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

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Presentation on theme: "HIV Updates Abdi Mohamed, Pharm.D Assistant Professor o Pharmacy Practice Husson University School of Pharmacy."— Presentation transcript:

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/AIDSReview of the history and epidemiology of HIV/AIDS Diagnosis of HIV infectionDiagnosis of HIV infection When to initiate therapyWhen to initiate therapy Overview of antiretroviral medicationsOverview of antiretroviral medications New DHHS adult and adolescent antiretroviral treatment guidelines.New DHHS adult and adolescent antiretroviral treatment guidelines. Importance of adherenceImportance of adherence

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

4 History of HIV First cases of AIDS were identified in 1981 in Los Angeles, CAFirst cases of AIDS were identified in 1981 in Los Angeles, CA Believed to be a zoonosis (transmitted from animal)Believed to be a zoonosis (transmitted from animal) HIV is a descendant of a Simian Immunodeficiency Virus (SIV)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).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-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 chimpanzeesHIV-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 Jun;70(6):

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

6 Transmission

7 Epidemiology 2012 US HIV data2012 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 7 G.J. Stine. AIDS update Mc Graw Hill p152

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

9 Diagnosis & Testing HIV antibody testing is performed by using an enzyme-linked immunosorbent assay (ELISA)HIV antibody testing is performed by using an enzyme-linked immunosorbent assay (ELISA) If positive repeat the testIf positive repeat the test Use Western blot (WB) to confirmUse Western blot (WB) to confirm Rapid immunoassy (e.g OraQuick)Rapid immunoassy (e.g OraQuick) Resistance testResistance 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 countCD4 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 cells/µL per yearAdequate response: CD4 increase cells/µL per year CD4 monitoringCD4 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

11 Use of HIV RNA Levels to Guide Therapy Decisions HIV RNAHIV 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)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 2013www.aidsetc.org

12 Other Test HLA-B*5701 ScreeningHLA-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 assayCoreceptor 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 CD4+ Count, cells/mm > 500 Offer if VL > 20,000 Offer if VL > 55,000 Consider if VL ≥ 100,000 Consider in certain groups ConsiderTreat Offer if VL > 20,000 Consider if VL > 55,000 Consider if VL ≥ 100,000 Consider in certain groups Treat Offer if VL > 20,000 Offer, but controversy exists Offer after discussion with patient Treat < 200 or symptomatic disease Treat DHHS: Changing Criteria for Initiating ART clinicaloptions.com/hiv

14 GuidelineSymptomatic/ AIDS CD4+ Count < 200 CD4+ Count CD4+ Count CD4+ Count > 500 DHHS (2/2012)Yes IAS-USA (7/2012)Yes British HIV Association (9/2012) Yes Defer* European AIDS Clinical Society (11/2012) Yes ConsiderDefer WHO (7/2010)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. Current Guidelines for Initiating ART 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.”“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 www.aidsetc.org

16 Recommendations for Initiating ART: 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 2013www.aidsetc.org16

17 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 2013www.aidsetc.org17

18 Potential Benefits of Early Therapy (2) Potential decrease in risk of many complications, including: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 2013www.aidsetc.org18

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 all CD4+ cell count levels  ↓ transmission Early ARTDelayed ART clinicaloptions.com/hiv

21 ANTIRETROVIRAL THERAPY

22 History of ART 22

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

24 24

25 Current ARV Medications NRTI  Abacavir (ABC)  Didanosine (ddI)  Emtricitabine (FTC)  Lamivudine (3TC)  Stavudine (d4T)  Tenofovir (TDF)  Zidovudine (AZT, ZDV) NNRTI  Delavirdine (DLV)  Efavirenz (EFV)  Nevirapine (NVP)  Etravirine (ETR)  Rilpivirine (RPV) PI  Atazanavir (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 Inhibitor  Enfuvirtide (ENF, T-20) CCR5 Antagonist  Maraviroc (MVC) February 2013www.aidsetc.org25 * EVG currently available only in coformulation with cobicistat (COBI)/TDF/FTC

26 Nucleoside Reverse Transcriptase Inhibitors (NRTI) Backbone of HIV combination therapyBackbone of HIV combination therapy HIV-1&2HIV-1&2 Minimal drug interactionsMinimal drug interactions Renal excreted except ABCRenal excreted except ABC Minimal cross resistance patternsMinimal cross resistance patterns

