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Establishing Multicenter… Alula MT et al.
DOI: http://dx.doi.org/10.4314/ejhs.v267i1.2S
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ORIGINAL ARTICLE
Establishing a Multicenter Longitudinal Clinical Cohort Study in
Ethiopia: Advanced Clinical Monitoring of Antiretroviral Treatment
Project
Alula M. Teklu1*, Eyuel Tsegaye1, Daniel Fekade2, Abraham Hailemelak3, William Weiss4, Elham
Hassen1, Nicole Simmons4, Solomon Zewdu1, Yifru Berhan5, Assefa Getachew6, Tesfalem Hagos9,
Achamyeleh Alebachew10, Melake Damena7, Yohannes Sitotaw, Yibeltal Assefa8, Girmay Medhin2,
Andrea Ruff4
OPEN ACCESS
Citation: Alula M. Teklu, Eyuel Tsegaye,
Daniel Fekade, et al. Establishing a
multicenter longitudinal Clinical Cohort
Study in Ethiopia: Advanced Clinical
Monitoring of Antiretroviral Treatment
Project. Ethiop J Health Sci
2017;27(si1):3-16. doi:
http://dx.doi.org/10.4314/ejhs.v27i1.2S.
Received: February 1, 2016
Accepted: August 12, 2016
Published: March 15, 2017
Copyright: © 2017 Alula MT et al. This
is an open access article distributed under
the terms of the Creative Commons
Attribution License, which permits
unrestricted use, distribution, and
reproduction in any medium, provided the
original author and source are credited.
Funding: Center for Disease Control and
Prevention (CDC)
Competing Interests: The authors
declare that this manuscript was approved
by all authors in its form and that no
competing interest exists.
Affiliation and Correspondence:
1ACM Project Implementation Office
(ACM), Addis Ababa, Ethiopia
2Addis Ababa University, Faculty of
Medicine, Addis Ababa, Ethiopia
3Jimma University, College of Health
Sciences, Jimma, Ethiopia
4John Hopkins Bloomberg School of
Public Health, Baltimore, United States
of America
5Hawassa University, College of Health
Sciences, Hawassa, Ethiopia
6Gondar University, College of Health
Sciences, Gondar, Ethiopia
7Haramaya University, College of
Health Sciences, Haramaya, Ethiopia
8Ethiopian Public Health Institute
9Mekelle University, College of Health
Sciences, Mekelle, Ethiopia
10Federal HIV Prevention and Control
Office of Ethiopia
*Alula M. Teklu, E-mail:
ateklu72@gmail.com
ABSTRACT
Background: The purpose of this paper is to describe the
establishment of the Advanced Clinical Monitoring of ART Project
in Ethiopia for monitoring and evaluation of the longitudinal
effectiveness of the ART program and to show the opportunities it
presents. This cohort was established in response to the 2005 call
by WHO for establishing additional mechanisms for stronger
monitoring of ART and the need for creating the platform to
generate evidence to guide the care given for the ever increasing
number of patients on ART in Ethiopia.
Method: A participatory and multi-stage process which started
from a consensus building workshop and steered by a mother
protocol as well as guiding documents which dictated the degree of
engagement and expectations was followed. The primary and
secondary aims of the study were agreed upon. A multi-site
longitudinal observational clinical cohort was established by a
consortium of stakeholders including seven Ethiopian medical
schools and their affiliated referral hospitals, John Hopkins
University, Ethiopian Public Health Institute, Ministry of Science
and Technology, US Centers for Disease Prevention and Control -
CDC-Ethiopia, and the Federal Ministry of Health. Adult and
adolescent cohorts covering the age range of 14+ years) and
pediatric cohorts covering those below age 14 years were the two
main cohorts. During the initial recruitment of these cohorts
information was extracted from existing documents for a total of
2,100 adult participants. In parallel, a prospective cohort of 1,400
adult and adolescent patients were enrolled for ART initiation and
follow-up. Using similar recruitment procedures, a total of 120
children were enrolled in each of retrospective and prospective
cohorts. Replacement of participants were made in subsequent
years based on lost follow up and death rates to maintain adequacy
of the sample to be followed-up.
Achievements: Between January 2005 and August 2013 a total of
4,339 patients were followed for a median of 41.6 months and data
on demographic characteristics, baseline and ongoing clinical
Ethiop J Health Sci. Vol. 27, Special issue No. 1 March 2017
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features, hospitalization history, medication and
laboratory information were collected. 39,762
aliquots and 25,515 specimens of plasma and dry-
blood-spots respectively were obtained and stored
longitudinally from October 2009 to August 2013.
The project created a research platform for
researchers, policy and decision makers.
Moreover, it encouraged local and international
investigators to identify and answer clinically and
programmatically relevant research questions
using the available data and specimens. Calls for
concept notes paired with multiple trainings to
stimulate investigators to conduct analyses further
boosted the potential for doing research.
Conclusions: A comprehensive and resourceful
mechanism for scientific inquiry was established
to support the national HIV/ART program. With
meaningful involvement and defined roles,
establishment of a study, which involved multiple
institutions and investigators, was possible. Since
ACM is the largest multi-site clinical cohort of
patients on antiretroviral treatment in Ethiopia---
which can be used for research and for improving
clinical management---considering options to
sustain the project is crucial.
