Malaria transmission factors and immunity play major roles in treatment response according to two Ugandan studies

Both more frequent malaria infections and infection with multiple strains of the malaria parasite can affect responses to antimalarial treatments, according to two Ugandan studies published in the April 1^st and the April 15^th issues of the Journal of Infectious Diseases. However, the effects are dichotomous.

One study concluded that people living in areas with a high intensity (frequency) of malaria transmission had better responses to treatment than those living in areas where transmission is less common — and that this single characteristic better explained geographical differences in treatment response than the presence of antimalarial drug resistance. The second study, on the other hand, found that co-infection with more than two strains of the malaria parasite was associated with a poorer response to treatment, irrespective of whether the individual came from an area with high or low malaria transmission intensity.

Both phenomena are likely have an immunological explanation as people (children) who are repeatedly exposed to the parasite are more likely to acquire immunity (if they survive infection), while a very diverse infection may confound the immune system’s ability to mount an effective response.

Resistance vs. transmission intensity

To see how great a role resistance or transmission intensity play in the differences observed in treatment responses in Ugandan malaria studies, the first team of researchers conducted resistance tests on samples drawn from individuals enrolled in clinical trials at six sites from different regions of Uganda with varying transmission intensities.

The studies involved 2084 patients ≥6 months old who had uncomplicated P. falciparum malaria, who were randomised to receive CQ plus SP or amodiaquine (AQ) plus SP.

Patients' samples were screened for the presence of known genetic markers of resistance to CQ (the pfcrt Thr-76 mutation) and SP (the dhfr/dhps quintuple mutation). The researchers then assessed the relationship between the level of transmission intensity, the prevalence of molecular markers of drug resistance and the risk of treatment failure. Treatment outcomes were classified according to World Health Organization (WHO) guidelines as either early treatment failure (ETF), late clinical failure (LCF), late parasitological failure (LPF), or adequate clinical and parasitological response.

Geographical variations in treatment response

Both studies grew out of an observation of striking differences in treatment outcomes across sites in malaria studies conducted in Uganda. Since resistance to the former first-line malaria treatments, chloroquine (CQ) and sulfadoxine-pyrimethamine (SP) has become fairly widespread, several large scale studies have been conducted to help guide malaria treatment policy in the country. These studies generally evaluated dual combination regimens — which have sometimes incorporated CQ or SP despite the presence of resistance to one or both drugs.

However, in the case of malaria, drug resistance might better be characterised as a decrease in sensitivity since malaria parasites are rarely completely resistant to SP. Even when the parasite is partly resistant, host factors, such as age (a surrogate for acquired immunity) and parasite density, are also associated with the response to antimalarial treatment. Acquired immunity probably contributes to the malaria control when drugs are less than completely effective. Similarly, transmission intensity has been associated with acquired immunity and inversely with severity of disease — people from areas of infrequent malaria transmission are less likely to acquire resistance to the parasite and, when infected, more likely to develop more severe forms of the disease, with serious complications like cerebral malaria.

Results

There were significant differences across sites in a number of baseline characteristics. For example, at the three sites with the highest transmission intensities, more than 90% of the patients were under five years of age, compared to 61–80% under the age of five at the three sites with the lowest transmission intensities. Patients from the two sites with the highest transmission intensity had both lower parasite burdens and higher complexity of infection (both p

CQ resistance was observed in more than 95% of the samples tested at all of the sites. The frequency of five possible SP resistance mutations varied by mutation. Overall, 61–91% of patients were infected with parasites containing one or more of the resistance-conferring mutations, and there was no clear relationship between the prevalence of resistance and transmission intensity.

Younger age and higher parasite burdens were associated with a greater risk of treatment failure. Having all six of the resistance-conferring mutations was also more likely to be associated with treatment failure on CQ/SP but only at sites with lower transmission intensity. A similar but not statistically significant trend was seen for patients on AQ/SP. Overall, the risk of treatment failure decreased with increasing transmission intensity for both CQ/SP (73% to 19%) and AQ plus SP (38% to 2%). Restricting the analyses to patients infected with parasites containing all six mutations of interest did not affect these trends.

The study did not conclude that resistance does not increase the risk of failure — it clearly does for the individual patient. “However,” wrote the researchers “levels of mutations did not explain differences in the risk of treatment failure at the population level.”

Complexity of infection

The second and slightly larger study (in 3072 subjects) evaluated whether being infected with a higher number of malaria strains (complexity of infection — screened by genotype) is associated with poorer treatment responses in participants in clinical trials of CQ/SP and AQ/SP. This study also included patients taking one of the artemisinin-based combinations (ACTs) which are now widely recommended as standard-of-care treatment for malaria, in this particular case, artesunate (AS) plus AQ.

The risks of treatment failure were surprisingly high at some sites for each arm, even AQ/AS, with the rate of failure ranging from 57% to 84% for CQ/SP, from 20% to 47% for AQ/SP, and from 9% to 56% for AQ/AS.

The study found that complexity of infection was significantly more common at sites with higher transmission, although at these same sites, there was also an inverse relationship between parasite burden and complexity (probably due to greater age and acquired immunity at those sites). However, when age and parasite burden were controlled for, patients infected with three strains had almost three times the odds of treatment failure (odds ratio, 2.93 [95% confidence interval, 2.51–3.43]; p<.0001 across="" all="" also="" and="" aq="" arms="" compared="" consistent="" cq="" each="" failure="" grew="" increased="" increasing="" infected="" infecting="" more="" number="" of="" one="" or="" over="" p="" risk="" strains="" strains.="" the="" those="" three="" treatment="" two="" vs.="" was="" with="">

The researchers postulate that a higher complexity of infection would be expected to increase the probability of harbouring a strain with resistance conferring mutations — however as the previous study observed, resistant parasites are already ubiquitous. Another explanation is that being infected with three or more strains give the parasite the ability to evade the host immune response.

Regardless of the explanation, the studies illustrate the complexity of managing malaria, even with the new artemesinin combination therapies — which may not be the magic bullet that some hope — and suggest that there are gaps in the understanding of the disease that could complicate ongoing efforts to 'roll back malaria.'

Treatments and vector (mosquito) control that significantly reduce transmission intensity would probably reduce the complexity of infection — but without an effective vaccine, such approaches could risk reducing acquired immunity, ironically leading to poorer responses to treatment. There is a substantial body of evidence that acquired immunity to malaria is lost without frequent exposure to the parasite, and people who leave malarial regions and return years later discover that they are no longer immune — this could happen everywhere where vector control is only partially successful. The same phenomenon is observed in people with HIV disease, who lose their acquired immunity to malaria as they progress towards AIDS.

The researchers conclude by calling for a multifaceted approach to malaria control that includes better treatment, an effective vaccine, and improved case management. Indeed, pursuing a consistent and universal free treatment policy should contribute significantly to reducing the diversity of malarial strains in circulation — but this can only be achieved within the construct of improved and integrated approach to healthcare delivery.