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 September 2009

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.

3. 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

6. 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

7. HIV VIRION

8. 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

9. 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

10. 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

11. 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

12. 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

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

18. ART Drug Classes and Mechanisms 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

19. ART Drug Classes and Mechanisms of Action: Integrase Inhibitors 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) Antisense drugs- mirror HIV genetic code, lock onto virus and block replication

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. 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).

25. Regimen Simplification (2) 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 Panel on Clinical Practices for Treatment of HIV Infection. (2008).

26. Regimen Simplification (3) 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.

27. 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/mm 3  data supporting this recommendation are stronger for those with a CD4 T-cell count <200 cells/mm 3 and with a history of AIDS than for those with CD4 T-cell counts between 200 and 350 cells/mm 3 Panel on Clinical Practices for Treatment of HIV Infection. (2008).

28. 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).

29. Indications for Initiation of ART (3)  In patients with CD4 count >350 cells/mm 3 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).

30. 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).

31. 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).

32. 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).

33. 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).

34. 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

35. 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

36. 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).

37. 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 HIV/HBV co-infection Efavirenz* OR PI-based (ritonavir-boosted) Tenofovir + emtricitabine 1,2 (coformulated) + NRTIs NNRTI-based Atazanavir + ritonavir qd Darunavir + ritonavir qd Fosamprenavir + ritonavir bid Lopinavir/ritonavir (coform) qd or bid Atazanavir + ritonavir qd Darunavir + ritonavir qd Fosamprenavir + ritonavir bid Lopinavir/ritonavir (coform) qd or bid Tenofovir + emtricitabine 1,2 (coformulated) + NRTIs

38. 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* Atazanavir ¹ (unboosted) qd Fosamprenavir (unboosted) bid Fosamprenavir + ritonavir qd Saquinavir + ritonavir PI-based NNRTI-based + Alternative Dual NRTIs (see next slide)

39. Initial ART: Alternative Dual NRTIs NRTIs: for patients who have tested negative for HLA-B*5701 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

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

41. 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

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

43. 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

44. 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 )

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

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

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

48. 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.

49. 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

50. 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)

51. 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

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

53. 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

54. 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

55. 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.

56. 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)

57. 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

58. 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

59. 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.

60. When to Evaluate PVL (3) 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

61. 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

62. 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

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

64. 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

65. 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

66. 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

67. 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)

68. 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

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

70. 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)