27 Abacavir(ABC, Ziagen) ABC 300mg PO twice day or 600mg PO dailyABC 300mg PO twice day or 600mg PO daily Part of Epzicom and TrizivirPart of Epzicom and Trizivir HLA-B*5701-positive patients should not receive ABCHLA-B*5701-positive patients should not receive ABC –Positive status should be recorded as an ABC allergy Life threatening if re-challengedLife threatening if re-challenged ToxicityToxicity –Hypersensitivity (HSR) ≈ 4% Fever, rash, fatigue, malaiseFever, rash, fatigue, malaise Occur within 6 weeksOccur within 6 weeks Don’t rechallengeDon’t rechallenge HLA-B*5701HLA-B* mg tablet or 20mg/ml solution 27

28 Zidovudine (AZT, Retrovir) ZDV 300mg BIDZDV 300mg BID Part of Combivir and TrizivirPart of Combivir and Trizivir First-line regimen for pregnant womenFirst-line regimen for pregnant women ToxicityToxicity –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

29 Twin Drugs Lamivudine (3TC)/ Epivir Emtricitabine (FTC)/ Emtriva 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

30 Tenofovir (TDF, Viread) FDA approved for HIV and HBVFDA approved for HIV and HBV In 2012, Truvada was approved by the FDA for pre-exposure prophylaxis (PrEP)In 2012, Truvada was approved by the FDA for pre-exposure prophylaxis (PrEP) Usually doseUsually dose –300 mg daily ToxicityToxicity –Well tolerated but rarely can lead to acute renal failure, Fanconi’s syndrome, proteinuria, – May contribute to decrease in bone mineral density 30

31 NRTI Co-formulated Regimen TruvadaTruvada –1 tablet once a daily TDF 300mg + FTC 200mgTDF 300mg + FTC 200mg CombivirCombivir –1 tablet twice a day 3TC 150mg + AZT 300 mg3TC 150mg + AZT 300 mg EpzicomEpzicom –1 tablet once daily 3TC 300mg + ABC 600mg3TC 300mg + ABC 600mg Trizivir Trizivir –1 tablet twice a day 3TC 150mg + AZT 300mg + ABC 300 mg3TC 150mg + AZT 300mg + ABC 300 mg 31

32 Adverse Effects: NRTIs All 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 2013www.aidsetc.org32

33 Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) First GenerationFirst Generation –Delavirdine [DLV, RESCRIPTOR®] –Efavirenz [EFV, SUSTIVA®] –Nevirapine [NVP, VIRAMUNE®] Second GenerationSecond Generation –Etravirine [ETR, INTELENCE®] –Rilpivirine [RPV, EDURANT] 33

34 Non-Nucleoside Reverse Transcription Inhibitors (NNRTI) HIV-2 is resistantHIV-2 is resistant Limitation of first generation NNRTILimitation of first generation NNRTI –Low genetic barrier to resistance Long half-livesLong half-lives

35 Efavirenz (EFV, Sustiva) Dosing recommendationDosing 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 ToxicitiesToxicities –CNS side effects (4 weeks) drowsiness, insomnia, vivid dreams, and impaired concentrationdrowsiness, insomnia, vivid dreams, and impaired concentration –Rash –Hyperlipidemia –Potentially teratogenicity to humans Pregnancy category DPregnancy category D 35

36 Nevirapine (NVP, Viramune) Extended release formulation was approved in 2011Extended release formulation was approved in 2011 Dose recommendationDose recommendation –200mg PO QD x 2 weeks; 200mg PO BID ToxicityToxicity –Rash including SJ syndrome –Hepatotoxicity (BB) Female with CD4 > 250 or male with CD4> 400Female with CD4 > 250 or male with CD4> 400 Liver disease (HBV, HCV or alcoholics)Liver disease (HBV, HCV or alcoholics) –Child Pugh class B or C is contraindicated 36

37 Rilpivirine (RPV, Edurant) Approval: FDA-approved May 20, 2011for treatment-naïve adultsApproval: FDA-approved May 20, 2011for treatment-naïve adults 25 mg tablet daily25 mg tablet daily –Take with 400 Kcal food Fixed doseFixed dose –Tenofovir-Emtricitabine-Rilpivirine (Complera) Toxicity (low): depression, insomnia, headache, and rashToxicity (low): depression, insomnia, headache, and rash Pregnancy : category BPregnancy : category B 37

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

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

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

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

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

43 NRTI+NNRTI Co-formulated Regimen AtriplaAtripla –EFT 600mg + FTC 200mg + TDF 300mg FTC+TDF= TruvadaFTC+TDF= Truvada –1 tablet once daily at or before bedtime CompleraComplera –RPV 25mg + FTC 200mg + TDF 300mg FTC+TDF= TruvadaFTC+TDF= Truvada 1 tablet once daily with a meal1 tablet once daily with a meal –Avoid antacids –PPI is contraindicated 43

