Presentation on theme: "HIV Updates Abdi Mohamed, Pharm.D"— Presentation transcript:
1 HIV Updates Abdi Mohamed, Pharm.D Assistant Professor o Pharmacy PracticeHusson University School of Pharmacy
2 Objectives Review of the history and epidemiology of HIV/AIDS Diagnosis of HIV infectionWhen to initiate therapyOverview of antiretroviral medicationsNew 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 SyndromeCD4 count < 200/mm3 orCD4 % < 14%
4 History of HIVFirst cases of AIDS were identified in 1981 in Los Angeles, CABelieved 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 chimpanzeesChen Z, Telfier P, Gettie A, Reed P, Zhang L, Ho DD, Marx PA. J Virol Jun;70(6):
5 Etiology HIV was identified as the etiologic agent of AIDS until 1983 Two typesHIV-1HIV-2Both them cause similar conditionThey differ in transmission and progressionHIV-1 more virulent and more easily transmissibleBarre-Sinoussi F, Chermann JC, et al. Science May 20;220(4599):
7 G.J. Stine. AIDS update 2012. Mc Graw Hill p152 Epidemiology2012 US HIV dataAnnually HIV infection 60,000People living with HIV 1.62 millionHIV patients not in care ~55%1 in 5 (20%) are unaware of their infectionBy race, blacks/African Americans face the most severe burden of HIVG.J. Stine. AIDS update Mc Graw Hill p152
8 Progression of HIV Death 2007 The Hopkins HIV guide 2-3 wks 2-3 wks Viral transmissionViral transmissionAcute retroviral syndromeRecovery + seroconversionAvg. 1.5yrsDeathAvg. 8 yrsAsymptomatic chronic HIV infSymptomatic HIV/AIDS2007 The Hopkins HIV guide
9 Diagnosis & TestingHIV antibody testing is performed by using an enzyme-linked immunosorbent assay (ELISA)If positive repeat the testUse Western blot (WB) to confirmRapid immunoassy (e.g OraQuick)Resistance testgenotype (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 countThe major indicator of immune functionMost recent CD4 count is best predictor of disease progressionA key factor in determining urgency of ART or need for OI prophylaxisImportant in determining response to ARTAdequate response: CD4 increase cells/µL per yearCD4 monitoringCheck 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
11 Use of HIV RNA Levels to Guide Therapy Decisions May influence decision to start ART and help determine frequency of CD4 monitoringCritical in determining response to ARTGoal of ART: HIV RNA below limit of detection (ie, < copies/mL, depending on assay)Commercially available assays do not detect HIV-2February 2013
12 Other Test HLA-B*5701 Screening Coreceptor tropism assay 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 fileCoreceptor tropism assayShould be performed to detect whether HIV-1 isolates use CCR5 or CXR4 or both.Requires plasma HIV RNA ≥ 1000 copies/mLMaraviroc is considered for patient with virologic failure
13 DHHS: Changing Criteria for Initiating ART CD4+ Count, cells/mm3199820012006200820092012> 500Offer if VL > 20,000Offer if VL > 55,000Consider if VL ≥ 100,000Consider in certain groupsConsiderTreatConsider if VL > 55,000Offer, but controversy existsOffer after discussion with patient< 200 or symptomatic diseaseclinicaloptions.com/hiv
14 Current Guidelines for Initiating ART Symptomatic/ AIDSCD4+ Count < 200CD4+ CountCD4+ CountCD4+ Count > 500DHHS (2/2012)YesIAS-USA (7/2012)British HIV Association (9/2012)Defer*European AIDS Clinical Society (11/2012)ConsiderDeferWHO (7/2010)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
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)February 2013
16 Recommendations for Initiating ART: CD4 Count or Clinical Category Recommended for all CD4 counts:CD4 count <350 cells/µL (AI)CD4 count cells/µL (AII)CD4 count >500 cells/µL (BIII)February 2013
17 Recommendations for Initiating ART: Prevention Perinatal transmissionRecommended for all HIV-infected pregnant women (AI)Sexual transmissionRecommended for all who are at risk of transmitting HIV to sexual partners (AI for heterosexuals, AIII for other transmission risk groups)February 2013
18 Potential Benefits of Early Therapy (2) Potential decrease in risk of many complications, including:HIV-associated nephropathyLiver disease progression from hepatitis B or CCardiovascular diseaseMalignancies (AIDS defining and non-AIDS defining)Neurocognitive declineBlunted immunological response owing to ART initiation at older agePersistent T-cell activation and inflammationFebruary 2013
19 When to Start Therapy Delayed ART Drug toxicity Preservation of limited Rx optionsRisk of resistance (and transmission of resistant virus)Delayed ART
