Changing Therapy

Changing Therapy

Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents

published October 2006

AETC NRC Slide Set

10/06

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The user is cautioned that, due to the rapidly changing field of HIV care, this information could become out of date quickly.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

About this Presentation

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Changing Therapy:Contents

Considerations Treatment regimen failure Treatment options Testing for resistance Treatment interruption

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Changing Therapy:Considerations

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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Possible causes: 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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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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Limited prior treatment with single drug resistance:

Change 1 drug PK enhancement Change to new regimen

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Limited prior treatment with >1 drug resistance:

Change drug classes and/or add new active drugs

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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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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:

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 cross-

resistance 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 TestingClinical Setting/

RecommendationRationale

Recommended:Acute HIV infection, if treatment is to be started

Chronic HIV infection before starting ART

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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RecommendationRationale

Recommended:Pregnancy

Virologic failure during ART

Suboptimal suppression of VL after starting ART

Maximize the number of active drugs.

Determine role of resistance in drug failure and maximize the number of active drugs in the new regimen

To guide treatment decisions.

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Recommendation

Rationale

USUALLY NOT RECOMMENDED:

After discontinuation of drugs

Plasma VL <1,000 HIV RNA copies/mL

Resistance mutations may become minor species in the absence of selective drug pressure

Resistance assays unreliable if HIV RNA is low

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Interruption of Antiretroviral Therapy

Many possible reasons for short- or long-term 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 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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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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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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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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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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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

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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

Documents

Changing Therapy