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ARV 2008: ¿Un mundo, dos estándares de cuidado?
XIII Curso Internacional de Enfermedades Infecciosas,XIV Seminario Integral del Sida
Cali-Colombia, 2008
Pedro Cahn
Identificar la opciIdentificar la opcióón correcta:n correcta:
a)a) El porcentaje de cobertura de ARV en el El porcentaje de cobertura de ARV en el mundo es del 48% mundo es del 48%
b)b) Las recomendaciones de OMS para inicio de Las recomendaciones de OMS para inicio de terapia ARV indican que se debe iniciar con 350 terapia ARV indican que se debe iniciar con 350 CD4/mm3 CD4/mm3
c)c) D4T/3TC/D4T/3TC/NevirapinaNevirapina es la combinacies la combinacióón mas n mas frecuentemente utilizada en frecuentemente utilizada en ÁÁfrica. frica.
d)d) La lipodistrofia no afecta a las personas de La lipodistrofia no afecta a las personas de raza raza negra.negra.
e)e) No sNo séé, vine a aprender., vine a aprender.
AIDS 2008
Timeline of ARV Development
’87 ’91 ’92 ’94 ’95 ’96 ’97 ’98 ’99 ’00’88 ’89 ’90 ’01 ’02 ’03’93 ’05’04 ’06
ZDV
’07
’87 ’91 ’92 ’94 ’95 ’96 ’97 ’98 ’99 ’00’88 ’89 ’90 ’01 ’02 ’03’93 ’05’04 ’06
ddC
3TC
NNRTINRTI
PIEntry
inhibitor
ddI
IDV
SQR LPV/r
TDFNVP
DRVTPV
T-20
ZDV d4T ABC
DLV
EFV FTC
RTV
NFV ATV
FPV
’07
23 unique ARV agents, at the first year of FDA approval
MVC
Timeline of ARV Development
APV
Retrovirus life cycleRetrovirus life cycle
Entry inhibitorsENF MRV
VCV TNX355AMD11070
Reverse transcriptase
inhibitorsZDV NVPddI DLVTDF EFV d4T ABCFTC 3TCTMC 125 278RCV APC
IntegraseinhibitorsGS9137
Raltegravirothers
Protease inhibitorsSQV IDVRTV NFVFPV LPVATV TPV
DRV
Maturationinhibitorbevirimat
Egger, 2007
10
Response to HIV therapy in resource-poor and resource-rich regionsVirologic responses after initiating therapy• Virologic response to first ART: Switzerland vs South Africa:
– 967 pts in Swiss HIV Cohort (median CD4+ = 212 cells/mm3)– 1856 pts in Cape Town (median CD4+ = 81 cells/mm3)
• Similar virologic responses when adjusted for age, gender, CD4+ cell count, year of starting therapy, and disease stage
• More ART modifications among Swiss, often to improve convenience and tolerability
Mortality during the first year of HAART• Estimated mortality of 15% in sub-Saharan Africa vs 5% in Europe and
North America • Early mortality seen after initiation of ART possibly due to pre-existing
condition or immune restoration
Egger M, et al. 14th CROI, Los Angeles 2007, #62
11
CD4 count at start of ART, 2003–5
• Comparison of the regional variation of CD4+ counts at the time ART therapy initiated
• Review of data from 42 countries, 176 sites; n=33,008
• Since 2000, CD4+ cell count at initiation has increased in Sub-Saharan Africafrom 50 to 100 cells/mm3; in developed countries it has remained stable at~150–200 cells/mm3
Egger M, et al. 14th CROI, Los Angeles 2007, #62
North AmericaUS 187Canada 164South AmericaBrazil 159Argentina 181Sub-Saharan AfricaSouth Africa 87Botswana 97Malawi 97AustralasiaIndia 103Vietnam 53Japan 192China 163Australia 239
Median CD4+ counts at the start of therapy, by region/country
ESTAMOS COMENZANDO
DEMASIADO TARDE!
