Professional Documents
Culture Documents
APPENDIX 1
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Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011
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Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators
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Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011
Results summary
EWIs 1-3 (prescribing practices, loss to follow-up and
retention on first-line ART at 12 months,
respectively) were monitored at 93%-99% of clinics.
EWI 5 (on-time appointment-keeping) was monitored
in 65% of clinics
EWIs 4 and 6 (on-time ARV pickup and ARV supply
continuity, respectively) at a minority of clinics (17%
and 34%, respectively).
EWI 8 (viral load at 12 months) was monitored in 2%
of clinics.
EWI 7 (pill count) was monitored by only two
countries (<1% of sites) and data were not included
in our analyses.
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Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators
Results summary 2
Among participating clinics, most in Africa and Asia met
the target for EWI 1, prescribing practices (all >73%). In
Latin America and the Caribbean (LAC), 46% of clinics
met the EWI 1 target.
Overall, 69% of clinics met the target for EWI 2 (loss to
follow-up), and 67% met the EWI 3 target (retention on
first-line ART).
17% of 352 clinics met the EWI 4 target (on-time drug
pickup). In Africa, 15% of 321 clinics met the target; in
Asia, 0% of 10 clinics met the target; in LAC 57% of 21
clinics met the target.
58% of clinics met the target for EWI 5 (on-time
appointment keeping).
65% of clinics met the EWI 6 target (ARV supply
continuity). Of the 100 clinics in Asia that monitored EWI
6, 89% met the target.
Results summary 3:
Pediatric EWI
Six countries monitored pediatric EWIs 2006-2009
Thailand contributed 296 (89%) of 331 sites
monitored.
High percentages of clinics in all countries met
targets for EWIs 1 and 2.
Lower percentages were reported by some countries
for EWI 3 and EWI 5.
No countries monitored EWI 4; only two countries
monitored EWI 6.
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Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011
Discussion
Regional and global results were heavily influenced
by country-specific data. For example, Thailands
EWI monitoring contributed 902 (43%) of 2,107 adult
clinics in this analysis, and 296 (89%) of 331
pediatric clinics.
Few countries monitored EWI 7: standardized
adherence
Few countries had the capacity to monitor EWI 8:
viral load, because most countries do not perform
viral loads routinely.
Discussion
Only 21/50 countries (42%) had records enabling
abstraction of on-time antiretroviral drug (ARV)
pickups (EWI 4).
Many countries could not monitor all their selected
EWIs in all sites because of medical and pharmacy
record limitations.
Many countries took action to improve records and
clinic/program functioning following EWI monitoring.
Examples follow.
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Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators
Quality of Records
Losses to follow-up
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Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011
Conclusions
As pediatric ART is scaled up, monitoring of
pediatric EWI will become increasingly
important.
EWI have been monitored in 50 countries,
generating results that supported public
health actions at a clinic and program level.
Our task here is to prioritize and simplify the
EWI to make them and the process of
abstraction.
Representative sampling of sites should also
be a priority.
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Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators
APPENDIX 2
Concentrated epidemic
Injection drug use - major driver.
Harm reduction interventions expanded.
2|
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Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011
Sustainability challenges
90% of HIV treatment and care budget funded by external donors.
3 | HIV services delivered through donor projects.
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Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators
5|
6|
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Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011
Cohort Event
HIV DR EWIs
Monitoring
TB/HIV PMTCT
Sometimes different definitions. Efforts to harmonize. Need for core national indicators.
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Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators
Indicators
9|
(VAAC 2009, 2010) Net cohort = 4531 adults and 313 children at month 12
10 |
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Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011
11 |
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Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators
28.3%
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Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011
16 |
16
Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators
Summary
21 |
Additional slides
22 |
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Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011
10
8
Adjusted Odd Ratio
5 5.04
4
3.26
3
2.17
2
1.52
1
1.10
Adjusted Odds Ratio
1.06
1.05
1.03
1.00
0.95
0.94 0.94
0.93
0.90
0.85
0.80
Side-effect Chance HLC Information Quality Satisfaction w Social
24 | from HCPs Support Connectedness
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Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators
17 |
Regions
Hanoi City 4 406 90.1% 1 3.0% 1
Northern 8 932 79.1% 0.41 (0.21-0.81)* 5.4% 1.86 (0.73-4.73)
Provinces
Ho Chi Minh City 7 2665 82.4% 0.51 (0.25-1.03) 6.0% 2.11 (0.95-4.71)
Southern 8 528 72.2% 0.28 (0.13-0.60)** 6.1% 2.12 (0.64-7.04)
Provinces
Number of patients
>500 7 2829 82.3% 1 5.9% 1
201-500 7 909 82.2% 0.99 (0.62-1.60) 5.5% 0.93 (0.47-1.85)
101-200 6 564 79.6% 0.84(0.53-1.34) 1.6% 0.26 (0.15-0.44)***
<100 7 229 68.6% 0.47 (0.28-0.79)** 12.7% 2.31 (1.26-4.24)**
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Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011
19 |
Comparison of
Viet Nam tool and WHO electronic tool
20 |
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Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators
APPENDIX 3
Map of Namibia
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Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011
Background
on
HIV/AIDS
First
4
cases
of
HIV
were
reported
in
1986
Strong
political
will
and
MoHSS
commitment
to
HIV/
AIDS
Global
Fund
HIV/AIDS
funding
since
2004
PEPFAR
funding
since
2004
Prevalence
in
general
population
(15+):
13.3%
(2008/09)
By
March
2011,
over
92,000
PLHIV
and
among
whom
approximately
ten
percent
(10%)
on
life
saving
treatment
45
main
sites
providing
ART
services
Namibia
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Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators
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Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011
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Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators
9 NA NA
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Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011
EWI 4a: On-time ARV drug pick-up 90% Limitations on EDT data
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Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators
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Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators
Lessons
Learnt
Collecting
data
annually
by
central
level
is
dicult
and
not
sustainable
EWIs
must
be
integrated
into
routine
program
monitoring
EWI
exercise
helped
identify
gaps
in
health
information
systems
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Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011
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Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators
APPENDIX 4
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Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011
Standards : Norm-referencing
Standards are defined by examination of the performance of existing
programs
Example :
Poor : central value
Good : > central value
May use different summary measures (e.g. above / below Q3)
Problems :
Thresholds my reflect poor existing practice
Failure of aspiration
More about ranking than good or best practice
Standards : Criterion-referencing
Standards are defined by desirable levels of performance :
Usually evidence-based for example
Measles vaccine coverage : 80% highly desirable
Problems :
Need for evidence
sometimes only expert opinion available
or sometimes only expert opinion available
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Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators
Mixed methods
Possible to use mixed methods
Three class indicators :
Poor : central value (mean or median)
Good : from central to criteria-reference
Excellent : criteria-reference
Three class indicators frequently used in private-sector monitoring
and evaluation (corporate metrics) activities and known as
SCORE-CARDING
Sometimes called balanced score-carding balance is a
reference to a mix of indicators addressing a full set of business
processes (i.e. a comprehensive indicator set)
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Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011
Score-carding
In brief :
Indicator-set created
Triage system (i.e. standards for poor and excellent) established
Routine data collection
Analysis / presentation by traffic-light method (aim for all green)
Advantages :
Allows mixed method thresholds
Politically clever does not fail everyone at start
Clear presentation of results preferred by managers due to
simplicity of reading / interpretation
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Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators
APPENDIX 5
Systematic Review HIVDR EWI Targets Version 25 July, 2011
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Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011
INTRODUCTION
To monitor and evaluate the effectiveness of HIV programs, routinely collected data is organized
into programmatic indicators. These indicators can guide funders and government agencies on how best
to identify problems and allocate resources within programs. Over 200 indicators have been generated by
different funding agencies for HIV programs, resulting in UNAIDS developing an online registry to
document these indicators at a single source [1]. Many of these indicators are ascribed targets which act
as a yardstick to measure results. The targets aim to provide clarity for all stakeholders (funders,
Within the field of HIV care and prevention multiple United Nations (UN) based agencies have
provided guidance on how to set targets [2-5]. Targets need to be ambitious so as to mobilize increased
resources and effort to improve outcomes, but also be realistic on what can be achieved if specific barriers
are overcome. This advice also supports the development of targets at a national level, helping countries
to: define and prioritize their efforts, promote accountability, reflect priority areas of the national program
and facilitate efforts to mobilize resources. However, there are also global targets in the field of HIV care
such as targets within the UN General Assembly declaration of commitment on HIV/AIDS [6], and the
The World Health Organization (WHO) has developed a Global Strategy for HIV Drug
Resistance Prevention and Assessment using a public health approach [8]. The foundation of WHO's
prevention and assessment strategy is the routine monitoring at all ART sites, or a large number of
representative ART sites within a country of HIV drug resistance (HIVDR) early warning indicators
(EWIs). HIVDR EWIs assess factors at antiretroviral therapy (ART) sites which are known to create
situations, which favour the emergence of drug resistant HIV. EWI results may be used to optimize
patient care and make ART clinic- and national program-level adjustments to minimize the emergence of
preventable HIVDR.
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Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators
The WHO recommends a target for each EWI that facilities should reach to prevent emergence of
drug resistance in ART patients. Current EWI targets are based on a review of the published medical
literature and consensus of international experts. Additionally, it is not recommended that individual
countries set more lenient targets but if countries choose they may set more stringent targets. [9]
Therefore, while EWI targets provide global guidance, their ability to be tailored to national requirements
Current targets were developed in 2004-5 at a time when the provision of free ART in low- and
middle-income countries (LMICs) using a public healthy model of care had only recently commenced.
Since that time there has been rapid scale up of antiretroviral therapy (ART) provision in LMIC treatment
programs [10], and increasing amounts of published research relevant to EWIs in these settings.
This review aims to summarize currently available evidence relevant to HIVDR EWI targets and
whether the evidence supports use of the current targets, or adjustment of the targets.
METHODS
Methods relevant to all EWIs are considered in this section as general methods. Methods specific
to individual EWIs will be detailed under the section for the relevant EWI.
Search strategy
Searches were performed on the online database Ovid MEDLINE for the following EWIs: EWI 2
and 3 (lost to follow up [LTFU] and retention on first line ART), EWI 4 (on time ARV pick-up), EWI 5
(on time appointment keeping), EWI 6 (ART stock-outs) and EWI 8 (virological suppression). We
limited the searches to studies published: in English, from January 2003 to May 2011, and excluded
studies on children (< 13 years old). Our search strategy combined all sets of terms under the following
Medical Subject Headings (MeSH) to identify HIV infected participants receiving ART: HIV or HIV
from LMICs we combined all sets of terms under the following MeSH: Africa or Asia or Caribbean
region or central America or Latin America or south America, in addition to the following terms:
resource limited or resource constrained or developing countries or low income countries or low
and middle income countries or africa or afrika or "sub saharan" or southern africa or asia or
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Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011
Using search terms specific to the relevant EWI we searched the online conference abstract
databases for the International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention
and the International AIDS Conference (2009-2010) and the Conference on Retroviruses and
Reference lists from recent reviews on patient outcomes in resource limited settings consistent
When more than one study reported on the same EWI in the same cohort of patients we included
the study containing the most detailed information on the EWI of interest. If two studies were considered
Study selection
We included original research studies or abstracts that reported on HIV infected individuals
receiving combination ART in LMICs. Studies were included if they were specifically designed to report
on the EWI of interest or where it was a secondary finding. Studies could be cross-sectional or cohort
studies, and may be prospective or retrospective. Clinical trials were included for EWIs pertaining to viral
suppression, appointment keeping or adherence (EWIs 4, 5, and 8). Clinical trials were excluded for:
LTFU, retention on first line ART and stock-outs (EWIs 2, 3 and 6) due to the importance of these EWIs
We excluded studies where most patients were children (defined as < 13 years old), patients
Selected studies could be excluded at one of 3 steps. All titles of identified studies were reviewed
and certain studies excluded, abstracts of remaining studies were then reviewed and further studies
excluded. The final potential point of exclusion was after retrieving and reviewing original research
For each EWI the following data was extracted to a Microsoft Excel spreadsheet: first author,
year of publication, country or countries, healthcare facility, healthcare setting (public, private, non-
governmental organization), healthcare provider, whether patient pays for ART, dates observed, number
of sites, number receiving ART, baseline demographics (age, gender, CD4 count, clinical stage), ART
regimen, whether ART nave at baseline, study definition of the EWI, proportion meeting study definition
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Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators
of EWI, and whether the study definition will likely lead to a lower or higher estimate of the EWI of
Data analysis
Proportions of patients meeting the study definition of the EWI of interest were derived from text,
and tables within studies. Proportions derived from graphs used the exact value when available, if the
exact value was not available and the proportion was estimated from the graph axes this was noted.
Where appropriate, summary estimates of the proportions obtained from studies were determined by
reporting the median estimate, range of estimates and calculating weighted means, with weighting by
cohort size. Data presented as incidence density (e.g. person years) was converted to cumulative
EWI Definitions
Percentage of adult patients initiating ART at the site who are initially prescribed, or who initially
Key Questions
Is there data that does not support the initial prescribing of an appropriate first-line regimen?
o A WHO recommended first line regimen [18] would be an example relevant to LMICs
which are:
regimens and are only recommended when NNRTIs cannot be tolerated or are
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Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011
Discussion
ARV monotherapy has led to reductions in levels of circulating HIV since the first clinical
trials with the NRTI zidovudine in the late 1980s [19] and subsequently protease inhibitors (PIs) in the
mid 1990s [20]. Despite these initial advances, subsequent elevations in HIV viral load and the
development of ARV resistance [21] while receiving monotherapy lead to increasing investigation of
combination ARV therapy. Clinical trials of different ARV combinations reported the superiority of
double NRTIs over NRTI monotherapy [22], and subsequently the combination of 3 ARVs, including
either a protease inhibitor or non-nucleoside reverse transcriptase inhibitor, over double NRTI
regimens [23-25]. In addition, concerns about inferior virological efficacy of triple NRTI containing
regimens versus NNRTI containing regimens [26] has led to recommendations that initial ARV
regimens should contain a minimum of 3 active drugs made up of a double NRTI backbone and a third
non-NRTI ARV, typically a NNRTI or protease inhibitor [PI] [18, 27]. These recommendations are
also consistent with data from an LMIC, Cote dIvoire, where double-NRTI regimens were initiated in
some patients due to the increased cost of triple ARV regimens, with the double-NRTI regimens
Data is not available to support not prescribing an appropriate first line regimen (e.g. triple
ARV NNRTI based regimen). There is no justification to change the current prescribing practices
In this review the areas of loss to follow up (LTFU) and retention on first line ART will be
considered in one section. Important findings will be discussed separately for the 2 EWIs. Current
summarized EWI definitions, and key questions this review attempts to answer for these EWIs are as
follows.
EWI Definitions
o Percentage of patients initiating ART at the site who are lost to follow-up 12 months after
o Percentage of adult patients initiating ART at the site who are taking an appropriate first-
o Percentage of patients initiating ART at the site whose initial ART regimen was changed
during the first 12 months to a regimen that includes a different drug class
Suggested target: 0%
Key Questions:
What is the current reported range and summary estimates of LTFU and retention on first line
Do these estimates support the currently published targets, or a change to the targets?
Search strategy In addition to search terms outlined within the general methods section, search
terms used specifically for EWIs 2 and 3 were: attrition or retention or lost to follow up or
Study selection Studies were included if they report the proportion of individuals LTFU and / or
retained after 12 months of ART. Any definition of LTFU or retention was accepted. Where
cohorts did not report 12 month outcomes but a median duration of follow up, studies were
included if the median duration of follow up was 9 to 15 months. Studies were included if they
reported on ART programs providing service delivery (i.e. non-research settings). The search
Data extraction and management Definitions used for LTFU and retention were sought from
reviewed studies. Proportions of subjects meeting these definitions were obtained, and if
available; the proportion of subjects who died, transferred out of the ART program, stopped ART
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Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011
and switched to second line ART. If this data (death, transfer out, stop, or switch to second line)
was not available this was noted. Due to limitations of available data and to provide consistency
across all studies the denominator in estimates of LTFU and retention obtained from studies
include subjects who died or were transferred out. (i.e. different from EWI 2 and 3 definitions)
Data analysis Median estimate, range of estimates and weighted mean (the summary estimates)
were determined for papers and / or abstracts with any definition of LTFU. The summary
estimates were also determined for papers that defined LTFU most similar to EWI 2; where
median period of follow up was 12 to 15 months, and patients were defined as LTFU when lost
from care 3 or 4 months. Additionally the summary estimates were determined for papers that
defined LTFU in a way that would likely generate lower estimates of LTFU (i.e. classify less
people as LTFU); where median period of follow up was < 12 months,, and / or defined as LTFU
when lost from care 6 months. Lastly, the summary estimates were determined for papers that
reported patient tracing, and for papers where tracing did not occur or was not reported. Estimates
of retention were documented in 3 possible ways: 1) as reported in the study; 2) calculated from
data in the study and including patients transferred out in the numerator (i.e. Retained on ART);
and 3) calculated from data in the study excluding patients transferred out from the numerator
(i.e. Retained on ART at the original site/s). For an estimate of retention to be calculated the
study had to report at least the number of patients who were LTFU and died. If data on transfer
out, ART stop or switch to second line ART was available this data was also incorporated into the
retention estimate. In situations where there was concern with overlap of patient cohorts (multi-
country studies by Medecines Sans Frontieres [MSF], the International Epidemiologic Databases
to Evaluate AIDS [IeDEA], and the WHO) implicated studies were excluded from calculations of
summary estimates. Summary estimates were also calculated for death, ART stop, transfer out
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Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators
Figure 1: Search strategy and study selection EWI 2 and 3. Reasons for exclusion were: duplicate, not
on ART, not HIV infected, research setting (not service delivery), not a study of patient outcomes, not
Results
In total 65 studies were identified that met inclusion criteria, 43 papers (Table 1) [29-71] and 22
conference abstracts. (Table 2) [72-93] Studies reported on 21 countries from sub-Saharan Africa, 4
multi-country cohorts from sub-Saharan Africa, 4 countries from South East Asia, 1 from South America,
In regard EWI 2, LTFU ranged from 0.3 - 34.8% across all studies (n=213,821), and in 8 cohorts
where the definition of LTFU was most similar to EWI 2 the range was 0.3 - 31.9% (n=43,871) [30, 35,
39, 43, 45, 48, 53, 56, 59, 61, 65, 67]. (Table 3) In 9 papers where the definition of LTFU would most
likely lead to lower estimates of patients lost, the range was 1.7 34.8% (n=58,810) [41, 44, 46, 47, 50,
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Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011
52, 57, 66, 71]. Weighted means of LTFU across these 3 categories were similar: 14.7% across all
studies, 12.1% when defined similarly to EWI 2 and 14.7% in studies that would likely lead to lower
estimates of LTFU than EWI 2. Studies that reported patient tracing had a lower weighted mean LTFU of
8.1% and a range of 0.3 18.5% (n=21,265), while studies without patient tracing or those not
mentioning whether patient tracing occurred had a weighted mean LTFU of 15.4% and a range of 0.8
34.8% (n=192,556).
