1. 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
June 2008

2. 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.

4. 10 States or Dependent Areas Reporting Highest Number of AIDS cases: 2005 (CDC, 2007)
State/Dependent Area # AIDS Cases
1. New York 6,299
2. Florida 4,960
3. California 4,088
4. Texas 3,113
5. Georgia 2,333
6. Illinois 1,922
7. Maryland 1,595
8. Pennsylvania 1,510
9. New Jersey 1,278
10. Puerto Rico 1,033

5. Cumulative AIDS cases: 2005 (CDC, 2007)
Area Adults/ Children Total
______________ Adolescents <13 years ____
1. New York 170,035 2, ,377
2. California 138, ,019
3. Florida 99,290 1, ,809
4. Texas 66, ,227
5. New Jersey 47, ,431
6. Illinois 32, ,595
7. Pennsylvania 31, ,977
8. Georgia 30, ,405
9. Maryland 28, ,116
10. Puerto Rico 28, ,092

6. HIV Virion

7. 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

8. 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

9. 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

10. 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

11. Sites of Action of ARVs
NRTIs: Incorporate into DNA and block reverse transcriptase
NNRTIs: Bind to reverse transcriptase
PIs: Bind to protease to inhibit viral protein cleavage
Fusion Inhibitors: Interact with virus to inhibit virus-cell fusion Feinberg & Maenza (2005).
CCR5 antagonist: bind to CCR5 co-receptor

12. Antiretroviral Therapy (ART)
ART- use of antiretroviral drugs to treat HIV disease
Highly Active Antiretroviral Therapy (HAART)-regimens combining several antiretroviral drugs

13. 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

14. 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

15. ART Drug Classes and Mechanisms 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

16. ART Drug Classes and Mechanisms 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

17. ART Drug Classes and Mechanisms of Action: FIs (Entry Inhibitors)
Fusion Inhibitors (FIs)
Block fusion of HIV with cell membrane preventing HIV ‘s ability to infect cells
COULD SAY THAT THERE ARE 2 TYPES OF ENTRY INHIBITORS: FUSION INHIBITORS & CCR5 ANTAGONISTS

18. ART Drug Classes and Mechanisms of Action: CCR5 Antagonists
Bind to and block the CCR5 co-receptor of the immune cell, thereby preventing HIV from entering and infecting the cell

19. ART Drug Classes and Mechanisms of Action: Integrase Inhibitors
Prevent integration of HIV DNA into the nucleus of infected cells

20. 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

21. ART Drugs in Clinical Trials: Classes 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
IF THE IDEA IS TO FOCUS ONLY ON NOVEL CLASSES, WOULD DELETE CCR5 FROM THIS LIST.

22. 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

23. 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

24. 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
Panel on Clinical Practices for Treatment of HIV Infection. (2008).

25. Indications for Initiation of ART (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).

26. Indications for Initiation of ART (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).

27. 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)
Panel on Clinical Practices for Treatment of HIV Infection. (2008).

28. 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
Panel on Clinical Practices for Treatment of HIV Infection. (2008).

29. 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
Panel on Clinical Practices for Treatment of HIV Infection. (2008).

30. 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
Panel on Clinical Practices for Treatment of HIV Infection. (2008).

31. DHHS Categories for Initial ART
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)

32. 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

33. Initial ART: Preferred
NNRTI-based
NRTI Options¹
Efavirenz*
Abacavir + lamivudine²
Tenofovir + emtricitabine³ OR +
PI-based (ritonavir-boosted)
Atazanavir + ritonavir
Fosamprenavir + ritonavir (BID)
Lopinavir/ritonavir (BID)
* Avoid Efavirenz 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-B*5701
³ Tenofovir + emtricitabine or lamivudine is preferred in patients with
HIV/HBV co-infection

34. Initial ART: Alternative
NNRTI-based
Nevirapine*
PI-based
+ Alternative Dual NRTIs (see next slide)
Atazanavir¹
Fosamprenavir
Fosamprenavir + ritonavir (1x/day)
Lopinavir/ritonavir (1x/day)²
Saquinavir + ritonavir
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
² May be insufficient if HIV RNA >100,000 copies/mL

35. Initial ART: Alternative Dual NRTIs
(in order of preference):
zidovudine/lamivudine* (coformulated)
didanosine + (lamivudine or emtricitabine*)
* Emtricitabine may be used in place of lamivudine or vice versa

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

37. 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

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

39. 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

40. Dual NRTIs Advantages and Disadvantages
Established backbone of combination therapy
Minimal drug interactions
Disadvantages
Lactic acidosis and hepatic steatosis (especially with d4T, ddI, ZDV )

41. Adverse Effects: Fusion Inhibitor
Enfuvirtide
Injection-site reactions
Hypersensitivity reaction
Increased risk of bacterial pneumonia in clinical trials
CONSIDER ADDING: “…IN CLINICAL TRIALS” AFTER “BACTERIAL PNEUMONIA”

42. Adverse Effects: CCR5 Antagonist
Maraviroc
Abdominal pain
Upper respiratory tract infections
Cough
Hepatotoxicity
Musculoskeletal symptoms
Rash
THE ORTHOSTATIC HYPOTENSION WAS APPARENTLY ONLY AT HIGH DOSES (IE NOT DOSES USED IN PRACTICE)

43. Adverse Effects: Integrase Inhibitor
Raltegravir
Nausea
Headache
Diarrhea
CPK elevation

44. Adult/ Adolescent Recommendations
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;
Available at

45. 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 - November 2, 2007.
Available at:

46. 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)

47. 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

48. 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 cells/mm3 per year

49. 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

50. CD4 T Cell Percentage
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

51. Plasma Viral Load (PVL) (1)
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)

52. 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 weeks of ART initiation or change

53. 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

54. When to Evaluate PVL (2)
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.

55. When to Evaluate PVL (3)
After initiation or change in ART, every 2-8 weeks
for initial assessment of ART efficacy
to decide whether to change therapy
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

56. When to Evaluate PVL (4)
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

57. 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
2ND BULLET: RESISTANCE TESTING ALSO ASSISTS WITH SELECTION OF INITIAL REGIMEN GIVEN ~14% PREVALENCE OF INFECTION WITH VIRUS RESISTANT TO 1 OR MORE DRUGS. MAYBE SOMETHING ALONG THESE LINES SHOULD BE A SUB-BULLET UNDER FIRST BULLET

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

59. 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

60. 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

61. 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

62. 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)

63. 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; ABC not used at this time for initial therapy)
TROPISM ASSAY: (IF MARAVIROC IS BEING CONSIDERED)—BUT REALLY SHOULDN’T BE CONSIDERING THIS DRUG AT THIS POINT FOR INITIAL THERAPY.

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

65. 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)