A Randomized Clinical Trial to Measure the Impact of Retreatment With an Artemisinin-based Combination on Malaria Incidence and Its Potential Selection of Resistant Strains

RATIONALE Following the World Health Organization (WHO) guidelines, most African countries have opted for ACT. Several clinical trials on ASAQ, an ACT, completed in Africa have shown an efficacy > 90% (3-5). Furthermore, after The polymerase chain reaction (PCR) analysis, over 75 % of ASAQ & AL treatment failures have been classified as new infections, while recrudescences have low parasite densities. ASAQ is safe and easy administered, with a good treatment adherence. Therefore, effectiveness may be close to efficacy . ASAQ has now been developed as fixed-dose combination and registered. The Democratic Republic of Congo (DRC) has also chosen ASAQ as first-line treatment for uncomplicated malaria.

Efficacy of the 6 dose regimen of AL has been demonstrated in semi-immune and non-immune populations in Asia and Africa to be consistently greater than 95%, with rapid parasite and symptom clearance and significant gametocidal effect. In Uganda, AL has already been chosen as first-line treatment for uncomplicated malaria.

In DRC and Uganda, quinine is the rescue treatment for malaria. It is cheap, widely available and generally considered to be effective but is not popular due to the unwanted side effects. Quinine has a very short half life, therefore repeated dosing is required. In an efficacy study of quinine and artemisinin for uncomplicated malaria in Vietnam, recrudescence rates were 16% after 7 days of quinine monotherapy. In studies conducted in Gabon, Plasmodium falciparum in Vitro sensitivity to quinine was high and had not changed over the past decade. Although quinine monotherapy shows high efficacy in the setting of clinical trials, it has considerable disadvantages, mainly because of its poor tolerability and the prolonged treatment course. Poor adherence carries a high risk of treatment failure, particularly because quinine causes a syndrome of adverse effects known as cinchonism that includes primarily tinnitus, nausea, and vertigo. Other reported side effects are high tone hearing impairment, dizziness, hypotension as well as headache and visual disturbances. As result of these side effects, some studies have reported poor compliance to treatment. A randomized trial in Thailand reported 71% adherence Such poor adherence to the 7-days regimen is associated with a high risk of treatment failure, which can contribute to the development and spread of resistance. Furthermore, in field circumstances patients are often re-treated with the recommended first line drug, i.e. ASAQ.

As quinine is effective against all species of malaria including chloroquine-resistant strains of P. falciparum, it is widely used for the treatment of severe malaria. Therefore, it should be protected from resistance by a rational use, as its effectiveness in uncomplicated malaria is lower than ACT.

Rationale Considering the facts that: over 90% of treatment failure to ASAQ or AL are new infections, parasitaemia is low in case of recrudescence occurring from day 14 and in real-life situations patients are re-treated with the same first line drug, there is the need to assess the role of the first line treatment as rescue treatments. This efficacy will be compared to quinine + clindamycin and another ACT treatment in line with the WHO guideline, and another ACT treatment to provide clear guidelines. The investigators hypothesize that re-treatment with the first line ACT treatment beyond 14 days is as efficacious as any other rescue treatment, without the risk of selecting drug resistant strains. Furthermore, a prolonged follow up will allow the assessment of the epidemiological, parasite related risk factors for repeated malaria infection and to collect samples for immunological risk factors for repeated malaria attacks.