Tedavi seenekleri

TEDAV SEENEKLERDr. Fatma Sargn

stanbul Medeniyet niversitesi, Gztepe Eitim ve Aratrma Hastanesi

Tedavi SeenekleriZaman tnelinde Antiretroviraller (ART),

Onayl antiretroviraller (Amerika,Avrupa,Trkiye),

Antiretroviral snflar,

Klavuzlar ne diyor?

Antiretroviraller Zaman TnelindeStart of the EpidemicddIddCd4T3TC, SAQRTV, IDV, NVPNFV, DLV, COM, SAQEFV, ABCAPV19811984199419921991198519871995199619971999199820002001200220032005LPV/r, ddI-EC, TZVTDFEFV-600, 3TC-300, d4T-XRT-20, NFV625, ATV, FTC, FPV Kivexa, Truvada2004SQV tab, TPV, Kaletra tab*ZDV=AZT*Nucleoszidler NucleotideDier Antiretroviraller3This is a time lime of ART development, since the initial case of HIV formally described back in 198125 years have pastmany drugs have been developed. Antiretroviraller Zaman TnelindeStart of the EpidemicEtravirineViramune XRComplera2006200720082011DarunavirAtriplaMaravirocRaltegravir4This is a time lime of ART development, since the initial case of HIV formally described back in 198125 years have pastmany drugs have been developed.

Saquinavir

Zidovudine

Enfurvitide (T-20)ART-Yapsal Deiim5As time has passed increasingly complex molecules have been developed as drugs against HIV, the largest one here T20 has to be given by injection because of this

Proteaz nhibitrlerinin bir haftalk dozlar(1996)Antiretroviraller Zaman TnelindeStart of the EpidemicddIddCd4T3TC, SAQRTV, IDV, NVPNFV, DLV, COM, SAQEFV, ABCAPV19811984199419921991198519871995199619971999199820002001200220032005LPV/r, ddI-EC, TZVTDFEFV-600, 3TC-300, d4T-XRT-20, NFV625, ATV, FTC, FPV Kivexa, Truvada2004SQV tab, TPV, Kaletra tab*ZDV=AZT*Nucleoszidler NucleotideDier Antiretroviraller7This is a time lime of ART development, since the initial case of HIV formally described back in 198125 years have pastmany drugs have been developed. Olumsuzluklar

LipodistrofiDislipidemiHepatotoksisiteGastrointestinal

UyumDiren

8Problems associated with antiretroviral treatments are summarized on this slide. Lipodystrophy, in the form of lipoatrophy or lipohypertrophy, can be particularly disturbing due to the physical disfigurement which is also effectively a disclosure of HIV-positivity. The effects of HAART on lipid metabolism can also lead to serious health concerns such as coronary heart disease and insulin resistance.Complex treatment regimens comprising large numbers of pills often needing to be taken at different times of the day, make adherence to HAART a major challenge for patients, particularly in later regimens. Hepatic toxicity is also a major concern with some agents particularly in patients co-infected with HBV or HCV. Antiretroviral resistance is a major problem, with patients loosing more and more treatment options with successive treatment switches. The most common side effects of HAART are gastrointestinal. Although these are not serious they can also be a major barrier to treatment adherence. ANTRETROVRALLERNRTI bazl rejimlerGiri nhibitrleri (Koresptr antagoniztleri, ntegraz inhibitrleri)

PI bazl rejimler

NNRTI bazl rejimlerNkleozid/Nkleotid Revers Transkriptaz nhibitrleri (NRTI)Combivir (T)Lamivudine (3TC) + zidovudine (AZT=ZDV)GSK1997