Key Words: Ethiopia, HIV clinical cohort,
Antiretroviral therapy, Establishing Longitudinal
Cohort Study, ART Monitoring and Evaluation
INTRODUCTION
The Ethiopian government began a limited program
of making antiretroviral therapy (ART) available for
a fee in 2003(1). In early 2005, ART was made
available nationwide without payment, with support
from the Ethiopian government, the U.S. President’s
Emergency Program for AIDS Relief (PEPFAR),
and the Global Fund to Fight AIDS, Tuberculosis
and Malaria(2).
The prevalence of HIV in 2014 was 1.2% (3) and
the incidence rate was reported as 15,000 by
2016(4).With 79.0% coverage of eligible patients,
Ethiopia had put 492,649 patients on ART by the
end of 2013(5). The PEPFAR program provided
technical and financial assistance to support the
rapid nation-wide scale up of free ART(6). Ethiopia
used the WHO consolidated guideline of ART for
treatment and preventing HIV infection (7)
The introduction of free ART was paired with
introduction of monitoring and evaluation (M&E)
tools(8) to routinely track key program performance
and outcome indicators. This routine M&E system
provided limited and primarily aggregated
information about the effectiveness of antiretroviral
treatment. The data were not sufficiently detailed to
explore important demographic, clinical, laboratory
or pharmaceutical determinants of treatment
effectiveness.
Moreover, a WHO consultation on
development of a Standardized ARV Treatment
Outcome Monitoring System held in October, 2005
called for the development of a standardized
outcome monitoring system that would provide
additional information on treatment program
success at facility, subnational and national levels.
Consequently, a study allowing the detailed
monitoring of a cohort of patients participating in
the national free ART program at the referral
hospitals of seven Ethiopian university medical
schools was initiated. The Advanced Clinical
Monitoring of ART in Ethiopia study (ACM ) was
designed to provide the platform for advanced
monitoring of the ART program in Ethiopia..
Longitudinal cohort studies of HIV/AIDS
patients in a clinic setting have been critical in
fostering our understanding both of the natural
history of HIV disease and of the effectiveness of
treatment in a real-world setting.
The purpose of ACM was to provide
comprehensive data about the study cohort, and to
make these data available to health care providers,
hospital and clinic managers, researchers, national
and regional health officials and other policy
makers, enabling on-going improvements in
prevention and treatment of HIV in Ethiopia based
on critical analysis of data/specimens through
research.
The objectives of the ACM included the
following: supporting the Ethiopian antiretroviral
treatment program with the intention of improving
ART delivery by establishing a multi-site patient
registry, cohort database and specimen repository,
supporting the successful implementation of ART
programs at each participating hospital by providing
information that enable better patient level care, and
clinic management; and, supporting the national
ART program by providing detailed information
about care processes, treatment adherence, virologic
indicators and patient outcomes from the selected
sites. The project also intended to facilitate
operational research to refine national and
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international implementation strategies for ART
program.
METHODS
The cohort establishment process, began from a
consensus building workshop with participation of
the collaborating institutes and others who were
involved in HIV care and treatment. The primary
and secondary aims of the study were defined in this
meeting. The primary aims included: (a) evaluation
of treatment effectiveness, (b) assessment of
monitoring protocols, (c) assessment of adverse
effects of treatment, (d) assessment of adherence,
and, (e) insight into potential causes of early
mortality. The secondary aims included: (a)
assessment of guideline compliance, (b) monitoring
of drug resistance development, (c) assessment of
the impact of PMTCT on treatment effectiveness,
(d) assessment of utilization rates for various kinds
of care, and (4) an assessment of access to ART
care.
The study design of ACM was an ambi-directional
follow up study which included retrospective data
abstraction and prospective data collection. Its
establishment required site-specific follow up
cohorts, and a governance structure with supporting
documentation and legal backing. The following are
the key approaches followed in establishing this
clinical cohort.
Structure and Governance:
The seven Ethiopian medical faculties with their
affiliated hospitals, and five participating
institutions, agreed to collaborate in the
development, management and governance of the
ACM project (Figure 1). The collaborating
institutions were:
1. The Federal Ministry of Health of Ethiopia
through the HIV/AIDS/STIs Prevention and
Control Program (HAPCO)
2. Addis Ababa University/Tikur Anbessa
Hospital (AAU)
3. National Defense University/Armed Forces
Teaching General Hospital (NDU)
4. Gondar University/Gondar University Hospital
5. Jimma University/Jimma University
Specialized Hospital
6. Hawassa University/Hawassa University
Referral Hospital
7. Haramaya University/ Hiwot Fana Hospital
8. Mekelle University/Mekelle Hospital
9. The Ethiopian Public Health Institute (EPHI,
formerly called “Ethiopian Health and
Nutrition Research Institute” or EHNRI)
10. Ministry of Science and Technology (formerly
called “Ethiopian Science and Technology
Commission” or ESTA)
11. The Johns Hopkins University – Bloomberg
School of Public Health (JHU)
12. The United States Centers for Disease Control
& Prevention (CDC- Ethiopia).
