Antiretroviral Therapy Management

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Antiretroviral Therapy Management

• Jennifer Janelle, MD
• Alachua County Health Department
• Malcolm Randall VA Medical Center

2
Disclosure of Financial Relationships

• This speaker has no significant financial
  relationships with commercial entities to
  disclose.

This slide set has been peer-reviewed to ensure
that there areno conflicts of interest
represented in the presentation.
3
Objectives

• Review the natural history of HIV infection
• Describe target sites of drugs with FDA approval
  for treatment of HIV
• Overview current DHHS guidelines for HIV therapy
• Timing of initiation of therapy
• Indications for changing therapy
• Co-morbid conditions

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Typical Time Course of Untreated HIV
Nature Reviews Immunology 3, 343-348 (April 2003)
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(No Transcript)
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Use of CD4 Cell Levels to Guide Therapy Decisions

• CD4 count
• Most recent CD4 count is best predictor of
  disease progression and is the most important
  consideration in decision to start ART
• Important in determining response to ART
• Adequate response CD4 increase 100-150 cells/mm³
  per year
• CD4 monitoring
• Check at baseline (x 2) and at least every 3-6
  months

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Use of HIV RNA Levels to Guide Therapy Decisions

• HIV RNA
• 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 (x 2) and at least every 3-4
  months in stable patients
• Immediately prior to initiating therapy
• 2-8 weeks after start or change of ART

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Factors Affecting Progression

• Accelerated progression
• Extremes of age
• Syncytium inducing virus
• Poor immune response

• Slowed progression
• Viral mutants
• Chemokine receptor mutations
• Antiretroviral therapy

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Baseline Evaluation

• Complete HP
• Laboratory testing
• HIV antibody
• CD4 cell count
• Plasma HIV RNA
• CBC, chemistry profile, BUN, Cr, transaminase
  levels

• Fasting glucose and lipids
• RPR or VDRL
• Hepatitis A,B,C serology
• Toxoplasma IgG
• Resistance test (genotype)

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Testing for Drug Resistance

• Rationale
• Identification of resistance mutations may
  optimize treatment outcomes
• Transmitted resistance in 6-16 of
  HIV-infected1-4
• Caveats
• 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
• In patients on therapy, perform while patient is
  taking ART, or 4 weeks after discontinuing
  therapy
• Interpret in combination with history of ARV
  exposure and ARV adherence

1. J Infect Dis, 2004. 189(12)2174-80. 2. J
Infect Dis, 2005. 192(6)958-66. 3. BMJ, 2005.
331(7529)1368 4. HIV Clin Trials, 2007.
8(1)1-8.
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Testing for Drug Resistance

• Before initiation of ART
• Genotype recommended for all at entry to care
• Recommended for all pregnant women

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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)

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Indications for ART

• Treat all with
• History of AIDS-defining illness
• CD4 count lt200 cells/mm³
• Strong evidence of decreased mortality and
• morbidity if ART is given to patients with
  symptoms
• of AIDS or CD4 lt200 cells/mm³

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Indications for ART

• Treat all (regardless of CD4 count)
• Pregnant women
• HIV-associated nephropathy (HIVAN)
• Not clearly related to CD4 decline ART may
  preserve renal function
• Hepatitis B coinfection, if HBV treatment is
  needed
• Tenofovir lamivudine or emtricitabine is
  recommended
• If ART is not started, HBV therapy should not
  include agents that may select for resistance to
  ARVs

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When to Start ART

• Exact CD4 at which to initiate therapy not known,
  but evidence points to starting at higher CD4
  counts
• Earlier ART may result in better immunologic
  responses and better clinical outcomes
• Current recommendation ART for all patients with
  CD4 lt350 cells/mm³, certain others regardless of
  CD4

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Considerations in Initiating ART

• 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

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Considerations in Initiating ART

• ART should be considered life-long therapy
• Interruption of ART not recommended, except for
  serious toxicities or inability to take oral
  medications
• Usually causes immediate virologic rebound, with
  CD4 decline

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Goals of Antiretroviral Therapy (ART)

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

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Goals of Therapy

• Prevention of vertical transmission
• Prevention of transmission to sexual partners

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

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Tools to Achieve Goals

• 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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Other Helpful Studies

• HLA-B5701 screening
• Recommended before starting abacavir, to reduce
  risk of hypersensitivity reaction (HSR)
• HLA-B5701-positive patients should not receive
  abacavir
• Positive status should be recorded as an abacavir
  allergy
• If HLA-B5701 testing is not available, abacavir
  may be initiated, after counselling and with
  appropriate monitoring for HSR

