DOI: 10.1111/j.1468-1293.2008.00664.xHIV Medicine (2009), 10, 152–156
Impact of a modified directly administered antiretroviraltreatment intervention on virological outcome inHIV-infected patients treated in Burkina Faso and Mali
CM Pirkle,1 C Boileau,2 V-K Nguyen,3 N Machouf,4 S Ag-Aboubacrine,5 PA Niamba,6 J Drabo,7 S Koala,8 C Tremblay9 andS Rashed10,111Unite´ de Sante´ Internationale, Centre de Recherche du Centre Hospitalier de l’Universite´ de Montre´al, Montre´al, Canada,2Institute for Health and Social Policy, McGill University, Montre´al, Canada, 3De´partement de Me´decine Sociale etPre´ventive, Universite´ de Montre´al, Montre´al, Canada, 4Clinique l’Actuel, Montre´al, Canada, 5Unite´ de Me´decine Interne,Hoˆpital National du Point G, Bamako, Mali, 6Unite´ de Dermatologie, Centre Hospitalier Universitaire Yalgado-Oue´draogo,Ouagadougou, Burkina Faso, 7Centre Hospitalier National Yalgado-Ouagadogou, Ouagadogou, Burkina Faso, 8Projet FondsMondial de Lutte contre le SIDA, la Tuberculose et le Paludisme, Ouagadogou, Burkina Faso, 9De´partement de Microbiologieet Immunologie, Centre de Recherche du Centre Hospitalier de l’Universite´ de Montre´al, Montre´al, Canada, 10Unite´ dePe´diatrie, Hoˆpital Maisonneuve-Rosemont, Montre´al, Canada and 11SIDA-3 project, Mali
ObjectiveThis study explores whether viral load measurements can be used in resource-limited settings totarget those in need of adherence assistance. It was hypothesized that high plasma viral loads (pVLs)( 500 HIV-1 RNA copies/mL) were the result of poor antiretroviral therapy adherence andamenable to improvement with adherence assistance.
DesignA single-arm, multicentre pilot study was conducted from November 2003 to March 2004 on 606treatment-experienced patients who had initiated an antiretroviral regimen in Mali and BurkinaFaso 6 months before study enrolment. In these patients, those whose pVL was 500 copies/mLwere offered 1 month of modified directly administered antiretroviral treatment (mDAART) withweekly follow-up visits from pharmacists or adherence counsellors.
MethodsAn adherence questionnaire was given to all cohort patients and viral load was used to screenfor patients with 500 copies/mL. mDAART participants included cohort patients with
500 copies/mL, who completed the adherence questionnaire. Genotypic analyses were conducted
on samples taken prior to and after the intervention. The intervention was considered effective whenthere was a decrease of 1 log10 in pVL.
ResultsmDAART was effective in over one-third of the intervention participants, while in two-thirds no decreasein pVL was observed. The majority of mDAART participants had major resistance mutations.
ConclusionspVL measurement was useful to identify patients who needed adherence assistance. However,because it was performed 6 months after starting treatment, mDAART came too late for mostparticipants, as they had already developed important resistance mutations that might have beenavoided with better laboratory monitoring.
Correspondence: Catherine Pirkle, Unite´ de Sante´ Internationale, Universite´de Montre´al, E´difice Saint-Urbain, 3875 rue Saint-Urbain, Montre´al, QC,
Although the roll-out of antiretroviral treatment (ART) in
Canada H2W 1V1. Tel: 1 514 890 8000 ext 15927; fax: 1 514 412 7108;e-mail: email@example.com
sub-Saharan Africa initially raised concerns about the
successful ART programmes are now in operation acrossthe continent with approximately a quarter of the
4.6 million people in need currently receiving treat-
In a multicentred cohort of patients recruited from three
ment . With initiatives such as the Global Fund and
community (n 5 218) and three hospital-based (n 5 388)
President’s Emergency Plan for AIDS Relief (PEPFAR) and
ART delivery sites in Ouagadougou (Burkina Faso) and
an estimated $8.3 billion investment in HIV treatment in
Bamako (Mali), we conducted a single-arm pilot study from
resource-limited settings, critical debates have emerged
November 2003 to March 2004. In this study, we offered
over how best to deliver and scale up ART .
mDAART to patients whose pVL was 500 copies/mL.
One such debate centres on the provision of laboratory
Eligible patients consisted of treatment-experienced cohort
technologies in resource-limited countries and around
participants who had initiated a highly active antiretroviral
concerns that limited resources should be applied to
therapy regimen at least 6 months before study enrolment.
prevention measures and the initiation of treatment, rather
Cohort participants whose pVL was 500 copies/mL
than the performance of expensive laboratory tests to
were offered 1 month of mDAART with weekly follow-up
monitor patients already receiving treatment . As
visits with pharmacists or adherence counsellors. The inter-
countries struggle to scale up ART delivery, there are
vention was carried out by an accompagnateur (a family
concerns that adopting technologies such as viral load
member, a friend, or a health care professional) chosen by
monitoring will over-tax already overdrawn laboratories
the patient. All mDAART providers were given instructions
and greatly limit the abilities of countries to expand
on how to monitor the doses using a follow-up chart.
