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HIV update 2014 Kees Brinkman patiëntendag 17 Januari 2014
Totaal volwassenen OLVG AMC-UvA Erasmus MC UMCU St Elisabeth Zkh MCH - Westeinde UMCG Slotervaart Zkh AZM MC Jan van Goyen Rijnstate Haga Zkh - Leyweg LUMC UMC St Radboud Maasstad Zkh Catharina Zkh VUMC MST Kennemer Gasthuis Isala Klinieken - Sophia St Lucas Andreas Zkh MCA MC Leeuwarden Flevo Zkh Admiraal De Ruyter Zkh MC Zuiderzee
18.707 2.670 2.380 1.952 1.309 880 805 707 684 637 630 598 586 571 569 537 488 463 410 367 366 298 259 230 138 125 48
overzicht eind 2012
HIV infectie
HIV cyclus
snelheid van transmissie
HIV CCR5 CXCR4
gp-120
T-cel
4-8 uur
CD4 RNA
24-48 uur
reverse transcriptase
DNA integrase
protease
Virus productie: 108-1010 virusdeeltjes/dag Pope & Haase pg 847-
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belang CD4 cellen candida PCP
800-1200
toxoplasmose viral load
200 / mm3
CMV MAC CD4
CD4
• Rakai (Uganda) • 453 HIV-disc. couples • 11.6 % TR / year
% partners infected
viral load en besmettings risico
HIV beloop
30
20
10
0 <400
weken
2-10 jaren
4003500
3500- 10'000- >50000 10'000 50'000
HIV-RNA load (cp/ml)
Quinn, NEJM, 2000; 342:921-9.
HIV beloop en transmissiekans
moment van diagnose HIV load
kliniek
CD4 800-1200
diagnose
HIV transmissie kans
200 / mm3
weken
THERAPIE
2-10 jaren
patiënt met vroege infectie = bron voor 50% nieuwe infecties
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hiv medicijnen
atta inh chm ibit ent ors
HIV CCR5CCR5 blockers CXCR4 maraviroc, …
gp-120
• fusion inhibitors
maturation inhibitors
CD4
viral load
• T20
reverse transcriptase
CD4
• NRTI’s • AZT, ddC, ddI, d4T, 3TC, ABC,FTC • TDF
integrase
weeks
• NVP, EFV • ETR • RLP
protease
• PI’s • RTV, SQV, IND, NLF, fAMP, • LPV, ATV, • TPV, DRV
INSTI • raltegravir • elvitegravir • dolutegravir
goedgekeurde hiv medicijnen: 1987 - 2013 30 25 EFV TDF ABC LPV/r RTV IDV NFV APV DLV NVP 3TC SQV
20 15 10 5 0
AZT
years
time
• Non-NRTI’s
ETR ENF RAL ATV MVC FTC DRV FPV TPV
DTG EVG RPV
doel van behandeling: “volledige” virus onderdrukking
1996 “triple combinatie = standaard” HIV RNA <500 copies/ml
ddC d4T ddI
1987 1989 1991 1993 1995 1997 1999 2001 2003 2005 2007 2009 2011
Gulick et al.
2013
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2006 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
1996 -2008: simplificatie 2008
iedereen HAART? wanneer te starten? waarmee starten? richlijnen
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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)
§ 350-500 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 350-500
> 500
EACS[1]
Yes
Yes
Consider
Consider
US DHHS[2]
Yes
Yes
Yes
Yes
IAS-USA[3]
Yes
Yes
Yes
Yes
WHO[4]
Yes
Yes
Yes
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, 2012.
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 2013. 2. DHHS. Guidelines. February 2013. 3. IAS-USA. Guidelines. July 2012. 4. WHO. ART Guidelines. June 2013.
2012 Elvitegravir/cob = Efavirenz
• 2013-2014 – elvitegravir (201312) – dolutegravir (20147?) – generiek: 3TC, NVP, EFZ, ABC
• 2015-2016….. – TAF (new TDF) – MK-NNRTI? – BMS-NRTI ? – generiek TDF, ATV, ritonavir etc
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2013 Dolutegravir better Efavirenz
huidige ontwikkeling: nieuwe 3-combi’s: 1x daags 1
TDF/FTC vs ABC/3TC
Atripla Approved 2007
Truvada/RPV
juni 2012
complera® eviplera®
Quad/Stribild Elvitegravir/cob/ TVD
FDA approved aug ‘12 NL approval: dec ‘13
Registrational Treatment-Naive Clinical Trials: Cross-Study Comparison*
HIV RNA <50 c/mL at Week 48
FLAMINGO DTG(n=242) GS-103 EVG/cob (n=353) GS-102 EVG/cob(n=348) * SPRING-2 DTG (n=411) * SINGLE DTG (n=414) GS-103 ATV + RTV (n=355) STARTMRK RAL (n=281) GS-102 ATRIPLA (n=352) ARTEMIS DRV + RTV (n=343) FLAMINGO DAR/r (n=242) ECHO/TRHIVR RPV (n=550) ECHO/TRHIVR EFV (n=546) STARTMRK EFV (n=282) GS 934 EFV (n=244) ARTEMIS LPV/r (n=346) CASTLE ATV + RTV (n=440) ABT 730 LPV/r qd (n=333) CASTLE LPV/r (n=443) ABT 730 LPV/r bid (n=331) GS-903 EFV (n=299) ASSERT EFV (n=193) GS 934 EFV (n=243) MERIT ES MVC (n=311) MERIT ES EFV (n=303) HEAT LPV/r (n=345) HEAT LPV/r (n=343) ASSERT EFV (n=192)
welke keuze…..?
90 90 88 88 88 87 86 84 84 83 83 82 82 80 78 78 77 76
• persoonlijk NRTI Backbone FTC/TDF 3TC/ABC 3TC/ZDV 3TC+TDF
71 70
– generieke middelen
68 68 68 67 0
10
• 1x daags • voedsel inname? • interacLes?
• prijs
76 76
59 20 30 40 50 60 70 80 % of Patients with HIV-1 RNA <50 copies/mL at Week 48
– veiligheid – eenvoud
• AZT/NVP/3TC 90
100
*This slide depicts data from multiple studies published from 2004-2012. Not all regimens have been compared head-to-head in a clinical trial
23 23
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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 HIV viral load:
CD4 cell count:
AIDS and death • AIDS down significantly since cART, but still occurs
AIDS
• Mortality overall still higher than in gender- and agematched general population Mortality
• Mortality of patients successfully treated from an earlier stage of infection approaches that of general population
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bezwaar • levenslang pillen – therapie trouw belangrijk!!!
levenslang HAART = een leven lang?
• bijwerkingen? – korte termijn: • huiduitslag, dromen, diarree
– lange termijn: • nier? hart? botten? 29
future developments
Increasing age of patients in care
• A modelling study showed that in 2015, the HIVinfected population will be twice as large as in 2005. 600
data 2000 data 2005 500
2005: 9151 patients 2015: 18,275 patients
model 2005
number of patients
model 2015
• • •
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
400
60+ years: ± 2100 persons
300
200
80+ years: ± 150 persons 100
0 0
31
10
20
30
40
50
60
70
80
90
100
age [years]
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zwangerschappen: geen hiv bij baby 25 (WITS studie, n=1542)
20 15 10
HIV
5
THERAPIE = PREVENTIE
0 no ART
ZDV mono Duo-therapy
HAART
OR (duotherapie vs. ZDV):
0.30 (95% CI 0.09-1.02)
OR (HAART vs. ZDV):
0.27 (95% CI 0.08-0.94) 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
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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: 350-550 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 350-550 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 2011. 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 2011. 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
