A multicentre, randomised, non-inferiority clinical trial comparing a nifurtimox-eflornithine combination to standard eflornithine monotherapy for late stage Trypanosoma brucei gambiense human African trypanosomiasis in Uganda.

BACKGROUND: While the combination of nifurtimox and eflornithine (NECT) is currently recommended for the treatment of the late stage human African trypansomiasis (HAT), single-agent eflornithine was still the treatment of choice when this trial commenced. This study intended to provide supportive evidence to complement previous trials. METHODS: A multi-centre randomised, open-label, non-inferiority trial was carried out in the Trypanosoma brucei gambiense endemic districts of North-Western Uganda to compare the efficacy and safety of NECT (200 mg/kg eflornithine infusions every 12 h for 7 days and 8 hourly oral nifurtimox at 5 mg/kg for 10 days) to the standard eflornithine regimen (6 hourly at 100 mg/kg for 14 days). The primary endpoint was the cure rate, determined as the proportion of patients alive and without laboratory signs of infection at 18 months post-treatment, with no demonstrated trypanosomes in the cerebrospinal fluid (CSF), blood or lymph node aspirates, and CSF white blood cell count < 20 /µl. The non-inferiority margin was set at 10%. RESULTS: One hundred and nine patients were enrolled; all contributed to the intent-to-treat (ITT), modified intent-to-treat (mITT) and safety populations, while 105 constituted the per-protocol population (PP). The cure rate was 90.9% for NECT and 88.9% for eflornithine in the ITT and mITT populations; the same was 90.6 and 88.5%, respectively in the PP population. Non-inferiority was demonstrated for NECT in all populations: differences in cure rates were 0.02 (95% CI: -0.07-0.11) and 0.02 (95% CI: -0.08-0.12) respectively. Two patients died while on treatment (1 in each arm), and 3 more during follow-up in the NECT arm. No difference was found between the two arms for the secondary efficacy and safety parameters. A meta-analysis involving several studies demonstrated non-inferiority of NECT to eflornithine monotherapy. CONCLUSIONS: These results confirm findings of earlier trials and support implementation of NECT as first-line treatment for late stage T. b. gambiense HAT. The overall risk difference for cure between NECT and eflornithine between this and two previous randomised controlled trials is 0.03 (95% CI: -0.02-0.08). The NECT regimen is simpler, safer, shorter and less expensive than single-agent DFMO. TRIAL REGISTRATION: ISRCTN ISRCTN03148609 (registered 18 April 2008).

Including refugees in disease elimination: challenges observed from a sleeping sickness programme in Uganda.

BACKGROUND: Ensuring equity between forcibly-displaced and host area populations is a key challenge for global elimination programmes. We studied Uganda's response to the recent refugee influx from South Sudan to identify key governance and operational lessons for national sleeping sickness programmes working with displaced populations today. A refugee policy which favours integration of primary healthcare services for refugee and host populations and the availability of rapid diagnostic tests (RDTs) to detect sleeping sickness at this health system level makes Uganda well-placed to include refugees in sleeping sickness surveillance. METHODS: Using ethnographic observations of coordination meetings, review of programme data, interviews with sleeping sickness and refugee authorities and group discussions with health staff and refugees (2013-2016), we nevertheless identified some key challenges to equitably integrating refugees into government sleeping sickness surveillance. RESULTS: Despite fears that refugees were at risk of disease and posed a threat to elimination, six months into the response, programme coordinators progressed to a sentinel surveillance strategy in districts hosting the highest concentrations of refugees. This meant that RDTs, the programme's primary surveillance tool, were removed from most refugee-serving facilities, exacerbating existing inequitable access to surveillance and leading refugees to claim that their access to sleeping sickness tests had been better in South Sudan. This was not intentionally done to exclude refugees from care, rather, four key governance challenges made it difficult for the programme to recognise and correct inequities affecting refugees: (a) perceived donor pressure to reduce the sleeping sickness programme's scope without clear international elimination guidance on surveillance quality; (b) a problematic history of programme relations with refugee-hosting districts which strained supervision of surveillance quality; (c) difficulties that government health workers faced to produce good quality surveillance in a crisis; and (d) reluctant engagement between the sleeping sickness programme and humanitarian structures. CONCLUSIONS: Despite progressive policy intentions, several entrenched governance norms and practices worked against integration of refugees into the national sleeping sickness surveillance system. Elimination programmes which marginalise forced migrants risk unwittingly contributing to disease spread and reinforce social inequities, so new norms urgently need to be established at local, national and international levels.