1. ANTIRETROVIRAL RESISTANCE IN CLINICAL PRACTICE
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ANTIRETROVIRAL RESISTANCE IN 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
Category
Criterion
Action
Virological
50 cp/mL at ≥ 24 wks
Switch regimen
Immunological
Failure to gain 50 cells in 1st yr
Assess for other causes
Clinical
New illnesses
May not warrant switch
Check for IRIS
Check prophylaxis

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.

10. 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

11. Protease Structure

12. PI Binding Site

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

14. 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

15. 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

16. 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

17. 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)

18. 3TC/FTC Resistance A conundrum
If initial regimen contains 3TC/FTC fails, resistance to 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)

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

20. Resistance Tests Techniques: - Genotype - Phenotype
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

21. 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

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

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

24. Truvada AZT + tenofovir Never use tenofovir + ddI
How to switch NRTIs
Initial NRTI
Option 1
Option 2
Truvada
Continue Truvada**
AZT + tenofovir
AZT + abacavir
Abacavir + 3TC
Truvada AZT + tenofovir
AZT + ddI
Abacavir + AZT/ddI
AZT/d4T + 3TC
Truvada Tenofovir +
abacavir
abacavir +
ddI
AZT/d4T + ddI
tenofovir +
Never use tenofovir + ddI

25. How to switch NNRTIs and PIs
Initial Agent
Replacement
NNRTI
Boosted PI (Aluvia,
or Atazanavir/ritonavir PI
Get expert opinion

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

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