Insecticide resistance status of the malaria mosquitoes: Anopheles gambiae and Anopheles funestus in eastern and northern Uganda.

BACKGROUND: Uganda's malaria burden includes the sixth highest number of annual deaths in Africa (10,500) with approximately 16 million cases (2013) and the entire population at risk. The President's Malaria Initiative has been supporting the malaria control interventions of indoor residual spraying (IRS) and distribution of long-lasting insecticidal nets (LLIN) in Uganda since 2007. These interventions are threatened by emerging and spreading insecticide resistance, known to exist in Ugandan malaria vectors. Pyrethroid insecticides have been used in agriculture since the early 1990s and in IRS programmes from the mid-2000s until 2010. A universal LLIN coverage campaign was executed in 2013-2014, distributing pyrethroid-treated LLINs throughout the country. This study investigated insecticide susceptibility, intensity, and oxidase detoxification in Anopheles gambiae sensu lato and Anopheles funestus to permethrin and deltamethrin in four eastern Ugandan sites. METHODS: The susceptibility status of An. gambiae and An. funestus to bendiocarb, permethrin and deltamethrin was determined using the CDC (Centers for Disease Control and Prevention) bottle bioassay. Presence of oxidative enzyme detoxification mechanisms were determined by pre-exposing mosquitoes to piperonyl butoxide followed with exposure to discriminating doses of deltamethrin- and permethrin-coated CDC bottles. Resistance intensity was investigated using serial dosages of 1×, 2×, 5× and 10× the diagnostic dose and scored at 30 min to determine the magnitude of resistance to both of these LLIN pyrethroids. Testing occurred in the Northern and Eastern Regions of Uganda. RESULTS: Anopheles gambiae and An. funestus were fully susceptible to bendiocarb where tested. Anopheles gambiae resistance to deltamethrin and permethrin was observed in all four study sites. Anopheles funestus was resistant to deltamethrin and permethrin in Soroti. Oxidative resistance mechanisms were found in An. gambiae conferring pyrethroid resistance in Lira and Apac. 14.3% of An. gambiae from Tororo survived exposure of 10× concentrations of permethrin. CONCLUSIONS: Both An. gambiae and An. funestus are resistant to pyrethroids but fully susceptible to bendiocarb at all sites. Susceptibility monitoring guided the Ministry of Health's decision to rotate between IRS insecticide classes. Intensity bioassay results may indicate encroaching control failure of pyrethroid-treated LLINs and should inform decision-makers when choosing LLINs for the country.

Closing the access barrier for effective anti-malarials in the private sector in rural Uganda: consortium for ACT private sector subsidy (CAPSS) pilot study.

BACKGROUND: Artemisinin-based combination therapy (ACT), the treatment of choice for uncomplicated falciparum malaria, is unaffordable and generally inaccessible in the private sector, the first port of call for most malaria treatment across rural Africa. Between August 2007 and May 2010, the Uganda Ministry of Health and the Medicines for Malaria Venture conducted the Consortium for ACT Private Sector Subsidy (CAPSS) pilot study to test whether access to ACT in the private sector could be improved through the provision of a high level supply chain subsidy. METHODS: Four intervention districts were purposefully selected to receive branded subsidized medicines - "ACT with a leaf", while the fifth district acted as the control. Baseline and evaluation outlet exit surveys and retail audits were conducted at licensed and unlicensed drug outlets in the intervention and control districts. A survey-adjusted, multivariate logistic regression model was used to analyse the intervention's impact on: ACT uptake and price; purchase of ACT within 24 hours of symptom onset; ACT availability and displacement of sub-optimal anti-malarial. RESULTS: At baseline, ACT accounted for less than 1% of anti-malarials purchased from licensed drug shops for children less than five years old. However, at evaluation, "ACT with a leaf" accounted for 69% of anti-malarial purchased in the interventions districts. Purchase of ACT within 24 hours of symptom onset for children under five years rose from 0.8% at baseline to 26.2% (95% CI: 23.2-29.2%) at evaluation in the intervention districts. In the control district, it rose modestly from 1.8% to 5.6% (95% CI: 4.0-7.3%). The odds of purchasing ACT within 24 hours in the intervention districts compared to the control was 0.46 (95% CI: 0.08-2.68, p=0.4) at baseline and significant increased to 6.11 (95% CI: 4.32-8.62, p<0.0001) at evaluation. Children less than five years of age had "ACT with a leaf" purchased for them more often than those aged above five years. There was no evidence of price gouging. CONCLUSIONS: These data demonstrate that a supply-side subsidy and an intensive communications campaign significantly increased the uptake and use of ACT in the private sector in Uganda.

Artemether-lumefantrine versus dihydroartemisinin-piperaquine for treating uncomplicated malaria: a randomized trial to guide policy in Uganda.