CONFRONTING FAILURE:NEW DRUGS, HOW TO USE IT
• Goal: Virological supression < 50 copies• How: Use at least 2 active drugs, one new class if possible• When: Switch as early as possible• Why:
Avoid accumulation of resistance mutations (GSS)Avoid increases in fold changes (PSS)Preserve active drugs for OBRPreserve CD4 levels
Suboptimal Initial Response/First Failure in Resource Unconstrained Settings
• Typically picked up early through VL monitoring• All potential reasons evaluated• Goal of therapy remains maximal virologic suppression
– i.e., VL <50 copies/ml, achievable in ~90% of patients
• Tailoring regimens to individual needs– Resistance testing used to assist with choice recognizing its
limitations [amplification at low virus loads, mixtures (importance of low-frequency variants)
– TDM
Treatment Failurein Resource Limited Settings
• Lack of widespread availability of CD4 and VL testing implies that completeness of response to any line of therapy may not be fully assessed and treatment failure will be picked up later– Greater degree of drug resistance will occur
• Lack of individualized drug resistance testing• Need for a public health approach, while pushing for
wider availabilty of appropriate monitoring tools
• Goal of therapy is to reduce morbidity and mortality, so CD4 conservation and maximal
virologic suppression should be persued
Limited use of second-line
• Only 40,000 (2%) on 2nd line at end 2006– limited provision in public sector– high cost: $1000 – 2500 pa– only some countries have universal access – HIV-TB co-management– ?? switch rates (4% annual in DART)
• Much more focus on scaling up first-line– Clear what to use; many FDCs– Price competition: d4T/3TC/NVP for $121 pa
Need for second-line will rise
-100'000200'000300'000400'000500'000600'000700'000800'000900'000
2006 2007 2008 2009 2010
Total number ofpeople needing2nd line ARVs(high estimate)
Total number ofpeople needing2nd line ARVs(low estimate)
The number of people is forecast to grow at a compound rate of around 40% between 2006 and 2010
Depending on the switch rate –at which patients develop resistance to 1st line ARVs and therefore need to change to 2nd line therapies – between 500,000 and 800,000 people could need 2nd line ARVs by 2010
- Universal access includes second-line - Significant pressure from activist communities- Earmarked resources: UNITAID; GFATM; PEPFAR- Action of Clinton Foundation and others-Only 40,000 (2%) on 2nd line at end 2006
25 years of AIDS25 years of AIDS
9 In 1991-1993, HIV prevalence in young pregnant women in Uganda and in young men in Thailand begins to decrease, the first major downturns in the epidemic in developing countries
10 Highly Active Antiretroviral Treatment launched
11 Scientists develop the first treatment regimen to reduce mother-to-child transmission of HIV
12 UNAIDS is created
13 Brazil becomes the first developing country to provide antiretroviral therapy through its public health system
14 The UN General Assembly Special Session on HIV/AIDS. Global Fund to fight AIDS, Tuberculosis and Malaria launched
15 WHO and UNAIDS launch the "3 x 5" initiative with the goal of reaching 3 million people in developing world with ART by 2005
16 Global Coalition on Women and AIDS launched
40
30
20
10
0
50
35
25
15
5
45
Milli
on
1980 1985 1990 1995 2000 2005
1 2 3 45 6
8
9
11
12
13
14
1516
7
10
1 First cases of unusual immune deficiency are identified among gay men in USA, and a new deadly disease noticed
2 Acquired Immune Deficiency Syndrome (AIDS) is defined for the first time
3 The Human Immunodeficiency Virus (HIV) is identified as the cause of AIDS
4 In Africa, a heterosexual AIDS epidemic is revealed
5 The first HIV antibody test becomes available6 Global Network of People living with HIV/AIDS
(GNP+) (then International Steering Committee of People Living with HIV/AIDS) founded
7 The World Health Organisation launches the Global Programme on AIDS
8 The first therapy for AIDS –zidovudine, or AZT -- is approved for use in the USA
People People living living with HIVwith HIV
Children Children orphaned orphaned by AIDS in by AIDS in subsub--Saharan Saharan AfricaAfrica
1.1
Impact of AIDS on life expectancy in five African countries, 197Impact of AIDS on life expectancy in five African countries, 19700––20102010
Life expectancy at birth (years)
Source: United Nations Population Division (2004). World Population Prospects: The 2004 Revision, database.
