Transcript Diapositiva 1

Leading by Example in the
Public Health Approach to ART
Framework for the International AIDS Society-Convened
2nd Global Experts Summit
Vancouver-2009
Optimization of ART Drug
Regimens
Pedro Cahn
Major Management Trends in HIV in Wealthy Countries
• Routine, voluntary, opt-out HIV screening in
health care settings
• Earlier initiation of HAART leads to better
outcomes
• Resistance testing at diagnosis, regardless of
treatment initiation
• Refinement of initial HAART regimens
• Using multiple active drugs to achieve full
suppression in treatment-experienced patients
– No longer exclusive for treatment-naïve patients
Major Management Trends in HIV in LMIC Countries
• HIV test performed usually in late stages
• Later initiation of HAART leads to worst outcomes
• Resistance testing mostly not available in LIC, available
(with limitations) in MIC
• Initial HAART regimens are compact but with acute and
chronic toxicity
• Low proportion of patients have access to 2nd line
therapies. Triple class failure almost not treated in low
income and in some middle income countries.
• Prevention does not match treatment efforts
• Sustainability??
FACTS
• ART is potent enough to reduce VL by 6 orders
of magnitude
• VL reduction drives to immune recovery
• Immune recovery reduces morbidity, need for
hospitalization and mortality due to AIDS
• ART impacts on incidence cardiovascular, liver,
renal and “non-AIDS”associated cancers
• ART save lives, with impact at individual and
population level
AIDS: INCIDENCE RATE PER MILION
91
81
65
66
64
65
58
58
58
60
51
47
43
35
40
HAART
24
28
15
06
20
04
20
02
20
00
20
98
19
96
19
94
19
19
90
92
9
6
19
19
88
100
90
80
70
60
50
40
30
20
10
0
National AIDS Program, Argentina
FACTS
•
•
•
•
About 3 million people on ART
About 6.7 million still in need
Western guidelines call for earlier start
Current guidelines for LMIC still calling for
relatively late start. Last update circa 3
years ago.
FACTS
• HAART is cost-effective
• Cost-effectiveness ratio
increases with earlier
start1
• Models predict costaverting in scenarios of
HAART expansion2,3
C/E per
QALY
ARV vs.
No ARV
CD4 <50
USD
13,00023,000
26,000
CD4 < 200 17,000
CD4 < 500 14,000
1.Wilkin, CID 2008
2. Granich R: Lancet 2009
3. Lima; J Infect Dis. 2008
Limitations and obstacles:
Lost to follow-up
• Over 20% LTFU in LMIC1
• Main reasons: Advanced disease and payment for
services2
• Poverty and logistics3 : ART interruption driven by stock
shortages (OR 3.25), binge drinking (2.87), slimming
symptoms (1.23). Conclusion: “Food supply programs
and minimization of ARV shortage may reduce ART
interruptions”
• Hidden costs in health care delivery might jeopardize
success of “free services”4 Over 50% of the delivery
costs in rural Tanzania was for transport.
1 Bull World Health Organ 2008
2. Morris K:www.thelancet.com/infection; 2008
3. Marcellin F: Tropical Medicine and Int. Health, 2008
4. Kruk M: Tropical Medicine and Int. Health, 2008
HIV-Infected Patients in the HAART Era Have a
10-Year Shorter Expected Survival than Age and
Gender-Matched Controls
Survival from age 25 years
Probability of Survival
1
Population controls
0.75
Late HAART
(2000-2005)
0.5
Early HAART
(1997-1999)
0.25
0
Pre-HAART (1995-1996)
25
30
35
40
45
50
55
60
65
70
Age, y
Adapted from Lohse N, et al. Ann Intern Med 2007;146:87-95
Goals of HAART: A story of three eras
 1996-2001: To reduce the incidence of opportunistic
infections and AIDS-related deaths by stopping and
reversing immunologic failure
 2002-2007: To avoid emergence of resistance mutations
by keeping viral load below 50 copies/mL
 2008-…..: To reduce non-AIDS morbidity and mortality
NA-ACCORD: Survival Benefit With Earlier vs Deferred HAART
Immediate treatment: initiated HAART within 1.5 years of first CD4+ cell count in 351-500 cells/mm3
range
Deferred treatment: did not initiate HAART within 1.5 years of first CD4+ cell count in 351-500 cells/mm3
range. Included patients who did not initiate treatment after reaching CD4+ cell count < 350 cell/mm3
Parameter Associated With
Risk of Death
Relative Hazard (95% CI)
P Value
Deferral of HAART until < 350 cells/mm3
(vs starting at 350-500 cells/mm3)
1.7
CROI 2009:Abstr 71
Advantage
shown at 500 CD4
Female
sex
1.1 level
Older age (per 10 yrs)
1.6
Baseline CD4+ cell count
(per 100 cells/mm3 increase)
0.1

.290
< .001
0.9
1.0
< .001
.083
2.5
Increased relative hazard of death with deferral of HAART remained
unchanged when adjusted for IDU or for HCV coinfection, which were both
independent predictors of mortality
Kitahata, et al. ICAAC/IDSA 2008. Abstract 896b.
