Related Articles

The North American Opiate Medication Initiative (NAOMI) is a randomized controlled trial evaluating the feasibility and effectiveness of heroin-assisted treatment (HAT) in the Canadian context. Our objective is to analyze the profile of the NAOMI participant cohort in the context of illicit opioid use in Canada and to evaluate its comparability with patient profiles of European HAT studies. Recruitment began in February 2005 and ended in March 2007. Inclusion criteria included opioid dependence, 5 or more years of opioid use, regular opioid injection, and at least two previous opiate addiction treatment attempts. Standardized assessment instruments such as the European Addiction Severity Index and the Maudsley Addiction Profile were employed. A total of 251 individuals were randomized from Vancouver, BC (192, 76.5%), and Montreal, Quebec (59, 23.5%); 38.5% were female, the mean age was 39.7 years (SD:8.6), and participants had injected drugs for 16.5 years (SD:9.9), on average. In the prior month, heroin was used a mean of 26.5 days (SD:7.4) and cocaine 16 days (SD;12.6). Vancouver had significantly more patients residing in unstable housing (88.5 vs. 22%; p < 0.001) and higher use of smoked crack cocaine (16.9 days vs. 2.3 days in the prior month; p < 0.001), while a significantly higher proportion of Montreal participants reported needle sharing in the prior 6 months (25% vs. 3.7%; p < 0.001). In many respects, the patient cohort was similar to the European trials; however, NAOMI had a higher proportion of female participants and participants residing in unstable housing. This study suggests that the NAOMI study successfully recruited participants with a profile indicated for HAT. It also raises concern about the high levels of crack cocaine use and social marginalization.

Background

Updated, accurate and comprehensive information on the distribution of human African trypanosomiasis (HAT), also known as sleeping sickness, is critically important to plan and monitor control activities. We describe input data, methodology, preliminary results and future prospects of the HAT Atlas initiative, which will allow major improvements in the understanding of the spatial distribution of the disease.

Methods

Up-to-date as well as historical data collected by national sleeping sickness control programmes, non-governmental organizations and research institutes have been collated over many years by the HAT Control and Surveillance Programme of the World Health Organization. This body of information, unpublished for the most part, is now being screened, harmonized, and analysed by means of database management systems and geographical information systems (GIS). The number of new HAT cases and the number of people screened within a defined geographical entity were chosen as the key variables to map disease distribution in sub-Saharan Africa.

Results

At the time of writing, over 600 epidemiological reports and files from seventeen countries were collated and included in the data repository. The reports contain information on approximately 20,000 HAT cases, associated to over 7,000 different geographical entities. The oldest epidemiological records considered so far date back to 1985, the most recent having been gathered in 2008. Data from Cameroon, Central African Republic, Chad, Congo, Equatorial Guinea and Gabon from the year 2000 onwards were fully processed and the preliminary regional map of HAT distribution is presented.

Conclusion

The use of GIS tools and geo-referenced, village-level epidemiological data allow the production of maps that substantially improve on the spatial quality of previous cartographic products of similar scope. The significant differences between our preliminary outputs and earlier maps of HAT transmission areas demonstrate the strong need for this systematic approach to mapping sleeping sickness and point to the inaccuracy of any calculation of population at risk based on previous maps of HAT transmission areas. The Atlas of HAT will lay the basis for novel, evidence-based methodologies to estimate the population at risk and the burden of disease, ultimately leading to more efficient targeting of interventions. Also, the Atlas will help streamline future field data collection in those parts of Africa that still require it.

Background

Human African trypanosomiasis (HAT), also known as sleeping sickness, is a fatal parasitic disease caused by trypanosomes. Current treatment options for HAT are scarce, toxic, no longer effective, or very difficult to administer, in particular for the advanced, fatal stage of the disease (stage 2, chronic HAT). New safe, effective and easy-to-use treatments are urgently needed. Here it is shown that fexinidazole, a 2-substituted 5-nitroimidazole rediscovered by the Drugs for Neglected Diseases initiative (DNDi) after extensive compound mining efforts of more than 700 new and existing nitroheterocycles, could be a short-course, safe and effective oral treatment curing both acute and chronic HAT and that could be implemented at the primary health care level. To complete the preclinical development and meet the regulatory requirements before initiating human trials, the anti-parasitic properties and the pharmacokinetic, metabolic and toxicological profile of fexinidazole have been assessed.

