1 REVIEW ARTICLE Update on field use of the available drugs for the chemotherapy of human African trypanosomiasis P. P. SIMARRO1*, J. FRANCO1,A.DIARRA2, J. A. RUIZ POSTIGO3 and J. JANNIN1 1 World Health Organization, HTM/NTD 20, avenue Appia 1211, Geneva 27, Switzerland 2 World Health Organization, IST/CA, P.O. Box 820, Libreville, Gabon 3 World Health Organization, CTD/DCD, P.O. Box3: 7608, Nasr City, Cairo 11371, Egypt (Received 27 October 2011; revised 9 December 2011 and 4 January 2012; accepted 5 January 2012) SUMMARY Despite the fact that eflornithine was considered as the safer drug to treat human African trypanosomiasis (HAT) and has been freely available since 2001, the difficulties in logistics and cost burden associated with this drug meant that the toxic melarsoprol remained the drug of choice. The World Health Organization responded to the situation by designing a medical kit containing all the materials needed to use eflornithine, and by implementing a training and drugs distribution programme which has allowed a transition to this much safer treatment. The introduction of the combination of nifurtimox and eflornithine (NECT) has accelerated the shift from melarsoprol to the best treatment available, due to reduced dosage and treatment time for eflornithine that has significantly lessened the cost and improved the burden of logistics encountered during treatment and distribution. The decrease in the use of more dangerous but cheaper melarsoprol has meant a rise in the per patient cost of treating HAT. Although NECT is cheaper than eflornithine monotherapy, an unexpected consequence has been a continuing rise in the per patient cost of treating HAT. The ethical decision of shifting to the best available treatment imposes a financial burden on HAT control programmes that might render long-term application unsustainable. These factors call for continuing research to provide new safer and more effective drugs that are simple to administer and cheaper when compared to current drugs. Key words: African trypanosomiasis, melarsoprol, eflornithine, nifurtimox, treatment combinations. INTRODUCTION campaign with the newly established Campaign for Access to Essential Medicines and Médecins Sans By the end of the last century a growing number Frontières (MSF) to secure and maintain trypano- of cases of human African trypanosomiasis (HAT) cidal drug production. As a result, in 2001, the two were not responding to the old and far from ideal manufacturers Aventis and Bayer committed not drugs available to treat HAT (Legros et al. 1999). only to ensure manufacture but also to donate the Moreover, the production of some drugs was drugs to the World Health Organization for free threatened, either by increasing price (pentamidine), distribution. halted production (eflornithine) or planned cessation However, whilst discussing the chemotherapy of of production (nifurtimox, suramin and melarsoprol) HAT throughout the first years of the 21st century, (Van Nieuwenhove, 2000). No new drugs were in the several commentators have complained about the pipeline. primacy of the use of melarsoprol to treat second- This review gives a comprehensive summary of the stage gambiense HAT. The major issue being process followed to ensure availability of drugs for melarsorpol’s unacceptable toxicity whilst the less the treatment of HAT and the efforts to ensure the toxic, albeit cumbersome to administer, eflornithine access of patients to the best treatment. The financial has been available for over 20 years (Chappuis et al. burden of such ethical decision is discussed. 2005; Balasegaram et al. 2006; Robays et al. 2008; Priotto et al. 2008). ACCESS TO TREATMENT Indeed, the choice of drug to treat HAT depends on the subspecies of trypanosome and the stage of The World Health Organization created in 1999 a the disease, as judged by results of a diagnostic network to ensure availability and affordability of lumbar puncture to determine whether parasites have anti-trypanosomal drugs and started a joint advocacy become manifest within the central nervous system. fi * Corresponding author: HTM/NTD, 20, avenue Appia However, the logistics and nancial capacity of 1211 Geneva 27, Switzerland. Tel: +41 22 791 1345. Fax: the national sleeping sickness control programmes +41 22 791 4777. E-mail: [email protected] (NSSCPs) and the technical level of staff responsible Parasitology, Page 1 of 5. © Cambridge University Press 2012 doi:10.1017/S0031182012000169 P. P. Simarro and others 2 for administering treatment also impact greatly These positive results led to the WHO Expert on local drug policy. Therefore, even though Committee on the Selection and Use of Essential eflornithine, considered as the safer drug to treat Medicines (held in March 2009) to recommend the HAT, was made freely