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Assessment Strategies and Interventions to
Minimize the Selection and Transmission of
Drug Resistant HIV in Resource Limited
Settings
Silvia Bertagnolio, MD
World Health Organization
Geneva, Switzerland
ART in Resource-Limited Settings
 6.6 million on ART in low- and middleincome countries at the end of 2010
- 22-fold increase since 2001
- 1.4 million people started ART in 2010
Recently infected populations
WHO surveys of Transmitted Drug Resistance (n=2788)
4.0%
3.5%
NNRTI
NRTI
PI
Overall prevalence of any
DRM: 3.7% (95% CI 3%-4.4%)
2.5%
2.0%
1.5%
I47V
D30N
I54T
I85V
F53L/Y
M46I/L
L74V
V75A/T
M41L
L210W
T69D
K70R
K219E/N/Q/R
D67N/G
T215D/F/I/S/Y
M184I/V
V106A/M
Y188C/L
G190A/S
K101E
Y181C
K103N/S
any PI
NRTI/NNRTI
0.0%
any NRTI
0.5%
Gupta et al., Antivir Ther, 2011:
Overall Transmitted HIVDR: 2.5% - 4 %
any NNRTI
1.0%
any SDRM
Percent of Pa ents
3.0%
Bertagnolio S et al., CROI 2011; Jordan M et al, Antiviral Therapy, 2011
5.7% (95% CI 4.8-6.7)
2.2%
Hamers
1.4%
3.4%
1.3%
1.1%
Chronically
Infected,
ARVs-naive
populations
R et al., CROI 2011 # 622
10.0%
9.0%
NNRTI
NRTI
PI
7.0%
6.0%
≥1 TAMs: 1.3% (N = 19; 13 pathway 2)
≥3 TAMS: 0.3% (N = 4)
5.0%
4.0%
WHO surveys:
HIVDR (n=1503)
3.0%
2.0%
1.0%
Y1
81
K 1 C/
03 I
N/
G1 S
90
A
Y1 K10
8 1
ot 8C/ E
he H
r N /L
N
M RT
18 I
T2 4I/
15 V
F
K2 /I/S
19
E/
N
M
41
K7 L
0E
D6 / R
7G
/N
K6
5
L R
ot 74I
he /V
rN
RT
I
I8
5V
M
46
ot I/L
he
rP
I
0.0%
an
yS
an D R
yN M
N
a R
NR ny TI
TI NR
&N TI
NR
T
an I
y
PI
Percent of Pa ents
8.0%
Bertagnolio S, CROI 2011
Jordan M, Antiviral Therapy, 2011
Number of people receiving ART in low
and middle income countries
Emergence of HIVDR is inevitable
• Time since start of ART scale-up a risk
factor for TDR
(OR 1.38 per year, p<0.001)
Hammers R et al, CROI, 2011
Source: WHO, 2010
HIVDR testing realities: RLS
• TDR is associated with poor virological outcome
Wittkop, Lanc Infect Dis, 2011
• Lack of accessible
individual
• Individualized
approach
for HIVDRHIVDR
testing currently
testing
should
not
be
an
excuse
to
limit
not routinely available nor recommended
optimization of patient care and global
• Expensive: would take away resources from other
efforts to minimize HIVDR
important priorities
Jordan M, CID, 2011
• Complex: limited capacity and infrastructure
• Limited treatment options leave little room for
regimen change based on genotyping results
What is the public health impact of expanded
ART access on HIVDR?
• Will HIVDR increase to alarming levels?
• Earlier treatment initiation of ART (CD4 <350):
• Yes50% increase in the number of people
estimated
• for
No ART
eligible
(UNAIDS, 2010)
• Maybe
•
Median time from seroconversion to CD4 <200 and
<350 cell/mm3: 4.19 and 7.93 years, respectively
• Additional 3.7 years of exposure to ART
(S.Lodi,
•
CID, in press)
The longer the exposure to ARVs, the greater the risk of
developing HIVDR
YES!
NO! of expanded ART
HIVDR in an inevitable consequence
coverage and prevention interventions using ARVs
"Expanded coverage can reduce HIV
• MAYBE….
incidence
in populations,
and
therefore
the
 1. Fear
of
resistance
should
not
be
an
argument
against
More people on ART=more people failing ART
actualofnumber
of new resistant infections"
expansion
ART
coverage
More people failing ART=more
people with HIVDR
Gill VS et al. Clin Infect Dis. 2010
 2. Routine,
virus standardized, population-based surveillance
of HIVDR
is imperative
Therefore,
the relative contribution to new infections
fromprogrammatic
people that are
failing ARTofwith
HIVDR
will
 3. Robust
evaluation
factors
associated
increase
with HIVDR
is a critical component of successful ART
scale-up
 4. Operational
research
to identify
practices
 Increased
proportion
of newbest
infections
thatisare
essential
resistant among those which are not averted
R.F.Baggaley et al. Curr Opin HIV and AIDS, 2011
What can
countries do to
minimize
emergence and
transmission of
HIVDR?
Factors critical to the success of global ART
scale-up
and the minimization of HIVDR
1. Patient
factors
2. Drug/regimen factors
Stigma/discrimination
• 3.Suboptimal
Programmatic
factors
regimens
3 times more likely to be non-adherent
1.
