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 protected] 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 [2]. 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 [3].
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 [4]. 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 [5]. 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 [4]. 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) [7]. 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 [9].
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 [8], 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 [9]; nonnucleoside reverse transcriptase inhibitor (NNRTI) resis- tance mutations were K103N (57.1%), Y181C (32.1%) and adherence was a problem in the cohort [8] and largely G190A/S (22.2%). See Sylla et al. [9] 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 [8]. 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 [9]. 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 [13]. 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 [7]. 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 [4]. 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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