Methods and Findings

Standard in vitro and in vivo anti-parasitic activity assays were conducted to assess drug efficacy in experimental models for HAT. In parallel, a full range of preclinical pharmacology and safety studies, as required by international regulatory guidelines before initiating human studies, have been conducted. Fexinidazole is moderately active in vitro against African trypanosomes (IC50 against laboratory strains and recent clinical isolates ranged between 0.16 and 0.93 µg/mL) and oral administration of fexinidazole at doses of 100 mg/kg/day for 4 days or 200 mg/kg/day for 5 days cured mice with acute and chronic infection respectively, the latter being a model for the advanced and fatal stage of the disease when parasites have disseminated into the brain. In laboratory animals, fexinidazole is well absorbed after oral administration and readily distributes throughout the body, including the brain. The absolute bioavailability of oral fexinidazole was 41% in mice, 30% in rats, and 10% in dogs. Furthermore, fexinidazole is rapidly metabolised in vivo to at least two biologically active metabolites (a sulfoxide and a sulfone derivative) that likely account for a significant portion of the therapeutic effect. Key pharmacokinetic parameter after oral absorption in mice for fexinidazole and its sulfoxide and sulfone metabolites are a Cmax of 500, 14171 and 13651 ng/mL respectively, and an AUC0–24 of 424, 45031 and 96286 h.ng/mL respectively. Essentially similar PK profiles were observed in rats and dogs. Toxicology studies (including safety pharmacology and 4-weeks repeated-dose toxicokinetics in rat and dog) have shown that fexinidazole is well tolerated. The No Observed Adverse Event Levels in the 4-weeks repeated dose toxicity studies in rats and dogs was 200 mg/kg/day in both species, with no issues of concern identified for doses up to 800 mg/kg/day. While fexinidazole, like many nitroheterocycles, is mutagenic in the Ames test due to bacterial specific metabolism, it is not genotoxic to mammalian cells in vitro or in vivo as assessed in an in vitro micronucleus test on human lymphocytes, an in vivo mouse bone marrow micronucleus test, and an ex vivo unscheduled DNA synthesis test in rats.

Conclusions

The results of the preclinical pharmacological and safety studies indicate that fexinidazole is a safe and effective oral drug candidate with no untoward effects that would preclude evaluation in man. The drug has entered first-in-human phase I studies in September 2009. Fexinidazole is the first new clinical drug candidate with the potential for treating advanced-stage sleeping sickness in thirty years.

Author Summary

This article describes the preclinical profile of fexinidazole, a new drug candidate with the potential to become a novel, oral, safe and effective short-course treatment for curing both stage 1 and 2 human African trypanosomiasis and replace the old and highly problematic treatment modalities available today. Fexinidazole is orally available and rapidly metabolized in two metabolites having equivalent biological activity to the parent and contributing significantly to the in vivo efficacy in animal models of both stage 1 and 2 HAT. Animal toxicology studies indicate that fexinidazole has an excellent safety profile, with no particular issues identified. Fexinidazole is a 5-nitroimidazole and, whilst it is Ames-positive, it is devoid of any genetic toxicity in mammalian cells and therefore does not pose a genotoxic risk for use in man. Fexinidazole, which was rediscovered through a process of compound mining, is the first new drug candidate for stage 2 HAT having entered clinical trials in thirty years, and has the potential to revolutionize therapy of this fatal disease at a cost that is acceptable in the endemic regions.

Most treatment studies of opioid-dependent populations have focused predominantly on heroin users, despite a recent increase in those dependent upon prescription opioids. A key methodological challenge involved in studying the latter group involves defining the population. Specifically, researchers must decide whether to include 1) concurrent heroin users and 2) individuals with pain. The multi-site Prescription Opioid Addiction Treatment Study is examining treatments for this population. This paper describes various inclusion criteria considered by the study team related to heroin use and pain. The goal was to recruit a distinct but generalizable population of individuals dependent upon prescription opioids.

Background

Human African trypanosomiasis (HAT), or sleeping sickness, is a fatal neglected tropical disease if left untreated. HAT primarily affects people living in rural sub-Saharan Africa, often in regions afflicted by violent conflict. Screening and treatment of HAT is complex and resource-intensive, and especially difficult in insecure, resource-constrained settings. The country with the highest endemicity of HAT is the Democratic Republic of Congo (DRC), which has a number of foci of high disease prevalence. We present here the challenges of carrying out HAT control programmes in general and in a conflict-affected region of DRC. We discuss the difficulties of measuring disease burden, medical care complexities, waning international support, and research and development barriers for HAT.

Discussion

In 2007, Médecins Sans Frontières (MSF) began screening for HAT in the Haut-Uélé and Bas-Uélé districts of Orientale Province in northeastern DRC, an area of high prevalence affected by armed conflict. Through early 2009, HAT prevalence rate of 3.4% was found, reaching 10% in some villages. More than 46,000 patients were screened and 1,570 treated for HAT during this time. In March 2009, two treatment centres were forced to close due to insecurity, disrupting patient treatment, follow-up, and transmission-control efforts. One project was reopened in December 2009 when the security situation improved, and another in late 2010 based on concerns that population displacement might reactivate historic foci. In all of 2010, 770 patients were treated at these sites, despite a limited geographical range of action for the mobile teams.