EmtrivaEmtricitabine (FTC)Gilead 2003Epivir (T)Lamivudine (3TC)GSK1995Epzicom,KivexaAbacavir (ABC)+ Lamivudine (3TC)GSK2004Hivid*Zalcitabine (dideoxycytidine )(ddC)Roche1992Retrovir (T)Zidovudine (AZT=ZDV) GSK1987Trizivir (T)*Abacavir (ABC)+ Zidovudine (AZT)+Lamivudine (3TC)GSK2000Truvada (T)Tenofovir (TDF) + Emtricitabine (FTC)Gilead2004Videx ecdidanosine (ddI EC)BMS2000Videx (T)*Didanosine (ddI)BMS1991Viread (T)Tenofovir (TDF)Gilead2001Zerit (T)*Stavudine (d4T)BMS1994Ziagen (T)*Abacavir (ABC)GSK1998* Piyasada yok.,ddC satlmyor (Dnyada). Retrovir infzyon var.10Non-Nkleozid Revers Transkriptaz nhibitrleri (NNRTI)Edurant*Rilpivirine (RPV)Janssen-cilag2011ntelenceEtravirine (ETV)Janssen-cilag

2008Rescriptor*Delavirdine (DLV)Pfizer1997Sustiva, StocrinEfavirenz (EFV)BMS, MSD1998ViramuneNevirapine (NVP)Boehringer Ing1996Viramune XRNevirapine (NVP)

Boehringer Ing

2011*Avrupada henz onay yok.Sustiva Almanya,Stocrin Avusturya.Etravirine first line terapide Avrupa onay yok..11Proteaz nhibitrleri (PI)AgeneraseAmprenavir (APV)GSK1999AptivusTipranavir (TPV)Boehringer I.2005Crixivan(T)ndinavir (IDV)Merck1996Fortovase*Saquinavir Roche1997nviraseSaquinavir mesylate (SQV)Roche1995Kaletra(T)Lopinavir / ritonavir (LPV/RTV)Abbott2000Lexiva, TelzirFosamprenavir (FOS-APV)GSK2003Norvir(T)Ritonavir (RTV)Abbott1996Prezista(T)Darunavir (DRV)Tibotec2006ReyetazAtazanavir (ATV)BMS2003ViraceptNelfinavir (NFV)Agouron Phar1997SQV, Fortovase satlmyor. Telzir Trkiyede onayl ancak satta deil.Tipranavirin first line terapide avrupoada onay yok.12

Atripla (ATP)Tenofovir (TDF)+Emtrisitabin (FTC)+Efavirenz (EFV)BMS, MSD, Gilead2006Complera* (CPL)Tenofovir(TDF)+Emtrisitabin(FTC)+Rilpivirin (RPV)Gilead 2011Trizivir (TZV)

Zidovudin (AZT)+Lamivudin (3TC)+Abacavir (ABC)Viiv healthc ok Snfl Kombinasyonlar *complera avrupada onay almad.Trizivir Trkiyede onayl, satta deil.Atiripla first line terapide avrupa onay yok13

Fuzeon (T-20)

EnfuvirtideRoche2003Celsentri, Selzentry

MaravirocPfizer2007 Giri nhibitrleriFirst line terapide Avrupa onay yok.14Isentress

RaltegravirMSD2007ntegraz nhibitrleri ANTRETROVRALLERNRTI bazl rejimlerGiri nhibitrleri (Koresptr antagoniztleri, ntegraz inhibitrleri)

KlavuzlarPI bazl rejimler

NNRTI bazl rejimler

RTProvirusProteinsRNARNARTViral olgunlamaRevers transkriptazRNARNADNADNADNAAntiretroviral ajanlarn hedefleriFzyonIntegrasyonViral proteazPA-457raltegravirelvitegravir

ENF T-20

Reseptr blokerlerimaraviroc17Nkleozid/Nkleotid Revers Transkriptaz nhibitrleri (NRTI)CombivirLamivudine (3TC) + zidovudine (AZT=ZDV)GSK1997