In addition to the numbers who died and were LTFU, critical to interpreting estimates of retention
on first line ART is understanding the number of patients who transferred out, stopped ART, or switched
to second line therapy. (Table 3) 14 studies reported the proportion of patients transferred out with
retention ranging from 60.6 91.6% (n=17,908) when including patients transferred out, and a range of
49.7 89.1% when excluding patients transferred out. Weighted mean estimates of retention for these 2
categories are 81.0% and 73.3% respectively. When considering all studies that either reported a
proportion retained or where retention could be calculated from study data 61 studies, made up of 83
cohorts (n=535,438), were identified. In this large group of patients the range of estimates for retention is
49.7 91.0% with a weighted mean of 77.1% patients retained (retention estimates calculated from study
data excluded transfer out, stop or switch if reported). Performing the same analysis less 1 study that
accounted for the majority of subjects [87] (n=253,134), did not change the range of estimates and
Of the reviewed studies, only a small number reported on switch to second line ART or ART
stop. 5 studies reported on patients switching ARV class or to second line treatment; 3 studies with 1%
switch [39, 54, 56], 1 study with 2% switch [61] and 1 study with 7% switch [47]. With a weighted mean
of 2.0% switched (Range 0.2 7.0%). 9 studies (29 cohorts) reporting ART stop resulted in weighted
mean of 2.7% stopped ART (Range 0.3 8.5%). 49 studies, made up of 71 cohorts and 511,608subjects,
provided estimates of the proportion of subjects who died, and ranged from 0.5 29.7% with a weighted
mean of 6.4%. However, excluding 1 study that accounted for the majority of subjects [87] (n=253,134)
the weighted mean for death from the remaining 36 studies increased to 7.7%.
Discussion
Weighted means for LTFU are consistently 12 - 15% when any definition of LTFU is accepted or
when studies are separated into groups that have more lenient or stringent definitions of LTFU. It is not
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Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators
clear why estimates of LTFU are similar among groups with different durations of follow up and periods
lost to care, and whether studies with short duration of follow up (< 12 months) and longer periods lost (
6 months) would have different summary estimates for LTFU if definitions similar to EWI 2 were used.
Further, studies that reported patient tracing programs had the interesting but not unexpected finding of a
lower weighted mean LTFU (8.1%), compared to programs without, or not reporting tracing (15.4%). An
understanding of whether patient tracing is present within an ART program or at a site may therefore be
A critical difference between the presentation of this data, and EWIs 2 and 3 is how the
proportion LTFU or retained is calculated. In the data presented, the denominator of the proportion is all
individuals who started ART, unlike EWI 2 where patients who have died or transferred out are excluded
and EWI 3a where patients transferred out are excluded. How this reflects on targets for these EWIs can
be demonstrated by using the following weighted means derived from this review: LTFU 15%, died 8%,
transfer out 8%, switch 2% and stop ART 3%. By excluding death and transfer out in EWI 2 these
categories have to be excluded from both numerator and denominator, hence the proportion LTFU using
EWI 2 changes from 15% , to 15 / (100 8 8) = 18%. A similar discussion about retention is more
complicated due to the different ways summary estimates for retention can be determined. Summary
estimates for retention calculated in this review include many studies where only LTFU and death were
excluded from the total number of ART starters which could lead to increased estimates of retention
compared to calculating retention by subtracting the summary estimates for the different sub-groups of
those not retained (i.e. LTFU, died, transfer out, switch and stop). Additionally, in many other included
studies the study definition of retention is accepted and the method for calculating retention is not
reported, also potentially leading to increased estimates of retention if the study definition did not
incorporate the different sub-groups for those not retained. If we take the approach where we consider all
the sub-groups relevant to EWI 3a we will likely gain the most stringent definition of retention. Therefore
based on these summary estimates (LTFU 15%, died 8%, transfer out 8%, switch 2% and stop ART 3%)
and the fact that EWI 3a excludes transfer out from the analysis we derive the following for retention;
(100 15 8 8 2 3) / (100-8) = 70%. Importantly only 2 of the 83 studies actually report all these
relevant sub-groups [39, 54] suggesting caution when interpreting this most stringent definition of
retention based on the weighted means of LTFU, transfer out, switch and ART stop derived from
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Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011
different groups of studies. An alternate approach would be to consider the proportion retained in the 14
studies that reported the proportion transferred out, importantly only 3 of these studies report on ART
switch [39, 47, 54] and 5 on ART stop [35, 39, 50, 54, 58]. Therefore, if we take the weighted mean for
those retained on ART at the original site (73%), and adjust this proportion to also exclude transfer out
from the denominator; 73 / (100 8) = 79% could also act as a new adjusted figure for retention on ART
at the original site. Lastly, overall retention rates reported from all studies, weighted mean 77%
(n=535,408), without further adjustment may provide the most powerful representation of average levels
of retention in LMICs.
EWI 2 the current target of 20% is below average rates of LTFU from available data even
when this data is manipulated to account for the EWI definition excluding death and transfer out.
Lowering this target to 15% using the same EWI definition (excluding death and transfer out)
would be consistent with current average rates of LTFU in the reviewed data. As EWI targets act
as guidance for countries to not set more lenient targets but can set more stringent targets if they
choose, a new EWI 2 target of 15% would guide countries to achieve no worse than the average
EWI 3a the current target of 70% retention using the EWI definition is consistent with average
rates of retention even when using the most conservative method to calculate retention
(subtracting all subgroups not retained [LTFU, died, transfer out, switch, stop] from 100%).
However, very few studies report using this stringent definition and alternative methods for
Increasing this target to 75% would more accurately reflect average retention using the EWI
definition, and would act as a target under which more lenient retention targets would not be
recommended.
EWI 3b Only 5 studies reported on patients switching ARV class or to second line treatment
and all reported small numbers of patients switching. Despite only a small number of studies
being available the current target of 0% may be too stringent based on this data. Increasing this
target from 0% to 2% would make the new target consistent with the average switch to second
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Current summarized EWI definitions, and key questions this review attempts to answer for this
EWI Definitions
EWI 4a - Percentage of patients picking up prescribed ARV drugs on time (3 consecutive pick-
EWI 4b - Percentage of patients initiating ART at the site who picked up all prescribed ARV
Key Questions:
What is the current reported range of estimates for picking up all prescribed ARVs on time when
Do these estimates support the currently published targets, or a change to the targets?
Search strategy In addition to search terms outlined within the general methods section, search
terms used specifically for EWI 4 were: compliance or adherence or all terms under the
MeSH Medication Adherence or Patient Compliance, AND the terms pill count or pick
Study selection Studies were included if they reported Pharmacy Adherence Measures
(Medication Possession Ratio, Pill Count or Pill Pick-up) where the duration of adherence
assessment was from 3 12 months. Where the duration of adherence assessment was the first 12
months of ART these studies were considered comparable to EWI 4b with other studies
patients who have picked up all their ARVs on time (either over 3 pickups or 12 months), only
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studies where the proportion of patients 100% adherent by a Pharmacy Adherence Measure
(PAM) were included. This prerequisite was imposed because a patient <100% adherent by a
PAM will not have picked up all their ARVs on time. The search strategy and study selection is
summarized in Figure 2.
Data extraction and management Definitions for the PAM and the proportion of patients
meeting that definition were obtained from selected studies. While the proportion of subjects who
died or were LTFU was reported in some studies adherence estimates were not reported for these
patients, hence all adherence data retrieved was for patients that were alive and actively enrolled
in ART programs. One study did collect adherence data on some patients who were subsequently
LTFU, died or transferred out, but importantly the duration of adherence assessment for these
patients only included the period from ART start until the last visit in the clinic [67].
Data analysis The list and range of estimates for included studies was determined. Due to the
small number of heterogeneous studies fitting inclusion criteria weighted means were not
calculated.
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Figure 2: Search strategy and study selection EWI 4. Reasons for exclusion were: duplicate, not on ART,
not HIV infected, not a study of patient outcomes, not LMIC, insufficient information, study of children,
Results
In total 7 studies were identified that met inclusion criteria, 6 papers [37, 67, 94-97] and 1
conference abstract [98] (Table 4) Studies included 2 single country cohorts from sub-Saharan Africa, 3
multi-country cohorts from sub-Saharan Africa, 1 from Asia and 1 from South America.
Four studies were included for EWI 4a and all had a duration, or median duration, of adherence
assessment of approximately 6 months. The range of estimates for 100% adherence ranged from 43
64% in these 4 studies (n=11,714). (Table 5) The 3 studies reporting the proportion 100% adherent for
patients receiving their first 12 months of ART, had estimates ranging from 12 28% (n=30,603). Study
definitions were all deemed to potentially create higher estimates of on time ARV pick-up than the EWI
definition. Reasons included the selection of a population who had already achieved virological
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Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011
suppression and were likely more adherent [96], or exclusion of individuals that subsequently died or
became LTFU who would likely be less adherent [37, 94, 95]. One study that included subjects who
became LTFU was also different from the EWI definition in that the assessment of adherence concluded
at the last time the patient visited the clinic, compared to the EWI definition where patients who become
LTFU after a baseline ARV pick-up are classified as not picking up their pills on time [67].
In the process of reviewing studies for inclusion it became apparent that many studies reported
the proportion of study subjects who were > 90 or 95% adherent but did not report the proportion of
subjects who were 100% adherent. While the literature search did not focus on identifying studies
reporting the proportion of patients with > 90 or 95% adherence, a number of papers were identified
where this was the case. Therefore, summary estimates for those > 95% adherent have been presented
from a group of papers to help interpret current EWI 4 targets and definitions. A systematic review of the
abstracts and any remaining papers may identify more studies reporting the proportion for subjects with >
95% adherence. Therefore, 8 studies (11 cohorts) were identified that fitted the original inclusion criteria
for studies comparable to EWI 4a, [67, 94, 99-104] and 5 studies for EWI 4b, [37, 95, 102, 105, 106] but
differed by reporting a proportion of patients > 95% adherent. The range of estimates were appreciably
higher, 49 89% for EWI 4a (n=14,723), and 37 87% (n=31,340) for EWI 4b using this new adherence
threshold. An alternative presentation of this data is stating that; 7 of the 11 estimates for the > 95%
threshold for EWI 4a were higher than all the estimates for the 100% threshold, and all the estimates with
the > 95% threshold for EWI 4b were higher than all the estimates for EWI 4b with the 100% threshold.
Discussion
Conclusions regarding targets for EWI 4 are limited by the number of studies available reporting
the proportion of subjects that are 100% adherent. Despite the small of number of studies, the target of
90% of patients being 100% adherent over a period of 3 pick-ups (EWI 4a) or the first 12 months of ART
(EWI 4b) appears too high, but the limited data does not provide clear guidance on how to revise this
target downwards. An alternative approach to adjusting the current target based on picking up all ARVs
on time would be to review studies looking at an altered definition of the EWI where the threshold of
adherence is lowered to 90 or 95%. Estimates of adherence in LMICs in general are higher than high
income countries (HICs), so there is the potential for considerable variability in the proportions meeting
these different high adherence thresholds (i.e. > 90%, 95%, or 100% adherence) [107]. In addition,
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studies are more likely to report the proportion of subjects 100% adherent when adherence is measured by
self report compared to PAMs where thresholds < 100% are more commonly used [14, 107], adding
further weight to a literature review which focuses on adherence data reporting on thresholds < 100%.The
data presented in this review for a 95% adherence threshold reveals considerably higher proportions of
patients meeting this threshold, and a larger number of available studies to guide the setting of targets
even though all available data (e.g. conference abstracts) were not systematically reviewed for this altered
definition of EWI 4.
Based on available data the current target for EWI 4a and 4b appears too high but it is unclear to
what extent the current target should be revised downwards due to limitations of available data.
Alternative approaches to reviewing literature for on time ARV pick-up have been discussed
Current summarized EWI definitions, and key questions this review attempts to answer for this
EWI Definitions
o EWI 5a - Percentage of ART patients who attend clinical consultations within 7 days of
o EWI 5b - Percentage of patients initiating ART at the site who attended all clinical
consultations within 7 days of the scheduled or expected appointment during the first 12
months of ART
Key Questions:
What is the current reported range of rates for attending ART clinic appointment on time when
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Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011
Do these estimates support the currently published targets, or a change to the targets?
Search strategy In addition to search terms outlined within the general methods section, search
terms used specifically for EWI 5 were: appointment or attendance or all terms under the
MeSH Appointments and Schedules or Referral and Consultation, AND the terms on time
or date or all terms under the MeSH Time Factors or Chronology as Topic.(Appendix 3).
Study selection Studies were included if they reported on patients attending clinical consultations
Where patients were assessed over the first 12 months of ART these studies were considered
consultations). Studies were only included if they reported on patients attending a consultation
within 7 days of the scheduled or expected consultation to be consistent with the EWI definition
of On Time clinic appointment keeping. The search strategy and study selection is summarized
in Figure 3.
Data extraction and management Definitions for clinical appointment keeping and the
proportion of patients meeting that definition were obtained from selected studies. Whether
studies included patients who were subsequently LTFU after their baseline clinical appointment
was sought, as the EWI definition includes these patients and could be a source of variability
Data analysis The list and range of estimates for included studies was determined. Median
estimate and weighted mean was calculated for the group of studies most comparable to EWI 5a.
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Figure 3: Search strategy and study selection EWI 5. Reasons for exclusion were: duplicate, not on
ART, not HIV infected, not a study of patient outcomes, not LMIC, insufficient information, study of
Results
In total 7 studies were identified that met inclusion criteria, 2 papers [100, 108] and 5 conference
abstracts [72, 83, 109-111]. (Table 6) Studies included 4 single country cohorts from sub-Saharan Africa,
Five studies were comparable to EWI 5a and 2 studies comparable to EWI 5b. Two papers from
sub-Saharan Africa reported the proportion keeping appointments using different definitions of attending
on time. [100, 108] For both papers the more lenient definition of on time attendance was utilized when
calculating summary estimates (Table 6). The remaining studies reporting on clinical appointment
keeping were all conference abstracts, 1 of which reported a range of estimates in Vietnam using the EWI
definition without reporting one proportion for a single group of patients, hence this study is not included
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as part of the summary estimates [83]. (Table 7) The 7 cohorts contributing to the summary estimates for
EWI 5a all define on time appointment keeping over 3 or 4 months. The proportion on time ranges from
53 93% with a weighted mean of 84.0% (n=13,137), and when the large cohort of Neethling et al
[110](n=9,603) is excluded from this calculation the weighted mean is revised down to 75.8% (n=3,534).
The 2 studies reporting on time appointment keeping over the first 12 months of ART, include one
abstract of a large South African population (n=11,397) where 63% of patients were on time and a
smaller multi-country cohort (n=566) where 70% of patients consistently attended within 8 days of the
scheduled appointment.
Discussion
The selected studies all had similar definitions for on time clinic appointment keeping as both
EWI 5a and 5b. Interestingly all studies relevant to EWI 5a assessed on time appointment keeping over 3
or 4 months with 3 of 5 studies providing estimates where patients could be up to 7 days late to the
scheduled consultation [100, 110, 111]. Only one study definitely included patients who became LTFU
after their baseline clinical appointment [111], as does the EWI definition, but it is unclear how the
inclusion or exclusion of these patients would affect estimates of on time clinic appointment keeping.
Weighted means were calculated using the more lenient definition of on time (up to 3 days late) in the
study by Chalker et al [100] for EWI 5a and by Blacher et al for EWI 5b meaning that the cohorts
contributing to the weighted means included only one cohort (Kenya cohort of Chalker et al[n=373]) that
definitely used the most stringent definition of on time (attending on or before the scheduled
appointment). Therefore, the weighted means provide the most lenient summary estimates available from
the selected studies. For EWI 5a the weighted means happen to straddle the current target for EWI 5a
depending on whether the one study with a disproportionate number of patients [110] is included (84.0%)
or excluded (75.8%) . Both the studies found relevant to EWI 5b provide estimates of on-time
appointment keeping (63 and 70%) below the current recommended target of 80%.
EWI 5a Despite the small number of studies available all are defined in a manner similar to
EWI 5a. The current target of 80% is consistent with current average rates of on time clinic
appointment keeping in the reviewed data. Based on this review, maintaining the current target
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would guide countries to achieve no worse than the average rate of on time appointment keeping,
EWI 5b Due to the lack of data, guidance on this target is unclear. Based on the 2 studies found
the current target appears too high but it is uncertain to what extent the current target should be
Current summarized EWI definitions, and key questions this review attempts to answer for this
EWI Definitions
EWI 6a and 6b - Percentage of months in a designated year in which there were no ARV drug
stock-outs
EWI 6c1 Percentage of patients whose regimen was stopped, switched, substituted or
o Suggested target: 0%
EWI 6c2 Percentage of patients whose regimen was stopped, switched, substituted or
incompletely dispensed due to ARV stock-out during the first 12-monts of ART
o Suggested target: 0%
Key Questions:
Are ARV stock-outs reported at the level of the site or affecting patient populations in LMICs?
Is there data to support the safety of treatment interruptions or switching of ARVs, or ART
Search strategy In addition to search terms outlined within the general methods section, search
terms used specifically for EWI 5 were: stock out or drug supply or stock shortage or out
of stock. (Appendix 4)
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Study selection Studies were included if they reported on stock-outs of ARVs at a site, or
reported on patients whose regimen was stopped, switched, substituted or incompletely dispensed
over a period of 9 15 months. This range was used as all variants of EWI 6, whether they be site
or patient based, assess outcomes over a 12 month period. If patients were assessed over the first
12 months of ART then these studies were considered comparable to EWI 6c2, with other patient
based studies considered comparable to EWI 6c1. Studies using data obtained from pharmacy
records or from patient surveys were included. Due to the potential for recall bias from survey
data to underestimate outcomes, studies were still included where patients were on ART for > 15
months and stock-outs were assessed by patient survey. The search strategy and study selection is
summarized in Figure 4.