Summary

In conflict settings where HAT is prevalent, targeted medical interventions are needed to provide care to the patients caught in these areas. Strategies of integrating care into existing health systems may be unfeasible since such infrastructure is often absent in resource-poor contexts. HAT care in conflict areas must balance logistical and medical capacity with security considerations, and community networks and international-response coordination should be maintained. Research and development for less complicated, field-adapted tools for diagnosis and treatment, and international support for funding and program implementation, are urgently needed to facilitate HAT control in these remote and insecure areas.

Histone acetylation is one of the key regulatory mechanisms controlling transcriptional activity in eukaryotic cells. In higher eukaryotes, a number of nuclear histone acetyltransferase (HAT) enzymes have been identified, most of which are part of a large multisubunit complex. This diversity, combined with the large number of potentially acetylable lysines on histones, suggested the existence of a specific regulatory mechanism based on the substrate specificity of HATs. Over the past decade, intensive characterisations of the HAT complexes have been carried out. However, the precise mode of action of HATs, and particularly the functional differences amongst these complexes, remains elusive. Here we review current insights into the functional role of HATs, focusing on the specificity of their action. Studies based on biochemical as well as genetic approaches suggested that HATs exert a high degree of specificity in their acetylation spectra and in the cellular processes they regulate. However, a different view emerged recently from genomic approaches that provided genome-wide maps of HAT recruitments. The careful analysis of genomic data suggests that all HAT complexes would be simultaneously recruited to a similar set of loci in the genome, arguing for a low specificity in their function. In this review, we discuss the significance of these apparent contradictions and suggest a new model that integrates biochemical, genetic and genome-wide data to better describe the functional specificity of HAT complexes.

Aims

Research on drug dependence often involves the administration of drugs of abuse to experienced drug users under controlled laboratory conditions. The primary objective of this study was to assess whether participation in such research alters the frequency of heroin use by non-treatment seeking opioid-dependent volunteers after study completion.

Design

Data were examined from four inpatient studies involving controlled opioid administration.

Setting

Substance Use Research Center at Columbia University, New York State Psychiatric Institute.

Participants

Sixty-nine heroin dependent volunteers.

Measurements

Participants’ self-reported heroin use prior to and one month after study participation was compared using a Wilcoxon test. Because a number of participants reported that they had stopped using heroin, a logistic regression was used to identify correlates of heroin cessation one month after study completion.

Findings

One hundred one participants entered laboratory studies and 69 completed them. Self-reported heroin use significantly decreased one month after study participation [1.7 (+/− 2) bags per day] compared to baseline [6.8 (+/− 4.2) bags per day], p < 0.001 among the 69 completers. In addition, 42% of the completers were heroin abstinent one month after study completion. Being African American, having a history of opioid dependence treatment, reporting heavier heroin use at baseline, and a longer history of heroin use were correlated with cessation of heroin use.

Conclusions

These findings demonstrate that participation in opioid administration studies does not increase subsequent heroin use and for some individuals leads to accessing opioid dependence treatment and cessation of heroin use in the short term.

A decade of research in Switzerland, The Netherlands, Germany, and Spain now constitutes a massive body of work supporting the use of heroin treatment for the most difficult patients addicted to opiates. These trials concur on this method's safety and efficacy and are now serving as a prelude to the institution of heroin treatment in clinical practice throughout Europe.

While the different sampling and research protocols for heroin treatment in these studies were important to the academic claims about specific results and conclusions that could be drawn from each study, the overall outcomes were quite clear – and uniformly positive. They all find that the use of prescribed pharmaceutical heroin does exactly what it is intended to do: it reaches a treatment refractory group of addicts by engaging them in a positive healthcare relationship with a physician, it reduces their criminal activity, improves their health status, and increases their social tenure through more stable housing, employment, and contact with family.

The Canadian trial (NAOMI), now underway for over a year, but not yet completed, now faces a dilemma about what to do with its patients who have successfully completed 12 months of heroin and must be withdrawn from heroin and transferred to other treatments in accordance with the research protocol approved by Government of Canada, federal granting body and host institutions. The problem is that the principal criterion for acceptance to NAOMI was their history of repeated failure in these very same treatment programs to which they will now be referred.

The existence of the results from abroad (some of which were not yet available when NAOMI was designed and initiated) now raises a very important question for Canada: is it ethical to continue to prohibit the medical use of heroin treatment that has already been shown to be feasible and effective in numerous medical studies throughout the world? And while this is being worked out, is it acceptable to require patients who have been successfully treated with heroin in Canada, to be forced to move back to less effective treatments (treatments that failed to be efficacious in the past)?

