Human Immunodeficiency Virus Human Immunodeficiency Virus and Antiretroviral Therapy 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 June 2008
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Human Immunodeficiency Virus and Antiretroviral Therapy Lucille Sanzero Eller, PhD, RN Associate Professor Rutgers, The State University of New Jersey.
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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 AETCJune 2008
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.
10 States or Dependent Areas Reporting Highest 10 States or Dependent Areas Reporting Highest Number of AIDS cases: 2005 (CDC, 2007)Number of AIDS cases: 2005 (CDC, 2007)
State/Dependent Area # AIDS Cases1. New York 6,2992. Florida 4,9603. California 4,0884. Texas 3,1135. Georgia 2,3336. Illinois 1,9227. Maryland 1,5958. Pennsylvania 1,5109. New Jersey 1,27810. Puerto Rico 1,033
Cumulative AIDS cases: 2005 Cumulative AIDS cases: 2005 (CDC, 2007)(CDC, 2007)
Area Adults/ Children Total
______________ Adolescents <13 years____
1. New York 170,035 2,342 172,377
2. California 138,361 658 139,019
3. Florida 99,290 1,519 100,809
4. Texas 66,836 391 67,227
5. New Jersey 47,659 772 48,431
6. Illinois 32,314 281 32,595
7. Pennsylvania 31,619 358 31,977
8. Georgia 30,179 226 30,405
9. Maryland 28,804 312 29,116
10. Puerto Rico 28,693 399 29,092
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 CCR5 or CXCR4 co-receptor)
– Viral membrane fuses with cell membrane
– Viral contents released into cell
HIV Replication Cycle (2)HIV Replication Cycle (2)
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
HIV Replication Cycle (3)HIV Replication Cycle (3)
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
HIV Replication Cycle (4)HIV Replication Cycle (4)
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
Sites of Action of ARVsSites of Action of ARVs
1. NRTIs: Incorporate into DNA and block reverse transcriptase
2. NNRTIs: Bind to reverse transcriptase
3. PIs: Bind to protease to inhibit viral protein cleavage
4. Fusion Inhibitors: Interact with virus to inhibit virus-cell fusion Feinberg & Maenza (2005).
–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)
Attachment and fusion inhibitors- block CD4, CXCR4 receptors, preventing attachment and fusion
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
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
Panel on Clinical Practices for Treatment of HIV Infection. (2008).
Indications for Initiation of ART Indications for Initiation of ART (2)(2)
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)
Panel on Clinical Practices for Treatment of HIV Infection. (2008).
Indications for Initiation of ART Indications for Initiation of ART (3)(3)
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
Panel on Clinical Practices for Treatment of HIV Infection. (2008).
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)
Panel on Clinical Practices for Treatment of HIV Infection. (2008).
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
Panel on Clinical Practices for Treatment of HIV Infection. (2008).
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
Panel on Clinical Practices for Treatment of HIV Infection. (2008).
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
Panel on Clinical Practices for Treatment of HIV Infection. (2008).
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
* * 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 For patients who have tested negative for HLA-B*5701² For patients who have tested negative for HLA-B*5701³ Tenofovir + emtricitabine or lamivudine is preferred in patients with ³ Tenofovir + emtricitabine or lamivudine is preferred in patients with HIV/HBV co-infectionHIV/HBV co-infection
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 tenofovir² May be insufficient if HIV RNA >100,000 copies/mL² May be insufficient if HIV RNA >100,000 copies/mL
Panel on Antiretroviral Guidelines for Adult and Adolescents.
Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. January 29, 2008; 1-128.
Available at http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf
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 - November 2, 2007.