Data extraction and management Definitions for ARV stock-outs and the proportion of patients
meeting that definition were obtained from selected studies. If studies also reported associations
Data analysis The list and range of estimates for included studies was determined.
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Figure 4: Search strategy and study selection. EWI 6. Reasons for exclusion were: duplicate, not on
ART, not HIV infected, not a study of patient outcomes, not LMIC, insufficient information, study of
Results
In total 10 studies were identified that met inclusion criteria, 7 papers [112-118] and 3 conference
abstracts [119-121]. (Table 8) Studies included 9 single country cohorts from sub-Saharan Africa and 1
multi-country study from the Caribbean. 2 studies used the EWI definition and both reported on the
number of sites with ARV stock-outs [115, 121]. The remaining 8 studies all reported on the proportion
of patients affected by stock-outs, with 5 of these 8 studies using surveys to question patients about stock-
outs [112-114, 116, 117] and the remaining 3 studies using clinic and pharmacy records to establish
Only one study, that documented a range of outcomes using EWI definitions, reported no ARV
stock-outs [115]. The other study using EWI definition in Caribbean countries reported 64% of sites
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having ARV stock-outs [121]. The remaining 8 studies report a range of 1-28% of patients experiencing
stock-outs, with the list of estimates (%) as follows: 1, 1.5, 7, 10, 11, 17, 26 and 28. In addition 2 of the
studies report associations between ARV stock-outs and other outcomes; Marcellin et al [114] report
association between ARV shortages and treatment interruptions > 48 hrs, and Pasquet et al [118] report
ARV discontinuations > 1 month in length due to a stock-out being associated with death and patient
LTFU.
Discussion
In both LMICs and HICs clinical trials reporting on structured interruptions of ART have
reported higher rates of opportunistic disease, severe morbidity and death [122, 123]. In addition,
unplanned treatment interruptions of more than 48 hrs for patients receiving NNRTI based regimens has
been reported to predict virological rebound and the development of HIV drug resistance in both LMICs
The studies reporting on stock-outs presented in this review are particularly heterogeneous. For
example, the different methods used to assess for stock-outs such as questioning patients a method
affected by recall bias, versus using clinic and pharmacy records. Also, the variable periods of time
individuals had been receiving ART, and the fact that some studies reported on stock-outs at the site or
pharmacy level while others reported on stock-outs directly impacting patients. Despite this
heterogeneity, the observation that ARV stock-outs occur in LMICs and lead to alterations and
interruptions in ART regimens is critically important in the setting of previous studies reporting negative
clinical outcomes due to both structured and unplanned treatment interruptions. Further, no data was
There are no data to support the changing of regimens (switch or substitution) or the interruption
of treatment due to ARV stock-outs. Maintaining the current targets (0% for EWI 6a and b, 100% for
EWI 6c1 and 6c2) would guide countries to always have the necessary ARVs to prevent unnecessary
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Current summarized EWI definitions, and key questions this review attempts to answer for this
EWI Definitions
o Percentage of patients initiating ART at the site whose viral load is <1000 copies/ml after
Key Questions:
What is the current reported range and summary estimates of virological suppression after 12
Do these estimates support the currently published targets, or a change to the targets?
Search strategy In addition to search terms outlined within the general methods section, search
terms used specifically for EWI 8 were: virologic or hiv rna or resistance or genotype or
all terms under the MeSH Viral Load AND the terms one year or twelve months or first
Study selection Studies were included if they report the proportion of individuals with a
virological outcome after 12 months of ART. Any definition of virological suppression (or
failure) was accepted that reported a proportion of patients below (or above) a threshold of HIV
viral load measured in copies/mL from plasma after 12 months of ART. Studies were excluded if
they only reported a change in HIV viral load from baseline. Where cohorts did not report 12
month outcomes but a median duration of follow up, studies were included if the median duration
of follow up was 9 to 15 months. Both clinical trials and studies that reported on ART programs
providing service delivery (i.e. non-research settings) were included. The search strategy and
Data extraction and management Definitions used for virological suppression were sought
from reviewed studies. Proportions of subjects meeting these definitions were obtained, and if
available; the proportion of subjects who died, transferred out of the ART program, stopped ART
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and switched to second line ART. If this data (death, transfer out, stop, or switch to second line)
was not available this was noted. Whether the proportion with virological outcome was an on-
treatment analysis (denominator includes only patients tested for HIV viral load at 12 months) or
intention-to-treat (denominator includes the number of starters for whom viral load testing was
intended) was noted. In addition to reported intention-to-treat (ITT) analyses, ITT analyses were
also calculated from raw data when available and sample sizes for these ITT calculations was
noted. Additionally, and consistent with the EWI definition, the proportion that stopped ART
were included, and the proportion transferred out excluded from the denominator when reported.
Studies only reporting the proportion with virological failure were converted into a proportion
with virological suppression so it could be more easily compared to the EWI target. If studies also
reported outcomes for the emergence of HIV drug resistance this was data was also extracted.
Data analysis Median estimate, range of estimates and weighted means were determined for
studies categorized into on-treatment (OT) and ITT analyses. The median estimate, range of
estimates and weighted mean were also determined for OT and ITT analyses where the threshold
for virological suppression was 1,000 copies/mL and for studies where the thresholds were 500
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Figure 5: Search strategy and study selection EWI 8. Reasons for exclusion were: duplicate, not on
ART, not HIV infected, research setting (not service delivery), not a study of patient outcomes, not
Results
In total 53 studies were identified that met inclusion criteria, 36 papers [28, 31, 45, 58, 59, 103,
108, 126-154] and 17 conference abstracts [76, 78, 155-169]. (Tables 9 and 10) Studies included 38
single country cohorts from sub-Saharan Africa, 6 multi-country cohorts (5/6 from sub-Saharan Africa), 4
cohorts from Asia and 4 LMIC cohorts from the Caribbean and Americas. 8 studies each reported 2 or
more results for the proportion with virological suppression by using different thresholds of plasma HIV
RNA [31, 127, 141, 142, 145, 149, 151, 158]. Only 1 study required more than one viral load below a
threshold of HIV RNA for an individual to be classified as having virological suppression. [158] 2
different studies reported on the same sub-Saharan cohort of patients but each study used different
thresholds for virological suppression so both studies were included [129, 148].When including all patient
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cohorts regardless of the virological threshold used, 53 cohorts reported the proportion with virological
suppression in OT analyses and 29 cohorts for ITT analyses. (Table 11) The weighted mean of virological
suppression at 12 months for the 53 OT analyses was 90.6% (n=69,115, median estimate 87%, range 49 -
97%). Thirteen cohorts reported OT analyses with virological thresholds 1,000 copies/mL with a
weighted mean 94.3% suppressed (n=42,804), and for the 11 cohorts where the threshold was 1,000
copies/mL , 94.4% were suppressed (n=38,161, median estimate 87%, range 74 96%). The majority of
cohorts (n=41) reported OT outcomes using thresholds of detectable HIV in plasma 500 copies/mL, of
which 28 used the threshold of 400 copies/mL. For 61,383patients in 41 cohorts using thresholds 500
copies/mL, 89.2% were virologically suppressed (median estimate 83%, range 49 97%). Importantly,
with all the weighted means for OT analyses the abstract by Fox et al [158] accounts for 32,603 subjects.
Additionally this is the only study that requires subjects to record 2 viral loads between 6 and 12 months
of treatment below an HIV RNA threshold. This definition of virological suppression potentially
classifies more individuals as virologically suppressed compared to all other studies in this review that
define virological suppression based on one viral load test at 12 months. Weighted means for OT analyses
excluding the study by Fox et al are noted as part of Table 11, and are 5-9% lower than when the Fox et al
study is included.
Twenty nine cohorts reported ITT analyses for 19,527patients and the weighted mean of
virological suppression was 69.8% (median estimate 70%, range 50 92%). 26 of 29 cohorts use
thresholds to define suppression that are 500 copies/mL, with 19 of the cohorts using the threshold 400
copies/mL. For the 13,032patients in the 26 studies with thresholds 500 copies/mL 68.9% were
virologically suppressed (median estimate 70%, range 50-92%). Only 4 ITT analyses reported the
proportion with virological suppression using a threshold of 1,000 copies/mL. For the 1201 patients in
these 4 studies a weighted mean 77.1% were suppressed (list of estimates: 69, 69, 83 and 87%). Notably,
no ITT analyses were identified using a threshold for virological suppression > 1,000 copies/mL.
Discussion
Summary estimates for virological suppression at 12 months are higher in OT compared to ITT
analyses, and also as the threshold of plasma HIV RNA below which patients are defined as being
suppressed increases. This is not unexpected, as individuals who have died or become LTFU in ITT
analyses are considered unsuppressed, and definitions of virological suppression using higher thresholds
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(e.g. 1,000 copies/mL) will also allow patients with low level viraemia to be considered suppressed as
The current EWI target, 70% virologically suppressed at 12 months, is consistent with the
weighted mean of the most stringent definition of virological suppression in this review (i.e. thresholds
500 copies/mL in ITT analyses). Importantly the EWI definition differs from this stringent definition in
2 ways; it uses a more lenient threshold for virological suppression (1,000 copies/mL), and also excludes
In this review, only 5 studies reported transfer out data which was excluded from the estimate of
virological suppression as per the EWI definition [58, 126, 135, 144, 146], and only one of these studies
used a threshold of 1000 copies/mL to define suppression [126]. Interestingly, in this single study from
Uganda with definitions most similar to the EWI definition, 69% of patients were suppressed at 12
months. Apart from these 5 studies, it is unclear how patients who may have transferred out have been
accounted for in other studies. Possibilities include; these patients have been incorporated into the
denominator of ITT analyses and this detail has not been reported, or OT analyses have been reported
which do not require the inclusion of those transferred out. On the assumption that there is a degree of
transfer out in all cohorts which has not been reported in ITT analyses we could adjust the estimates of
virological suppression using an approximation of the proportion transferred out from care after 12
months of ART in LMICs. Previous analysis in this review around EWIs 2 and 3 yielded a weighted
mean of 7.7% transferred out after 12 months ART (n=17,908) in a different population but as this figure
was derived from programs in LMICs providing ART it could serve as a useful approximation of the
proportion transferred out. Adjusting the summary estimates for virological suppression to exclude
transfer out would lead to an overall small rise in the summary estimate for virological suppression at 12
months. For example adjusting the ITT weighted mean to remove those transferred out from the
In addition to how transfer out may affect how we consider this data we also need to consider the
threshold for defining virological suppression. Within ITT analyses which are more similar to the EWI
definition than OT analyses, there are only 4 studies that use the same threshold as EWI 8 to define
virological suppression, 1,000 copies/mL . The weighted mean of these 1,201 patients is 77.1%,
considerably higher than the mean of 68.9% for studies with lower thresholds. Ultimately, conclusions
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from this review about ITT analyses using a threshold of 1,000 copies/mL are limited as there are only 4
studies with this definition. Nevertheless, average rates of virological suppression for the 1,000 copies/mL
threshold in ITT analyses are likely higher than the proportion suppressed in studies with thresholds 500
copies/mL, a finding which is also seen in OT analyses where there is data for increased numbers of
The current target is consistent with the average proportion of patients meeting a more stringent
definition of virological suppression than EWI 8. In the setting of the potential for upward adjustment of
current ITT weighted means to cater for: patients who may have transferred out, and to accommodate the
EWI threshold of 1,000 copies/mL the current target of 70% represents guidance that may be too lenient.
Raising the target to 75% would serve as more accurate guidance for countries to aim for rates of
virological suppression consistent with average rates of virological suppression using the current EWI
definition.
CONCLUSIONS
This review strives to place current targets for HIVDR EWIs in the context of currently available
literature. Revision of the targets aims to provide guidance for countries to achieve levels of program
function that are at least consistent with average rates of these outcomes based on the available literature.
Additionally, countries are able to set more stringent targets than the revised targets presented here.
EWI 4a and 4b (On time ARV pick-up) current target of 90% patients picking up all ARVs
on time is too high but unclear to what extent to lower target. Consider review of data with
EWI 5a (On time appointment keeping) maintain at 80%. EWI 5b limited data but current
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EWI 6a and 6b (Stock-outs) maintain at 100%. EWI 6c1 and 6c2 - maintain at 0%.
ACKNOW LEDGEMENTS
James H. McMahon MBBS MPH (Infectious Diseases Unit, The Alfred Hospital, Melbourne, Australia
and Department of Public Health and Community Medicine, Tufts University, Boston, USA)
Michael Jordan MD MPH (World Health Organization, Geneva, Switzerland and Tufts University
School of Medicine, Boston, USA)
Elizabeth Richardson MLS MEd (Hirsh Health Sciences Library, Boston, USA)
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Table 1. EWI 2 and 3 (LTFU and Retention on First line) - Papers
% retained
Study
Baseline on ART at
Study definition of %
features ART original
definition retention on meeting
(median regimens % site/s
LTFU will first line (if study
Country Pay age, % (all ART Time Study % retained (excludes TF Patient
Study HC HC Dates Site Starting % likely lead not defined definition % TF
(cohort or Provider s for male, nave at since ART definition % Died ART on ART out / stop / Tracing
(year) facility setting observed s (n) ART (n) LTFU to lower or then % of out
data source) ART median baseline start LTFU stop (include switch from
higher retained on retention
CD4, WHO unless TF out) numerator if
estimates ART on first
clinical stated) reported,
than EWI 2 columns are line
stage) most similar
calculated)
to EWI 3a)
May et Cote Clinics NGO NGO No Initiated Mul 2117 35, 26%, Regime Mean Not attend 11.5 Lower 8.7% NR Not defined NR NR 79.7% Yes
al [57] d'Ivoire (CEPRE ART Jan tipl 129, 82% n NR 10.6 clinic for > 6 % (shorter (also no
(2010) (Abidjan - F) 2004 - e advanced months months (Max duration of data on 2nd
CEPREF) Mar 2007 (Max 1 F/U 1 yr) F/U and lost line switch )
yr) for 6
months)
As Malawi Hospita Public MOH No Initiated 1 3028 36, 41%, Regime Mean Not attend 12.4 Lower 8.9% NR Not defined 79.1% 14% 65.1% Yes
above (Lilongwe l and ART Jan 127, 96% n NR 9.84 clinic for > 6 % (shorter (also no
Lighthouse) partner 2004 - advanced months months (Max duration of data on 2nd
s Mar 2007 (Max 1 F/U 1 yr) F/U and lost line switch )
(Lighth yr) for 6
ouse) months)
Tassie 61 LMICs Mixed Mixed Mixed Mix Started Mul 297048 NR Regime 12 Variable for Mea Unclear NR NR Proportion Mean of NR NR Mean of NR
et al (WHO / ed ART 2007 tipl ns NR months different n of of ART 79.9% 79.9%
[64] UNICEF / e sites (period 20.1 starters
(2010) UNAIDS) defining % alive and
LTFU ranges on ART at
from - 12 months
missing last (also no
appointment data on 2nd
Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011
32
Lowran Rwanda Clinics Public MOH No Initiated 30 3194 37, 35%, NNRTI 12 Not 4.9% Similar to
4.6% 0.3 Alive and 86.9% 91.2% 4.3% 86.7% No
ce et al (National ART Jan 141, regimen months attended EWI % on ART at (86.9%
[54] sample) 2004 - s clinic for > clinic 0.2%
(2009) Dec 2005 90 days where ART switch to
initiated. 2nd line)
Also < 1%
switched to
2nd line
(7/3192)
Bisson Botswana Region Public MOH No Initiated 1 410 37, 40%, 97% Median Last contact 16.6 Lower 7.1% NR in care and 76.3% NR NR 76.3% Yes
et al (Gaborone - al ART Feb 81 NNRTI duration with clinic or % (shorter had refilled
[34] IDCC) Hospita 2003 - regimen F/U 44 pharmacy > duration of script for
(2008) l August s, 12% weeks 30 days after F/U) HAART in
2003 prior (10 last Higher (lost prior 30
ARV mths) scheduled for 1 month) days (also
exposur visit no data on
e 2nd line
switch )
Bedelu South Africa Hospita Public NGO No Initiated 1 430 NR Regime median Not defined 19.3 Unclear 13.5 NR Not defined 67.2% 4.0% 63.2% NR
et al (Lusikisiki) l (MSF) Jan 2005 ns NR 12 % % (also no
[32] and - June months data on 2nd
(2007) MOH 2005. line switch )
Followed
to July
2006
As As above Clinic Public NGO No Initiated 12 595 NR Regime median Not defined 2.2% Unclear 16.8 NR Not defined NR NR 81.0% Yes
above (MSF) Jan 2005 ns NR 12 % (also no
and - June months data on 2nd
MOH 2005. line switch )
Followed
to July
2006
Etard Senegal Clinic Public MOH Part Initiated Unc 404 37, 45%, 42% PI 12 6 months 1.7% Lower (lost 11.6 NR Not defined NR NR 86.6% Yes
et al ial Aug 1998 lear 128 regimen months with no for 6 % (also no
[44] - April ( , 95% contact, or months) data on 2nd
(2006) 2002. 3) ART willingness line switch )
Observed nave at to resume
to Sep baseline ART (after
2005 phone calls
and home
visits)
Ferradi Malawi District Public MOH No 2001 (no 1 1308 35, 36%, 98% 12 Not 5% Similar to 19% NR "On 76% NR NR 76% Yes
ni et al (Chiradzulu) Hospita and month) - 112, NNRTI months attended EWI HAART"
[45] l NGO April 2004 Stage I regimen clinic > 2 (not died,
(2006) (MSF) and II s (3 pts months after LTFU, stop.
