HIV update HIV cyclus overzicht eind Kees Brinkman patiëntendag 17 Januari HIV infectie snelheid van transmissie

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1 HIV update 2014 Kees Brinkman patiëntendag 17 Januari 2014 Totaal volwassenen OLVG AMC-UvA Erasmus MC UMCU St Elisabeth Zkh 880 MCH - Westeinde 805 UMCG 707 Slotervaart Zkh 684 AZM 637 MC Jan van Goyen 630 Rijnstate 598 Haga Zkh - Leyweg 586 LUMC 571 UMC St Radboud 569 Maasstad Zkh 537 Catharina Zkh 488 VUMC 463 MST 410 Kennemer Gasthuis 367 Isala Klinieken - Sophia 366 St Lucas Andreas Zkh 298 MCA 259 MC Leeuwarden 230 Flevo Zkh 138 Admiraal De Ruyter Zkh 125 MC Zuiderzee 48 overzicht eind 2012 HIV cyclus HIV infectie snelheid van transmissie gp-120 HIV CCR5 CXCR4 T-cel 4-8 uur CD4 reverse transcriptase RNA uur DNA integrase Virus productie: virusdeeltjes/dag protease Pope & Haase pg 847-1

2 HIV beloop belang CD 4 cellen viral load en besmettings risico 200 / mm weken 2-10 jaren candida PCP viral load CD 4 toxoplasmose CMV MAC CD 4 Rakai (Uganda) 453 HIV-disc. couples 11.6 % TR / year % partners infected < '000 HIV-RNA load (cp/ml) 10'000- > '000 Quinn, NEJM, 2000; 342: HIV beloop en transmissiekans moment van diagnose HIV load CD kliniek diagnose 200 / mm 3 transmissie kans HIV THERAPIE weken 2-10 jaren patiënt met vroege infectie = bron voor 50% nieuwe infecties 2

3 hiv medicijnen attachment inhibitors gp-120 HIV CCR5 CCR5 blockers maraviroc, CXCR4 maturation inhibitors fusion inhibitors T20 CD4 viral load reverse transcriptase CD 4 NRTI s AZT, ddc, ddi, d4t, 3TC, ABC,FTC TDF Non-NRTI s NVP, EFV ETR RLP INSTI raltegravir elvitegravir dolutegravir integrase protease PI s RTV, SQV, IND, NLF, famp, LPV, ATV, TPV, DRV weeks time years doel van behandeling: volledige virus onderdrukking goedgekeurde hiv medicijnen: AZT ddc d4t ddi EFV ABC RTV IDV NFV DLV NVP 3TC SQV TDF LPV/r APV ENF ATV FTC FPV TPV ETR RAL MVC DRV DTG EVG RPV triple combinatie = standaard HIV RNA <500 copies/ml Gulick et al. 3

4 TDF/FTC better than AZT/3TC Non nucleosides (NNRTI s) welke cart?? efavirenz (EFZ) etravirine (ETR) nucleosides (NRTI s) 3rd drug: efavirenz nevirapine (NVP) 2x rilpiverine (RLP) zidovudine (AZT) protease remmers (PI s) lamivudine (3TC) (=FTC) indinavir/r tenofovir (TDF) lopinavir/r (kaletra ) didanosine (ddi) saquinavir/r abacavir (ABC) fosamprenavir/r stavudine (d4t) atazanavir/r darunavir/r integrase remmers (INSTI s) raltegravir overig Gallant et al. NEJM elvitegravir/cobi maraviroc enfuvirlde (s.c.) dolutegravir : simplificatie 2008 iedereen HAART? wanneer te starten? waarmee starten? richlijnen 4