This essay discusses this dilemma and places it in the broader context of ethics, science, and health policy. It makes the case for continuation of the current successful patients in heroin treatment and the institution of heroin treatment to all Canadian patients living with active addictions who qualify.

Heroin addiction is a wide-reaching problem with a spectrum of damaging social consequences. Currently approved heroin addiction medications include drugs that bind at the same receptors (e.g. opioid receptors) occupied by heroin and/or its metabolites in the brain, but undesired side effects of these treatments, maintenance dependence and relapse to drug taking remains problematic. A vaccine capable of blocking heroin’s effects could provide an economical, long-lasting and sustainable adjunct to heroin addiction therapy without the side effects associated with available treatment options. Heroin, however, presents a particularly challenging vaccine target as it is metabolized to multiple psychoactive molecules of differing lipophilicity, with differing abilities to cross the blood brain barrier. In this review, we discuss the opiate scaffolding and hapten design considerations to confer immunogenicity as well as the specificity of the immune response towards structurally similar opiates. In addition, we detail different strategies employed in the design of immunoconjugates for a vaccine-based therapy for heroin addiction treatment.

Treatment research with opioid-dependent populations has not traditionally distinguished between those dependent on prescription opioids versus dependent upon heroin. Evidence suggests there is a substantial subpopulation of individuals with opioid dependence resulting largely or exclusively from prescription opioid use. Because this subpopulation may respond to treatment differently from heroin users, a method for discriminating DSM-IV opioid dependence due to prescription opioid use would provide more precision when examining this population. This paper describes an innovative method using a currently available diagnostic instrument, to diagnose DSM-IV opioid dependence and distinguish between dependence resulting from prescription opioids versus dependence upon heroin.

Human African trypanosomiasis (HAT) has been a major public health problem in South Sudan for the last century. Recurrent outbreaks with a repetitive pattern of responding-scaling down activities have been observed. Control measures for outbreak response were reduced when the prevalence decreased and/or socio-political crisis erupted, leading to a new increase in the number of cases. This paper aims to raise international awareness of the threat of another outbreak of sleeping sickness in South Sudan. It is a review of the available data, interventions over time, and current reports on the status of HAT in South Sudan. Since 2006, control interventions and treatments providing services for sleeping sickness have been reduced. Access to HAT diagnosis and treatment has been considerably diminished. The current status of control activities for HAT in South Sudan could lead to a new outbreak of the disease unless 1) the remaining competent personnel are used to train younger staff to resume surveillance and treatment in the centers where HAT activities have stopped, and 2) control of HAT continues to be given priority even when the number of cases has been substantially reduced. Failure to implement an effective and sustainable system for HAT control and surveillance will increase the risk of a new epidemic. That would cause considerable suffering for the affected population and would be an impediment to the socioeconomic development of South Sudan.

Pentamidine has a long history in the treatment of human African trypanosomiasis (HAT) and leishmaniasis. Early guidelines on the dosage of pentamidine were based on the base-moiety of the two different formulations available. Confusion on the dosage of pentamidine arose from a different labelling of the two available products, either based on the salt or base moiety available in the preparation. We provide an overview of the various guidelines concerning HAT and leishmaniasis over the past decades and show the confusion in the calculation of the dosage of pentamidine in these guidelines and the subsequent published reports on clinical trials and reviews. At present, only pentamidine isethionate is available, but the advised dosage for HAT and leishmaniasis is (historically) based on the amount of pentamidine base. In the treatment of leishmaniasis this is probably resulting in a subtherapeutic treatment. There is thus a need for a new, more transparent and concise guideline concerning the dosage of pentamidine, at least in the treatment of HAT and leishmaniasis.

Background

Human African trypanosomiasis (HAT) is an infectious disease with a large global health burden occurring primarily in Central and Eastern Africa. Most current treatments have poor blood brain barrier (BBB) penetration, which prevent them from targeting the most lethal stage of the infection. In addition, current therapeutics suffer from a variety of limitations ranging from serious side effects to difficulties with treatment administration. Therefore it is of crucial importance to find new treatments that are safe, affordable, and effective against both sub-species of Trypanosoma brucei.

Methods

Semi-synthetic derivatization of the fungally-derived natural product merulin A (1) has led to the discovery of new development candidates for the protozoan parasite T. brucei, the causative agent of HAT. Creation of an initial SAR library based around the merulin scaffold revealed several key features required for activity, including the endoperoxide bridge, as well as one position suitable for further derivatization. Subsequent synthesis of a 20-membered analogue library, guided by the addition of acyl groups that improve the drug-like properties of the merulin A core, resulted in the development of compound 12 with an IC50 of 60 nM against T. brucei, and a selectivity index greater than 300-fold against HeLa and immortalized glial cells.