treatment . However, with the concerns around the ‘rapid
Nonmedical providers were given further information on
emergence of resistant viral strains, spelling doom for the
individual, curtailing future treatment options, and leadingto the transmission of the resistant virus’ [1, p. 410], thesetechnologies may be essential to assuring ART sustain-
Meticulous adherence to treatment has been shown to be
the most important factor in delaying the development of
Trained interviewers collected data on demographic
drug resistance . It is also widely recognized as a crucial
characteristics (age, gender, marital status, literacy, country
determinant of therapeutic success, as proper adherence is
of residence and distance from health centre), adherence
strongly correlated with virological and clinical outcome
behaviour (adherence in the last week, treatment inter-
[4,6]. However, knowledge of effective strategies to
ruption and knowledge of ART), treatment (currently
increase adherence is limited, particularly in these settings
prescribed and previous ART, and time on current ART)
. Modified directly administered antiretroviral therapy
and clinical status [CD4 cell counts, body mass index (BMI:
(mDAART), in which the administration of one to two doses
kg/m2) and self-reported health] using a close-ended
per day is witnessed, has been proposed as a strategy to
questionnaire and patient medical files.
improve adherence and treatment outcomes, as well as apublic health strategy to prevent the development of drug
CD4 cell counts, viral load, and genotypic analysis
All measurements were taken prior to and after the
We describe an intervention using plasma viral load
intervention. CD4 cells were quantified by flow cytometry
(pVL) measurements to target those in need of adherence
using the Becton Dickinson FACSCaliburt system (Becton-
assistance in a cohort of patients from Burkina Faso and
Dickinson, Mountainview, CA, USA) in Ouagadougou and
Mali in West Africa. This intervention explores whether
FACScan (BD Biosciences, San Jose, CA, USA) in Bamako.
viral load measurements, in conjunction with mDAART,
Viral load was measured in Montre´al, Canada, using the
can be used in resource-limited settings to help prevent
COBAS Amplicor HIV-1 Monitor Test, version 1.5 (Roche
unnecessary switches to expensive second-line treat-
Diagnostics, Branchburg, NJ, USA), according to the manu-
ments. We had initial evidence from a cross-sectional
facturer’s instructions. The methods used for the genotypic
study suggesting that adherence was less than optimal
analysis have been described in detail elsewhere .
in this cohort. The assumption was that high pVL(4500 HIV-1 RNA copies/mL) was attributable either to
poor adherence or to treatment failure and, because ofprevious evidence , adherence was believed to be the
The primary study outcome was the log10 difference in pVL
following the 1-month mDAART intervention. We considered
r 2009 British HIV Association HIV Medicine (2009) 10, 152–156
the intervention effective when there was a decrease of at
Table 1. Baseline characteristics of the cohort patients vs. modified
directly administered antiretroviral treatment (mDAART) participants
10 in pVL following the intervention.
Viral load testing was used to screen 606 patients who had
received ART for 6 months at six sites in Burkina Faso
and Mali. Eighty-five patients had pVL 4500 copies/mL
(range 508–160 000 copies/mL) and were considered eligi-
ble for the mDAART intervention. Fifty-six of these
patients agreed to, and completed, both the intervention
The overwhelming reason for nonparticipation in the
intervention was an inability to find an accompagnateur.
The 29 eligible nonparticipants differed significantly from
their mDAART counterparts in terms of BMI, pVL and
having ever interrupted treatment. Compared with eligible,
but nonparticipating cohort patients, mDAART participants
had a higher BMI (22.85 vs. 21.01; P 5 0.028) and a lower
pVL (4.18 vs. 4.46; P 5 0.081), and were more likely to have
interrupted treatment (79.4 vs. 20.6%; P 5 0.038).
Characteristics of the 56 mDAART participants, as well as
patients from the remainder of the cohort, at initial pVL
screening are presented in Table 1. Compared with the
remainder of the cohort, there was a borderline-significantly
higher proportion of men among the mDAART participants
demographic variables, there were no significant differencesbetween groups. In accordance with their virological status,
*Knows how to read and write in French.
mDAART participants were more immunologically suppressed
Body mass index was calculated as weight (kg) divided by the square of
(CD4o200 cells/mL) and less likely to report good health.
Concerning adherence-related behaviours, mDAART partici-
ART, antiretroviral therapy; BMI, body mass index; NNRTI, nonnucleoside
pants were more likely to report treatment interruptions and
reverse transcriptase inhibitor; PI, protease inhibitor; pVL, plasma viral load;
less likely to have good ART knowledge. Finally, mDAART
participants had been on treatment for longer and were morelikely to have been on a protease inhibitor (PI)-containing orother type of regimen compared to non-mDARRT participants.
There was a borderline-significant difference in the proportions
of mDAART participants and cohort patients on second-linetreatments (21.8 vs. 12.8%, respectively; P 5 0.063).
>Genotyping was performed on 34 of the 56 patients
participating in mDAART. The remaining 22 samples could
not be sequenced because of sample degradation. Figure 1
presents the effects of mDAART on pVL in genotyped andnongenotyped participants, according to resistance status.
