Upload
others
View
1
Download
0
Embed Size (px)
Citation preview
Stichting Rode Kruis Bloedbank STICHTING HIV
MONITORING
Welkom,
HIV Monitoring Part 7
Registratie verplicht!
Stichting Rode Kruis Bloedbank
Dag 1, deel 1: “Update, HIV behandeling”
19.00-19.05 Opening NASKHO
19.05-19.15 Opening ASNA
19.15- 19.45 Ontwikkelingen HIV behandeling Wereldwijd
19.45-20.05 HIV behandeling & therapie resistentie Curaçao
20.05-20.25 R[E]D Campaign Curaçao
20.25-20.45 Zaaldiscussie
STICHTING HIV MONITORING
HIV treatment update
Joep M.A. Lange
Department of Global Health
Academic Medical Center, University of Amsterdam
Amsterdam Institute for Global Health & Development
Treatment update
Treatment access figures
Guidelines
Drugs
Is HIV eradication feasible?
Complementary approaches
CNS
Antiretovirals for HIV prevention
5Towards Universal Access – Scaling up priority HIV/AIDS interventions in the health sector. WHO/UNAIDS/UNICEF, Sep 2009
Treatment access is going well
Number of people receiving antiretroviral therapy in low- and middle-income
countries, 2002-2007
6
But the economic crisis hit……..
$11.3
$8.8$7.9
$6.1$5.0
$3.2$1.6$1.4
$13.8
0
10
20
30
2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010
US
D b
illi
on
Resources Available for HIV services
Resource needs for country defined UA
Resource needs
Available resources
7
At Front Lines, AIDS War Is Falling ApartDonald McNeil Jr, May 9, 2010
Dinavance Kamukama, 28, front right, with her cousins in Kampala, Uganda.
She is on a waiting list for AIDS medication.
Treatment update
Treatment access figures
Guidelines
Drugs
Is HIV eradication feasible?
Complementary approaches
CNS
Antiretovirals for HIV prevention
HIV treatment guidelines
IAS-USA (International AIDS Society-USA):
– Treatment should be considered for asymptomatic subjects with CD4 cell counts > 500/µL.
WHO (World Health Organization):
– Start at CD4+ cell counts < 350/µl, immediately, regardless of clinical symptoms. This includes pregnant women.
Why start earlier?
Biological plausibility
Overwhelming evidence that it increases survival
Safer / more tolerable / simpler drugs
Prevents “non-HIV-related disease”
Will reduce HIV transmission
No immune reconstitution syndrome
“Health systems light” (task shifting)
Treatment update
Treatment access figures
Guidelines
Drugs
Is HIV eradication feasible?
Complementary approaches
CNS
Antiretovirals for HIV prevention
RT
Provirus
ProteinsRNA
DNA
RNA
DNA
DNA
RT
Protease inhibitors
RT-inhibitors
-Nt/sRTI
NNRTI
Integrase inhibitor
RNA
RNA
Entry-inhibitors:
Fusion inhib.
CCR5 antagon.
DNA
DNA
DNA
Current antiretroviral drug classes
*Dates indicate FDA approval.
Timeline for development of antiretroviral agents (1987-2008)
Grant & Zolopa, 2010
Antiretroviral Agents Approved for Clinical Use and in Phase I, II & III Clinical Trials
(by end 2010; Marco Vitoria)
Approved Antiretroviral Agents
NRTIs PIs NNRTIs Fusion
Inhibitors Entry
Inhibitors Integrase Inhibitors
Maturation Inhibitors
Zidovudine Saquinavir Nevirapine Enfuvirtide Maraviroc Raltegravir
Didanosine Ritonavir Delavirdine
Stavudine Indinavir Efavirenz
Lamivudine Nelfinavir Etravirine
Abacavir Lopinavir/ ritonavir
Tenofovir Atazanavir
Emtricitabine Fosamprenavir
Tipranavir
Darunavir
Major Investigational Antiretroviral Agents in Phase III Trials
Apricitabine (AVX-201)
Rilpivirine (TMC-278)
Vicriviroc (SCH-D)
Elvitegravir (GS-9137)
Major Investigational Antiretroviral Agents in Phase I/II Trials
Elvucitabine (ACH-126443)
TMC-310911 Lersivirine (UK-453061)
Ibalizumab (TMB-355)
GSK-1349572 Bevirimat (MPC-4326)
Amdoxovir (DAPD)
CPT-518 GSK-2248761
(IDX-12889) BMS-626529 PA-1050040
Racivir RDEA-806 BMS-663068
CMX-157 PRO-140
INCB-9741
TBR-652
Currently Available Coformulated Antiretroviral Agents
Approved Coformulations Type
Lamivudine/zidovudine Dual NRTI
Abacavir/lamivudine/zidovudine Triple NRTI
Abacavir/lamivudine Dual NRTI
Emtricitabine/tenofovir Dual NRTI
Efavirenz/emtricitabine/tenofovir NNRTI + dual NRTI
Efavirenz/lamivudine/tenofovir NNRTI + dual NRTI
Lopinavir/ritonavir Boosted PI
Coformulations under study Type
Rilpivirine/emtricitabine/tenofovir NNRTI + dual NRTI
Elvitegravir/cobicistat/emtricitabine/tenofovir Boosted integrase inhibitor + dual
NRTI
Marco Vitoria, 2010
Copyright 2007 Merck & Co., Inc., Whitehouse Station, New Jersey, USA All rights reserved.