18% PI last Also no
Stage III regimen scheduled data on 2nd
55% ), 97% visit (tracing line switch)
Stage IV ART attempted)
27% nave
33
Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators
67
68
Wools- Kenya 1 Public AMPAT So Nov 2001 8 2059 37, 40%, 95.1% Median Not 24.5 Lower 5.4% NR Not defined NR NR 70.1% NR
Kalous (Western) Region H me - Feb 86, Stage NNRTI duration attended % (shorter (also no
tian et al, 1 progra pai 2005 I 33% regimen F/U 40 clinic > 3 (12 duration of data on 2nd
al [71] district m d Stage II s weeks months mont F/U) line switch)
(2006) Hospita 12% (9.2 h
l, 6 Stage III mths) LTFU
clinics 38% 22.4
Stage IV %)
17%
Kabug Uganda Tertiary Public MOH Part Aug 1998 1 321 38, 51%, HAART Median Not defined NR NR NR Alive and in 56.0% NR NR 56.0% NR
o et al care and ial - Dec 79 44%, duration care at 1
[51] Hospita partner 2002 2NRTI F/U 16.8 year = not
(2005) l s 37%, months Died or
none/un LTFU (also
known no data on
for 59 2nd line
(18%) switch)
Wester Botswana Region Public MOH No April 2001 1 153 36, 41%, 100% 12 Miss 2 8.4% ? Higher (? 15.3 NR Not defined 76.3% 5.2% 71.1% NR
et al (Gaborone - al - Nov 96, Stage NNRTI months( consecutive Lost for 2 % (also no
[70] IDCC) Hospita 2003 I 2% regimen visits (i.e. months) data on 2nd
(2005) (Different l (Different Stage 2 s likely miss line switch)
patients to patients 21% for 2
Bisson PloS to Bisson Stage III months) and
One) PloS One) 30% not
Stage IV contacted
47% on 2
attempts
Macha Kenya Clinics Privat Private Yes Oct 1996 5 300 NR , 72% on 12 Not defined NR NR NR Remaining 78% 78% No
ria et al (Nairobi) e clinicia - June 60%, 80 HAART months on ART
[55] ns 2001 (3NRTI, (also no
(2003) NNRTI data on 2nd
or PI line switch)
regimen
)
Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011
Charal Sth. Africa Hospita Privat Compa No Oct 2002 69 2262 41, 95%, NNRTI 12 "Stopped 8.3% Unclear 4.2% See Not defined 82.6% 5.5% 77.1% NR
ambou ls and e ny - Dec 158, regimen months treatment" = LTF (also no
s et al Clinics (Work (Anglo 2005 Stage III s due to U data on 2nd
[36] place) Americ 45% patient line switch)
(2007) an) Stage IV request, not
27% returning to
clinic or for
ART, or non-
adherence
Bisson Botswana Clinic Privat Private Yes Initiated 1 346 37, 42%, Regime 12 No viral load 12.4 Unclear 5.2% NR Not defined 82.4% 12.1 70.2% NR
et al (Gaborone) e clinicia ART Dec between ns NR months tests after % (also no %
[33] (Different to ns 1999 - 80 and ART start, data on 2nd
(2006) other 2 Jan 2004 113, then not line switch)
Gaborone contactable
studies as by phone
private) and no
record of
ART pick up
34
Lauren Cameroon Hospita Public Public Yes Oct 2000 19 788 39, 48%, cART Median Did not 25.1 Similar to 6.6% NR Not defined NR NR 68.3% NR
t et al (Douala) ls and and and - Dec 123, CDC for all duration attend in 3 % EWI (also no
[53] Clinics Privat Private 2003 stage B but one, of F/U months prior data on 2nd
(2005) (10 e clinicia 57% 85.5% 13 to the chart line switch)
private ns CDC nave at months review
9 stage C baseline
public) 33%
Marsto Kenya Clinic NGO AMREF No Feb 2003 1 283 Mean 36, 99% 12 No clinic 13.0 Similar to 7.0% NR alive and 81% NR NR 80% (81% Yes
n et al (Kibera) , MOH - Feb 30%, 157, NNRTI months visit in 3 % EWI on ART at (Paper -1%
[56] 2005 Stage I/II regimen months prior 12 months says changed
(2007) 29% s, 1% to censor 81% ARV class)
Stage III PI date even
23% regimen though
Stage IV s 100-13-
48% 7=80)
Karche Kenya District Public MOH No Apr 2004 1 124 31, 29%, NNRTI Median
Not 15.3 Lower 12.1 NR Not defined NR NR 72.6% No
r et al (Migori) Hospita and - Sept 189, CDC regimen duration
attended % (Shorter % (also no
[52] l partner 2005 Stage C s F/U 9
within 4 duration of data on 2nd
(2007) (GTZ) 46% months
months after F/U) line switch)
a scheduled
appointment
Hawkin Kenya Hospita NGO Local No Initiated 1 1286 36, 99% Median missed clinic 34.8 Lower 1.1% NR Not 64.1% 4.9% 52.2% No
s et al (Nairobi l clinicia ART Sept 40.9%, NNRTI duration visits and % (shorter defined. (64.1% -
[47] Saint ns 2004 - 121 regimen 11.6 failure to duration of 7% TF out -
(2007) Marys) Aug 2006 s months collect ART F/U) patients 7% switch
refills for 3 switched ARV class)
months ARV class
Coetze Sth Africa Clinics Public MOH, No Initiated 3 287 31, 30%, 99% Median not attended 0.3% Similar to 13.2 3.1 Not 83.3% 1.0% 81.3% Yes
e et al (Khayelitsha NGO May 2001 43, NNRTI duration services EWI % % defined. (83.3 - TF
[39] - NB: earlier (MSF) - Dec regimen 13.9 (clinic + 1% out 1%
(2004) than Lancet 2002, s months other switched to switch 2nd
data 2010) Censored services not second line line)
July 2003 defined) for regimen
3 months
after last
scheduled
appointment
Vella et Sth Afrcia Clinics Public MOH No Initiated 32 2835 34, 33% NR 11 Not defined NR NR NR retained 81% NR NR 81% Yes
al [69] (Kwa Zulu Mar 2004 months on
(2010) Natal) - May treatment
2006. = attended
Followed in 3 months
to July 1 prior to
2007 censor.
(also no
data on 2nd
line switch)
Palom Mozambiqu Clinics Public DREAM No Initiated 5 3749 34, 38%, 97% Median Not 2.8% Similar to 10.5 NR Not 86.7% NR 84.7% Yes
bi et al e, Malawi. progra Feb 2002 192, NNRTI duration attending EWI % defined. (86.7% -
[61] Guinea- m - Jan Stage III regimen 14.5 clinic for > 3 2% 2% switch
(2009) Conkary 2006. or IV 37% s, 3% months months switched to to 2nd line)
Followed 3NRTI a second
to June regimen line at 1
2007 s year
35
Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators
69
70
Unge Kenya Clinic NGO AMREF No Jan 2005 1 830 Mean 35, 97% 12 No 12 month NR NR NR On care 74.0% NR NR 74.0% Yes
et al (Kibera) NB: , MOH - Sept 35%, NNRTI, months outcome and in
[68] Recruited 2007 Mean 2% treatment
(2009) after CD4 203 NRTI (LTFU =
Marston only, not
2007 study 1% PI attended >
regimen 90 days
s post ART
run out
date. Also
no data on
2nd line
switch)
Chung Kenya Clinic NGO Coptic No Initiated 1 1231 NR (All > No data 12 Not 10.0 Higher (Lost NR NR Not being 90.0% NR NR 90.0% NR
et al (Nairobi - Hope Mar 2006 15 y.o.) on months attending % for 1 month) LTFU (i.e.
[38] Coptic Center - Dec regimen clinic > 30 no mention
(2010) Center) 2007 s days after of death,
last TF out,
scheduled Also no
pharmacy data on 2nd
appointment line switch)
or 120 days
after last
clinic visit if
no
pharmacy
data
Toure Cote Clinics Public Public Part Initiated 18 Less 36, 30%, 94% 12 last contact 18% Similar to NR NR Not defined NR NR NR
et al d'Ivoire and and ial ART May than 123, NNRTI month with care EWI (also no
[67] (Abidjan) Privat Private 2004 - 10211 Stage I regimen center > 3 data on 2nd
(2008) NB: May e clinicia Feb 2007 and II s (NB: months and line switch)
Lancet 2010 ns, 19% for not known
is only Stage III 10211 to be dead
CEPREF 69% persons or TF out
clinic data. Stage IV )
Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011
36
DeSilv Nigeria (Jos) Clinic NGO Faith No Initiated 1 1552 34, 29%, 99% Mean No clinic 8.8% Similar to 6.7% NR Not defined NR NR 84.5% NR
a et al Alive Dec 2004 112 NNRTI duration records for > EWI (also no
[43] Progra - Apr regimen of F/U 3 months data on 2nd
(2009) m 2006. s, 1% 14.6 line switch)
Followed PI months
to Dec regimen
2006 s
Jansse Cambodia Clinic Public MOH No initiated 2 2497 median NNRTI 12 to 18 Not defined 6.5% Unclear 16.8 NR Still alive 76.7% 17.9 58.8% NR
ns et al (Siem Reap, and ART Mar CD4 53 regimen months % and in %
[49] Takeo) NGO 2002 - s (assume active F/U.
(2007) (MSF) Dec 2005 'almost median (also no
all 15 data on 2nd
patients months) line switch)
'
Barth Sth Africa Clinic NGO Local No Initiated 1 609 35, 29%, 100% 12 Not defined 15.0 Unclear 19.0 NR Alive and in 66% NR NR 66% Yes
et al (Ndlovu) NGO Sept 2003 67, Stage NNRTI months % % care. (also
[31] - Apr I 10% regimen no data on
(2008) 2006 Stage II s 2nd line
10% switch)
Stage III
62%
Stage IV
17%
Assefa Ethiopia Mixed Public MOH No Initiated 353 60476 NR 100% 12 Not on ART 18.4 Higher 8.6% NR Alive and 73.0% NR NR 73.0% No
et al Sept 2003 NNRTI months and not % (potentially on ART
[29] - Oct regimen known to only miss
(2010) 2007 s have died at one appt to
12 months be lost)
Bacha India Hospita Public MOH No Initiated 3 927 35. 66%, 16% 12 missed clinic 11.0 Lower (not 11.2 NR Alive and 77.9% NR NR 77.9% Yes
ni et al (Mumbai, ls Oct 2004 119, receive months visits for 3 % followed to % on ART
[30] Tambaram - Jan d prior months 15 months)
(2010) Chennai, 2005 ART,
Hyderabad) 100%
NNRTI
regimen
s
Cornell South Africa Mixed Public MOH No Initiated 8 44177 35, 32%, NR 12 > 6 months 14.4 Lower 6.6% NR Enrolled in 80.0% NR NR 78.40% Yes
et al (IeDEA-Sth ART from 103, months without % (longer ART
[41] Africa) Jan 2002 Stage I patient period LTFU programme
(2010) - Dec 9% Stage contact and shorter and not
2007 II 12% duration of dead or
Stage III F/U) LTFU
48%
Stage IV
32%
Hong Namibia NR Public MOH No Initiated 9 1620 NR 100% 12 EWI 17.5 Same as NR NR EWI 0.2% for Yes
et al ART after NNRTI months definition % EWI definition EWI 3b
[48] Jan 2007 regimen (not returned (Proportion translate
(2010) s to pharmacy of patients s into
or clinic < 90 switching 99.8%
days after to second
last ART line ART at
run-out date 12 months)
and who
were not TF
out, stopped
37
Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators
71
72
ART, or
died)
Moore Malawi Region Public MOH No Initiated 1 300 mean 36, 100% 12 Failure to 2.7% Higher 14.3 5.3 Alive and 72.3% 77.6% 5.3% 72.3% Yes.
et al (Blantyre) al 2005 39%, NNRTI months attend clinic (shorter % % on ART in
[58] Hospita mean regimen 4 weeks period LTFU) the study
(2010) l 157, s after Lower (not clinic
Stage IV scheduled followed to
29% appointment 15 months)
Muteve Sth Africa Hospita Public MOH No Initiated 16 3010 34-37, 100% 12 No clinic 3.7% Lower (not 10.9 NR Alive and 84% 85.4% 1.4% 84.0% Yes
dzi et (Kwa-Zulu l and ART Oct 22%, 91- NNRTI months visit for 90 followed to % on ART in
al [59] Natal) Clinics 2004 - 128, NR regimen days 15 months) the study
(2010) Sept 2007 s clinic
Sharm India (Delhi - Referral Public MOH No Initiated 1 631 Mean 36, 100% 12 NR 18.5 Unclear 13.0 NR NR Being 68.5% NR 68.5% Yes
a et al AIIMS) Hospita ART May 80%, 110, NNRTI months % % followed
[62] l 2005 - Stage I regimen in clinic
(2010) Oct 2006 13% s
Stage II
5% Stage
III 51%
Stage IV
31%
Tassie Cambodia NR NGO NGO No Initiated 1 606 NR NR 12 no recorded 4.4% Lower (not 9.6% 4.8 Alive on 81.1% NR NR 81.1% NR
et al (Kampong (MSF) ART Jan - months visit for 90 followed to % ART at the
[65] Cham) Dec 2005 days from 15 months) original site
(2010) the last visit
As Cambodia NR NGO NGO No Initiated 1 610 NR NR 12 no recorded 0.8% Lower (not 3.3% 8.5 Alive on 87.4% NR NR 87.4% NR
above (Phnom (MSF) ART Jan - months visit for 90 followed to % ART at the
Penh) Dec 2005 days from 15 months) original site
the last visit
As Burkina NR NGO NGO No Initiated 1 899 NR NR 12 no recorded 15.9 Lower (not 6.0% 5.8 Alive on 72.3% NR NR 72.3% NR
above Faso (Pissy) (MSF) ART Jan - months visit for 90 % followed to % ART at the
Dec 2005 days from 15 months) original site
the last visit
As DRC NR NGO NGO No Initiated 1 1065 NR NR 12 no recorded 8.1% Lower (not 16.7 1.3 Alive on 73.9% NR NR 73.9% NR
Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011
above (Kinshasa) (MSF) ART Jan - months visit for 90 followed to % % ART at the
Dec 2005 days from 15 months) original site
the last visit
As Kenya NR NGO NGO No Initiated 1 860 NR NR 12 no recorded 8.5% Lower (not 6.4% 3.0 Alive on 82.1% NR NR 82.1% NR
above (Busia) (MSF) ART Jan - months visit for 90 followed to % ART at the
Dec 2005 days from 15 months) original site
the last visit
As Kenya NR NGO NGO No Initiated 1 954 NR NR 12 no recorded 10.9 Lower (not 10.6 1.6 Alive on 76.9% NR NR 76.9% NR
above (Hornabay) (MSF) ART Jan - months visit for 90 % followed to % % ART at the
Dec 2005 days from 15 months) original site
the last visit
As Kenya NR NGO NGO No Initiated 1 435 NR NR 12 no recorded 11.3 Lower (not 5.3% 5.7 Alive on 77.7% NR NR 77.7% NR
above (Kibera) (MSF) ART Jan - months visit for 90 % followed to % ART at the
Dec 2005 days from 15 months) original site
the last visit
As Kenya NR NGO NGO No Initiated 1 549 NR NR 12 no recorded 13.5 Lower (not 4.2% 5.8 Alive on 76.5% NR NR 76.5% NR
above (Mathare) (MSF) ART Jan - months visit for 90 % followed to % ART at the
Dec 2005 days from 15 months) original site
the last visit
As Malawi NR NGO NGO No Initiated 1 1599 NR NR 12 no recorded 11.6 Lower (not 9.4% 1.4 Alive on 77.6% NR NR 77.6% NR
above (Chiradzulu) (MSF) ART Jan - months visit for 90 % followed to % ART at the
Dec 2005 days from 15 months) original site
38
the last visit
As Malawi NR NGO NGO No Initiated 1 1359 NR NR 12 no recorded 8.9% Lower (not 12.7 2.4 Alive on 76.0% NR NR 76.0% NR
above (Thyolo) (MSF) ART Jan - months visit for 90 followed to % % ART at the
Dec 2005 days from 15 months) original site
the last visit
As Mozambiqu NR NGO NGO No Initiated 1 1208 NR NR 12 no recorded 20.3 Lower (not 1.9% 1.8 Alive on 76.0% NR NR 76.0% NR
above e (AltoMae) (MSF) ART Jan - months visit for 90 % followed to % ART at the
Dec 2005 days from 15 months) original site
the last visit
As Mozambiqu NR NGO NGO No Initiated 1 1294 NR NR 12 no recorded 10.2 Lower (not 5.0% 3.8 Alive on 81.0% NR NR 81.0% NR
above e (Mavalan) (MSF) ART Jan - months visit for 90 % followed to % ART at the
Dec 2005 days from 15 months) original site
the last visit
As Mozambiqu NR NGO NGO No Initiated 1 278 NR NR 12 no recorded 4.3% Lower (not 5.4% 5.0 Alive on 85.2% NR NR 85.2% NR
above e (Moatize) (MSF) ART Jan - months visit for 90 followed to % ART at the
Dec 2005 days from 15 months) original site
the last visit
As Nigeria NR NGO NGO No Initiated 1 713 NR NR 12 no recorded 9.7% Lower (not 5.7% 1.7 Alive on 82.9% NR NR 82.9% NR
above (Lagos) (MSF) ART Jan - months visit for 90 followed to % ART at the
Dec 2005 days from 15 months) original site
the last visit
As Uganda NR NGO NGO No Initiated 1 1137 NR NR 12 no recorded 13.4 Lower (not 3.9% 2.9 Alive on 79.8% NR NR 79.8% NR
above (Arua) (MSF) ART Jan - months visit for 90 % followed to % ART at the
Dec 2005 days from 15 months) original site
the last visit
As Zambia NR NGO NGO No Initiated 1 559 NR NR 12 no recorded 3.4% Lower (not 12.0 0.9 Alive on 83.7% NR NR 83.7% NR
above (Kapiri (MSF) ART Jan - months visit for 90 followed to % % ART at the
Kawama) Dec 2005 days from 15 months) original site
the last visit
As Zimbabwe NR NGO NGO No Initiated 1 222 NR NR 12 no recorded 13.5 Lower (not 11.5 0.5 Alive on 74.4% NR NR 74.4% NR
above (Bulawayo) (MSF) ART Jan - months visit for 90 % followed to % % ART at the
Dec 2005 days from 15 months) original site
the last visit
As Zimbabwe NR NGO NGO No Initiated 1 173 NR NR 12 no recorded 3.3% Lower (not 15.9 0.5 Alive on 80.4% NR NR 80.4% NR
above (Murrambin (MSF) ART Jan - months visit for 90 followed to % % ART at the
da) Dec 2005 days from 15 months) original site
the last visit
As India (YRG) NR Public MOH No Initiated 1 767 NR NR 12 no recorded 31.9 Lower (not 3.6% 6.0 Alive on 58.9% NR NR 58.9% NR
above and and ART Jan - months visit for 90 % followed to % ART at the
Privat clinicia Dec 2005 days from 15 months) original site
e ns the last visit
As Kenya NR Public MOH No Initiated 1 4111 NR NR 12 no recorded 15.0 Lower (not 6.7% 3.8 Alive on 74.6% NR NR 74.6% NR
above (AMPATH) ART Jan - months visit for 90 % followed to % ART at the
Dec 2005 days from 15 months) original site
the last visit
As Zimbabwe NR Public MOH No Initiated 1 378 NR NR 12 no recorded 4.0% Lower (not 6.3% 1.6 Alive on 88.6% NR NR 88.6% NR
above (Connaught) ART Jan - months visit for 90 followed to % ART at the
Dec 2005 days from 15 months) original site
the last visit
O'Brie Congo Rural NGO NGO No During 2 236 37, 31%, NNRTI Mean NR 8.5% Unclear 12.3 NR NR NR NR 79.2% NR
n et al (Pool) Hospita (MSF) 2007 104, and PI duration %
[60] l Stage I regimen of F/U 9
(2009) and II 3% s months
Stage III
53%
39
Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators
73
74
Stage IV
44%
Culbert Congo Rural NGO NGO No Initiated 1 494 37, 34%, 100% 12 NR 5.4% Unclear 7.9% NR NR NR NR 86.7% NR
et al (Bukavu) Hospita (MSF) ART May 123, NNRTI months
[42] l 2002 - Stage I regimen
(2007) Jan 2006 3% Stage s
II 12%
Stage III
49%
Stage IV
34%
Johann Tanzania Clinic NGO NGO No Initiated 1 320 35, 30%, 100% Mean missed 9.7% Lower (, 29.7 2.2 NR 60.6% 10.9 49.7% Yes
essen (Manyara) (Luther ART Oct NR, Stage NNRTI duration appointment shorter % % %
et al an 2003 - I and II regimen of F/U s for 3 duration of
[50] Church) Nov 2006 3% Stage s 10.9 months F/U, not
(2008) III 31% months followed to
Stage IV 15 months)
66%
Chang Uganda Clinic NGO NGO No Initiated 1 360 38, 66%, 100% 12 Did not visit 8.0% Lower (not 18.0 2.0 Alive and 72.0% 72.0% 1.0% 71.0% NR
et al (Kampala) (Reach ART Oct 81-107, NNRTI months the clinic in followed to % % active on
[35] Out - 2003 - Jul Stage I regimen 90 days 15 months) ART at one
(2009) Faith 2004 and II s year
based) 26%
Stage III
49%
Stage IV
24%
Chi et Zambia Clinics Public MOH No Initiated 18 37039 35, 39%, 100% 12 NR 13.8 Unclear 9.9% 3.1 Alive and 73.2% NR NR 73.2% NR
al [37] (Lusaka) ART Apr 110-132, NNRTI months % % active in
(2009) 2004 - Stage I regimen the
Sept 2007 and II s program
30%
Stage III
59%
Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011
Stage IV
10%
Notes: HC, healthcare; ART, antiretroviral therapy; WHO, World Health Organization; LTFU, lost to follow up; EWI, early warning indicator; TF, transfer; NR,
not reported; F/U, follow up; MOH, ministry of health; NGO, non-governmental organization; MSF, medecines sans frontiers; NNRTI. Non-nucleoside reverse
transcriptase inhibitors; PI, protease inhibitors; NRTI, nucleoside reverse transcriptase inhibitors;
40
Table 2. EWI 2 and 3 (LTFU and Retention on First line) Abstracts
%
retained
on ART
at
Baseline Study
original
features definition %
ART % site/s
(median LTFU will Study meeting
regimens retaine (excludes
Author Star age, % Time likely definition study
Pati (all ART Study % % d on % TF out / Patient
and HC HC Dates Site ting male, since lead to % of definitio
Country Provider ent nave at definition LTF ART ART TF stop / Tracing
meeting facility setting observed s (n) ART median ART lower or Died retention n of
pays baseline LTFU U stop (includ out switch
(n) CD4, start higher on first retentio
unless e TF from
WHO estimates line n on
stated) out) numerato
clinical than first line
r if
stage) WHO EWI
reported,
most
similar to
EWI 3a)
Chinh Vietnam Hospita Public MOH No Initiated 1 889 30, 77%, NR (all Median NR 4.0% Unclear 5.0% NR still in 88.6% 88.6% 1.2 87.6% NR
et al (Ho Chi l Sep 2005 - 143,Stage first line duratio follow-up %
[79] Minh City) Dec 2007 III / IV regimens) n F/U on first-
CROI 51% All 'ART 10 line ART
(2010) nave' but months (excludes
76% prior LTFU,
ARV death,
exposure switch for
treatment
failure)
Cortes Chile NR Public MOH No Oct 2001 - 29 3045 36.9, 100% 12 NR 2.3% Unclear 7.1% NR Maintena 66.2% NR NR 66.2% NR
et al (Chilean Sept 2008 84.7%, HAART months nce on
[81] AIDS NR, NR (63% first ART
CROI cohort) NNRTI, regimen
(2010) 15% PI) (?
