nynj-nurse-mod1-09.ppt

Human Immunodeficiency Virus and
Antiretroviral Therapy
Lucille Sanzero Eller, PhD, RN
Associate Professor
Rutgers, The State University of New Jersey
College of Nursing
Local Performance Site of the NY/NJ AETC
September 2009

Objectives
1. Discuss the epidemiology of HIV in the U.S.
2. Describe the HIV replication cycle.
3. Discuss ARV therapy.
4. Identify methods of evaluation of ART
effectiveness.

Age of persons with HIV/AIDS
diagnosed during 2007
CDC. HIV/AIDS in the United States. August 21, 2009. Accessed on
September 14, 2009 at:
http://www.cdc.gov/hiv/resources/factsheets/us.htm

Transmission categories: adults/ adolescents
with HIV/AIDS diagnosed in 2007
CDC. HIV/AIDS in the United States. August 21, 2009. Accessed on
September 14, 2009 at:
http://www.cdc.gov/hiv/resources/factsheets/us.htm

HIV Replication Cycle (1)
1. Binding and Fusion
– Virion’s gp120 and gp41 proteins bind to
cell surface receptors (CD4 and either the
CCR5 or CXCR4 co-receptor)
– Viral membrane fuses with cell
membrane
– Viral contents released into cell

2. Reverse Transcription and Integration
– Viral enzyme reverse transcriptase is used to
copy viral RNA into viral DNA
– Viral DNA is transported into cell nucleus and
spliced into cell’s DNA by HIV enzyme integrase
– Viral DNA persists in latent state until cell
activation

3. Transcription and Translation
– Upon activation of infected cell, viral DNA
is transcribed into messenger RNA
(mRNA) and the genetic material for next
generation of HIV
– mRNA is transcribed into viral proteins
and enzymes

4. Assembly, Budding and Maturation
– HIV proteins/enzymes and viral RNA assemble
into new viral particles
– Virus buds from the cell
– Protease enzyme cleaves long protein strands
into small functional HIV proteins and enzymes
– Mature HIV particles now able to infect other
cells and replicate

Antiretroviral Therapy (ART)
 ART- use of antiretroviral drugs to treat HIV
disease
 Highly Active Antiretroviral Therapy
(HAART)-regimens combining several
antiretroviral drugs
– To be successful, antiretroviral regimens need
to contain at least two, and preferably three,
active drugs from multiple drug classes

Primary Goals of ART
 Reduce HIV-related morbidity and prolong
survival
 Improve quality of life
 Restore and preserve immunologic function
 Maximally and durably suppress viral load
 Prevent vertical HIV transmission

ART Drug Classes and Mechanisms
of Action: NRTIs
 Nucleoside Reverse Transcriptase Inhibitors
(NRTIs)
(Reverse transcriptase changes viral RNA to DNA)
– Block RT before HIV genetic code combines
with infected cell’s genetic code
– Mimic building blocks used by RT to copy HIV
genetic material, so disrupt copying of HIV
genetic code

of Action: NNRTIs
 Nonnucleoside Reverse Transcriptase
Inhibitors (NNRTIs)
–Block RT before HIV genetic code
combines with infected cell’s genetic
code
–Physically prevent RT from
working

of Action: PIs
 Protease Inhibitors (PIs)
–Block protease enzyme that cuts long
protein strands into small functional
proteins and enzymes needed to
assemble mature virus
–Prevent maturation of new viral
particles

of Action: FIs (Entry Inhibitors)
 Fusion Inhibitors (FIs)
–Block fusion of HIV with cell
membrane preventing HIV ‘s ability to
infect cells

of Action: CCR5 Antagonists
 CCR5 Antagonists
– Bind to and block the CCR5 co-receptor of
the immune cell, thereby preventing HIV
from entering and infecting the cell

of Action: Integrase Inhibitors
 Integrase inhibitors
–Prevent integration of HIV DNA into
the nucleus of infected cells

ART Drugs in Clinical Trials: Classes and
Mechanisms of Action (1)
 Gene therapies- block HIV genes
 Maturation inhibitors- inhibit development of
HIV’s internal structures in new virions
 Zinc finger inhibitors- break apart structures
holding HIV inner core together

ART Drugs in Clinical Trials: Classes and
Mechanisms of Action (2)
Antisense drugs- mirror HIV genetic code,
lock onto virus and block replication

Factors to Consider in Selecting Initial
ART Regimen (1)
 Comorbidity
 Patient adherence potential
 Convenience (e.g., pill burden, dosing
frequency, and food and fluid
considerations)
 Potential adverse drug effects and drug
interactions with other medications

Factors to Consider in Selecting Initial
ART Regimen (2)
 Pregnancy potential
 Results of genotypic drug resistance testing
 Gender and pretreatment CD4 T-cell count if
considering nevirapine
 HLA B*5701 testing if considering
abacavir

Regimen Simplification (1)
 Regimen simplification is a change in
established effective therapy to
– reduce pill burden and dosing frequency,
– enhance tolerability, or
– decrease specific food and fluid
requirements
Panel on Clinical Practices for Treatment of HIV Infection. (2008).