Figure 1: Advanced clinical monitoring (ACM) project organization, January 1, 2005 to August 31, 2013,
Ethiopia ACM.
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The organizations agreed to work under a
Memorandum of Understanding (MOU) with a
Steering Committee making key decisions and
providing guidance, and a Project Implementation
Office (PIO) (located at EPHI) overseeing day-to-
day implementation of activities.
Each stakeholder had designated
responsibilities, as stipulated in the MOU, to
achieve the common goal of the project. The seven
Ethiopian universities and their respective hospitals
were considered as study sites because these
facilities were engaged in provision of HIV care
services including ART, and followed a high
volume of patients. Moreover, they were located in
geographically distant places covering a wide
catchment population of the country, and were
equipped with infrastructure and research centers.
Site level offices were established in the ART
clinics of the hospitals to manage data extraction,
data entry, enrollment and data as well as specimen
collection. There were 3 employees (Site Study
Coordinator, Data Manager and Junior Data
Manager) serving the ACM project in each of the
seven sites.
The other stakeholders included: (a) Ethiopian
Federal Ministry of Health represented by the
HIV/AIDS/STIs Prevention and Control
Program/HAPCO (HAPCO was the owner of the
national HIV program and responsible for guiding
the National ART Program), (b) The Federal
Ministry of Science and Technology provided
regulatory guidance, (c) The Johns Hopkins
University Bloomberg School of Public Health
through a CDC-funded project in Ethiopia called the
Technical Support for the Ethiopian HIV/AIDS
ART Initiative (TSEHAI) served as the PIO, to
providing technical guidance and support to the
national program, regional health bureaus, and
hospitals and clinics participating in the free ART
program, (d) CDC-Ethiopia was the funding
agency, (e) The Ethiopian Public Health Institute
(previously known as Ethiopian Health and
Nutrition Research Institute - EHNRI), was the hub
of the collaboration where the central data and
specimens were kept and the coordination office
was stationed (see Fig 1 and 2).
Fig 2. Specimen and Data Flow of the advanced clinical monitoring (ACM) project, January 1, 2005 to
August 31, 2013, Ethiopia. Specimens from the 2 sites in Addis Ababa were being sent same day as
collected and those from out of Addis were being sent within 2 weeks after partial processing.
Note: communication was bidirectional with the intent of ensuring quality of data and specimens.
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Organization of the project - Each collaborating
institution signed an MOU, and a letter of support
was provided by the funding agency (CDC).
According to the MOU, a Steering Committee,
formed by members selected from each
participating institution, was the governing body of
the consortium. The Steering Committee was
composed of representatives who were elected by
the member institutions. The Steering Committee
was governed by a bylaws. There were sub-
committees which served specific purposes. The
Steering Committee had standing meetings on a
quarterly basis. Extra-ordinary meetings were held
as deemed necessary. The establishment of the
collaboration through the signing of the MOU was
accomplished over a period of two and a half years.
An umbrella study protocol was also developed
during this period and was approved by the national
research ethics review committee under the
Ministry of Science and Technology and the
Institutional Review Boards of EPHI and the Johns
Hopkins University Bloomberg School of Public
Health, as well as the science office of CDC.
Several amendments to the umbrella protocol were
made during the follow up time and approved by the
different ethics committees to address emerging
issues with the most recent version of the umbrella
protocol being version 4.0.
The day-to-day activities of ACM were
managed by the PIO under the directions of the
Steering Committee. An electronic data
management system was created by the PIO. The
database included seven-site level databases and a
central database at EPHI where clinical and
laboratory data from the seven sites were merged,
cleaned and stored for analytic use.
Specimen collection and storage mechanism
was also established which included central storage
in -80 degree Celsius deep freezers at EPHI. Data
collection and data quality assurance activities were
handled by study-site level study staff who worked
at the seven hospitals. These staff were employed
by the project and supervised by the PIO. They
were expected to work collaboratively with staff
members of the clinics, laboratories and
pharmacies. All study sites had office space
dedicated for ACM. The specimen collection was
done by the hospital laboratory staff and in return
they were receiving payment for the additional
activities of collecting, processing and shipping of
specimens related directly to the ACM study.
Since ACM project was created as a research
platform for scientific inquiries, mechanisms to
encourage and enhance the practice of research
were put in place.
One mechanism included calls for concept
notes. The calls were disseminated widely and the
Research and Scientific Inquiry Sub-committee,
working under direction of the main Steering
Committee, reviewed concept notes and protocols,
and guided researchers to align concept
notes/protocols with the primary and secondary
aims of ACM and to focus research questions on
relevant and high priority areas for the national
ART program. The key functional units in
facilitating the actual implementation of this were
the PIO and the host institution.
Daily Implementation – having a governance
structure, some guiding documents and a mother
protocol was not considered sufficient for
smooth running. An office responsible for the
actual execution was needed. Since the recipient of
the funding was JHU, it was tasked to establish the
PIO which was mandated to oversee the daily
activities. The PIO had dual reporting lines – to the
Steering Committee and to the JHU-TSEHAI
project office.
