Visceral leishmaniasis and HIV co-infection: WHO releases new guideline with region-specific treatment recommendations

“Optimal region-specific treatment regimens are needed because parasite virulence and drug susceptibility differ,said Dr Saurabh Jain, Physician, Global Leishmaniasis Programme, WHO Department for the Control of Neglected Tropical Diseases. “In addition, very few studies have been conducted in the past in leishmaniasis-endemic regions other than Europe, which has made it difficult to formulate recommendations tailored to specific geographical contexts.

The new recommendations are based on the results of studies conducted in India³ by Médecins Sans Frontières and its partners, and in Ethiopia⁴ by drugs for neglected diseases initiative and partners. They are expected to increase treatment access and improve treatment outcomes, thereby benefiting national programs for the control of neglected tropical diseases, HIV, tuberculosis and vector-borne diseases. Up to 5-7% of visceral leishmaniasis patients in India are infected with HIV – the highest rate in South Asia; a significant proportion also suffer from another fatal comorbidity: tuberculosis.⁵

New evidence and better treatment

The new guideline updates 2010 Recommendations which were based on limited evidence extrapolated mainly from experience in countries around the Mediterranean basin where zoonoses L. infante is the main species involved. The recommended treatment was daily injections of liposomal amphotericin B (AmBisome) for up to 38 days.

However, evidence from studies in Ethiopia and India shows that the new treatment regimen combining liposomal amphotericin B with oral miltefosine is more effective. In India, treatment outcome was superior, with relapse-free survival of 96% versus 88% for standard treatment.

“We welcome the new recommendations along with key indicators to monitor co-infected patient outcomes, as this has the potential to accelerate efforts to eliminate kala azar as a public health problem,” said Roderico H. Ofrin, WHO Representative in India.

In Ethiopia, visceral leishmaniasis-HIV co-infection has increased by 20-30% since the early 1980s, with the highest co-infection rate in the world. Although the rate has decreased somewhat, coinfection nevertheless remains a major public health issue. The new combination regimen showed increased efficacy (88%) compared to the current standard treatment (55%).⁶

“We have a long history of using different medications and regimens to treat VL–HIV-positive patients, who were less effective and with high toxicity, relapse and mortality,” said Mr. Tesfahun Bishaw Mengistie, Leishmaniasis Focal Point, Directorate of Disease Prevention and Control, Federal Ministry of Health, Addis Ababa, Ethiopia. “We welcome the new recommendations as they ensure better management of this complex condition.

Visceral leishmaniasis and HIV co-infection

Leishmania and HIV co-infections have challenged the control and elimination of visceral leishmaniasis, as people infected with HIV are particularly vulnerable to the disease. Leishmania and HIV are mutually reinforcing, posing significant clinical and public health challenges.

Both conditions suppress the immune system, resulting in more severe morbidity with limited treatment options and higher relapse rates, exposure to drugs with increased toxicity, and higher mortality rates.

First reported in the mid-1980s in southern Europe, co-infection is now documented in no less than 45 countries. High rates are reported in Brazil, Ethiopia and the state of Bihar in India.

Co-infected patients are vulnerable not only to other comorbid conditions such as tuberculosis and cryptococcal meningitis, but also to varying degrees of stigma and human rights issues.

The new WHO guideline offers hope for co-infected patients and fills an important gap by allowing countries where both diseases are prevalent to adapt the guideline for the treatment of complex clinical cases.

Leishmaniasis – the disease

Leishmaniasis is caused by a protozoan parasite of more than 20 Leishmania species. Over 90 species of sandflies are known to transmit Leishmania parasites. There are 3 main forms of the disease:

Visceral leishmaniasis: Fatal if untreated, it is characterized by irregular bouts of fever, weight loss, enlargement of the spleen and liver, and anemia.

Cutaneous leishmaniasis: The most common form that causes skin lesions, mainly ulcers, on exposed parts of the body, leaving lifelong scarring and severe disability or stigma.

Mucocutaneous leishmaniasis: Causes partial or total destruction of the mucous membranes of the nose, mouth and throat.

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1. Most cases of visceral leishmaniasis occur in Brazil, East Africa and India, with approximately 50,000 to 90,000 new cases worldwide each year; only 25-45% of cases are reported to WHO. Visceral leishmaniasis remains one of the major parasitic diseases with epidemic and mortality potential. In 2020, more than 90% of new cases were reported to WHO by 10 countries: Brazil, China, Ethiopia, Eritrea, India, Kenya, Somalia, South Sudan, Sudan and Yemen.

2. Infection or disease transmissible from human to animal under natural conditions.

3. AmBisome Monotherapy and AmBisome-Miltefosine Combination Therapy for the Treatment of Visceral Leishmaniasis in Human Immunodeficiency Virus (HIV) Co-infected Patients in India: A Randomized, Open-Label, Parallel-Arm, Phase 3 Trial
   https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciac127/6527047

4. A Randomized Trial of AmBisome Monotherapy and AmBisome and Miltefosine Combination for Treating Visceral Leishmaniasis in HIV-Coinfected Patients in Ethiopia
   https://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0006988

5. Visceral leishmaniasis and pulmonary tuberculosis co-infection pose a public health problem in many countries. Leishmaniasis infection may alter protective immune response to BCG vaccine against tuberculosis https://parasitesandvectors.biomedcentral.com/articles/10.1186/1756-3305-6-79accessed June 1, 2022.

6. Current standard treatment for HIV/visceral leishmaniasis co-infection includes single injections of liposomal amphotericin B (LAmB). The new treatment is a combination of the oral treatment miltefosine and LAmB.