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innovir Institute

bringing science to life. innovir Institute. ANTIRETROVIRAL RESISTANCE IN CLINICAL PRACTICE. Steven Miller Medical Director. Classes of ARVs. NRTIs - AZT, d4T, ddI, abacavir, 3TC, FTC, tenofovir (Target enzyme: Reverse Transcriptase)

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innovir Institute

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  1. bringing science to life innovirInstitute ANTIRETROVIRAL RESISTANCEIN CLINICAL PRACTICE Steven Miller Medical Director

  2. Classes of ARVs • NRTIs- AZT, d4T, ddI, abacavir, 3TC, FTC, tenofovir (Target enzyme: Reverse Transcriptase) • NNRTIs- nevirapine, efavirenz, etravirine, rilpivirine (Target enzyme: Reverse Transcriptase) • Integrase Inhibitors- raltegravir, dolutegravir (Target enzyme: Integrase) • Protease Inhibitors- lopinovir, atazanavir, darunavir, ritonavir • Entry and fusion inhibitors- maraviroc, enfuvirtide (Target: Cell surface receptors)

  3. Goals of ART • Established:- Reduce HIV related morbidity and mortality- Improve quality of life- Restore and preserve immune function- Maximally and durably suppress viraemia (<50 cp/mL) • Emerging:- Decrease risk for IRIS- Decrease morbidity and mortality from non-HIV related disease- Achieve normal life expectancy- Decrease lifetime risk of transmission to others

  4. Defining Resistance • Clinically safe doses of antiretroviral medication/s lose their antiviral effect

  5. Adequate Response Phase 1: Rapid (6-8 week) decline > 1 log; inhibition of virus in activated CD4’s Phase 2: Slower (8-24 week)decline to < 50 cp/mL;inhibition of virus in resting CD4 cells and macrophages

  6. Types of treatment failure

  7. Virological failure • Serial determination of Viral Load:- early: VL decline < 1 log within 8 wks - late: VL above 50 cp/mL at 24 wks; or VL increase from <50 cp/mL to ≥ 50 cp/mL persistently (? > 200/1 000)

  8. Pathways to Resistance • Drug-Resistant Variants • Pre-existing • Transmitted • Selected Subinhibitory Drug Levels Host Immune Failure Recombination (Re-infection) Persistent viral replication Evolution of drug resistance Drug failure Source: Adapted from Hirsch, et al. JAMA 1998; 279:1984.

  9. Mechanisms - Drugs no longer able to bind to their target site (steric exclusion) - Removal of drug from an incomplete DNA copy of the viral genome

  10. Protease Structure

  11. PI Binding Site

  12. G - C - T - A - G DNA G-C- AZT-Incomplete DNA Removal of Drug

  13. Consequences of Resistance • Rebound in plasma and tissue viraemia • Alterations in viral fitness • Impact on the susceptibility to other ARVs,even if not yet used (cross-resistance) • Changes in viral tropism

  14. Primary & Secondary Mutations • Primary:- at, or near, the active site- significant impact on susceptibility • Secondary:- may be pre-existing (“polymorphisms”)- have less impact on the level of resistance • Both primary and secondary mutations accumulate over time

  15. Mutations accumulate • Resistance following single mutation:- 3TC, FTC, NNRTIs, indinavir, atazanavir, tenofovir • Resistance following accumulation of mutations: other NRTIs, Aluvia, other boosted PIs • Mutations accumulate proportional to the time on virologically failing regimen • For first-line therapy, this can result in almost total NRTI resistance as well as NNRTI resistance

  16. Resistance is irreversible • Every genetic variant of HIV is archived in the human immune system • Archiving 1: - viral DNA persists within long-lived cells (e.g. resting CD4, memory CD4 cells)- replication competent- not necessarily present in plasma- may cause “blips”- re-emerges as dominant population under selective pressure 1. Persaud, et al. J I D 2007 (March)

  17. 3TC/FTC Resistance • A conundrum • If initial regimen contains 3TC/FTC fails, resistanceto this agent is almost universal • This appears to be of little clinical relevance when switching ART provided:- a virologically active, boosted PI is used- a virologically active NRTI forms part of the combination 1. Persaud, et al. J I D 2007 (March)

  18. NNRTI Resistance • Complete cross-resistance between Nevirapine and Efavirenz • Cannot sequence these two drugs 1. Persaud, et al. J I D 2007 (March)

  19. Resistance Tests • Purpose:- to distinguish between virological and non-virological causes of resistance - to optimise further ART • Techniques:- Genotype - Phenotype • Caution:- cellular mechanisms of resistance not assessed - requires an adequate level of viraemia

  20. Indications for Resistance Testing • Primary infection • Failed prophylaxis- includes infants • Treatment naïve- if >5% prevalence of primary transmitted resistance • Treatment experienced- women with prior NVP monotherapy (MTCTp)- if patient on prolonged failing regimen- following second regimen failure

  21. Benefits • Avoid unnecessary switching of drugs • Exclude adherence problems • Perform directed treatment switches • Use active drugs durably • Avoid unnecessary toxicities from inactive drugs

  22. Nomenclature for Mutations Reverse Transcriptase Wild Type Amino Acid (methionine) RT M184V Mutated Amino Acid (valine) Position of Amino Acid in RT

  23. How to switch NRTIs Never use tenofovir + ddI

  24. How to switch NNRTIs and PIs

  25. Survival benefit of HAART • Fully suppressive HAART expected to yield normal lifespan • Emergence of resistance remains the greatest impediment to achieving this goal

  26. www.innovirinstitute.com Clinical Care Web Facility

  27. This presentation may be viewed online @ www.innovirinstitute.com Clinical Care Web Facility

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