Host Institution for data and specimen – Since the
seven participating local institutions were all
interested in being the host, a mechanism for fair
selection had to be established. The Steering
Committee agreed on the following criteria to select
the host institution: mandate (does the institution
have a related mandate relevant to ACM?),
neutrality (is the institution free of conflict of
interest?), location (accessible to most participating
institutions), potential to take over (able to maintain
the cohort after external funding phased out),
utilization potential (which institution can use the
data and specimens optimally?) and management
capacity (which institution can manage the project
more resourcefully?). EPHI was selected as the host
institution because it was the research arm of the
Federal Ministry of Health, with unique technical
and physical capabilities to handle the biological
data, while at the same time was neutral to all
contributing institutions.
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Epidemiological Cohort Development:
The two primary cohorts of ACM were 1) an adult
and adolescent cohort, and 2) a pediatric cohort,
created by considering age during the consent
process. The primary cohorts were each sub-divided
into database and repository cohorts. While data
were collected on both cohorts, plasma and DBS
specimens were collected every six months only
from participants in the repository cohort. The
ACM enrolled a group of initial patients and then
recruited subsequent replacement participants each
year. The number of replacement participants was
determined based on the number of participants lost
to follow up and the number of cohort members
who died in the previous calendar year. Each cohort
had a retrospective period (data collected from
active participants collected prior to enrollment) and
a prospective period (data collected from active
participants during enrollment and onwards) (Table
1).
Table 1: Total number of participants enrolled in advanced clinical monitoring (ACM) project by study-
site, January 1, 2005 to August 31, 2013, Ethiopia.
University
Hospital
Cohorts
Adults (Age> 14)
Children (Age <14)
Addis Ababa University
Tikur Anbessa Hospital
573
63
National Defense University
Armed Forces General Hospital
558
41
Gondar University
Gondar Referral Hospital
620
65
Jimma University
Jimma Referral Hospital
544
49
Mekelle University
Mekelle Referral Hospital
590
54
Haramaya University
Hiwot Fana Referral Hospital
535
49
Hawassa University
Hawassa Univ. Referral Hospital
542
56
Total
3,962
377
Adult and Adolescent Cohort (Age >14 years) -
The initial group of participants (400 per site)
enrolled in this cohort were divided into existing
(ART-experienced) and new (ART-naïve) groups.
A total of 300 ART experienced participants were
sampled from a registry of patients receiving ART
care at each site. In addition, 100 ART-naïve
patients were recruited prospectively to constitute
the initial cohort. Subsequently, each study-site
planned and enrolled on a replacement basis, to
ensure representativeness, a total of at least 60 new
participants in a given calendar year per the
protocol.
Pediatric Cohort (Age < 14 years) - The initial
group of participants (40 per site) enrolled in this
cohort were divided into existing (ART-
experienced) and new (ART-naïve) groups. A total
of 200 ART experienced participants were sampled
from a registry of patients receiving ART care in the
study sites. In addition, 20 ART-naïve patients were
recruited prospectively to constitute the initial
cohort. Subsequently, each site planned and
enrolled on a replacement basis, to ensure
representativeness, a total of at least 10 new
participants in a given calendar year.
Adult and Adolescent Repository Cohort (Age >14
years) - The initial group of participants (100 per
site) were enrolled prospectively into the adult and
adolescent repository cohort. Each site sought to
recruit all eligible participants from the Database
Adult and Adolescent Cohort at their ART initiation
visit immediately following their consent to
participate in the database cohort. Once the site
reached a total of 100 participants, subsequent
enrollment was on a replacement basis as sample
size fell below 100.
Pediatric Repository Cohort (Age <14 years) - The
initial group of participants (20 per site) were
prospectively enrolled into the pediatric repository
cohort. Each site sought to recruit all eligible
participants from the Database Pediatrics Cohort at
their ART initiation visit immediately following
their consent to participate in the database cohort.
Once the site reached a total of 20 participants,
subsequent enrollment was on a replacement basis
as sample size fell below 20.
Participant Enrolment and Follow up - Site level
enrollment and data/specimen collection activities
were done according to standard operating
procedures. All patients who initiated ART on or
after January 1, 2005 were eligible for enrollment
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regardless of their status at the time of enrollment.
Given the retrospective nature of some of the data,
the sampling frame included patients who had died
by the time the study began. All enrolled
participants were given unique identifiers and
random selection was done so that all eligible
patients had equal chance of being approached for
enrollment
Patients who were alive and randomly selected
as potential participants were approached when they
came for their routine visit and, in a confidential
setting, asked if they wanted to provide informed
consent to participate in the ACM. If a participant
agreed to participate in ACM, they signed a consent
form and were enrolled in the database cohort.
Parental consent was obtained for those pediatric
participants <10 years of age and those older than
10 years of age, in addition to the written parental
consent, a verbal assent was also obtained from the
children. Participants were compensated for their
time. If patients declined to participate, the next
eligible patient was approached. Participants
enrolled in only the database cohort were expected
to provide data during their routine follow up visits;
while those enrolled in both the database and
repository cohorts were expected to come to the
facility for routine visits and provide specimens
every six months.
