Update of Antiretroviral Agents in

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• Update of Antiretroviral Agents in
• Adults and Adolescents 2009

Asso.Prof. Narin Hiransuthikul MD, MPH,
PhD Dep. of Preventive Social Medicine Faculty
of Medicine Chulalongkorn UNiversity
November 23,2009
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Management of HIV/AIDS (1)

• During past 28 years, HIV/AIDS has been
  transformed from
• almost fatal disease manageable disease

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Management of HIV/AIDS (1)

• Optimal ART can provide -durable
  virologic,immunologic and clinical benefits
  -minimal toxicities and drug resistance
  -potentially normal life span

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• 3 million people worldwide
• were receiving ART
• 6.7 million were still in need
• 2.7 million new infected cases

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Recent Issues Influencing ART in
HIV/AIDS 2008

• Recent approval of 3 novel ARVs

- Chemokine coreceptor antagonist
Maraviroc (CCR5 antagonist) - Integrase strand
transfer inhibitor Raltegravir - 2nd
generation NNRTI Etravirine
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Recent Issues Influencing ART in
HIV/AIDS 2008

• Recent approval of 3 novel ARVs

• New data that better inform the choice of ARV for
  initial Rx and Mx of treatment failure

• New pathogenetic insights into the role of HIV in
  previously considered non-AIDS related
  conditions

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Goals of ART

• Eradication of HIV?
• Not possible with currently available ARV
  medications

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HIV Eradication ?
Not now but a step closer

• Persistent reservoir of latent HIV-infected cells
• There are at least two major reservoirs for HIV
  that contribute on an ongoing basis to viral
  persistence

1. Latent CD4 (memory) cells
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Reservoir of Latent HIV Infected CD4T-Lymphocytes
Based on an estimate of 10 6 cells in latent
reservoirs ,
73 years of CART would be
required for eradication
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HIV Eradication ?
Not now but a step closer

• Persistent reservoir of latent HIV-infected cells
• There are at least two major reservoirs for HIV
  that contribute on an ongoing basis to viral
  persistence

1. Latent CD4 (memory) cells
2. Latent non-CD4 (memory) cells
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ART Goals Tools to Achieve Them
Goals

• Maximal and durable suppression of HIV-RNA
• Restore CD4 number and function
• Reduce inflammation and immune activation
• Normalize survival
• Improve QOL
• Prevention of vertical transmission
• Prevention of transmission to sexual partners

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SMART Inflammatory Markers StronglyAssociated
With Mortality and CVD Events
SMART Strategies in Management of ART
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SMART Inflammatory Markers StronglyAssociated
With Mortality and CVD Events
SMART Strategies in Management of ART
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Pathogenic Mechanisms Possibly Involved in
Accelerated Aging and Contributing to Non-AIDS
in HIV Infected Patients
Reiss P. CID 2009491602
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ART Goals Tools to Achieve Them
Goals
Tools

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

• Maximal and durable suppression of HIV-RNA
• Restore CD4 number and function
• Reduce inflammation and immune activation
• Normalize survival
• Improve QOL
• Prevention of vertical transmission
• Prevention of transmission to sexual partners

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Baseline Evaluation

• Complete History and Physical examination
• Laboratory testing
• HIV antibody
• CD4 cell count
• Plasma HIV RNA
• Resistance test (genotype)
• CBC, chemistry profile, BUN, Cr, transaminase
• Fasting glucose and lipids
• RPR or VDRL
• Hepatitis A, B, C serology
• Toxoplasma IgG

DHHS guidelines, 2008
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Before Initiating ART Additional Tests

• Tuberculin skin test
• Chest X ray (if clinically indicated)
• Gynecologic exam with Pap smear
• Testing for chlamydia and gonorrhea
• Ophthalmology exam
• (CD4 cell count lt100 cells/µL)

DHHS guidelines, 2008
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TAS Guidelines 2008Baseline Evaluation (1)

• Complete History and Physical examination
• Laboratory testing
• HIV antibody
• CBC, CD4 cell count
• Plasma HIV RNA
• AST,ALT, serum creatinine, FBS, serum lipid
  profiles
• RPR or VDRL
• HBsAg
• Urinalysis
• Chest X-rays

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TAS Guidelines 2008Baseline Evaluation (2)

• PAP smear should be performed in HIV-infected
  women
• Fundoscopic exam to evaluate for CMV retinitis
  should be done in patients with CD4 counts lt
  50 cells/mm3
• Other Laboratory testing
• Anti-HCV antibody should be tested in patients
  with Hx of IVDU

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Considerations in Initiating ART (1)

• Willingness of patient to begin and the
  likelihood of adherence
• Degree of immunodeficiency(CD4 cell count)
• Plasma HIV RNA
• Risk of disease progression
• Potential benefits and risks of therapy
• ART availability, affordability (cost), ADR,
• Drug-drug interaction