Significance

We report the semi-synthetic optimization of the merulin class of endoperoxide natural products as development candidates against T. brucei. We have identified compounds with low nM antiparasitic activities and high selectivity indices against HeLa cells. These compounds can be produced economically in large quantities via a one step derivatization from the microbial fermentation broth isolate, making them encouraging lead candidates for further development.

A positive reinforcement contingency increased opioid abstinence during outpatient dose tapering (4, 2, then 0 mg/day during Weeks 1 through 3) in non-treatment-seeking heroin-dependent volunteers who had been maintained on buprenorphine (8 mg/day) during an inpatient research protocol. The control group (n  =  12) received $4.00 for completing assessments at each thrice-weekly visit during dose tapering; 10 of 12 lapsed to heroin use 1 day after discharge. The abstinence reinforcement group (n  =  10) received $30.00 for each consecutive opioid-free urine sample; this significantly delayed heroin lapse (median, 15 days).

The continued northwards spread of Rhodesian sleeping sickness or Human African Trypanosomiasis (HAT) within Uganda is raising concerns of overlap with the Gambian form of the disease. Disease convergence would result in compromised diagnosis and treatment for HAT. Spatial determinants for HAT are poorly understood across small areas. This study examines the relationships between Rhodesian HAT and several environmental, climatic and social factors in two newly affected districts, Kaberamaido and Dokolo. A one-step logistic regression analysis of HAT prevalence and a two-step logistic regression method permitted separate analysis of both HAT occurrence and HAT prevalence. Both the occurrence and prevalence of HAT were negatively correlated with distance to the closest livestock market in all models. The significance of distance to the closest livestock market strongly indicates that HAT may have been introduced to this previously unaffected area via the movement of infected, untreated livestock from endemic areas. This illustrates the importance of the animal reservoir in disease transmission, and highlights the need for trypanosomiasis control in livestock and the stringent implementation of regulations requiring the treatment of cattle prior to sale at livestock markets to prevent any further spread of Rhodesian HAT within Uganda.

Author Summary

Human African Trypanosomiasis (HAT) or sleeping sickness is a parasitic disease of humans, transmitted by the tsetse fly. There are two different forms of HAT: Rhodesian (in eastern sub-Saharan Africa), which also affects wild and domestic animals, and Gambian (in western and central sub-Saharan Africa). Diagnosis and treatment of the two diseases differ, and disease characterisation is based on prior knowledge of known geographical disease distributions. Presently, the two forms of HAT do not overlap in any area: Uganda is the only country which sustains active transmission of both types.

In recent years, Rhodesian HAT has spread into areas of Uganda that had not previously been affected, thus narrowing the gap between areas of Rhodesian and Gambian HAT transmission. This spread has raised concerns of a potential overlap of the two types of the disease, which would severely complicate their diagnosis and treatment. Earlier work indicated that Rhodesian HAT was introduced to Soroti district due to the movement of untreated cattle from affected areas. Here we show that the continued spread of HAT in Uganda (to a further 2 districts) may also have occurred due to cattle movements, despite legal requirements to treat livestock from affected areas prior to sale at markets. These findings can assist in the targeting of HAT control efforts in Uganda and show that the stringent implementation of animal treatments at livestock markets should be a priority.

In the past decade, the utilization of ambulance data to inform the prevalence of nonfatal heroin overdose has increased. These data can assist public health policymakers, law enforcement agencies, and health providers in planning and allocating resources. This study examined the 672 ambulance attendances at nonfatal heroin overdoses in Queensland, Australia, in 2000. Gender distribution showed a typical 70/30 male-to-female ratio. An equal number of persons with nonfatal heroin overdose were between 15 and 24 years of age and 25 and 34 years of age. Police were present in only 1 of 6 cases, and 28.1% of patients reported using drugs alone. Ambulance data are proving to be a valuable population-based resource for describing the incidence and characteristics of nonfatal heroin overdose episodes. Future studies could focus on the differences between nonfatal heroin overdose and fatal heroin overdose samples.

Background

Heroin coming into the United States historically comes from three widely dispersed geographical regions: Southwest Asia, Southeast Asia and Mexico. A fourth source of US-bound heroin, from Colombia, originated in the early 1990s. The fact that the four heroin sources produce differing morphologies and qualities of heroin has not been critically examined. In addition, it is not well established how the contemporary competing dynamics of interdiction, or restriction of heroin flows across international boundaries, and neoliberal, e.g., global expansion of free trade, policies are affecting heroin markets. This paper will highlight changes in the US heroin market, including source trends, the political economy of the now dominant source and the resultant effects on the heroin risk environment by US region.