Sample selection and size determination -
Retrospective cohort participants were selected
randomly from the list of all potentially eligible
registered patients from the ART database. All
participants were given an equal chance of being
selected. A computer program using uniform
distribution was applied to generate random
numbers to select study participants. A total of
2,100 ART experienced participants were selected
from the seven sites. Prospective cohort participants
were selected randomly at ART initiation until the
required sample size was reached.
The sample size for cohort development was
determined considering the available resources and
multiple analyses and research topics raised by
investigators. Various intra cluster correlation
coefficient (ICC) values were considered for site
comparison. Hence a total of 2,800 adults, with 700
participants in repository cohort, and 280 pediatric
participants, with 140 in the repository cohort, was
considered a sufficient sample size to answer
project objectives.
Data and Specimen Management Information
System Development:
Data on clinical and demographic characteristics,
ongoing medical care, and clinical and laboratory
outcomes were collected on all participants in the
cohort. Plasma specimens were also obtained and
stored every six months for viral load and resistance
testing, and for other studies to be specified on
subsamples of the overall cohort.
The project used the National ART forms
(ART intake forms, ART follow up forms,
laboratory and Pharmacy Drug Dispense form) and
ACM specific forms (Patient Information form
(PATI), Outpatient care (OCARE), Outpatient
Clinical Laboratory Abstraction form (OCLA),
Tuberculosis abstraction form (TB), Hospitalization
form (HOSP), Visit form (VIST), Termination
(TERM), Mortality form (MORT), Maternity Data
Abstraction form (MATR) and Specimen Collection
and Processing form (SCPF). ACM specific
instruments were pre-tested and modifications made
regularly through version control.
Except for specimen collection purposes with
specific appointments and corresponding coverage
of transportation expenses, patient visits were
limited to the required clinical visits for routine care
and no study-specific appointments were given to
patients.
Antiretroviral Treatment Information System
for Ethiopia (ARTISE), an ACCESS-based
database, was deployed at each participating site to
collect patient data. ARTISE functionality included
a data entry template, patient tracking, database
backup, generating ad hoc reports and de-
identification programming. The De-identification
process eliminated patient identifiers information
like names, address, medical card numbers, and all
possible combination keys, etc. before data
extraction and transportation. The ARTISE system
linked the unique ACM ID number with a one to
one function to all participants so that data and
specimen users were blinded while accessing the
resources centrally. On a quarterly basis, a de-
identified ARTISE backup was transported to
Ethiopian Public Health Institute to be consolidated
and stored in a SQL-based Central Database (CDB).
CDB was created through a structured process of
requirements, specification, design, implementation,
testing, and deployment. The functions of the CDB
included ARTISE site data consolidation, provision
of coding guide for each exported data field,
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laboratory information management for specimens,
analytical dataset export, and built-in and ad-hoc reporting (Fig 3).
Figure 3: Data and specimen flow to central data and specimen warehouse at Ethiopian Public Health
Institute (EPHI), January 1, 2005 to August 31, 2013, Ethiopia. All de-identified data was gathered in the
central database, a SQL server based system developed specifically for this purpose.
Laboratory Management - As shown in Figure 2,
specimens were collected from all ART naïve
repository participants at the time of enrollment and
every 6 months thereafter for 24 months;
subsequent specimen collections were every 12
months. With the exception of Addis Ababa sites
(Tikur Anbessa and Armed Forces Hospitals),
plasma and DBS specimens were collected,
processed and transported from each site to EPHI
on a bi-monthly basis.
All whole blood specimens collected from
participants in sites outside of Addis (5 out 7 sites)
were used to provide Dried Blood Spots (DBS) and
the remaining were processed into plasma aliquots
and stored temporarily on site at -20-degree freezer.
The processed plasma aliquots and DBS were
shipped to the central repository at EPHI within 15
days of collection. All plasma specimens were
transported using dry ice to maintain the cold chain.
Whole blood specimens collected from participants
in the Addis sites (2 out 7 sites) were transported
within six hours of collection to EPHI for further
processing into DBS and plasma aliquots. All
specimens received at the central repository in EPHI
were counterchecked with corresponding
documentation to ensure accuracy and timeliness
and were permanently stored in -80 0C deep
freezers. In addition to storing the merged site
datasets, the SQL-based central database also stored
the repository database and mapped all the
specimens for easy retrieval.
Data Preparation and Analysis- In general,
customized datasets were prepared for researchers
based on variables needed to answer their research
questions. Data cleaning and preparation of datasets
were the mainstay of the data management unit. An
overall descriptive analysis of the patients in the
database is provided in Table 2.
Ethical review:
Given the fact that multiple Ethiopian universities,
JHU and CDC had their own institutional review
boards (IRBs), approval at multiple levels appeared
to be required. To expedite the process, the EPHI
institutional review board was designated to
represent all the local university IRBs. Following
the review and approval from the EPHI IRB, the
protocol was simultaneously submitted to the
National Research and Ethics Committee at the
Ministry of Science and Technology in Ethiopia, the
IRB at Johns Hopkins University Bloomberg
School of Public Health, and the science office of
the CDC.