5 Starting Antiretroviral Therapy in 2012: A Compendium of Interactive Cases Starting Antiretroviral Therapy in 2012: A Compendium of Interactive Cases clinicaloptions.com/hiv clinicaloptions.com/hiv DHHS Guidelines, 2013: When to Start 2013 Update: EACS Guidelines for Treatment of HIV-Infected Pts in Europe ART recommended for all HIV-infected patients; strength of recommendation varies according to CD4+ cell count Recommendation for ART initiation remains at CD4+ cell counts < 350 cells/mm3 CD4+ Cell Count Recommendation < 350 cells/mm³ Start ART (AI) cells/mm³ Start ART (AII) > 500 cells/mm³ Start ART (BIII) ART can be considered at higher CD4+ counts, depending on pt readiness Guideline AIDS or HIVRelated Symptoms < 350 CD4+ Cell Count > 500 EACS[1] Consider Consider US DHHS[2] IAS-USA[3] WHO[4] Not addressed Clinical Conditions Favoring Initiation of Therapy Regardless of CD4+ Cell Count History of AIDS-defining illness (AI) Pregnancy (AI) HIV-associated nephropathy (AII) HBV coinfection (AII) Patients at risk of transmitting HIV to sexual partners (AI, heterosexuals; AIII, others) HCV coinfection* (BII) Patients > 50 years of age (BIII) *Including those with high CD4+ cell count and/or with cirrhosis. Some pts with CD4+ counts > 500 cells/mm³ may elect to defer ART until after HCV therapy is completed. DHHS Guidelines for Antiretroviral Therapy in Adults and Adolescents. March 27, nieuwe medicijnen? Changes in initial regimen recommendations in EACS guidelines: NNRTIs: NVP now alternative rather than preferred Boosted PIs: LPV/RTV now alternative rather than preferred INSTIs: TDF/FTC/EVG/COBI added as alternative regimen 1. EACS. February DHHS. Guidelines. February IAS-USA. Guidelines. July WHO. ART Guidelines. June Elvitegravir/cob = Efavirenz elvitegravir (201312) dolutegravir (20147?) generiek: 3TC, NVP, EFZ, ABC TAF (new TDF) MK-NNRTI? BMS-NRTI? generiek TDF, ATV, ritonavir etc 5

6 huidige ontwikkeling: nieuwe 3-combi s: 1x daags Dolutegravir better Efavirenz TDF/FTC vs ABC/3TC Atripla Approved 2007 Truvada/RPV complera eviplera juni 2012 Quad/Stribild Elvitegravir/cob/ TVD FDA approved aug 12 NL approval: dec 13 FLAMINGO DTG(n=242) 90 GS-103 EVG/cob (n=353) 90 GS-102 EVG/cob(n=348) 88 * SPRING-2 DTG (n=411) 88 * SINGLE DTG (n=414) 88 GS-103 ATV + RTV (n=355) 87 STARTMRK RAL (n=281) 86 GS-102 ATRIPLA (n=352) 84 ARTEMIS DRV + RTV (n=343) 84 FLAMINGO DAR/r (n=242) ECHO/TRHIVR RPV (n=550) ECHO/TRHIVR EFV (n=546) Registrational Treatment-Naive Clinical Trials: Cross-Study Comparison* HIV RNA <50 c/ml at Week 48 STARTMRK EFV (n=282) GS 934 EFV (n=244) 80 ARTEMIS LPV/r (n=346) 78 CASTLE ATV + RTV (n=440) 78 ABT 730 LPV/r qd (n=333) 77 CASTLE LPV/r (n=443) 76 ABT 730 LPV/r bid (n=331) 76 GS-903 EFV (n=299) 76 ASSERT EFV (n=193) 71 GS 934 EFV (n=243) 70 MERIT ES MVC (n=311) MERIT ES EFV (n=303) HEAT LPV/r (n=345) 68 HEAT LPV/r (n=343) 67 ASSERT EFV (n=192) % of Patients with HIV-1 RNA <50 copies/ml at Week 48 *This slide depicts data from multiple studies published from Not all regimens have been compared head-to-head in a clinical trial NRTI Backbone FTC/TDF 3TC/ABC 3TC/ZDV 3TC+TDF 23 welke keuze..? persoonlijk veiligheid eenvoud 1x daags voedsel inname? interacles? prijs generieke middelen AZT/NVP/3TC 6