4th IAS Conference, July 2007, abstract TUAB104
HIV RNA <50 Copies/mL (95% CI)[Non-Completer=Failure]
0 2 4 8 12 16 24 32 40 48
Week
0
20
40
60
80
100
Pe
rce
nt o
f P
atie
nts
with
HIV
RN
A <
50
co
pie
s/m
L
m518p4 r50 7 July 10, 2007
Raltegravir 100 mg b.i.d. (n=39)
Raltegravir 200 mg b.i.d. (n=40)
Raltegravir 400 mg b.i.d. (n=41)
Raltegravir 600 mg b.i.d. (n=40)
Efavirenz 600 mg q.d. (n=38)
Plasma human immunodeficiency virus (HIV) RNA (as determined by ultrasensitive assay with a lower limit of detection of <.3 copy/mL [19]).
Hatano H et al. J Infect Dis. 2011;203:960-968
© The Author 2011. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: [email protected]
© 2010 Lippincott Williams & Wilkins, Inc. Published by Lippincott Williams & Wilkins, Inc.
Fig. 2: rilpivirine (TMC278) vs. SOC
Efficacy and safety of TMC278 in antiretroviral-naive HIV-1 patients: week 96 results of a phase IIb randomized trial.Pozniak, Anton; Morales-Ramirez, Javier; Katabira, Elly; Steyn, Dewald; Lupo, Sergio; Santoscoy, Mario; Grinsztejn, Beatriz; Ruxrungtham, Kiat; Rimsky, Laurence; Vanveggel, Simon; Boven, Katia
AIDS. 24(1):55-65, January 2, 2010.DOI: 10.1097/QAD.0b013e32833032ed
Fig. 2 . Virological and immunological efficacy. (a) Proportion of patients with viral load less than 50 copies/ml through 96 weeks [time to loss of virological response (TLOVR) algorithm]. Intent-to-treat population;
Quad® vs. standard of care
Treatment update
Treatment access figures
Guidelines
Drugs
Is HIV eradication feasible?
Complementary approaches
CNS
Antiretovirals for HIV prevention
Long-Term Control of HIV by CCR5
Delta32/Delta32 Stem-Cell Transplantation
Gero Hütter, M.D., Daniel Nowak, M.D., Maximilian Mossner,
B.S., Susanne Ganepola, M.D., Arne Müßig, M.D., Kristina
Allers, Ph.D., Thomas Schneider, M.D., Ph.D., Jörg Hofmann,
Ph.D., Claudia Kücherer, M.D., Olga Blau, M.D., Igor W. Blau,
M.D., Wolf K. Hofmann, M.D., and Eckhard Thiel, M.D.
N Engl J Med 2009;360:692-8.Update: Allers K et al. Blood. Online publication Dec 8 2010
Treatment update
Treatment access figures
Guidelines
Drugs
Is HIV eradication feasible?
Complementary approaches
CNS
Antiretovirals for HIV prevention
HIV causes depletion of Gut associated CD4+ T cells and disruption of mucosal barrier
Brenchley et al, J Exp Med 2004
• Epithelial cell apoptosis
• Blunted villi
• Loss of tight junctions Leading to:
• Local inflammation
• Malabsorption
• Systemic immune activation
HIV causes depletion of gut associated CD4+ T cells and disruption of mucosal barrier
24
HIV replication
Immune
Activation
Gut
Mucosal damage
Microbial
Translocation
Immune
Deficiency
Chronic immune activation is a stronger predictor of disease progression than viral load or CD4+ count
Source: Giorgi 1999 JID 179: 859-870
Box plot of virus burden and 3 immunological markers that showed significant difference
between HIV-1-infected groups with different
survival times after CD4+ T cells fell to ≤ 50/mm2.
