Transcript Drug Resistance

KITSO AIDS Training Program
Lecture 8:
ARV Resistance and Treatment
Failure
delivered by
Dr. Daniel J. Baxter, ACHAP
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.
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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.
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 subtherapeutic 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.
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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.
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.
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!
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.
Factors Leading to Resistance (2)
 High replication rate
 High mutation rate – resistance
 Latent reservoirs of HIV
Virus
Drug
Patient
 Adherence <100%
 Toxicity or inconvenience
• Inadequate
potency
• Inadequate
durability
• Drug-drug
interactions
• Poor tolerability
• Inconvenience
Virus Related
Factors 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.
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 related
Factors Leading to Resistance
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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.
Virus and Drug related
Factors 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.
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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.
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
Mutations required Single
Drugs
High
Multiple,
stepwise
3TC, EFV, PIs and
NVP
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.
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.
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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
Patient related Factors Leading
to Resistance
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Patient Factors
• Lack of adherence to potent regimen
– Intolerance
– Toxicity
– Inconvenience
– Not taking drug properly (with food,
adequate liquid, etc.)
– Missing doses
– Drug holidays
Durability of an ARV regimen
depends on:
Genetic barrier (Virus)
Drug levels (Drug)
Adherence (Patient)
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.
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