Excluded
changes
due to
toxicity,
'administr
ative
causes',
viral
failure,
'simplifica
tion')
Serenat South Mixed Public MOH, No June 2005 NR 840, NR, 33%, NR 12 NR NR Unclear NR NR for NR NR NR NR 77.0% NR
a et al Africa (91%), PEPFA - Sept 673 NR, NR months for for 12
[91] (PEPFAR NGO / R 2009 (? 12 12 month
CROI sites) Private no mont mont s
(2010) (9%) for hs hs
12
mon
th
anal
41
Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators
75
76
ysis)
Okello Uganda Hospita Public, NGO No 2005-2009 NR 1869 26, 39%, 100% 12 NR NR Unclear NR NR for Not NR for NR NR 92.0% NR
et al (Mildmay) l NGO (Mildm (?1) NR, NR initiating months for for 12 defined 12 for
[90] IAS ay) HAART 12 12 month months 12
(2010) mont mont s mo
hs hs nth
s
Eramov 12 Mixed Mixed mixed No 2007-2008 NR 3181 NR NR 12 NR 6.8% Unclear 8.0% 6.3% NR NR NR NR 79% NR
a et al European months
[85] IAS countries
(2010) (former
USSR, but
not
Estonia,
Russia,
Turkmenist
an)
Duong Vietnam Mixed Public MOH No 2008 27 1222 NR NR 12 EWI LTFU 5.6% EWI NR NR EWI 81.2% NR NR 81.2% NR
et al 1 months definition definition retention
[83] IAS (114 definition
(2010) 32
adul
ts)
Geng et Uganda Region Public MOH No 2004-2007 1 3,62 NR NR 12 no visit 3 NR NR NR NR Attended 82.0% NR NR 82% No
al [86] (Mbarara) al 8 months months at 12 clinic in (tracing
IAS Hospita after mont previous sub-
(2010) l expected hs 3 months study
return and on altered
ART in retention
previous estimate
30 days to 89%)
Mossd Tanzania District Public, MOH No 2005-2008 1 1463 40, 35%, 76% 12 NR 12.9 Unclear 8.8% NR NR NR NR NR 78.3% NR
Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011
Auld et Mozambiq Mixed Mixed Mixed NR 2004-2007 30 2596 34, 38%, 88% on 1.3 NR 22.8 Unclear 4.3% NR NR NR NR NR 72.9% NR
al [74] ue 153, NR NRTI or years % (3.4
IAS (nationally NNRTI (19.8 /100
(2010) represent. regimens /100 pers
sample) pers on
on year
year s)
s)
Darin et Nigeria Mixed Mixed Mixed No Jan 2006 - NR 8418 35.2, 100% 48 NR 19.8 Unclear 0.5% 1.2% NR NR NR NR 78.50% NR
al [82] (Abuja, Dec 2007 77.9%, NNRTI weeks %
IAS Ibadan, NR, NR regimen
(2010) Lagos)
Jahn et Malawi Mixed Public MOH No 2004-2009 339 2531 NR, NR, NR 12 NR NR NR 5% NR Alive and 79% NR NR 79% NR
al [87] (Lilongwe) 54 NR, 10% months on ART
IAS Stage IV
(2010)
Chaso Thailand NR Public MOH No 2006 6 304 38, 1.2:1 100% 12 NR NR NR 8.9% NR NR NR NR NR 88.5% NR
mbat (Nonthabur M:F, 56, NNRTI months
[78] et i, Chiang NR regimen
al IAS Rai,
(2010) Lumpang,
Lumphun)
Asiimw Lesotho Clinics Private Private No May 2006 14 3394 30, 6%, 100% Median NR 9.7% Unclear 3.0% NR NR NR NR NR 87.3% NR
e et al (Apparel clinicia - Dec 2008 173, NNRTI duratio (includes
[73] IAS Alliance) ns 19.1% regimen n F/U stops, TF
(2009) Stage 13 out but
III/IV months values
NR)
Khan et South District Public Public No July 2004 - 1 685 NR, 27%, NR 12 NR 0.7% Unclear 13.2 NR Failure to 84.1% 85.3% 1.2 84.1% NR
al [88] Africa hospita June 2005 NR, NR months % collect
IAS (Ladysmith l ARVs due
(2009) Provincial to death,
Hospital) LTFU or
TF out
Cohen Lesotho 10 care Public, MOH, No 2006-2008 15 4064 NR NR 12 NR 2.5% Unclear 9.3% NR NR NR NR NR 88.2% NR
et al (Scott) (14), NGO MSF months
[80] IAS district
(2009) hospita
l (1)
Ehmer Lesotho, mixed Mixed Mixed No 2005-2008 8 4362 38, 35%, NR 12 NR 13.9 Unclear 10.3 NR NR NR NR NR 75.8% NR
et al Mozambiq ART 121, 73% months % %
[84] IASue, initiation Stage
(2009) Tanzania, III/IV
Zimbabwe
(Solidarme
d)
Somi et Tanzania mixed Public MOH No Initiated 43 2,78 37, 32%, NR 12 NR 20.0 Unclear 5.0% 5% Alive and 70% NR NR 70% NR
al [92] (National Oct 2004 - 1 114, 77% months % (LTFU not on ART
CROI Represent Aug 2007 Stage defined)
(2011) ative III/IV
Sample)
43
Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators
77
78
Ahonkh South NR NGO PEPFA No Initiated 71 11,3 NR, 48- NR 12 missing all 17.0 Lower NR NR NR NR NR NR NR NR
ai et al Africa R and Jan 2004 - 97 106, NR, months scheduled % (missing (9%
[72] (Catholic NGO Dec 2008 NR appointme for 12 died
CROI Relief (CRS) nts during months) in
(2011) Services) the first 12 the
months first
7
mont
hs)
Bertagn Africa NR Public MOH NR 2002 - 6 829 NR NR 12 WHO EWI 12.9 Same 9.2% 0.8% On first 86.1% 80.3% 14. 65.9% NR
olio et (multiple 2010 months definition % (76/8(5/633 line ART (545/633 (666/82 5% (546/829)
al [76] countries) (excludes (82/6 29) ) at 12 ) 9) (12
CROI TF out and 33) months 0/8
(2011) death from (exclude 29)
denominat TF out
or) and death
from
denomina
tor)
Balestr IeDEA- Mixed NR NR NR 92.5% of NR 19,1 40, NR, 85% ART 12 NR 32.8 Unclear 4.3% NR NR Unclear NR NR 62.90% NR
e et al West patients 31 159, 85% nave, months %
[75] Africa after 2004 advanced 87%
CROI (Benin clinical started
2011 Cote stage NNRTI
d'Ivoire, regimens
Gambia,
Mali
Nigeria,
Senegal)
Notes: HC, healthcare; ART, antiretroviral therapy; WHO, World Health Organization; LTFU, lost to follow up; EWI, early warning indicator; TF, transfer; NR,
not reported; F/U, follow up; MOH, ministry of health; NGO, non-governmental organization; MSF, medecines sans frontiers; NNRTI. Non-nucleoside reverse
transcriptase inhibitors; PI, protease inhibitors; NRTI, nucleoside reverse transcriptase inhibitors;
Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011
44
Table 4. EW I 4 (On tim e ARV pick up) Papers and Abstracts
ART Proportio
Characteristics Study definition will
regimens Duration of n who
of study likely lead to lower
(all ART adherence were
HC Dates Sampl population Type of pharmacy or higher estimates
Simila HC Patien Sites nave at assessme 100%
Author Country settin Provider observe e size Design (median age, adherence measure of on time ARV pick
r EWI facility t pays (n) baseline nt (months adherent
g d (n) %male, median and study definition up than EWI (3
unless over which using
baseline CD4, pickups (a), or 12
otherwise assessed) study
clinical stage) months (b))
stated) definition
4b Chi et al Zambia Mixed Public MOH No Initiated 18 27115 Retrospectiv 35, 38%, 132, NNRTI 12 months MPR measure. 28% Higher (excluded
[37] (2009) Apr 2004 e cohort Stage I or II 33% regimens (0 12) 100% - [(days late to (estimated those who died,
- Apr Stage III 59% pharmacy visits 3) / from LTFU, stopped ART
2007 Stage IV 9% days on ART] graph) who may have been
NB: "less 3" to less adherent)
account for routine
provision of 3 days
extra ART
4b Muyingo et Uganda Research Public DART No Initiated 3 2957 RCT NR, 35%, NR, Triple NRTI 12 months DPR measure. 12% Higher (excluded
al [95] (Kampala, Centers (Trial) Trial Jan 2003 NR 83%, NNRTI (0 12) (Days ART dispensed those who died,
(2008) Entebbe), - Oct regimens - Days ART returned) LTFU, stopped ART
Zimbabwe 2004 17% / Days between visits who may have been
(Harare)) less adherent)
4a Nachega et 9 sub-Saharan Clinics Private Private insure Jan 1998 Multiple 946 Retrospectiv Mean 37, 37%, 100% NNRTI 6 months MPR measure. 60% Higher (all achieved
al [96] countries clinicians d - Mar e Cohort 130 to 157, NR. regimens (varied) Months ART claims viral suppression
(2007) 2003 (NB: All had to submitted (all ARVs) / before adherence
achieve viral months from start to assessed)
suppression to death/leaving/censor (NB: 35% of the
be included) larger study
population [n=2821]
were 100% adherent,
followed median 2.2
yrs)
4a Toure et al Cote d'Ivoire, Clinics NGO, Public Partial Initiated 18 10211 Retrospectiv 36, 30%, 123, 94% NNRTI Variable, MPR measure. 47% Higher (If LTFU
[67] (2008) Abidjan public and ART May e cohort Stage I and II regimens Median 7.7 Days ART given to adherence
(CEPREF and and private 2004 - 19% Stage III months patient / Days since assessment stopped
Aconda private clinicians Feb 2007 69% Stage IV (from ART ART start to last visit, at last visit)
program) 12% start) or censor if last visit
was after censor date
4a Ross- Ethiopia, Hospitals NGO, Public NR Unclear 16 (4 / 488 Retrospectiv Mean 36, 37%, NNRTI and Variable MPR measure. 64% Higher (Had to have
Degnan et Kenya, Rwanda and public and (study country) e cohort NR, Stage I 9% PI regimens Median 6 Days with ART / Days at least 6 months
al [97] and Uganda Clinics and private conducte Stage II 25% II (proportions months since ART start follow up to be in
(2010) private clinicians d after 19% Stage III NR). (from ART study)
2006) 54% Stage IV 4% prior start)
11% ART
4a Gill et al China Clinic Public MOH NR June 1 69 Prospective Mean 36, 74, NNRTI 6 months Pill count measure. 43% Higher (excluded
[94] (2010) 2006 - cohort 319, NR regimens, (varied) Actual number of pills those who died,
May 25% nave at in bottle / expected stopped ART who
2007 baseline number of pills may have been less
adherent)
4b Ceccato et Brazil (Belo Clinic Public MOH No 2006 1 531 Cross 31-40, NR, NR, 46% 12 months MPR measure. 14% Higher (with study
al [98] IAS Horizonte) sectional NR NNRTI (NR) Average time definition may
2010 regimens, between potentially not be on
12% PI dispensations over 12 time every month)
regimens. months was 35
47
Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators
79
80
NR if nave days
Notes: EWI, early warning indicator; HC, healthcare; ART, antiretroviral therapy; PC, Pill Count; MPR, Medication Possession Ratio; ARV,
Antiretroviral; NNRTI. Non-nucleoside reverse transcriptase inhibitors; WHO, World Health Organization; LTFU, lost to F/U; NR, not reported;
NRTI, nucleoside reverse transcriptase inhibitors;
F/U, follow up; MOH, ministry of health; PI, protease inhibitors; TF, transfer
Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011
48
Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators
Table 5. Sum m ary estim ates for EW I 4. On tim e ARV pick -up
a
Includes one cohort [67] with 10211 patients
b
Includes one cohort [37]with 27115 patients
c
Includes 2 papers from original definition [67, 94] and 6 new papers [99-104]. 1
study [103] reported different adherence estimates for a standard of care (SOC) and
intervention arm, the SOC estimate was used. 1 paper reported [104] a Pill Count (PC)
and a Medication Possession Ratio (MPR) measure, the MPR measure was used.
d
Includes 2 papers from original definition [37, 95] and 3 new papers [102, 105,
106]. 1 paper [106] reported different adherence estimates for a SOC and
intervention arm, the SOC estimate was used. 1 paper reported [95] a PC and a MPR
measure, the MPR measure was used.
