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Initiating Antiretroviral Therapy in HIV-Infected Patients

Initiating Antiretroviral Therapy in HIV-Infected Patients. Yumi Lee, PharmD , BCPS NYSCHP- Royal Counties September 14, 2011. Objectives. Identify the CD4 cell parameters where initiation of therapy is appropriate Recognize the advantages and disadvantages of early versus deferred therapy

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Initiating Antiretroviral Therapy in HIV-Infected Patients

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  1. Initiating Antiretroviral Therapy in HIV-Infected Patients Yumi Lee, PharmD, BCPS NYSCHP- Royal Counties September 14, 2011

  2. Objectives Identify the CD4 cell parameters where initiation of therapy is appropriate Recognize the advantages and disadvantages of early versus deferred therapy Identify the preferred regimens as per treatment guidelines Understand the benefits and detriments of recommended treatment regimens

  3. History of HIV • 1981- Beginning of HIV/AIDS epidemic • Outbreak of rare cancer and pneumonia in homosexuals (Kaposi’s sarcoma and PCP) • Blood sample of African man who died of mysterious illness in 1959 later confirmed to be HIV • 1984- Patient “zero” • Canadian flight attendant died of AIDS • 8,000 confirmed cases in US and 3,700 deaths • 1987- Treatment arrives • FDA approved Zidovudine (Retrovir®) • 100,000 – 150,000 cases of HIV and AIDS

  4. History of HIV (cont’d…) • 1992- Combination therapy arrives • Addition of Zalcitabine (Hivid®) marks beginning of combination therapy • 1996- Protease inhibitors arrive • Triple therapy introduced • 2000’s- More antiretrovirals released • 4.9 million people newly infected in 2005 • 40.3 million people worldwide living with HIV/AIDS • 2006- Origins of HIV discovered • Simian form of HIV (SIV) entered humans by monkey bites or ingesting monkey meat and brains

  5. HIV Life Cycle Binding and fusion Reverse transcription Integration Transcription Assembly Budding

  6. Clinical Progression of HIV Relationship of CD4 and viral load

  7. Goals of Antiretroviral Therapy (ART) Durable suppression of HIV viral load Restoration of immune function Prevention of HIV transmission Prevention of drug resistance Improvement in quality of life

  8. Initiation of Antiretroviral Therapy: What is the recommended CD4 threshold?

  9. DHHS 2009: When to Start? DHHS: US Department of Health and Human Services *Panel divided: 55% strongly recommend and 45% moderately recommend ◊50% favor initiating therapy at this stage; 50% view initiating therapy at this stage at optional http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf.

  10. SMART Study • Immediate arm: ART immediately after randomization • Deferred arm: CD4 250 and 350 as on and off switch • Primary endpoints • Opportunistic infection (OI) or death from any cause • Fatal or nonfatal OI • Serious non-AIDS events • Fatal and non-fatal OI plus serious non-AIDS events Emery S, et al. J Infect Dis. 2008;197:1133-1144.

  11. SMART: Subgroup Analysis *Fatal and nonfatal OI plus serious non-AIDS events. (OI= opportunistic infection) Subgroup analysis investigated optimal threshold for initiating ART (n= 477) Immediate group experienced substantially fewer events compared with deferred group Emery S, et al. J Infect Dis. 2008;197:1133-1144.

  12. NA-ACCORD Study • Established in 2006, examining 22 HIV research cohorts (n=17,517) • Two analyses comparing • Initiation of ART in CD4 >350 – 500 vs. CD4 ≤350 (n=8,362) • Initiation of ART in CD4 >500 vs. CD4 ≤500 (n=9,155) • Adjusted for lead-time bias allowed ART to be initiated within 1.5 yrs after baseline CD4 • Primary outcome: All cause mortality • *Cohort study not randomized trial* Kitahata MM, et al. N Engl J Med. 2009;360:1815-1826.

