HIV RNA >500 copies/mL** * Assumes no resistance in samples with HIV RNA <500 copies/mL ** Represents 63% of total study population Richmond

  22. Causes of Resistance: Lessons Learned • Learning curve during applications of consensus treatment guidelines • AZT monotherapy • Sequential monotherapy • 2NRTI and PI ( i.e. AZT, 3TC and non-boosted PI) • Borderline therapeutic drug levels and significant drug interactions • High Adherence Requirements

  23. Global resistance in naïve patients study • WATCH: Worldwide Analysis of resistance Transmission over time of Chronically and acute infected HIV-1 Patients1 • RT & PI mutations from 6,054 naïve pts • Source: Europe 3252, Africa 1162, Asia 653, Latin America 806, North America 290 • Results: 8.9% >1 mutation • Europe 11.3%; NA 9.3%, Africa 5.7%, Latin America 5%, East Asia 9.4%, S/SE Asia 5.3%, 1.8% multiclass resistance Resistance by ARV class 1. Bowles E, et al. XVI IAS, Toronto 2006, MOPE0388; 2. Bowles E, et al. 4th EHDRW, Monte Carlo 2006, #7

  24. Study of resistance in pts age 12-24 from 15 US cities (n=55) HIV-infected w/in 180 days using “detuned” assay Genotype (GT) and Phenotype (PT) obtained Major mutations defined by IAS-USA Drug Resistance Mutations Group 1 pt had GT + PT resistance to ARV in all 3 classes Primary resistance in ARV-naïve adolescents Viani R, et al. 13th CROI, Denver, CO, February 5-8, 2006. Abst. 21

  25. The HIV Family HIV-2 HIV-1 HIV-1 less pathogenic Group: O M N (Cameroon) Clade: A,C,F B E Others (Africa)(US, Europe) (SE Asia) Levy JA. HIV and the Pathogenesis of AIDS. 2nd ed. Washington, DC: American Society for Microbiology; 1998:152-158.

  26. North 0.2 Horn 11.0 C A/G A/G Western 5.0 A Eastern 10.5 Central 6.0 C Southern 20.0 Distribution of HIV-1 Subtypes in Africa

  27. Can Resistance Testing Be Used forNon-Clade B HIV-1 Subtypes? • Do the assays yield any results? • Yes, at least for kit-based genotyping assays • Do the results have the same interpretation? • Mostly yes • Exception • Some secondary PI mutations are more common in non-clade B viruses • M36I, for example, is wild type for clade C

  28. SDNVP and Resistance2005 • Resistance in child: 13% - 52% • Resistance in mothers: 39% - 75% resistance • Clade A 19% • Clade D 36% • Clade C 69%

  29. Conclusions • Different HIV-1 subtypes seem to possess distinct potentials for drug related resistance mutation acquisition, including alternative routes and substitutions. • This may affect the future design of antiretroviralregimens and salvage regimens in distinct areas of the world where non-B isolates dominate the HIV/AIDS epidemic.

  30. Why new strategies are needed to avoid resistance The mainstream strategy of sequencing, as a whole, has not been successful. • Cross-resistance is a major problem and can prevent rational sequencing of drugs • Novel drugs or “new drugs” in a class may not be available or effective once resistance develops

  31. The Impact of Cross Resistance “First shot is your best shot” Rate of Treatment Failure in EuroSIDA Cohort (n = 8507) Mocroft, et al, Antivir Ther, 2000.

  32. Viral Suppression by Country (by Year 1 Sites)

  33. ART drug resistance mutations in ART experienced patients in Nigeria E. Idigbe, T. Salawu, B. Osotimehin, B. Chaplin,J-L Sankalé, J Idoko, E Ekong, R Murphy , PJ Kanki Nigerian Institute of Medical Research (NIMR), Lagos Nigeria Federal Ministry of Health, Abuja, Nigeria National Action Committee AIDS, Abuja, NigeriaHarvard School of Public Health, Boston, MA, USAJos University Teaching Hospital, Jos, NigeriaHarvard PEPFAR (APIN Plus), Lagos, Nigeria. Northwestern University, Chicago USA Supported by AIDS Prevention Initiative Nigeria – funded by the Bill & Melinda Gates Foundation, DAIDS-NIAID/NIH, the Federal Ministry of Health and NACA.

  34. Resistance Patterns to the Baseline Regimen of Patients with viral loads greater 3000 c/ml .

  35. Response to d4T/3TC/NVP in mothers based on previous history of single-dose NVP 68%* 52%* 38%* % With Virologic Suppression N=143 N=47 N=66 N=40 N=61 N=119 *significant Joudain et al. NEJM 4/04

  36. What will we do with surveillance information?

  37. DHHS Guidelines: Recommendations for Using Drug-resistance Assays (Updated 5/04/06) *New recommendations as of DHHS Guidelines update 5/04/06. Adapted from DHHS Guidelines (5/04/06). Available at: http://aidsinfo.nih.gov. Accessed May 9, 2006.

  38. Regimen Selection by Line of Therapy Percentage n=951 n=601 n=369 n=451 Line of Therapy Base: All treated patients Q1 2006 data Line of therapy change defined as a switch of any component of the patient’s ARV regimen. ISIS market research data, Synovate US HIV Monitor Q1 2006.

  39. Public Health Approach to Treatment • Utilize 1st line regimens with predictable mutations and “dead end mutational pattern” • Utilize 1st line regimens which allow for rational 2nd line therapies • Be willing to change 1st line therapeutic approach based on resistance data despite costs • Invest more heavily on community treatment support/adherence programs to ensure high level initial adherence

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