DHHS guidelines, 2008 TAS guidelines, 2008
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Considerations in Initiating ART (2)

• ART should be considered lifelong therapy
• Importance of adherence
• Risk of IRIS
• Interruption of ART is not recommended, except
  for serious toxicities or inability to take oral
  medications
• Usually causes immediate virologic rebound, with
  CD4 decline

DHHS guidelines, 2008 TAS guidelines, 2008
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Use of CD4 Cell Levels to Guide Therapy Decisions

• CD4 count
• The major indicator of immune function
• Most recent CD4 count is best predictor of
  disease progression
• CD4 count usually is the most important
  consideration in decision to start ART
• Important in determining response to ART
• Adequate response CD4 increase 100-150 cells/µL
  per year
• CD4 monitoring
• Check at baseline (x2) and at least every 3-6
  months

DHHS guidelines, 2008
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Use of HIV RNA Levels to Guide Therapy Decisions

• HIV RNA
• Less important than CD4 count, but may influence
  decision to start ART and determine frequency of
  CD4 monitoring
• Critical in determining response to ART
• Goal of ART HIV RNA below limit of detection
  (ie, lt40 to lt80 copies/mL, depending on assay)
• RNA monitoring
• Check at baseline (x2) and at least every 3-4
  months in stable patients
• Immediately prior to initiating therapy
• 2-8 weeks after start or change of ART

DHHS guidelines, 2008
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Testing for Drug Resistance

• Before initiation of ART
• Resistance testing (genotype) recommended for all
  at entry to care, and for all pregnant women
• Transmitted resistance in 6-16 of HIV-infected
  patients
• Identification of resistance mutations may
  optimize treatment outcomes
• In absence of therapy, resistance mutations may
  decline over time and become undetectable by
  current assays, but may persist and cause
  treatment failure when ART is started
• Patients with virologic failure
• Perform while patient is taking ART, or 4 weeks
  after discontinuing therapy
• Interpret in combination with history of ARV
  exposure and ARV adherence

DHHS guidelines, 2008
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Drug Resistance Testing Recommendations (1)
DHHS guidelines, 2008
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Drug Resistance Testing Recommendations (2)
DHHS guidelines, 2008
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Drug Resistance Testing Recommendations (3)
DHHS guidelines, 2008
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Other Studies Before Treatment with Specific ARVs

• HLA-B 5701 screening
• Recommended before starting abacavir, to reduce
  risk of hypersensitivity reaction (HSR)
• HLA-B 5701-positive patients should not receive
  ABC
• Positive status should be recorded as an ABC
  allergy
• If HLA-B 5701 testing is not available, ABC may
  be initiated, after counseling and with
  appropriate monitoring for HSR
• Coreceptor tropism assay
• Should be performed when CCR5 antagonist is being
  considered
• Consider for patients with virologic failure on a
  CCR5 antagonist

Not FDA approved for initial ARV therapy.
DHHS guidelines, 2008
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When to Start Therapy

• According to the current guidelines, what
  criteria should one use to determine when to
  start ART?

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Guideline Recommendations for Initiation of ART
1. DHHS guidelines. November 3, 2008. Available
at http//www.aidsinfo.nih.gov. Accessed
January 12, 2009. 2. Hammer SM, et al. JAMA.
2008300555-570.
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2008 European GuidelinesWhen to Start
1. EACS. Available at http//www.eacs.eu/guide/1_
Treatment_of_HIV_Infected_Adults.pdf. 2. British
HIV Association. Available at http//www.bhiva.or
g/cms1222226.asp.
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Indications for Initiation of ART
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When to Start Therapy

• What special considerations pertain when
  considering therapy initiation in a patient with
  comorbidities?

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Comorbidities to Consider When Deciding When to
Initiate HAART

• Cardiovascular disease
• Bone health
• Renal impairment
• HIV-associated nephropathy
• Hepatic dysfunction
• HCV/HBV coinfection
• Psychiatric disease

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When to Start Therapy

• Should some patients start therapy earlier than
  the thresholds recommended in treatment
  guidelines?

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Early Treatment Initiation

• HIV-1 RNA gt 100,000 copies/mL
• CD4 cell count decline gt 100 cells/mm3/year
• Older age
• HCV coinfection
• HBV coinfection
• Presence of risk factors for non-AIDS diseases
• Cancer, cardiovascular disease
• HIV-associated nephropathy

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When to Start Therapy

• What special considerations pertain when one
  considers whether to start ART in a patient who
  presents with primary infection?

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Guideline Recommendations on Treating Acute
Infection
1. DHHS guidelines. Available at
http//www.aidsinfo.nih.gov. Accessed January 12,
2009. 2. Hammer SM, et al. JAMA.2008300555-570.