7 genezing? HAART winst/ risico - HIV positief met HAART - R5 virus - acute leukemie: noodzaak tot beenmergtransplantatie - donor Δ32 deletie: geen CCR5-3x overleefd = genezen cart: virologisch & immunologisch succes in treatment-naïve patients AIDS and death HIV viral load: CD4 cell count: AIDS down significantly since cart, but still occurs AIDS Mortality overall still higher than in gender- and agematched general population Mortality of patients successfully treated from an earlier stage of infection approaches that of general population Mortality 7

8 bezwaar levenslang pillen therapie trouw belangrijk!!! bijwerkingen? korte termijn: huiduitslag, dromen, diarree lange termijn: nier? hart? botten? levenslang HAART = een leven lang? 29 Increasing age of patients in care future developments A modelling study showed that in 2015, the HIVinfected population will be twice as large as in data 2000 data 2005 model 2005 model : 9151 patients 2015: 18,275 patients Median age of patients in care = 47 years 50 years or older 1996: 9% 2013: 37% (6% 65 years) Expected increase in age-related comorbidities number of patients years: ± 2100 persons 80 + years: ± 150 persons age [years] 8

9 zwangerschappen: geen hiv bij baby 25 (WITS studie, n=1542) HIV 5 THERAPIE = PREVENTIE 0 no ART ZDV mono Duo-therapy HAART OR (duotherapie vs. ZDV): 0.30 (95% CI ) OR (HAART vs. ZDV): 0.27 (95% CI ) Cooper e.a. J AIDS 2002 PMTCT UNAIDS program seksuele preventie: HAART!!! Zwitsers standpunt (January 2008) als virus onmeetbaar is: kans op seksuele besmetting van partner: «bijna onmogelijk» GEEN pleidooi tegen condooms; eigen keuze! waarom dit standpunt? één standpunt HIV uit strafrecht bij kleine incidenten geen PEP 9

10 treatment as prevention HPTN 052: Immediate vs Delayed ART in Serodiscordant Couples HIV-infected, sexually active serodiscordant couples; CD4+ cell count of the infected partner: cells/mm3 (N = 1763 couples) treatment as prevention HPTN 052: HIV Transmission Reduced by 96% in Serodiscordant Couples Total HIV-1 Transmission Events: 39 (4 in immediate arm and 35 in delayed arm; P <.0001) Immediate ART Initiate ART at CD4+ cell count cells/mm3 (n = 886 couples) Delayed ART Initiate ART at CD4+ cell count 250 cells/mm3* (n = 877 couples) Linked Transmissions: 28 Unlinked or TBD Transmissions: 11 *Based on 2 consecutive values 250 cells/mm3. Primary efficacy endpoint: virologically linked HIV transmission Primary clinical endpoints: WHO stage 4 events, pulmonary TB, severe bacterial infection and/or death Delayed Arm: 27 Immediate Arm: 1 Couples received intensive counseling on risk reduction and use of condoms DSMB recommended release of results as soon as possible following April 28, 2011, review; follow-up continues but all HIV-infected partners offered ART after release of results Cohen MS, et al. IAS Abstract MOAX0102. Cohen MS, et al. N Engl J Med. 2011;[Epub ahead of print]. P <.001 Single transmission in patient in immediate ART arm believed to have occurred close to time therapy began and prior to HIV-1 RNA suppression Cohen MS, et al. IAS Abstract MOAX0102. Cohen MS, et al. N Engl J Med. 2011;[Epub ahead of print]. Zwitsers standpunt notities bezwaar andere SOA preventie voordeel bewust met seksuele risico s bezig eerder start cart bij discordantie? ook bij incidentele partners?! stigmaê 10

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