A phylogenetic study of dengue virus in urban Vietnam shows long-term persistence of endemic strains.

Dengue virus (DENV) causes repeated outbreaks of disease in endemic areas, with patterns of local transmission strongly influenced by seasonality, importation via human movement, immunity, and vector control efforts. An understanding of how each of these interacts to enable endemic transmission (continual circulation of local virus strains) is largely unknown. There are times of the year when no cases are reported, often for extended periods of time, perhaps wrongly implying the successful eradication of a local strain from that area. Individuals who presented at a clinic or hospital in four communes in Nha Trang, Vietnam, were initially tested for DENV antigen presence. Enrolled positive individuals then had their corresponding household members invited to participate, and those who enrolled were tested for DENV. The presence of viral nucleic acid in all samples was confirmed using quantitative polymerase chain reaction, and positive samples were then whole-genome sequenced using an amplicon and target enrichment library preparation techniques and Illumina MiSeq sequencing technology. Generated consensus genome sequences were then analysed using phylogenetic tree reconstruction to categorise sequences into clades with a common ancestor, enabling investigations of both viral clade persistence and introductions. Hypothetical introduction dates were additionally assessed using a molecular clock model that calculated the time to the most recent common ancestor (TMRCA). We obtained 511 DENV whole-genome sequences covering four serotypes and more than ten distinct viral clades. For five of these clades, we had sufficient data to show that the same viral lineage persisted for at least several months. We noted that some clades persisted longer than others during the sampling time, and by comparison with other published sequences from elsewhere in Vietnam and around the world, we saw that at least two different viral lineages were introduced into the population during the study period (April 2017-2019). Next, by inferring the TMRCA from the construction of molecular clock phylogenies, we predicted that two of the viral lineages had been present in the study population for over a decade. We observed five viral lineages co-circulating in Nha Trang from three DENV serotypes, with two likely to have remained as uninterrupted transmission chains for a decade. This suggests clade cryptic persistence in the area, even during periods of low reported incidence.

Drug-Drug Interactions With the Hepatitis B Virus Capsid Assembly Modulator JNJ-56136379 (Bersacapavir).

The capsid assembly modulator JNJ-56136379 (bersacapavir) disrupts hepatitis B virus replication. It is metabolized via cytochrome P450 (CYP) 3A, but little is known about the drug-drug interactions of JNJ-56136379 when combined with drugs that inhibit or are metabolized by CYP3A. In a phase 1, open-label trial (NCT03945539), healthy adults received 1 dose of JNJ-56136379 with and without 21 days of prior exposure to itraconazole 200 mg (CYP3A inhibitor). In a second phase 1, open-label trial (NCT03111511), healthy women received 1 dose of drospirenone/ethinyl estradiol and midazolam before and after 15 days of JNJ-56136379. Itraconazole increased the area under the plasma concentration-time curve (AUC) of JNJ-56136379 by 38%. JNJ-56136379 reduced the maximum observed concentration and AUC of midazolam (CYP3A substrate) by 42%-54%, increased AUC of ethinyl estradiol by 1.6-fold, but had no effect on drospirenone pharmacokinetics. Overall, these results demonstrated that a strong CYP3A inhibitor (itraconazole) modestly increased JNJ-56136379 exposure. Furthermore, JNJ-56136379 was a weak inducer of CYP3A (midazolam) and increased ethinyl estradiol exposure; coadministration of high-dose estrogen-based contraceptives and JNJ-56136379 is not recommended.

Combining rapid diagnostic tests to estimate primary and post-primary dengue immune status at the point of care.

