Download 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.
2
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.
4
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.
5
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.
6
Treatment Failure (4)
If viral replication due to subtherapeutic
ARV levels persists, ARV resistance will
eventually develop.
7
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.
16
Drug related
Factors Leading to Resistance
17
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
22
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.
23
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.
30
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
34
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.
37
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.
38
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.
39
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.
40