Background and rationale
Malaria remains one of the major public health problems of the developing world and Uganda, Nigeria and the Democratic Republic of Congo (DRC) contribute about 50 % of the malaria burden in Africa. Malaria is the leading cause of morbidity and mortality in Uganda, accounting each year for approximately 8-13 million reported episodes and approximately 40,000 deaths in children under five years of age. Prompt effective treatment of the disease with effective therapy remains one of the major strategies for the control/elimination of malaria. However, malaria chemotherapy poses unique challenges in much of rural Africa where the disease is highly endemic, often resulting in several clinical attacks per person per year that require repeated treatments over a relatively short period of time. For decades, chloroquine (CQ) was the mainstay of antimalarial therapy, but the emergence and spread of Plasmodium falciparum resistance to CQ and to other monotherapies challenged control efforts. Since 2000, the choice of the most appropriate treatment for uncomplicated malaria in Africa has become increasingly complex because efficacy could vary depending on malaria transmission intensity. Use of combination antimalarial therapy, particularly artemisinin-based combination therapy, has since 2001 been recommended by the World Health Organisation (WHO) in an effort to improve therapeutic efficacy and limit/delay the spread of resistance. However, the evaluation of these regimens in most of Africa, including Uganda, is not systematically done. Further, despite the WHO recommendations for combination therapy for un-complicated falciparum malaria, quinine (QN) monotherapy is still widely used in most African countries, including Uganda, as a second line treatment for uncomplicated malaria and data on an appropriate rescue therapy are lacking. In June 2000, the combination of CQ + sulphadoxine pyremithamine (SP) was selected to replace CQ monotherapy as first-line treatment for uncomplicated falciparum malaria in Uganda. This choice was not ideal as it consisted of two drugs that were clearly failing. In 2004, Uganda adopted artemether-lumefantrine (AL) as the first line regimen for the treatment of uncomplicated falciparum malaria, with artesunate-amodiaquine as the alternative first line regimen and quinine as the second line regimen.
In view of this changing malaria case management landscape in Uganda, we designed a series of comparative studies. Our general objective was to describe malaria control efforts in Uganda and evaluate the most appropriate treatment options for the primary and recurrent malaria episodes so as to generate evidence for the formulation of a rational antimalarial treatment policy in Uganda and other African countries with similar malaria transmission instensity. Our specific objectives were: a) to describe the historical and contemporary malaria epidemiology and the current control efforts in Uganda; b) to investigate the efficacy of artemisinin versus non artemisin based combination therapies for the treatment of uncomplicated malaria in Uganda; c) to investigate the most efficacious artemisinin-based combination therapies (ACT’s) for the treatment of uncomplicated malaria in Ugandan children and d) to determine the appropriate rescue therapy for patients with recurrent malaria following therapy with ACT’s.
Design and methods
Between 2000 and 2011, we conducted several randomized clinical trials (RCTs) to assess the efficacy, safety and tolerability of various combination therapies (non artemisinin and artemisinin based) for the treatment of uncomplicated falciparum malaria in Ugandan children. In addition, we investigated the safety and efficacy of quinine, artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DHA-PQP) as rescue treatment for uncomplicated malaria in Ugandan children.
Artemisinin versus non-artemisinin combination therapy studies
In the earlier studies, we compared the efficacy, safety and tolerability of the artemisinin-based versus the non-artemisinin based combination therapies in four districts in Uganda with varying malaria transmission intensity. The study sites, selected for geographic diversity and varying malaria transmission intensity, were: Jinja (peri-urban, mid eastern Uganda, medium endemicity; entomological inoculation rate (EIR) = 7), Arua (rural, northwest Uganda high endemicity; EIR = 393), Apac (rural, northern Uganda, very high endemicity; EIR = 1564), and Tororo (rural, eastern Uganda, high endemicity; EIR = 591). We enrolled 2,160 patients aged 6 months or more with uncomplicated falciparum malaria. Patients were randomized to receive CQ + SP, amodiaquine (AQ) plus SP or AQ + artesunate (AS). Primary endpoints were the 28-day risk of parasitological failure, both unadjusted and adjusted by genotyping to distinguish recrudescence from new infections. A total of 2,081 patients completed the follow-up, of whom 1,749 (84%) were children < 5 years of age. The risk of recrudescence after treatment with CQ + SP was high, varying between 22% and 46% at the four sites and was significantly lower (P<0.01) with AQ + SP or AQ + AS (7-18% and 4-12%, respectively). Compared to AQ + SP, AQ + AS was associated with a lower risk of recrudescence but a higher risk of new infection.