BACKGROUND: Characterising dengue virus (DENV) infection history at the point of care is challenging as it relies on intensive laboratory techniques. We investigated how combining different rapid diagnostic tests (RDTs) can be used to accurately determine the primary and post-primary DENV immune status of reporting patients during diagnosis. METHODS AND FINDINGS: Serum from cross-sectional surveys of acute suspected dengue patients in Indonesia (N:200) and Vietnam (N: 1,217) were assayed using dengue laboratory assays and RDTs. Using logistic regression modelling, we determined the probability of being DENV NS1, IgM and IgG RDT positive according to corresponding laboratory viremia, IgM and IgG ELISA metrics. Laboratory test thresholds for RDT positivity/negativity were calculated using Youden's J index and were utilized to estimate the RDT outcomes in patients from the Philippines, where only data for viremia, IgM and IgG were available (N:28,326). Lastly, the probabilities of being primary or post-primary according to every outcome using all RDTs, by day of fever, were calculated. Combining NS1, IgM and IgG RDTs captured 94.6% (52/55) and 95.4% (104/109) of laboratory-confirmed primary and post-primary DENV cases, respectively, during the first 5 days of fever. Laboratory test predicted, and actual, RDT outcomes had high agreement (79.5% (159/200)). Among patients from the Philippines, different combinations of estimated RDT outcomes were indicative of post-primary and primary immune status. Overall, IgG RDT positive results were confirmatory of post-primary infections. In contrast, IgG RDT negative results were suggestive of both primary and post-primary infections on days 1-2 of fever, yet were confirmatory of primary infections on days 3-5 of fever. CONCLUSION: We demonstrate how the primary and post-primary DENV immune status of reporting patients can be estimated at the point of care by combining NS1, IgM and IgG RDTs and considering the days since symptoms onset. This framework has the potential to strengthen surveillance operations and dengue prognosis, particularly in low resource settings.

Data driven evaluation of healthy volunteer characteristics at screening for phase I clinical trials to inform on study design and optimize screening processes.

Protocols for clinical trials describe inclusion and exclusion criteria based on general and compound-specific considerations to ensure subject safety and data quality. In phase I clinical trials, healthy volunteers (HVs) are screened against these criteria that often specify predefined eligibility ranges for vital signs, electrocardiogram, and laboratory tests. HVs are excluded if baseline parameters deviate from these ranges even though this may not indicate underlying pathology, which could delay trial execution. Data from 3365 HVs participating in 9670 screening visits for 94 phase I HV trials, conducted between December 2008 and May 2019 at the Janssen Clinical Pharmacology Unit, were retrospectively analyzed. Commonly predefined protocol ranges were overlaid with HV data to estimate predicted screen failure rates (SFRs). Of the overall population, 91% was White and 64% were men with mean age of 42.8 ± 12.5 years. High predicted SFRs are related to cardiovascular/metabolic (body mass index, heart rate [HR], blood pressure [BP], and corrected QT Fridericia's formula [QTcF]), renal (estimated glomerular filtration rate [eGFR]), liver (alanine aminotransferase [ALT], and total bilirubin), and coagulation (prothrombin time [PT]) parameters. Predicted SFRs increased with age for high systolic and diastolic BP, QTcF interval, and eGFR. In contrast, lower SFRs in the older age groups were seen for low diastolic BP, liver function test, ALT, PT, and total bilirubin. This analysis can be used to inform on study design, protocol inclusion and exclusion criteria, and to optimize the screening process. Data-driven critical appraisal of proposed inclusion and exclusion criteria using a risk-based approach may significantly reduce screen failure rates without compromising subjects' safety.

Clopidogrel, a CYP2C8 inhibitor, causes a clinically relevant increase in the systemic exposure to the active metabolite of selexipag in healthy subjects.

AIMS: Selexipag is a prostacyclin receptor agonist approved for the treatment of pulmonary arterial hypertension. Cytochrome P450 (CYP) 2C8 is involved in the metabolism of selexipag and its active metabolite, ACT-333679. This study evaluated the interaction of selexipag and clopidogrel, a CYP2C8 inhibitor. METHODS: The study had a 2-treatment, 1-sequence, crossover design. Pharmacokinetics (PK) and CYP2C8 genotype were assessed in healthy male subjects administered selexipag (200 µg twice daily [b.i.d.]) alone or with clopidogrel (300 mg single dose or 75 mg once daily [o.d.]). PK modelling and simulation were conducted to support dosing recommendations. RESULTS: Clopidogrel had a comparatively small effect on selexipag (<1.5-fold difference in any PK variable). For ACT-333679, the major contributor to the drug effect, the area under the plasma concentration-time curve during a dose interval and the maximum plasma concentration increased 2.25-fold (90% confidence interval [CI] 2.06, 2.46) and 1.69-fold (90% CI 1.55, 1.84), respectively with clopidogrel 300 mg and 2.70-fold (90% CI 2.45, 2.96) and 1.90-fold (90% CI 1.72, 2.11), respectively with clopidogrel 75 mg. The effect of clopidogrel on selexipag and ACT-333679 exposure was comparable for all identified CYP2C8 genotypes. PK simulations predicted comparable exposure to ACT-333679 following selexipag 400 µg b.i.d., 400 µg o.d. in combination with clopidogrel 75 mg o.d and 200 µg b.i.d. with clopidogrel 75 mg o.d. CONCLUSION: Results suggest that ACT-333679 exposure can be maintained within the therapeutic range by reducing selexipag dosing frequency to o.d. or dose to half, when selexipag is coadministered with clopidogrel.