“CLASSIC” TREATMENT PARADIGM
•
•
•
•
Reduce mortality
Reduce AIDS-associated morbidity
Recover immune function
Achieve maximal viral load suppression
NEW PARADIGM
•
•
•
•
•
Reduce mortality
Reduce AIDS-associated morbidity
Reduce non AIDS-associated morbidity
Recover immune function
Achieve maximal viral load suppression
in all stages
Recommendations for initiating ART in adults and
adolescents based on clinical stage and availability of
immunological markers
WHO Clinical
Staging
CD4 testing not
available
1
2
Do not treat [A-III]
CD4 testing available
Treat if CD4 cell count < 200/mm3[A-III] a
Do not treat b [B-III]
3
Treat [A-III]
Consider treatment if CD4 cell count <
350/mm3 a c d and initiate ART before CD4
cell count drops below 200/mm3 e [B-III]
4
Treat [A-III]
Treat irrespective of CD4 cell count [A-III]
a
CD4 cell count advisable to assist with determining need for immediate therapy for situations as pulmonary TB and severe bacterial infections, which may occur
at any CD4 level.
b A total lymphocyte count of ≤ 1,200/mm 3 can be substituted for the CD4 count when the latter is unavailable and mild HIV disease exist. It is not useful in the
asymptomatic patients. Thus, in the absence of CD4 cell count and TLC, patients with WHO Adult Clinical Stage 2 should not be treated.
c
Initiation of ART is recommended for all HIV-infected patients with CD4< 350/mm3 and pulmonary TB or severe bacterial infection.
d
Initiation of ART is recommended in all HIV-infected pregnant women with WHO Clinical Stage 3 disease and CD4< 350 cells/mm 3.
e The precise CD4 cell level above 200/mm 3 at which ARV treatment should be started has not been established.
WHO-2006
When Is Antiretroviral Therapy Started?

Review of data from 2003-2005 from 176 sites in 42 countries (N =
33,008)

Since 2000, CD4+ cell count at initiation in developed countries stable at
approximately 150-200 cells/mm3, increasing in sub-Saharan Africa from
50-100 cells/mm3
164
200
187
179
123
102
86
125
181
Egger M, et al. CROI 2007. Abstract 62.
122 100
97
97
87
163
192
157 206
95
103 53
72 134
239
OPTIMIZATION
1. Start earlier
 How early?
 Science favors earlier start
 Funding shortages may push back the threshold
 Reality check: We are starting too late, even for current
WHO standards
 Proposal: Let’s go stepwise. Expand VCT and ARV rollout
to all eligible patients within current guidelines.
Use the Tetris strategy to address equity
 Research questions: 1) What are the obstacles for testing
expansion in different countries?
2) What are the obstacles beyond cost for ART rollout?
WHO Adult Guidelines-2006:
Aiming to simple and standard ARV
regimens
First-Line ART
ART Treatment Failure
Second-Line ART
First-Line regimens
Hakim: HIV 9, Glasgow
OPTIMIZATION
2. Start safer
 Current regimens in LIC are toxic
 Neuropathy, lypodistrophy affect adherence and
discourages naïve patients to enter treatment programs
 Reality check: Triomune is cheap. Countries still have
large stocks
 Proposal: Face off of d4T from guidelines. Advice
countries to stop buying Triomune. Negotiate costs with
producers. Foster patent licensing
Limited use of second-line
•
Only 40,000 (2%) on 2nd line at end
2006. [About 4% in 2008]
– 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)
900'000
800'000
Total number of
people needing
2nd line ARVs
(high estimate)
700'000
600'000
500'000
- 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
400'000
Total number of
people needing
2nd line ARVs
(low estimate)
300'000
200'000
100'000
2006
2007
2008
2009
2010
Relationship Between Viral
Suppression and Mortality
 Prospective, population-based
Danish HIV Cohort Study
Proportion of Detectable Viral Loads Over
6-18 Months After Initiation of HAART
– N = 3919 HIV-infected patients
100% (all values VL ≥ 400)
1%-99% (of values VL ≥ 400)
0% (all values VL < 400)
– On HAART ≥ 18 months
 Higher risk of death with transient
or lack of viral suppression
0.25
Cumulative Mortality
 Stratified based on proportion of
detectable VL (> 400 copies/mL)
during the period 6 to 18 months
after initiation of HAART
0.20
0.15
0.10
0.05
– Consistent with shorter-term studies 0.00
0
Lohse N, et al. ICAAC 2005. Abstract H-515
CID2006;42:136-144
.