Burden
on factors
the health
system:
-Patient
Inappropriate
prescribing
practices
Lance S Rintamaki, et al. AIDS Patient Care and STDs. 2006
Increasing
demand
- Use
of non QA
drugsof services
Limited(PMTCT)
human resources and infrastructure
Adherence
Sd-NVP
2. Antiretroviral drug/regimen factors
Fragile drug
procurement
andhours
supply
Treatment
interruption
of 48
or
- Drug-drug
interactions
management
systems
more
associated
with
virological failure and
- Drug toxicity
3.selection
ART
programmatic
factors
Lack
ofofroutine
VL monitoring
drug resistant
HIV
- High pill burden Oyugi JH, et al. AIDS 2007
- Sustaining high quality service while
decentralizing
care
• Boulle A, JAMA 2008; Maartens G, Antivir Ther 2009;
Parienti l, CID, 2009; Shah Sl, AIDS Res Hum Retr 2011;
- Weak M&E
system assessing quality of care and
treatment outcomes
Four-Step Approach
Step 1:
Assess HIVDR
1. Assess transmitted and acquired HIVDR using
standardized methods
2. Routine monitoring of patients, clinic and
programmatic factors contributing to HIVDR
Step 2:
•
Operational Research
Use findings from step 1 to guide operational
research
– Characterize areas of programmatic weakness
– Identify appropriate targeted interventions
Four-Step Approach
Step 3: Implement targeted intervention
• Using operational research findings (step 2).
Step 4: Evaluate impact of intervention
• Ideally, using same methods applied in step 1
Countries Implementing One or More
WHO HIVDR Surveys (Feb 2011)
Laboratories accredited by WHO
Laboratories undergoing assessment
Step 1
Step 1
WHO HIVDR Global Assessment Strategy
Transmission of DR
HIV in recently
infected population
Emergence of
HIVDR in treated
patients
ART site factors
associated with HIVDR
Emergence
Surveillance
Monitoring Surveys *
Early Warning
Indicators
Genotyping
Laboratory
Genotyping, VL
Laboratory
Non-Laboratory;
Data collection
only
TDR classified
<5%
5-15%
>15%
HIVDR prior ART and at 12
months; VL suppression
at 12 months; use results
for programmatic
adjustments
Areas to directly target for
improvement
PUBLIC HEALTH ACTION
*Surveys to monitor HIV DR prevention and associated factors in sentinel ARV treatment sites
WHO HIVDR EWI
• 50 countries monitored HIVDR EWI
• 131,686 patients initiating ART in the period 2004–09
• 2,107 ART clinics
% clinics
meeting target
Target
Lost to follow-up (LTFU) at 12 months
69%
≤20%
Retention on appropriate 1st line ART at
12 months
67%
≥ 70%
On time pill pick-up
17%
≥90%
On time appointment keeping
Drug stock out at the level of ART clinic
58%
65%
≥ 80%
0%
Indicator
Bennett DE et al. (unpublished data)
LTFU Study (Malawi, Lilongwe)
• Assessment: of 3846 ever started ART, 48% LTFU
• Operation research goals:
– Understand true outcomes of LTFU
– Risk factors for tracing success
• Findings: 1800 pts LTFU consented tracing
60% untraceable
(no phone or address)
Weigel R, et al
BMC Infectious Diseases 2011
40% possible to
trace
50% on ART at clinic
40% on ART in other clinics
10% stopped ART
74% traced
41% died
59% alive
Step 2 LTFU Study (Malawi,
Step 3 Lilongwe)
Step 4
OPERATIONAL
INTERVENTION
IMPACT
RESEARCH
ASSESSMENT
Having a phone number
recorded doubled odds of
successful tracing
(aOR 2.07, p<0.001)
Regular collection of
contact information
introduced
Clinic is now able
to successfully
trace 85% (instead
of 40%) of LTFU
50% of LTFU were alive
and still on ART at the
clinic: "2 wks after last
missed visit is too early to
trigger active tracing"
Time before active
Not assessed
tracing altered from 2
to 3 weeks after last
missed visit
40% of LTFU were silent
transfer out
Improved information Not assessed
transfer between
facilities prevent
costly tracing
(Not implemented)
Sustainability of HIV response
• In 2010, international resources for
HIV declined
– 2011: 16 billion $ earmarked of 24 billions $
estimated to be needed
• In 56 countries, international
donors account for at least 70% of
HIV resources
HIVDR surveillance sustainability
• Global Fund to fight AIDS, Tuberculosis and
Malaria (GF)
– largest funder of HIV programs internationally
• In 2002, mechanisms to encourage countries to
implement HIVDR surveillance
• We reviewed documentation for funded HIV
grants to assess grantee use of GF resources to
support HIVDR Surveillance
HIVDR surveillance sustainability
• 147 HIV grants funded (2004-2008)
– Only 22% (32/147) requested funding for
Additional
assessments will be
HIVDR
Surveillance
required to evaluate the barriers to
using Global Fund grants to support
• Baseline information and field experience
HIVDR Surveillance
suggest countries make limited use of GF
resources to support national HIVDR
surveillance activities
Kelley K et al. (submitted to CID)
Take-Home Messages
 Fear of resistance -- not an argument against expansion
of ART
 Robust programmatic evaluation of factors associated
with HIVDR -- a critical component of successful ART
scale-up
 Routine, standardized, population-based surveillance of
HIVDR is imperative --- must be integrated into routine
M & E programmes
 Operational research to identify best practices essential
 Funders and national governments must step up to
support and sustain population based HIVDR
surveillance and efforts optimizing patient care
Acknowledgments
The Bill and Melinda Gates Foundation
Michael R. Jordan
Neil Parkin
Andrew Phillips
Andrea De Luca
Marco Vitoria
My son Alessandro….who was born 2
months ago and actively attempted
to abort the preparation of this
presentation …..