Human Immunodeficiency Virus and Antiretroviral Therapy

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/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).

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/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).

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. 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)

35. Current Antiretroviral Medications

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 NRTIs NNRTI-based Tenofovir + emtricitabine1,2(coformulated) + OR PI-based (ritonavir-boosted) NRTIs Atazanavir + ritonavir qd Darunavir + ritonavir qd Fosamprenavir + ritonavir bid Lopinavir/ritonavir (coform) qd or bid Tenofovir + emtricitabine1,2(coformulated) + **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

38. Initial ART: Alternative NNRTI-based + Alternative Dual NRTIs (see next slide) PI-based + Alternative Dual NRTIs (see next slide) 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

39. 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

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 athttp://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.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)