This process, with parallel review by three
different institutions, with different time intervals
for review, where each of the IRBs could require
changes that then needed to be re-reviewed, delayed
the initiation of the study. Final clearance was
secured nine months after submission of the first
version of the ACM protocol. Another challenge
that further prolonged the review process was the
gap in the Ethiopian Research Ethics Guidelines
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regarding use of data obtained from patients who
were already dead or who were lost to follow up
and could not be tracked to seek informed consent.
This lack of guidance led to multiple consultative
meetings between the research team and the
National Research Ethics Committee to reach
consensus. While the study was allowed to use data
from patients who had died, the IRB was not willing
to allow inclusion of patients who were not in
follow up and whose final status was unknown.
ACM secured required approvals for
continuation on an annual basis.
Accomplishments:
After three years of preparatory work, the ACM
project initiated enrollment in 2009. As shown in
Table 1 and Figure 4, a total of 3,962 adults and 377
children were enrolled in the study. The sites had
comparable contributions with a mean of 566 adults
(542-620) and 54 children (41-65) per site.
ACM provided collaborators the opportunity to
form a research consortium which involved seven
local universities, one international university,
CDC, the Ministry of Science and Technology, the
Ethiopian Public Health Institute and the Ministry
of Health. To the best of our knowledge ACM
continues to be the largest research collaboration in
the country. In addition to the fact that it serves as a
platform for national and international
collaboration, the lessons learned in terms of
processes for establishing a large multi-site cohort
study are worth discussing.
Figure 4: Advanced clinical monitoring (ACM) multisite database and repository cohort enrollment by year,
January 1, 2005 to August 31, 2013, Ethiopia.
As summarized in Table 2 and 3a, among the
adults, 62% (n=2,452) were female and 38%
(n=1,510) were male. Most of the participants were
in the 25-39 year age category, and only 10% were
older than 50 years. At the time of enrollment, the
majority of the study participants (57%) had a
baseline CD4 count of 50-200 and more than 66%
of the participants were in WHO stage 3 and 4.
At initiation of treatment, the most commonly
prescribed NRTIs for retrospective cohort patients
were AZT (38%) and d4T (33%). In 2009,
following the introduction of Tenofovir, the trend
changed to TDF as the most prescribed NRTI
(53.6%). Efavirenz (EFV) and NVP were the only
NNRTIs prescribed, with NVP accounting for
56.5%. Cotrimoxazole prophylactic treatment
(CPT) was prescribed to more than 90% of the
patients, but INH was given to only 4% (n=160).
TB treatment was initiated for 15.4% (n=604) of
patients. As seen on table 3b, with a total of 39,762
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aliquots and 25,515 DBS, a large pool of specimens
was created. The mean follow-up period of patients
on ART was 44 months with median follow-up of
41.6 months.
The project conducted workshops and
advanced data analysis trainings for participating
university investigators to support their studies and
answer relevant scientific inquiries using available
data and the specimen repository more
resourcefully.
Table 2: Patient Characteristics of advanced clinical monitoring (ACM) participants at ART initiation,
January 1, 2005 to August 31, 2013, Ethiopia.
* There are some missing values
Adult and Adolescent Multisite Cohort
Pediatrics Multisite Cohort
Variables
n (%)
Variables
n (%)
Sex (n=3962)
Female
2,452(61.89%)
Sex
(n=377)
Female
183(48.54%)
Age (Years)
(3962)
14-17
28 (0.71%)
Age
(Years)
(377)
<1
15(3.98%)
18-19
23 (0.58%)
1-4
102(27.06%)
20-24
215 (5.43%)
25-29
766 (19.33%)
5-9
196(51.99%)
30-34
877 (22.14%)
35-39
847 (21.38%)
10-14
64(16.98%)
40-44
507 (12.80%)
45-49
303 (7.65%)
50+
396 (9.99%)
CD4 Count
(3827*)
<50
569 (14.87%)
CD4
Count
(293*)
<100
10 (3.41%)
50 - 200
2,193(57.30%)
50 - 200
86 (29.35%)
200 - 350
992 (25.92%)
200 - 350
97 (33.11%)
350 - 500
48 (1.25%)
350 - 500
39 (13.31%)
≥ 500
25 (0.65%)
≥500
61 (20.82%)
Functional
Status(3880*)
Working
2,825(72.81%)
Functional
Status
(339)
Appropriate
163(48.08%)
Ambulatory
882(22.73%)
Delay
164(48.38%)
Bedridden
173(4.46%)
Regression
12(3.54%)
WHO Stage
(3893 *)
WHO stage I
451 (11.58%)
WHO
Stage
(368 *)
WHO stage I
32 (8.70%)
WHO stage II
823 (21.14%)
WHO stage II
101(27.45%)
WHO stage III
1,961(50.37%)
WHO stage III
168(45.65%)
WHO stage IV
658 (16.90%)
WHO stage IV
67 (18.21%)
ARV Regimen
(3962)
d4T+3TC+NVP
961 (24.26%)
ARV
Regimen
(375)
d4T+3TC+NVP
121 (5.6%)
d4T+3TC+EFV
351 (8.86%)
d4T+3TC+EFV
21 (0.60%)
AZT+3TC+NVP
1,066
(26.90%)
AZT+3TC+NVP
184(49.07%)
AZT+3TC+EFV
438 (11.06%)
AZT+3TC+EFV
39 (10.40%)
TDF+3TC+NVP
210 (5.30%)
TDF+3TC+NVP
1 (0.03%)
TDF+3TC+EFV
898 (22.67%)
TDF+3TC+EFV
0 (0.00%)
Other
38 (0.96%)
Other
30(8.00%)
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Table 3a: Total number of participants enrolled in advanced clinical monitoring (ACM) project by cohort,
January 1, 2005 to August 31, 2013, Ethiopia.