  13. NA-ACCORD Study www.clinicaloptions.com/HIV Kitahata MM, et al. N Engl J Med. 2009;360:1815-1826.

  14. ART Cohort Collaboration www.clinicaloptions.com/HIV Analysis of 15 cohorts from US and Europe (n=24,444) The Lancet 2009;373:1352-1363. www.clinicaloptions.com/HIV

  15. Panel Split: CD4 >500 cells/mm3 DHHS. Available at: http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf.

  16. START : Enrolling Patients • Randomize trial underway • Follow up period for 4 – 5 years • Study endpoints: Fatal AIDS or non-fatal serious AIDS events (cardiovascular, liver, renal, and cancer), and all-cause mortality ClinicalTrials.gov. NCT00867048.

  17. Initiation of Antiretroviral Therapy: What are the preferred ART regimens?

  18. Antiretroviral Agents

  19. Antiretroviral Agents

  20. DHHS: Preferred Regimens *Should not be used in first trimester of pregnancy or women in child-bearing age ◊ Should not be used in patients who require >20mg omeprazole equivalent per day US Department of Health and Human Services guidelines. 2009.

  21. Efavirenz-Based Regimen Why? Why not? • Long track record • Unbeaten clinical trial • Convenience • Forgiving missed doses • CNS adverse events • Teratogenic in 1st trimester • Low genetic barrier to resistance • Lower CD4 increase than other drug classes

  22. Boosted PI-Based Regimen Why? Why not? • Long track record • Greater CD4 increase vs. Efavirenz • Boosted Atazanavir as good as Efavirenz with less resistance risk at failure • Preferred in pregnancy • GI adverse effects • Greater pill burden • Lipid elevation • Lipohypertrophy • Increased tenofovir renal toxicity?

  23. Raltegravir-Based Regimen Why? Why not? • Very well tolerated • As effective as EFV with better tolerability • No lipid effects • Not known to be teratogenic • Rapid virologic suppression • Greater CD4 increase vs EFV • No long-term data • Twice daily dosing • Resistance risk at virologic failure similar to EFV

  24. DHHS: Alternative Regimens *Should not be used in females with CD4 >250 and males with CD4 >400 ◊Associated with increased MI risk ~LPV/r + ZDV/3TC recommended in pregnancy US Department of Health and Human Services guidelines. 2009.

  25. DHHS: Others Regimens *CCR5 tropism assay necessary US Department of Health and Human Services guidelines. 2009.

  26. Initiation of Antiretroviral Therapy: What standard tests should be preformed?

  27. Patient Evaluation

  28. Viral Resistance Test Resistance testing recommended for all antiretroviral-naive patients, regardless of infection duration *Test source patient especially if treated with antiretroviral drugs. 1.)DHHS guidelines. January 12, 2009. 2) Hirsch MS, et al. Clin Infect Dis. 2008;47:266-285. 3) EACS Guidelines Version 3.

  29. Genotype vs. Phenotype

  30. Initiation of Antiretroviral Therapy: Patient Case

  31. HIV Screening MS is a 33-yr-old woman visiting you, her new primary care physician. As you take her medical history, she mentions that she had an abnormal Pap smear a few yrs ago. You ask her if she has ever been tested for HIV. She says no and also says that she is confident that she has not acquired HIV. Is there a basis for you to encourage her to be tested at this time? Yes, she is in a high-risk group Yes, all adults up to 64 yrs of age should be tested No, I do not think that she needs testing www.clinicaloptions.com/hiv

  32. HIV Screening Yes, all adults up to 64 yrs of age should be tested CDC recommends HIV screening for all patients: 13-64 years old unless local prevalence has been documented to be <0.1% Initiating TB treatment Seeking treatment for STDs www.clinicaloptions.com/hiv

  33. Patient Evaluation MS does test positive for HIV-1 infection. After informing the patient about her diagnosis, which tests related to HIV should be performed immediately, in addition to CD4+ count and HIV-1 RNA? Genotypic resistance testing Genotypic and phenotypic resistance testing Resistance testing and viral tropism testing Resistance testing and hepatitis B serology www.clinicaloptions.com/hiv

