... konulu sunumlar: "Kan transfüzyonları ve HIV Bulaş – Güncel tedavi"— Sunum transkripti:
1 Kan transfüzyonları ve HIV Bulaş – Güncel tedavi Prof. Dr. Volkan KortenMarmara Üniversitesi Tıp Fakültesiİnfeksiyon Hast. ve Klin. Mikrobiyoloji AD
2 HIV/AIDS VAKALARI (1 Ekim 1985-30 Haziran 2007) 2073 HIV, 638 AIDS vakası, Toplam 2711 Altan P, 2007
3 MUHTEMEL GEÇiŞ YOLUNA GÖRE HIV/AIDS VAKALARI (1 Ekim Haziran n:2404)n:5, n:10 hemofiliAltan P, 2007
4 Uygun viral antikor ve antijen (P24) taramasına rağmen Kan, donörden infeksiyonun çok erken dönemlerinde “seronegatif pencere periyodu”toplanırsa HIV bulaşı mümkünBu nedenle bazı ülkelerde havuzlanmış kanlara “nükleik asid amplifikasyon testleri” uygulanıyor. NAT ile pencere 16 g → 10 gNAT sonrası bulaş: HIV (1:1.4 milyon)HCV 1.2 m, HBV 150 binTRENDS in Molecular Medicine 2002;8:355-8
5 Avrupa Birliği - ABD Sadece serolojik testlerle bulaş 1:1.3 milyon, NAT ile 1: 2-4 milyonNAT’ın maliyet-yarar oranı çok düşükYanlış kan transfüzyonları ve immunolojik yan etkileri önlemek çok daha önemliTransfusion Clinique et Biologique 2003;10:1–5.
7 HIV’in yoğun görüldüğü ülkeler Nijerya (erişkin ~ % 5)Kan bankalarından rastgele serolojik taramada negatif çıkmış 500 kanAntijen (+): 6 (%1.2) = WB: 4 şüpheli, PCR (+): 3Epideminin yoğun görüldüğü Afrika ülkelerinde transfüzyonla bulaş önemli bir sorunTransactions of the Royal Society of Tropical Medicine and Hygiene (2008) 102, 284—287
8 Antiretroviral ilaçlar etki mekanizması MS18Antiretroviral ilaçlar etki mekanizmasıSlide 1.2PI buraya etkiliProteaseNNRTIBuraya etkiliViral assemblyTranslationProtein cleavageRNA and reverse transcriptionTranscriptionInjection of capsid contentsThe combination of STOCRIN™ and indinavir (IDV) provides effective therapy because the combination takes advantage of the different modes of action of these drugs. Together, these agents attack HIV at two critical points in the viral replication cycle.1STOCRIN acts early in virion assembly. By binding directly to reverse transcriptase and thus blocking the conversion of viral RNA into DNA, STOCRIN prevents the virus from using the host cell’s mechanisms to create another generation of viral particles.1,2IDV, on the other hand, acts at the final stages of virion assembly. A competitive inhibitor of HIV protease, IDV blocks the cleavage of viral particles into functional enzymes and proteins. Viral proteins formed in the presence of IDV are defective and noninfectious, incapable of establishing new cycles of infection.1IntegraseRNADNAProvirus (circular structure)MaturationIntegration of Provirus DNA into Host DNAHIV particleBindingCompleted HIV particleAdapted from HIV/AIDS Handbook. 4th ed. Boston: Total Learning Concepts, 1999; Ritchie DJ. In: Powderly WG, ed. Manual of HIV Therapeutics. Philadelphia: Lippincott-Raven, 1997:33-41.
