Visceral leishmaniasis, also called kala-azar, is a parasitic disease that strikes 400,000 people every year and kills around 1 in 10 of its victims. The disease has proven difficult to treat, in part because a large percentage of patients who take the drug of choice, miltefosine, relapse after treatment, coming down with the same disease all over again. Miltefosine is one of the few drugs available to cure leishmaniasis. Doctors and scientists have long suspected that drug resistance was behind the failure of miltefosine, but that does not appear to be the case. Parasites with greater infectivity play a key role in treatment failure, according to a study published in mBio®, the online open-access journal of the American Society for Microbiology, on October 8.
"Parasites from relapsed patients show an increased capacity to infect host cells. They are essentially a worse, potentially more dangerous form of the parasite," says co-author Dr. Manu Vanaerschot of the Institute of Tropical Medicine (ITM) in Antwerp, Belgium.
The authors write that it remains to be seen whether miltefosine treatment causes the increased infectivity of the parasite, or if treatment failure aides the development of this more aggressive parasite.
Miltefosine is at the heart of a vast program aimed at ending kala-azar on the Indian subcontinent (India, Bangladesh and Nepal), but 6.8 % of Indian patients redevelop symptoms of the disease within 6 months after treatment and 20.0 % of Nepalese patients relapse within 12 months after miltefosine treatment.
ITM researchers joined hands with their colleagues of the BP Koiral Institute of Health Sciences in Dharan, Nepal, in the context of the Kaladrug-R project funded by the European Commission. Parasites collected from patients before and after treatment have been fingerprinted and are very close genetic matches, indicating that these patients are not simply re-infected with new parasites once their treatment ends; they are still carrying the same strain that sickened them before treatment. Other work of the same research group revealed another surprising fact: parasites from relapsed patients were sensitive to miltefosine, so the failure of treatment was not due to drug resistance, a common suspect in cases where infectious disease treatment fails.
With re-infection and drug resistance now crossed off the list of possible reasons for the high relapse rate, the researchers took a closer look at the parasites to see what factors might really be at work. They found that patients who relapsed were infected with parasites that have a greater infectivity, meaning they were more capable of infecting human cells.
The precise link between infectivity and treatment failure is not known, write the main author Keshav Rai and his colleagues, but they propose that parasites with greater infectivity might cause a greater parasite load in the patient, making the case more difficult to treat. Another possibility is that they are able to evade the drug by hiding in areas of the body which are difficult to penetrate.
Vanaerschot says he and his colleagues saw a similar correlation between infectivity and treatment failure in patients who had been treated with the types of drugs that used to be favored in the region, pentavalent animonials. "At the time we thought that it was a very special case. But now that we've also seen this in parasites treated with other drugs, this indicates that it might be a more common problem than we originally thought."
Co-author Prof. Dr. Jean-Claude Dujardin, Head of ITM’s Department of Biomedical Scientist and lecturer at the University of Antwerp, say the findings are a wake-up call about the possible effects a therapy might have on pathogens.
"We don’t know yet whether patients relapse because of parasites with higher infectivity or whether treatment failure has generated these more aggressive forms. When we develop a drug to fight against a pathogen, we need anyhow to think about possible collateral damage. We need surveillance to see if more aggressive parasites start to spread."
“This is not only important for developing countries. Each year around 700 patients contract kala-azar in Southern Europe. Some patients, most of which are also HIV-positive, are treated with Miltefosine. Moreover, the medicine is also used to cure the very frequent canine leishmaniasis. Surveillance is therefore of the essence,” says Dujardin.