  34. Patient Evaluation MS does test positive for HIV-1 infection. After informing the patient about her diagnosis, which tests related to HIV should be performed immediately, in addition to CD4+ count and HIV-1 RNA? Genotypic resistance testing Genotypic and phenotypic resistance testing Resistance testing and viral tropism testing Resistance testing and hepatitis B serology www.clinicaloptions.com/hiv

  35. Additional Patient Information 33 yrs old Weight: 232 lbs Height: 5'6" BP: 145/90 mm Hg Fasting glucose: 126 mg/dL (6.99 mmol/L) Taking oral contraceptives, no other medications No baseline resistance on genotypic resistance test www.clinicaloptions.com/hiv

  36. Initiation of Therapy The patient has HIV-1 RNA of 7000 copies/mL and a CD4+ cell count of 495 cells/mm³. What would you recommend about starting antiretroviral therapy? Start therapy as soon as she has had time to adjust to her diagnosis Defer therapy until CD4+ cell count declines to < 350 cells/mm³ www.clinicaloptions.com/hiv

  37. Initiation of Therapy Start therapy as soon as she has had time to adjust to her diagnosis Conditions Favoring Delay of Therapy Significant barriers to adherence Presence of comorbidities that complicate or prohibit antiretroviral therapy (eg, scheduled surgery that might force treatment interruption) Elite controllers or long-term nonprogressors Delay of antiretroviral initiation suggested only for patients with higher CD4+ cell counts www.clinicaloptions.com/hiv

  38. Pre-Treatment Evaluation You have consulted with the patient and agree that she should start therapy. Would you obtain any additional testing at this time? Renal function tests Pregnancy test All of the above Something else www.clinicaloptions.com/hiv

  39. Pre-Treatment Evaluation You have consulted with the patient and agree that she should start therapy. Would you obtain any additional testing at this time? Renal function tests Pregnancy test All of the above Something else www.clinicaloptions.com/hiv

  40. Results of Tests UA: trace proteinuria CLCr 70 mg/mL/1.73 m² Pregnancy test negative www.clinicaloptions.com/hiv

  41. Initiating Therapy Which initial regimen would you choose? Efavirenz + tenofovir/emtricitabine Atazanavir/ritonavir + tenofovir/emtricitabine Darunavir/ritonavir + tenofovir/emtricitabine Raltegravir + tenofovir/emtricitabine www.clinicaloptions.com/hiv

  42. Initiating Therapy Which initial regimen would you choose? Efavirenz + tenofovir/emtricitabine Atazanavir/ritonavir + tenofovir/emtricitabine Darunavir/ritonavir + tenofovir/emtricitabine Raltegravir + tenofovir/emtricitabine www.clinicaloptions.com/hiv

  43. Initial Regimen Chosen Atazanavir/ritonavir + tenofovir/emtricitabine Patient tolerated this regimen well and viral suppression was maintained for 1.5 yrs However, renal function has declined slowly Current CrCl: 48 mg/mL www.clinicaloptions.com/hiv

  44. Modification of Initial Regimen Would you consider modifying her regimen? I would change her NRTIs I would continue her NRTIs and change the dosage I would stop NRTIs and proceed with atazanavir/ritonavir monotherapy I would change to a whole new regimen I would NOT change her regimen at this time www.clinicaloptions.com/hiv

  45. Modification of Initial Regimen Would you consider modifying her regimen? I would change her NRTIs I would continue her NRTIs and change the dosage I would stop NRTIs and proceed with atazanavir/ritonavir monotherapy I would change to a whole new regimen I would NOT change her regimen at this time www.clinicaloptions.com/hiv

  46. Useful Websites www.aidsinfo.nih.gov www.clinicaloptions.com www.aids-ed.org www.hivinsite.ucsf.edu www.depts.washington.edu/hivaids

  47. Thank you! Any questions?

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