Visceral Leishmaniasis: Complex treatments

When it comes to “special” groups, safety during treatment of VL is crucial^[1]. These groups usually relate to factors which will have a bearing on VL treatment such as immunosuppression, malnutrition and nutrition supplementation, co-infections, pregnancy and interruption of treatment. Appropriate management of the complication or co-morbidity will improve the treatment outcome.

1. Presence of co-infections

HIV-VL co-infection

The spread of HIV in the developing world is well-documented. HIV suppresses cell-mediated immunity which has significant impact on visceral leishmaniasis^[2], whether the VL infection if pre- or post- HIV infection. HIV and VL influence each other reciprocally – VL stimulates the replication of HIV and aggravates the immune suppression. Clinical VL is more likely to develop if the patient has HIV^[3]. Co-infected patients often have atypical or non-specific symptoms.

The diagnosis and treatment of VL in HIV positive patients is challenging. Existing RDTs (Step 2.3) are either not sensitive in co-infected patients in East Africa, or not yet evaluated in the Indian subcontinent. Initial improvement is often seen but relapses occur in a higher proportion of patients, who are likely to become less and less responsive to each treatment round.

The management of coinfected patients is highly complex and needs to be considered on a case by case basis. Both the WHO^{[4, 5]}and MSF have produced material on HIV-VL coinfection in endemic countries with some key recommendations:

• Screen all VL patients for HIV and all HIV patients for VL. This is already done in some countries. VL should be confirmed by parasitology where possible, and test of cure conducted to rule out treatment failures. This is because serological tests in these patients can give false negative results.
• AmBisome is currently the first drug of choice for treatment of HIV-VL patients. A combination or miltefosine and AmBisome has also resulted in good outcomes, and should be considered for refractory cases. The combination of miltefosine and AmBisome in 2 cycles showed an efficacy of 90% in Africa, which is much higher than can be achieved with AmBisome monotherapy in this region. It is currently in the process of being adopted as a 1st line treatment for HIV/VL in Africa.
• Highly Active Anti-Retroviral Therapy (HAART) should be started on completion of VL treatment and a parasitological test of cure should be carried out.
• HIV-VL patients should sleep under insecticide impregnated bed nets. HIV-VL patients typically have high numbers of parasites in the skin and blood which would be a source for further transmission of VL
• Patients require regular and prolonged follow up, likely to involve a number of different agencies
• There is a high risk of TB in these patients
• There is evidence for a protective effect of pentamidine as secondary prophylaxis in patients with CD4 counts <200 in the African setting. In Asia, there is yet no evidence to support prophylaxis.

TB-VL

Tuberculosis (TB) is a major cause of global morbidity and mortality with the greatest burden in low and middle-income countries^[6]. There are increasing reports of patients with TB-VL co-infections; in India, up to 20% of HIV-VL patients have TB as well. As yet, there are no specific guidelines for the management of such cases. A successful outcome has been achieved using conventional anti-leishmanial and anti-tuberculosis drugs^[7]but it is clear that VL-co-infections present a complex challenge for diagnosis and treatment^[8]. In VL there is a higher incidence of extrapulmonary TB. Concurrent treatment for TB and VL is important to achieve cure of VL.

Malaria-VL

Malaria coinfection can be dangerous in VL because patients are already weak, have ineffective spleen function, and are already anemic. Treatment of both at the same time needs care and attention because of overlap of drug side effects. The combination of the antimalarial quinine, with SSG results in cardiovascular side effects (including arrhythmia/QT prolongation). These kind of patients need strict follow up and appropriate laboratory investigations to monitor response.

2. Pregnancy

Visceral leishmaniasis is life threatening for the mother and may have consequences for the fetus. The clinical signs of VL are similar in pregnancy as in others. Pregnancy is usually accompanied by a decrease in cellular immunity and an increase in humoral immunity which can result in an increased risk of infection by some parasitic agents (whose immunity is based on T-helper 1 cells like leishmaniasis). There have been case reports of placental transmission. Pregnant women have a higher risk of early relapse, whereas newborns infected with Leishmania can have a late appearance of symptoms. Both mother and newborn should be followed up closely for at least 6 months in case of treatment of VL in pregnancy.

There are no adequate and well-controlled studies in pregnant women. The FDA has categorized “pregnancy risk categories” based on animal studies, but only for AmBisome and amphotericin B. AmBisome is the treatment of choice and is usually safe to use during pregnancy. All pregnant women who are able to receive AmBisome should be treated; those who are unable should be discussed with senior clinicians.

The other anti-leishmanial drugs are not recommended. Pentavalent antimonials and paromoycin are known to be embryotoxic and may lead to miscarriage. Miltefosine is known to cause fetal abnormalities (teratogenic) in animal studies. Therefore these drugs are not recommended for the treatment of VL during pregnancy.

3. Interruption of treatment

Where treatment regimes are more than one day, drug interruption can be due to medical reasons or due to the patient (poor compliance can occur in cases of insecurity and/or displacement). It is important to consider the treatment duration, type of treatment and length of time treatment has been discontinued for. For the combination of antimonials and paromomycin for 17 days, (first line in Africa), 5 days or less interruption will need to be handled differently to that of a 15+ day interruption

• If treatment is discontinued for less than 5 days the original dosing regimen can be continued until complete.
• If treatment is interrupted for 5 -15 days the treatment regimen can be resumed but a test of cure (parasitological) must be done at the end of the treatment
• If the treatment interruption is for 2 weeks or more re-diagnosis, re-admission and a new treatment regimen must be considered, with a test of cure before discharging the patient

4. Malnutrition

Malnutrition is a known risk factor for the development of severe visceral leishmaniasis^[9]. The generalised immunosuppression caused by malnutrition allows progression of disease due to the host’s inability to control infection. Malnutrition is caused by prolonged fever and loss of appetite. Despite no clear evidence to support this, it is advisable that malnourished VL patients also receive nutritional support alongside their VL treatment.