EmtrivaEmtricitabine (FTC)Gilead 2003EpivirLamivudine (3TC)GSK1995Epzicom,KivexaAbacavir (ABC)+ Lamivudine (3TC)GSK2004HividZalcitabine, dideoxycytidine (ddC)*Roche1992RetrovirZidovudine (AZT=ZDV) GSK1987TrizivirAbacavir (ABC)+ Zidovudine (AZT)+Lamivudine (3TC)GSK2000TruvadaTenofovir (TDF) + Emtricitabine (FTC)Gilead2004Videx ecdidanosine (ddI EC)BMS2000VidexDidanosine (ddI)BMS1991VireadTenofovir (TDF)Gilead2001ZeritStavudine (d4T)BMS1994ZiagenAbacavir (ABC)GSK1998Azidotimidin,ddC satlmyor.18Nkleozid/Nkleotid Revers Transkriptaz nhibitrleri (NRTI)Combivir

Lamivudine (3TC) + zidovudine (AZT=ZDV)GSK1997

Epzicom,Kivexa

Abacavir (ABC)+ Lamivudine (3TC)GSK2004TrizivirZidovudine (AZT)+Lamivudine (3TC)+Abacavir (ABC)GSK2000Truvada

Tenofovir (TDF) + Emtricitabine (FTC)Gilead2004Azidotimidin,ddC satlmyor.19Hangi NRTI? (AZT/3TC) Combivir

Uzun dnem etkileri biliniyorLipodistrofi riskiHamilelerde neriliyorBOSa geii iyi

(TDF/FTC) Truvada

EtkinRenal disfonksiyon?Kemik zerine etki?

(ABC/3TC) Kivexa

HSR iin HLA testiMI riski?Yksek viral ykte etkinlikte azalma?

Others:

d4T/3TC:lipoatrofid4T/ddI:lipoatrofi, mitochondrial toksisiteTDF/ddI:toksisiteddI/3TC:?

Combivir:En ok kullanlm olan-Truvada: en popler20AntiretrovirallerNRTI bazl rejimlerGiri nhibitrleri (Koresptr antagoniztleri, ntegraz inhibitrleri)

KlavuzlarPI bazl rejimler

NNRTI bazl rejiimlerNon-Nkleozid Revers Transkriptaz nhibitrleri (NNRTI)Edurant*Rilpivirine (RPV)Janssen-cilag2011ntelenceEtravirine (ETV)Janssen-cilag

2008Rescriptor*Delavirdine (DLV)Pfizer1997Sustiva, StocrinEfavirenz (EFV)BMS, MSD1998ViramuneNevirapine (NVP)Boehringer Ing1996Viramune XRNevirapine (NVP)

Boehringer Ing

2011*Avrupada henz onay yok.22NNRTI1990da tanmlandlar,

Etkinlii tedavi naive hastada PIlar kadar iyi,

Yar mrleri uzun,

Tedavini durdurulmas planlanyorsa NNRTI birka gn nce kesilmeli,

NNRTI deneyimli hastada biraz daha az olabiklir,

23Nevirapine=VRAMUNElk NNRTI (1997),Lopinavir/r ile edeer etkinlikte (2010),Toksik hepatit,Hipersensitivite,CD4 dzeyleri,Tek doz kullanmda toksisite? (2NN, ARTEN)NNRTINevirapineEfavirenzMSS yan etki+/-+++Hepatotoksisite+++Dislipidemi-+++Jinekomasti-+++Dknt++++NNRTINevirapineEfavirenzEtravirineRilpivirineDelavirdineEtkinlik+++++++++++++++Genetik bariyer+++++++++Teratojenite-++++MSS yan etkisi+/-+++++Hepatotoksisit+++Dislipidemi-++++Dknt+++++++++++++QT uzama+++ ANTRETROVRALLERNRTI bazl rejimlerGiri nhibitrleri (Koresptr antagoniztleri, ntegraz inhibitrleri)

KlavuzlarPI bazl rejimler

NNRTI bazl rejimler

RTProvirusProteinsRNARNARTViral olgunlamaRevers transkriptazRNARNADNADNADNAAntiretroviral ajanlarn hedefleriFzyonIntegrasyonViral proteazPA-457raltegravirelvitegravir