Primary ACM
cohorts
Cohort type
Gender
Total
Male
Female
Multisite Adult and
Adolescent
Database Cohort
1,125
1,855
2,980
Repository Cohort
385
597
982
Multisite Pediatrics
Database Cohort
125
106
231
Repository Cohort
69
77
146
Total
1,704
2,635
4,339
Table 3b: Total number of samples collected by visit for repository cohort participant in advanced clinical
monitoring (ACM) project, September 2009 to August 31, 2013, Ethiopia
Laboratory
sample/Specimen
Visits after ART Initiation for Repository Cohorts (months)
M0
M6
M12
M18
M24
M30
M36
M42
Total
Total number of
aliquots stored
8,762
6,985
6,290
5,756
5,128
4,056
2,429
356
39,762
Total number of
DBS spots collected
5,640
4,465
3,995
3,650
3,295
2,595
1,615
260
25,515
The ACM platform enabled researchers to
determine predictors of survival among adults on
ART (15), common causes of hospitalization and
outcomes among pediatric patients on ART (16),
magnitude of drug toxicity (17), timeliness of HIV
care (18) and mortality of patients on ART with
TB co-infection (19). Answers to more research
questions are in the pipeline and the authors
anticipate many more research activities based on
the data and specimens collected by ACM.
Challenges:
Funding - Though this project was of national
importance, it was solely funded by PEPFAR
through CDC-Ethiopia. When the CDC funding
came to an end, active follow up of participants
and data and specimen collection were suspended.
However, with the support of EPHI, use of the
available data and specimens to address key
research and programmatic questions is being
encouraged and facilitated.
Data use - Although the data and specimens were
being analyzed to address research aims, little was
done early on to support public health decision-
making, and therefore data and specimens were
not likely to been used to their full potential.
Specimen use - All research activities requiring
use of specimens needed to come with associated
funding. Except for the limited viral loads done
through the CDC funding, no advanced tests have
been done. The routine laboratory investigations
including CD4, blood chemistry and other basic
laboratory data are available at the facility level
and results are documented and captured on the
ACM database.
DISCUSSION AND LESSONS LEARNED:
Establishment of the ACM project responded to
the need for an African cohort that would enable
certain research questions to be addressed. The
five-country study by Dalal et al.(13), reflected on
the need for a longitudinal as opposed to cross
sectional study, and the ACM Project
demonstrates its feasibility. The retention rate at
month 6 was more than 80 percent, which is
higher than found by Dalal et.al (13). Publications
showing the process of establishment of specific
cohort studies are very scarce.
There are over 30 large HIV cohort studies
ongoing, according to the Forum for Collaborative
HIV Research. Some of the largest are Euro-SIDA
with 60 clinical centers in Europe, the Swiss HIV
Cohort with 7 centers, and the HIV Research
Network with 17 centers in the U.S.(10) However,
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14
the vast majority of these multi-site cohort studies
are being carried out in high resource settings –
U.S., Europe and/or Australia. ACM has been able
to stimulate generation of local evidence.
Seven essential research questions were
answered in the first round of research activity,
and an additional 18 are in the pipeline.
With more than 4,000 patients, ACM is larger
than many of the cohort studies in Africa. The
AFRICOS study has 3,600 patients. The multi-
centre prospective cohort network of pediatric
clinics in West Africa, which involves seven
countries, has 1,415 participants. But it was
comparable to the cohort study involving 3
countries by Koole et al. which has 4,147 patients
included though it was a retrospective cohort
study (14)
ACM is a multi-site clinical cohort with the
potential to provide valuable information about the
effectiveness of the ART program, the survival of
patients on ART, incidence of ART-related
toxicities, and other more research questions. The
fact that ACM has readily available
longitudinally-collected specimens with
corresponding clinical and socio-demographic
data makes it an ideal platform for researchers.
Establishing and running a multi-site cohort study
requires creation of a functional system that will
guide the collaboration. A multi-site, multi-partner
clinical cohort establishment also requires a long-
term commitment and advance planning for
maintenance of the cohort.
Establishing the cohort –Starting with a clear
study purpose, and ensuring meaningful
involvement of all stakeholders by creating the
venue for consultative engagement, were crucial.
Developing the rules of collaboration as well as
defining the roles and responsibilities of each
institution at the inception played a crucial role in
building ownership. The discussion of how to
integrate the implementation office and its
functions, including the data and specimen
warehousing within EPHI, gave ACM the chance
to continue even after donor funding was
discontinued.
