Download Guidelines for the Use of Antiretroviral Agents in Adults

Changing Therapy
Guidelines for the Use of Antiretroviral
Agents in Adults and Adolescents
published October 2006
AETC NRC Slide Set
About this Presentation
These slides were developed using the October 2006
guidelines. The intended audience is clinicians
involved in the care of patients with HIV.
The user is cautioned that, due to the rapidly
changing field of HIV care, this information could
become out of date quickly. Finally, it is intended that
these slides be used as prepared, without changes in
either content or attribution. Users are asked to honor
this intent.
-AETC National Resource Center
http://www.aidsetc.org
10/06
Changing Therapy:
Contents
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Considerations
Treatment regimen failure
Treatment options
Testing for resistance
Treatment interruption
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Changing Therapy:
Considerations
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Clinical status
HIV RNA level on 2 tests
CD4+ T cell count
Remaining treatment options
Potential viral resistance
Medication adherence
Patient education
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Changing Therapy: Treatment
Regimen Failure
 Virologic failure:
 Incomplete virologic response: HIV RNA >400
copies/mL after 24 wks, >50 after 48 wks
 Virologic rebound: repeated detection of HIV RNA
after viral suppression
 Immunologic failure:
 CD4 increase of <25-50 cells/µL in first year of
therapy
 CD4 decrease below baseline, on therapy
 Clinical failure:
 occurrence of HIV-related events (after >3 months on
therapy; excludes immune reconstitution syndromes)
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Treatment Regimen Failure:
Assessment
 Review antiretroviral history
 Physical exam for signs of clinical progression
 Assess adherence, tolerability, pharmacokinetic
issues
 Resistance testing (while patient is on
therapy)
 Identify treatment options
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Treatment Regimen Failure:
Assessment
 Possible causes:
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Suboptimal adherence
Medication intolerance
Pharmacokinetic issues
Suboptimal drug potency
Viral resistance
 Approach depends on cause of regimen
failure and remaining antiretroviral options
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Treatment Regimen Failure:
Assessment
Therapeutic options:
 Clarify goals: If extensive resistance, viral
suppression may not be possible, but aim to
reestablish maximal virologic suppression
 Remaining ARV options
 Base treatment choices on expected efficacy,
tolerability, adherence, future treatment
options, past medication history, and
resistance testing
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Virologic Failure: Changing an
ARV Regimen (1)
General principles:
 Prefer at least 2 fully active agents to design a new
regimen
 Determined by ARV history and resistance testing
 If 2 active agents are not available, consider
ritonavir-boosted PI plus optimized ARV
background, and/or reusing prior ARVs to provide
partial activity
 Consider potent ritonavir-boosted PI and a drug with
a new mechanism of action (e.g., entry inhibitor)
plus an optimized ARV background: may have
significant activity
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Virologic Failure: Changing an
ARV Regimen (2)
General principles (2):
 In general, 1 active drug should not be added
to a failing regimen because drug resistance
is likely to develop quickly. In some patients
with advanced HIV and few treatment options,
this may be considered to reduce the risk of
immediate clinical progression.
 Consult with experts
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Treatment-Experienced
Patients: Goals of Therapy
Limited prior treatment:
 Maximum viral suppression
 Consider early change to prevent further resistance
mutations
Extensive prior treatment:
 Preservation of immune function
 Prevention of clinical progression
 Balance benefits of partial viral suppression with risk
of additional resistance mutations
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Changing Therapy: Treatment
Options
Limited prior treatment with low HIV RNA:
 Intensification (e.g., tenofovir)
 Pharmacokinetic (PK) enhancement
 Change to new regimen
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Changing Therapy: Treatment
Options
Limited prior treatment with single drug
resistance:
 Change 1 drug
 PK enhancement
 Change to new regimen
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Changing Therapy: Treatment
Options
Limited prior treatment with >1 drug
resistance:
 Change drug classes and/or add new
active drugs
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Changing Therapy: Treatment
Options
Prior treatment with no resistance identified:
 Consider nonadherence or possibility that
patient was off medications at time of
resistance test
 Consider resuming same regimen or starting
new regimen and repeat resistance testing
early (2-4 wks)
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Changing Therapy: Treatment
Options
Extensive prior treatment with resistance:
 Avoid adding single active drug
 Seek expert advice
 If few or no treatment options, consider
continuing same regimen. Other possible
strategies:
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PK enhancement
Therapeutic drug monitoring
Retreatment with prior medications
Multidrug regimens (limited by complexity, tolerability)
New ARV drugs, e.g., enfuvirtide, investigational drugs
Treatment interruptions not recommended
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Testing for Drug Resistance
 Recommended in case of virologic failure, to
determine role of resistance and maximize
the number of active drugs in a new regimen
 Combine with obtaining a drug history and
maximizing drug adherence
 Research supports use in certain settings
 Perform while patient is taking ART (or within
4 weeks of regimen discontinuation)
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Genotyping
 Detects drug resistance mutations in specific
genes, e.g., reverse transcriptase and protease
 Sequencing or probing
 Results within 1-2 weeks
 Interpretation of mutations and crossresistance is complex
 Consultation with specialists is recommended
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Phenotyping
 Measures the ability of viruses to grow in
various concentrations of antiretroviral drugs
 Results within 2-3 weeks
 More expensive than genotyping
 The ratio of the IC50s of the test and reference
viruses is reported as the fold increase in IC50,
or fold resistance
 Interpretation may be complex
 Consultation with specialists is recommended
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Drug Resistance Testing:
Limitations
 Lack of uniform quality assurance
 Relatively high cost
 Insensitivity for minor viral species
(<10-20%)
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Drug Resistance Testing
 Resistance assays should be
performed while the patient is taking
antiretroviral regimen
 Data suggesting the absence of
resistance should be interpreted
carefully in relation to the prior
treatment history
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Drug Resistance Testing
Clinical Setting/
Recommendation
Recommended:
Acute HIV infection, if
treatment is to be started
Chronic HIV infection
before starting ART
Rationale
Determine if resistant virus was
transmitted; guide treatment
decisions. Consider resistance
testing if treatment is deferred
Transmitted drug-resistant virus is
common in some areas; is more
likely to be detected earlier in the
course of HIV infection; consider
resistance testing earlier in the
course of infection
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Drug Resistance Testing
Clinical Setting/
Recommendation
Recommended:
Pregnancy
Rationale
Maximize the number of active
drugs.
