Lecture 8:

ARV Resistance and Treatment Failure

delivered byDr. Daniel J. Baxter, ACHAP

KITSO AIDS Training Program

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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.

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.

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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.

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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.

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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.

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Treatment Failure (4)

If viral replication due to subtherapeutic ARV levels persists, ARV resistance will eventually develop.

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.

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.

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.

• Treatment failure must be addressed promptly.

• Patients should not be kept on a failing regimen for much more than a month!

To Minimize the Chance of Resistance

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.

• Inadequate potency

• Inadequate durability

• Drug-drug interactions

• Poor tolerability

• Inconvenience

Virus Drug

Patient

Adherence <100%Toxicity or inconvenience

Factors Leading to Resistance (2)High replication rateHigh mutation rate – resistanceLatent reservoirs of HIV

Virus RelatedFactors Leading to Resistance

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 20-30

years.

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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.

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Drug relatedFactors Leading to Resistance

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.

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.

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.

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.

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Virus and Drug relatedFactors Leading to Enhanced

Resistance

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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.

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.

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.

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.

Drugs with High Genetic Barrier

• 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.

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

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.

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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.

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?

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).

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

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Patient related Factors Leading to Resistance

Patient Factors

• Lack of adherence to potent regimen

– Intolerance– Toxicity– Inconvenience– Not taking drug properly (with food,

adequate liquid, etc.)– Missing doses– Drug holidays

Genetic barrier (Virus)

Drug levels (Drug)

Adherence (Patient)

Durability of an ARV Durability of an ARV regimen regimen depends on:depends on:

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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.

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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.

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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.

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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.