Comprehensive Guideline Summary

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Comprehensive Guideline Summary

• Guidelines for the Use of Antiretroviral Agents
  in Adults and Adolescents
• October 2006
• AETC NRC Slide Set

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About this Presentation
These slides were developed using the October
2006 Treatment 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information could become out of date quickly.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 NRC http//www.aidsetc.org
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Guidelines for the Use of Antiretroviral Agents
in HIV-Infected Adults and Adolescents
Developed by the Panel on Clinical Practices for
Treatment of HIV Infection convened by the
Department of Health and Human Services (DHHS)
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Guidelines Outline

• Overview
• Initiation of Therapy
• Changing Therapy
• Special Issues

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What the Guidelines Address

• Laboratory testing (viral load, CD4T cells,
  resistance)
• When to initiate therapy
• When to change therapy
• Therapeutic options
• Adherence
• ART-associated adverse effects

• continued

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What the Guidelines Address

• Treatment of acute HIV infection
• Special considerations in adolescents, pregnant
  women, injection drug users, and patients
  coinfected with HIV and hepatitis B, hepatitis C,
  or tuberculosis
• Prevention counseling for HIV-infected patients

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Web Sites to Access the Guidelines

• http//www.aidsetc.org
• http//aidsinfo.nih.gov

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Goals of Therapy Tools to Achieve Goals

• Improvement of quality of life
• Reduction of HIV-related morbidity and mortality
• Restoration and/or preservation of immunologic
  function
• Maximal and durable suppression of viral load

• Selection of ARV regimen
• Preservation of future treatment options
• Rational sequencing of therapy
• Maximizing adherence
• Use of resistance testing in selected clinical
  settings

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Improving Adherence

• Support and reinforcement
• Simplified dosing strategies
• Reminders, alarms, timers, and pill boxes
• Ongoing patient education
• Trust in primary care provider

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Use of HIV RNA CD4 T Cell Levels to Guide
Therapy Decisions

• Syndrome consistent with acute HIV infection
• Initial evaluation of new HIV diagnosis
• Every 3-4 months in the untreated patient
• Immediately prior to initiating therapy
• 2-8 weeks after initiating therapy
• Every 3-4 months in patients on therapy
• As clinically indicated

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Testing for Drug Resistance

• Adjunct to guide antiretroviral therapy
• Combine with obtaining a drug history and
  maximizing drug adherence
• Research supports use in certain settings
• Genotyping vs. phenotyping
• Limitations of resistance testing and specific
  indications

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The Use of Drug Resistance Testing
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The Use of Drug Resistance Testing
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Benefits and Risks of Deferred Therapy

• RISKS
• Possibility of irreversible immune system
  depletion
• Increased possibility of progression to AIDS
• Possible increased risk of HIV transmission

• BENEFITS
• Avoid negative effects on quality of life
• Avoid drug-related toxicity
• Preserve future drug options
• Delay development of drug resistance
• Decrease total time on medications

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Indications for Initiation of Therapy Chronic
Infection
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Indications for Initiation of Therapy Chronic
Infection
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Current Antiretroviral Medications

• PI
• Amprenavir APV
• Atazanavir ATV
• Darunavir DRV
• Fosamprenavir FPV
• Indinavir IDV
• Lopinavir LPV
• Nelfinavir NFV
• Ritonavir RTV
• Saquinavir SQV
• hard gel HGC
• tablet INV
• Tipranavir TPV
• Fusion Inhibitor
• Enfuvirtide T-20

• NRTI
• Abacavir ABC
• Didanosine DDI
• Emtricitabine FTC
• Lamivudine 3TC
• Stavudine D4T
• Zidovudine ZDV
• Tenofovir TDF
• NNRTI
• Delavirdine DLV
• Efavirenz EFV
• Nevirapine NVP

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Components of Initial ART DHHS Categories

• Preferred
• Clinical data show optimal efficacy and
  durability
• Acceptable tolerability and ease of use
• Alternative
• Clinical trial data show efficacy but also show
  disadvantages in ARV activity, durability,
  tolerability, or ease of use (compared to
  preferred components)
• may be the best option in select individual
  patients
• Other possible options
• Inferior efficacy or greater or more serious
  toxicities

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Initial Treatment Preferred Components
NNRTI Option
NRTI Options

• Tenofovir emtricitabine
• Zidovudine lamivudine

OR

PI Options

• Avoid in pregnant women and women with
  significant pregnancy potential.
• Emtricitabine can be used in place of
  lamivudine and vice versa.

