1. KITSO AIDS Training Program
Lecture 8: ARV Resistance and Treatment Failure delivered by Dr. Daniel J. Baxter, ACHAP
ARV Resistance

2. Learning Objectives
Know the importance of drug resistance as a cause of treatment failure.
Understand the principles of ARV drug resistance.
Know the main causes of ARV drug resistance.

3. KITSO AIDS Training Program
Drug Resistance
Resistance reduces the ability of a drug, or combination of drugs, to block or reduce the replication of HIV.
As a result, viral load increases and CD4 count or CD4% decreases.
ARV Resistance

4. Treatment Failure
ARV resistance is an important cause of treatment failure, which almost always means virologic failure.
Treatment (i.e., virologic) failure occurs when viral load is not suppressed to < 400 initially, or after being initially suppressed, the viral load later becomes detectable.

5. Treatment Failure (2)
Treatment (virologic) failure can be thought of as falling into two general categories:
Subtherapeutic blood/tissue levels of ARV(s).
ARV resistance.

6. Treatment Failure (3)
Causes of treatment failure due to sub-therapeutic blood levels of ARVs:
Non-adherence.
Drug-drug interactions.
Poor absorption (e.g., ddI, NFV).
Gastroenteritis.
Incorrect level of ARV (e.g., pediatric calculations, d4T/ddI dose in adults).
Inadequate potency or durability of ARV regimen.

7. Treatment Failure (4)
If viral replication due to subtherapeutic ARV levels persists, ARV resistance will eventually develop.

8. How does drug resistance occur? (1)
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How does drug resistance occur? (1)
HIV drug resistance is a consequence of viral replication in the presence of ARV drugs.
Reverse transcriptase is a very error prone enzyme and thus causes many mutations (on average, 1 mutation per life cycle).
These mutations are completely random and by chance.
ARV Resistance

9. HIV Mutations May Affect:
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HIV Mutations May Affect:
Virulence - the ability of the virus to invade a cell.
Viral fitness - the ability of the virus to compete with wild type virus.
Response to ARVs, that is, ARV resistance.
Immune response: HIV may escape antibody and CD8 immune control.
ARV Resistance

10. How does drug resistance occur? (2)
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How does drug resistance occur? (2)
Faster viral replication leads to a higher chance of HIV mutations, some of which can cause resistance to the ARV drugs.
Once mutations make HIV resistant to one ARV drug, it can then quickly develop other mutations which can cause resistance to related ARV drugs, including an entire class of drugs
e.g., if replication is allowed to persist, resistance to AZT can extend to other NRTIs and thus limit future treatment options.
ARV Resistance

11. To Minimize the Chance of Resistance
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To Minimize the Chance of Resistance
Treatment failure must be addressed promptly.
Patients should not be kept on a failing regimen for much more than a month!
ARV Resistance

12. Factors Leading to Resistance (1)
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Factors Leading to Resistance (1)
VIRUS related
DRUG related
PATIENT related
One or more of these factors can lead to ARV resistance in a given patient.
ARV Resistance

13. Factors Leading to Resistance (2)
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Factors Leading to Resistance (2) 1
High replication rate
High mutation rate – resistance
Latent reservoirs of HIV
Inadequate potency
Inadequate durability
Drug-drug interactions
Poor tolerability
Inconvenience
Virus
Drug
Patient
Adherence <100%
Toxicity or inconvenience
ARV Resistance

14. Virus Related Factors Leading to Resistance
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Virus Related Factors Leading to Resistance
ARV Resistance

15. KITSO AIDS Training Program
Virus related Factors
High replication rate of HIV.
Turnover of 10 billion virions daily.
Frequent errors made during replication.
High mutation rate.
20 billion mutations daily.
Latent reservoirs of HIV.
Enable drug resistant HIV to hide for years.
ARV Resistance

16. Latent Reservoirs and Resistance
ARV resistance, once it develops, is probably life-long, since resistant HIV can hide in latent cellular reservoirs, which can be activated many years later.
Once a patient is resistant to an ARV drug, that drug will probably be ineffective in the future. HIV does not “forgive” treatment errors or nonadherence.

17. Drug related Factors Leading to Resistance
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Drug related Factors Leading to Resistance
ARV Resistance

18. KITSO AIDS Training Program
Drug Related Factors
Inadequate potency (strength).
Drug interactions leading to suboptimal drug levels.
Inadequate durability of drug potency (e.g., dual therapy).
Poor tolerability.
Inconvenience of regimen.
ARV Resistance

19. KITSO AIDS Training Program
Potency
Viral escape depends on the rate of residual viral replication, which is increased if there is:
Inadequate potency, e.g. mono and dual therapy.
With a more potent regimen, there is decreased replication and decreased chance to develop drug resistance mutations.
ARV Resistance

20. Adequate Drug Levels are Crucial to Control HIV Replication
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Adequate Drug Levels are Crucial to Control HIV Replication
High drug levels delay or prevent development of resistance.
Low drug levels encourage viral replication, ARV resistance, viral rebound and ultimate clinical deterioration.
ARV Resistance

21. KITSO AIDS Training Program
Drug Levels (2)
Drug levels depend upon:
Dose (e.g., pediatric ARV dosing, ddI/d4T doses in adults).
- Absorption (e.g., ddI, NFV food requirements).
- Drug-drug interactions.
- Intracellular metabolism (e.g., NRTIs).
- Hepatic metabolism.
- Adherence.
ARV Resistance

22. Virus and Drug related Factors Leading to Enhanced Resistance
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Virus and Drug related Factors Leading to Enhanced Resistance
ARV Resistance

23. Mutations and Resistance
For certain ARVs, only one mutation is needed to stop the drug from working.
For other ARVs, multiple, step-wise mutations must occur before the drug loses affect.