A clue from nature
Rhesus macaque vs Sooty mangabey
Infected with SIV Infected with SIV
High levels of viral replication High levels of viral replication
AIDS and death No AIDS, normal life span
Chronic immune activation No immune activationSilvestri, Immunity 2003
Jiang et al (2009) JID
Microbial translocation decreases with HAART but remains elevated
HAART (viral suppressed) patients have persistent T-cell activation
Protein
source
Prebiotic
Oligosaccharides
lcPUFA Blend
(EPA, DHA, GLA)
N-acetyl cysteine
(NAC)
Micronutrients
Improved gut integrity
Immune preservation
Improved nutritional status
NR100157(75g/d, 314 kcal)
NR100157 nutritional concept for HIV-1 infected patients
• Improve gut microbiota balance• Decrease systemic CD4 activation• Increase NK activity• Increase Th1 response
Glutathione (GSH) precursor
•Anti-oxidants•Prevention micronutrient depletion
Improvement gut integrity
Anti-inflammatory
BITE StudyLange JMA et al. EACS 2009
NR100157 reduces in CD4+ decline and chronic immune activation but not viral load
NR100157 significantly slows the decline in CD4+ T-cell count in HIV-infected patients not on HAART
-100
-80
-60
-40
-20
0
20
40
0 13 26 39 52
Weeks
Ch
an
ge in
CD
4+
cell
co
un
t
- 28 cells
- 68 cells
P=0.030
*
Active
Control
-100
-80
-60
-40
-20
0
20
40
-100
-80
-60
-40
-20
0
20
40
0 13 26 39 52
Weeks
Ch
an
ge in
CD
4+
cell
co
un
t
- 28 cells
- 68 cells
P=0.030
*
Active
Control
-100
-80
-60
-40
-20
0
20
40
-100
-80
-60
-40
-20
0
20
40
0 13 26 39 52
Weeks
Ch
an
ge in
CD
4+
cell
co
un
t
- 28 cells
- 68 cells
P=0.030
*
Active
Control
-100
-80
-60
-40
-20
0
20
40
Treatment update
Treatment access figures
Guidelines
Drugs
Is HIV eradication feasible?
Complementary approaches
CNS
Antiretovirals for HIV prevention
HIV-related CNS disease?
Recent cohort studies show
15-60% cognitive impairment
Cornelissen M et al.
Antiviral Therapy: in press.
Treatment update
Treatment access figures
Guidelines
Drugs
Is HIV eradication feasible?
Complementary approaches
CNS
Antiretovirals for HIV prevention
Fig. 2 Kaplan-Meier estimates of cumulative probability of HIV infection in the tenofovir and placebo gel arms.
Q Abdool Karim et al. Science 2010;329:1168-1174
Published by AAAS
iPrEX trialGrant RM, et al. N Engl J Med 2010;363:2587-99
The spectrum of engagement in HIV care and its relevance to
“Test and Treat” strategies for prevention of HIV infection.
Gardner EM et al. Clin Infect Dis 2011;52:793-800.
.
“HIV incidence has not declined in the US
despite almost 15 years of widespread
access to combination therapy.”
Gardner EM et al. Clin Infect Dis 2010;52:793-800.
Gardner EM et al. Clin Infect Dis 2010;52:793-800.
Conclusions (1)
Treatment access figures:
– worries about continued funding
Guidelines:
– move towards earlier treatment
Drugs:
– newcomers will not necessarily replace current
leaders
Conclusions (2)
Is HIV eradication feasible?
– yes, but….
Complementary approaches
– Non-antiretroviral interventions may be
beneficial
CNS
– CNS penetration is important!
Conclusions (3)
Antiretovirals for HIV prevention:
– Some proof of concept systemic and local PrEP
– Yet, efficacy only moderate
– Explanation FEM-PrEP results?
