7.8.1 Failure within 14 days

Treatment failure within 14 days of receiving an ACT is very unusual. Of 39 trials of artemisinin or its derivatives, which together enrolled 6124 patients, 32 trials (4917 patients) had no failures at all by day 14. In the remaining 7 trials, failure rates at day 14 ranged from 1% to 7%. The majority of treatment failures occur after 2 weeks of initial treatment. In many cases failures are missed because patients presenting with malaria are not asked whether they have received antimalarial treatment within the preceding 1-2 months. Recurrence of falciparum malaria can be the result of a reinfection, or a recrudescence (i.e. failure). In an individual patient it may not be possible to distinguish recrudescence from reinfection, although if fever and parasitaemia fail to resolve or recur within 2 weeks of treatment then this is considered a failure of treatment. Wherever possible treatment failure must be confirmed parasitologically - preferably by blood slide examination (as HRP2-based tests may remain positive for weeks after the initial infection even without recrudescence). This may require transferring the patient to a facility with microscopy; transfer may be necessary anyway to obtain second-line treatment. Treatment failures may result from drug resistance, poor adherence or unusual pharmacokinetic properties in that individual. It is important to determine from the patient's history whether he or she vomited previous treatment or did not complete a full course. Treatment failures within 14 days should be treated with a second-line antimalarial (see section 7.8.3).

7.8.2 Failure after 14 days

Recurrence of fever and parasitaemia more than 2 weeks after treatment, which could result either from recrudescence or new infection, can be retreated with the first-line ACT. Parasitological confirmation is desirable but not a precondition. If it is a recrudescence, then the first-line treatment should still be effective in most cases. This simplifies operational management and drug deployment. However, reuse of mefloquine within 28 days of first treatment is associated with an increased risk of neuropsychiatric sequelae and, in this particular case, second-line treatment should be given. If there is a further recurrence, then malaria should be confirmed parasitologically and second-line treatment given.

7.8.3 Recommended second-line antimalarial treatments

On the basis of the evidence from current practice and the consensus opinion of the Guidelines Development Group, the following second-line treatments are recommended, in order of preference:

• alternative ACT known to be effective in the region,
• artesunate + tetracycline or doxycycline or clindamycin,
• quinine + tetracycline or doxycycline or clindamycin.

The alternative ACT has the advantages of simplicity, and where available, co-formulation to improve adherence. The 7-day quinine regimes are not well tolerated and adherence is likely to be poor if treatment is not observed.

Summary of recommendations on second-line antimalarial treatment for uncomplicated falciparum malaria