DHHS Revised Adult and Adolescent Guidelines 1292008

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DHHS Revised Adult and Adolescent Guidelines
1/29/2008

• Swati Modi, M.D.
• Faculty, Florida/Caribbean AETCAssistant
  Professor, University of Florida Center for
  HIV/AIDS Research, Education and Service (UF
  CARES), Pediatric Infectious Disease and
  Immunology, University of Florida College of
  Medicine, Jacksonville, Florida.

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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.
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Course Objectives

• As a result of attending this 1 hour course on
  HIV/AIDS, the participant will be able to
• Recognize current recommendation of when to start
  HIV therapy
• Recognize current DHHS guidelines regarding
  preferred and alternative Anti-retroviral therapy
  and be familiar with antiretrovirals which are
  not recommended
• Recognize when an HIV regimen is failing
• Identify indications for drug resistance testing
• Be familiar with implications of treatment
  interruption in HIV therapy and identify acute
  HIV syndrome
• Identify and locate the latest Department of
  Health and Human Service adult and adolescent
  guidelines to treat HIV

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When to Start..

• Current recommendation ART for all patients with
  CD4 lt350 cells/mm³, certain others regardless of
  CD4 depending on presence of co-morbid
  conditions.
• Current recommendations no longer define a group
  of people who should not be treated
• Other major determinant for timing of initiation
  of therapy
• Concern about adherence to therapy
• Depression
• Substance abuse

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Special considerations in patients presenting
with an opportunistic disease

• Early initiation of ART near time of initiation
  of OI treatment (within 1st 2 weeks) should be
  considered for most patients with an acute OI,
  excluding TB.
• For TB disease, awaiting a response to OI therapy
  may be warranted before initiation of ART.
  Experts recommend making the decision based upon
  the immunological status of the patient
• CD4 count lt100 cells/µL ART should be started
  after 2 weeks of TB treatment to reduce
  confusion about overlapping toxicities, drug
  interactions, and the occurrence of paradoxical
  reactions or IRIS
• CD4 count of 100200 cells/µL ART may be
  delayed until the end of the 2-month intensive
  phase of anti-TB treatment
• CD4 count gt200 cells/µL ART could be started
  during the anti-TB maintenance phase
• CD4 count gt350 cells/µL ART could be started
  after finishing anti-TB treatment

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Potential Benefits of Early Therapy (CD4 count
gt350 cells/µL)

• Maintain higher CD4 count prevent irreversible
  immune system damage
• Decrease risk of HIV-associated complications
• eg, TB, NHL, KS, peripheral neuropathy,
  HPV-associated malignancies, HIV-associated
  cognitive impairment
• Decrease risk of nonopportunistic conditions and
  non-AIDS-associated conditions
• eg, CV, renal, and liver disease malignancies
  infections
• Decrease risk of HIV transmission

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Potential Risks of Early Therapy (CD4 count gt350
cells/µL)

• ARV-related side effects and toxicities
• Drug resistance (attributable to ART failure)
• Inadequate time to learn about HIV,
  treatment,and adherence
• Increase in total time on ART greater chance
  oftreatment fatigue
• Current ART may be less effective or more
  toxicthan future therapies
• Transmission of ARV-resistant virus, if
  incompletevirologic suppression

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HAART at higher CD4 T-cells

• Treat all (regardless of CD4 count)
• Pregnant women
• HIV associated Nephropathy (HIVAN)
• Co-Infection with hepatitis B, requiring
  treatment for HBV

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HIVAN (HIV Associated Nephropathy)

• HIVAN Most common cause of Chronic Renal Failure
  in persons living with HIV infection.
• More common in black than in white patients.
• Not related to CD4 T-cell depletion, ongoing
  viral replication appears to be directly involved
  in renal injury.
• Antiretroviral therapy in patients with HIVAN has
  been associated with preserved renal function and
  prolonged survival, and therefore should be
  initiated in individuals with diagnosis of HIVAN
  regardless of CD4 cell counts.
• Keep in mind that NRTIs except Abacavir are
  renally excreted and so may require dose
  adjustment depending on creatinine clearance.

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HIV/HBV Co-Infection

• Treat BOTH infections to prevent development of
  HBV resistant mutants
• HBV resistance to lamivudine monoterapy 40 at 2
  years, 90 at 4 years
• Elevation in transaminases Think of IRIS vs.
  Antiretroviral therapy as a cause. However keep
  HBeAg seroconversion in mind.
• Discontinuation of emtricitabine, lamivudine, and
  tenofovir may potentially cause serious
  hepatocellular damage resulting from reactivation
  of HBV

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Antiretroviral therapy
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Sites of Action of ART
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Current Antiretroviral Medications
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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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Tests Prior to Initiating Therapy

• HLA-B5701 screening
• Recommended before starting abacavir, to reduce
  riskof hypersensitivity reaction (HSR)
• HLA-B5701-positive patients should not receive
  ABC
• Positive status should be recorded as an ABC
  allergy
• If HLA-B5701 testing is not available, ABC may
  be initiatedafter counseling and with
  appropriate monitoring for HSR
• Coreceptor tropism assay
• Should be performed when a CCR5 antagonistis
  being considered
• Consider in patients with virologic failure on
  aCCR5 antagonist

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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, neuropsychiatric side
  effects
• Potential drug interactions (CYP450)

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

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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

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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.
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Antiretroviral Components Recommended for
Treatment of HIV-1 Infection in Treatment Naïve
Patients
(http//AIDSinfo.nih.gov)
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Cardiovascular Safety of Abacavir (ABC)