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Other Helpful Studies

• Co-receptor tropism assay
• Should be performed when CCR5 antagonist is being
  considered
• Consider in patients with virologic failure on a
  CCR5 antagonist

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Sites of Action of ART
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Current Antiretroviral Medications
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Initial Treatment Choosing Regimens

• Combination of NNRTI or PI plus 2 NRTIs preferred
  for most patients
• Fusion inhibitor, CCR5 antagonist, integrase
  inhibitor not recommended in initial ART
• Few clinical endpoints to guide choices
• Advantages and disadvantages to each type of
  regimen
• Individualize regimen choice

www.aidsetc.org
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Considerations in Choosing Regimen

• Comorbidities
• Adherence potential
• Dosing convenience
• Potential adverse effects
• Potential drug interactions
• Pregnancy potential
• Results of drug resistance test
• Gender and CD4 count, if considering nevirapine
• HLA B5701 testing, if considering abacavir

www.aidsetc.org
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Antiretroviral Components in Initial Therapy
NNRTIs

• DISADVANTAGES
• Low genetic barrier to resistance - single
  mutation
• Cross-resistance among most NNRTIs
• Rash hepatotoxicity
• Potential drug interactions (CYP450)

• ADVANTAGES
• Long half-lives
• Less metabolic toxicity (dyslipidemia, insulin
  resistance) than with some PIs
• PI options preserved for future use

www.aidsetc.org
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Antiretroviral Components in Initial Therapy PIs

• ADVANTAGES
• Higher genetic barrier to resistance
• PI resistance uncommon with failure (boosted PI)
• NNRTI options preserved for future use

• DISADVANTAGES
• Metabolic complications (fat maldistribution,
  dyslipidemia, insulin resistance)
• GI intolerance
• Potential for drug interactions (CYP450),
  especially with ritonavir

www.aidsetc.org
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ARV 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.
www.aidsetc.org
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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

www.aidsetc.org
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Initial Treatment Preferred Components
NNRTI Option
NRTI Options¹

• Abacavir lamivudine²
• Tenofovir emtricitabine³

OR

PI Options

• Avoid in pregnant women and women with
  significant pregnancy potential
• ¹ Emtricitabine can be used in place of
  lamivudine and vice versa
• ² For patients who have tested negative for
  HLA-B5701
• ³ Tenofovir emtricitabine or lamivudine is
  preferred in patients with HIV/HBV coinfection

www.aidsetc.org
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Initial Treatment Alternative Components
NNRTI Option
PI Options

• Nevirapine should not be initiated in women
  with CD4 counts gt250 or men with CD4 counts gt400
• ¹ Atazanavir must be boosted with ritonavir if
  used with tenofovir
• ² May be insufficient if HIV RNA gt100,000
  copies/mL

www.aidsetc.org
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Initial Treatment Alternative Components
NRTI Options (in order of preference)

• Zidovudine lamivudine¹
• Didanosine (emtricitabine or lamivudine)

• ¹ Emtricitabine can be used in place of
  lamivudine and vice versa

www.aidsetc.org
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ARVs Not Recommended in Initial Treatment (1)
Should not be given to pregnant women
www.aidsetc.org
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ARVs Not Recommended in Initial Treatment (2)
www.aidsetc.org
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Should Not Be Offered at Any Time

• ARV regimens not recommended
• Monotherapy with NRTI
• Dual NRTI therapy
• 3-NRTI regimen (except abacavir/lamivudine/zidovud
  ine or possibly tenofovir lamivudine/zidovudine,
  when other regimens are not desirable)

www.aidsetc.org
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ARVs Not Recommended in Initial Treatment (2)
www.aidsetc.org
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Should Not Be Offered at Any Time

• 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
• 2-NNRTI combination
• Atazanavir indinavir
• Nelfinavir in pregnancy and in women with
  significant potential for pregnancy

www.aidsetc.org
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Adverse Effects NNRTIs

• All NNRTIs
• Rash
• Drug-drug interactions
• Nevirapine
• Rash including Stevens-Johnson syndrome
• Hepatotoxicity (may be severe and
  life-threatening risk higher in patients with
  higher CD4 counts at the time they start
  nevirapine)
• Efavirenz
• Neuropsychiatric, teratogenic in nonhuman
  primates (FDA Pregnancy Category D)

www.aidsetc.org
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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

www.aidsetc.org
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Adverse Effects PIs

• Atazanavir
• Hyperbilirubinemia
• PR interval prolongation
• Nephrolithiasis
• Darunavir
• GI intolerance
• Rash
• Hepatotoxicity

