Artemisinin-Based Combination Therapy (ACT)

ARTEMISININ-BASED COMBINATION THERAPY (ACT)

Noting that use of antimalarial drugs singly has failed to curtail the prevalence of malaria globally, particularly due to emergence of chloroquine-resistant followed by multidrug-resistant P. falciparum, the WHO has recommended that acute uncomplicated resistant falciparum malaria should be treated only by combining one of the artemisinin compounds with another effective erythrocytic schizontocide. In choosing the companion drug, the most important consideration is its elimination t½ (governing stay in the body), because effective concentrations in blood must be maintained for at least 3 asexual cycles of the parasite, i.e. 6 days, to exhaust the parasite burden. Therefore, short t½ drugs have to be given for 7 days, while longer acting drugs can be given for 1–3 days. However, long t½ drugs allow sub-inhibitory concentrations to persist in the blood facilitating selection of resistant mutants. Combining a short t½ drug with a long t½ drug in the conventional 3 day regimen runs the risk of de facto monotherapy after the short t½ drug is eliminated. This risk is minimized by choosing a short t½ drug that reduces the parasite load rapidly and drastically. Artemisinin compounds fillin this requirement, as they rapidly kill > 95% plasmodia. They leave only a small biomass of the parasites to be eliminated by the long t½ drug, reducing the chances of selecting resistant mutants. Advantages of ACT over other antimalarials are:

·     Rapid clinical and parasitological cure.

·     High cure rates (>95%) and low recrudescence rate.

· Absence of parasite resistance (the components prevent development of resistance to each other).

·     Good tolerability profile.

The ACT regimens for oral treatment of uncomplicated resistant falciparum malaria that are already in use in India, and those being clinically evaluated are given in the box. They are not to be used in severe or complicated malaria, for which parenteral drugs are needed.

Artesunatesulfadoxine + pyrimethamine (AS/S/P)

This ACT has been adopted as the first line drug for falciparum malaria in chloroquineresistant areas under the ‘National antimalaria drug policy’ of India, and has replaced chloroquine in 73 districts. However, this does not imply that it is the most effective/best ACT, because it is not effective against multidrugresistant strains which are nonresponsive to S/P. Moreover, no comparative evaluation of this regimen against AS/MQ or artemether/ lumefantrine, etc. has been done to establish the relative efficacy/tolerability.

Artesunate-mefloquine (AS/MQ)

It has been extensively used in Thailand, Myanmar and several other countries; found to be highly effective, well tolerated and is now the first line treatment for uncomplicated falciparum malaria in Southeast Asia. Many areas in the far East already have mefloquine-resistant P. falciparum. By combining with artesunate, further spread of mefloquine-resistance has been prevented.

Artemether-lumefantrine

Lumefantrine is an orally active, high efficacy, long-acting erythrocytic schizontocide, related chemically and in mechanism of action to halofantrine and mefloquine. It acts in the food vacuole of plasmodia to inhibit haeme polymerization.

Additionally, nucleic acid and protein synthesis of the parasite is affected. Like the others, vivax hypnozoites are not affected. Lumefantrine is highly lipophilic; absorption starts after 2 hours of ingestion and peaks at 6–8 hours; action is slower than chloroquine. Plasma protein binding is 99%, and it is metabolized predominantly by CYP3A4. It inhibits the isoenzyme CYP2D6. Terminal t½ is 2–3 days, which is prolonged to 4–6 days in malaria patients.

Lumefantrine has been used only in combination with artemether, and is the only ACT currently available as fixed dose combination tablets. The two components protect each other from plasmodial resistance. As such, no clinically relevant resistance has developed so far. Clinical efficacy is high (>95% cure rate) and comparable to artesunatemefloquine. It is active even in multidrug-resistant areas, including mefloquine-resistant. While artemether quickly reduces parasite biomass and resolves symptoms, lumefantrine prevents recrudescence. Gametocytes are rapidly killed, cutting down transmission.

Lumefantrine-artemether is administered with food, preferably fatty food or milk, which markedly enhances lumefantrine (and to some extent artemether) absorption. It is generally well tolerated; side effects are—headache, dizziness, sleep disturbances, abdominal pain, arthralgia, pruritus and rash. Some studies indicate that it is better tolerated than artesunate mefloquine. Lumefantrine-artemether should not be given with drugs metabolized by CYP2D6 (metoprolol, neuroleptics, tricyclic antidepressants, etc), or with drugs which prolong QTc interval. It is contraindicated in first trimester of pregnancy and during breastfeeding.

Dihydroartemisinin (DHA) Piperaquine

Piperaquine is a bisquinoline congener of chloroquine developed in China as a high efficacy long-acting (t½ 2–3 weeks) erythrocytic schizontocide with a slower onset of action. The mechanism of action is similar to chloroquine, and it is equally active against sensitive, but more active against chloroquine resistant P. falciparum. In 1978, piperaquine replaced chloroquine in China, where it has been extensively used for mass prophylaxis as well as treatment of malaria.

Piperaquine has been combined with DHA in a dose ratio of 8:1 (ARTEKIN) and extensively evaluated in multidrug resistant areas of Cambodia, Thailand, Vietnam, etc. with high success rate. In clinical trials, efficacy of DHApiperaquine fixed dose combination has been found comparable to artemether-lumefantrine or artesunate-mefloquine. Safety profile of DHApiperaquine is good and it is well tolerated even by children. However, dizziness, vomiting and other g.i. symptoms are common; rashes are rare. It is undergoing clinical trials in India.

Artesunate-Pyronaridine

Pyronaridine is a watersoluble Mannich base erythrocytic schizontocide with high efficacy and mechanism of action similar to chloroquine, that has been used in China for > 30 years. It is active against both chloroquine-sensitive and resistant P. falciparum and other malarial species. The onset of action is slower and duration long. It is concentrated in RBCs and metabolized with a terminal t½ of 7 days. Weak analgesic, antipyretic actions are produced at higher doses.

Clinical efficacy of artesunate-pyronaridine fixed dose combination (dose ratio 1:3) has been tested in falciparum malaria in China and Africa with >95% success and no recrudescence in 28 days. Multi-drugresistant P. falciparum and P. vivax also respond. Phase II clinical trials have been completed in India. Artesunate-pyronaridine is well tolerated. Side effects noted are abdominal pain, vomiting, headache, dizziness, loss of appetite, palpitation and transient ECG changes, but no serious reactions have occurred.

Artesunate-Amodiaquine (AS/AQ)

Though the extent of cross resistance between chloroquine and amodiaquine is uncertain, several trials in Africa have found amodiaquine to cure 41–79% P. falciparum infections in chloroquine resistant areas. Addition of artesunate improved the cure rate to 68–85%. Administered as separate tablets, the two drugs have been effectively used to treat resistant falciparum malaria in Africa. A fixed-dose combination of the two has been produced and is being tested for efficacy and tolerability in Africa, Southeast Asia and India. Early results are encouraging, and it is likely to emerge as a low cost ACT.

Arterolane (RBx 11160)-piperaquine

Arterolane is an orally active synthetic trioxolane congener of artemisinin with rapid and potent erythrocytic schizontocidal action on plasmodia, including multidrug-resistant P. falciparum. Like artemisinins, it is short-acting (t½ 2–4 hours) and has shown efficacy in treating falciparum malaria. Trials are being conducted in India and it is likely to be combined with piperaquine to yield a low cost and well tolerated ACT.

Artesunate-chlorproguanil-dapsone

Since chlorproguanildapsone combination (Lapdap) is already in use for treatment of malaria in several countries, a fixed dose combination by addition of artesunate is being clinically tried as an alternative low cost ACT.