20 When to Start Therapy: Balance Now Favors Earlier ART Drug toxicityPreservation of limited Rx optionsRisk of resistance (and transmission of resistant virus)↑ potency, durability, simplicity, safety of current regimens↓ emergence of resistance↓ toxicity with earlier therapy↑ subsequent treatment optionsRisk of uncontrolled viremia at all CD4+ cell count levels↓ transmissionDelayed ARTEarly ARTclinicaloptions.com/hiv
25 Current ARV Medications NRTIAbacavir (ABC)Didanosine (ddI)Emtricitabine (FTC)Lamivudine (3TC)Stavudine (d4T)Tenofovir (TDF)Zidovudine (AZT, ZDV)NNRTIDelavirdine (DLV)Efavirenz (EFV)Nevirapine (NVP)Etravirine (ETR)Rilpivirine (RPV)PIAtazanavir (ATV)Darunavir (DRV)Fosamprenavir (FPV)Indinavir (IDV)Lopinavir (LPV)Nelfinavir (NFV)Ritonavir (RTV)Saquinavir (SQV)Tipranavir (TPV)Integrase Inhibitor (II)Raltegravir (RAL)Elvitegravir* (EVG)Fusion InhibitorEnfuvirtide (ENF, T-20)CCR5 AntagonistMaraviroc (MVC)* EVG currently available only in coformulation with cobicistat (COBI)/TDF/FTCFebruary 2013
26 Nucleoside Reverse Transcriptase Inhibitors (NRTI) Backbone of HIV combination therapyHIV-1&2Minimal drug interactionsRenal excreted except ABCMinimal cross resistance patterns
27 Abacavir(ABC, Ziagen) ABC 300mg PO twice day or 600mg PO daily Part of Epzicom and TrizivirHLA-B*5701-positive patients should not receive ABCPositive status should be recorded as an ABC allergyLife threatening if re-challengedToxicityHypersensitivity (HSR) ≈ 4%Fever, rash, fatigue, malaiseOccur within 6 weeksDon’t rechallengeHLA-B*5701300mg tablet or 20mg/ml solution
28 Zidovudine (AZT, Retrovir) ZDV 300mg BIDPart of Combivir and TrizivirFirst-line regimen for pregnant womenToxicityNausea, malaise, headache, insomnia, lipoatrophyAnemia and neutropenia are the most frequent dose-limiting adverse effects100mg tab, 300mg cap,10mg/ml IV and 10mg/ml solution
29 Twin Drugs Lamivudine (3TC)/ Epivir Emtricitabine (FTC)/ EmtrivaFDA approved for treatment of HIV and HBVDose300mg PO dailyToxicityMinimal ≈ placeboheadacheHepatitis flare (BB)Approved for HIV but also used to treat HBVDose200mg PO dailyToxicityMinimal ≈ placeboheadacheHepatitis flare (BB)
30 Tenofovir (TDF, Viread) FDA approved for HIV and HBVIn 2012, Truvada was approved by the FDA for pre-exposure prophylaxis (PrEP)Usually dose300 mg dailyToxicityWell tolerated but rarely can lead to acute renal failure, Fanconi’s syndrome, proteinuria,May contribute to decrease in bone mineral density
31 NRTI Co-formulated Regimen Truvada1 tablet once a dailyTDF 300mg + FTC 200mgCombivir1 tablet twice a day3TC 150mg + AZT 300 mgEpzicom1 tablet once daily3TC 300mg + ABC 600mgTrizivir3TC 150mg + AZT 300mg + ABC 300 mg
32 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
34 Non-Nucleoside Reverse Transcription Inhibitors (NNRTI) HIV-2 is resistantLimitation of first generation NNRTILow genetic barrier to resistanceLong half-lives
35 Efavirenz (EFV, Sustiva) Dosing recommendation600mg PO once daily at or before bedtimeTake on empty stomach to reduce side effectsCo-formulated with TDF/FTC (Atripla)No hepatic (caution) or renal dose adjustmentToxicitiesCNS side effects (4 weeks)drowsiness, insomnia, vivid dreams, and impaired concentrationRashHyperlipidemiaPotentially teratogenicity to humansPregnancy category DAdministration with food especially high fat meal may increase CNS side effects. False positive reported with cannabinoid and benzodiazepine screening
36 Nevirapine (NVP, Viramune) Extended release formulation was approved in 2011Dose recommendation200mg PO QD x 2 weeks; 200mg PO BIDToxicityRash including SJ syndromeHepatotoxicity (BB)Female with CD4 > 250 or male with CD4> 400Liver disease (HBV, HCV or alcoholics)Child Pugh class B or C is contraindicated
37 Rilpivirine (RPV, Edurant) Approval: FDA-approved May 20, 2011for treatment-naïve adults25 mg tablet dailyTake with 400 Kcal foodFixed doseTenofovir-Emtricitabine-Rilpivirine (Complera)Toxicity (low): depression, insomnia, headache, and rashPregnancy : category B
38 ANTIRETROVIRAL THERAPY Rilpivirine (TMC-278) vs. Efavirenz in ARV-Naive ECHO and THRIVE: Study DesignRilpivirine: 25 mg qd + TDF/FTC (n = 346)Study FeaturesProtocol - 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*ECHO1xEfavirenz: 600 mg qd + TDF/FTC (n = 344)Rilpivirine: 25 mg qd + 2NRTIs* (n = 340)THRIVE1xEfavirenz: 600 mg qd + 2NRTIs* (n = 338)*2 NRTIs: ECHO: Tenofovir + Emtricitabine (TDF/FTC) THRIVE: Tenofovir + Emtricitabine; Zidovudine + Lamivudine; Abacavir + LamivudineSource: Cohen C, et al. 17th International AIDS Conference. 2010:THLBB206.
