Post-treatment Effects of Ivermectin (IVM) or Diethylcarbamazine (DEC) in Loiasis

Ivermectin is currently used for mass drug distribution for the control of onchocerciasis and elimination of lymphatic filariasis in Africa. Due to the occurrence of severe neurologic adverse events in individuals with concomitant Loa loa infection and high levels of circulating microfilariae, drug distribution has been halted in many areas in Cameroon, Democratic Republic of Congo and other Loa-endemic countries. Diethylcarbamazine citrate (DEC) is the treatment of choice for Loa loa infection in the United States and other non-endemic countries, but can also be associated with the development of severe adverse reactions, including fatal encephalopathy, that are correlated with the number of circulating microfilariae in the blood. The cause of these reactions is unknown, and it is not known if post-treatment reactions to DEC and ivermectin both have the same underlying mechanism. Post-treatment reactions to both medications are accompanied by a dramatic interleukin-5 (IL-5)-dependent increase in eosinophilia and evidence of eosinophil activation. Preliminary data suggests that, unlike post-treatment responses in Wolbachia-containing filariae, inflammatory mediators commonly seen in bacterial infections and malaria, including tumor necrosis factor (TNF)-alpha and IL-1-beta, are not increased post-treatment with DEC. The aim of this study is to characterize the immunologic mechanisms of ivermectin and DEC posttreatment reactions so that it can be established whether or not these posttreatment reactions have the same underlying mechanism. An understanding of the pathophysiology of these post-treatment reactions is necessary in order to develop strategies to prevent these reactions in the future. We plan to randomize 20 subjects with low- to- moderate numbers of circulating Loa loa microfilariae to receive a single oral dose of either ivermectin (200 mcg/kg) or DEC (8 mg/kg) in an inpatient setting in Cameroon. Signs and symptoms, blood microfilarial levels, complete blood counts, intracellular and serum cytokine levels and markers of eosinophil activation will be assessed at baseline, 4 and 8 hours, and 1, 2, 3, 5, 7, and 9 and 14 days post-treatment and compared between the two treatment groups. Subjects who received ivermectin will be treated with single dose DEC (8 mg/kg) on day 14. All subjects will then be followed at 6 and 12 months post-hospitalization to determine whether they have experienced Loa-specific symptoms (eyeworm or Calabar swellings). Mf count and complete blood count (CBC) with differential will be obtained at each follow-up visit. Subjects with Loa-specific symptoms or mf counts > 100 mf/mL at the 6 month time point will be offered a full treatment course. If > 50% of subjects meet criteria for full DEC treatment at the 6, month time point, all subjects will be treated and the study will enter a follow-up phase with a visit at 12 months (6 months after the full treatment course ).

• INCLUSION CRITERIA (SCREENING):

A subject will be eligible for participation in the screening portion of this protocol if all of the following criteria apply:

• male or non-pregnant and not breastfeeding female subjects,
• age 20-60 years (per participant self-report)
• resident of Akonolinga
• Loa microfilaremia from 20 to 5000 mf/mL from the prior screening in the village or did not participate in the prior screening
• consent to a blood draw to screen for infection with Loa loa
• must be willing to have blood samples stored

Exclusion criteria

(SCREENING):

A subject will not be eligible for participation in the screening portion of this study if any of the following conditions apply:

• Known to be pregnant (by history) or breastfeeding
• Chronic medical conditions, including but not limited to diabetes, renal or hepatic insufficiency, immunodeficiency, psychiatric disorder, seizure, that in the investigators judgments are deemed to be clinically significant
• History of hypersensitivity reaction to DEC or IVM

Inclusion criteria

(INTERVENTIONAL STUDY):

A subject will be eligible for participation in the interventional portion of the study only if all of the following additional inclusion criteria apply:

• Loa loa microfilaremia between 20 and 2,000 mf/mL blood drawn between 11:30 am and 2:30 pm measured within 30 days prior to the baseline visit
• The subject agrees to storage of samples for study

Exclusion criteria

(INTERVENTIONAL STUDY):

A subject will not be eligible to participate in the interventional portion of the study if any of the following conditions are fulfilled at the time of enrollment:

• Pregnancy (by serum or urine beta-HCG) or breastfeeding
• Chronic kidney or liver disease
• Hgb < 10 gm/dL
• Filarial infection other than Loa loa or M. perstans (O. volvulus, or W. bancrofti)
• Use of DEC or IVM within the past 6 months
• Use of immunosuppressive therapies, including steroids, within the past month
• Any condition that in the investigator s opinion places the subject at undue risk by participating in the study

EXCLUSION OF CHILDREN AND PREGNANT WOMEN:

Pregnant women and children (the age of consent in Cameroon is 20 years of age) will be excluded from this study since it involves administration of medications contraindicated in pregnancy and more than minimal risk with no prospect of direct benefit, respectively.