African trypanosomiasis medical therapy


 * Pilar Almonacid

Overview

 * Medical treatment of East African trypanosomiasis should begin as soon as possible and is based on the infected person’s symptoms and laboratory results. Medication for the treatment of East African trypanosomiasis is available through the CDC. Hospitalization for treatment is necessary. Periodic follow-up exams that include a spinal tap are required for 2 years. If a person fails to receive medical treatment for East African trypanosomiasis, death will occur within several weeks to months.


 * Medication for the treatment of West African trypanosomiasis is available. Hospitalized treatment of West African trypanosomiasis should begin as soon as possible and is based on the infected person’s symptoms and laboratory results. Hospitalization for treatment is necessary. Periodic follow-up exams that include a spinal tap are required for 2 years. West African trypanosomiasis is fatal if it is not treated.

Pharmacotherapy
Pentamidine isethionate and suramin (under an investigational New Drug Protocol from the CDC Drug Service) are the drugs of choice to treat the hemolymphatic stage of West and East African Trypanosomiasis, respectively. Melarsoprol is the drug of choice for late disease with central nervous system involvement (infections by T.b. gambiense or T. b. rhodiense). The current standard treatment for first stage disease is:
 * Intravenous pentamidine (for T.b. gambiense); or
 * Intravenous suramin (for T.b. rhodesiense)

The current standard treatment for second stage (late stage) disease is: Alternative first line therapies include:
 * Intravenous melarsoprol 2.2 mg/kg daily for 10 consecutive days.
 * Intravenous melarsoprol 0.6 mg/kg on day 1, 1.2 mg/kg iv melarsoprol on day 2, and 1.2 mg/kg/day iv melarsoprol combined with oral 7.5 mg/kg nifurtimox twice a day on days 3 to 10; or
 * Intravenous eflornithine 50 mg/kd every six hours for 14 days.

In areas with melarsoprol resistance or in patients who have relapsed after melarsoprol monotherapy, the treatment should be:
 * melarsoprol and nifurtimox, or
 * eflornithine

The following traditional regimens should no longer be used:
 * (old "standard" 26-day melarsoprol therapy) Intravenous melarsoprol therapy (3 series of 3.6 mg/kg/day intravenously for 3 days, with 7-day breaks between the series) (this regimen is less convenient and patients are less likely to complete therapy) ;
 * (incremental melarsoprol therapy) 10-day incremental-dose melarsoprol therapy (0.6 mg/kg iv on day 1, 1.2 mg/kg iv on day 2, and 1.8 mg/kg iv on days 3–10) (previously thought to reduce the risk of treatment-induced encephalopathy, but now known to be associated with an increased risk of relapse and a higher incidence of encephalopathy) ;

According to a treatment study of Trypanosoma gambiense caused human African trypanosomiasis, use of eflornithine (DMFO) resulted in fewer adverse events than treatment with melaroprol.

All patients should be followed up for two years with lumbar punctures every six months to look for relapse.

History of treatment for sleeping sickness
Suramin was introduced in 1920 to treat the first stage of the disease. By 1922, Suramin was generally combined with Tryparsamide (another pentavalent organo-arsenic drug) in the treatment of the second stage of the gambiense form. It was used during the grand epidemic in West and Central Africa in millions of people and was the mainstay of therapy until 1969.

Pentamidine, a highly effective drug for the first stage of the disease, has been used since 1939. During the fifties, it was widely used as a prophylactic agent in Western Africa, leading to a sharp decline in infection rates. At the time, it was thought that eradication of the disease was at hand.

The organo-arsenical melarsoprol (Arsobal) was developed in the 1940s, and is effective for patients with second stage sleeping sickness. However, 3 - 10% of those injected have reactive encephalopathy (convulsions, progressive coma, or psychotic reactions), and 10 - 70% die; it can cause brain damage in those that survive the encephalopathy. However, due to its effectiveness, melarsoprol is still used today. Resistance to melarsoprol is increasing, and combination therapy with nifurtimox is currently under research.

Eflornithine (difluoromethylornithine or DFMO), the most modern treatment, was developed in the 1970s by Albert Sjoerdsmanot and underwent clinical trials in the 1980s. The drug was approved by the United States Food and Drug Administration in 1990, but Aventis, the company responsible for its manufacture, halted production in 1999. In 2001, however, Aventis, in association with Médecins Sans Frontières and the World Health Organization, signed a long-term agreement to manufacture and donate the drug.

The genome of the parasite has been decoded and several proteins have been identified as potential targets for drug treatment. The decoded DNA also revealed the reason why generating a vaccine for this disease has been so difficult. T. brucei has over 800 genes that manufacture proteins that the disease mixes and matches to evade immune system detection.

An international research team working in the Democratic Republic of the Congo, Southern Sudan and Angola involving Immtech International and University of North Carolina at Chapel Hill have completed a Phase IIb clinical trial and commenced a Phase III trial in 2005 testing the efficacy of the first oral treatment for Sleeping Sickness, known at this point as "DB289".

Recent findings indicate that the parasite is unable to survive in the bloodstream without its flagellum. This insight gives researchers a new angle with which to attack the parasite.

A new treatment based on a truncated version of the apolipoprotein L-1 of high density lipoprotein and a nanobody has recently been found to work in mice, but has not been tested in humans.