49
81
82
Table 6. EWI 5 (On time appointment keeping) Papers and Abstracts
ART
Characteristic Study definition will
regimen Proportion
s of study Duration of likely lead to lower
s (all meeting
population adherence or higher estimates
Dates ART Study definition of on study
HC HC Patien Sites Start (median age, assessme of on time
EWI Author Country Provider observe Design nave at time appointment definition of
facility setting t pays (n) ART (n) %male, nt (months appointment
d baseline keeping on time
median over which keeping than EWI (3
unless appointment
baseline CD4, assessed) pickups (a), or first
otherwis keeping
clinical stage) 12 months (b))
e stated)
5a Chalker et Kenya Hospitals Public MOH NR Oct 2006 19 373 Retrospectiv 37, 32%, NR, NR 4 months Percentage attending 78.3% Higher (did not
al [100] and and NGO and - June e cohort NR (varied) appointments on or include patients
(2010) Clinics others 2007 before the scheduled LTFU)
day Lower (did not miss
by up to 7 days)
As As above Rwanda Hospitals Public MOH NR Oct 2006 20 285 Retrospectiv 37, 38%, NR, NR 4 months as above 78.4% As above
above and - June e cohort NR (varied)
Clinics 2007
As As above Uganda Hospitals Public MOH NR Oct 2006 19 408 Retrospectiv 37, 32%, NR, NR 4 months As above 71.7% As above
above and and NGO and - June e cohort 79% Stage (varied)
Clinics others 2007 III/IV
As As above Ethiopia Hospitals Public MOH NR Oct 2006 20 565 Retrospectiv 33, 45%, NR, NR 4 months As above 73.5% As above
above - June e cohort 83% Stage (varied)
2007 III/IV
As As above Rwanda Hospitals Public MOH NR Oct 2006 20 285 Retrospectiv 37, 38%, NR, NR 4 months Percentage attending 93.4% As above
above and - June e cohort NR (varied) within 3 days of
Clinics 2007 scheduled
appointment
As As above Uganda Hospitals Public MOH NR Oct 2006 19 408 Retrospectiv 37, 32%, NR, NR 4 months As above 76.3% As above
above and and NGO and - June e cohort 79% Stage (varied)
Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011
51
regimens
5a Atukunda Uganda NR NR NR NR Aug 15 763 Cross NR, NR, NR, NR 3 months Not missed 93% Similar to EWI 5a
et al [109] (Kampala) 2008 sectional NR (varied) appointments in the (unclear if LTFU
IAS 2010 last 3 months included)
5a Ugoji et al Nigeria Hospital Public MOH NR May - 1 1140 Retrospectiv NR, NR, NR, NR 3 months Attended within 7 days 53% Similar to EWI 5a
[111] IAS and NGO and October e cohort NR (0-3) of scheduled (included patients
2010 partners partners 2009 appointment LTFU)
(IHV,
PEPFAR)
? 5a or Duong et al Vietnam Mixed Mixed Mixed NR Data 31 11432 ? Cohort or NR, NR, NR, NR NR EWI study Range 52- EWI definition
5b [83] IAS collected adults cross NR 99% across
2010 2009 789 sectional 31 sites. (5
children sites < 80%)
5a Neethling South Clinic Public MOH No May 1 9603 Cross NR, NR, NR, NR 4 months Attended within 7 days 87% Similar to EWI 5a
et al [110] Africa 2007 - sectional NR (NR) of scheduled (unclear if LTFU
IAS 2009 (Themba Aug appointment included)
Lethu) 2008
5b Ahonkhai et South NR NGO PEPFAR No Initiated 71 11,397 Retrospectiv NR, 48-106, NR 12 months Not missed any 63% Similar
al [72] Africa and NGO Jan 2004 e cohort NR, NR appointments in first
CROI 2011 (Catholic (CRS) -Dec 12 months ART
Relief 2008
Services)
Notes: HC, healthcare; ART, antiretroviral therapy; ; EWI, early warning indicator; NGO, non-governmental organization; MOH, ministry of health; LTFU, lost to F/U; TF,
transfer; NR, not reported; F/U, follow up; IAS, International AIDS Society meeting; IHV, Institute of Human Virology; PEPFAR, Presidents Emergency Fund for AIDS
Relief
52
Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators
83
Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011
a
For 1 paper [100] reporting on 4 sub-Saharan countries with 2 different definitions for on time
appointment keeping, one estimate was taken for each country with the more lenient definition (up to 3
days late) used where possible
b
One cohort [72] (n=11397, 63% patients on time), the other cohort [108] (n=566, 70% patients on time)
53
84
Table 8. EWI 6 (Stock-outs) Papers and Abstracts
85
86
12% (survey)
6c2 McCurdy Uganda Clinic Public MOH No Initiated 1 453 Retrospectiv 34, 29%, 135, 100% 12 months Proportion who 7% Lower (no data on
et al (Mbarara - 2005 - e Cohort NR NNRTI change active drug stop, incomplete
[120] UARTO) 2009 regimens components of dispensing)
CROI ART excluding
(2010) clinical reasons
(clinic and
pharmacy records)
6c1 Ssali et Uganda Clinic NR NR NR 2005 - 1 3738 Retrospectiv NR, NR, NR, NR NR (< 5 Substituted within 1.5% Unclear (duration of
al [119] (Masaka) 2009 (6.5% e Cohort NR years) the first line F/U unclear, only for
IAS paed) regimen due to drug substitution)
(2010) drug stock out
(clinic and
pharmacy records)
6b Jack et Caribbean NR NR NR NR 2008 58 20794 Cross NR, NR, NR, NR NR EWI definition. 64% of EWI definition
al [121] (10 sectional NR Sites with stock- sites had
IAS countries) out in any month stock-outs
(2010) over 12 months. over 12
months
Notes: EWI, early warning indicator; HC, healthcare; ART, antiretroviral therapy; ARV, Antiretroviral; MOH, ministry of health; LTFU, lost to follow up; NR, not reported;
NNRTI. Non-nucleoside reverse transcriptase inhibitors; PI, protease inhibitors; NRTI, nucleoside reverse transcriptase inhibitors; NGO, non-governmental organization;
F/U, follow up;
Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011
55
Table 9. EWI 8 (Virological suppression) Papers
Baseline Study
ART
features definition will
regimen %
(median Study Proportion likely lead to
s (all Time to HIVDR
Patie Dates Site Start age, % definition meeting study lower or % %
Study HC HC Provid Study ART since % % 2nd outcomes if
Country nt observe s ART male, of VL definition of VL higher ART TF
(year) facility setting er Design nave at ART Died LTFU line reported
pays d (n) (n) median suppressio suppression +/- estimates of stop out
baseline start AR
CD4, WHO n EWI definition VL
unless T
clinical suppression
stated)
stage) than EWI
Bussma Botswana Clinics Public MOH No Initiated 5 650 RCT 33, 31%, 100% 12 VL < 400 92% (OT, Higher (RCT 3.4% 2.4% NR NR At 1 year,
n et al (Gaborone Dec 199, Stage I NNRTI months copies/mL n=586) and OT 5.3% of
[132] - Princess 2002 - 31% Stage regimens 86% ITT (n=624 analysis, also patients on
(2009) Marina 2004. II 25% [Include those ITT analysis ZDV/ddI
Hospital) Followed Stage III who died or doesn't containing
to Apr 34% Stage LTFU]) include stop ART had VF
2006 IV 9% and switch) with
resistance
compared
with 1.0% on
nonZDV/ddI
containing
ART
Bourge Cameroon Clinic Public MOH Partial Initiated 1 109 Cohort 36, 34%, 100% 12 VL < 400 97.3% (OT, Higher (for OT NR at NR at NR NR 4 of 9
ois et al (Yaound) and Jan 2001 150, Stage I NNRTI months copies/mL n=75) analysis) 12 12 at 12 at 12 patients with
[130] NGO - Apr 12% Stage II regimens 86.9% (ITT, Lower mths mths mths mths VL > 5000
(2005) (MSF) 2003 14% Stage n=84 [not (threshold copies
III 54% defined]) 400 copies) developed
Stage IV HIVDR over
20% 30 months
F/U
Seyler Cote Clinic Public MOH Partial Mar Mul 101 Prospe 36, 38%, 100% 12 VL < 200 51% (OT, n=29) Higher (for OT NR at NR NR NR
et al d'Ivoire and 1999 - tipl ctive 135, Stage I NNRTI months copies/mL ITT not possible analysis) 12
[152] (Abidjan - UNAID Aug e Cohort 2% Stage II regimens and not defined Lower mths
(2003) Cotrame) S 2002 12% Stage (threshold
III 48% 200 copies)
Stage IV
39%
Ferradin Malawi District Public MOH No Jan - 1 398 Cross 34, 31%, 99% Median VL < 1000 87% (OT, Higher (OT, NR in NR in NR NR In 52 samples
i et al (Chiradzulu Hospita and April section 114, Stage I NNRTI duratio copies/mL n=397) shorter this this in (> 1000
[45] ) l NGO 2004 al and II 18% regimens n 9.5 duration of sampl sampl this copies), 84%
(2006) (MSF) Stage III , 98% months F/U) e e sam had NRTI
58% Stage ART ple mutations,
IV 24% nave 94% had
NNRTI
mutations
Laurent Senegal Unclear Public MOH Partial Initiated Unc 176 Prospe 38, 48%, 47% 12 VL < 500 77% (OT, Higher (for OT 8.8% NR NR NR 12.5% (n=22)
et al (Free Aug lear ctive 144 NNRTI, months copies/mL n=143) 63% analysis) (at 9.1 developed
[143] if in 1998 - Cohort 43% PI (ITT, n=176 Lower mths HIVDR at
(2005) clinica Apr 2001 (n=80 and 10% [based on entire (threshold media median 30
l trial) also in 2NRTI sample]) 500 copies) n F/U) months F/U.
Clinical regimens (Resistance
trial) . 92% by class: 10%
ART NRTI, 9%
56
Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators
87
88
nave NNRTI, 8%
PI)
Gandhi Sth Africa District Public MOH, No Initiated 1 119 Prospe Mean 34, 100% 12 VL < 400 94% (OT, n=98) Lower 11.0% 5.9% NR NR 5 of 6
et al (Msinga) Hospita and ART Oct ctive 44%, 79, NNRTI months copies/mL 88% (ITT, (threshold patients with
[136] l Partner 2003 - cohort regimens n=105, [Study 400 copies) detectable VL
(2009) Jan 2006 definition, at 12 months
includes LTFU had HIVDR
and not death])
78% (ITT, n=118
[Includes LTFU
and death])
Ahoua Uganda Region Public MOH No Initiated 1 229 Retrosp 37, 34%, NNRTI 12 VL < 1000 89% (OT, ITT same as 5.0% 17.0% 1.0% 5.0% In 20 samples
et al (Arua) al and Sept ective 100, Stage regimens months copies/mL n=229), 69% EWI definition > 1000 copies
[126] Hospita NGO 2004 - cohort III and IV , 98% (ITT, n=297 70% had
(2009) l (MSF) Jul 2005 with 18% ARV [Includes those HIVDR to 1
cross nave at who died, LTFU, ARV. (15% to
section baseline stopped]) EFV and NVP,
al VL 45% to 3TC
analysis and NNRTI,
and 10%
extensive
HIVDR)
Mujugir Botswana Hospita Public MOH No Initiates 1 349 Retrosp 35, 41%, 22 100% 9 VL < 400 92% (OT, n is Higher (OT, 22% 13.5% NR 1.1%
a et al (Gaborone) l Feb - ective NNRTI months copies/mL unclear) also ITT (at 12 (at 12 (at
[146] (Prince Mar cohort regimens 60% (ITT, n is analysis, as a mths) mths) 12
(2009) ss 2002 unclear 9 mth mths
Marina [Includes death outcome) )
/ IDCC) and LTFU])
Fielding Sth Africa Hospita Private Compa No Initiated 39 1760 Retrosp 41, 97%, NNRTI 12 VL < 400 72% (OT, Lower 9.9% 11.4% See 12.1 1.2
et al ls and (Workpl ny prior Jul ective 156, 73% regimens months copies/mL n=953) 51% (threshold (LTFU LTFU % %
[135] Clinics ace) (Anglo 2004. cohort Stage III and (ITT, n=1328 400 copies) +
(2008) Americ Followed IV [Excludes TF out stop)
an) to Mar and those with
2006 no VL test])
Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011
Bisson sub- NR Private Private Privat Initiated Mul 872 Retrosp 55% < 35 100% 12 VL < 1000 74% (OT, Higher (OT NR NR NR NR
et al Saharan (workpl clinicia e Dec tipl ective yrs old, NNRTI months copies/mL n=872) analysis)
[129] Africa (9 ace) ns insura 2000 - e cohort 37%, 165 regimens
(2008) countries) nce Feb
2003
Nacheg sub- Clinics Private Private No Initiated Mul 7776 Retrosp 37, 38%, 97% 12 VL < 400 62% (OT, Higher (OT) NR NR NR NR
a et al Saharan (workpl clinicia (insure Jan 1999 tipl ective 146 NNRTI, months copies/mL n=3192) Lower
[148] Africa (9 ace) ns d, no - Aug e cohort 3% PI (threshold
(2009) countries) copay 2006 regimens 400 copies)
ment)
Garrido Angola Clinic NR NR NR NR 1 294 Cross 36, 28%, 89% Median VL < 1000 74% (OT, Higher (OT NR NR NR NR 18 of 23
et al section 144 NNRTI Duratio copies/mL n=294) analysis) samples had
[137] al regimens n 12.6 HIVDR
(2008) , 20% months mutations
prior (including 15
ARV with M184V,
exposur 9 with K103N)
e
Vanni et Brazil Clinic Public MOH No Jan 2002 1 126 Retrosp 37, 69% 60% 12 VL < 400 65% (ITT, n=? Lower NR NR NR NR
al [153] (Ribeira - Dec ective EFV months copies/mL [Dropouts and (threshold
(2007) Porto) 2003 cohort regimens switches were 400 copies)
, 40% treatment
57
Nelfinavi failures])
r
regimens
.
Ndembi Uganda Resear Public DART No Initiated 2 600 RCT 37, 28%, 99, 50% 48 VL < 50 77% NNRTI Lower 4.2% 2.0% 1.0% 0% 0%
et al (Kampala, ch (Trial) Trial Jan - (300 WHO stage NNRTI , weeks copies/mL group (threshold
[149] Entebbe - Centers Oct 2004 in III 55% 50% 62% 3NRTI <50 copies)
(2010) DART sub each Stage IV 3NRTI group (ITT, Higher (RCT)
study) arm) 18% regimen n=600)
As 600 48 VL < 1000 87% NNRTI Higher (RCT) 4.2% 2.0% 1.0% 0% 0% 89 specimens
above (300 weeks copies/mL group (> 1000
in 79% 3NRTI copies) had
each group (ITT, genotypic
arm) n=600) results.