Comparison of a transdermal contraceptive patch with a newly sourced adhesive component versus EVRA patch: A double-blind, randomized, bioequivalence and adhesion study in healthy women.

OBJECTIVE: To evaluate the bioequivalence of norelgestromin and ethinyl estradiol (NGMN-EE) and adhesion of a transdermal contraceptive patch containing a newly sourced adhesive component (test) compared with the marketed (reference) patch. STUDY DESIGN: In this randomized, double-blind, 2-way crossover study, healthy women received single 7-day application of both test and reference patches. Treatment phase included two treatment periods of 11 days each separated by a 21-day washout period starting from day of patch removal (day 8) of treatment period 1. Assessments included NGMN and EE pharmacokinetics (PK), adhesion using European Medicines Agency (EMA) 5-point scale, irritation potential and application-site reactions, and safety. Patches were bioequivalent if 90% CIs of ratios of means of test/reference for AUC168h, AUCinf, and Css fell within 80-125%. Patch adhesion was comparable if ratios of mean cumulative adhesion percentage values of test/reference were ≥90.0%. RESULTS: Seventy women were randomized; 57 completed both treatments with ≥80% adhesion (score 0-1). Bioequivalence of test and reference patches was demonstrated as 90% CI of ratio of geometric means for AUC168h, AUCinf, and Css for NGMN and EE fell within 80-125%. Both patches had similar adhesion properties (geometric mean ratio was 100.3% [90% CI, 93.2-107.9]). Similar rates of mild-to-moderate itching (11% vs 10%) and erythema events (79% vs 74%) were reported for test and reference patches, respectively, on day 8. CONCLUSIONS: The test patch with the newly sourced adhesive component is bioequivalent to the currently marketed NGMN-EE transdermal patch and has similar adhesion and irritation potential. IMPLICATIONS STATEMENT: The norelgestromin and ethinyl estradiol transdermal patch containing a newly sourced adhesive component is bioequivalent to the currently marketed patch for both active moieties. Both patches had similar adhesion, irritation potential, and safety profiles.

Effect of Fluconazole and Itraconazole on the Pharmacokinetics of Erdafitinib in Healthy Adults: A Randomized, Open-Label, Drug-Drug Interaction Study.

BACKGROUND AND OBJECTIVES: Erdafitinib, an oral selective pan-fibroblast growth factor receptor (FGFR) kinase inhibitor, is primarily metabolized by cytochrome P450 (CYP) 2C9 and 3A4. The aim of this phase 1 study was to assess the pharmacokinetics and safety of erdafitinib in healthy participants when coadministered with fluconazole (moderate CYP2C9 and CYP3A inhibitor), and itraconazole (a strong CYP3A4 and P-glycoprotein inhibitor). The effect of CYP2C9 genotype variants (*1/*1, *1/*2, *1/*3) on the pharmacokinetics of erdafitinib was also investigated. METHODS: In this open-label, parallel-group, single-center study, eligible healthy adults were randomized by CYP2C9 genotype to receive Treatment A (single oral dose of erdafitinib 4 mg) on day 1, Treatment B (fluconazole 400 mg/day orally) on days 1-11, or Treatment C (itraconazole 200 mg/day orally) on days 1-11. Healthy adults randomized to Treatment B and C received a single oral 4-mg dose of erdafitinib on day 5. The pharmacokinetic parameters, including mean maximum plasma concentration (Cmax), area under the curve (AUC) from time 0 to 168 h (AUC168h), AUC from time 0 to the last quantifiable concentration (AUClast), and AUC from time 0 to infinity (AUC∞) were calculated from individual plasma concentration-time data using standard non-compartmental methods. RESULTS: Coadministration of erdafitinib with fluconazole increased Cmax of erdafitinib by approximately 21%, AUC168h by 38%, AUClast by 49%, and AUC∞ by 48% while coadministration with itraconazole resulted in no change in erdafitinib Cmax and increased AUC168h by 20%, AUClast by 33% and AUC∞ by 34%. Erdafitinib exposure was comparable between participants with CYP2C9 *1/*2 or *1/*3 and with wild-type CYP2C9 genotype. The ratio of total amount of erdafitinib excreted in the urine (inhibited to non-inhibited) was 1.09, the ratio of total amount of excreted metabolite M6 was 1.21, and the ratio of the metabolite to parent ratio in the urine was 1.11, when coadministration of erdafitinib with itraconazole was compared with single-dose erdafitinib. Treatment-emergent adverse events (TEAEs) were generally Grade 1 or 2 in severity; the most commonly reported TEAE was headache. No safety concerns were identified with single-dose erdafitinib when administered alone and in combination with fluconazole or itraconazole in healthy adults. CONCLUSION: Coadministration of fluconazole or itraconazole or other moderate/strong CYP2C9 or CYP3A4 inhibitors may increase exposure to erdafitinib in healthy adults and thus may warrant erdafitinib dose reduction or use of alternative concomitant medications with no or minimal CYP2C9 or CYP3A4 inhibition potential. TRIAL REGISTRATION: ClinicalTrials.gov identifier number: NCT03135106.