• Fosamprenavir
• GI intolerance
• Rash
• Indinavir
• Nephrolithiasis
• GI intolerance
• Lopinavir/ritonavir
• GI intolerance

www.aidsetc.org
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Adverse Effects PIs (2)

• Nelfinavir
• Diarrhea
• Byproduct of manufacturing (EMS) has been
  teratogenic and carcinogenic in animal studies
• Ritonavir
• GI intolerance
• Hepatitis

• Saquinavir
• GI intolerance
• Tipranavir
• GI intolerance
• Rash
• Hyperlipidemia
• Liver toxicity
• Cases of intracranial hemorrhage

www.aidsetc.org
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Adverse Effects NRTIs

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

www.aidsetc.org
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Adverse Effects NRTIs

• Abacavir
• Hypersensitivity reaction
• (HLA B5701)
• Rash
• Didanosine
• GI intolerance
• Pancreatitis
• Peripheral neuropathy
• Stavudine
• Peripheral neuropathy
• Pancreatitis

• Tenofovir
• Headache
• GI intolerance
• Renal impairment
• Zidovudine
• Headache
• GI intolerance
• Bone marrow suppression

www.aidsetc.org
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Overlapping Toxicities

• Peripheral neuropathy
• didanosine, isoniazid, stavudine, zalcitabine
• Bone marrow suppression
• cidofovir, dapsone, hydroxyurea, ribavirin,
  TMP-SMZ, zidovudine
• Hepatotoxicity
• nevirapine, efavirenz, isoniazid, macrolides,
  maraviroc, NRTIs, PIs
• Pancreatitis
• didanosine, pentamidine, ritonavir, stavudine,
  TMP-SMZ

www.aidsetc.org
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ARV-ARV Interactions Dose Modification or
Cautious Use

• Efavirenz, nevirapine, or etravirine with PIs
• Atazanavir tenofovir
• Didanosine tenofovir
• Didanosine stavudine
• Maraviroc many PIs
• Maraviroc efavirenz or etravirine

www.aidsetc.org
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Adverse Effects Fusion Inhibitor

• Enfuvirtide
• Injection-site reactions
• Hypersensitivity reaction
• Increased risk of bacterial pneumonia

www.aidsetc.org
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Adverse Effects CCR5 Antagonist

• Maraviroc
• Abdominal pain
• Upper respiratory tract infections
• Cough
• Hepatotoxicity
• Musculoskeletal symptoms
• Rash
• Orthostatic hypotension

www.aidsetc.org
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Adverse Effects Integrase Inhibitor

• Raltegravir
• Nausea
• Headache
• Diarrhea
• CPK elevation

www.aidsetc.org
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Measurement of Success of ART Regimen

• HIV RNA less than 400 copies/mL after 24 weeks
• HIV RNA less than 50 copies after 48 weeks
• Achieve and maintain adequate CD4 increase with
  virologic suppression
• Avoidance of HIV-related events
• After 3 months of therapy
• Does not include immune reconstitution syndromes

www.aidsetc.org
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Indicators of Antiretroviral Treatment Failure

• HIV RNA greater than 400 copies/mL after 24 weeks
• HIV RNA greater than 50 copies/mL after 48 weeks
• Rebound in viral load after suppression
• Failure to achieve and maintain adequate CD4
  increase despite virologic suppression
• Clinical progression of HIV despite treatment

www.aidsetc.org
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Treatment-Experienced Patients ARV Treatment
Failure

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

www.aidsetc.org
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Treatment-Experienced Patients Virologic Failure

• Management
• Clarify goals aim to reestablish maximal
  virologic suppression (eg, lt50 copies/ML)
• Evaluate remaining ARV options
• Newer agents have expanded treatment options
• Base ARV selection on medication history,
  resistance testing, expected tolerability,
  adherence, and future treatment options
• Avoid treatment interruption, which may cause
  viral rebound, immune decompensation, clinical
  progression

www.aidsetc.org
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Virologic Failure Changing an ARV Regimen

• General principles
• Add at least 2 (preferably 3) fully active agents
  to an optimized background ARV regimen
• Consider potent ritonavir-boosted PIs and drugs
  with new mechanisms of action plus an optimized
  ARV background
• In general, 1 active drug should not be added to
  a failing regimen (drug resistance is likely to
  develop quickly)
• Consult with experts (you are not alone!)

www.aidsetc.org
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Special Issues

• Acute HIV Infection
• Treatment for Pregnant Women

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Acute Retroviral SyndromeCommon Signs and
Symptoms