Methods

Using a structural and historical framework this paper examines two decades of secondary data sources, including government and drug control agency documents, on heroin flows together with published work on the political and economic dynamics in Latin America.

Results

Co-occurring neoliberal economic reforms may have contributed to paradoxical effects of US/Colombian interdiction efforts. Since entering the US market, heroin from Colombia has been distributed at a much higher quality and lower retail price. An increasingly exclusive market has developed with Mexican and Colombian heroin gaining market share and displacing Asian heroin. These trends have had dramatic effects on the risk environment for heroin consumers. An intriguing factor is that different global sources of heroin produce substantially different products. Plausible associations exist between heroin source/form and drug use behaviours and harms. For example, cold water-soluble powdered heroin (sources: Asia, Colombia) may be associated with higher HIV prevalence in the US, while low-solubility “black tar” heroin (BTH; source: Mexico) is historically used in areas with reduced HIV prevalence. BTH is associated with soft tissue infections caused by Clostridium bacteria.

Conclusion

Source and type of heroin are structural factors in the risk environment of heroin users: source dictates distribution and type predicts practice. How specific types of heroin are used and with what risk is therefore distributed geographically. Continued flux in the heroin market and its effects on the risk environment for drug users deserves further attention.

Background

Histone modifications have been implicated in the regulation of transcription and, more recently, in DNA replication and repair. In yeast, a major conserved histone acetyltransferase, Hat1p, preferentially acetylates lysine residues 5 and 12 on histone H4.

Results

Here, we report that a nuclear sub-complex consisting of Hat1p and its partner Hat2p interacts physically and functionally with the origin recognition complex (ORC). While mutational inactivation of the histone acetyltransferase (HAT) gene HAT1 alone does not compromise origin firing or initiation of DNA replication, a deletion in HAT1 (or HAT2) exacerbates the growth defects of conditional orc-ts mutants. Thus, the ORC-associated Hat1p-dependent histone acetyltransferase activity suggests a novel linkage between histone modification and DNA replication. Additional genetic and biochemical evidence points to the existence of partly overlapping histone H3 acetyltransferase activities in addition to Hat1p/Hat2p for proper DNA replication efficiency. Furthermore, we demonstrated a dynamic association of Hat1p with chromatin during S-phase that suggests a role of this enzyme at the replication fork.

Conclusion

We have found an intriguing new association of the Hat1p-dependent histone acetyltransferase in addition to its previously known role in nuclear chromatin assembly (Hat1p/Hat2p-Hif1p). The participation of a distinct Hat1p/Hat2p sub-complex suggests a linkage of histone H4 modification with ORC-dependent DNA replication.

Background

The current treatments for human African trypanosomiasis (HAT), Chagas disease and leishmaniasis (collectively referred to as the kinetoplastid diseases) are far from ideal but, for some, there has been significant recent progress. For HAT the only advances in treatment over the past two decades have been the introduction of an eflornithine/nifurtimox co-administration and a shorter regime of the old standard melarsoprol.

Sources of data

PubMed.

Areas of Agreement

There is a need for new safe, oral drugs for cost-effective treatment of patients and use in control programmes for all the trypanosomatid diseases.

Areas of controversy

Cutaneous leishmaniasis is not on the agenda and treatments are lagging behind.

Growing points

There are three compounds in development for the treatment of the CNS stage of HAT: fexinidazole, currently due to entry into phase II clinical studies, a benzoxaborole (SCYX-7158) in phase I trials and a diamidine derivative (CPD-0802), in advanced pre-clinical development. For Chagas disease, two anti-fungal triazoles are now in clinical trial. In addition, clinical studies with benznidazole, a drug previously recommended only for acute stage treatment, are close to completion to determine the effectiveness in the treatment of early chronic and indeterminate Chagas disease. For visceral leishmaniasis new formulations, therapeutic switching, in particular AmBisome, and the potential for combinations of established drugs have significantly improved the opportunities for the treatment in the Indian subcontinent, but not in East Africa.

Areas timely for developing research

Improved diagnostic tools are needed to support treatment, for test of cure in clinical trials and for monitoring/surveillance of populations in control programmes.

Background

Human African trypanosomiasis (HAT), also known as sleeping sickness, persists as a public health problem in several sub-Saharan countries. Evidence-based, spatially explicit estimates of population at risk are needed to inform planning and implementation of field interventions, monitor disease trends, raise awareness and support advocacy. Comprehensive, geo-referenced epidemiological records from HAT-affected countries were combined with human population layers to map five categories of risk, ranging from “very high” to “very low,” and to estimate the corresponding at-risk population.

Results

Approximately 70 million people distributed over a surface of 1.55 million km2 are estimated to be at different levels of risk of contracting HAT. Trypanosoma brucei gambiense accounts for 82.2% of the population at risk, the remaining 17.8% being at risk of infection from T. b. rhodesiense. Twenty-one million people live in areas classified as moderate to very high risk, where more than 1 HAT case per 10,000 inhabitants per annum is reported.