ENF T-20

Reseptr blokerlerimaravirocvicriviroc28Here is the life-cycle of HIV within a cell and the points at which drugs can be used to interfere with this processProteaz nhibitrleri (PI)AgeneraseAmprenavir (APV)GlaxoSmithKline1999AptivusTipranavir (TPV)Boehringer Ingelheim2005Crixivanndinavir (IDV)Merck1996FortovaseSaquinavir,sat yokHoffmann-La Roche1997nviraseSaquinavir (SQV)Hoffmann-La Roche1995KaletraLopinavir / r (LPV/RTV)Abbott Laboratories2000Lexiva, TelzirFosamprenavir (FOS-APV)GlaxoSmithKline2003NorvirRitonavir (RTV)Abbott Laboratories1996PrezistaDarunavir (DRV)Tibotec, Inc.2006ReyetazAtazanavir (ATV)Bristol-Myers Squibb2003ViraceptNelfinavir (NFV)Agouron Pharmaceuticals199729Proteaz nhibitrleriTipranavirLopinavir/rDarunavirAtazanavirEtkinlikPI direncinde+++PI direncinde+++Dislipidemi++++--nslin direnci++-Sarlk+++la etkileimiEfavirenzLop,silden,strPPIGIS yan etki++--Dknt+/++Transaminaz y.+++-+Doz2x42x2/1x42x21x2Tipranavir sadece tedavi deneyimlilerde onayl. Darunavir deneyimli ve naivelerde onayl.30Neden glendirilmi PI?Ritonavir; gl bir CYP3A4 inhibitr,Dier PIlar ile etkileiyor,

Yan etki fazla,Plazma dzeyleri llmeli (ciddi karacier hastalklarnda)

Sitokrom p 450 nin izoenzimi31Hangi PI?Glendirilmi PIlar daha stn,

Karlatrmal almalar:

r/LPV = r/FPV (KLEAN)r/LPV = r/SQV (Gemini)r/LPV = r/ATV (Castle)r/LPV =/< r/DRV (Artemis)

AntiretrovirallerNRTI bazl rejimlerGiri nhibitrleri (Koresptr antagoniztleri, ntegraz inhibitrleri)

KlavuzlarPI bazl rejimler

NNRTI bazl rejiimlerGiri nhibitrleriKoreseptrlereBalanmaCCR5 or CXCR4

CCR5 antagonistleri

Virus-HcreFzyonuFusion inhibitrleri

gp41gp120V3 loopCD4eTutunmaCD4Hcre membranCD4 attachmentinhibitorleriMoore JP, et al. Proc Natl Acad Sci USA 2003;100:1059860234An understanding of the mechanism by which HIV gains entry into the host cell has led to the identification of several potential new targets for antiretroviral (ARV) drugs. The entry of HIV into CD4-expressing cells can be divided into three discrete sequential steps, each of which offers potential targets for new ARV drugs.1 First, the attachment of the viral glycoprotein 120 (gp120) to the CD4 receptor leads to subtle conformational changes in gp120. [Click to advance animation] These changes expose structural elements on the V3 loop that then bind to a co-receptor, either CCR5 or CXCR4. [Click to advance animation] This in turn induces a structural rearrangement in gp41 which is then able to insert a hydrophobic fusion peptide region into the target cell membrane. This brings the virus and cell membranes into close apposition to initiate fusion and ultimately entry of the viral core into the target cell.HIV entry inhibitors can be classified into distinct classes targeting different steps in the entry process. This slide indicates the points of action of some of the classes of inhibitors/antagonists that are in clinical development: CD4 attachment inhibitors, CCR5 antagonists and fusion inhibitors. MVC is the first CCR5 antagonist to be approved for use in treatment-experienced HIV-1-infected patients.