Botswana
South Africa
Swaziland
Zambia
Zimbabwe
1970–1975 1975–1980
1980–19851985–1990
1990–19951995–2000
2000–20052005–2010
7065
60
55
50
45
4035
30
25
20
4.1
Projected population structure with and without the AIDS epidemic, Botswana, 2020
80757065605550454035302520151050
020406080100120140 0 20 40 60 80 100 120 140
Males Females Deficits due to AIDS
Projected population structure in 2020
Population (thousands)
Age
in y
ears
Source: US Census Bureau, World Population Profile 2000
HIV prevalence by age group among antenatal clinic attendees in South Africa, 2000‒2005
2000 2001 2002 2003 2004 2005
Age range
Source: Department of Health (2006, National HIV and Syphilis Prevalence Survey South Africa; 2003, National HIV and Syphilis Antenatal Sero-Prevalence Survey in South Africa)
<20
20‒24
25‒30
30‒34
40+
35‒39
45
40
35
30
25
20
15
10
5
0
(%) HIVPrevalence
Figure 3
Access to mother-to-child prevention services (all pregnant women)
Comparison of 2003 and 2005 data on the coverage Comparison of 2003 and 2005 data on the coverage of antiretroviral therapy, access to motherof antiretroviral therapy, access to mother--toto--child prevention services child prevention services
and coverage of HIVand coverage of HIV--infected mothers who received antiretroviral prophylaxis infected mothers who received antiretroviral prophylaxis to prevent motherto prevent mother--toto--child transmissionchild transmission
Coverage of antiretroviral therapy
7.0
20.0
0
5
10
15
20
25
2003 2005
%
7.69.0
0
5
10
15
20
25
2003 2005
%
Coverage of HIV-infected mothers who received antiretroviral prophylaxis
3.3
9.2
0
5
10
15
20
25
2003 2005
%
Sources: WHO/UNAIDS (2006). Progress on global access to HIV antiretroviral therapy: a report on “3 by 5” and beyond; USAID et al. (2006). Coverage of selected services for HIV/AIDS prevention, care and support in low and middle income countries in 2003 and 2005. 3.2
Number of people receiving ARV therapy in low- and middle-income countries, 2002—2006
end
2002
mid
-200
3en
d 20
03m
id-2
004
end
2004
mid
-200
5en
d 20
05m
id-2
006
end-
2006
0
200
400
600
800
1 000
1 200
1 400
1 600
1 800
2 000
Peop
le re
ceiv
ing
AR
V th
erap
y (in
thou
sand
s)
North Africa and the Middle EastEurope and Central AsiaEast, South and South-East AsiaLatin America and the CaribbeanSub-Saharan Africa
Unmet need in low- and middle-income countries according to region, December 2006
0
500 000
1 000 000
1 500 000
2 000 000
2 500 000
3 000 000
3 500 000
4 000 000
4 500 000
5 000 000
Sub-SaharanAfrica
Latin Americaand the
Caribbean
East, South andSouth-East Asia
Europe andCentral Asia
North Africa andthe Middle East
Num
ber o
f peo
ple
Unmet need ARVtherapyReceiving ARVtreatment in Dec 2006
68% of the total unmet need
Wealth, poverty and HIV: Wealth, poverty and HIV: countries grouped by region and HIV prevalencecountries grouped by region and HIV prevalence
01020304050607080
over 20
%
10-205-101-5LatinAmerica
andCaribbean
Asia*AfricaAll (48)
% of population living on less that $1 per day
Relative income of richest 10% to poorest 10% *except Japan
Industrializedcountries
Countries with HIV prevalenceover 1.9% in 2002
Countries according to level ofHIV prevalence in 2001 (%)
Source: UN Population Division( 2005a). Most figures relate to 2002, or earlier.4.3
Projected reduction in African agricultural Projected reduction in African agricultural labourlabour force force due to HIV and AIDS by 2020due to HIV and AIDS by 2020
Sources: ILO (2004). HIV/AIDS and work: global estimates, impact and responses
Projected labor force loss (%) by year
NamibiaBotswanaZimbabwe
MozambiqueSouth Africa
KenyaMalawi
UgandaUR Tanzania
Central African RepublicCôte d’Ivoire
Cameroon
0 5 10 15 20 25 30
2020 2000
4.8
Es el costo el principal obstáculo?
IMPACTO ECONÓMICO DE LA EPIDEMIA
• En África reduce 1-2% el crecimiento económico
• Impacto demográfico:
Hasta 60% de adolescentes no vivirán hasta cumplir 60
• La mortalidad entre 15-49 años es 20 veces mayor
que en el mundo desarrollado
• Impacto cualitativo: ¿Quiénes mueren?
• Pérdida del sostén familiar, incremento de los gastos
• Emigración
The World Bank
45% of Eligible US Patients Not On HAART
CROI 2005: Teshale E, et al. Abstract 167.
820,000746,000 – 894,000820,000
746,000 – 894,000PLWHAPLWHA
480,000441,000 – 519,000480,000
441,000 – 519,000EligibleEligible
340,000320,000 – 860,000340,000
320,000 – 860,000In careIn care
268,000253,000 – 283,000268,000
253,000 – 283,000On HAARTOn HAART
31
Disparities in care and outcome:New data confirm continuing problems• Analysis examining years of life lost
due to HIV/AIDS• Compared with normal life
expectancy, 9.6 years lost if patients receive guideline concordant care
• Additional 5 years lost on average as a result of “real world” prescribing and use of HAART
• Minorities and women found to have significantly more years of life lost due to HIV because of “real life”HAART use– Due to late initiation of HAART and
premature discontinuation of HAART
Losina E, et al. 14th CROI, Los Angeles 2007, #142
4.33.9
5.35.8
6.4
5.3
0
1
2
3
4
5
6
7
8
Overall WomenCategory axis
Life
exp
ecta
ncy
lost
(yea
rs)
White Black Hispanic
Richest 20% Poorest 20%
GLOBAL INCOME
82,7%82,7%
1.4%1.4%
1,300 millones de personas viven con menos de 1 u$ por día
¿Es el costo el principal obstáculo?
