Introduction
History
Early observations on relapse
Discovery of the liver stages
Phenotypic variation in P. vivax
Relapse intervals
Effects of sporozoite inoculum
Effects of immunity
Effects of drugs
Contrasting artificial with natural infections
The proportion of infections which relapse
Proportion of incident P. vivax infections followed by ≥1 relapse (%) | Mean number of relapses per incident infection |
---|---|
90
| 8.3 |
80
| 4.0 |
70
| 2.3 |
60
| 1.5 |
50
| 1.0 |
40
| 0.67 |
30
| 0.43 |
20
| 0.25 |
10
| 0.11 |
Thus if "x" is the fraction of patients experiencing one or more relapses, then the fraction experiencing "n" or more relapses is approximately xn
Geographic distribution
The effects of age
Drug effects on relapse
Consider two groups of patients who represent two extremes | |
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Without radical treatment group A has an 80% relapse rate (eg some soldiers who fought in the Pacific in the Second World War) | |
Without radical treatment group B has a 20% relapse rate (eg some soldiers who fought in the Korean War) | |
Assuming a fixed fractional proportion of relapses and no acquisition of immunity, then the total number of relapses/100 patients is | |
group A = 395, | group B = 24. |
These numbers represent the minimum number of viable activatable hypnozoites (VAH) i.e. there are 16 times more in group A compared to group B. It is likely that the distribution of VAH is random among the patients and therefore conforms to a Poisson distribution. | |
If primaquine at a dose of 0.25 mg base/kg (15 mg adult dose) reduces the number of viable activatable hypnozoites (VAH) by 90%, and there is no difference in susceptibility between the groups, and this effect is consistent across all patients then the post treatment number of VAH is | |
group A = 39 or 40 | group B = 2 or 3. |
Thus we would expect 13 to 20 times more relapses in group A compared to group B. | |
This hypothetical example simply points out that the apparent differences in primaquine "resistance" may reflect differences in the biology of the parasite rather than drug susceptibility per se. |
Vivax malaria following falciparum malaria
The periodicity of relapse
The biology of relapse
Relapses of vivax malaria arise from activation of latent hypnozoites (ALH)
1. Mixed species infections
2. Heterologous genotypes
3. Natural versus artifical infection relapse rates
4. Long-latency also occurs in the tropical frequent relapse "Chesson" P. vivax phenotypes
Mechanisms of hypnozoite activation
Implications for epidemiological assessment
Implications for the emergence of anti-malarial drug resistance
Implications for genetic diversity
Practical implications
1. | A substantial proportion of the population in P. vivax endemic areas harbours latent but activatable hypnozoites. Some of these may derive from inoculations which were not followed by any illness. |
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2. | If relapse rates exceed 50%, then relapse becomes the predominant cause of vivax malaria. |
3. | Spontaneous or activated relapse followed by asymptomatic parasitaemia may be an important source of P. vivax transmission. |
4. | Reducing P. vivax transmission will have a smaller than currently predicted effect on the incidence and prevalence of vivax malaria initially. |
5. | Reducing P.falciparum transmission may reduce the incidence of P.vivax infections and reduce P.vivax transmission. However any effect on the incidence of clinical disease would probably be delayed because reducing falciparum malaria will also reveal vivax malaria by lifting suppression in mixed infections, and a reduction in vivax incidence will reduce immunity. A single radical treatment for all malaria infections may be justified in areas where both parasites are prevalent (i.e. ACT + radical primaquine regimen) [143]. |
6. | It is very difficult to exclude the presence of long-latency P. vivax phenotypes in studies conducted in vivax endemic areas. Long-latency phenotypes may be prevalent over a much wider area of the tropics than currently thought. |
7. | Assessment of the efficacy of interventions requires characterization of the prevalent relapse phenotypes. |
8. | Assessments of radical curative activity where long-latency phenotypes are prevalent require one year's follow-up. Genotyping should assist in assessing long-latency relapse. |
9. | The proportion of genotypically different (heterologous) relapses will fall as transmission intensity falls |