44 Adverse Effects: NNRTIs All NNRTIs:All NNRTIs: –Rash, including Stevens-Johnson syndrome –Hepatotoxicity (especially NVP) –Drug-drug interactions 44

45 Protease Inhibitors Atazanavir [ATV, REYATAZ®]Atazanavir [ATV, REYATAZ®] Darunavir [DRV, PREZISTA®] Darunavir [DRV, PREZISTA®] Fosamprenavir [FPV, LEXIVA®] Fosamprenavir [FPV, LEXIVA®] Indinavir [IDV, CRIXIVAN®] Indinavir [IDV, CRIXIVAN®] Lopinavir/Ritonavir [LPV/r, KALETRA®] Lopinavir/Ritonavir [LPV/r, KALETRA®] Nelfinavir [NFV, VIRACEPT®] Nelfinavir [NFV, VIRACEPT®] Ritonavir [RTV, NORVIR®] Ritonavir [RTV, NORVIR®] Saquinavir [SQV, INVIRASE®] Saquinavir [SQV, INVIRASE®] Tipranavir [TPV, APTIVUS®] Tipranavir [TPV, APTIVUS®] 45

46 ARV Components in Initial Therapy: PIs ADVANTAGES Higher genetic barrier to resistanceHigher genetic barrier to resistance PI resistance uncommon with failure (boosted PI)PI resistance uncommon with failure (boosted PI) NNRTIs and II preserved for future useNNRTIs and II preserved for future use DISADVANTAGES Metabolic complications (fat maldistribution, dyslipidemia, insulin resistance) GI intolerance Potential for drug interactions (CYP450), especially with RTV February 2013www.aidsetc.org46

47 Atazanavir (ATV, Reyataz) Recommended doseRecommended dose –Naïve patient 400 mg once daily or400 mg once daily or 300 mg + 100mg RTV once daily300 mg + 100mg RTV once daily –Take with food –Avoid acid suppressing agents ToxicityToxicity –Hyperbilirubinemia –PR prolongation –Nephrolithiasis, cholelithiasis 47

48 Darunavir (DRV, Prezita) DoseDose –ARV naïve or experienced patients with no mutation 800mg mg RTV once daily800mg mg RTV once daily –ARV experienced patient with at least one mutation –DRV must be boosted with RTN –Take with food ToxicityToxicity –DRV contains a sulfonamide moiety, Avoid patients with a sulfa allergy→ RashAvoid patients with a sulfa allergy→ Rash –GI (N/V/D) –Hyperlipidemia 48

49 Lopinavir/Ritonavir (LPV/r, Keletra) The only boosted PI that is coformulated with low-dose ritonavirThe only boosted PI that is coformulated with low-dose ritonavir –LPV 200mg + RTV 50mg or LPV 100mg + RTV 25mg preferred regimen for pregnant womenpreferred regimen for pregnant women ToxicitiesToxicities –GI (N/V/D) –Hyperlipidemia (especially ↑triglycerides) –Potential increased MI risk 49

50 Ritonavir (RTV, Norvir) Booster for other PIBooster for other PI – mg per day in 1-2 divided doses FormulationFormulation –100mg soft gel capsules, 100mg tablet –80mg/mL solution 43% alcohol43% alcohol ToxicitiesToxicities –GI (N/V/D) –Hyperlipidemia –Hyperglycemia 50

51 Integrase Inhibitors RaltegravirRaltegravir Elvitegravir* (EVG)Elvitegravir* (EVG) Currently being studied in phase III clinical trialsCurrently being studied in phase III clinical trials –Dolutegravir (S/GSK ) 51 * EVG currently available only in coformulation with cobicistat (COBI)/TDF/FTC

52 Integrase Inhibitors Virologic response noninferior to EFVVirologic response noninferior to EFV appears to be active against HIV2appears to be active against HIV2 Fewer adverse events than with EFVFewer adverse events than with EFV RAL has fewer drug-drug interactions than with PIs or NNRTIs (not true of EVG/COBI)RAL has fewer drug-drug interactions than with PIs or NNRTIs (not true of EVG/COBI) NNRTIs and PIs preserved for future useNNRTIs and PIs preserved for future use February 2013www.aidsetc.org52

53 Raltegravir (RAL, Isentress) Indicated for both naïve and experienced ptIndicated for both naïve and experienced pt Dose recommendationDose recommendation –400mg po twice a day with or without food –When combined with other ART dose stays same ToxicitiesToxicities –Diarrhea, Nausea –Fatigue –Myalgia –Abnormal liver function 53

