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).

Bioefficacy of long-lasting insecticidal nets against pyrethroid-resistant populations of Anopheles gambiae s.s. from different malaria transmission zones in Uganda.

BACKGROUND: There are major concerns over sustaining the efficacy of current malaria vector control interventions given the rapid spread of resistance, particularly to pyrethroids. This study assessed the bioefficacy of five WHO-recommended long-lasting insecticidal nets (LLINs) against pyrethroid-resistant Anopheles gambiae field populations from Uganda. METHODS: Adult An. gambiae from Lira, Tororo, Wakiso and Kanungu districts were exposed to permethrin (0.75%) or deltamethrin (0.05%) in standard WHO susceptibility tests. Cone bioassays were used to measure the bioefficacy of four mono-treated LLINs (Olyset®, Interceptor®, Netprotect® and PermaNet® 2.0) and one combination LLIN (PermaNet® 3.0) against the four mosquito populations. Wireball assays were similarly conducted to determine knockdown rates. Species composition and kdr mutation frequency were determined for a sample of mosquitoes from each population. Chemical assays confirmed that test nets fell within target dose ranges. RESULTS: Anopheles gambiae s.s. predominated at all four sites (86-99% of Anopheles spp.) with moderate kdr L1014S allelic frequency (0.34-0.37). Confirmed or possible resistance to both permethrin and deltamethrin was identified for all four test populations. Reduced susceptibility to standard LLINs was observed for all four populations, with mortality rates as low as 45.8% even though the nets were unused. The combination LLIN PermaNet®3.0 showed the highest overall bioefficacy against all four An. gambiae s.l. populations (98.5-100% mortality). Wireball assays provided a more sensitive indicator of comparative bioefficacy, and PermaNet 3.0 was again associated with the highest bioefficacy against all four populations (76.5-91.7% mortality after 30 mins). CONCLUSIONS: The bioefficacy of mono-treated LLINs against pyrethroid-resistant field populations of An. gambiae varied by LLIN type and mosquito population, indicating that certain LLINs may be more suitable than others at particular sites. In contrast, the combination LLIN PermaNet 3.0 performed optimally against the four An. gambiae populations tested. The observed reduced susceptibility of malaria vectors to mono-treated LLINs is of particular concern, especially considering all nets were unused. With ongoing scale-up of insecticidal tools in the advent of increasing resistance, it is essential that those interventions with proven enhanced efficacy are given preference particularly in areas with high resistance.

The Affordable Medicines Facility-malaria--a success in peril.

The Affordable Medicines Facility-malaria (AMFm) has put into place a bold financing plan for artemisinin-combination therapy in a pilot phase in seven countries covering half the population at risk of malaria in Africa. A report of the AMFm independent evaluation, conducted by ICF International and the London School of Hygiene and Tropical Medicine, describes the success of the programme in the pilot sites: Ghana, Kenya, Madagascar, Niger, Nigeria, Tanzania (mainland and Zanzibar) and Uganda, comparing availability and affordability of high-quality artemisinin-combination therapies before and after AMFm launched. Proof of concept was achieved: AMFm increased availability and kept prices low, meeting its initial, ambitious benchmarks in most settings. Despite this overwhelming success, opposition to the programme and dwindling resources for malaria control conspire to cripple or kill AMFm.

Malaria in Uganda: challenges to control on the long road to elimination. II. The path forward.

In the recent past there have been several reports of successes in malaria control, leading some public health experts to conclude that Africa is witnessing an epidemiological transition, from an era of failed malaria control to progression from successful control to elimination. Successes in control have been attributed to increased international donor support leading to increased intervention coverage. However, these changes are not uniform across Africa. In Uganda, where baseline transmission is very high and intervention coverage not yet to scale, the malaria burden is not declining and has even likely increased in the last decade. In this article we present perspectives for the future for Uganda and other malaria endemic countries with high baseline transmission intensity and significant health system challenges. For these high burden areas, malaria elimination is currently not feasible, and early elimination programs are inappropriate, as they would further fragment already fragmented and inefficient malaria control systems. Rather, health impacts will be maximized by aiming to achieve universal coverage of proven interventions in the context of a strengthened health system.