– Need to restrict use to HIV-negatives: logistical
nightmare
– Test and Treat may be easier to implement than
PrEP, but poor retention in care big obstacle
2010 Update Curaçao
HIV Treatment and Resistance to Anti-Retroviral Drugs in Curaçao
28 april 2011
Frank de Wolf
45
2010 Update Curaçao
• Population registered and monitored
• Late presentation and start of treatment
• cART and treatment outcome
• Mortality and survival
• Therapy failure and drug resistance
46
2010 Update: Population monitored
• 98 (15%) of registered patients were diagnosed in or before 1995; 34 (35%) died before June 2010
• 516 patients were diagnosed between 1996 and 2010
• From 59 patients the date of diagnosis is unknown
Registered:
673
Alive:
549 (82%)
Deceased:
124 (18%)
In (outpatient) clinical
care in 2010: 421 (77%)
47
2010 Update: Gender & Transmission Risk Group
Alive & in f’up,N=421
Alive & LTFN=128
DeadN=124
TotalN=673
N % N % N % N %
gender, male 259 62 71 55 90 73 420 62
female 162 38 56 45 34 27 253 38
transmission
MSM 94 22 9 7 14 11 117 17
heterosexual 285 68 89 70 78 63 452 67
other/unknown 42 10 30 23 32 26 104 15
48
2010 Update: Country of Birth and of Infection
Alive & in f’up,N=421
Alive & LTFN=128
DeadN=124
TotalN=673
N % N % N % N %
Country of birth
Antilles 311 74 83 65 110 89 504 75
Haiti 38 9 29 23 7 6 74 11
Dom Rep 30 7 7 5 4 3 41 6
Country of infection 389 58
Antilles 341 88
Haiti or Dom Rep 18 5
Netherlands 16 4
HIV subtype 186 28
B 184 99
49
2010 Update: Age at year of diagnosis
• Median age at diagnosis: 38 yrs
P<0.001
0
5
10
15
20
25
30
35
40
<13
13-17
18-24
25-34
35-44
45-54
55-64
65+
leefti jd bi j diagnose [jaar]
%
mannen vrouwen
• 11 were 12 years or younger
• 12 were between 13 and 18 yrs
50
2010 Update: Late Presentation
• Median CD4 cell count at diagnosis: 321 (98-499) cells/mm3
51
2010 Update: Late Presentation
• Median CD4 cell count at diagnosis: 321 (98-499) cells/mm3
• Median CD4 cell count at first visit: 273 (96-451) cells/mm3
52
2010 Udate: Late Presentation
• Median CD4 cell count at diagnosis: 321 (98-499) cells/mm3
• Median CD4 cell count at first visit: 273 (96-451) cells/mm3
• Did not differ significantly from the count a diagnosis (p=0.7)
• Median time between diagnosis and first visit: 0.28 (0.12-2.02) year
53
2010 Update: Stage of infection at diagnosis
Presentation with advanced stage of disease: presenting for care with a CD4 count below 200 cells/µL or presenting with an AIDS defining event.
Late presentation presenting for care with a CD4 count below 350 cells/µL or presenting with an AIDS defining event.
55
2010 Update: CD4 at Start of Treatment
• Median CD4 cell count at diagnosis: 321 (98-499) cells/mm3
• Median CD4 cell count at first visit: 273 (96-451) cells/mm3
• Did not differ significantly from the count a diagnosis (p=0.7)
• Median CD4 cell count at start of cART: 132 cells/mm3
56
Late Presentation and Start of Treatment
• Median CD4 cell count at diagnosis: 321 (98-499) cells/mm3
• Median CD4 cell count at first visit: 273 (96-451) cells/mm3
• Did not differ significantly from the count a diagnosis (p=0.7)
• Median CD4 cell count at start of cART: 132 cells/mm3
0
100
200
300
400
500
diagnose start cART start cART
med
iaan
CD4
[cel
len/
mm
3]
P<0.001
P=0.02 • 14% had experienced an AIDS defining disease by the time treatment was started
57
2010 Udate: Time to Start cART
• Almost 50% of the patients started cART within a year from HIV diagnosis
• Between 2002 and 2010 on average 2 CD4 cell measurements were performed annually per patient
• HIV plasma RNA was measured 1,8 times per year per patient
• The frequency of clinical visits was on average 2,3 per year
58
2010 Update: Drug Combinations Used Over Time
• 449 (67%) started cART
• 260 started between 2004 and 2010:
– 68% with combivir plus LOP/r
– 16% with truvada plus EFV
• 415 patients started cART naive
59
2010 Update: CD4 Cell Response to cART
• 51% had increasing CD4 cell counts by at least 150 cells/mm3
during the first 6 months of treatment
• After 2 years: 82%
• CD4 counts reached a plateau at approximately 400 cells/mm3
after 2 years of cART
60
2010 Update: VL Response to cART
• 81% achieved a viral load level <500 copies/ml within 6 months of treatment; 74% <80copies/ml
• The proportion of patients with a viral load level <500 copies/ml decreased from 81% after 48 weeks to 70% after 5 years of treatment; 75% and 60% <80 copies/ml
61
2010 Update: Survival Since Start of cART
