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HIV Updates

HIV Updates. Abdi Mohamed, Pharm.D Assistant Professor o Pharmacy Practice Husson University School of Pharmacy. Objectives. Review of the history and epidemiology of HIV/AIDS Diagnosis of HIV infection When to initiate therapy Overview of antiretroviral medications

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HIV Updates

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  1. HIV Updates Abdi Mohamed, Pharm.D Assistant Professor o Pharmacy Practice Husson University School of Pharmacy

  2. Objectives Review of the history and epidemiology of HIV/AIDS Diagnosis of HIV infection When to initiate therapy Overview of antiretroviral medications New DHHS adult and adolescent antiretroviral treatment guidelines. Importance of adherence

  3. What is HIV? • HIV is a lentivirus • HIV = Human Immunodeficiency Virus • It destroys CD4 cells (T-cells and macrophage) • AIDS = Acquired immunodeficiency Syndrome • CD4 count < 200/mm3 or • CD4 % < 14%

  4. History of HIV First cases of AIDS were identified in 1981 in Los Angeles, CA Believed to be a zoonosis (transmitted from animal) HIV is a descendant of a Simian Immunodeficiency Virus (SIV) SIVs bear a very close resemblance to HIV-1 and HIV-2 (two types of HIV). HIV-2 is similar to SIVsm, a strain of SIV found in the sooty mangabey (also known as the White-collared monkey), which is indigenous to western Africa. HIV-1, was recently discovered to relate to SIVcpz, the SIV strain found in chimpanzees Chen Z, Telfier P, Gettie A, Reed P, Zhang L, Ho DD, Marx PA. J Virol. 1996 Jun;70(6):3617-27

  5. Etiology Barre-Sinoussi F, Chermann JC, et al. Science. 1983 May 20;220(4599):868-71. • HIV was identified as the etiologic agent of AIDS until 1983 • Two types • HIV-1 • HIV-2 • Both them cause similar condition • They differ in transmission and progression • HIV-1 more virulent and more easily transmissible

  6. Transmission

  7. Epidemiology • 2012 US HIV data • Annually HIV infection 60,000 • People living with HIV 1.62 million • HIV patients not in care ~55% • 1 in 5 (20%) are unaware of their infection • By race, blacks/African Americans face the most severe burden of HIV G.J. Stine. AIDS update 2012. McGraw Hill p152

  8. Progression of HIV 2-3 wks 2-3 wks 2-4 wks Viral transmission Viral transmission Acute retroviral syndrome Recovery + seroconversion Avg. 1.5yrs Death Avg. 8 yrs Asymptomatic chronic HIV inf Symptomatic HIV/AIDS 2007 The Hopkins HIV guide

  9. Diagnosis & Testing • HIV antibody testing is performed by using an enzyme-linked immunosorbent assay (ELISA) • If positive repeat the test • Use Western blot (WB) to confirm • Rapid immunoassy (e.gOraQuick) • Resistance test • genotype (detects mutations that confers HIV drug resistance) • Phenotype (culture based on viral replication assays in the absence or presence of drugs)

  10. Use of CD4 Cell Levels to Guide Therapy Decisions • CD4 count • The major indicator of immune function • Most recent CD4 count is best predictor ofdisease progression • A key factor in determining urgency of ART or need for OI prophylaxis • Important in determining response to ART • Adequate response: CD4 increase 50-150 cells/µL per year • CD4 monitoring • Check at baseline (x 2) and at least every 3-6 months* * May consider every 6-12 months in clinically stable patients on ART with sustained HIV RNA suppression and CD4 status well above threshold for opportunistic infection risk. www.aidsetc.org

  11. Use of HIV RNA Levels to Guide Therapy Decisions • HIV RNA • May influence decision to start ART and help determine frequency of CD4 monitoring • Critical in determining response to ART • Goal of ART: HIV RNA below limit of detection (ie, <20-75 copies/mL, depending on assay) • Commercially available assays do not detect HIV-2 www.aidsetc.org