• Fever
• Lymphadenopathy
• Pharyngitis
• Rash
• Myalgia or arthralgia
• Diarrhea

• Headache
• Nausea and vomiting
• Hepatosplenomegaly
• Weight Loss
• Thrush
• Neurological symptoms

www.aidsetc.org
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Acute HIV Infection Diagnosis

• Maintain high level of suspicion in patients with
  compatible clinical syndrome risks
• Plasma HIV RNA HIV antibody test
• Often, detectable HIV RNA with negative or
  indeterminate HIV antibody test
• Low-positive HIV RNA (lt10,000 copies/mL) may be
  false positive
• Qualitative HIV RNA test can be used
• If diagnosis is made by HIV RNA testing,
  confirmatory serologic testing should be
  performed subsequently

www.aidsetc.org
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Acute HIV Infection Treatment

• Possible benefits
• Decrease the severity of acute disease
• Alter the viral set point
• Reduce the rate of mutation
• Preserve immune function
• Reduce risk of viral transmission

• Possible risks
• Drug-related toxicity
• Earlier emergence of drug resistance
• Limitation of future treatment options
• Potential need for indefinite treatment
• Adverse effects on quality of life

www.aidsetc.org
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Acute HIV Infection Treatment

• Limited outcome data from clinical trials
  therapy based largely on theoretic considerations
• Treatment considered optional for patients with
  acute and recent HIV infection who do not
  otherwise meet criteria for ART
• Potential benefits and risks should be weighed
• Consider enrolling patients in clinical trials

www.aidsetc.org
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Acute HIV Treatment Regimen

• ARV regimen selection and monitoring are same as
  for chronic infection
• Resistance testing (genotype) is recommended
  before ART selection
• Resistance to NNRTIs is more common than
  resistance to PIs consider using PI-based
  regimen if ART is initiated before resistance
  test results are available

www.aidsetc.org
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Treatment for Pregnant Women

• To reduce risk of perinatal transmission
• Antiretroviral therapy recommended in all
  pregnant women
• Suppress HIV viral load at least to lt1000
  copies/mL

See also the US Public Health Services Task
Force Recommendations for Use of Antiretroviral
Drugs in Pregnant HIV-1-Infected Women for
Maternal Health and Interventions to Reduce
Perinatal HIV-1 Transmission in the United
States.
www.aidsetc.org
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Treatment for Pregnant Women

• In women not already on ARVs, consider delaying
  treatment until 10-12 weeks gestation
• In women already on ARVs, consider continuing
  therapy, though effects of ARVs on fetus in first
  trimester are uncertain
• Perform resistance testing before starting ARV
  therapy or prophylaxis, and in women on ARV
  therapy with detectable HIV RNA

www.aidsetc.org
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Treatment for Pregnant Women

• Regimen considerations
• Potential pharmacokinetic changes caused by
  pregnancy, different dosing requirements
• Potential adverse effects of ARVs on pregnant
  women
• Impact on perinatal HIV transmission risk
• Potential short- and long-term ARV effects on the
  fetus and newborn

www.aidsetc.org
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Safety and Toxicity of ART in Pregnant Women
NRTIs

• Clinical trial data in human pregnancy available
  for zidovudine, lamivudine, didanosine, stavudine
• Mitochondrial toxicity possible with all NRTIs
• Increased risk of lactic acidosis/hepatic
  steatosis with didanosine stavudine

This combination should be used only if no
other alternatives are available.
www.aidsetc.org
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ARV Use in Pregnant Women NRTIs
www.aidsetc.org
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ARV Use in Pregnant Women NRTIs
www.aidsetc.org
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Antiretroviral Drug Use in Pregnant Women NNRTIs
www.aidsetc.org
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ARV Use in Pregnant Women PIs
www.aidsetc.org
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ARV Use in Pregnant Women PIs
www.aidsetc.org
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ARV Use in Pregnant Women PIs
www.aidsetc.org
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ARV Use in Pregnant Women PIs
DHHS Panel on Antiretroviral Therapy Guidelines
for Adults and Adolescents Notice on Nelfinavir
FDA-Pfizer Letter - September 13, 2007
www.aidsetc.org
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ARV Use in Pregnant Women Entry Inhibitors
Adapted from www.aidsetc.org
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Conclusions

• We have discussed natural history of HIV
  infections
• Interventions for HIV infection
• When to start ART
• Recommended first regimens
• How to determine success of regimen
• What to do when regimen fails
• Special issues in HIV treatment
• Acute HIV
• Pregnancy

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Web Sites to Access the Guidelines

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