18
36
54
72
Months After Baseline
(baseline = 18 months after HAART initiation)
Second-Line ART in Malawi
Hosseinipour M- 17th IAC, Mexico City, 2008
Virologic failure >400 copies/ml
 96 patients (16 clinical, 87
CD4)
– 93% failing 1st-line ART
found to have NNRTI
mutations
• Median number of NNRTI
mutations: 2 (range: 0-3)
 56% had TAMs
 Mutations identified
– NNRTI mutations: 93%
• Y181C: 55%
• G190A: 30%
• K103N: 28%
– M184V/I: 81%
– TAMs: 56%
•
•
•
•
•
•
T215Y: 73%
D67N: 53%
K70R: 36%
M41L: 36%
K219Q/E: 23%
L210W: 23%
• ≥ 3 mutations: 44%
17% predicted
to have
• 2 mutations:
28% no active NRTIs
22% to
50%
predicted
• 1
mutation:
28% to have no fully active drugs in
second-line regimen, depending on NRTI backbone
selected
Hakim: HIV 9, Glasgow
Prevalence of mutations at 24 and 48 weeks
Weekmore
24
Week 48
See CROI 2009: Mutation
Posters 605-610 to learn
(n=41*)
about consequences of late switching and lack(n=24)
of VL monitoring
Overall, prevalence of
resistance was higher at 48
compared to 24 weeks.
The proportion of samples
with 4-6 TAMS at 24 and 48
weeks was 4% and 39%
respectively, all with coexisting M184V
Hakim: HIV 9, Glasgow
May 2007
M184V
K65R
M41L
D67NG
K70R
L210W
T215FY
K219QEN
Total TAMs: 0
1-3
4-6
TAM Group** I
II
I and II
15(62%)
3 (12%)
7 (29%)
9 (38%)
8 (33%)
0 (0%)
7 (29%)
1 (4%)
10 (42%)
13 (54%)
1 (4%)
5(36%)
4(11%)
5(36%)
32 (78%)
6 (15%)
17 41%)
23 (56%)
23 (56%)
3 (7%)
17 (41%)
9 (22%)
11 (27%)
18 (44%)
12(39%)
2 (7%)
11(37%)
17(57%)
*excluding 3 patients with BL NRTI resistance
** TAM I=41L, 67NG, 210W, 215Y; TAM II= 67N, 70R, 215F, 219QEN
Note: no MDR mutations /insertions/deletions were observed
OPTIMIZATION
3. Provide 2nd line therapy timely
 Current availability falling short
 Keeping patients on failing regimens induces resistance in a timedependant manner

Benefits at a population level jeopardized

Reality check: 2nd line still expensive.
 Proposal: Lobby donors to show that benefits driven from first line
therapy might be spoiled if 2nd line therapy is not available.
 Research questions:
1) Explore innovative therapy strategies
2) Gather further evidence regarding ART as prevention
When to Switch from 1st Line to 2nd Line ARV
Regimens for Treatment Failure
WHO Clinical
Staging
Clinical Failure
(CD4 and VL not
available)
Immunologic
Failure
(VL not available)
Immunologic
and Virologic
Failure
(CD4 and VL available)
1
N/A
Do Not Switch
Consider
Switch
2
N/A
Do Not Switch
Consider
Switch
3
Consider
Switch
Switch
Switch
4
Switch
Switch
Switch
Clinical failure is
defined as a
occurrence of new or
recurrent WHO
clinical stage 3 or 4
event (excluding
IRIS).
CD4 failure is
defined as a fall to (or
below) the pretreatment baseline or
a 50% drop from the
on-treatment peak
level or persistent
levels < 100
cells/mm3.
Virological failure is
provisionally defined
as a plasma HIV-1
RNA level >10,000
copies/ml after a
minimum of 6 months
on therapy.
When to Switch from 1st Line to 2nd Line ARV
Regimens for Treatment Failure
WHO Clinical
Staging
Clinical
Failure
(CD4 and VL
not available)
Immunologic
Failure
(VL not
available)
Immunologic
and Virologic
Failure
(CD4 and VL
available)
1
N/A
Do Not
Switch??