Overcoming the challenges of iris scanning to identify minors (1-4 years) in the real-world setting.

OBJECTIVE: Biometric identification techniques for pediatric use are limited. This investigation studied iris scanning in minors aged 1-4 in two exploratory studies in Belgium (n = 197) and Sierra Leone (n = 230), and in a subsequent clinical study in Sierra Leone (n = 635). Images of participants' irises were captured using a camera, while a survey assessed the ease of use with children. RESULTS: The image capture success rate per individual was high; 86.0% of the participants had ≥ 2 successful captures. Iris scan quality and surface were similar in all age groups and in the matching population database. When including feasibility in the analysis of minors aged 3-4, sensitivity and specificity were non-inferior compared to using the biometric of a guardian. However, the quality of iris scanning in minors aged 1-4 was worse than the iris scanning reference quality in adults. A mean total usability score of 1.55 ± 0.27 was calculated; a usability threshold of 1.45 is required for routine use. Overall, this technique is feasible in minors aged 3-4, replacing the use of guardian biometrics. Additional work is ongoing to improve this technique further, striving for uniformity from the age of 1.

Brief Report: Long-term Outcomes and Their Determinants in Patients on Antiretroviral Treatment in Ethiopia, 2005/6-2011/12: A Retrospective Cohort Study.

BACKGROUND: Antiretroviral treatment (ART) programs in many resource-limited settings have expanded treatment toward universal access. Ethiopia is one of the countries that has been scaling up ART toward universal access, but with very few data on long-term outcomes and their determinants. The objective of this study was to identify the level of long-term outcomes and their determinants in patients on ART in Ethiopia. METHODS: A retrospective cohort study was conducted in 3 health facilities (2 hospitals and 1 health center) between July and September, 2014. Loss to follow-up, death, attrition, and retention were the primary outcomes. Data were collected from patient registers and medical records for the period 2005/6-2011/12. RESULTS: A total of 11,731 patients were included in the study. The overall retention rate was 78 per 100 person-months. Retention rates were 82%, 74%, and 72% at 24, 60, and 84 months on ART, respectively. Retention was associated with male sex, adolescent age, marital status, advanced HIV disease, illiteracy, and peer-support services; however, long-term retention was associated independently with only male sex [with adjusted hazard ratio (aHR) 0.68 (0.56 to 0.77)], married patients [with aHR 0.62 (0.54 to 0.72)], and peer-support services [with aHR 1.62 (1.58 to 1.66)]. DISCUSSION AND CONCLUSIONS: ART programs have lost most of their patients during the first 24 months on ART. It is, therefore, imperative that HIV/ART programs ensure people are tested, linked to care, and initiated on ART early. ART programs should also design and implement interventions, including peer-support services, which are targeted to male, adolescent, unmarried, and illiterate patients.

Sustainability of a community-based anti-retroviral care delivery model - a qualitative research study in Tete, Mozambique.