54 Stribild (Quad Pill) Approved August 2012Approved August 2012 Elvitegravir 150mg + cobicistat 150mg + emtricitabine 200mg + tenofovir 300mgElvitegravir 150mg + cobicistat 150mg + emtricitabine 200mg + tenofovir 300mg Stribild PO daily with foodStribild PO daily with food Cobicistat is used to increase the levels of elvitegravirCobicistat is used to increase the levels of elvitegravir AEAE –Decreased CrCl –Nausea, diarrhea

55 EVG/COBI/TDF/FTC recommended as “alternative” regimen in treatment-naive patients with ClCr > 70 mL/min (BI) [1]EVG/COBI/TDF/FTC recommended as “alternative” regimen in treatment-naive patients with ClCr > 70 mL/min (BI) [1] BenefitsBenefits –Noninferior to EFV/TDF/FTC, [2] ATV/RTV + TDF/FTC [3] –1-tablet, once-daily dosing LimitationsLimitations –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, Sax PE, et al. Lancet. 2012;379: DeJesus E, et al. Lancet. 2010;379: EVG/COBI/TDF/FTC: “Alternative” First-line Regimen

56 DISADVANTAGES II Twice-daily dosingTwice-daily dosing Lower genetic barrier to resistance than PIsLower genetic barrier to resistance than PIs COBI has many drug-drug interactionsCOBI has many drug-drug interactions COBI may cause or worsen renal impairmentCOBI may cause or worsen renal impairment Myopathy, rhabdomyolysis, skin reactions reported with RAL (rare)Myopathy, rhabdomyolysis, skin reactions reported with RAL (rare) February 2013www.aidsetc.org56

57 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

58 New DHHS Treatment guidelines Feb, 2013

59 Initial Treatment: Choosing Regimens 3 main categories: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 patientsCombination of NNRTI, PI, or II + 2 NRTIs preferred for most patients Fusion inhibitor, CCR5 antagonist not recommended in initial ARTFusion inhibitor, CCR5 antagonist not recommended in initial ART Few clinical end points to guide choicesFew clinical end points to guide choices Advantages and disadvantages to each type of regimenAdvantages and disadvantages to each type of regimen Individualize regimen choiceIndividualize regimen choice DHHS guideline; February 2013www.aidsetc.org59

60 Initial Regimen: Recommended/Preferred Agents DHHS Guidelines. Feb 2013; Thompson MA, et al. JAMA. 2010;304; EFVATV/RTV DRV/RTV RAL TDF/FTC +

61 Initial Regimen: Recommended/Alternative RPVLPV/RTV FPV/RTV EVG/COBI/TDF/FT C TDF/FTC or ABC/3T + 9. DHHS Guidelines for Antiretroviral Therapy in Adults and Adolescents. March DHHS Panel Statement. September 18, 2012.

62 CYP450 and Drug Metabolism CYP1A2 CYP2E1 CYP3A4 CYP2C CYP2D6 Adapted from Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 9 th ed. 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

63 3A4 2C192D62C9 1A22E12A62B62C8 Induced by:RTV, NFV, TPV EFV, NVP Inhibited by:RTV, NFV, IDV, SQV, DLV Induced by:RTV, NFV Inhibited by:DLV Induced by:EFV, NVP Inhibited by:RTV Induced by:RTV, NFV Inhibited by:EFV, DLV Induced by:RTV, NFV ? Effect of ARV on Drug Metabolism From Fichtenbaum CJ. Clin Pharmacokinet 2002:41(14):

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 ART  Providers may elect to defer ART, based on an individual patient’s clinical or psychosocial factors February 2013www.aidsetc.org64

65 Immunization MMWR / February 4, 2011 / Vol. 60 / No. 4 65

66 ART Approved & Unapproved Drugs 66

67 References Chen 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 2012G.J. Stine. AIDS update Mc Graw Hill 2012 Thompson MA, et al. JAMA. 2012;308: Thompson 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 WHO Guidelines for Antiretroviral Therapy for HIV Infection in Adults and Adolescents. July DHHS Guidelines for Antiretroviral Therapy in Adults and Adolescents. March DHHS Guidelines for Antiretroviral Therapy in Adults and Adolescents. Feb 2013 Cohen M, et al. N Engl J Med. 2011;365: DHHS Panel Statement. September 18, Sax PE, et al. Lancet. 2012;379: DeJesus E, et al. Lancet. 2010;379: ww.hivinsite.com


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