24. Single Mutations and Resistance
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Single Mutations and Resistance
Certain single mutations will cause the HIV to be completely resistant to a drug, or even to an entire class (eg., NNRTIs).
Drugs in which such single mutations cause complete resistance are said to have a LOW GENETIC BARRIER to the development of resistance.
ARV Resistance

25. Drugs with Low Genetic Barrier
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Drugs with Low Genetic Barrier
3TC
All NNRTI drugs (NVP and EFV)
Cross-class resistant mutations can appear with just one mutation, which renders all NNRTIs ineffective.
Resistance to NVP causes resistance to EFV, and vice versa.
ARV Resistance

26. Multiple Mutations and Resistance
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Multiple Mutations and Resistance
Some drugs require multiple, step-wise mutations for HIV to become resistant.
For these drugs resistance is not all or nothing, but instead is gradual.
Drugs which require multitple mutations for resistance have a High Genetic Barrier.
ARV Resistance

27. Drugs with High Genetic Barrier
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Protease inhibitors
All NRTIs except 3TC.
The longer a failing regimen is continued, the greater the number of mutations which will occur and which will lead to greater resistance, including cross-class resistance.
ARV Resistance

28. Summary of drugs based on Genetic Barrier
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Summary of drugs based on Genetic Barrier
Barrier type
Low
High
Mutations required
Single
Multiple, stepwise
Drugs
3TC, EFV, NVP
PIs and NRTIs –but not 3TC
ARV Resistance

29. KITSO AIDS Training Program
Failing Regimens
Always repeat the viral load as soon as possible to be certain a patient is really failing treatment.
If a patient’s ARV regimen is failing, determine the likely cause(s) of failure: low drug levels (poor absorption, nonadherence, drug-drug interactions, etc.), ARV resistance.
As a rule, ARV resistance is suspected as a cause of treatment failure only after other causes have been ruled out.
ARV Resistance

30. Failing Regimens (2)
If resistance is suspected as the cause of treatment failure, then the regimen should be changed as quickly as possible.
Early change of a failing regimen avoids the increased accumulation of mutations and thus additional resistance mutations that could compromise the success of the second regimen.

31. KITSO AIDS Training Program
Example Case
A patient is on (AZT+3TC) + EFV for 18 months and has 2 consecutive viral loads that are over 5000 copies/ ml, after previous total suppression
What has probably happened?
ARV Resistance

32. KITSO AIDS Training Program
Case Discussion
Exclude lack of adherence, sub-optimal drug levels, etc, and address such problems if present.
HIV mutations affecting 3TC and EFV are almost certainly present (low genetic barrier). AZT will probably not have been affected yet (high genetic barrier).
ARV Resistance

33. KITSO AIDS Training Program
Case Discussion (2)
Next option would avoid ALL NNRTIs because of CROSS-CLASS resistance
Also avoid definitely 3TC (and if possible AZT)
e.g., ddI / d4T / NFV or LPV/r
ARV Resistance

34. Patient related Factors Leading to Resistance
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Patient related Factors Leading to Resistance
ARV Resistance

35. KITSO AIDS Training Program
Patient Factors
Lack of adherence to potent regimen
Intolerance
Toxicity
Inconvenience
Not taking drug properly (with food, adequate liquid, etc.)
Missing doses
Drug holidays
ARV Resistance

36. KITSO AIDS Training Program
Durability of an ARV regimen depends on:
Genetic barrier (Virus)
Drug levels (Drug)
Adherence (Patient)
ARV Resistance

37. Resistance Assay
A blood test which can assist in determining the resistance profile in a given patient.
Very expensive.
Should be obtained only if the patient is failing second line regimen and only after consultation with an HIV specialist.

38. Resistance Assay (2)
Should be drawn while the patient is still on the failing ARV regimen and has a viral load greater than 1000.
At best, can only predict which ARVs will not be effective, not which ARVs will work.
Cannot replace careful treatment history and expert opinion.

39. Key Points
ARV resistance is an important cause of treatment failure, but other causes must also be considered and ruled out.
ARV resistance is a consequence of viral replication and can be minimized by suppressing viral load below the limits of detection—i.e., HAART.

40. Key Points (2)
Never replace one NNRTI for another within a failing regimen.
Do not keep a patient on a failing regimen for more than a month or so.