39 Pooled ECHO and THRIVE: Virologic Response ( ITT-TLOVR) ANTIRETROVIRAL THERAPYRilpivirine (TMC-278) vs. Efavirenz in ARV-Naive ECHO and THRIVE: Week 48 ResultsPooled 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.
40 48 Week Data: Virologic Failure ANTIRETROVIRAL THERAPYRilpivirine (TMC-278) vs. Efavirenz in ARV-Naive ECHO and THRIVE: Results48 Week Data: Virologic FailureAll regimens included 2 NRTIsSource: Cohen C, et al. 17th International AIDS Conference. 2010:THLBB206.
41 48 Week Data: Discontinuation Due to Adverse Effects ANTIRETROVIRAL THERAPYRilpivirine (TMC-278) vs. Efavirenz in ARV-Naive ECHO and THRIVE: Results48 Week Data: Discontinuation Due to Adverse EffectsAll regimens included 2 NRTIsSource: Cohen C, et al. 17th International AIDS Conference. 2010:THLBB206.
42 ANTIRETROVIRAL THERAPY Rilpivirine (TMC-278) vs. Efavirenz in ARV-Naive ECHO and THRIVE: ResultsConclusions:Rilpivirine demonstrated high response rateRilpivirine virologic failure rate higher than efavirenz (9.0% vs 4.8%)Rilpivirine had significant tolerability advantage over efavirenzSource: Cohen C, et al. 17th International AIDS Conference. 2010:THLBB206.
43 NRTI+NNRTI Co-formulated Regimen AtriplaEFT 600mg + FTC 200mg + TDF 300mgFTC+TDF= Truvada1 tablet once daily at or before bedtimeCompleraRPV 25mg + FTC 200mg + TDF 300mg1 tablet once daily with a mealAvoid antacidsPPI is contraindicated
44 Adverse Effects: NNRTIs All NNRTIs:Rash, including Stevens-Johnson syndromeHepatotoxicity (especially NVP)Drug-drug interactions
46 ARV Components in Initial Therapy: PIs ADVANTAGESHigher genetic barrier to resistancePI resistance uncommon with failure (boosted PI)NNRTIs and II preserved for future useDISADVANTAGESMetabolic complications (fat maldistribution, dyslipidemia, insulin resistance)GI intolerancePotential for drug interactions (CYP450), especially with RTVFebruary 2013
47 Atazanavir (ATV, Reyataz) Recommended doseNaïve patient400 mg once daily or300 mg + 100mg RTV once dailyTake with foodAvoid acid suppressing agentsToxicityHyperbilirubinemiaPR prolongationNephrolithiasis, cholelithiasis
48 Darunavir (DRV, Prezita) DoseARV naïve or experienced patients with no mutation800mg mg RTV once dailyARV experienced patient with at least one mutationDRV must be boosted with RTNTake with foodToxicityDRV contains a sulfonamide moiety,Avoid patients with a sulfa allergy→ RashGI (N/V/D)Hyperlipidemia
49 Lopinavir/Ritonavir (LPV/r, Keletra) The only boosted PI that is coformulated with low-dose ritonavirLPV 200mg + RTV 50mg or LPV 100mg + RTV 25mgpreferred regimen for pregnant womenToxicitiesGI (N/V/D)Hyperlipidemia (especially ↑triglycerides)Potential increased MI risk
50 Ritonavir (RTV, Norvir) Booster for other PImg per day in 1-2 divided dosesFormulation100mg soft gel capsules, 100mg tablet80mg/mL solution43% alcoholToxicitiesGI (N/V/D)HyperlipidemiaHyperglycemia
51 Integrase Inhibitors Raltegravir Elvitegravir* (EVG) Currently being studied in phase III clinical trialsDolutegravir (S/GSK )* EVG currently available only in coformulation with cobicistat (COBI)/TDF/FTC
52 Integrase Inhibitors Virologic response noninferior to EFV appears to be active against HIV2Fewer adverse events than with EFVRAL has fewer drug-drug interactions than with PIs or NNRTIs (not true of EVG/COBI)NNRTIs and PIs preserved for future useFebruary 2013