2
N/A
Do Not
Switch??
Switch
3
Switch
Switch
Switch
4
Switch
Switch
Switch
Switch
Clinical failure is
defined as a
occurrence of new or
recurrent WHO
clinical stage 3 or 4
event (excluding
IRIS).
CD4 failure is
defined as a fall to (or
below) the pretreatment baseline or
a 50% drop from the
on-treatment peak
level or persistent
levels < 100
cells/mm3.
Virological failure is
provisionally defined
as a plasma HIV-1
RNA level > 1000 or
5000 copies/ml after
a minimum of 6
months on therapy.
OPTIMIZATION
4. Monitor your treatments
 VL monitoring improves quality of care and survival
 VL monitoring reduces risk of resistance and
preserves treatment options
 Misclassification of ART failure by clinical and CD4
criteria can be as high as 45%1 resulting in
unnecessary switch of ART
 PCR infant diagnosis rapidly expanding
 VL is already being performed in several LMIC
 Many research projects already built capacity for VL
1: Hosseinipour, IAS 2007
OPTIMIZATION
4. Monitor your treatments
Reality check:
 Human resources, logistics, climate issues, electrical
power shortages
 Financial constraints: Different funders, competing
priorities
 Point of care, cheap and simple technologies not yet
widely available
(But see CROI 2009 Posters 1006-1009: Dried blood
spots and Poster 1003: Pooled VL testing)
OPTIMIZATION
4. Monitor your treatments
Proposal:
 Consensus statement to help to set an attractive
market for producers
 Bulk purchasing needed in order to reduce costs.
 “ Brazilian package” to assure supply of consumables
and technicians training
 Universal access to VL monitoring not feasible in the
short term, but a minimum standard has to be set as
a goal for the short term.
 Urgent research program needed to test those
standards. (VL: How frequently, what thresholds,
what techniques)
ART-LINC vs. ART-CC:
Cumulative mortality after
12 months on HAART
6.4% (5.1-7.7)
1.8% (1.5-2.2)
Braitstein et al; Lancet 2006; 367: 817–24
Mortality During First Year of HAART in
Latin America & Caribbean
 Death rates vary widely among Latin American, Caribbean countries
• Probability of death higher in Haiti, Honduras, and Peru*
Probability of Death
0.14
Haiti (n = 1672)
Honduras (n = 329)
Peru (n = 873)
Overall (n = 5152)
Chile (n = 547)
Brazil (n = 522)
Mexico (n = 416)
Argentina (n = 794)
0.12
0.10
0.08
0.06
0.04
0.02
0.00
0
3
6
Months
9
12
*Adjusting for BL CD4+ cell count at HAART initiation decreased probability of death, but rate remained
higher in Haiti and Honduras.
Tuboi SH, et al. IAC 2008. Abstract MOAB0203.
OPTIMIZATION
1. Start earlier
2. Start safer
3. Provide 2nd line therapy timely
4. Monitor your treatments
5. Integrate AIDS programs with
HC systems
Two Paediatric Epidemics
 High-resource countries
– New perinatal infections are rare
– Effective treatment available
– Aging cohort of infected children
– Concerns long-term complications of treatment
 Low-resource countries
– 1,000 infants are newly infected each day
– Diagnosis of infection in infants problematic
– Problems with drug access
– Treatment when available is started late.
Courtesy C. Giaquinto
Estimated Number of HIV-Infected Children Needing
and Number Receiving Antiretroviral Treatment
By Region as of December 2007
# Needing ART
# Receiving ART
800,000
600,000
400,000
200,000
0
Sub-Saharan
Africa
ARV Coverage
13%
Latin America/
Caribbean
67%
Source: World Health Organization, April 2007
E/S/SE Asia
21%
Europe/
Central Asia
20%
N Africa/
Middle East
<1%
Risk of developing AIDS/death according to age at
ART initiation (EIC, AIDS in press)
 early treatment: <3 months
 deferred treatment: >3 months
crude HR= 5.0; 95% CI:2.0-12.6
HR adjusted for cohorts = 3.0;
95% CI: 1.2-7.9
Courtesy C. Giaquinto
Probability of Death or a First Event, According to Treatment Group
(CHER Trial)
Probability of death
Median time from
randomization to therapy
21 weeks, deferred
Probability of death
or CDC event
Violari A et al.
