Efficacy, Safety and Tolerability of Pyronaridine-artesunate in Asymptomatic Malaria-infected Individuals: a Randomized Controlled Trial

BACKGROUND: Pyronaridine-artesunate (PA) is a registered artemisinin-based combination therapy, potentially useful for mass drug administration campaigns. However, further data are needed to evaluate its efficacy, safety and tolerability as full or incomplete treatment in asymptomatic Plasmodium falciparum-infected individuals. METHODS: This phase II, multi-center, open label, randomized clinical trial was conducted in The Gambia and Zambia. Participants with microscopically confirmed asymptomatic P. falciparum infection were randomly assigned (1:1:1) to receive a 3-day, 2-day, or 1-day treatment regimen of PA (180:60 mg), dosed according to bodyweight. The primary efficacy outcome was polymerase chain reaction (PCR)-adjusted adequate parasitological response (APR) at day 28 in the per-protocol population. RESULTS: A total of 303 participants were randomized. Day 28 PCR-adjusted APR was 100% for both the 3-day (98/98) and 2-day regimens (96/96), and 96.8% (89/94) for the 1-day regimen. Efficacy was maintained at 100% until day 63 for the 3-day and 2-day regimens but declined to 94.4% (84/89) with the 1-day regimen. Adverse event frequency was similar between the 3-day (51.5% [52/101]), 2-day (52.5% [52/99]), and 1-day (54.4% [56/103]) regimens; the majority of adverse events were of grade 1 or 2 severity (85% [136/160]). Asymptomatic, transient increases (>3 times the upper limit of normal) in alanine aminotransferase/aspartate aminotransferase were observed for 6/301 (2.0%) participants. CONCLUSIONS: PA had high efficacy and good tolerability in asymptomatic P. falciparum-infected individuals, with similar efficacy for the full 3-day and incomplete 2-day regimens. Although good adherence to the 3-day regimen should be encouraged, these results support the further investigation of PA for mass drug administration campaigns. CLINICAL TRIALS REGISTRATION: NCT03814616

Scaling up paediatric HIV care with an integrated, family-centred approach: an observational case study from Uganda.

Family-centred HIV care models have emerged as an approach to better target children and their caregivers for HIV testing and care, and further provide integrated health services for the family unit's range of care needs. While there is significant international interest in family-centred approaches, there is a dearth of research on operational experiences in implementation and scale-up. Our retrospective case study examined best practices and enabling factors during scale-up of family-centred care in ten health facilities and ten community clinics supported by a non-governmental organization, Mildmay, in Central Uganda. Methods included key informant interviews with programme management and families, and a desk review of hospital management information systems (HMIS) uptake data. In the 84 months following the scale-up of the family-centred approach in HIV care, Mildmay experienced a 50-fold increase of family units registered in HIV care, a 40-fold increase of children enrolled in HIV care, and nearly universal coverage of paediatric cotrimoxazole prophylaxis. The Mildmay experience emphasizes the importance of streamlining care to maximize paediatric capture. This includes integrated service provision, incentivizing care-seeking as a family, creating child-friendly service environments, and minimizing missed paediatric testing opportunities by institutionalizing early infant diagnosis and provider-initiated testing and counselling. Task-shifting towards nurse-led clinics with community outreach support enabled rapid scale-up, as did an active management structure that allowed for real-time review and corrective action. The Mildmay experience suggests that family-centred approaches are operationally feasible, produce strong coverage outcomes, and can be well-managed during rapid scale-up

Client flow pathway into HIV care and treatment within family-centred approach.

<p>Figure demonstrates the patient flow at integrated facilities; the pathway has been adapted from the WHO Integrated Management of Adult Illness sequence of care. Entry points into family-based points including outpatient care, maternal and child health clinics, antenatal care, inpatient admissions, and community-based outreach. Clients then proceed through triage assessments, education and support as required, assessment of client and family health status, care and treatment as required, positive prevention for HIV-infected clients, and follow-up care services.</p

Cumulative trend of uptake of paediatric care after introduction of family-based approach at Mildmay main site in 2003.

<p>Figure demonstrates uptake trends from 1999 to 2010 for three key indicators: number of children and adolescents enrolled in HIV care, number on cotrimoxazole prophylaxis, and number on ART. Uptake data shows sharp increases for all three indicators at 2003, when the family-based approached was introduced at Mildmay.</p

Service approach at health facilities before and after family-centred approach.

<p>Figure describes several service delivery components (e.g. scheduling, counseling, medication refills, and community engagement) before and after the family-centred approach. The figure demonstrates considerable effort to re-align the service approach to make it family-friendly, for example, same-day scheduling for families or fast-tracking families with children for services.</p

Possibilities for integrated service package for family-centred care.

<p>Figure displays recommended services listed within four sub-headings: HIV and TB care, paediatric and adult primary care, psychosocial and economic support, and administrative services.</p

Capacity building for integrating family-centred care at partner facilities.

<p>Figure describes the courses designed by Mildmay and made available during partner facility service integration, as needs assessments determine. These include short-term (week) courses on skills sets like pediatric HIV nursing or laboratory skills, modular courses on more advanced subjects like community-based HIV care and health systems approaches, and training for community volunteers on HIV/AIDS basics and counseling skills.</p