 Rationales behind regimen
simplification are
– to improve the patient’s quality of life
– improve medication adherence
– avoid long-term toxicities
– reduce the risk of virologic failure

Potential candidates for regimen simplification:
1) are receiving treatments that are no longer
preferred or alternative choices for initial therapy
2) were prescribed a regimen in the setting of
treatment failure at a time when there was an
incomplete understanding of resistance or drug-
drug interaction data, or
3) were prescribed a regimen prior to availability of
newer options that might be easier to administer
and/or more tolerable.

Indications for Initiation of ART (1)
 All patients with a history of an AIDS-
defining illness or with a CD4 count <350
CD4+ T cells/mm3
 data supporting this recommendation are
stronger for those with a CD4 T-cell count
<200 cells/mm3 and with a history of AIDS
than for those with CD4 T-cell counts between
200 and 350 cells/mm3

 Regardless of CD4 count, ART should be
initiated in
– Pregnant women
– Patients with HIV-associated nephropathy
– Patients co-infected with Hepatitis B when HBV
treatment is indicated (treat with fully
suppressive drugs active against both HIV and
HBV)

 In patients with CD4 count >350 cells/mm3
who do not meet any of the specific
conditions listed previously
 Optimal time to initiate therapy is not well
defined
 Patient scenarios and comorbidities should
be considered

Benefits of Early ART (1)
 Maintain higher CD4 and prevent potential
irreversible damage to the immune system
 Decrease risk for HIV-associated
complications (Tb, non-Hodgkin’s
lymphoma,KS, peripheral neuropathy, HPV-
associated malignancies, and HIV-
associated cognitive impairment)

Benefits of Early ART (2)
 Decrease risk of non-opportunistic
conditions (CVD, renal disease, liver
disease, and non–AIDS-associated
malignancies and infections)
 Decrease risk of transmission to others

Risks of Early ART (1)
 Development of treatment-related side
effects/toxicities
 Development of drug resistance
 Less time to learn about HIV and its
treatment and less time to prepare for
adherence

Risks of Early ART (2)
 Increased total time on medication, with
greater chance of treatment fatigue
 Premature use of ART before development
of more effective, less toxic, better studied
combinations
 Transmission of drug-resistant virus

 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
Panel on Clinical Practices for Treatment of HIV Infection. (2008)
DHHS Categories for Initial ART


Current Antiretroviral Medications
NRTI
Abacavir
Didanosine
Emtricitabine
Lamivudine
Stavudine
Tenofovir
Zidovudine
NNRTI
Delavirdine
Efavirenz
Etravirine
Nevirapine
PI
•Atazanavir
Darunavir
Fosamprenavir
Indinavir
Lopinavir
Nelfinavir
Ritonavir
Saquinavir
Tipranavir
Fusion Inhibitor
 Enfuvirtide
CCR5 Antagonist
 Maraviroc
Integrase Inhibitor
 Raltegravir
Fixed-dose Combinations
•Zidovudine/ lamivudine
•Zidovudine/lamivudine/abacavir
•Abacavir/lamivudine
•Emtricitabine/tenofovir
•Efavirenz/emtricitabine
/tenofovir

Initial ART
 The most extensively studied combination
antiretroviral regimens for treatment-naïve
patients generally consist of:
– two NRTIs plus one NNRTI, or
– two NRTIs plus a PI (with or without ritonavir
boosting).


Initial ART: Preferred
**Avoid Efavirenz in pregnant women and women with significant pregnancy
potential
1 Emtricitabine can be used in place of lamivudine and vice versa
2 Tenofovir + emtricitabine or lamivudine is preferred in patients with
HIV/HBV co-infection
Efavirenz*
OR
PI-based (ritonavir-boosted)
Tenofovir +
emtricitabine1,2
(coformulated)
+
NRTIs
NNRTI-based
Atazanavir + ritonavir qd
Darunavir + ritonavir qd
Fosamprenavir + ritonavir bid
Lopinavir/ritonavir (coform) qd or bid
Tenofovir +
emtricitabine1,2
(coformulated)
+
NRTIs