N Engl J Med 2008;359:2233-2244
Children in low-resource countries who receive ART are
starting treatment when already severely immune deficient
Baseline
Median Age
Baseline
Median CD4*
% RNA undetectable
on HAART
Janssens/Cambodia 2007 N=212
6.0 yrs
6%
74% <400 (17 mos)
George/Haiti 2007 N=100
6.3 yrs
12%
56% <50 (12 mos)
Wamawala/Kenya 2007 N=67
4.4 yrs
6%
67% <400 (6 mos)
Reddi/S Africa 2007 N=151
5.7 yrs
8%
80% <50 (12 mos)
Puthanakit/Thailand 2007 N=107
7.7 yrs
5%
70% <50 (3.7 yrs)
Kamya/Uganda 2007 N=250
9.2 yrs
8.6%
74% <400 (12 mos)
Kekitiinwa/Uganda 2008 Abs 584 N=876
7.6 yr
8%
70% <400 (6 mos)
* Recommended threshold: 25%
Courtesy C. Giaquinto
Antiretroviral Drugs Approved in
Adults but Not Yet Approved in Children
N(t)RTI
NNRTI
PIs
Entry/Fusion
Inhibitors
Integrase
Inhibitors
ABC
EFV
ATV
Enfurvirtide
RAL
ddI
NVP
DRV
MVC
FTC
Etravirine
FosAMP
3TC
IDV
d4T
LPV/r
TDF
NFV
Ritonavir
SQV
TPV
Courtesy C. Giaquinto
Pediatric Adherence Challenges
Courtesy Peter Havens MD
Courtesy C. Giaquinto
The Challenge of Pediatric HIV Infection
in Resource-Poor Countries
 While high rates of HIV infection in women, few women
know they are infected and there is poor access to ARV
to prevent MTCT.
 Children often present to health system with advanced
disease.
 Rapid progression and high mortality due to HIV in
children, yet few receive treatment.
 Early treatment would prevent many deaths but infant
diagnosis not available.
Courtesy C. Giaquinto
Paediatric Treatment in Low Resource Countries
What is Available for Adults
FDCs that allow one pill once or twice daily
What has been Available for Children
d4T
d4T
5
mg/m
5
l
mg/m
l
3TC
Giving 3 different liquids hard to transport/store/give
10
3TC
mg/ml
10
NVP
mg/ml
10 mg/ml
NVP
10 mg/ml
Splitting adult tablets, risking inappropriate dose
and associated risk toxicity or underdosing=resistance
Research priorities: Pediatric formulations
Scored crushable FDCs
• More than d4T/3TC/NVP preparations
• QD pills
• Crushable and dispersable tablets/granules
• Appropriate drug ratios for children based on PK
• Dual as well as triple FDC
• Adherence strategies for kids and teenagers
Modified from C. Giaquinto
MDGs decided by UN to be reached in 2015, aiming to
reduce global poverty and improve life standards
Known G8 HIV commitments 2008-2010 compared with “fair share” commitments
as a proportion of world GDP
(in millions) given US$ 61 billion needs
Commitment
proportional to
GDP
Canada (184, 1590
Germany (*720, 3720
Italy (200, 2380
Japan (318, 4940
Russia (120, 1400
Known HIV
commitments
UK (*537, 3110
US (19430, 15500
0
10000
20000
30000
40000
•Figures are mostly based on the Toyako Framework for Health Report of the Health Experts Group Annex. Note that due to
different methodologies for reporting HIV contributions and their focus on health systems strengthening, the United Kingdom
figure is the specific amount earmarked for the Global Fund for 2008 to 2010, and figure for Germany is an estimate based on
funds intended for the Global Fund and 2007 HIV funding levels.
*Global GDP proportions are based on International Monetary Fund values for 2007
Sept 19, 2008
Dow soars 400 points in response
to government rescue plan
Treasury Secretary Henry Paulson holds a news conference at the Treasury
Department today in Washington, D.C. Paulson said the Treasury would
insure money-market mutual funds as one part of a massive government
bailout that is attempting to stabilize the current financial crisis.
Treasury Secretary Paulson outlines a plan to purchase hundreds of
billions of dollars of bad debt from troubled banks and insure individual
investors against losses in money-market mutual funds.
The European Central Bank is fighting desperately against the
financial crisis. The institution offered banks €70 billion in liquidity
loans on Tuesday, bringing the global total offered by central banks
that day to €112 billion.
No money available to help this people……
VANCOUVER 1996:
ONE WORLD, ONE HOPE
VANCOUVER 2009:TWO APPROACHES TO CARE, NOT
TWO STANDARDS OF CARE