INTRODUCTION: To overcome patients' reported barriers to accessing anti-retroviral therapy (ART), a community-based delivery model was piloted in Tete, Mozambique. Community ART Groups (CAGs) of maximum six patients stable on ART offered cost- and time-saving benefits and mutual psychosocial support, which resulted in better adherence and retention outcomes. To date, Médecins Sans Frontières has coordinated and supported these community-driven activities. METHODS: To better understand the sustainability of the CAG model, we developed a conceptual framework on sustainability of community-based programmes. This was used to explore the data retrieved from 16 focus group discussions and 24 in-depth interviews with different stakeholder groups involved in the CAG model and to identify factors influencing the sustainability of the CAG model. RESULTS: We report the findings according to the framework's five components. (1) The CAG model was designed to overcome patients' barriers to ART and was built on a concept of self-management and patient empowerment to reach effective results. (2) Despite the progressive Ministry of Health (MoH) involvement, the daily management of the model is still strongly dependent on external resources, especially the need for a regulatory cadre to form and monitor the groups. These additional resources are in contrast to the limited MoH resources available. (3) The model is strongly embedded in the community, with patients taking a more active role in their own healthcare and that of their peers. They are considered as partners in healthcare, which implies a new healthcare approach. (4) There is a growing enabling environment with political will and general acceptance to support the CAG model. (5) However, contextual factors, such as poverty, illiteracy and the weak health system, influence the community-based model and need to be addressed. CONCLUSIONS: The community embeddedness of the model, together with patient empowerment, high acceptability and progressive MoH involvement strongly favour the future sustainability of the CAG model. The high dependency on external resources for the model's daily management, however, can potentially jeopardize its sustainability. Further reflections are required on possible solutions to solve these challenges, especially in terms of human resources.

Four-year retention and risk factors for attrition among members of community ART groups in Tete, Mozambique.

OBJECTIVE: Community ART groups (CAG), peer support groups involved in community ART distribution and mutual psychosocial support, were piloted to respond to staggering antiretroviral treatment (ART) attrition in Mozambique. To understand the impact of CAG on long-term retention, we estimated mortality and lost-to-follow-up (LTFU) rates and assessed predictors for attrition. METHODS: Retrospective cohort study. Kaplan-Meier techniques were used to estimate mortality and LTFU in CAG. Individual- and CAG-level predictors of attrition were assessed using a multivariable Cox proportional hazards model, adjusted for site-level clustering. RESULTS: Mortality and LTFU rates among 5729 CAG members were, respectively, 2.1 and 0.1 per 100 person-years. Retention was 97.7% at 12 months, 96.0% at 24 months, 93.4% at 36 months and 91.8% at 48 months. At individual level, attrition in CAG was significantly associated with immunosuppression when joining a CAG, and being male. At CAG level, attrition was associated with lack of rotational representation at the clinic, lack of a regular CD4 count among fellow members and linkage to a rural or district clinic compared with linkage to a peri-urban clinic. CONCLUSIONS: Long-term retention in this community-based ART model compares favourably with published data on stable ART patients. Nevertheless, to reduce attrition, further efforts need to be made to enroll patients earlier on ART, promote health-seeking behaviour, especially for men, promote a strong peer dynamic to assure rotational representation at the clinic and regular CD4 follow-up and reinforce referral of sick patients.

Four-year retention and risk factors for attrition amongmembers of community ART groups in Tete, Mozambique

objectiveCommunity ART groups (CAG), peer support groups involved in community ARTdistribution and mutual psychosocial support, were piloted to respond to staggering antiretroviraltreatment (ART) attrition in Mozambique. To understand the impact of CAG on long-term retention,we estimated mortality and lost-to-follow-up (LTFU) rates and assessed predictors for attrition.methodsRetrospective cohort study. Kaplan­Meier techniques were used to estimate mortality andLTFU in CAG. Individual- and CAG-level predictors of attrition were assessed using a multivariableCox proportional hazards model, adjusted for site-level clustering.resultsMortality and LTFU rates among 5729 CAG members were, respectively, 2.1 and 0.1 per100 person-years. Retention was 97.7% at 12 months, 96.0% at 24 months, 93.4% at 36 monthsand 91.8% at 48 months. At individual level, attrition in CAG was significantly associated withimmunosuppression when joining a CAG, and being male. At CAG level, attrition was associatedwith lack of rotational representation at the clinic, lack of a regular CD4 count among fellowmembers and linkage to a rural or district clinic compared with linkage to a peri-urban clinic.conclusionsLong-term retention in this community-based ART model compares favourably withpublished data on stable ART patients. Nevertheless, to reduce attrition, further efforts need to bemade to enrol patients earlier on ART, promote health-seeking behaviour, especially for men,promote a strong peer dynamic to assure rotational representation at the clinic and regular CD4follow-up and reinforce referral of sick patients.keywordsantiretroviral therapy, community participation, health services accessibility, HIV, peersupportIntroductionIn the past decade, the scale-up of antiretroviral therapy(ART) was spectacular. In low- and middle-income coun-tries, 9.7 million people were reported on ART at theend of 2012. But still, it is not enough. Still 1.7 millionpeople died because of AIDS in 2011 (WHO 2013a). Toreduce AIDS-related deaths, WHO recommends a newtarget of 25.9 million receiving ART in low- and middle-income countries, an unprecedented public health chal-lenge (WHO 2013b). A major bottleneck is attrition onART, which includes patients who died or who are lostto follow-up (LTFU). A meta-analysis from more than 17countries revealed a patient attrition of 30.0% and35.4% at 24 and 36 months, respectively (Fox & Rosen2010). Transport costs and distance are the mostfrequently cited barriers to adherence (Govindasamyet al.2012).In Mozambique, with a prevalence of 11.5% amongadults, more than 1.5 million Mozambicans are livingwith HIV (Ministry of Health Mozambique 2010). At theend of 2012, only 42% (308 577) of the 690 000 esti-mated in need were on ART (WHO 2012). Meanwhile,almost one-third of the people living with HIV/AIDS(PLWHA) who had started ART were either dead orLTFU (Ministry of Health Mozambique 2012a). Thedecentralisation of ART care, which aimed to decreasethe burden on overloaded clinics and increase accessibil-ity for the patients, was hampered by a lack of infrastruc-ture, a lack of human resources for health and514© 2014 John Wiley & Sons LtdTropical Medicine and International Healthdoi:10.1111/tmi.12278volume 19 no 5 pp 514­521 may 2014