  12. Other Test HLA-B*5701 Screening Recommended before starting any regiment containing abacavir, to reduce risk of hypersensitivity reaction (HSR) Positive patient should not receive ABC and ABC allergy should be recorded in file Coreceptor tropism assay Should be performed to detect whether HIV-1 isolates use CCR5 or CXR4 or both. Requires plasma HIV RNA ≥ 1000 copies/mL Maraviroc is considered for patient with virologic failure

  13. DHHS: Changing Criteria for Initiating ART clinicaloptions.com/hiv

  14. Current Guidelines for Initiating ART *If a patient with CD4+ count > 350 cells/mm³ wishes to start ART to reduce the risk of transmission to partners, that wish should be respected and ART started. †With the exception of an HIV-positive partner in a serodiscordant relationship, who should be offered antiretroviral therapy at CD4+ count > 350 cells/mm³ to prevent transmission to the uninfected partner. clinicaloptions.com/hiv

  15. Recommendations for Initiating ART ART is recommended for treatment • “ART is recommended for all HIV-infected individuals to reduce the risk of disease progression.” • The strength of this recommendation varies on the basis of pretreatment CD4 count (stronger at lower CD4 levels) www.aidsetc.org

  16. Recommendations for Initiating ART: CD4 Count or Clinical Category www.aidsetc.org

  17. Recommendations for Initiating ART: Prevention www.aidsetc.org

  18. Potential decrease in risk of many complications, including: HIV-associated nephropathy Liver disease progression from hepatitis B or C Cardiovascular disease Malignancies (AIDS defining and non-AIDS defining) Neurocognitive decline Blunted immunological response owing to ART initiation at older age Persistent T-cell activation and inflammation Potential Benefits of Early Therapy (2) www.aidsetc.org

  19. When to Start Therapy • Drug toxicity • Preservation of limited Rx options • Risk of resistance (and transmission of resistant virus) Delayed ART

  20. When to Start Therapy: Balance Now Favors Earlier ART • Drug toxicity • Preservation of limited Rx options • Risk of resistance (and transmission of resistant virus) • ↑ potency, durability, simplicity, safety of current regimens • ↓ emergence of resistance • ↓ toxicity with earlier therapy • ↑ subsequent treatment options • Risk of uncontrolled viremia at allCD4+ cell count levels • ↓ transmission Delayed ART Early ART clinicaloptions.com/hiv

  21. Antiretroviral therapy

  22. History of ART

  23. Current ARV Classes HAART Protease inhibitors (PI) Reverse Transcriptase inhibitors (RTI) Entry Inhibitors Integrase Inhibitor Nucleotide/Nucleoside Reverse Transcriptase Inhibitors (NRTI) Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI)

  24. Current ARV Medications * EVG currently available only in coformulation with cobicistat (COBI)/TDF/FTC www.aidsetc.org

  25. Nucleoside Reverse Transcriptase Inhibitors (NRTI) • Backbone of HIV combination therapy • HIV-1&2 • Minimal drug interactions • Renal excreted except ABC • Minimal cross resistance patterns

  26. Abacavir(ABC, Ziagen) • ABC 300mg PO twice day or 600mg PO daily • Part of Epzicom and Trizivir • HLA-B*5701-positive patients should not receive ABC • Positive status should be recorded as an ABC allergy • Life threatening if re-challenged • Toxicity • Hypersensitivity (HSR) ≈ 4% • Fever, rash, fatigue, malaise • Occur within 6 weeks • Don’t rechallenge • HLA-B*5701 300mg tablet or 20mg/ml solution

  27. Zidovudine (AZT, Retrovir) • ZDV 300mg BID • Part of Combivir and Trizivir • First-line regimen for pregnant women • Toxicity • Nausea, malaise, headache, insomnia, lipoatrophy • Anemia and neutropenia are the most frequent dose-limiting adverse effects 100mg tab, 300mg cap, 10mg/ml IV and 10mg/ml solution