Initial ART: Alternative
Nevirapine should not be initiated in women with CD4 counts >250 or men with
CD4 counts >400
¹ Atazanavir must be boosted with ritonavir if used with tenofovir
Nevirapine*
Atazanavir¹ (unboosted) qd
Fosamprenavir (unboosted) bid
Fosamprenavir + ritonavir qd
Saquinavir + ritonavir
PI-based
NNRTI-based
+ Alternative Dual
NRTIs (see
next slide)
+ Alternative Dual
NRTIs (see
next slide)

Initial ART: Alternative Dual NRTIs
NRTIs:
abacavir/lamivudine (coformulated) (for patients
who have tested negative for HLA-B*5701
didanosine + (lamivudine or emtricitabine*)
zidovudine/lamivudine* (coformulated)
* emtricitabine may be used in place of lamivudine or
vice versa

NNRTI Class Advantages
 Save PI options for future use
 Long half-lives
 Less metabolic toxicity
(hyperlipidemia, insulin resistance)
than with some PIs

NNRTI Class Disadvantages
 Low genetic barrier to resistance (single
mutation confers resistance): greater risk
for resistance with failure or treatment
interruption
 Cross resistance among approved NNRTIs
 Skin rash
 Potential for CYP450 drug interactions
 Transmitted resistance to NNRTIs more
common than resistance to PIs

PI Class Advantages
 Save NNRTI for future use
 Higher genetic barrier to resistance
 PI resistance uncommon with failure
(boosted PIs)

PI Class Disadvantages
 Metabolic complications
 Gastrointestinal side effects
 Liver toxicity
 CYP3A4 inhibitors & substrates: potential
for drug interactions
 PR interval prolongation
 Absorption depends on food and low gastric
pH

Dual NRTIs Advantages and
Disadvantages
 Advantages
– Established backbone of combination
therapy
– Minimal drug interactions
 Disadvantages
– Lactic acidosis and hepatic steatosis
(especially with stavudine, didanosine,
zidovudine )

Adverse Effects: Fusion
Inhibitor
 Enfuvirtide
– Injection-site reactions (subcutaneous
injection)
– Hypersensitivity reaction
– Increased risk of bacterial pneumonia in
clinical trials

Adverse Effects: CCR5 Antagonist
 Maraviroc
– Abdominal pain
– Upper respiratory tract infections
– Cough
– Hepatotoxicity
– Musculoskeletal symptoms
– Rash

Adverse Effects: Integrase Inhibitor
 Raltegravir
– Nausea
– Headache
– Diarrhea
– CPK elevation

Adult/ Adolescent Recommendations
Panel on Antiretroviral Guidelines for Adults
and Adolescents. Guidelines for the use of
antiretroviral agents in HIV-1-infected adults
and adolescents. Department of Health and
Human Services. November 3, 2008; 1-139.
Available at
http://www.aidsinfo.nih.gov/ContentFiles/Adultand
AdolescentGL.pdf.

Perinatal Recommendations
 Public Health Service Task Force
Recommendations for Use of Antiretroviral
Drugs in Pregnant HIV-Infected Women for
Maternal Health and Interventions to Reduce
Perinatal HIV Transmission in the United
States - July 8, 2008.
Available at:
http://aidsinfo.nih.gov/contentfiles/PerinatalGL.pdf

Evaluation Prior to ART Initiation
The following should be assessed:
 CD4 cell count
 HIV RNA
 Drug Resistance Testing
 Co-receptor Tropism
 HLA-B*5701 Screening (if ABC being
considered)

CD4 T Cell Count (1)
 T-4 cells, CD4+ lymphocytes, helper cells
 Lymphocytes with CD4 protein molecules
on cell surface
 Cells most often infected by HIV
 Indicator of degree of immune compromise

CD4 T Cell Count (2)
 Normal range 500-1600 cells/mm3
 AIDS case definition = CD4 <200 cells/mm3
 With adequate viral suppression
– Accelerated CD4 response first 3 months of
treatment
– Average CD4 increase 100-150 cells/mm3 per
year

When to Evaluate CD4 T Cell Count
 When patient first tests HIV positive (check
CD4 count twice at baseline)
 Every 3-6 months to
– Determine when to initiate ART
– Assess immune response to ART
– Assess need to initiate chemoprophylaxis for
opportunistic infections

CD4 T Cell Percentage (1)
 The percentage of total lymphocytes
comprised of CD4 cells
 More stable than CD4 count
 Normal range is 20% to 40%
 CD4 percentage <14% is an indicator of
AIDS

CD4 T Cell Percentage (2)
 CD4 count may be influenced by factors
that may affect total WBC and lymphocyte
percentages. In the following cases, CD4
percentage may be a more appropriate
indicator of immune function:
– Use of bone marrow–suppressive medications
or the presence of acute infections
– Splenectomy or coinfection with HTLV-1 may
cause misleadingly elevated absolute CD4
counts.
– Alpha-interferon may reduce CD4 count without
changing the CD4 percentage.