10 Geliştirilmekte olan yeni antiretroviraller: Varolan ilaç sınıfları TNX-355CCR5 inhibitorsCXCR4 inhibitorsMaturatio PA-457MK-0518GS-9137Entry inhibitorsReverse transcriptase inhibitorsMature virusProtease inhibitorsIntegrase inhibitors
11 Yeni antiretrovirallerin piyasaya verilme tahminleri CXCR4 inhibitorsEntry inhibitors(anti-gp120, CCR5)GS-9137Maturation inhibitorsVicrivirocIntegrase inhibitorsMaravirocTNX-355MK-0518Bevirimat (PA-457)20062007200820092010Etravirine (TMC125)TMC278PIsBrecanavirNNRTIApricitabineNRTI
12 TEDAVİ HEDEFLERİ Etkinlik Maksimal ve uzun süreli viral yük baskılanmasıTedaviye uyum çok önemliTolerabiliteGünlük aktivitelere olan etkiyi minimale indirmekTedaviye uyumu, böylece etkinliği etkileyebilirEmniyetZarar verme: emin bir tedavi rejimi sağlaKurtarma rejimine olanak sağlaİlerideki tedavi seçeneklerine olanak sağla
13 Başlangıç tedavisi: NNRTI’ler AvantajlarPI-temelli rejimlere göre daha az yağ dağılımı ve dislipidemi problemiGelecekte PI seçeneği korunurDezavantajlarTek mutasyonla - dirençNNRTI’ler arası çapraz dirençRaş; hepatotoksisitePotansiyel ilaç etkileşimleri (CYP450)
14 Başlangıç tedavisi: PI’leri AvantajlarEn uzun prospektif bilgiGelecekte NNRTI seçeneği korunurDezavantajlarMetabolik komplikasyonlar (yağ dağılımı, dislipidemi, insulin rezistansı)Daha fazla potansiyel ilaç etkileşimleri (CYP450), özellikle ritonavir ile
15 NRTI’ler: advers etkiler Tüm NRTI’ler:Laktik asidoz ve KC yağlanması (stavudine ile daha yüksek)Lipodistrofi (stavudine ile daha yüksek)The combined use of didanosine and stavudine as a 2-NRTI backbone can result in a high incidence of toxicities, particularly peripheral neuropathy, pancreatitis, and lactic acidosis [50, 87, 99].This combination has been implicated in several deaths in HIV-1 infected pregnant women secondary to severe lactic acidosis with or without hepatic steatosis and pancreatitis . In general, a combination containing didanosine and stavudine should be avoided unless other 2-NRTI combinations have failed or have caused unacceptable toxicities, and where potential benefits outweigh the risks of toxicities (DIII).
16 Antiretroviral ilaçların gelişim çizelgesi Combivir 00Truvada 089499DLV02 ?9897NVPddC95ABCTDF97ZDVddId4TEFV06-07FTC3TC’87’88’89’90’91’92’93’94’95’96’97’98’99’00’01’02’03’04’05’06’07Speaking Notes:Once again you see all the ARVs currently approved for use in the US market, this time mapped by their year of release.Note that from 1987 to 1995, the first 5 ARV drugs developed were all nucleoside analogues.Thus, when the idea of combining drugs together arose, the first combinations utilized drugs that were then available, i.e., a pair of nucleosides: either zidovudine (Retrovir) and zalcitabine (Hivid), didanosine (Videx), or lamivudine (Epivir), or the combination of lamivudine (Epivir) and stavudine (Zerit).NRTISQRNFVLPV/rATV01NNRTIFPVDRVPI97APVRTVTPVEntry inhibitorT-20MVC98IDV
17 Daha önce tedavi almamış hastalarda başlangıç tedavisi: Rejimi seçmek Göz önüne alınması gereken faktörler:Ko-morbidite (KC, psikiyatrik, kardiyovasküler hastalık, tüberküloz, gebelik)Uyum potansiyeliDoz uygunluğu (hap sayısı, doz aralığı)Potansiyel yan etkilerPotansiyel ilaç etkileşimleriGebe kalma riskiDirenç testi sonuçlarıCins ve CD4 sayısı, eğer nevirapine düşünülüyorsa
18 Kronik infeksiyonda tedavi başlama endikasyonları Klinik kategoriCD4+ T hücre sayısıPlasma HIV RNAÖnerilerSemptomatik (AIDS, şiddetli semptomlar), gebeler, HIVAN, HepB ko-inf.Herhangi bir değerTedavi etAsemptomatik, AIDS<200 hücre /µLAsemptomatik>200 hücre/µL, fakat <350 hücre/µLThe decision to begin therapy for the asymptomaticpatient is complex and must be made in the setting ofcareful patient counseling and education.Considerations of initiating antiretroviral therapyshould be primarily based on the prognosis of diseasefreesurvival as determined by baseline CD4+ T cellcount [60-62] (Figure A and Tables 4a, 4b). Alsoimportant are baseline viral load [60-62], readiness ofthe patient to begin therapy; and assessment ofpotential benefits and risks of initiating therapy forasymptomatic persons, including short-and long-termadverse drug effects; the likelihood, after counselingand education, of adherence to the prescribed treatmentregimen.Recommendations vary according to the CD4 countand viral load of the patient, as follows.<200 CD4+ T cell count, with AIDS-defining illness,or symptomatic. Randomized clinical trials providestrong evidence of improved survival and reduceddisease progression by treating symptomatic patientsand patients with <200 CD4+ T cells/mm3 [63-66].Observational cohorts indicate a strong relationshipbetween lower CD4+ T cell counts and higher plasmaHIV RNA levels in terms of risk for progression toAIDS for untreated persons and antiretroviral-naïvepatients beginning treatment. These data provide strongsupport for the conclusion that therapy should beinitiated in patients with CD4+ T cell count <200cells/mm3 (Figure A and Table 4a) (AI) [60, 61].CD4+ T cell count, patientasymptomatic. The optimal time to initiateantiretroviral therapy among asymptomatic patientswith CD4+ T cell counts >200 cells/mm3 is unknown.For these patients, the strength of the recommendationfor therapy must balance other considerations, such aspatient readiness for treatment and potential drugtoxicities.After considering available data in terms of the relativerisk for progression to AIDS at certain CD4+ T cellcounts and viral loads, and the potential risks andbenefits