  28. Emtricitabine (FTC)/ Emtriva Twin Drugs Lamivudine (3TC)/ Epivir FDA approved for treatment of HIV and HBV Dose 300mg PO daily Toxicity Minimal ≈ placebo headache Hepatitis flare (BB) Approved for HIV but also used to treat HBV Dose 200mg PO daily Toxicity Minimal ≈ placebo headache Hepatitis flare (BB)

  29. Tenofovir (TDF, Viread) • FDA approved for HIV and HBV • In 2012, Truvada was approved by the FDA for pre-exposure prophylaxis (PrEP) • Usually dose • 300 mg daily • Toxicity • Well tolerated but rarely can lead to acute renal failure, Fanconi’s syndrome, proteinuria, • May contribute to decrease in bone mineral density

  30. NRTI Co-formulated Regimen • Truvada • 1 tablet once a daily • TDF 300mg + FTC 200mg • Combivir • 1 tablet twice a day • 3TC 150mg + AZT 300 mg • Epzicom • 1 tablet once daily • 3TC 300mg + ABC 600mg • Trizivir • 1 tablet twice a day • 3TC 150mg + AZT 300mg + ABC 300 mg

  31. All NRTIs: Lactic acidosis and hepatic steatosis (highest incidence with d4T, then ddI and ZDV, lower with TDF, ABC, 3TC, and FTC) Lipodystrophy(higher incidence with d4T) Adverse Effects: NRTIs www.aidsetc.org

  32. Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) • First Generation • Delavirdine [DLV, RESCRIPTOR®] • Efavirenz [EFV, SUSTIVA®] • Nevirapine [NVP, VIRAMUNE®] • Second Generation • Etravirine [ETR, INTELENCE®] • Rilpivirine [RPV, EDURANT]

  33. Non-Nucleoside Reverse Transcription Inhibitors (NNRTI) • HIV-2 is resistant • Limitation of first generation NNRTI • Low genetic barrier to resistance • Long half-lives

  34. Efavirenz (EFV, Sustiva) • Dosing recommendation • 600mg PO once daily at or before bedtime • Take on empty stomach to reduce side effects • Co-formulated with TDF/FTC (Atripla) • No hepatic (caution) or renal dose adjustment • Toxicities • CNS side effects (4 weeks) • drowsiness, insomnia, vivid dreams, and impaired concentration • Rash • Hyperlipidemia • Potentially teratogenicity to humans • Pregnancy category D

  35. Nevirapine (NVP, Viramune) • Extended release formulation was approved in 2011 • Dose recommendation • 200mg PO QD x 2 weeks; 200mg PO BID • Toxicity • Rash including SJ syndrome • Hepatotoxicity (BB) • Female with CD4 > 250 or male with CD4> 400 • Liver disease (HBV, HCV or alcoholics) • Child Pugh class B or C is contraindicated

  36. Rilpivirine(RPV, Edurant) • Approval: FDA-approved May 20, 2011for treatment-naïve adults • 25 mg tablet daily • Take with 400 Kcal food • Fixed dose • Tenofovir-Emtricitabine-Rilpivirine (Complera) • Toxicity (low): depression, insomnia, headache, and rash • Pregnancy : category B

  37. ANTIRETROVIRAL THERAPY Rilpivirine (TMC-278) vs. Efavirenz in ARV-Naive ECHO and THRIVE: Study Design Rilpivirine: 25 mg qd + TDF/FTC(n = 346) ECHO 1x Efavirenz: 600 mg qd + TDF/FTC(n = 344) Rilpivirine: 25 mg qd + 2NRTIs*(n = 340) THRIVE 1x Efavirenz: 600 mg qd + 2NRTIs*(n = 338) *2 NRTIs: ECHO: Tenofovir + Emtricitabine (TDF/FTC)THRIVE: Tenofovir + Emtricitabine; Zidovudine + Lamivudine; Abacavir + Lamivudine Source: Cohen C, et al. 17th International AIDS Conference. 2010:THLBB206.