Plasma Viral Load (PVL) (1)
 Most important indicator of response to
therapy
 PVL testing can detect HIV RNA a few days
after infection
 3 types of FDA approved tests for PVL
– Polymerase Chain Reaction (PCR)
– Branched DNA (bDNA)
– Nucleic acid sequence based amplification
(NASBA)

Plasma Viral Load (PVL) (2)
 Significant change in PVL is a 3-fold
increase or decrease
 Changes are expressed as “log” changes;
change of 0.5 log10 copies/ml is meaningful
 “Undetectable” PVL refers to PVL below
limits of assay detection
 “Undetectable” PVL should be achieved
within 16-24 weeks of ART initiation or
change

When to Evaluate PVL (1)
 In presence of symptoms consistent with
acute HIV infection
 To establish diagnosis when HIV antibody
test is negative or indeterminate
– Should be confirmed by ELISA and Western Blot
performed 2-4 months after initial negative or
indeterminate test

 For baseline evaluation of newly diagnosed
HIV infection, use in conjunction with CD4
count to determine whether to initiate or
defer therapy.
 For patients not on ART, every 3-4 months
to assess PVL changes, use in conjunction
with CD4 count to determine whether to
initiate ART.

 After initiation or change in ART, within 2-8
weeks for initial assessment of ART efficacy
 Then every 4-8 weeks until undetectable
 During stable therapy, every 3-4 months
– to assess virologic effect of therapy
– To decide whether to continue or change
therapy
– Goal of ART- PVL undetectable

 In the case of a clinical event or a significant
decline in CD4 T cells
– to determine association with a changing or
stable PVL
– To decide whether to continue, initiate or
change therapy

Resistance Testing
 Testing recommended for all at entry to care
whether ART is initiated or deferred
 Assists in selecting active drugs in initial regimen
and when changing ART regimens in cases of
virologic failure
 Recommended for all pregnant women prior to
initiating ART and for those entering pregnancy
with detectable viral load while on ART
 Recommended when managing suboptimal
viral load reduction

Co-receptor Tropism Assay
 Should be performed when CCR5 antagonist
is being considered
 Consider in patients with virologic failure on
a CCR5 antagonist

HLA-B*5701 Screening
 Recommended before starting abacavir, to reduce
risk of hypersensitivity reaction (HSR)
 Positive status should be recorded as an abacavir
allergy
 If HLA-B*5701 testing is not available, abacavir
may be initiated, after counseling and with
appropriate monitoring for HSR

Labwork Do’s and Don’ts
 To minimize variability in results
– Draw blood for CD4 counts at same time of day
(AM or PM)
– Use same laboratory for testing
– Over time, same type of test should be done
– Defer testing 2-4 weeks after acute illness or
vaccination
– Because of variability, base treatment decisions
to initiate or change ART on 2 or more similar
values on CD4 counts and viral load

Key Points (1)
1. HIV prevalence varies by race and region.
2. Goals of ART:
– Reduce HIV-related morbidity and prolong
survival
– Improve quality of life
– Restore and/or preserve immune function
– Maximally and durably suppress viral load
– Prevent vertical HIV transmission

Key Points (2)
3. Current ARV mechanisms of action:
– Block reverse transcriptase to disrupt copying
of HIV genetic code (NRTIs; NNRTIs)
– Block protease enzyme, preventing maturation
of new virions (PIs)
– Prevent fusion of HIV with cell membranes
(Fusion inhibitors)
– Block CCR5 co-receptor (CCR5 antagonists)
– Prevent integration of HIV DNA into the nucleus
of infected cells (integrase inhibitors)

Key Points (3)
4. The following should be assessed
prior to initiation of therapy
 CD4 cell count
 HIV RNA
 Drug Resistance Testing
 Coreceptor Tropism Assays
 HLA-B*5701 Screening (if ABC being
considered; Abacavir is not a preferred
option for initial therapy

Key Points (4)
5. Considerations in Initiation of ART
– Comorbidity
– Adherence potential
– Convenience
– Potential adverse drug effects/drug
interactions

Key Points (5)
5. Considerations in Initiation of ART (cont.)
– Pregnancy potential
– Genotypic drug resistance
– Gender and pretreatment CD4 T-cell count
(nevirapine)
– HLA B*5701 testing (abacavir)

nynj-nurse-mod1-09.ppt

Recommended

Recommended

More Related Content

Similar to nynj-nurse-mod1-09.ppt

Similar to nynj-nurse-mod1-09.ppt (20)

Recently uploaded

Recently uploaded (20)

nynj-nurse-mod1-09.ppt