Adapting a community-based ART delivery model to the patients' needs: a mixed methods research in Tete, Mozambique.

BACKGROUND: To improve retention in antiretroviral therapy (ART), lessons learned from chronic disease care were applied to HIV care, providing more responsibilities to patients in the care of their chronic disease. In Tete--Mozambique, patients stable on ART participate in the ART provision and peer support through Community ART Groups (CAG). This article analyses the evolution of the CAG-model during its implementation process. METHODS: A mixed method approach was used, triangulating qualitative and quantitative findings. The qualitative data were collected through semi-structured focus groups discussions and in-depth interviews. An inductive qualitative content analysis was applied to condense and categorise the data in broader themes. Health outcomes, patients' and groups' characteristics were calculated using routine collected data. We applied an 'input--process--output' pathway to compare the initial planned activities with the current findings. RESULTS: Input wise, the counsellors were considered key to form and monitor the groups. In the process, the main modifications found were the progressive adaptations of the daily CAG functioning and the eligibility criteria according to the patients' needs. Beside the anticipated outputs, i.e. cost and time saving benefits and improved treatment outcomes, the model offered a mutual adherence support and protective environment to the members. The active patient involvement in several health activities in the clinics and the community resulted in a better HIV awareness, decreased stigma, improved health seeking behaviour and better quality of care. CONCLUSIONS: Over the past four years, the modifications in the CAG-model contributed to a patient empowerment and better treatment outcomes. One of the main outstanding questions is how this model will evolve in the future. Close monitoring is essential to ensure quality of care and to maintain the core objective of the CAG-model 'facilitating access to ART care' in a cost and time saving manner.

A qualitative assessment of a community antiretroviral therapy group model in Tete, Mozambique.

BACKGROUND: To improve retention on ART, Médecins Sans Frontières, the Ministry of Health and patients piloted a community-based antiretroviral distribution and adherence monitoring model through Community ART Groups (CAG) in Tete, Mozambique. By December 2012, almost 6000 patients on ART had formed groups of whom 95.7% were retained in care. We conducted a qualitative study to evaluate the relevance, dynamic and impact of the CAG model on patients, their communities and the healthcare system. METHODS: Between October 2011 and May 2012, we conducted 16 focus group discussions and 24 in-depth interviews with the major stakeholders involved in the CAG model. Audio-recorded data were transcribed verbatim and analysed using a grounded theory approach. RESULTS: Six key themes emerged from the data: 1) Barriers to access HIV care, 2) CAG functioning and actors involved, 3) Benefits for CAG members, 4) Impacts of CAG beyond the group members, 5) Setbacks, and 6) Acceptance and future expectations of the CAG model. The model provides cost and time savings, certainty of ART access and mutual peer support resulting in better adherence to treatment. Through the active role of patients, HIV information could be conveyed to the broader community, leading to an increased uptake of services and positive transformation of the identity of people living with HIV. Potential pitfalls included limited access to CAG for those most vulnerable to defaulting, some inequity to patients in individual ART care and a high dependency on counsellors. CONCLUSION: The CAG model resulted in active patient involvement and empowerment, and the creation of a supportive environment improving the ART retention. It also sparked a reorientation of healthcare services towards the community and strengthened community actions. Successful implementation and scalability requires (a) the acceptance of patients as partners in health, (b) adequate resources, and (c) a well-functioning monitoring and management system.