NVP arm -
75% K103N
and 71%
M184V,
Abacavir arm
- 88% M184V
Anonwa Thailand Resear Public STACC No Initiated 7 272 RCT Mean age 100% 48 VL < 400 96% (OT, n=164 Lower NR 6.0% NR NR NA
ronich ch (Trial) ATO ART 34, 39%, boosted weeks copies/mL [All on (threshold
et al Centers Trial after CDC Cat A PI continuous 400 copies)
[127] 2001 71%, Cat B regimen. treatment from Higher (RCT,
(2008) 28% Cat C both arms]) also OT)
2% 79% (ITT n=129
[Exclude
treatment
interruption arm
and ITT for all in
continuous
treatment arm])
As 48 VL < 50 93% (OT, Lower NR 6.0% NR NR NA
above weeks copies/mL n=164) (threshold 50
69% (ITT n=129) copies)
Analysis as Higher (RCT,
above also OT)
Idoko et Nigeria Referral Public 175 Clinical 35, 40%, 67, 100% 48 VL < 400 (All OT, n=145) Lower
al [139] (Jos) Hospita trial Stage I 3% NNRTI weeks copies/mL 91% daily DOT, (threshold
(2007) l Stage II 12% regimens 88% twice 400 copies)
Stage III weekly DOT, Higher (OT)
43% Stage 84% weekly
IV 38% DOT, 79% no
DOT
Bussma Botswana Region Public MOH No Initiated 1 633 Retrosp 35, 40%, 67, 100% 12 VL < 400 91% (OT, n = Higher (OT) 17.3% 8.9% NR NR
n et al (Gaborone al Jan - ective Stage I 3% NNRTI months copies/mL 467 67% (ITT, Lower at 12
[131] - Princess Hospita Aug Cohort Stage II 12% regimens n=633 [Includes (threshold mths
(2008) Marina l 2002 Stage III 43 death and LTFU) 400 copies)
Hospital) Stage IV 38
(NB
different to
[132])
Kouanf Cameroon Hospita Public MOH Partial Enrolled 1 249 Cross 35 to 40 99% 12 VL < 500 78% (OT, Higher (OT) NA NA NA NA NA 11 of 34
ack et (Yaound) l Nov section years, 29%, NNRTI months copies/mL n=249) Lower samples (>
al [141] 2006 - al NR, NR regimens (threshold 1000 copies)
(2009) Oct 2007 500 copies) had 1 major
58
Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators
89
90
mutation
As 12 VL < 1000 84% (OT, Higher (OT) NA NA NA NA NA
above months copies/mL n=249)
Djoman Cote Clinics Public
MOH Partial Initiated 6 276 Retrosp 35, 50%, 80% PI, 1 year VL < 200 50% (ITT, Lower unclea unclea
d et al d'Ivoire and ART Aug ective 182 (study 19% copies/mL n=276. [ITT (threshold r r
[28] (Abidjan) partner 1998 - cohort patients NNRTI defined as those 200 copies)
(2003) s May from a group or 1% who returned for
(UNAID 2000 with these 3NRTI 1 visit after
S, features) regimens start])
CDC)
Sarna Kenya Clinics Public MOH No Initiated 3 137 RCT 37, 36%, 96 NNRTI 12 VL < 400 82% (OT, n=137 Higher (OT) unclea unclea
et al (Mombasa) (2), and Sept to 106, NR regimens months copies/mL [78% control Lower r r
[103] Private partner 2003 - arm 88% DOT (threshold
(2008) (1) s Nov arm]) 400 copies)
2004
Landma Senegal Hospita Public MOH No Initiated 1 40 Clinical Mean 38, 100% 12 VL < 400 94% (OT, n=35) Higher (OT, 7.5% 5.0% 0% 0%
n et al (Dakar) l and Jun - trial 40%, NNRTI months copies/mL 83% (ITT, n=40) RCT)
[142] Partner Dec Median 111, regimens Lower
(2009) (Pharm 2004 CDC cat A (threshold
a) 7.5% cat B 400 copies)
70% cat C
22.5%
As VL < 50 83% (OT, n=35) Higher (OT, 7.5% 5.0% 0% 0%
above copies/mL73% (ITT, n=40) RCT)
Lower
(threshold 50
copies)
Barth et Sth Africa Clinic NGO Local No Initiated 1 609 Retrosp 35, 29%, 67, 100% 12 VL < 400 83% (OT, Higher (OT) 19.0% 15.0% NR NR
al [31] (Ndlovu) NGO Sept ective Stage I 10% NNRTI months copies/mL n=407) 55% Lower
(2008) 2003 - Cohort Stage II 10% regimens (ITT, n=609) (threshold
Apr 2006 Stage III 400 copies)
62% Stage
IV 17%
As VL < 50 70% (OT, Higher (OT) 19.0% 15.0% NR NR
Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011
59
400 copies) F/U) F/U)
Ramad Tanzania Referral Public MOH Partial Jun - 1 150 Cross 41, 37%, 100% median VL < 400 68% (OT, Higher (OT) NA NA NA NA 15 of 27 (>
hani et (Kilimanjaro Hospita Aug section 114 NNRTI 12 copies/mL n=150) Lower 1000 copies)
al [151] ) l 2008 al regimens months (threshold had 1
(2007) 400 copies) mutation to
NRTI or
NNRTI
As VL < 1000 77% (OT, Higher (OT) NA NA NA NA
above copies/mL n=150)
Kamya Uganda Clinic Public MOH No Initiated 1 526 Prospe Mean 37, 100% 12 VL < 400 87% (OT, Lower 10% 0.4% NR NR
et al (Makerere, Apr 2004 ctive 31%, 99, NNRTI months copies/mL n=454) 75% (threshold (for a (for a
[140] Ulago) - Jun Cohort Stage I 0.4% regimens (range (ITT, n=523) 400 copies) larger larger
(2007) 2005 Stage II 11% 285 - cohort cohort
Stage III 485 ) )
54% Stage days)
IV 34%
Charles Haiti Clinic NGO NGO No Initiated 1 146 Retrosp NR, 34%, 78% 12 VL < 50 49% (OT, n=79) Higher (OT) 19% 15% NR NR
et al (GHES ART Mar ective 129, Stage I NNRTI months copies/mL Lower (with (with
[133] KIO) 2003 - Cohort 12% Stage II regimens (threshold 50 media media
(2008) Dec and III 40% copies) n F/U n F/U
2005 Stage IV 18 18
49% mths) mths)
Blacher Kenya, Referral Public MOH No Initiated 3 661 Clinical 32, 100%, 41% 12 VL < 400 87% (OT, Higher (OT NR NR NR NR 4.8
et al Zambia Hospita ART May trial Stage I and previous months copies/mL n=563) 74% analysis) %
[108] l and 2005 - II 43% Stage sdNVP, (ITT, n=661) Lower
(2010) Clinics Jan 2007 III 49% 100% (threshold
Stage IV 8% NNRTI 400 copies)
regimens
Fatti et South Hospita Public MOH No Initiated 59 2920 Retrosp 34, 32%, 100% 12 VL < 400 87% (OT, Higher (OT 6.3%
al [134] Africa ls and and ART Dec 3 ective 114, Stage NNRTI months copies/mL n=6725) analysis)
(2010) (Western Clinics NGO 2004 - Cohort III and IV regimens Lower
Cape, (Absolu Dec 76% (threshold
Eastern te 2007 400 copies)
Cape, KZ- return
Natal, for kids)
Mpumalan
ga [not
IeDEA])
Hegazi The Clinic Public MOH No Initiated 1 147 Retrosp 36, 39%, 75% 12 VL < 100 75% (OT, n=79) Higher (OT
et al Gambia and ART Oct ective NR, NR NNRTI months copies/mL analysis)
[138] NGO 2005 - Cohort regimens Lower
(2010) (NIH Jan 2007 , 25% (threshold
study boosted 100 copies)
site) PI
regimens
Lester Kenya Hospita Public MOH No Initiated 3 538 RCT 37, 35%, 100% 12 VL < 400 71% (OT, Higher (OT 10.2% 8.2% NR 0.9% NR
et al (Nairobi l and ART May 161-168, NNRTI months copies/mL n=402), 53% analysis)
[144] [Pumwani, Clinics 2007 - Stage I 21%, regimens (ITT, n=533 Lower
(2010) Coptic Oct 2008 Stage II excludes TF out (threshold
Hope 23%, Stage from denom) 400 copies)
center], III 38%,
Kajiado) Stage IV 4%
Lyagob Uganda Resear Public DART No Initiated 2 300 RCT NR, NR, 100% 12 VL < 200 71% (OT, Higher (OT 6.3%
a et al (Kampala, ch (Trial) Trial Jan - (DART 108, Stage 3NRTI months copies/mL n=272), 64% analysis)
[145] Entebbe - Centers Oct 2004 substu III 51%, (AZT/3T (ITT, n=300) Lower
60
Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators
91
92
(2010) DART sub dy) Stage IV C/TDF) (threshold
study) 25% 400 copies)
As VL < 1000 77% (OT, Higher (OT 6.3% 47 /64 +ve
above copies/mL n=272), 69% analysis) VLs had
(ITT, n=300) genotype and
no baseline
HIVDR. 41/47
(87%) had an
NRTI
mutation
Moore Malawi Region Public MOH No Initiated 1 300 Prospe mean 36, 100% 12 VL < 400 83% (OT, Higher (OT 14.3% 2.7% 5.3% 5.3% NR
et al (Blantyre) al 2005 ctive 39%, mean NNRTI months copies/mL n=212), 62% analysis)
[58] Hospita cohort 157, Stage regimens (ITT, n=284 i.e. Lower
(2010) l IV 29% excludes TF out (threshold
from denom) 400 copies)
Muteve Sth Africa Hospita Public MOH No Initiated 16 3010 Retrosp 34-37, 22%, 100% 12 VL < 25 77% (OT, Higher (OT 10.9% 3.7% NR 1.4% NR
dzi et al (KZ- Natal l and ART Oct ective 91-128, NR NNRTI months copies/mL n=758) analysis)
[59] [not IeDEA- Clinics 2004 - Cohort regimens Lower
(2010) SA]) Sept (threshold 25
2007 copies)
Oyomo Asia Mixed Mixed Mixed NR Initiated 17 784 Prospe NR, 75%, 69% 12 VL < 400 79% (OT, n=204 Higher (OT
pito et (TAHOD) ART ctive NR, NR NNRTI months copies/mL from low income analysis)
al [150] after cohort regimens sites), 84% (OT, Lower
(2010) 2000 , 29% PI n=581 from high (threshold
regimens income sites) 400 copies)
, 2%
3NRTI
regimens
Zhou et Asia Mixed Mixed Mixed NR Recruite 18 1676 Prospe 36, 74%, 63% 12 VL < 400 82% (OT, Higher (OT
al [154] (TAHOD) d after ctive 140, CDC NNRTI months copies/mL n=1676. analysis)
(2010) 2003 cohort Stage A regimens Includes high Lower
(date of 58% Stage , 35% PI income sites) (threshold
ART B 6% Stage regimens 400 copies)
initiation C 38% , 2%
Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011
NR)
Notes: HC, healthcare; ART, antiretroviral therapy; WHO, World Health Organization; LTFU, lost to follow up; EWI, early warning indicator; TF, transfer; HIVDR, HIV
drug resistance; RCT, randomized clinical trial; NNRTI. Non-nucleoside reverse transcriptase inhibitors; VL, viral load; OT, on treatment; ITT, intention to treat; NR, not
reported; F/U, follow up; ZDV, zidovudine; VF, virological failure; MOH, ministry of health; NGO, non-governmental organization; MSF, medecines sans frontieres; mths,
months; PI, protease inhibitors; NRTI, nucleoside reverse transcriptase inhibitors; VL, viral load; 3NRTI, triple nucleoside reverse transcriptase inhibitors; EFV, efavirenz;
NVP, nevirapine; DOT, directly observed therapy; NA, not applicable;
61
Table
10.
EWI
8
(Virological
suppression)
Abstracts
Baseline
Study
features
ART
Proportion
definition
will
(median
Proportion
HC
regimens
Study
meeting
likely
lead
to
age,
%
Time
Study
meeting
Translate
VL
%
to
Association
Author
facility,
Start
(all
ART
definition
study
lower
or
%
%
Patient
Dates
Sites
Study
male,
since
definition
of
study
failure
/
%
%
2nd
with
HIVDR
and
Country
HC
ART
nave
at
of
VL
definition
higher
ART
TF
pays
observed
(n)
Design
median
ART
VL
definition
of
rebound
into
Died
LTFU
line
outcome
meeting
setting,
(n)
baseline
failure
/
of
VL
estimates
of
stop
out
CD4,
start
suppression
VL
VL
suppression
ART
Provider
unless
rebound
failure
/
VL
WHO
suppression
stated)
rebound
suppression
clinical
than
EWI
stage)
Marconi
Argentina
NR,
NR,
No
NR
1
104
Retrosp 35,
100%
1
NR
NR
NR
7.7%
(OT,
92.3%
(OT,
Higher
(OT),
NR
NR
NR
NR
NR
All
patients
et
al
(Rosario)
NR
ective
"mostly
HAART
year
n=104)
n=104)
Unclear
(no
who
had
VF
[162]
IAS
cohort
male",
threshold
had
baseline
2010
NR,
NR
defined)
HIVDR
Kiragga
Uganda
Hospital,
No
NR
1
559
Prospect NR,
100%
12
NR
NR
NR
24.9%
(OT,
75.1%
(OT,
Higher
(OT),
NR
NR
NR
NR
NR
et
al
(IDI
cohort)
Mixed,
ive
71.2%,
NNRTI
mths
n=105)
n=105)
Lower
(all
had
[160]
IAS
Mixed
cohort
regimen
immunolgical
2010
failure)
Unclear
(no
threshold
defined)
Chasom Thailand
Mixed,
No
Initiated
6
304
Retrosp 38;
1.2:1
100%
12
NR
NR
>
1000
5.9%
(OT,
94.1%
(OT,
Higher
(OT)
8.9%
NR
NR
NR
NR
1of
5
with
bat
et
al
(Nonthabu Public,
Feb
Sep
ective
M:F;
56;
NNRTI
mths
copies/mL
n=269)
n=269),
baseline
[78]
IAS
ri,
Chiang
MOH
2006
cohort
NR
regimen
83.2%
(ITT,
HIVDR
had
2010
Rai,
n=304
[include
VF
at
1
year.
Lumpang,
those
who
died
15
of
264
Lumphun)
and
remaining
with
no
2%])
baseline
HIVDR
had
VF
at
1
yr.
(7
of
the
15
developed
HIVDR)
Crabtree Mexico
Clinic
No
2001- 1
348
Retrosp 33,
72%,
100%
12
NR
NR
any
VL
>
50
7.5%
(OT,
93.3%
(OT,
Higher
(OT)
NR
at
NR
at
NR
NR
NR
-Ramirez
(INCMNS 2007
ective
NR,
NR
HAART
mths
copies/mL
n=348)
n=348)
Lower
12
12
et
al
Z),
Public,
cohort
from
6
-
12
(threshold
50
mths
mths
[157]
IAS
MOH
months
copies)
2010
Scarsi
et
Nigeria
NR,
NR,
No
Jan
2006
-
NR
5894
Retrosp 34.2,
74.6%
48
NR
NR
>1000
10.1%
(OT,
89.9%
(OT,
Higher
(OT)
19.6 See
NR
See
al
[167]
(PEPFAR
NR
Dec
2007
ective
24.8%,
AZT/3TC/ week copies/mL
n=2366),
n=2366)
Lower
(VL
%
died
died
IAS
2010
programs)
cohort
NR,
NR
NVP;
s
at
24
AND
29.7%
(ITT,
70.3%
(ITT,
outcome
at
6
died
25.4%
48
weeks
n=?
Include
n=?)
and
12
LTFU,
TDF/3TC/ 19.6%
months)
or
TF
NVP
(n=5894)
out
to
OT
data)
Stafford
Uganda,
NR,
AIDS
No
NR
NR
737
Cross- NR
100%
9-15
NR
88.1%
(OT,
NR
NR
NR
Higher
(OT)
NR
NR
NR
NR
NR
et
al
Zambia
relief
sectiona NNRTI
mths
n=737)
[168]
IAS
(IHV)
sites,
NR
l
regimens
2009
Chang
et
Uganda
Clinic,
NR,
No
May
2006
15
1338
RCT
NR
NR
48
NR
NR
>400
10.6%
(OT,
89.4%
(OT,
Higher
(OT)
NR
NR
NR
NR
NR
al
[156]
(Rakai)
NR
-
June
week copies/ml
n=606)
n=606)
Lower
IAS
2009
2008
s
(threshold
58
Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators
93
94
400
copies)
Calmy
et
IeDEA
of
Mixed,
No
NR
NR
3020
Retrosp 34,
37%,
96%
12
<
500
89%
(OT,
NR
NR
NR
Higher
(OT)
NR
NR
NR
NR
NR
al
[155]
ART-LINC
Mixed,
ective
91,
NR
NNRTI
mont copies/mL
n=3020)
Lower
IAS
2009
countries
Mixed
cohort
regimen
hs
(threshold
500
copies)
Messou
Cote
Clinic,
NR,
No
Feb
2006
3
1545
Prospect NR
100%
12
NR
NR
300
25%
(OT,
75.0%
(OT,
lower
39.1 NR
NR
NR
NR
51%
with
VF
et
al
d'Ivoire
NR
-
May
ive
NNRTI
mont copies/ml
n=928)
n=928)
(threshold
%
had
1
[164]
2007
cohort
regimen
hs
300
copies)
mutation
CROI
(NNRTI
2010
91.5%,
3TC/FTC
69%
and
ZDV
and/or
d4T
9.4%).
McIntire
7
African
NR,
NR,
NR
NR
NR
500
RCT
34,
NR,
50%
48
NR
NR
<1
log
VL
14%
(ITT,
86%
(ITT,
Higher
(RCT)
NR
NR
NR
NR
NR
et
al
countries
NR
(OCTAN 121,
NR
NNRTI
week drop
at
12
n=500)
n=500)
Lower
[163]
E
II)
regimen,
s
weeks
,
(threshold
CROI
50%
or
>
400
400
copies
2010
LPV/r
copies/mL
and
need
for
regimen
at
or
after
early
VL
drop)
24
weeks
Ratsela
South
NR,
NR,
No
2004- 6
1771
Random NR,
NR,
PI
or
12
<
400
66%
(ITT,
NR
NR
NR
Lower
NR
NR
NR
NR
NR
et
al
Africa
NR
2008
ized
106,
NR
NNRTI
mths
copies/mL
n=1771)
(threshold
at
48
[165]
(Military)
factorial
regimen
400
copies)
week
CROI
trial
s
2009
Geng
et
Uganda
Clinic,
No
June
6
350
Prospect NR
100%
1
NR
NR
400
8.8%
(OT,
91.2%
(OT,
Higher
(VF
NR
NR
NR
NR
NR
al
[159]
(Mbarara
Mixed,
2005-Aug
ive
NNRTI
year
copies
at
3
n=350
n=350)
threshold
CROI
UARTO
MOH
2008
cohort
or
6
mths
[cumulativ 10,000
2009
cohort)
followed
e
copies/mL,
by
>10,000
incidence])
initial
VL
copies/mL
suppression)
Lower
(cumulative
Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011
incidence
of
VF)
Lockman
Botswana
NR,
NR,
No
NR
1
178
RCT
NR,
0%,
100%
12
NR
NR
>
400
7.9%
(ITT,
92.1%
(ITT,
Higher
(RCT)
NR
NR
NR
NR
NR
et
al
(Mashi
NR
NR,
NR
NNRTI
nths
copies/mL
n=178)
n=178)
Lower
[161]
Study)
regimen
(threshold
CROI
400
copies,
2009
cumulative
incidence
of
VF)
Bertagno Africa
NR,
NR
2002
-
6
829
Prospect NR
NR
12
WHO
EWI
90%
(OT,
higher
(OT)
9.2%
12.9 0.8 14.5 0.2 Of
the
10%
lio
et
al
(many
Public,
2010
ive
mont definition
n=460)
%
%
%
%
(n=46)
not
[76]
countries)
MOH
cohort
hs
(threshold
suppressed,
CROI
NR)
43%
(i.e.
2011
n=20)
had
HIVDR
Fox
et
al
IeDEA-Sth
NR,
NR,
NR
NR
8
44,20 Retrosp NR,
41%,
100%
12
2
VLs
(
2
96%
(OT,
Higher
(OT,
NR
NR
NR
NR
NR
[158]
Africa
NR
progr 4
ective
121,
>
NNRTI
mont weeks
apart)
n=32525)
need
2
CROI
ams
cohort
65%
regimen
hs
<
400
copies
positive
viral
2011
Stage
after
24
loads)
III/IV
weeks
ART
Lower
(lower
VL
threshold)
59
As
above
`
2
VLs
(
2
96%
(OT,
Higher
(OT,
NR
NR
NR
NR
weeks
apart)
n=32603)
need
2
<
1000
positive
viral
copies
after
loads)
24
weeks
ART
As
above
2
VLs
(
2
97%
(OT,
Higher
(OT,
NR
NR
NR
NR
weeks
apart)
n=32759)
need
2
<
5000
positive
viral
copies
after
loads,
higher
24
weeks
VL
threshold)
ART
As
above
2
VLs
(
2
98%
(OT,
Higher
(OT,
NR
NR
NR
NR
weeks
apart)
n=32847)
need
2
<
10000
positive
viral
copies
after
loads,
higher
24
weeks
VL
threshold)
ART
Wester
Botswana
NR,
NR,
NR
NR
NR
434
RCT
34,
32%,
100%
12
NR
97%
(OT,
Higher
(OT)
5.5%
NR
NR
NR
NR
et
al
NR
199,
NR
NNRTI
mont n=?
410
i.e.
[169]
regimen
hs
434
less
CROI
deaths)
2011
Reynolds
Uganda
Institute,
NR
2004
-
1
559
Prospect NR,
NR,
Regimens
12
VL
<
400
88%
(OT,
Higher
(OT)
NR
NR
NR
NR
NR
HIVDR
et
al
(Kampala
-
NR,
NR
2008
ive
86-96,
NR
NR
mont copies/mL
n=441)
Lower
outcomes
[166]
IDI)
cohort
hs
69%
(ITT,
(threshold
reported
CROI
n=559)
400
copies)
after
3
years
2011
of
ART
Notes:
HC,
healthcare;
ART,
antiretroviral
therapy;
WHO,
World
Health
Organization;
LTFU,
lost
to
F/U;
EWI,
early
warning
indicator;
TF,
transfer;
HIVDR,
HIV
drug
resistance;
HAART,
highly
active
antiretroviral
therapy;
NNRTI.
Non-nucleoside
reverse
transcriptase
inhibitors;
mths,
months;
VL,
viral
load;
OT,
on
treatment;
ITT,
intention
to
treat;
NR,
not
reported;
F/U,
follow
up;
MOH,
ministry
of
health;
RCT,
randomized
clinical
trial;
VF,
virological
failure
60
Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators
95
Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011
a
Includes papers and abstracts
b
If proportions reported for 2 different thresholds in the one cohort then data for the threshold closest to
1000 copies/mL used
c
Same analysis excluding 1 abstract (Fox et al [158]) accounting for 32603 subjects resulted in weighted
mean 85.8%
d
Same analysis excluding 1 abstract (Fox et al [158]) accounting for 32603 subjects resulted in weighted
mean 88.9%
e
Same analysis excluding 1 abstract (Fox et al [158]) accounting for 32603 subjects resulted in weighted
mean 85.3%
f
Same analysis excluding 1 abstract (Fox et al [158]) accounting for 32603 subjects resulted in weighted
mean 81.6%
g
An additional abstract (Scarsi et al [167]) accounting for 5894 subjects was excluded from this analysis.
