Being Male, Quick Treatment Predict Leishmaniasis Relapse

Daniel M. Keller, PhD

July 10, 2012

July 10, 2012 (Bangkok, Thailand) — In a retrospective analysis of more than 6000 patients with primary visceral leishmaniasis (VL) treated with liposomal amphotericin B (LAmB), the only factors associated with relapse were being male and having a shorter time from the onset of symptoms to diagnosis. VL, also known as kala azar, is the most severe form of leishmaniasis and is the second greatest parasitic killer in the world, after malaria.

Here at the 15th International Congress on Infectious Diseases, epidemiologist Rama Mahajan, MSc, MPH, from the Operational Centre Barcelona-Athens, Médicins Sans Frontières (MSF), in New Delhi, India, said the research team analyzed a database of 6435 immunocompetent patients with primary VL treated from September 2007 to December 2011 in Bihar state, India. India has 70% of the worldwide burden of VL, and 90% of the reported cases are in Bihar, a particularly poor area in northeast India, on the Nepal border.

In cooperation with the Rajendra Memorial Research Institute, MSF has run a VL treatment project in the Vaishali district, an area of Bihar with a high level of endemic visceral Leishmania donovani. Patients with primary VL are treated with 4 doses of intravenous LAmB, 5 mg/kg per dose, over a period of 5 to 10 days. Patients are educated about the disease and told to return to the healthcare facility immediately if they experience any recurrence of symptoms.

In the project, the characteristics of any immunocompetent patient readmitted with biopsy-confirmed VL after having been treated for primary VL were compared with those of all immunocompetent patients admitted for primary VL treatment.

Initially the researchers looked at relapse rates in patients with HIV infection, and found a 26% rate of relapse after 2 years. "We wanted to rule out the confounding factor of HIV positivity, so we did this study on immunocompetent cases," Mahajan told Medscape Medical News. "We also did a predicting model analysis to determine the risk factors for relapse," he explained.

Relapse Risk With Early Treatment

Of the 6435 immunocompetent patients with primary VL treated during the study period, 80 presented again with parasite-confirmed relapses. Mahajan said this 1.2% observed relapse rate might underestimate the true rate because follow-up was passive and depended on patients presenting for further treatment.

Patients who were diagnosed 2 weeks after symptom onset in the primary disease, or sooner, had a doubling of risk for relapse, compared with those diagnosed later. For patients diagnosed at 2 to 4 weeks, the risk for relapse was about half that of patients diagnosed earlier (relative risk [RR], 0.48; 95% confidence interval [CI], 0.28 to 0.80; P = .004). For patients diagnosed at 8 to 12 weeks, relapse risk was about one quarter that of patients diagnosed earlier (RR, 0.23; 95% CI, 0.08 to 0.67; P = .003).

Males had a risk for relapse that was more than twice that of females (RR, 2.22; 95% CI, 1.36 to 3.66; P = .001). Age (even in patients younger than 5 years), hemoglobin level, spleen size, and nutritional status did not predict relapse.

The vast majority (91.4%) of parasite-confirmed relapses occurred more than 6 months after the completion of initial treatment, and 59% occurred 6 to 12 months after treatment. The average length of time between treatment completion and relapse confirmation was 385 ± 272 days (range, 104 to 1626 days). All relapses were successfully treated with LAmB.

When asked why people presenting for treatment earlier after symptom onset are at higher risk for relapse, Mahajan said that it could be that they have higher parasite loads, and thus more severe disease. He added that in the future, it might be worthwhile to document parasite load.

Of the more than 10,000 cases treated in the MSF project, about 60% have been male. He said the fact that men in Bihar do more outdoor work than females might partly explain their predominance and their greater risk for relapse. "They are more exposed, they usually do not wear shirts; maybe this is a risk," Mahajan noted, because the disease is transmitted by the bite of sand flies. "There is also underreporting [of VL] among females," he added.

Mahajan explained that it is impossible to tell if the recurrence of symptoms is a recurrence of the original disease or if people are getting reinfected. Since LAmB is delivered intravenously, compliance is not an issue, so recurrences are from either treatment failure or reinfection.

He said the World Health Organization recommends a 6-month follow-up for VL, "but we found that after liposomal amphotericin, 92% of relapse occurs after 6 months. The mean time to relapse is 13 months, so we recommend a longer follow-up period. Also, we need to get more male cases for follow-up."

Pankaj Baral, a PhD candidate at Mahidol University in Bangkok, Thailand, who was not involved in the study and who hails from an area near Bihar, told Medscape Medical News that the study is especially significant because it was done in an area with high levels of VL.

"It is very important to know the true picture [to enhance] our knowledge of the situation in that area," he said. "Another thing is that the study has been [conducted] in immunocompetent HIV-negative patients, so it also gives some idea of how prevalent it is in the [normal population there]."

There was no commercial funding of the study. Mahajan and Baral have disclosed no relevant financial relationships.

15th International Congress on Infectious Diseases (ICID): Abstract 42.008. Presented June 14, 2012.

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