Lancet 2007: 370:1569-77
La invisibilidad de los excluidos
¿POR QUÉ CONTINUA LA EPIDEMIA?….
• Para proveer acceso universal:Se requieren 15.000 millones de USD por año
• Costo estimado inicial de la invasión a Irak:100.000 M USD
• Capitales fugados de Argentina en 2001:20.000 M USD
EN GRAN MEDIDA POR EN GRAN MEDIDA POR DECISIONES POLDECISIONES POLÍÍTICASTICAS
Durante esta semana se producirán + de 35.000 muertes
potencialmente evitables con terapia ARV
LA TERAPIA ARV HACE LA DIFERENCIA
APRIL NOVEMBERCourtesy Joep Lange
Progress Report | April 200738 |
Table 1. Estimated number of people receiving antiretroviral therapy, people needing antiretroviral therapy and percentage coverage in low- and middle-income countries according to region, December 2006
Table 1. Estimated number of people receiving antiretroviral therapy, people needing antiretroviral therapy and percentage coverage in low- and middle-income countries according to region, December 2006
Geographical region Estimated number of people receiving
ARV therapy
Estimated need
Coverage
Sub-Saharan Africa 1 340 000 4 800 000 28%
Latin America and the Caribbean 355 000 490 000 72%
East, South and South-East Asia 280 000 1 500 000 19%
Europe and Central Asia 32 000 230 000 15%
North Africa and the Middle East 4 000 77 000 6%
Total2 015 000
[1.8 – 2.2 million]
7 100 000[6.0 – 8.4
million]
28%[24 – 34%]
Progress Report | April 200739 |
72% a72% aúún excluidos.n excluidos.Por cada persona Por cada persona
que accedeque accedeal tratamiento, al tratamiento,
6 contraen el HIV.6 contraen el HIV.
The case for expanding access to HAART to curb the growth of the HIV epidemic
Julio SG Montaner, Robert Hogg, Evan Wood, Thomas Kerr, Mark Tyndall, Adrian R Levy, P Richard Harrigan – Lancet 2006;368:531-36
HAART HAART CoverageCoverage
Uno termina siendo cómplice de lo que no intentó evitar
JP Sartre
ONE WORLDTWO STANDARDS OF CARE
• FDC (TDF/EMT/EFV)• Resistance testing• Baseline check-up• Frequent CD4 & VL
monitoring• Rtv-boosted PI’s• 3rd and 4th line
regimens
• FDC (d4T/3TC/NVP)• Not available• Limited• CD4 in some
settings, VL low %• Limited availability• Almost not availble
ONE WORLDTWO STANDARDS OF CARE
• ARV can be delivered all over the world• Success rates comparable to 1st world• Early mortality higher, due to late start• Guidelines compromised by cost,
procurement and lack of political will • The majority of patients in need still lack
access to WHO recommended ARVs• While expanding access to 1st line, push
for proven 2nd line therapies
• Tenemos drogas y sabemos como usarlas
• Sabemos como reducir la epidemia
• Hay dinero suficiente
• Hemos escuchado demasiadas declaraciones
políticamente correctas
• ¿Cuántos mas deberán morir ?
El mejor momento para plantar un árbol es hace 20 años .
La segunda mejor opción es hoy…
Identificar la opciIdentificar la opcióón correcta:n correcta:
a)a) El porcentaje de cobertura de ARV en el El porcentaje de cobertura de ARV en el mundo es del 48% mundo es del 48%
b)b) Las recomendaciones de OMS para inicio de Las recomendaciones de OMS para inicio de terapia ARV indican que se debe iniciar con 350 terapia ARV indican que se debe iniciar con 350 CD4/mm3 CD4/mm3
c)c) D4T/3TC/D4T/3TC/NevirapinaNevirapina es la combinacies la combinacióón mas n mas frecuentemente utilizada en frecuentemente utilizada en ÁÁfrica. frica.
d)d) La lipodistrofia no afecta a las personas de La lipodistrofia no afecta a las personas de raza raza negra.negra.
e)e) Lo siento, NO aprendLo siento, NO aprendíí..