Virologic failure during ART Determine role of resistance in
drug failure and maximize the
number of active drugs in the new
regimen
Suboptimal suppression of
VL after starting ART
To guide treatment decisions.
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Drug Resistance Testing
Clinical Setting/
Recommendation
Rationale
USUALLY NOT RECOMMENDED:
After discontinuation of
drugs
Resistance mutations may
become minor species in the
absence of selective drug
pressure
Plasma VL <1,000 HIV RNA
copies/mL
Resistance assays unreliable if
HIV RNA is low
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Interruption of
Antiretroviral Therapy
 Many possible reasons for short- or longterm treatment interruption
 Potential risks and benefits vary
according to the patient’s clinical and
immunologic status, duration of
interruption, and other factors
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Interruption of ART: Short-term
Possible scenarios include:
 Drug toxicity
 Illness that precludes oral medication
 Surgery
 Nonavailability of drugs
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Interruption of ART: Short-term
Considerations for stopping ARVs:
 In case of severe or life-threatening toxicity:
 Stop all drugs simultaneously
 When all ARVs have similar half-lives:
 Stop all drugs simultaneously
 When ARVs have different half-lives:
 Stopping all ARVs simultaneously may result in functional
monotherapy
 Consider staggered discontinuation, or substitution of
shorter half-life ARVs (see below)
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Interruption of ART:
After Pregnancy
 Women who started ART during pregnancy to
decrease risk of mother-to-child transmission
 If pretreatment CD4 is above currently
recommended ART starting levels and patient
wishes to stop therapy after delivery
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Interruption of ART: Long-term
Potential risks, including
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Viral rebound,
CD4 decline
Disease progression,
Development of drug resistance
Increase in risk of HIV transmission
Planned therapy interruptions cannot be
recommended outside of clinical trials.
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Interruption of ART: Long-term
Several scenarios:
 Patients who started ART during acute HIV
infection
 Optimal duration of treatment and consequences
of discontinuation are unknown; studies ongoing
 Patients with treatment failure, extensive ARV
resistance, and few available treatment
options
 Partial virologic suppression from ART has
clinical benefit
 Not recommended outside clinical trial setting
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Interruption of ART: Long-term
 Patients on ART with CD4 above levels
recommended for starting therapy; baseline
CD4 either above or below recommended
threshold:
 Conflicting and incomplete data; several studies
of structured treatment interruptions show
increased risk of disease progression and death
 CD4 decline after treatment interruption is related
to pretreatment CD4 nadir
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Interruption of ART:
ARV-Specific Issues
Discontinuation of efavirenz or nevirapine:
 These ARVs have long half-lives; stopping
drugs in an ART regimen simultaneously may
result in functional mono- or dual therapy
 The optimal interval between stopping these
and other ARVs is not known
 Consider substitution of a PI for the NNRTI
for a period of time before stopping all ARVs
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Interruption of ART:
ARV-Specific Issues
Discontinuation and reintroduction of
nevirapine:
 If nevirapine has been interrupted for more than 2
weeks, it should be restarted with the usual dose
escalation period
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Interruption of ART:
ARV-Specific Issues
Discontinuation of emtricitabine, lamivudine, or
tenofovir in patients with hepatitis B:
 Flare of hepatitis may occur on discontinuation of
any of these ARVs
 Monitor closely
 Consider initiating adefovir for HBV treatment
 Entecavir should not be used in patients not on
suppressive ART
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Interruption of ART: Long-term
If therapy must be discontinued, counsel
patients on:
 Need for close clinical and laboratory monitoring
 Risks of treatment interruption
 Behavioral guidelines to reduce risk of HIV
transmission
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Web Sites to Access the
Guidelines
 http://www.aidsetc.org
 http://aidsinfo.nih.gov
10/06
About This Slide Set
 This presentation was updated by Susa
Coffey, MD for the AETC National
Resource Center in October 2006 and
revised in April 2007.
 See the AETC NRC Web Site for the
most current version of this presentation.
http://www.aidsetc.org
10/06