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Initial Treatment Alternative Components
NNRTI Option
NRTI Options

• Abacavir lamivudine
• Didanosine (emtricitabine or lamivudine)

OR
PI Options

• Nevirapine should not be initiated in women with
  CD4 counts gt250 cells/mm3 or men with CD4 counts
  gt400 cells/mm3
• Atazanavir must be boosted with ritonavir if
  used in combination with tenofovir

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Initial Treatment Other Possible Options
Rationale
ARV drugs or regimens
These are considered acceptable but inferior to
preferred or alternative components. They may be
used in special circumstances.
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Antiretroviral Medications Not Recommended in
Initial Treatment (1)
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Antiretroviral Medications Not Recommended in
Initial Treatment (2)
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Antiretroviral Medications Not Recommended in
Initial Treatment (3)
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Antiretroviral Medications Should not be offered
at any time

• Regimens not recommended
• Monotherapy (except possibly zidovudine used to
  prevent perinatal HIV transmission)
• Dual NRTI therapy
• 3-NRTI regimen (except abacavir/lamivudine/
  zidovudine and possibly lamivudine/zidovudine
  tenofovir
• NRTI-sparing regimens

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Antiretroviral Medications Should not be
offered at any time

• Antiretroviral components not recommended
• Didanosine stavudine
• Stavudine zidovudine
• Emtricitabine lamivudine

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Antiretroviral Medications Should not be
offered at any time

• Antiretroviral components not recommended
• Efavirenz in pregnancy and in women with
  significant potential for pregnancy
• Nevirapine initiation in women with CD4 gt250
  cells/mm3 or men with CD4 gt400 cells/mm3

Women who are trying to conceive or who are not
using effective and consistent contraception.
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Antiretroviral Medications Should not be
offered at any time

• Antiretroviral components not recommended
• Atazanavir indinavir
• Amprenavir fosamprenavir
• Amprenavir oral solution in pregnancy, in
  children lt4 years, in renal or hepatic failure,
  or in patients treated with metronidazole or
  disulfiram
• Amprenavir oral solution ritonavir oral
  solution
• Saquinavir as single PI (unboosted)

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Antiretroviral Components in Initial Therapy
NNRTIs

• ADVANTAGES
• Less dyslipidemia and fat maldistribution than in
  PI-based regimens
• PI options preserved for future use

• DISADVANTAGES
• Resistance - single mutation
• Cross-resistance among NNRTIs
• Rash hepatotoxicity
• Potential drug interactions (CYP450)

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Antiretroviral Components in Initial Therapy PIs

• ADVANTAGES
• Longest prospective data
• NNRTI options preserved for future use

• DISADVANTAGES
• Metabolic complications (fat maldistribution,
  dyslipidemia, insulin resistance)
• Greater potential for drug interactions (CYP450),
  especially with ritonavir

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Antiretroviral Components in Initial Therapy
NRTIs

• DISADVANTAGES
• Lactic acidosis and hepatic steatosis reported
  with most NRTIs (rare)
• Triple NRTI regimens show inferior virologic
  response compared with efavirenz- and
  indinavir-based regimens

• ADVANTAGES
• Established backbone of combination therapy
• Minimal drug interactions
• PI and NNRTI preserved for future use

Triple NRTI regimen of abacavir lamivudine
zidovudine to be used only when a preferred or
alternative NNRTI- or PI-based regimen cannot or
should not be used as first-line therapy.
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Adverse Effects NRTIs