How to improve patient retention in an antiretroviral treatment program in Ethiopia: a mixed-methods study.

BACKGROUND: Patient retention, defined as continuous engagement of patients in care, is one of the crucial indicators for monitoring and evaluating the performance of antiretroviral treatment (ART) programs. It has been identified that suboptimal patient retention in care is one of the challenges of ART programs in many settings. ART programs have, therefore, been striving hard to identify and implement interventions that improve their suboptimal levels of retention. The objective of this study was to develop a framework for improving patient retention in care based on interventions implemented in health facilities that have achieved higher levels of retention in care. METHODS: A mixed-methods study, based on the positive deviance approach, was conducted in Ethiopia in 2011/12. Quantitative data were collected to estimate and compare the levels of retention in care in nine health facilities. Key informant interviews and focus group discussions were conducted to identify a package of interventions implemented in the health facilities with relatively higher or improving levels of retention. RESULTS: Retention in care in the Ethiopian ART program was found to be variable across health facilities. Among hospitals, the poorest performer had 0.46 (0.35, 0.60) times less retention than the reference; among health centers, the poorest performers had 0.44 (0.28, 0.70) times less retention than the reference. Health facilities with higher and improving patient retention were found to implement a comprehensive package of interventions: (1) retention promoting activities by health facilities, (2) retention promoting activities by community-based organizations, (3) coordination of these activities by case manager(s), and (4) patient information systems by data clerk(s). On the contrary, such interventions were either poorly implemented or did not exist in health facilities with lower retention in care. A framework to improve retention in care was developed based on the evidence found by applying the positive deviance approach. CONCLUSION: A framework for improving retention in care of patients on ART was developed. We recommend that health facilities implement the framework, monitor and evaluate their levels of retention in care, and, if necessary, adapt the framework to their own contexts.

Community-based antiretroviral therapy programs can overcome barriers to retention of patients and decongest health services in sub-Saharan Africa: a systematic review.

In sub-Saharan Africa models of care need to adapt to support continued scale up of antiretroviral therapy (ART) and retain millions in care. Task shifting, coupled with community participation has the potential to address the workforce gap, decongest health services, improve ART coverage, and to sustain retention of patients on ART over the long-term. The evidence supporting different models of community participation for ART care, or community-based ART, in sub-Saharan Africa, was reviewed. In Uganda and Kenya community health workers or volunteers delivered ART at home. In Mozambique people living with HIV/AIDS (PLWHA) self-formed community-based ART groups to deliver ART in the community. These examples of community ART programs made treatment more accessible and affordable. However, to achieve success some major challenges need to be overcome: first, community programs need to be driven, owned by and embedded in the communities. Second, an enabling and supportive environment is needed to ensure that task shifting to lay staff and PLWHA is effective and quality services are provided. Finally, a long term vision and commitment from national governments and international donors is required. Exploration of the cost, effectiveness, and sustainability of the different community-based ART models in different contexts will be needed.

Short and long term retention in antiretroviral care in health facilities in rural Malawi and Zimbabwe.

BACKGROUND: Despite the successful scale-up of ART services over the past years, long term retention in ART care remains a major challenge, especially in high HIV prevalence and resource-limited settings. This study analysed the short (<12 months) and long (>12 months) term retention on ART in two ART programmes in Malawi (Thyolo district) and Zimbabwe (Buhera district). METHODS: Retention rates at six-month intervals are reported separately among (1) patients since ART initiation and (2) patients who had been on ART for at least 12 months, according to the site of ART initiation and follow-up, using the Kaplan Meier method. 'Retention' was defined as being alive on ART or transferred out, while 'attrition' was defined as dead, lost to follow-up or stopped ART. RESULTS: In Thyolo and Buhera, a total of 12,004 and 9,721 patients respectively were included in the analysis. The overall retention among the patients since ART initiation was 84%, 80% and 77% in Thyolo and 88%, 84% and 82% in Buhera at 6, 12 and 18 months, respectively. In both programmes the largest drop in ART retention was found during the initial 12 months on ART, mainly related to a high mortality rate in the health centres in Thyolo and a high loss to follow-up rate in the hospital in Buhera. Among the patients who had been on ART for at least 12 months, the retention rates leveled out, with 97%, 95% and 94% in both Thyolo and Buhera, at 18, 24 and 30 months respectively. Loss to follow-up was identified as the main contributor to attrition after 12 months on treatment in both programmes. CONCLUSIONS: To better understand the reasons of attrition and adapt the ART delivery care models accordingly, it is advisable to analyse short and long term retention separately, in order to adapt intervention strategies accordingly. During the initial months on ART more medical follow-up, especially for symptomatic patients, is required to reduce mortality. Once stable on ART, however, the ART care delivery should focus on regular drug refill and adherence support to reduce loss to follow up. Hence, innovative life-long retention strategies, including use of new communication technologies, community based interventions and drug refill outside the health facilities are required.