Comparative efficacy of artemisinin based combination therapies (ACTs)
To evaluate the efficacy of various ACTs, we compared the efficacy and safety of AL with DHA-PQP in Kanungu district, an area of moderate malaria transmission intensity (EIR = 7). Patients aged 6 months to 10 years with uncomplicated falciparum malaria were randomized to one of the two treatments and followed for 42 days. Of 414 patients enrolled, 408 completed the follow-up. Patients treated with DHA-PQP had a significantly lower risk of recurrent parasitaemia (33.2% vs. 12.2%; risk difference = 20.9%, 95% CI 13.0–28.8%) and a lower risk of treatment failure due to recrudescence (5.8% vs. 2.0%; risk difference = 3.8%, 95% CI 20.2–7.8%) compared to those treated with AL. Patients treated with DHA-PQP had a lower risk of developing gametocytaemia after therapy (4.2% vs. 10.6%, p = 0.01). Both drugs were safe and well tolerated though DHA-PQP may be operationally preferable to AL because of the less intensive dosing schedule and requirements.
Appropriate rescue therapy in the era of ACTs
To determine the appropriate rescue therapy for uncomplicated falciparum malaria in the era of ACTs, we conducted a nested, randomized, open label, clinical trial of rescue therapy in children 6-59 months old with recurrent malaria infection during 28 days post treatment with ACT’s. Patients were randomly assigned to receive either quinine, AL or DHA-PQP and actively followed up for 28 days. Among 220 patients enrolled, 217 (98.6 %) were assigned an efficacy outcome and 218 (99.1 %) were assessed for safety. The risk of recurrent infection was significantly higher in patients treated with quinine (70 %, 74/110, HR= 3.9; 95 % CI: 2.4-6.7, p<0.0001) and AL (60%, 21/35, HR=3.3; 95 % CI: 1.8-6.3, p<0.0002), compared to DHA-PQP (25%, 18/72). Recrudescence tended to be lower in the DHA-PQP (1%, 1/72) than in the quinine (7%, 8/110) or AL (6 %, 2/35) group, though it was not statistically significant. No serious adverse events were reported. The study showed that, instead of using quinine, a recurrent infection occurring after an ACT treatment can be successfully treated with an alternative ACT.
Conclusions, policy implications and perspectives for the future
Our studies confirm that ACTs are currently the most effective treatment options for uncomplicated P. falciparum malaria in Ugandan children. The combination of AQ + AS is significantly superior to CQ + SP and AQ + SP in the treatment of uncomplicated P. falciparum malaria. AL is highly efficacious and comparable to DHA-PQP. However, in areas where malaria transmission is intense, the risk of recurrent parasitemia is higher in patients treated with AL and AQ + AS compared to those treated with DHA-PQP because the latter has a longer post-treatment prophylactic effect. Furthermore, we have demonstrated that recurrent infections occurring after an ACT treatment can be successfully treated with an alternative ACT rather than with quinine. The use of quinine as a second line regimen for uncomplicated falciparum malaria in Uganda and other African countries should be urgently reviewed because it is not supported by field evidence. The major challenges to the widespread use of ACTs for the primary and recurrent episodes are likely to be their high cost, and non-availability due to weak health care system.