human immunodeficiency virus and antiretroviral therapy

Human Immunodeficiency Virus and Human Immunodeficiency Virus and Antiretroviral TherapyAntiretroviral Therapy

Lucille Sanzero Eller, PhD, RNAssociate Professor

Rutgers, The State University of New Jersey College of Nursing

Local Performance Site of the NY/NJ AETC

September 2009

ObjectivesObjectives

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 Age of persons with HIV/AIDS diagnosed during 2007diagnosed 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 Transmission categories: adults/ adolescents

with HIV/AIDS diagnosed in 2007with 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 VIRIONHIV VIRION

HIV Replication Cycle (1)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)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 ARTPrimary 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 ART Drug Classes and Mechanisms of Action: NRTIsof 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

ART Drug Classes and Mechanisms ART Drug Classes and Mechanisms of Action: NNRTIsof 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

ART Drug Classes and Mechanisms ART Drug Classes and Mechanisms of Action: PIsof 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

ART Drug Classes and Mechanisms ART Drug Classes and Mechanisms of Action: FIs (Entry Inhibitors)of Action: FIs (Entry Inhibitors)

Fusion Inhibitors (FIs)

–Block fusion of HIV with cell membrane preventing HIV ‘s ability to infect cells

ART Drug Classes and Mechanisms ART Drug Classes and Mechanisms of Action: CCR5 Antagonistsof 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

ART Drug Classes and Mechanisms ART Drug Classes and Mechanisms of Action: Integrase Inhibitorsof Action: Integrase Inhibitors

Integrase inhibitors

–Prevent integration of HIV DNA into the nucleus of infected cells

ART Drugs in Clinical Trials: Classes ART Drugs in Clinical Trials: Classes and Mechanisms of Action (1)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 ART Drugs in Clinical Trials: Classes and Mechanisms of Action (2)and Mechanisms of Action (2)

Antisense drugs- mirror HIV genetic code, lock onto virus and block replication

Factors to Consider in Selecting Initial Factors to Consider in Selecting Initial ART Regimen (1)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 Factors to Consider in Selecting Initial ART Regimen (2)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 Regimen Simplification (1)(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 Indications for Initiation of ART (1)(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 Benefits of Early ART (1)(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 Benefits of Early ART (2)(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 Risks of Early ART (1)(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 Risks of Early ART (2)(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 ARTDHHS Categories for Initial ART

Current Antiretroviral MedicationsNRTIAbacavirDidanosine EmtricitabineLamivudineStavudineTenofovirZidovudine

NNRTIDelavirdineEfavirenzEtravirineNevirapine

PI•AtazanavirDarunavirFosamprenavirIndinavirLopinavirNelfinavirRitonavirSaquinavir 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 ARTInitial 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 Avoid Efavirenz in pregnant women and women with significant pregnancy potentialpotential

1 Emtricitabine can be used in place of lamivudine and vice versa1 Emtricitabine can be used in place of lamivudine and vice versa2 Tenofovir + emtricitabine or lamivudine is preferred in patients with 2 Tenofovir + emtricitabine or lamivudine is preferred in patients with HIV/HBV co-infectionHIV/HBV co-infection

Efavirenz*

ORPI-based (ritonavir-boosted)

Tenofovir + emtricitabine1,2 (coformulated)

+

NRTIsNNRTI-based

Atazanavir + ritonavir qdAtazanavir + ritonavir qd Darunavir + ritonavir qd Darunavir + ritonavir qd Fosamprenavir + ritonavir bid Fosamprenavir + ritonavir bid Lopinavir/ritonavir (coform) qd or bid Lopinavir/ritonavir (coform) qd or bid

Tenofovir + emtricitabine1,2 (coformulated)

+

NRTIs

Initial ART: AlternativeInitial ART: Alternative

Nevirapine should not be initiated in women with CD4 counts >250 or men with Nevirapine should not be initiated in women with CD4 counts >250 or men with CD4 counts >400 CD4 counts >400 ¹ Atazanavir must be boosted with ritonavir if used with tenofovir¹ Atazanavir must be boosted with ritonavir if used with tenofovir

Nevirapine*

Atazanavir¹ (unboosted) qdFosamprenavir (unboosted) bidFosamprenavir + ritonavir qdSaquinavir + 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 for patients

who have tested negative for HLA-B*5701who 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 AdvantagesNNRTI Class Advantages

Save PI options for future use Long half-lives Less metabolic toxicity

(hyperlipidemia, insulin resistance) than with some PIs

NNRTI Class DisadvantagesNNRTI 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 AdvantagesPI Class Advantages

Save NNRTI for future use Higher genetic barrier to resistance PI resistance uncommon with failure

(boosted PIs)

PI Class DisadvantagesPI 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 Dual NRTIs Advantages and DisadvantagesDisadvantages

Advantages– Established backbone of combination

therapy– Minimal drug interactions

Disadvantages– Lactic acidosis and hepatic steatosis

(especially with stavudine, didanosine, zidovudine )

Adverse Effects: Fusion Adverse Effects: Fusion InhibitorInhibitor

Enfuvirtide – Injection-site reactions (subcutaneous

injection)– Hypersensitivity reaction– Increased risk of bacterial pneumonia in

clinical trials

Adverse Effects: CCR5 AntagonistAdverse Effects: CCR5 Antagonist

Maraviroc – Abdominal pain– Upper respiratory tract infections– Cough– Hepatotoxicity– Musculoskeletal symptoms– Rash

Adverse Effects: Integrase InhibitorAdverse Effects: Integrase Inhibitor

Raltegravir – Nausea– Headache– Diarrhea– CPK elevation

Adult/ Adolescent RecommendationsAdult/ 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/AdultandAdolescentGL.pdf.

Perinatal RecommendationsPerinatal 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 InitiationEvaluation 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 CD4 T Cell Count (1)(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 CD4 T Cell Count (2)(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 CountWhen 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 CD4 T Cell Percentage (1)(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 CD4 T Cell Percentage (2)(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) Plasma Viral Load (PVL) (1)(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) Plasma Viral Load (PVL) (2)(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 When to Evaluate PVL (1)(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 TestingResistance 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 AssayCo-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 ScreeningHLA-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’tsLabwork 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 PointsKey Points (1) (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 PointsKey Points (2) (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 Key Points (3)(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


5. Considerations in Initiation of ART

– Comorbidity – Adherence potential– Convenience– Potential adverse drug effects/drug

interactions


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)

human immunodeficiency virus and antiretroviral therapy

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