Maintaining the cohort - Since there are close to
4,000 participants enrolled in ACM, and since
there is a need for site level staff, maintaining
follow up of participants at the ACM study sites
would have required continued funding.
However, given that all the structural issues were
addressed, maintaining ACM was not significantly
challenging. Though enrollment have been
suspended, we have learned that ACM has an
invaluable pool of data and specimens which can
be used to inform the ART program nationally,
and HIV/AIDS research globally.
Ethical clearance process - Though the process
was not as fast as we desired, delegation of one
IRB to be the local IRB on other institutions’
behalf expedited the process. Parallel submission
of the protocol has also enabled somewhat faster
clearance.
Stimulating scientific inquiries - Posting calls for
concept notes, followed by organizing consultative
workshops gave investigators the chance to review
scientific questions. Examination of data during
the consultative workshops also helped in
stimulating research by the busy clinicians.
Limitations - The project was not able to start
participant enrollment at the beginning of ART
initiation in 2005, hence we were forced to
include a retrospective cohort design with the
intention of understanding the early years of the
ART program. The transition away from donor
funding was challenging and alternative funding
mechanisms were not put in place by the time
funding from CDC ended, resulting in suspension
of the project.
Future analyses - The findings of the
aforementioned seven sub-studies have shown us
that many important questions can be answered
using the ACM cohort. Although additional
research questions can be answered using the
ACM data, it is strongly recommended that future
studies be geared towards informing decisions of
the national program, in addition to regional and
global issues. More emphasis should be placed on
timely availability and use of the data, on
increased networking, and on creating strong
collaboration with in-country and external
collaborators.
Disclaimer
The findings and conclusions in this report are
those of the author(s) and do not necessarily
Establishing Multicenter… Alula MT et al.
DOI: http://dx.doi.org/10.4314/ejhs.v27i1.2S
15
represent the official position of the Centers for
Disease Control and Prevention.
Attribution/ Acknowledgement
The Research has been supported by the
President’s Emergency Plan for AIDS Relief
(PEPFAR) through the Centers for Disease
Control and Prevention (CDC) under the terms of
Cooperative Agreement with Johns Hopkins
Bloomberg School of Public Health number
PS000858. We would like to express our
gratitude to the providers who routinely
documented the status of their patients on the
standard forms and last but not least, we would
like to thank all the study subjects who consented
and were followed in the project.
ACKNOWLEDGMENT
The Research has been supported by the
President’s Emergency Plan for AIDS Relief
(PEPFAR) through the Centers for Disease
Control and Prevention (CDC) under the terms of
Cooperative Agreement with Johns Hopkins
Bloomberg School of Public Health number
PS000858.
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Teklu, Melake Damen, Saro Abdella, Neaga
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16. Abraham Haileamlak, Tesfalem Hagos,
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Contributors: The following investigators contributed to study design and project government.
The following investigators contributed to manuscript preparation and/or revision:
Alula Teklu (lead), Eyuel Tsegaye, Abrham Hailemelak, Daniel Fekade, William Weiss, Elham Hassen,
Yifru Berhan, Andrea Ruff
The following investigators contributed to data preparation and/or analysis:
Eyuel Tsegaye
ACM Study Team:
Addis Ababa University: Daniel Fekade MD, MSC, Teshale Seboxa MD
Armed Force General Teaching Hospital: General Tesfaye Gidey
Gondar University: Assefa Getachew MD, Sisay
Jimma University: Abrham Hailemelak Professor of Pediatrics and Child Health
Mekelle University: Tesfalem Hagos MD,
Haramaya University: Melake Damena
Hawassa University: Yifru Birhan MD, Professor of OBGYN
Johns Hopkins University (JHU-TSEHAI): Alula M. Teklu, Rahel Adamu, Andrea Ruff, Solomon
Zewdu, Nicole Simmons, William Weiss, Aida Abashawul, Daniel Assefa, Hana Abera, Elham Hassen,
Eyuel Tsegaye, Dawit Lisanework, Lelisa Amanuel, Altaye Feleke, Tigist Nemera, Fikre Hailekiros,
Yodit Worku, Melkam Assefa, Lulit Girma, Filkad Jemal, Gelaye Worku, Rehmet Gashu, Alefe Meressa,
Dawit Mulu, Yisak Kassa, Lidya Tesfaye, Mulu Alemu , Zelalem Fiseha, Zeleke Alemu, Bizuayehu
Teshome, Liyu Asrat, Haymanot, Yonas Sime, Genet Elias, Saro Abdella, Jemal Tadesse, Abel Mamo,
Abiy Abebe, Wubante Taye
Ethiopian Science and Technology Agency/Later Ministry of Science and Technology: Dr Yeman
Teklai, Yohannes Sitotaw
Ethiopian Federal Ministry of Health: Achamyeleh Alebachew, MD, Taye Tolera, MD, PHD
Ethiopian Public Health Institute: Eshetu Lemma PHD, Almaz Abebe PHD, Desta Kassa PHD, Atsbeha
Geberexiaber
Center for Disease Control Ethiopia: Ashenafi Haile MD, Solomon Ahmed MD