When included, weighted mean for the 5 cohorts (n=7095) was 71.4%
65
96
Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators
APPENDIX 1
66
97
Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011
APPENDIX 2
67
98
Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators
APPENDIX 3
68
99
Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011
APPENDIX 4
69
100
Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators
APPENDIX 5
70
101
Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011
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138. Hegazi A, Bailey RL, Ahadzie B, Alabi A, Peterson K. Literacy, education and adherence to
antiretroviral therapy in The Gambia. AIDS Care 2010 Nov;22(11):1340-5.
139. Idoko JA, Agbaji O, Agaba P, et al. Direct observation therapy-highly active antiretroviral therapy
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140. Kamya MR, Mayanja-Kizza H, Kambugu A, et al. Predictors of long-term viral failure among
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2007 Oct 1;46(2):187-93.
141. Kouanfack C, Montavon C, Laurent C, et al. Low levels of antiretroviral-resistant HIV infection in a
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to monitor antiretroviral treatment and adequacy with the WHO recommendation for second-line
treatment. Clin Infect Dis 2009 May 1;48(9):1318-22.
142. Landman R, Poupard M, Diallo M, et al. Tenofovir-emtricitabine-efavirenz in HIV-I-infected adults
in Senegal: a 96-week pilot trial in treatment-naive patients. J Int Assoc Physicians AIDS Care
(Chic Ill) 2009 Nov-Dec;8(6):379-84.
143. Laurent C, Ngom Gueye NF, Ndour CT, et al. Long-term benefits of highly active antiretroviral
therapy in Senegalese HIV-1-infected adults. Journal of Acquired Immune Deficiency Syndromes:
JAIDS 2005 Jan 1;38(1):14-7.
144. Lester RT, Ritvo P, Mills EJ, et al. Effects of a mobile phone short message service on
antiretroviral treatment adherence in Kenya (WelTel Kenya1): a randomised trial. Lancet 2010 Nov
27;376(9755):1838-45.
145. Lyagoba F, Dunn DT, Pillay D, et al. Evolution of drug resistance during 48 weeks of
zidovudine/lamivudine/tenofovir in the absence of real-time viral load monitoring. Journal of
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146. Mujugira A, Wester CW, Kim S, et al. Patients with advanced HIV type 1 infection initiating
antiretroviral therapy in Botswana: treatment response and mortality. AIDS Research & Human
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147. Nachega JB, Chaisson RE, Goliath R, et al. Randomized controlled trial of trained patient-
nominated treatment supporters providing partial directly observed antiretroviral therapy. AIDS
2010 Jun 1;24(9):1273-80.
148. Nachega JB, Hislop M, Nguyen H, et al. Antiretroviral therapy adherence, virologic and
immunologic outcomes in adolescents compared with adults in southern Africa. J Acquir Immune
Defic Syndr 2009 May 1;51(1):65-71.
149. Ndembi N, Goodall RL, Dunn DT, et al. Viral rebound and emergence of drug resistance in the
absence of viral load testing: a randomized comparison between zidovudine-lamivudine plus
Nevirapine and zidovudine-lamivudine plus Abacavir. J Infect Dis 2010 Jan 1;201(1):106-13.
150. Oyomopito R, Lee MP, Phanuphak P, et al. Measures of site resourcing predict virologic
suppression, immunologic response and HIV disease progression following highly active
antiretroviral therapy (HAART) in the TREAT Asia HIV Observational Database (TAHOD). HIV
Medicine 2010 Sep;11(8):519-29.
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151. Ramadhani HO, Thielman NM, Landman KZ, et al. Predictors of incomplete adherence, virologic
failure, and antiviral drug resistance among HIV-infected adults receiving antiretroviral therapy in
Tanzania. Clin Infect Dis 2007 Dec 1;45(11):1492-8.
152. Seyler C, Anglaret X, Dakoury-Dogbo N, et al. Medium-term survival, morbidity and
immunovirological evolution in HIV-infected adults receiving antiretroviral therapy, Abidjan, Cote
d'Ivoire. Antiviral Therapy 2003 Oct;8(5):385-93.
153. Vanni T, Morejon KM, Santana RC, et al. Comparison of the effectiveness of initial combined
antiretroviral therapy with nelfinavir or efavirenz at a university-based outpatient service in Brazil.
Brazilian Journal of Medical & Biological Research 2007 Jul;40(7):963-9.
154. Zhou J, Sirisanthana T, Kiertiburanakul S, et al. Trends in CD4 counts in HIV-infected patients with
HIV viral load monitoring while on combination antiretroviral treatment: results from The TREAT
Asia HIV Observational Database. BMC Infectious Diseases 2010;10:361.
155. Calmy A, Balestre E, Boulle A, et al. Prediction of CD4 cell count slope in patients with virological
failure to first-line of antiretroviral combinations in resource-limited settings Available at:
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156. Chang L, Kagaayi J, Nakigozi G, et al. Effect of peer health workers and a mobile phone support
intervention on AIDS care in Rakai, Uganda: a cluster-randomized trial. Available at:
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157. Crabtree-Ramrez B, Caro-Vega Y, Sierra-Madero J. Late diagnosis of HIV infection results in a
higher mortality but not in virological failure after starting HAART. Available at:
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158. Fox M, van Cutsem G, Giddy J, et al. Rates and Predictors of Failure of First-line ART and Switch
to Second-line ART in South Africa: The IeDEA Southern Africa Collaboration. Available at:
http://www.retroconference.org/2011/Abstracts/41982.htm. Accessed 7/6/2011.
159. Geng E, Emenyonu N, Hunt P, et al. Frequent Occurrence of Virologic Re-suppression without
Change in Therapy after High-level Virologic Rebound in Africa. Available at:
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160. Kiragga A, Castelnuovo B, Kamya M, Moore R, Manabe Y. WHO immunologic criteria are more
predictive of treatment failure in patients from a Western cohort compared to a cohort in resource
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http://www.iasociety.org/Default.aspx?pageId=11&abstractId=200736853. Accessed 11/23/2010.
161. Lockman S, Smeaton L, Ogwu A, et al. Long-term Maternal and Pediatric Virologic Outcomes on
Nevirapine-based HAART following Receipt of Peripartum Single-dose Nevirapine or Placebo,
Botswana. Available at: http://www.retroconference.org/2009/Abstracts/36058.htm. Accessed
11/23/2010.
162. Marconi L, Parenti P, Weskamp M, Salztman A, Palazzi J, Lupo S. Start of HAART with and
without genotypic resistance testing in Argentina. Available at:
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163. McIntyre J, Hughes M, Mellors J, et al. Efficacy of ART with NVP+TDF/FTC vs LPV/r+TDF/FTC
among Antiretroviral-nave Women in Africa: OCTANE Trial 2/ACTG A5208. Available at:
http://www.retroconference.org/2010/Abstracts/39798.htm. Accessed 11/23/2010.
164. Messou E, Marie-Laure Chaix, Gabillard D, et al. Strong Association between Medication
Possession Ratio and Early Virological Outcomes in Adults on ART in Cte dIvoire. Available at:
http://www.retroconference.org/2010/Abstracts/38493.htm. Accessed 11/23/2010.
165. Ratsela A, Polis M. Phidisa II: A Randomized 2x2 Factorial Trial Comparing Initial Therapy of
Efavirenz with Lopinavir/Ritonavir and Zidovudine + Didanosine with Stavudine + Lamivudine in
Treatment-nave HIV-infected Persons with < 200 CD4+ Cells/mm3 or a Prior AIDS Diagnosis.
Available at: http://www.retroconference.org/2009/Abstracts/34300.htm. Accessed 11/23/2010.
80
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166. Reynolds S, Sendagire H, Newell K, et al. Routine VLM Reduces the Rate of Accumulated
Genotypic Resistance to Commonly Used ART in Uganda. Available at:
http://www.retroconference.org/2011/Abstracts/41522.htm. Accessed 7/6/2011.
167. Scarsi K, Darin K, Rawizza H, et al. TDF-3TC-NVP is inferior to AZT-3TC-NVP in a large ART
program in Nigeria. Available at:
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168. Stafford K, Hossain M, Mesubi R, et al. Viral suppression outcomes of patients using nevirapine in
combination with tenofovir and a cytosine analog ( 3TC or FTC) as a first line regimen in resource
limited settings. Available at:
http://www.iasociety.org/Default.aspx?pageId=11&abstractId=200721588. Accessed 11/23/2010.
169. Wester W, Blevins M, Bussmann H, et al. ZDV/3TC vs d4T/3TC Outcomes among HIV-1-infected
Adults Receiving First-line Combination ART in Botswana: Results from a Clinical Trial. Available
at: http://www.retroconference.org/2011/Abstracts/42293.htm. Accessed 7/6/2011.
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Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators
APPENDIX 6
Methods
Similar search strategies were performed in Ovid
Medline for the following EWIs
EWI 2 and 3 (Lost to follow up and retention on
first-line ART)
EWI 4 (on-time ARV pick-up)
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Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011
Relevant Articles
EWI 2 AND 3:Lost to Follow-up and Retention on ART
6 of16
EWI 4: On time ARV pick up
N=5; 1 Review with additional references-
Final N=12
EWI 5: ART clinic appointment keeping
0 of 8
EWI 6: ARV drug stockouts
N=2 of 6
EWI 8: Virological suppression (N=85)
N=23
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Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators
3-7 year olds initiating ART with advanced disease; regimens appropriate
115
Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011
Fenner
et
al
(2010)
Median
F/U:
Not
aeend
clinic
for
>
6
9.6%
17.3
mos
(Max
25.7
mos)
months
unAl
study
site
closure
Reddi
et
al
(2007)
Median
F/U:8
mos
No
communicaAon
and
0%
(IQR
3.5-13.5)
missing
at
least
3
monthly
follow-up
appointments/or
failure
to
collect
medicaAon
KIDS-ART-LINC
CollaboraAon
Median
F/U-20.3
mos
Not
aeended
clinic
for
6
10.3%
(2008)
(IQR;11.7-27.9)
mos
months
before
closure
of
the
local
database,
known
to
not
died
or
moved
Barth
RE.(2008)
12
months
aier
HAART
NR
17%
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Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators
Evans-Gilbert
et
al.
(2004)
Jamaica
37
6
yrs;
54.1%;
NR;
CDC
Stage
C
59.5%,
Stage
B
21.6%,
NR
ABSTRACT
Stage
A
16.2%,
Stage
N
2.7%
Fassinou
et
al.
(2004)
Cote
dIvoire
78
7.2
yrs;
56.4%;
<
2
yrs
402,
2-5
yrs
266,
>5
yrs
145;
NNRTI
22%,
PI
78%
Clinical
Stage
C
12,8%,
Stage
B
57.6%,
Stage
A
26.9%,
Stage
N
2.6%
Safreed-Horman
et
al.
Thailand
29
6.1
yrs;
52%;
12%;
NR
(2007)
Bikaako-Kajura
et
al.
(2006)
Uganda
42
12
yrs;
48%;
NR;
NR
NNRTI
Nyandiko et al. (2006) Kenya 279 6 yrs; 51%; 176; CDC Stage B or C 75% NNRTI
Reddi
et
al.
(2007)
South
Africa
151
5.7
yr;
49%;
7.4%;
WHO
Stage
4
22.5%,
Stage
3
NNRTI
71%,
PI
22%
47.7%,
Stage
2
12.6%,
Stage
1
17.2%
Eley
et
al.
(2004)
ABSTRACT
South
Africa
17
NR;
NR;
NR;
NR
NR
Myung et al. (2007) Cambodia 95 Mean 5.5 yrs; 57%; 255; NR NNRTI
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Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011
Dura6on
of
adherence
Type
of
pharmacy
adherence
measure
and
Propor6on
who
were
100%
Author
assessment
(months
over
study
deni6on
adherent
using
study
deni6on
which
assessed)
Nabukeera-Barungi
et
al
NR
Clinic
pill
counts,
3day
self
report,
clinic-based
>=
95%:
72-94%
(2007)
pill
counts,home
based
unannounced
pill
counts
(89
%,
94.1%,72%)
Byakika-Tusiime
et
al
ON-HAART:One
Unannounced
pill
count,
3-day
self
report,
30
On-HAART
mean:
88100
(2009)
assessment;
day
visual
analogue
scale
87.7/100/100
)
HAART
nave:
6
months
IniAaAng
HAART;mean:
98-100
(100/98.1/97.8
)
Plipat
et
al
(2007)
12
months
Pill
count,
calendar
method,
recording
missed
Mean
at
12
months:92%
ABSTRACT
(2,
6,
12
months)
doses,
physician
assessment
(99%,100%,97%)
Evans-Gilbert
et
al.
(2004)
6
months
Caregiver
Reports,
Pharmacy
Records
95%
ABSTRACT
Fassinou
et
al.
(2004)
21
months
(median)
Caregiver
Reports
79.5%
Natu
et
al.
(2007)
NR
Clinic
Visit
Adherence
88%
of
children
with
>85%
ABSTRACT
Outcome of interest Cohorts (n) Samples size (n) Mean of es6mates (%)
Average 89
118
Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators
Weigel
et
al
(2009)
Public
Paid
for
tx
Sept
2002- 1
98
months;
51%;
NR;
WHO
NNRTI
Clinic
and
peds
Jan
2004
N=47
Stage
3
53%,
Stage
2
47%
Malawi
formula6on
Prospec6ve
Libamba
et
al
(2007)
Public
No
2004-2005
60
NR*;
NR*;
NR*;
NR*
NR
Clinic
N=1999
Malawi
Retrospec6ve
119
Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011
Associa6ons
Propor6on
with
Time
since
Study
deni6on
of
ARV
mee6ng
study
Study
(year)
Sites
(n)
virological
or
start
of
ART
stock
out
deni6on
of
ARV
clinical
stock
out
outcomes
120
Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators
<1000 (N=1)
<400 (N=12)*
<50 (N=6)
<25 (N=2)
121
Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011
122
Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators
Limitations/Special Considerations
Little data on adherence and virologic suppression
in infants and children <three years of age
Little data on adolescence
123
Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011
All (unwtd) 147 40.8 140 19.3 21.5 (11.2, 31.8) <0.001
All (wtd)* 147 40.8 140 19.3 21.5 (11.2, 31.8) <0.001
124
Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators
Thank you
Acknowledgements:
Katie Lobner, MLIS; Welch Library; Johns Hopkins
School of Medicine
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Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011
APPENDIX 7
WHAT IF YOU CANT SAMPLE ALL CLINICS? SAMPLE SOME CLINICS!
Representative sample
Which clinics to sample?
Sample to include at least one examples of each mode / level of
delivery
Probability of inclusion approximately proportional to the
frequency of each mode / level of delivery (improves over time).
Where to sample?
Need a spatially representative sample if any reason to believe that
performance is likely to be geographically patchy. For example:
ARV stock-outs may be more frequent in outlying areas
Patient churn may be more likely in some urban sites
Additionally sample should be efficient even with small numbers
Type of sample
Sample to include all types of clinics
Purposive / hierarchical / stratified (i.e. fixed / program effects)
sample using an organogram of a program ...
Nurse-led
Primary
CO-led
URBAN Secondary
Tertiary
PROGRAM
Nurse-led
Primary
CO-led
RURAL
Cottage Hospital
Secondary
District
General Hospital
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Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators
The sample
First round :
At least one site from each end category / pathway is required :
All modes of delivery represented
Additional sites selected with probability proportional to the
number of sites at each end category / pathway
Subsequent rounds :
Previous round sample maintained and expanded with (e.g.)
additional sites selected with probability proportional to the number
of sites at each end category / pathway.
Process continues until all sites report EWIs it takes as long as it
takes but we get there in the end
URBAN Secondary
Tertiary
PROGRAM
Nurse-led
Primary
CO-led
RURAL
Cottage Hospital
Secondary
District
General Hospital
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Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011
APPENDIX 8
The sampling strategy is based on calculating a minimum sample size for each indicator at each site, based on
the number of eligible patients for each EWI. There are two types of 'eligible patients' -- those that initiated ART
for the first time, and those that were on ART (which includes both patients initiating ART and those on ART).
Table 2 presents the definition of eligible patients, by EWI.
? Patients on ART
(includes patients initiating ART, continuing ART
and transferring in on ART)
For EWIs xxxxx, the number of eligible patients at each site is the number of patients who initiated ART during
the 12-month period to be monitored. That is, if the EWI sample start date is in 2008, the sample size is
based on the number of patients who initiated ART at the site in 2008.
For EWIs xxxx, the number of eligible patients at each site is the number of patients on ART during the 12-month
period to be monitored, regardless of whether they initiated ART in that year or in a prior year. The simplest
method to arrive at this number is to use the number of patients on ART at the site at the midpoint of the
year. An alternative method is to take the number on ART on 1 January of the selected year, add this number
to the number on ART on 31 December of the selected year, and divide by two. This simple calculation will
give you the mean number of patients on ART during the year.
Using the annual number of eligible patients (Table 1) the sample size can be calculated using Table 3.
128
Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators
175 All
76110 75
111199 100
200250 110
251299 120
300350 130
351400 135
401450 140
451550 145
551700 155
701850 160
8511600 175
16012150 180
21514340 200
43415670 210
567110000 215
Note that separate sample size calculations must be made for each group of eligible patients (those initiating
ART and those on ART) at the site. The sample size for EWIs based on patients initiating ART will be lower than
those for EWIs based on patients on ART.
The sample sizes in Table 2 are the minimum sample sizes required to achieve a 95% confidence interval of
7%. If greater numbers can be abstracted, a more precise estimate will be obtained.
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Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011
Normally EWI should be monitored annually. However, countries with adequate resources may choose to
monitor EWI more frequently, for example by month or quarter, provided that the sample size used for each time
period does not fall below the minimum required sample size
Countries may choose to integrate EWI monitoring into other routine programme monitoring and evaluation
activities, which have random sampling strategies that differ from the sampling methodology presented by the
WHO. In such cases, the country should consult the regional HIVDR focal point and the WHO HIVDR team at
Headquarters (Geneva) to discuss options and feasibility.
WHO revised its guidance on sampling in EWI monitoring in November 2009 to include the use of a minimum
sample size for each indicator.
Under previous sampling guidance, countries selected EWI denominator periods rather than absolute number of
patients (sample size).
The new sampling guidance significantly decreases the burden of data abstraction and supports the calculation
of narrower confidence intervals.
130