Discussion

Updated estimates of the population at risk of sleeping sickness were made, based on quantitative information on the reported cases and the geographic distribution of human population. Due to substantial methodological differences, it is not possible to make direct comparisons with previous figures for at-risk population. By contrast, it will be possible to explore trends in the future. The presented maps of different HAT risk levels will help to develop site-specific strategies for control and surveillance, and to monitor progress achieved by ongoing efforts aimed at the elimination of sleeping sickness.

Author Summary

The present thrust towards the elimination of human African trypanosomiasis (HAT, or sleeping sickness) requires accurate information on how many people are at risk of contracting the disease, and where they live. This information is crucial to target field interventions effectively and efficiently, as well as to monitor progress towards the elimination goal. In this paper, a Geographic Information System was used to delineate areas at different levels of risk. To this end, accurate data on the spatial distribution of HAT cases (period 2000–2009) were collated and combined with maps of human population. A total of 70 million people are estimated to be at risk of contracting sleeping sickness in Africa. This population is distributed over a surface of one and a half million square kilometres, an area six times that of the United Kingdom. Half of the people and of the areas at risk are found in the Democratic Republic of the Congo.

An increase in illicit drug use in Northern Ireland may well have links to the resolution of political conflict, which started in the mid 1990s. Social issues, heretofore hidden, have emerged into the limelight and may be worsened by paramilitary involvement.1 Registered addicts in the four Health Board areas have shown an increase from 1997 with the greatest number resident within the Northern Board Area.2 As the prevalence of heroin use in Northern Ireland increased, the Department of Health and Social Services and Public Safety (DHSSPS) commissioned a report, to recommend the development of substitute prescribing services.3 A case series of pregnancies was reviewed, within the Northern Board Area, where the mother was taking opioid substitution therapy. This resulted in baseline data of outcome for both mother and baby specific to a Northern Ireland population. The different medications for opioid substitution are also assessed. This information will guide a co-ordinated approach that involves obstetrician, anaesthetist, psychiatrist, midwife and social worker to the care of these high-risk pregnancies. Eighteen pregnancies were identified in the study period. Sixteen of these had viable outcomes. One was a twin pregnancy. Outcome data was therefore available for 17 infants.

Information was obtained regarding patients' social and demographic background, drug taking behaviour and substitution regimen. Antenatal and intrapartum care was assessed and infants were followed up to the time of hospital discharge.

Background

Human African Trypanosomiasis (HAT), also referred to as sleeping sickness, and African Animal Trypanosomaisis (AAT), known as nagana, are highly prevalent parasitic vector-borne diseases in sub-Saharan Africa. Humans acquire trypanosomiasis following the bite of a tsetse fly infected with the protozoa Trypanosoma brucei (T.b.) spp. –i.e., T.b. gambiense in West and Central Africa and T.b. rhodesiense in East and Southern Africa. Over the last decade HAT diagnostic capacity to estimate HAT prevalence has improved in active case-finding areas but enhanced passive surveillance programs are still lacking in much of rural sub-Saharan Africa.

Methodology/Principal Findings

This retrospective-cross-sectional study examined the use of national census data (1999) to estimate population vulnerability and disability in Kenya's 7 tsetse belts to assess the potential of HAT-acquired infection in those areas. A multilevel study design estimated the likelihood of disability in individuals, nested within households, nested within tsetse fly habitats of varying levels of poverty. Residents and recent migrants of working age were studied. Tsetse fly's impact on disability was conceptualised via two exposure pathways: directly from the bite of a pathogenic tsetse fly resulting in HAT infection or indirectly, as the potential for AAT takes land out of agricultural production and diseased livestock leads to livestock morbidity and mortality, contributing to nutritional deficiencies and poverty. Tsetse belts that were significantly associated with increased disability prevalence were identified and the direct and indirect exposure pathways were evaluated.

Conclusions/Significance

Incorporating reports on disability from the national census is a promising surveillance tool that may enhance future HAT surveillance programs in sub-Saharan Africa. The combined burdens of HAT and AAT and the opportunity costs of agricultural production in AAT areas are likely contributors to disability within tsetse-infested areas. Future research will assess changes in the spatial relationships between high tsetse infestation and human disability following the release of the Kenya 2009 census at the local level.