53 Raltegravir (RAL, Isentress) Indicated for both naïve and experienced ptDose recommendation400mg po twice a day with or without foodWhen combined with other ART dose stays sameToxicitiesDiarrhea, NauseaFatigueMyalgiaAbnormal liver functionLow genetic barrier to resistance
54 Stribild (Quad Pill) Approved August 2012 Elvitegravir 150mg + cobicistat 150mg + emtricitabine 200mg + tenofovir 300mgStribild PO daily with foodCobicistat is used to increase the levels of elvitegravirAEDecreased CrClNausea, diarrhea
55 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)BenefitsNoninferior to EFV/TDF/FTC, ATV/RTV + TDF/FTC1-tablet, once-daily dosingLimitationsPotential for drug–drug interactionsLimited safety data; limited data in advanced disease, womenPossible increased risk proximal renal tubulopathyFood requirement1. DHHS Panel Statement. September 18, Sax PE, et al. Lancet. 2012;379:3. DeJesus E, et al. Lancet. 2010;379:
56 DISADVANTAGES II Twice-daily dosing Lower genetic barrier to resistance than PIsCOBI has many drug-drug interactionsCOBI may cause or worsen renal impairmentMyopathy, rhabdomyolysis, skin reactions reported with RAL (rare)February 2013
57 Entry Inhibitors Enfuvirtide (T-20, Fuzion) Maraviroc (MVC, Selzentry) Use for experienced patients90mg subcutaneous injection twice a dayReconstitute with 1.1ml sterile waterAdverse effectsInjection-site reactionsHSRIncreased risk of bacterial pneumoniaBlock the binding of gp120 to the chemokine receptor (CCR5)Coreceptor tropism assayCCR5 or CXCR4Adverse EffectsDrug-drug interactionsRashAbdominal painUpper respiratory tract infections
59 Initial Treatment: Choosing Regimens 3 main categories:1 NNRTI + 2 NRTIs1 PI + 2 NRTIs1 II + 2 NRTIsCombination of NNRTI, PI, or II + 2 NRTIs preferred for most patientsFusion inhibitor, CCR5 antagonist not recommended in initial ARTFew clinical end points to guide choicesAdvantages and disadvantages to each type of regimenIndividualize regimen choiceDHHS guideline; February 2013
60 Initial Regimen: Recommended/Preferred Agents TDF/FTC +EFVATV/RTVDRV/RTVRALDHHS Guidelines . Feb 2013; Thompson MA, et al. JAMA. 2010;304;
61 Initial Regimen: Recommended/Alternative TDF/FTC or ABC/3T +RPVLPV/RTVFPV/RTVEVG/COBI/TDF/FTC9. DHHS Guidelines for Antiretroviral Therapy in Adults and Adolescents. March 2012.10. DHHS Panel Statement. September 18, 2012.
62 CYP450 and Drug Metabolism CYP2E1CYP3A4CYP2CCYP2D6Key pointsMajority of drugs metabolizedby CYP3A4 and CYP2D6CYP3A4 and CYP2D6extensively involved withPI/NNRTI metabolismEnzymes can be induced orinhibitedAdapted from Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 9th ed.62
64 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 ARTProviders may elect to defer ART, based on an individual patient’s clinical or psychosocial factorsFebruary 2013
67 ReferencesChen Z, Telfier P, Gettie A, Reed P, Zhang L, Ho DD, Marx PA. J Virol Jun;70(6):G.J. Stine. AIDS update Mc Graw Hill 2012Thompson MA, et al. JAMA. 2012;308: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. Feb 2013Cohen M, et al. N Engl J Med. 2011;365:DHHS Panel Statement. September 18, 2012.Sax PE, et al. Lancet. 2012;379:DeJesus E, et al. Lancet. 2010;379:ww.hivinsite.com67
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