associated with initiating therapy, mostspecialists in this area believe that the evidence supportsinitiating therapy in asymptomatic HIV-infected personswith a CD4+ T cell count of cells/mm3 (BII).There is a paucity of data from randomized, controlledtrials concerning clinical endpoints (e.g., thedevelopment of AIDS-defining illnesses or death) forasymptomatic persons with >200 CD4+ T cells/mm3 toguide decisions on when to initiate therapy.Observational data from cohorts of HIV-infectedpersons provide some guidance to assist in riskassessment for disease progression.One source of observational data comes from cohortsof untreated individuals with regular measurements ofCD4+ T cell counts and HIV RNA levels. Table 4b istaken from a report by the CASCADE Collaboration,composed of 20 cohorts in Europe and Australia .The information in this table provides an estimate ofthe short-term (6-month) risk of AIDS progressionaccording to CD4+ T cell count, HIV RNA level, andage. These estimates can be considered in making thedecision about whether to start antiretroviral therapybefore the next clinic visit.Another source of observational data is from cohortsthat follow patients after the initiation of antiretroviraltreatment. A pooled analysis of 13 cohorts fromEurope and North America provide the most preciseinformation on prognosis following the initiation oftreatment . These data indicate that CD4+ T cellcount is a much more important prognostic indicatorthan viral load for those initiating therapy. In thisstudy, risk of progression was also greater for thosewith a viral load >100,000, older patients, thoseinfected through injecting drug use, and those with aprevious diagnosis of AIDS. The following chartshows the risk of progression to AIDS or death after 3years, according to CD4+ T cell count and HIV RNAlevel at the time antiretroviral therapy was initiated.These data are from a large subset of patients less than50 years old and without a history of an AIDSdefiningillness or injection drug use:CD4+ T cell count 3 yr-probabilityVL <105 VL >105cells/mm3 16 % 20%cells/mm3 12 % 16%cells/mm3 9.3 % 12%cells/mm3 4.7 % 6.1%>350 cells/mm3 3.4 % 4.4%These data provide strong support for therecommendation, based on observational cohort , thattherapy should be initiated before the CD4+ T cellcount declines to <200 cells/mm3. However,differences in risk for those with CD4+ T cell countsbetween 200–350 and >350 cells/mm3 are based on toofew events, and too short a follow-up period, to makereliable statements about when treatment should bestarted.Athough there are clear strengths to theseobservational data, there are also importantlimitations. Uncontrolled confounding factors couldimpact estimates in both studies. Furthermore, neitherstudy provides direct evidence on the optimum CD4+T cell count to begin therapy. Such data will have tocome from studies that follow patients who starttherapy at different CD4+ T cell counts greater than200 cells/mm3 and compare them with a similar groupof patients (e.g., with similar CD4+ T cell count andHIV RNA level) who defer treatment. To completelybalance the benefits and risks of therapy, follow-upwill have to examine progression to AIDS, majortoxicities, and death.>350 CD4+ T cell count, patient asymptomatic.There is little evidence on the benefit of initiatingtherapy in asymptomatic patients with CD4+ T cellcount > 350 cells/mm3. Most clinicians would defertherapy.• The deferred treatment approach is based on therecognition that robust immune reconstitution stilloccurs in the majority of patients who initiatetreatment while CD4+ T cell counts are in the 200–350 cells/mm3range. Also, toxicity risks andadherence challenges generally outweigh thebenefits of initiating therapy at CD4+ T cell counts>350 cells/mm3. In the deferred treatment approach,increased levels of plasma HIV RNA (i.e., >100,000copies/mL) are an indication for monitoring ofCD4+ T cell counts and plasma HIV RNA levels atleast every three months, but not necessarily forinitiation of therapy. For patients with HIV RNA<100,000 copies/mL, therapy should be deferred(DII).• In the early treatment approach, asymptomaticpatients with CD4+ T cell counts >350 cells/mm3and levels of plasma HIV RNA >100,000copies/mL would be treated because of the risk forimmunologic deterioration and disease progression(CII).An estimate of the short term risk of AIDS progressionmay be useful in guiding clinicians and patients as theyweigh the risks and benefits of initiating versusdeferring therapy in this CD4 cell range. As cited above,Table 4b provides an analysis of data from theCASCADE Collaboration, demonstrating the risk ofAIDS progression within 6 months for different strata ofCD4+ T cell count, viral load, and age. As seen in Table4b, a 55 year old with a CD4+ T cell count of 350 and aHIV viral load of 300,000 copies/mL has a 5% chanceof progression to an AIDS-defining diagnosis in 6months, compared with a 1.2% chance for a similarpatient with a viral load of 3,000 copies/mL.1/08
19 Kronik infeksiyonda tedavi başlama endikasyonları Klinik kategoriCD4+ T hücre sayısıÖnerilerAsemptomatik>350 hücre/µLOptimal başlama zamanı belli değil. Hasta senaryoları ve komorbiditeler göz önüne alınmalı≥100,000 kopye/mLYılda > 120 hücre CD4 düşüşüEfektif tedavisi olmayan durumlar (demans, PMLE, cryptosporidiosis vs)1/08
20 CD4+ hücre sayısına göre HAART başlangıcında kümülatif AIDS/ölüm olasılığı : ART Cohort Collaboration.Sterne J, CROI 2006; Abstract 525.