• DAD study group reported their analysis of
  association of NRTI use and risk of myocardial
  infarction (MI)
• A separate analysis conducted by GlaxoSmithKline
  using their internal database containing data
  from 54 clinical trials and post-marketing
  reports GlaxoSmithKline did not find any
  evidence of an increase in cardiovascular disease
  in their clinical trials among patients who
  received ABC.
• HEAT study Abacavir/lamivudine noninferior to
  tenofovir/emtricitabine in combination with
  once-daily Kaletra
• At this point, preliminary information available
  from these studies does not warrant a change in
  its current recommendations regarding the use of
  antiretroviral drugs in adults and adolescents
• Clinicians should consider all available
  information so that the optimal therapeutic
  choice for each patient is based on individual
  patient characteristics and the potential risks
  and benefits of each treatment component

http//aidsinfo.nih.gov/contentfiles/ABCComm.pdf
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ARVs Not Recommended in Initial Treatment (1)
Should not be given to pregnant women
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ARVs Not Recommended in Initial Treatment (2)
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ARVs Not Recommended as Part of Antiretroviral
Regimen
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Antiretroviral Regimens or Components That
ShouldNot Be Offered At Any Time
When constructing an antiretroviral regimen for
an HIV-infected pregnant woman, please consult
Public Health Service Task Force Recommendations
for the Use of Antiretroviral Drugs in Pregnant
HIV-Infected Women for Maternal Health and
Interventions to Reduce Perinatal HIV
Transmission in the United States in
http//www.aidsinfo.nih.gov/guidelines/. When
considering an antiretroviral regimen to use in
post-exposure prophylaxis, please consult
Updated U.S. Public Health Service Guidelines
for the Management of Occupational Exposures to
HIV and Recommendations for Postexposure
Prophylaxis in CDC MMWR Recommendations and
Reports. September 30, 2005/54 (RR 09) 117 and
Management of Possible Sexual,
Injection-Drug-Use, or Other Non-occupational
Exposure to HIV, Including Considerations Related
to Antiretroviral Therapy in CDC MMWR
Recommendations and Reports. January 21, 2005/54
(RR 02) 119.
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Should Not Be Offered at Any Time

• Efavirenz in pregnancy and in women with
  significant potential for pregnancy associated
  with significant teratogenic effects
• Nevirapine initiation in treatment-naïve women
  with CD4 gt250 cells/mm³ or men with CD4 gt400
  cells/mm³ Greater risk of symptomatic, including
  serious and life-threatening, hepatic events have
  been observed in these patient groups. Nevirapine
  should be initiated only if the benefit clearly
  outweighs the risk
• Atazanavir indinavir Both can cause grade 3 to
  4 hyperbilirubinemia and jaundice.
  Additive/Worsening effect?

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Comparison of Different Classes The Trials
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NNRTI Vs PI based Regimen as First Line Therapy

• A1424-034 study demonstrated comparable virologic
  and immunologic responses with atazanavir and
  efavirenz based regimens
• ACTG A5142- better virologic responses with
  efavirenz based regimen compared with
  lopinavir/ritonavir based regimen, but better CD4
  responses and less resistance following virologic
  failure with lopinavir/ritonavir plus two NRTIs.

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NNRTI Vs PI based Regimen as First Line Therapy

• Drug resistance to most PIs requires multiple
  mutations in the HIV protease, and it seldom
  develops following early virologic failure,
  especially when ritonavir boosting is used.
• Resistance to efavirenz or nevirapine, however,
  is conferred by a single mutation in reverse
  transcriptase, and develops rapidly following
  virologic failure
• In terms of convenience, NNRTI-based regimens are
  among the simplest to take, particularly with the
  coformulated tablet containing tenofovir,
  emtricitabine, and efavirenz, which allows for
  once daily dosing with a single pill.
• PI-based Currently preferred regimens are usually
  used with ritonavir (Boosting), may be dosed
  once- or twice daily, and generally require more
  pills in the regimen.

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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

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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

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Drug Resistance Testing Recommendations
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Drug Resistance Testing Recommendations (2)
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Clinical Progression

• Occurrence or recurrence of HIV-related events
  (after at least 3 months on an antiretroviral
  regimen), excluding immune reconstitution
  syndromes
• Management
• Rule out immune reconstitution syndrome which may
  respond toanti-inflammatory treatment
• may not warrant a change in therapy in the
  setting of suppressed viremia and adequate
  immunologic response

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Special Issues

• Treatment Interruptions
• Acute HIV infection

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Treatment Interruption

• No treatment interruption except if the patient
  is too sick or needs a surgery or part of a
  clinical trial
• May cause viral rebound, immune decompensation
  and clinical progression, development of drug
  resistance, increases risk of HIV transmission
• Increases risk of HIV and non-HIV related
  complications

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Short Term Interruption in ART

• In case of life threatening toxicity Stop all
  drugs simultaneously
• If it is planned short term interruption
• When all ARVs have similar half-lives Stop all
  drugs simultaneously
• When ARVs have different half-lives stopping all
  drugs at same time may result in functional
  monotherapy. Consider staggered discontinuation

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ART Interruptions ARV Specific Issues

• Discontinuation of Efavirenz, Etravirine or
  Nevirapine All have long half lives. Consider
  stopping them before the NRTI component to avoid
  potential mono therapy. Or Consider substitution
  of a NNRTI with a PI for a period of time before
  stopping all ARVs
• If the Nevirapine has been discontinued 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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Acute Retroviral Syndrome Common Signs and
Symptoms

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

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

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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

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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 by suppressing viral
  replication
• 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

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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

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Websites to Access the Guidelines

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

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Thank you!!