available in 2001, the inclusion of nifurtimox in the Model List of Essential difficulties in logistics (each patient requiring huge Medicines (EML) to be used in combination with doses of drug delivered in 56 infusions over 14 days eflornithine for the treatment of the second-stage of in 14 litres of sterile saline) meant that melarsoprol Trypanosoma brucei gambiense infection (World remained the drug of choice in spite of its toxicity: Health Organization, 2009). a 5% drug-induced death rate through reactive Following this inclusion, NECT was proposed as encephalopathy (Blum et al. 2001; Seixas, 2004; the best available therapeutic option to treat the Burri, 2010). The fact that treatment failures had second-stage of gambiense HAT. The World Health reached levels of 30% in some foci in Angola, the Organization secured a gratis donation of nifurtimox Democratic Republic of the Congo, South of Sudan through an agreement with Bayer to match the and Uganda (Moore, 2005) compounded the short- gratis donation of eflornithine by Sanofi-Aventis. comings of melarsoprol as a drug. The World Health Influenced by the impact of the kit for eflornithine Organization responded to the situation by designing the World Health Organization also designed a new a medical kit containing all the materials needed medical kit containing the combination in an easily to use eflornithine in a logistically simplified fashion. accessible form and facilitated the training of key staff Furthermore the organization supported a vigorous in disease endemic countries (DECs) to implement programme of capacity building and drug distri- the drug combination. bution to ensure that HAT victims had access to For the first-stage disease, fortunately, in spite of the best treatment available. the drugs having been used for over 70 years and However, the implementation of eflornithine as requiring parenteral administration, similar safety first-line treatment was accompanied by a number of and efficacy concerns have not yet emerged. concerns. The drug is trypanostatic, it has a short Unfortunately to treat the second stage of rhode- half-life in the body and the difficult administration siense HAT, melarsoprol remains the only drug schedule imposes the risk of insufficient compliance available. This article presents the relative rates of to the full treatment course. Furthermore, eflor- use of available drugs to treat the second stage of nithine resistance is easily selected in the laboratory gambiense HAT which accounts for 99·9% of the (Vincent et al. 2010). Then the risk of inducing second stage of HAT cases reported in 2010 (World resistance to eflornithine in the field, in addition to Health Organization, unpublished data) and discusses existing melarsoprol resistance, could lead to the about the financial and social consequences. emergence of untreatable second-stage HAT. It therefore became essential to determine whether THE PROCESS IN FACILITATING THE ACCESS combination therapies might improve efficacy and TO THE BEST TREATMENT reduce the risk of resistance (Moore, 2005). Clinical trials were conducted to assess efficacy of Eflornithine has been donated to the World Health combinations of eflornithine, melarsoprol and nifur- Organization since 2001 following an agreement timox, a drug labelled to be used in treating Chagas’ between the manufacturer and WHO and has been disease, with some reported efficacy in second-stage provided free of charge to DECs. Its better safety HAT (Janssens and De Muynck, 1977; Moens et al. profile, when compared to melarsoprol, rendered it 1984; Pepin et al. 1992). In each case combinations the best treatment, in principle, for second-stage yielded improved efficacy although all combinations gambiense HAT. However, its use as a first-line including melarsoprol retained unacceptable drug treatment was restricted to relatively wealthy non- toxicity (Priotto et al. 2006; Bisser et al. 2007; governmental organizations (NGOs) because even Checchi et al. 2007). when available free of charge due to its cumbersome Based on the preliminary data obtained during and logistically demanding administration regime these clinical trials, a multicentre, randomized, non- it proved prohibitively burdensome. Therefore only inferiority clinical trial comparing eflornithine the small fraction of cases detected by NGOs had monotherapy with the combination of nifurtimox access to eflornithine while most of the cases detected and eflornithine (NECT) was conducted between by NSSCPs continued to be treated with melarsoprol 2003 and 2008. The study concluded that the (Simarro et al. 2011). Only some NSSCPs could combination of nifurtimox and eflornithine had afford its use but in these cases its use was generally a comparable safety and efficacy with eflornithine reserved for