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Division of Parasitic Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta
Nearly a century ago, specific antimicrobial agents for the treatment of human African trypanosomiasis (HAT) were among the first achievements in the new science of drug discovery and development. However, few advances in HAT chemotherapy have been made in recent decades, and patients today are usually treated with drugs that were introduced before 1950. The infection is transmitted only in rural Africa and does not have a profitable market that would encourage drug development. This lack of progress is part of a larger trend in the global pharmaceutical industry. Investment in treatment for tropical parasitic diseases has plummeted, despite the increasing health burden of these infections. Less than 1% of the new chemical entities introduced during the mid-1970s through 1999 were developed for tropical disease indications, and few candidate drugs are in development [1]. Insufficient financial return has not only discouraged research and development but also caused companies to withdraw existing antiparasitic drugs from the market. Five years ago, when virtually every drug capable of curing central nervous system (CNS) infection was no longer produced or was threatened, it appeared that HAT might become untreatable [2, 3]. At present, these drugs are back in production and are available from the World Health Organization (WHO) through donation programs, but a method to ensure availability for the long term has not been identified.
During the past 2 decades, there has been an impressive resurgence of HAT caused by Trypanosoma brucei gambiense. It is a significant public health problem in large tracts of central Africa, with an estimated prevalence of 300,000500,000 cases [4]. Effective drugs are critical, not only because untreated infection is invariably fatal but also because chemotherapy is a key element of disease control. Humans constitute the epidemiologically important reservoir of T. brucei gambiense, and the cornerstone of control is active case detection through population screening, followed by treatment.
With increasing awareness of the disparity between pharmaceutical innovation and disease burden, the research landscape is starting to change. Among the numerous partnerships between the public and private sectors that have emerged to address this problem [5], there are 2 product-development groups exploring new treatment options for HAT. The Drugs for Neglected Diseases initiative is supporting drug discovery efforts and, in partnership with the WHO's Special Programme on Research and Training in Tropical Diseases, is assessing the utility and potential registration for HAT of nifurtimox, a drug that is indicated, at present, for the treatment of Chagas disease [6]. An international consortium to discover new drugs for tropical diseases, led by the University of North Carolina at Chapel Hill, has identified compounds in its chemical library that have had good activity against T. brucei in preclinical testing. The consortium also has an oral treatment for early-stage HAT in clinical development [7]. DB289, a diamidine derivative, is poised to begin phase 3 trials. If this proves to be effective, it will be a welcome advance. However, there will still be a pressing need for a safe, affordable drug that can cure late-stage disease, because the majority of patients with HAT have CNS involvement at the time of diagnosis, even when they are identified actively through population screening. Sequencing of the T. brucei genome and improvement of molecular tools are providing a wealth of potential antitrypanosomal drug targets [8], but it will be years before new therapies based on this research might be available.
To cope with the disease resurgence in the near term, the use of existing drugs must be improved. The 4 drugs registered for the treatment of HAT [9, 10] are far from ideal. They require parenteral administration, are toxic, and require regimens that are empirically based, lengthy, or difficult. Suramin and pentamidine do not penetrate the CNS and are used only for early-stage disease. Eflornithine, the only drug introduced in recent times, is less toxic than the others, but it requires 4 intravenous infusions daily, which is logistically difficult in the basic facilities where HAT is treated. Eflornithine is not useful for the East African form of the disease, which is caused by Trypanosoma brucei rhodesiense [11], and it may be less effective in patients coinfected with HIV [12]. For these reasons, melarsoprol, an organoarsenic compound, is still the most widely used drug for the treatment of HAT. Despite its high toxicity, it is likely to remain a mainstay of treatment for some time to come. Since its introduction in 1949, it has been administered by use of empirical and complicated regimens requiring 2536 days of hospitalization. The long duration of therapy limits hospital capacity and places an economic burden on families, who often provide several caretakers for the patient during the hospital stay.
In the current issue of the Journal of Infectious Diseases, Schmid et al. describe a multinational drug-utilization study of a 10-day melarsoprol regimen [13]. This is the last in a series of investigations [1417] that have aimed at replacing the empirically based protocol with a more rational scheme. The new 10-day schedule was developed from data collected in a long-overdue study of melarsoprol pharmacokinetics [14]. In a randomized, controlled clinical trial [16, 17], the new schedule was found to be comparable in safety and efficacy to an older, empirical regimen. The randomized trial was performed in upgraded facilities with specially trained staff. In this article, the authors demonstrate that the regimen is also effective when it is used in actual field conditions. The article illustrates that a simple, noncontrolled study design has real value in certain settings. In this instance, it was the only practical approach. Randomization of either patients or facilities would have been extremely difficult, given the lack of continental standardization in HAT diagnostic and disease staging protocols, the limited number of treatment centers, and the basic nature of facilities and staff training. In the future, controlled multinational clinical trials for HAT may be more feasible, because efforts are being made to establish a common approach to conducting trials, through a working group convened by the WHO.
A shorter course of treatment for late-stage HAT is an important advance. The new regimen is less burdensome for patients, families, and health-care workers. It delivers a lower cumulative dose of drug, is more cost-effective than the alternative schedules [18], and is better suited for use in combination chemotherapy. The International Scientific Council for Trypanosomiasis Research and Control endorsed the new schedule in 2003, and it is already being used widely as the schedule of choice by national programs in countries where T. brucei gambiense is endemic. It is important to note that the effectiveness of the 10-day regimen against T. brucei rhodesiense infection has not been evaluated, and it should not be used for that indication.
What should be the next research priority The development of HAT diagnostic tools has suffered from the same lack of investment as drug discovery. Improved methods of diagnosis, stage determination, and cure assessment would greatly increase the efficiency of clinical trials. For chemotherapy, the best hope in the near term lies in the use of existing drugs in combination. Various combinations of melarsoprol, eflornithine, and nifurtimox have been used with some success as compassionate treatment for patients who fail monotherapy with 1 of these drugs [1921]. These limited data from humans are consistent with the observation of synergism in animal models [22]. Additional work in model systems must be done to better define the optimum combinations. However, if synergism can be exploited, lower doses of individual drugs may be effective, which might reduce the toxicity or duration of therapy.
Combination therapy may offer some protection against the development of drug resistance, and recent observations have suggested that there is no time to lose. Although melarsoprol remains effective in most areas of Africa, elevated rates of melarsoprol-refractory infection have been observed in foci where T. brucei gambiense is endemic within Uganda [23], Angola [24], Sudan [25], and Democratic Republic of Congo (author's unpublished data). Ongoing sentinel surveillance for HAT treatment failure has identified several sites with melarsoprol failure rates that are >50% (author's unpublished data). Because of the technical challenges in isolation, cryopreservation, and study of the parasite, only a very few isolates from patients have undergone drug-susceptibility testing [26, 27]. The limited data available at present have not established drug resistance as the cause of the observed treatment failure, but it is suspected. Melarsoprol resistance has been found in laboratory isolates and has been linked to the loss of an aminopurine transporter, P2, that mediates uptake of the drug [2830]. At present, patients who fail melarsoprol monotherapy can usually be cured by use of eflornithine monotherapy. Eflornithine is trypanostatic, rather than trypanocidal. The short half-life, difficult administration, and questionable efficacy in immunocompromised patients suggest that this drug may be quite vulnerable to the eventual development of resistance. As the last safety net, it should be protected by use in combination therapy as soon as possible.
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