Management of Chronic Diseases in Sub-Saharan Africa: Cross-Fertilisation between HIV/AIDS and Diabetes Care.

There is growing attention for chronic diseases in sub-Saharan Africa (SSA) and for bridges between the management of HIV/AIDS and other (noncommunicable) chronic diseases. This becomes more urgent with increasing numbers of people living with both HIV/AIDS and other chronic conditions. This paper discusses the commonalities between chronic diseases by reviewing models of care, focusing on the two most dominant ones, diabetes mellitus type 2 (DM2) and HIV/AIDS. We argue that in order to cope with care for HIV patients and diabetes patients, health systems in SSA need to adopt new strategies taking into account essential elements of chronic disease care. We developed a "chronic dimension framework," which analyses the "disease dimension," the "health provider dimension," the patient or "person dimension," and the "environment dimension" of chronic diseases. Applying this framework to HIV/AIDS and DM2 shows that it is useful to think about management of both in tandem, comparing care delivery platforms and self-management strategies. A literature review on care delivery models for diabetes and HIV/AIDS in SSA revealed potential elements for cross-fertilisation: rapid scale-up approaches through the public health approach by simplification and decentralisation; community involvement, peer support, and self-management strategies; and strengthening health services.

Are Expert Patients an Untapped Resource for ART Provision in Sub-Saharan Africa?

Since the introduction of antiretroviral treatment, HIV/AIDS can be framed as a chronic lifelong condition, requiring lifelong adherence to medication. Reinforcement of self-management through information, acquisition of problem solving skills, motivation, and peer support is expected to allow PLWHA to become involved as expert patients in the care management and to decrease the dependency on scarce skilled medical staff. We developed a conceptual framework to analyse how PLWHA can become expert patients and performed a literature review on involvement of PLWHA as expert patients in ART provision in Sub-Saharan Africa. This paper revealed two published examples: one on trained PLWHA in Kenya and another on self-formed peer groups in Mozambique. Both programs fit the concept of the expert patient and describe how community-embedded ART programs can be effective and improve the accessibility and affordability of ART. Using their day-to-day experience of living with HIV, expert patients are able to provide better fitting solutions to practical and psychosocial barriers to adherence. There is a need for careful design of models in which expert patients are involved in essential care functions, capacitated, and empowered to manage their condition and support fellow peers, as an untapped resource to control HIV/AIDS.

Positive spill-over effects of ART scale up on wider health systems development: evidence from Ethiopia and Malawi.

BACKGROUND: Global health initiatives have enabled the scale up of antiretroviral treatment (ART) over recent years. The impact of HIV-specific funds and programmes on non-HIV-related health services and health systems in genera has been debated extensively. Drawing on evidence from Malawi and Ethiopia, this article analyses the effects of ART scale-up interventions on human resources policies, service delivery and general health outcomes, and explores how synergies can be maximized. METHODS: Data from Malawi and Ethiopia were compiled between 2004 and 2009 and between 2005 and 2009, respectively. We developed a conceptual health systems framework for the analysis. We used the major changes in human resources policies as an entry point to explore the wider health systems changes. RESULTS: In both countries, the need for an HIV response triggered an overhaul of human resources policies. As a result, the health workforce at health facility and community level was reinforced. The impact of this human resources trend was felt beyond the scale up of ART services; it also contributed to an overall increase in functional health facilities providing curative, mother and child health, and ART services. In addition to a significant increase in ART coverage, we observed a remarkable rise in user rates of non-HIV health services and an improvement in overall health outcomes. CONCLUSIONS: Interventions aimed at the expansion of ART services and improvement of long-term retention of patients in ART care can have positive spill-over effects on the health system. The responses of Malawi and Ethiopia to their human resources crises was exceptional in many respects, and some of the lessons learnt can be useful in other contexts. The case studies show the feasibility of obtaining improved health outcomes beyond HIV through scaled-up ART interventions when these are part of a long-term, system-wide health plan supported by all decision makers and funders.