Vaccines, antimalarials and recrudescence

doi:10.15406/ppij.2018.06.00160

eISSN: 2379-6367

Pharmacy & Pharmacology International Journal

Opinion Volume 6 Issue 2

Vaccines, antimalarials and recrudescence

Pierre Lutgen

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IFBV-BELHERB, Luxembourg

Correspondence: Pierre Lutgen, IFBV-BELHERB, BP 98 L-6905, Niederanven, Luxembourg

Received: February 20, 2018 | Published: March 7, 2018

Citation: Lutgen P. Vaccines, antimalarials and recrudescence. Pharm Pharmacol Int J. 2018;6(2):86–87. DOI: 10.15406/ppij.2018.06.00160

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Opinion

It has long been believed that latency was only present in Plasmodium vivax or Plasmodium ovale due to hypnozoites, exo-erythrocytic forms in the liver. The prevailing opinion until the middle of the last century was that the maximum duration of Plasmodium falciparum infections was less than 2 years. But asymptomatic carriers are common in endemic areas and the transfer of the parasites to nonimmune patients by blood transfusion is common knowledge. And in many cases the donors have been absent from countries with exposure to malaria for durations longer than 2 years.¹ Already in 1931 it was found in a cohort of 71 schoolchildren Puerto Rico that some Plasmodium falciparum infections continued for up to 121 weeks.² More recent cases of latency, dormancy and recrudescence accumulate. Recrudescence can occur with waning of immunity following departure from endemic areas. Pregnancy, particularly the primigravid state, is a risk factor for severe infection.^3‒6 In mice treated with artesunate recrudescence is related to dephosphorylation.⁷

Treatment failures and first signs of resistance to artemisinin soon become evident already evident in China with arteannuin B and artemisinin monotherapy in 1973. This was due to a novel effect: a small fraction of the parasites, as a result of chemotherapeutic pressure, become ‘dormant’. At the ring stage, the parasite cycle is halted, making the parasites unsusceptible to further dosing until wakening.⁸ The parasite encapsulates itself against the aggressive peroxide artesunate and reawakens at the end of the treatment. The same effect is called quiescence by a French research team.⁹ The dormancy effect is also evident for artemisone, a new artemisinin derivative.¹⁰ The resistance to ACTs leads to the survival of most fit populations of parasites which in turn lead to more virulent infections.¹¹ Severe recrudescence has also been noticed in the use of dihydroartemisinin-piperaquine and a large increase in the prevalence of parasitemia. Not only the load of asexual parasites increased after 4 months but also the load of gametocytes.¹²

A recent paper rings an alarm bell. Plasmodium chabaudi malaria parasites through a step-wise increase in artesunate dose evolve extremely rapidly slow clearance rates. These slower clearance rates provide fitness advantages to the parasite through increased overall density, recrudescence after treatment and increased transmission potential. Removal of only the susceptible parasites by artesunate treatment led to substantial increases in the densities of resistant parasites.¹³ Several recent studies show dramatic failure rates for sulfadoxine-pyrimethamine-IPT. In Malawi a recrudescence of 33% after PCR correction was noticed. 95% of the women with asymptomatic parasitaemia carried a quintuple mutant and the survival rate of the malaria infected primigravidae remained disastrous despite the treatment. Since many years it is well known that pyrimethamine-sulfadoxine (SP) even increases the gametocyte density. In a trial in South Africa the duration of gametocyte carriage increased from 3 to 22 weeks between 1998 and 2002.^14,15 Folate supplementation in pregnancy is universally recommended as part of antenate care. Although international guidelines recommend 0.4 or 0.6 mg daily, many countries in Sub-Saharan Africa use 5 mg daily, because the 5mg tablet is more widely available. Several studies have shown that folate can antagonize the antimalarial activity of sulfadoxine-pyrimethamine in vitro and in vivo.¹⁶

For chloroquine the situation is even worse. A 5-fold increase in gametytogenesis in Plasmodium falciparum has been documented.¹⁷ The situation is as dramatic for the RTS, S vaccine which protects only against sporozoites but does not induce clinical immunity against blood-stage parasites. The vaccine showed evidence of 35,9% efficacy in the first year after vaccination, but efficacy fell to 2.5% in the fourth year. The cohort with a high exposure index even showed a negative efficacy during the fifth year (Figure 1).¹⁸ Even if some people applaud for the 35.9% protection provided by this vaccine in the first year, it appears meaningless if one compares with the natural healing rate. A longitudinal study was conducted involving 273 children 1–10 years of age with acute, uncomplicated malaria in Kampala, Uganda. Malaria parasitemia was measured at enrollment, on day 3, and on day 7. Malaria parasitemia had completely cleared in 57.1% and 85.3% of children by day 3 and day 7, respectively.¹⁹ The effect of 8 antimalarial drugs on gametocyte production was studied in vitro. Exposure to antimalarial drugs resulted in an increase in the number of gametocytes in test cultures. None of the drugs tested statistically significantly reduced gametocyte numbers.²⁰ The situation appears to be disastrous for mefloquine monotherapy. Patients treated with mefloquine had a high risk for mosquito infectivity and transmissibility. A disaster is pending for Africa. Lariam is now forbidden in several European countries and remaining stocks are sold in Africa.²¹

Figure 1 5-fold increase in gametytogenesis in Plasmodium falciparum.

Concerning mass drug administration, recently in a paper sponsored by Bill Gates, the Global Fund and WHO the following conclusion is reached : Mass drug administration has the potential to reduce transmission for a limited time, but is not an effective replacement for existing vector control. Unless elimination is achieved, mass drug administration has to be repeated regularly for sustained effect.²² Very strange is the effect noticed in several papers or reports. Introducing LLINs (long lasting insecticide treated nets) in areas where ACTs are in broad use provokes a sharp jump in malaria incidence.^23,24 Hopefully a study from the Worcester Technical Institute shows that Artemisia annua dried leaves are able to reverse the resistance induced by artemisinin and derivatives.²⁵ In a recent clinical trial in RDCongo, treating uncomplicated malaria with either Artemisia annua or Artemisia afra was superior to the artesunate ACT treatment. At D14-28 gametocyte carriage was undetectable in Artemisia-treated patients, so transmission to the mosquito should be interrupted.²⁶ This is an African breakthrough. So far, WHO protocols only have addressed the decrease in parasite density of asexual forms. One may wonder why gametocydal action and transmission blocking potential were not a major issue for Bigpharma WHO ? Cui bono ?