BACKGROUND: Uganda recently adopted artemether-lumefantrine (AL) as the recommended first-line treatment for uncomplicated malaria. However, AL has several limitations, including a twice-daily dosing regimen, recommendation for administration with fatty food, and a high risk of reinfection soon after therapy in high transmission areas. Dihydroartemisinin-piperaquine (DP) is a new alternative artemisinin-based combination therapy that is dosed once daily and has a long post-treatment prophylactic effect. We compared the efficacy and safety of AL with DP in Kanungu, an area of moderate malaria transmission. METHODOLOGY/PRINCIPAL FINDINGS: Patients aged 6 months to 10 years with uncomplicated falciparum malaria were randomized to therapy and followed for 42 days. Genotyping was used to distinguish recrudescence from new infection. Of 414 patients enrolled, 408 completed follow-up. Compared to patients treated with artemether-lumefantrine, patients treated with dihydroartemisinin-piperaquine had a significantly lower risk of recurrent parasitaemia (33.2% vs. 12.2%; risk difference = 20.9%, 95% CI 13.0-28.8%) but no statistically significant difference in the risk of treatment failure due to recrudescence (5.8% vs. 2.0%; risk difference = 3.8%, 95% CI -0.2-7.8%). Patients treated with dihydroartemisinin-piperaquine also had a lower risk of developing gametocytaemia after therapy (4.2% vs. 10.6%, p = 0.01). Both drugs were safe and well tolerated. CONCLUSIONS/SIGNIFICANCE: DP is highly efficacious, and operationally preferable to AL because of a less intensive dosing schedule and requirements. Dihydroartemisinin-piperaquine should be considered for a role in the antimalarial treatment policy of Uganda. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN75606663.

Artemisinin combination therapies for treatment of uncomplicated malaria in Uganda.

OBJECTIVES: To compare the efficacy and safety of artemisinin combination therapies for the treatment of uncomplicated falciparum malaria in Uganda. DESIGN: Randomized single-blind controlled trial. SETTING: Tororo, Uganda, an area of high-level malaria transmission. PARTICIPANTS: Children aged one to ten years with confirmed uncomplicated P. falciparum malaria. INTERVENTIONS: Amodiaquine + artesunate or artemether-lumefantrine. OUTCOME MEASURES: Risks of recurrent symptomatic malaria and recurrent parasitemia at 28 days, unadjusted and adjusted by genotyping to distinguish recrudescences and new infections. RESULTS: Of 408 participants enrolled, 403 with unadjusted efficacy outcomes were included in the per-protocol analysis. Both treatment regimens were highly efficacious; no recrudescences occurred in patients treated with amodiaquine + artesunate, and only two occurred in those treated with artemether-lumefantrine. However, recurrent malaria due to new infections was common. The unadjusted risk of recurrent symptomatic malaria was significantly lower for participants treated with artemether-lumefantrine than for those treated with amodiaquine + artesunate (27% versus 42%, risk difference 15%, 95% CI 5.9%-24.2%). Similar results were seen for the risk of recurrent parasitemia (51% artemether-lumefantrine versus 66% amodiaquine + artesunate, risk difference 16%, 95% CI 6.2%-25.2%). Amodiaquine + artesunate and artemether-lumefantrine were both well-tolerated. Serious adverse events were uncommon with both regimens. CONCLUSIONS: Amodiaquine + artesunate and artemether-lumefantrine were both highly efficacious for treatment of uncomplicated malaria. However, in this holoendemic area, despite the excellent performance of both regimens in terms of efficacy, many patients experienced recurrent parasitemia due to new infections. Artemether-lumefantrine was superior to amodiaquine + artesunate for prevention of new infections. To maximize the benefit of artemisinin combination therapy in Africa, treatment should be integrated with strategies to prevent malaria transmission. The impact of frequent repeated therapy on the efficacy, safety, and cost-effectiveness of new artemisinin regimens should be further investigated.

Diagnostic accuracy of two rK39 antigen-based dipsticks and the formol gel test for rapid diagnosis of visceral leishmaniasis in northeastern Uganda.

The development of an accurate, practical, and affordable diagnostic test is essential to improve the management of visceral leishmaniasis (VL) in remote health centers. We evaluated the Formol Gel test (FGT) and two rK39 antigen-based dipsticks, the DUAL-IT L/M, and the Kalazar Detect for VL diagnosis in Amudat Hospital in Uganda. The DUAL-IT L/M was also evaluated for the diagnosis of malaria. All patients clinically suspect of VL were prospectively included in the study between October 2003 and March 2004. The gold standard used to define a VL case was a positive spleen aspirate or a direct agglutination test titer of >1:12,800 with an appropriate clinical response to antileishmanial therapy. A total of 131 VL and 112 non-VL patients were included in the analysis. The DUAL IT L/M was found to be more sensitive than the Kalazar Detect: 97% (95% confidence interval [95%CI] = 92 to 99%) versus 82% (95%CI = 74 to 87%). The Kalazar Detect and the DUAL IT L/M were highly specific (99% [95%CI = 95 to 100%] and 97% [95%CI = 92 to 99%], respectively). The FGT lacked both sensitivity (66% [95%CI = 57 to 73%]) and specificity (90% [95%CI = 83 to 94%]). The sensitivity of the DUAL IT L/M for malaria was only 57% (95%CI = 37 to 76%). The two rK39 dipsticks can be used for diagnostic confirmation of VL in this region. The DUAL-IT L/M without its malaria diagnostic component (DiaMed-IT LEISH) will be adopted as first-line test for VL in Uganda.