ReferencesMoore JP, Doms RW. The entry of entry inhibitors: A fusion of science and medicine. Proc Natl Acad Sci USA 2003;100:10598602.Celsentry=Selzentry(Maraviroc)CCR5 reseptrlerindeki deiiklik (viral gp 120nin balanmasn engeller),Dier ARTlere gre CD4 daha iyi ykseltir,Tropizm testleri yaplmal,Fuzeon(T-20, Enfuvirtide)SC enjeksiyon en nemli dezavantaj,

Hastalar Raltegravir gibi ajanlarla tedavi edilebilecekler. Enjeks blgesinde inflamasyon

36AntiretrovirallerNRTI bazl rejimlerGiri nhibitrleri (Koresptr antagoniztleri, ntegraz inhibitrleri)

KlavuzlarPI bazl rejimler

NNRTI bazl rejiimlerntegraz nhibitrleriHIV replikasyonunda nemli 3 enzim var;Revers transkriptazProteazntegraz; viral DNAnn konak genomuna integre olmasn salar.

nsan hcrelerinde bu enzim yok.Isentress(Raltegravir)3 snfa direnli, naive hastalarda,yi tolere ediliyor,Yan etki yok denebilir,Rifampisin ile kan dzeyi debilir, omeprazol ile artar,Renal yetersizlikte doz ayarlamas yok,Doz; 2x400 mg/gn.Isentress(Raltegravir)TDF/FTC+RALTDF/FTC+EFV ile etkinlii ayn

PIl rejimlerle karlatrmas yok

AntiretrovirallerNRTI bazl rejimlerGiri nhibitrleri (Koresptr antagoniztleri, ntegraz inhibitrleri)

KlavuzlarPI bazl rejimler

NNRTI bazl rejiimlerART nerileri198819982008DHHSAZT2RT+PI2RT+PI2RT+NNIASAZT2RT+PI2RT+PI2RT+NNEACS2RT+PI2RT+NNBHIVA2RT+NN2RT+PI2RT+NN(2RT+PI)Gncel neri2 NRTINNRTIPI/rRaltegravirMaravirocDHSS,2011Tercih edilen rejimler,Alternatif rejimler,Kabul edilebilir rejimler,Temkinli olunmas gereken rejimler,DHSS ,2011Tercih Edilen Rejimler Tedavi almam hastada neriler;

Tenofovir/emtrisitabin+ Efavirenz (AI)Tenofovir/emtrisitabin+ Atazanavir/r (AI)Tenofovir/emtrisitabin+ Darunavir/r (AI)Tenofovir/emtrisitabin+ Raltegravir (AI)

Efavirenz, teratojenik-Atazanavir omeprazolle etkielir-45DHSS ,2011Tercih Edilen Rejimler(Gebelerde)AZT/3TC+Lopinavir/r (AI)

(Tek doz Lopinavir/r nerilmez).

Alternatif Rejimler NNRTI bazl rejimler

ABC/3TC+Efavirenz (BI)TDF/FTC+RPV (BI)ABC/3TC+RPV (BIII)-PPI,HIV RNA

Rilpivirin;PPI ile kullanm kontrendike.HIV RNA 100 000 kopya zeri dikkatli ol.!47Alternatif Rejimler PI bazl rejimler

ABC/3TC+ATV/r (BI)ABC/3TC+DRV/r (BIII)

ABC/3TC veya TDF/FTC+FPV/r (BI)ABC/3TC veya TDF/FTC+LPV/r (BI)FPV ve LPV gnde bir veya iki doz olabilir48Alternatif Rejimler INSTI bazl rejimler

ABC/3TC+RAL (BIII)

ABC; HLA B5701,100 000 kopya, Yksek kardiyovaskler risk49Tedavi nerileri (EACS 2011)Efavirenz,Nevirapin

ABC/3TC veya TDF/FTC

TDF/FTCATV/rDRV/rLPV/rABC/3TC veya TDF/FTCRALTDF/FTCSQV/r FPV/r MVCZDV/3TC dd/3TC veya FTCART-TBC (EACS 2011)Efavirenz (800 mg)

Rifampisin

Efavirenz Rifabutin (450 mg/gn)ATV/r,DRV/r,LPV/r,SQV/r Rifabutin:150x3/haftada)

RaltegravirAlternatifMaravirocx2MaravirocRifampisinRifabutinmCV rifampisin ile doz artrlmal.51Kurtarma Tedavisi3 grup ARTe diren varsaNRTI, NNRTIs, PI

Ama;Virolojik stabilite (spresyon deil)CD4 dnde yavalama,TEEKKR EDERM