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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 • New DHHS adult and adolescent antiretroviral treatment guidelines. • Importance of adherence What is HIV? • HIV is a lentivirus • HIV = Human Immunodeficiency Virus • It destroys CD4 cells (Tcells and macrophage) • AIDS = Acquired immunodeficiency Syndrome – CD4 count < 200/mm3 or – CD4 % < 14% 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 Etiology • 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 Barre-Sinoussi F, Chermann JC, et al. Science. 1983 May 20;220(4599):868-71. 5 Transmission 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. Mc Graw Hill p152 7 Progression of HIV 2-3 wks Viral transmission 2-3 wks Acute retroviral syndrome Recovery + seroconversion Avg. 1.5yrs Avg. 8 yrs Asymptomatic chronic HIV inf 2-4 wks Symptomatic HIV/AIDS 2007 The Hopkins HIV guide Death 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.g OraQuick) • Resistance test – genotype (detects mutations that confers HIV drug resistance) – Phenotype (culture based on viral replication assays in the absence or presence of drugs) Use of CD4 Cell Levels to Guide Therapy Decisions • CD4 count – The major indicator of immune function – Most recent CD4 count is best predictor of disease 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. February 2013 www.aidsetc.org 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 February 2013 www.aidsetc.org 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 DHHS: Changing Criteria for Initiating ART CD4+ Count, cells/mm3 > 500 350-500 200-350 < 200 or symptomatic disease 1998 2001 Offer if VL > 55,000 Consider if Offer if VL VL > 20,000 > 55,000 Offer, but Offer if controversy VL > 20,000 exists Offer if VL > 20,000 Treat Treat 2006 2008 Consider if VL ≥ 100,000 Consider if VL ≥ 100,000 Offer after discussion with patient Consider in certain groups Consider in certain groups Treat clinicaloptions.com/hiv 2009 2012 Consider Treat Treat Treat Treat Treat Treat Treat Treat Treat Current Guidelines for Initiating ART Guideline Symptomatic/ AIDS CD4+ Count < 200 CD4+ Count 200-350 CD4+ Count 350-500 CD4+ Count > 500 DHHS (2/2012) Yes Yes Yes Yes Yes IAS-USA (7/2012) Yes Yes Yes Yes Yes British HIV Association (9/2012) Yes Yes Yes Defer* Defer* European AIDS Clinical Society (11/2012) Yes Yes Yes Consider Defer WHO (7/2010) Yes Yes Yes No† Not addressed *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 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) February 2013 15 www.aidsetc.org Recommendations for Initiating ART: CD4 Count or Clinical Category Recommended for all CD4 counts: CD4 count <350 cells/µL (AI) CD4 count 350-500 cells/µL (AII) CD4 count >500 cells/µL (BIII) February 2013 www.aidsetc.org 16 Recommendations for Initiating ART: Prevention Perinatal transmission Recommended for all HIV-infected pregnant women (AI) Sexual transmission Recommended for all who are at risk of transmitting HIV to sexual partners (AI for heterosexuals, AIII for other transmission risk groups) February 2013 www.aidsetc.org 17 Potential Benefits of Early Therapy (2) • 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 February 2013 18 www.aidsetc.org When to Start Therapy Drug toxicity Preservation of limited Rx options Risk of resistance (and transmission of resistant virus) Delayed ART 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 all CD4+ cell count levels ↓ transmission Delayed ART Early ART clinicaloptions.com/hiv ANTIRETROVIRAL THERAPY History of ART 22 Current ARV Classes HAART Protease inhibitors (PI) Reverse Transcriptase inhibitors (RTI) Nucleotide/Nucleosi de Reverse Transcriptase Inhibitors (NRTI) Entry Inhibitors Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI) Integrase Inhibitor 24 Current ARV Medications NRTI PI Abacavir (ABC) Didanosine (ddI) Emtricitabine (FTC) Lamivudine (3TC) Stavudine (d4T) Tenofovir (TDF) Zidovudine (AZT, ZDV) Atazanavir (ATV) Darunavir (DRV) Fosamprenavir (FPV) Indinavir (IDV) Lopinavir (LPV) Nelfinavir (NFV) Ritonavir (RTV) Saquinavir (SQV) Tipranavir (TPV) NNRTI Delavirdine (DLV) Efavirenz (EFV) Nevirapine (NVP) Etravirine (ETR) Rilpivirine (RPV) February 2013 Integrase Inhibitor (II) Raltegravir (RAL) Elvitegravir* (EVG) Fusion Inhibitor Enfuvirtide (ENF, T-20) CCR5 Antagonist Maraviroc (MVC) * 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 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 doselimiting adverse effects 100mg tab, 300mg cap, 10mg/ml IV and 10mg/ml solution 28 Twin Drugs Lamivudine (3TC)/ Epivir • FDA approved for treatment of HIV and HBV • Dose – 300mg PO daily • Toxicity – Minimal ≈ placebo • headache – Hepatitis flare (BB) Emtricitabine (FTC)/ Emtriva • 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 Adverse Effects: NRTIs • 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) February 2013 32 www.aidsetc.org 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 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) Study Features Protocol - Randomized, double-blind trial - Phase 3 - N = 690 (ECHO) and 678 (THRIVE) - Age > 18 - ARV-naïve - HIV RNA > 5,000 copies/ml - No baseline NNRTI mutations - Randomized to one of 2 arms - All given 2 NRTIs* ECHO 1x Efavirenz: 600 mg qd + TDF/FTC (n = 344) Rilpivirine: 25 mg qd + 2NRTIs* (n = 340) THRIVE 1x *2 NRTIs: ECHO: Tenofovir + Emtricitabine (TDF/FTC) THRIVE: Tenofovir + Emtricitabine; Zidovudine + Lamivudine; Efavirenz: 600 mg qd + 2NRTIs* (n = 338) Abacavir + Lamivudine Source: Cohen C, et al. 17th International AIDS Conference. 2010:THLBB206. 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. 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. 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. ANTIRETROVIRAL THERAPY Rilpivirine (TMC-278) vs. Efavirenz in ARV-Naive ECHO and THRIVE: Results Conclusions: • Rilpivirine demonstrated high response rate • Rilpivirine virologic failure rate higher than efavirenz (9.0% vs 4.8%) • Rilpivirine had significant tolerability advantage over efavirenz Source: Cohen C, et al. 17th International AIDS Conference. 2010:THLBB206. 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 Adverse Effects: NNRTIs • All NNRTIs: – Rash, including Stevens-Johnson syndrome – Hepatotoxicity (especially NVP) – Drug-drug interactions 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 ARV Components in Initial Therapy: PIs ADVANTAGES • Higher genetic barrier to resistance • PI resistance uncommon with failure (boosted PI) • NNRTIs and II preserved for future use February 2013 DISADVANTAGES • Metabolic complications (fat maldistribution, dyslipidemia, insulin resistance) • GI intolerance • Potential for drug interactions (CYP450), especially with RTV 46 www.aidsetc.org 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 50 Integrase Inhibitors • Raltegravir • Elvitegravir* (EVG) • Currently being studied in phase III clinical trials – Dolutegravir (S/GSK1249572) * EVG currently available only in coformulation with cobicistat (COBI)/TDF/FTC 51 Integrase Inhibitors • • • • Virologic response noninferior to EFV appears to be active against HIV2 Fewer adverse events than with EFV RAL has fewer drug-drug interactions than with PIs or NNRTIs (not true of EVG/COBI) • NNRTIs and PIs preserved for future use February 2013 www.aidsetc.org 52 Raltegravir (RAL, Isentress) • Indicated for both naïve and experienced pt • Dose recommendation – 400mg po twice a day with or without food – When combined with other ART dose stays same • Toxicities – – – – Diarrhea, Nausea Fatigue Myalgia Abnormal liver function 53 Stribild (Quad Pill) • Approved August 2012 • Elvitegravir 150mg + cobicistat 150mg + emtricitabine 200mg + tenofovir 300mg • Stribild PO daily with food • Cobicistat is used to increase the levels of elvitegravir • AE – Decreased CrCl – Nausea, diarrhea EVG/COBI/TDF/FTC: “Alternative” First-line Regimen • EVG/COBI/TDF/FTC recommended as “alternative” regimen in treatment-naive patients with ClCr > 70 mL/min (BI)[1] • Benefits – Noninferior to EFV/TDF/FTC,[2] ATV/RTV + TDF/FTC[3] – 1-tablet, once-daily dosing • Limitations – Potential for drug–drug interactions – Limited safety data; limited data in advanced disease, women – Possible increased risk proximal renal tubulopathy – Food requirement 1. DHHS Panel Statement. September 18, 2012. 