Author Summary

The tsetse fly's influence on human health occurs through direct and indirect exposure pathways. Directly, the fly is a vector for the disease human African trypanosomiasis (HAT), which it spreads to nearly 18,000 new victims each year. Indirectly, the fly is a vector for African Animal Trypanosomaisis (AAT) also known as nagana, which restricts agricultural production, limiting the availability of food and contributing to impoverished conditions across rural sub-Saharan Africa. This historical study used 1999 census data to determine the prevalence of disability among residents and migrants living within Kenya's 7 tsetse fly belts. The results showed that the HAT transmission cycle may differ for residents and migrants with mechanisms leading to exposures that are environmentally driven for residents and economically driven for migrants. The combined burdens of HAT and AAT and the opportunity costs of agricultural production in AAT areas are potential contributors to disability within these tsetse-infested areas. Incorporating reports on disability from the national census appears to be an important surveillance tool that would enhance future HAT surveillance programs in sub-Saharan Africa.

Objective: To evaluate an experimental heroin maintenance programme.

Design: Randomised trial.

Setting: Outpatient clinic in Geneva, Switzerland.

Subjects: Heroin addicts recruited from the community who were socially marginalised and in poor health and had failed in at least two previous drug treatments.

Intervention: Patients in the experimental programme (n=27) received intravenous heroin and other health and psychosocial services. Control patients (n=24) received any other conventional drug treatment (usually methadone maintenance).

Main outcome measures: Self reported drug use, health status (SF-36), and social functioning.

Results: 25 experimental patients completed 6 months in the programme, receiving a median of 480 mg of heroin daily. One experimental subject and 10 control subjects still used street heroin daily at follow up (difference 44%; 95% confidence interval 16% to 71%). Health status scores that improved significantly more in experimental subjects were mental health (0.58 SD; 0.07 to 1.10), role limitations due to emotional problems (0.95 SD; 0.11 to 1.79), and social functioning (0.65 SD; 0.03 to 1.26). Experimental subjects also significantly reduced their illegal income and drug expenses and committed fewer drug and property related offences. There were no benefits in terms of work, housing situation, somatic health status, and use of other drugs. Unexpectedly, only nine (38%) control subjects entered the heroin maintenance programme at follow up.

Conclusions: A heroin maintenance programme is a feasible and clinically effective treatment for heroin users who fail in conventional drug treatment programmes. Even in this population, however, another attempt at methadone maintenance may be successful and help the patient to stop using injectable opioids.

Key messages A heroin maintenance programme may be a useful treatment option for patients who do not succeed in conventional drug treatment programmes Patients randomly allocated to the Geneva heroin maintenance programme fared better that patients in conventional drug treatments in terms of street drug use, mental health, social functioning, and illegal activities Results of the trial apply only to a subgroup of severely addicted people who failed repeatedly in conventional drug treatments This evaluation does not distinguish between the effects of heroin itself and the effects of other medical and psychosocial services that were provided as part of the programme There was less demand for the heroin maintenance programme than anticipated and most control subjects declined entry into the programme at the end of the study

African sleeping sickness is endemic in sub-Saharan Africa where the WHO estimates that 60 million people are at risk for the disease. Human African trypanosomiasis (HAT) is 100% fatal if untreated and the current drug therapies have significant limitations due to toxicity and difficult treatment regimes. No new chemical agents have been approved since eflornithine in 1990. The pentamidine analog DB289, which was in late stage clinical trials for the treatment of early stage HAT recently failed due to toxicity issues. A new protocol for the treatment of late-stage T. brucei gambiense that uses combination nifurtomox/eflornithine (NECT) was recently shown to have better safety and efficacy than eflornithine alone, while being easier to administer. This breakthrough represents the only new therapy for HAT since the approval of eflornithine. A number of research programs are on going to exploit the unusual biochemical pathways in the parasite to identify new targets for target based drug discovery programs. HTS efforts are also underway to discover new chemical entities through whole organism screening approaches. A number of inhibitors with anti-trypanosomal activity have been identified by both approaches, but none of the programs are yet at the stage of identifying a preclinical candidate. This dire situation underscores the need for continued effort to identify new chemical agents for the treatment of HAT.

Efforts to control human trypanosomiasis, which sharply reduced the disease, must be sustained.

In the Democratic Republic of Congo (DRC), human African trypanosomiasis (HAT) reached unprecedented levels in the 1990s. To assess recent trends and evaluate control efforts, we analyzed epidemiologic and financial data collected by all agencies involved in HAT control in DRC from 1993 to 2003. Funds allocated to control populations, as well as to the population screened, doubled from 1993 to 1997 and from 1998 to 2003. The number of cases detected decreased from 26,000 new cases per year in 1998 to 11,000 in 2003. Our analysis shows that HAT control in DRC is almost completely dependent on international aid and that sudden withdrawal of such aid in 1990 had a long-lasting effect. Since 1998, control efforts intensified because of renewed donor interest, including a public-private partnership, and this effort led to a major reduction in HAT incidence. To avoid reemergence of this disease, such efforts should be sustained.