Fig. 1. The impact of modified directly administered antiretroviral
Major nucleoside reverse transcriptase inhibitor (NRTI)
treatment (mDAART) on plasma viral load according to resistance
resistance mutations were M184V (85.7%), Thymidine
r 2009 British HIV Association HIV Medicine (2009) 10, 152–156
Analog Mutation (TAM)-2 (42.9%) and TAM-1 (28.6%). Major
were able to bring their pVL below 50 copies/mL ;
nonnucleoside reverse transcriptase inhibitor (NNRTI) resis-
tance mutations were K103N (57.1%), Y181C (32.1%) and
adherence was a problem in the cohort  and largely
G190A/S (22.2%). See Sylla et al.  for a more detailed
responsible for the high viral loads observed in mDAART
description of resistance mutations detected in the cohort
participants, and we thus expected the intervention to be
(including mDAART participants and nonparticipants).
effective in most participants . Our results, however,
Viral load decreased by at least 1 log10 in one-third of
painted a more complex picture. As the majority of
mDAART participants (n 5 20; 35.7%), while in two-thirds
participants harboured major resistance mutations, our
no decrease was observed (n 5 36; 64.3%). However,
results suggest that, while adherence may have been the
among those not genotyped, the intervention was effective
underlying problem, our intervention came too late for
in over 70% of participants, probably reflecting their lower
average initial pVL (pVL 3.79 vs. 4.44 log10 copies/mL; see
Genotyping revealed that resistance was already a
Fig. 1). Of the 34 genotyped participants, 30 had major
problem upon mDAART initiation . Certain baseline
resistance mutations. In the majority of resistant partici-
characteristics (mDAART participants had been on ART
pants, there was no diminution in pVL post-mDAART
for significantly longer than their cohort counterparts
(n 5 27; 90%); in four participants, viral load increased by
and were significantly more likely to be taking an
more than 1 log10. Among genotyped participants, 78.6%
unboosted PI or other regimen compared to non–mDARRT
had both NRTI and NNRTI mutations and 76.7% had three
participants) hinted that resistance was the underlying
or more mutations. Of the three resistant participants who
reason for high pVL, as these factors have been associated
reduced their pVL by 1, none had dual NRTI/NNRTI
with drug resistance in the literature . Better laboratory
mutations and all had fewer than three mutations (results
monitoring may have prevented the high rates of resistance
not shown). These patients had the following major
found in our study by detecting those with elevated pVLs
resistance mutations: one patient with 184V one with
early enough for adherence assistance to be beneficial.
K103N and p225H, and one with K103N only.
One-third of mDAART participants did decrease their
Except for an ART regimen containing nevirapine (NVP)
pVL by more than 1 log10. In these participants, the
(P 5 0.057), no demographic or clinical variables were
mDAART intervention may have prevented unnecessary
associated with a 1 log10 decrease in pVL post-mDAART. In
treatment switches. As second-line treatments cost four-
those taking NVP, 13% decreased their pVL by 1 log10
times more than first-line treatments in Burkina Faso and
compared with 44% in those on a regimen not containing
Mali, this represents a significant saving in terms of
NVP; this association was not significant when sex and
potential treatment costs. However, as most samples in
CD4 cell count were taken into consideration.
these patients were not genotyped, we do not knowwhether these patients were harbouring important resis-
tance mutations that would eventually compromise theirtreatment regimen.
An important consideration in the management of patientson ART will be the level and quality of laboratory
monitoring necessary to retain effective and sustainabletreatment options, particularly with increasing concerns
Our results underscore the importance of improving the
over widespread drug resistance . Laboratory services are
laboratory capacities of resource-limited countries. As this
one of the most neglected areas of health provision in sub-
intervention demonstrated, adherence assistance came too
Saharan Africa, engendering a reliance on clinical
late for most participants, as they had already developed
symptoms to determine diagnosis and treatment . Recent
important resistance mutations that might have been
evidence suggests that an exclusive focus on clinical
avoided with more regular laboratory monitoring. The
symptoms has led to inappropriate treatment, increased
emergence of resistance, which could compromise future
morbidity and unnecessary loss of life [10–12]. In the case
treatment, justifies investment in technologies such as viral
of ART, it may also lead to expensive and unnecessary
load monitoring, to say nothing of the inherent benefits
changes to second-line treatments and/or the prolongation
associated with building local laboratory capacity.
of ineffective first-line therapies.
The goal of this intervention was to employ viral load
monitoring and mDAART to weed out those who neededadherence assistance from those who needed second-line
This study was supported by grants from the Canadian
treatments. The majority of cohort participants (74.9%)
Institutes for Health Research (CIHR/IRSC).
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Key role of proline L209 in connecting the distant quinone pockets in the reaction center of Rhodobacter sphaeroides J. Tandori†‡, P. Maroti‡, E. Alexov§, P. Sebban†¶, and L. Baciou† †Centre de Ge´ne´tique Mole´culaire, Centre National de la Recherche Scientifique, 91198 Gif-sur-Yvette, France; ‡Department of Biophysics, University ofSzeged, H-6722, Szeged, Hungary; and §How
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