  38. ANTIRETROVIRAL THERAPY Rilpivirine (TMC-278) vs. Efavirenz in ARV-Naive ECHO and THRIVE: Week 48 Results Pooled ECHO and THRIVE: Virologic Response ( ITT-TLOVR) 84.3% 82.3% 2NRTIs+ Rilpivirine (n = 686) 2NRTIs+ Efavirenz (n = 682) Source: Cohen C, et al. 17th International AIDS Conference. 2010:THLBB206.

  39. ANTIRETROVIRAL THERAPY Rilpivirine (TMC-278) vs. Efavirenz in ARV-Naive ECHO and THRIVE: Results 48 Week Data: Virologic Failure All regimens included 2 NRTIs Source: Cohen C, et al. 17th International AIDS Conference. 2010:THLBB206.

  40. ANTIRETROVIRAL THERAPY Rilpivirine (TMC-278) vs. Efavirenz in ARV-Naive ECHO and THRIVE: Results 48 Week Data: Discontinuation Due to Adverse Effects All regimens included 2 NRTIs Source: Cohen C, et al. 17th International AIDS Conference. 2010:THLBB206.

  41. ANTIRETROVIRAL THERAPY Rilpivirine (TMC-278) vs. Efavirenz in ARV-Naive ECHO and THRIVE: Results Source: Cohen C, et al. 17th International AIDS Conference. 2010:THLBB206.

  42. NRTI+NNRTI Co-formulated Regimen • Atripla • EFT 600mg + FTC 200mg + TDF 300mg • FTC+TDF= Truvada • 1 tablet once daily at or before bedtime • Complera • RPV 25mg + FTC 200mg + TDF 300mg • FTC+TDF= Truvada • 1 tablet once daily with a meal • Avoid antacids • PPI is contraindicated

  43. All NNRTIs: Rash, including Stevens-Johnson syndrome Hepatotoxicity (especially NVP) Drug-drug interactions Adverse Effects: NNRTIs

  44. Protease Inhibitors • Atazanavir [ATV, REYATAZ®] • Darunavir [DRV, PREZISTA®] • Fosamprenavir [FPV, LEXIVA®] • Indinavir [IDV, CRIXIVAN®] • Lopinavir/Ritonavir [LPV/r, KALETRA®] • Nelfinavir [NFV, VIRACEPT®] • Ritonavir [RTV, NORVIR®] • Saquinavir [SQV, INVIRASE®] • Tipranavir [TPV, APTIVUS®]

  45. ADVANTAGES Higher genetic barrier to resistance PI resistance uncommon with failure (boosted PI) NNRTIs and II preserved for future use DISADVANTAGES Metabolic complications (fat maldistribution, dyslipidemia, insulin resistance) GI intolerance Potential for druginteractions (CYP450), especially with RTV ARV Components in Initial Therapy: PIs www.aidsetc.org

  46. Atazanavir (ATV, Reyataz) • Recommended dose • Naïve patient • 400 mg once daily or • 300 mg + 100mg RTV once daily • Take with food • Avoid acid suppressing agents • Toxicity • Hyperbilirubinemia • PR prolongation • Nephrolithiasis, cholelithiasis

  47. Darunavir (DRV, Prezita) • Dose • ARV naïve or experienced patients with no mutation • 800mg + 100 mg RTV once daily • ARV experienced patient with at least one mutation • DRV must be boosted with RTN • Take with food • Toxicity • DRV contains a sulfonamide moiety, • Avoid patients with a sulfa allergy→ Rash • GI (N/V/D) • Hyperlipidemia

  48. Lopinavir/Ritonavir (LPV/r, Keletra) • The only boosted PI that is coformulated with low-dose ritonavir • LPV 200mg + RTV 50mg or LPV 100mg + RTV 25mg • preferred regimen for pregnant women • Toxicities • GI (N/V/D) • Hyperlipidemia (especially ↑triglycerides) • Potential increased MI risk

  49. Ritonavir (RTV, Norvir) • Booster for other PI • 100-400mg per day in 1-2 divided doses • Formulation • 100mg soft gel capsules, 100mg tablet • 80mg/mL solution • 43% alcohol • Toxicities • GI (N/V/D) • Hyperlipidemia • Hyperglycemia

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