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: journals.permissions@oup.com

© 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