IVM Alone vs ALB + IVM Against Onchocerciasis

Overview

Onchocerciasis is a vector-borne nematode parasitic disease that causes severe disability. Onchocerciasis affects approximately 33 million people, mostly in 30 countries in sub-Saharan Africa (with small foci in Latin America and Yemen) 1This disease causes blindness and severe skin disease and it is spread by black flies. O. volvulus adult worms live in subcutaneous nodules. O. volvulus adult worms are larger and less sensitive to available drug treatments than those of the species that cause Lymphatic Filariasis (LF). They also have a longer lifespan (approximately 14 years rather than the estimated 7 years for LF parasites). Several programs and developments have greatly improved the Onchocerciasis. situation since the 1970's when the Onchocerciasis Control Programme (OCP) in West Africa (green countries in the map) was initiated. OCP relied exclusively on vector (black fly) control in its early years. However, following the appearance of Ivermectin (Mectizan) on the scene in the late 1980's, OCP transitioned to become a drug distribution program with annual IVM MDA in 11 countries. OCP ended in 2002. This was replaced by the African Program for Onchocerciasis Control (APOC) which coordinates community directed distribution of IVM MDA in 28 African countries (including the former OCP countries). OCP and APOC have done a good job of reducing parasite infection intensities and Onchocerciasis disease rates in many endemic countries. Unfortunately, there is no real end in sight for the APOC approach (apart from a funding endpoint in 2015); while it may be possible to eliminate Onchocerciasis. In selected areas by MDA with IVM (alone, or combined with vector control), disease control programs in most African countries will require active maintenance for many years to come. While IVR has good activity against the parasite larvae that cause disease in the skin and eye (microfilariae or Mf), it does not kill O. volvulus adult worms, and they resume production of Mf that can lead to transmission of new Onchocerciasis. Cases by black flies after a few months. APOC activities are focused on areas with high infection rates (where disease risks are highest). However, extensive areas in Africa where fewer than 20% of adult men have Onchocerciasis nodules detectable by palpation are not receiving interventions for Onchocerciasis at this time. These areas are not disease free. (Onchocerciasis dermatitis can be severe in hypoendemic areas), and they also may serve as a source for reintroduction of the parasite into previously controlled areas after interventions stop.

Onchocerciasis control programs have relied on annual MDA with IVM at a dose of 150-200 µg/kg. This regimen kills skin (and eye) Mf, thereby reducing disease and (in some areas) transmission. However, standard IVM monotherapy has little macrofilaricidal activity against adult O. volvulus, and it does not permanently sterilize adult worms, which have a reproductive life span of 12-14 years. More effective drugs or dosing schedules that have embryo-static or macrofilaricidal activity could drastically reduce the number of years required to interrupt transmission of Onchocerciasis. IVM has activity against adult O. volvulus when it is given at high doses four times per year for several years. This regimen caused some adverse events, and is not practical for national control programs. By contrast, whereas ALB has little effect on O. volvulus Mf, the drug has embryo-toxic effects at standard doses manifest as partial suppression (by 66%) of skin Mf counts for at least one year. ALB given at doses of 800 mg produced a more sustained reduction in Mf relative to a dose of 400 mg, but higher doses did not improve efficacy. It is not known whether ALB produces transient or permanent female worm sterility. Administration of a single 400 mg dose of ALB combined with IVM 200 µg/kg failed to a show greater reduction in Mf or macrofilaricidal activity compared to IVM alone; however, combination therapy suppressed embryogenesis more than IVM alone. These studies involved small numbers of participants, used ALB only at a dose of 400 mg, and followed the participants for just one year. Thus, IVM combined with ALB at higher doses given more than once per year may generate more sustained reduction in Mf by reducing female fertility or by killing adult worms. IVM and ALB are very safe and highly effective anti-filarial drugs when given singly or in combination. ALB causes degenerative alterations in the tegument and intestinal cells of the worm by binding to the colchicine-sensitive site of tubulin, thus inhibiting its polymerization or assembly into microtubules. The loss of cytoplasmic microtubules leads to impaired uptake of glucose by larval and adult stages of the parasite, and depletes glycogen stores. Degenerative changes in endoplasmic reticulum and mitochondria of the germinal layer, and the subsequent release of lysosomal enzymes result in decreased production of adenosine triphosphate, which is the source of energy required for survival of the helminth. Due to diminished energy production, the parasite is immobilized and eventually dies. The drug has been shown to cause occasionally (\<1% of treated patients) reversible reductions in total white blood cell count. It has also been associated with slight increases in liver transaminases in \~16% of patients. The enzymes return to normal levels with cessation of treatment. These abnormalities are associated primarily with prolonged treatment for such diseases as neurocysticercosis and hydatid diseases, not single dose treatment which is being proposed here. ALB given with fatty foods as proposed in the current protocol will increase absorption and may increase the risk of adverse side effects. IVMis an avermectin compound of macrocyclic lactones derived from the bacterium Streptomyces avermitilis. The mechanism by which IVM kills LF microfilariae is not known with certainty, but the drug interferes with glutamate gated ion channels that can affect parasite contractility and release of immunomodulatory molecules by the parasite. IVM also has a direct effect on the central nervous system and muscle function as it enhances strength of inhibitory neurotransmission pathways. The main concern with use of IVM in animals and humans is neurotoxicity, which can be manifest as ataxia. Neurotoxicity has not been observed in humans given single dose IVM for LF or other parasitic infections, and the drug has been used to treat millions of people with LF and Onchocerciasis. Peak IVM serum concentrations are reached approximately 4-5 hours after administration. The half-life of IVM in various populations ranges from 12 to 56 hours 12. There is no evidence of drug:drug interaction between ALB and IVM. IVM can cause nausea, dizziness and occasionally pruritus, but these are infrequent, transient and usually mild. Major side effects occur with heavy infections of Loa loa; however, this parasite is not endemic in Ghana. In Ghana the chiefs and elders are the custodians of the land so they must first to be contacted for permission to enter their communities. The study objectives and procedures are then explained to them, and if they accept it then the research team is allowed to enter the communities to explain the research aims and procedures to their subjects.