• Of the 585 still alive as of 01/01/2005 or were diagnosed thereafter, 48 patients had died by June 2010
• The survival probability after 4 years was estimated to be 91%
• 226 patients started cART in or after 2005 and in this group 20 patients died
• The 4 year survival probability after start of cART in this group was estimated at 87%
Survival after start therapy since 2005
Survival since start follow-up
62
2010 Update: cART failure
• Therapy failure ocurred in 2002 in 57% of the pre-treated and 34% of the naive patients and declined over time to 10% and 18% in 2009
• 27% of the patients starting cART in 2006 or later failed their first regimen within 2 years of therapy success
• 50% of the patients experienced a cART regimen change within 1,5 years of starting their first regimen
63
2010 Update: Resistance level and MDR
alive dead total
N % N % N %
N 549 124 673
with a sequence 169 31 17 14 186 28
at least 1 RAMS 65 12 6 5 71 11
high-level resistance % of those with RAMS
PI 24 37 2 33 26 37
NNRT 26 40 2 33 28 39
3TC/FTC 52 80 4 67 56 79
other NRTI 11 17 0 0 11 15
classes % of those with RAMS
1 28 43 2 33 30 42
2 26 40 3 50 29 41
3 8 12 0 0 8 11
64
2010 Update: Resistance Profile cART Treated Patients
• In 66% high level resistance to at least one antiretroviral drug was found (Stanford algorithm)
• Resistance patterns are similar to those in the Netherlands, except for NNRTI (less than in NL)
0
10
20
30
40
50
fAPV
IDV
NFV
SQV
LPV/rATV TPV
DRV
EFVN
VP
3TC/FTCABC
AZTd4T
ddITD
F
ARV-middel
% r
esis
ten
t
65
2010 Update: Summary
• The number of HIV cases registered in Curaçao has increased by 87 (15%) since 2009 to 673
• The majority are men, originated from and infected through heterosexual contact in the Netherlands Antilles
• Patients are diagnosed at older age and in a late stage of infection, with CD4 cell counts below 350 cells/mm3
• In addition, patients start cART late and half of the patients are on cART within a year after HIV diagnosis
• On average, the follow-up of patients allows for an outpatient clinic visit frequency of more than twice a year, including CD4 cell counts and measurment of viral load
66
2010 Update: Summary
• Sustained response to cART needs improvement:
– The CD4 cell response to cART is good, although a plateau is reached at 400 cells/mm3 two years after start of cART
– The initial viral load response is good, however after 5 years of cART treatment the fraction of patients with a viral load <500 copies/ml is 70%
– Survival after 4 years of cART commenced in 2005 is 87%
• Major step: early diagnosis followed by early treatment
• cART virological failure rates have declined over time to levels below 20% in recent years
• Resistance associated mutations are found in almost one third of the failures tested and 11% of those with rams have high level triple class failure.
• Transmission of resistance seems to be limited
67
Acknowledgements
Curaçao:
Gonneke Hermanides
Karin Laurant
Cai Winkel
Izzy Gerstenbluth
Ashley Duits
Amsterdam:
Ard van Sighem
Yolanda Ruijs
Luuk Gras
Sima Zaheri
RED CAMPAIGN 2010 – 2013
Ministerio di salubridat,medio ambiente i naturalesa
RED CAMPAIGN 2010 – 2013
A PUBLIC/PRIVATE SECTOR PARTNERSHIP TO INCREASE
PUBLIC AWARENESS AND
EDUCATION.
HIV/AIDS/STI AWARENESS CAMPAIGN
Wat is er bereikt in 2010.
Girobank overdracht Campagne
Gecertificeerde Focal Points Selikor
Aantal mensen bereikt
Personeel van de bedrijven ongeveer 1940 medewerkers
hebben een sensitization training gehad
65 Focal Points getraind. 65 pre en post testen afgenomen.
600 klanten zijn geintervieuwd
Wekelijks op de vrijdagen media aandacht in lokale kranten
en TV
We kunnen inmiddels vaststellen dat het merendeel van de
bevolking op de hoogte is gebracht wat deze campagne
inhoud.
International Labor Organization
conferentie
Februari 2011 is er een Workplace policy Conferentie gehouden
samen met PAHO en GMN
Deelnemers aan deze conferentie: Afgevaardigen van kerken, SKC,
politie, onderwijs, gezondheidszorg, verzekeringswezen,
arbeidszaken, justitie, vakbonden, bedrijfsleven ea
Doel van de conferentie: bekendmaking van diverse doelstelling
ILO mbt hiv/aids op de werkvloer en het op termijn
implementeren van beleid.
Inzet 2011 middels Red Campaign jaar thema Think Red, Do safe.
Sensitization training geven over de workplace, en het verzorgen
van info sessie mbt soa’s Hiv en Aids, stigma’s en discriminatie
2012
Jaarthema zal zijn: Get tested, know your status
Van project naar beleid
Synchronisatie met Biba Amor