21 Yıllar içinde CD4 artışı – Johns Hopkins HIV Clinical Cohort Moore RD, CID 2007; 44:441–6
22 Non-AIDS–Related Death CASCADE: En düşük düzeydeki CD4+ hücre sayısı - AIDS ve AIDS-dışı olayları belirlerCASCADE Collaboration cohort: N = 9858En son ve en düşük CD4+ hücre sayısı< 350 hücre/mm3 altında geçirilen zamanAIDS-Related DeathNon-AIDS–Related DeathNadir CD4+ cell countvs ≥ 350vs ≥ 350vs ≥ 350vs ≥ 350< 50 vs ≥ 350< 50 vs ≥ 3500.011.00100.000.011.00100.00Liver Disease DeathNon-AIDS Cancer Deathvs ≥ 350vs ≥ 350vs ≥ 350vs ≥ 350< 50 vs ≥ 350< 50 vs ≥ 3500.011.00100.000.011.00100.00Marin B, et al. IAS Abstract WEPEB019.
23 Percentage With HIV-1 RNA < 50 copies/mL at Week 48 HAART etkinliği: > 65% cevap alınan çalışmalar (VL < haftada)COMBINE (NVP + ZDV/3TC)2NN (NVP BID + d4T + 3TC)ZODIAC (EFV + ABC QD + 3TC)M (LPV/RTV + d4T + 3TC)ZODIAC (EFV + ABC + 3TC)CNA30024 (EFV + ZDV + 3TC)2NN (NVP QD + d4T + 3TC)2NN (EFV + d4T + 3TC)CNA30024 (EFV + ABC + 3TC)M (LPV/RTV + FTC + TDF QD)FTC301 (EFV + FTC + ddI QD)DMP (EFV + D4T + 3TC)CLASS (EFV + ABC + 3TC)ANRS (EFV + ddI + 3TC)M (LPV/RTV + d4T + 3TC)Dart 1 (EFV + ddI EC + 3TC)GS903 (EFV + d4T + 3TC)GS903 (EFV + TDF + 3TC)ANRS 091 (EFV + ddI + FTC)NNRTIBoosted PIEfficacy is a primary factor in choosing between NNRTI-based and PI-based regimens.To investigate this issue, Bartlett and colleagues performed a systematic overview of clinical trials that evaluated 3-drug antiretroviral therapy in treatment-naive HIV-infected adults.They included 49 clinical trials involving more than 13,147 patients.The primary endpoint of the analysis was virologic responses, defined as the proportion of patients with HIV RNA < 50 copies/mL at Week 48, based on an intent-to-treat analysis.They also evaluated immunologic responses, defined as mean increases in CD4+ cell count at Week 48, using an on-treatment analysis.Among those regimens with > 65% efficacy, 2 agents stand out: efavirenz and lopinavir/ritonavir.30405060708090100Percentage With HIV-1 RNA < 50 copies/mL at Week 48Bartlett JA, et al. AIDS. 2006;20:
25 Akut veya yakın (< 6 ay) HIV infeksiyonunun tedavisi Tedavi opsiyonel (uzun süreli virolojik, immunolojik ve klinik fayda bilinmiyor)Teorik olarakakut hastalığın şiddetini azaltır,tam tahrip olmadan immun sistemi korur,viral mutasyonu azaltır,başlangıç viral platoyu değiştirir,GI lenfoid doku kaybını önler,bulaş riskini azaltır.Başlangıç direnç testi yapılmalı, yapılamıyor veya gecikecekse PI-temelli rejim
26 EACS – temas sonrası profilaksi TDF/FTC (Truvada)(alternatif: ZDV/3TC - Combivir)+LPV/r günde 2 kez4 hf
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