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..