2. Sax PE, et al. Lancet. 2012;379:2439-2448. 3. DeJesus E, et al. Lancet. 2010;379:2429-2438. DISADVANTAGES II • • • • • Twice-daily dosing Lower genetic barrier to resistance than PIs COBI has many drug-drug interactions COBI may cause or worsen renal impairment Myopathy, rhabdomyolysis, skin reactions reported with RAL (rare) February 2013 www.aidsetc.org 56 Entry Inhibitors Enfuvirtide (T-20, Fuzion) • Use for experienced patients • 90mg subcutaneous injection twice a day – Reconstitute with 1.1ml sterile water • Adverse effects – Injection-site reactions – HSR – Increased risk of bacterial pneumonia Maraviroc (MVC, Selzentry) • Block the binding of gp120 to the chemokine receptor (CCR5) • Coreceptor tropism assay – CCR5 or CXCR4 • Adverse Effects – Drug-drug interactions – Rash – Abdominal pain – Upper respiratory tract infections New DHHS Treatment guidelines Feb, 2013 Initial Treatment: Choosing Regimens • 3 main categories: – 1 NNRTI + 2 NRTIs – 1 PI + 2 NRTIs – 1 II + 2 NRTIs • Combination of NNRTI, PI, or II + 2 NRTIs preferred for most patients • Fusion inhibitor, CCR5 antagonist not recommended in initial ART • Few clinical end points to guide choices • Advantages and disadvantages to each type of regimen • Individualize regimen choice DHHS guideline; February 2013 59 www.aidsetc.org Initial Regimen: Recommended/Preferred Agents EFV ATV/RTV TDF/FTC + DRV/RTV RAL DHHS Guidelines . Feb 2013; Thompson MA, et al. JAMA. 2010;304;321-333. Initial Regimen: Recommended/Alternative RPV LPV/RTV TDF/FTC or ABC/3T + FPV/RTV EVG/COBI/TDF/FT C 9. DHHS Guidelines for Antiretroviral Therapy in Adults and Adolescents. March 2012. 10. DHHS Panel Statement. September 18, 2012. CYP450 and Drug Metabolism CYP2E1 CYP1A2 CYP2C CYP2D6 Key points •Majority of drugs metabolized by CYP3A4 and CYP2D6 •CYP3A4 and CYP2D6 extensively involved with PI/NNRTI metabolism •Enzymes can be induced or inhibited Adapted from Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 9th ed. Effect of ARV on Drug Metabolism Induced by: 3A4 Inhibited by: RTV Induced by: Induced by: Inhibited by: RTV, NFV, IDV, SQV, DLV RTV, NFV Inhibited by: EFV, DLV RTV, NFV ? RTV, NFV, TPV EFV, NVP Induced by: 2C19 2D6 2C9 RTV, NFV Inhibited by: DLV Induced by: 1A2 2E1 2A6 2B6 2C8 From Fichtenbaum CJ. Clin Pharmacokinet 2002:41(14):1195-1211. EFV, NVP Recommendations for Initiating ART: Considerations “Patients starting ART should be willing and able to commit to treatment and should understand the benefits and risks of therapy and the importance of adherence.” Patients may choose to postpone ART Providers may elect to defer ART, based on an individual patient’s clinical or psychosocial factors February 2013 www.aidsetc.org 64 Immunization MMWR / February 4, 2011 / Vol. 60 / No. 4 65 ART Approved & Unapproved Drugs 66 References • • • • • • • • • • • • • • • • • Chen Z, Telfier P, Gettie A, Reed P, Zhang L, Ho DD, Marx PA. J Virol. 1996 Jun;70(6):3617-27 G.J. Stine. AIDS update 2012. Mc Graw Hill 2012 Thompson MA, et al. JAMA. 2012;308:387-402. Williams I, et al. HIV Med. 2012;13(suppl 2):1-85. EACS Guidelines for the Treatment of HIV Infected Adults in Europe. November 2012. WHO Guidelines for Antiretroviral Therapy for HIV Infection in Adults and Adolescents. July 2010. DHHS Guidelines for Antiretroviral Therapy in Adults and Adolescents. March 2012. DHHS Guidelines for Antiretroviral Therapy in Adults and Adolescents. March 2012. DHHS Guidelines for Antiretroviral Therapy in Adults and Adolescents. Feb 2013 Cohen M, et al. N Engl J Med. 2011;365:493-505. DHHS Panel Statement. September 18, 2012. Sax PE, et al. Lancet. 2012;379:2439-2448. DeJesus E, et al. Lancet. 2010;379:2429-2438 ww.hivinsite.com www.clinicaloptions.com www.hivguidelines.org www.hopkins-aids.edu