• All NRTIs
• Lactic acidosis and hepatic steatosis (higher
  incidence with stavudine)
• Lipodystrophy (higher incidence with stavudine)

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Adverse Effects NRTIs

• Abacavir - hypersensitivity reaction
• Didanosine - GI intolerance, pancreatitis,
  peripheral neuropathy (PN)
• Stavudine - PN, pancreatitis
• Tenofovir - headache, GI intolerance, renal
  impairment
• Zidovudine - headache, GI intolerance, bone
  marrow suppression

Pregnant women may be at increased risk for
lactic acidosis and liver damage when treated
with stavudine didanosine. This combination
should be avoided in pregnant women, if possible.
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Adverse Effects NNRTIs

• All NNRTIs
• Rash
• Drug-drug interactions
• Nevirapine hepatotoxicity (may be severe and
  life-threatening), rash including Stevens-Johnson
  syndrome
• Efavirenz - neuropsychiatric, teratogenic in
  nonhuman primates (FDA Pregnancy Category D)

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Adverse Effects PIs

• All PIs
• Hyperlipidemia
• Insulin resistance and diabetes
• Lipodystrophy
• Elevated liver function tests
• Possible increased bleeding risk in hemophiliacs
• Drug-drug interactions

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Adverse Effects PIs

• Amprenavir, fosamprenavir - GI intolerance, rash
• Atazanavir - hyperbilirubinemia, PR interval
  prolongation
• Darunavir GI intolerance, rash
• Indinavir - nephrolithiasis, GI intolerance
• Lopinavir/ritonavir - GI intolerance
• Nelfinavir - diarrhea
• Ritonavir - GI intolerance, hepatitis
• Tipranavir - GI intolerance, rash,
  hyperlipidemia, liver toxicity, cases of
  intracranial hemorrhage

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Adverse Effects Fusion Inhibitors

• Enfuvirtide - injection-site reactions,
  hypersensitivity reaction, increased risk of
  bacterial pneumonia

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Treatment-Experienced Patients ARV Treatment
Failure

• Virologic failure
• HIV RNA gt400 copies/mL after 24 wks, gt50 after 48
  wks, or gt400 copies/mL after viral suppression
• Immunologic failure
• CD4 increase of lt25-50 cells/µL in first year of
  therapy, or decline in CD4 count to below
  baseline
• Clinical progression
• Occurrence of HIV-related events (after gt3 months
  on therapy excludes immune reconstitution
  syndromes)

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Treatment-Experienced Patients ARV Treatment
Failure

• Causes of treatment failure include
• Patient factors (CD4 nadir, VL, comorbidities,
  etc)
• Suboptimal adherence
• ARV toxicity and intolerance
• Pharmacokinetic problems
• Suboptimal drug potency
• Viral resistance

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Treatment-Experienced Patients ARV Treatment
Failure

• Therapeutic options
• Clarify goals in some, viral suppression may not
  be possible, but aim to reestablish maximal
  virologic suppression
• Evaluate remaining ARV options
• Base choices on expected tolerability, adherence,
  future treatment options, medication history, and
  resistance testing

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Treatment-Experienced Patients Goals of Therapy

• Limited prior treatment and drug resistance, with
  adequate treatment options
• Maximal viral suppression
• Consider early change to prevent further
  resistance mutations
• Intermediate prior treatment and drug resistance,
  with some available treatment options
• Maximal viral suppression, if possible.
• Preservation of immune function and prevention of
  clinical progression

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Treatment-Experienced Patients Goals of Therapy

• Extensive prior treatment and drug resistance,
  with some or no adequate treatment options
• Viral suppression may be difficult to achieve
• Preservation of immune function and prevention of
  clinical progression
• Balance benefits of partial viral suppression
  with risk of additional resistance mutations

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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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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 prepared by Susa Coffey, MD
  for the AETC National Resource Center in October
  2006.
• See the AETC NRC Web Site for the most current
  version of this presentation. http//www.aidsetc.o
  rg