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Pathogens (Basel, Switzerland) Sep 2022Background Human African trypanocide resistance (HATr) is a challenge for the eradication of Human African Trypansomiaisis (HAT) following the widespread emergence of... (Review)
Review
Background Human African trypanocide resistance (HATr) is a challenge for the eradication of Human African Trypansomiaisis (HAT) following the widespread emergence of increased monotherapy drug treatment failures against Trypanosoma brucei gambiense and T. b. rhodesiense that are associated with changes in pathogen receptors. Methods: Electronic searches of 12 databases and 3 Google search websites for human African trypanocide resistance were performed using a keyword search criterion applied to both laboratory and clinical studies. Fifty-one publications were identified and included in this study using the PRISMA checklist. Data were analyzed using RevMan and random effect sizes were computed for the statistics at the 95% confidence interval. Results: Pentamidine/melarsoprol/nifurtimox cross-resistance is associated with loss of the T. brucei adenosine transporter 1/purine 2 gene (TbAT1/P2), aquaglyceroporins (TbAQP) 2 and 3, followed by the high affinity pentamidine melarsoprol transporter (HAPT) 1. In addition, the loss of the amino acid transporter (AAT) 6 is associated with eflornithine resistance. Nifurtimox/eflornithine combination therapy resistance is associated with AAT6 and nitroreductase loss, and high resistance and parasite regrowth is responsible for treatment relapse. In clinical studies, the TbAT1 proportion of total random effects was 68% (95% CI: 38.0−91.6); I2 = 96.99% (95% CI: 94.6−98.3). Treatment failure rates were highest with melarsoprol followed by eflornithine at 41.49% (95% CI: 24.94−59.09) and 6.56% (3.06−11.25) respectively. HATr-resistant phenotypes used in most laboratory experiments demonstrated significantly higher pentamidine resistance than other trypanocides. Conclusion: The emergence of drug resistance across the spectrum of trypanocidal agents that are used to treat HAT is a major threat to the global WHO target to eliminate HAT by 2030. T. brucei strains were largely resistant to diamidines and the use of high trypanocide concentrations in clinical studies have proved fatal in humans. Studies to develop novel chemotherapeutical agents and identify alternative protein targets could help to reduce the emergence and spread of HATr.
PubMed: 36297157
DOI: 10.3390/pathogens11101100 -
Expert Review of Cardiovascular Therapy Dec 2020Human African Trypanosomiasis is a neglected tropical disease resulting from the infection with the parasite Trypanosoma brucei. Neurological compromise often dominates,...
INTRODUCTION
Human African Trypanosomiasis is a neglected tropical disease resulting from the infection with the parasite Trypanosoma brucei. Neurological compromise often dominates, and the impact of cardiovascular involvement has not been fully investigated. Recently, publications indicate that cardiovascular compromise is more frequent than previously thought. Early detection of cardiac complications may be of utmost importance for healthcare teams.
AREA COVERED
As a part of the 'Neglected Tropical Diseases and other Infectious Diseases involving the Heart' (the NET-Heart Project), the purpose of this article is to review all the information available regarding cardiovascular implications of this disease, focusing on diagnosis and treatment, and proposing strategies for early detection of cardiac manifestations. An electronic systematic literature review of articles published in MEDLINE, PubMed and EMBASE was performed. From 50 initial studies, 18 were selected according to inclusion criteria. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement was used for conducting and reporting this review.
EXPERT OPINION
Cardiovascular compromise through infiltrative and inflammatory mechanisms seems to be frequent, and includes a wide spectrum of severity. Conventional 12-lead electrocardiogram could be a useful test for screening cardiovascular manifestations and used as a guide for considering specific treatments or more sophisticated diagnostic tools.
Topics: Animals; Electrocardiography; Heart Diseases; Humans; Mass Screening; Trypanosomiasis, African
PubMed: 32967478
DOI: 10.1080/14779072.2020.1828066 -
Tropical Medicine and Infectious Disease Aug 2022African trypanocide resistance is an emerging public health emergency whose control requires a revisit on farmer's knowledge, attitudes, and practices in developing... (Review)
Review
BACKGROUND
African trypanocide resistance is an emerging public health emergency whose control requires a revisit on farmer's knowledge, attitudes, and practices in developing countries. African animal trypanocide resistance (AATr) is rife in an environment where drug use and policy decisions are disjointed. The objective of the study was to identify community factors responsible for the development of AATr. This was important since diminazene aceturate (DA), isometamidium chloride (ISM), and homidium bromide (HB) have existed for over 30 years and no new drugs have been provided to farmers.
METHODS
An electronic keyword search across 12 databases was conducted using a search criterion from 1806 to June 2022. This generated a total of 24 publications, but after removing duplicates, review articles, and nonrelated articles, a total of eight papers were included in the analysis by following the PRISMA checklist. A meta-analysis was conducted on the data extracted and the risk ratio and inverse variance at 95% confidence interval were calculated using RevMan.
RESULTS
All the eight articles in the study showed that DA was the most preferred trypanocide in both West and Eastern Africa. Poor farmer knowledge of AATr and limited drug options were major drivers for trypanocide resistance. In addition, farmer treatments, use of untrained personnel, poor administration, poor dosing, and preparation of trypanocides were major drivers for the development of AATr and similarities were identified in DA and ISM practices (P = 0.13).
CONCLUSIONS
AATr is spread in developing countries due to a lack of community knowledge, attitudes, and drug-use practices. This situation could be reversed through interdisciplinary collaborations in endemic communities by promoting effective treatments and responsible drug handling.
PubMed: 36136616
DOI: 10.3390/tropicalmed7090205 -
Frontiers in Veterinary Science 2022African animal trypanocide resistance (AATr) continues to undermine global efforts to eliminate the transmission of African trypanosomiasis in endemic communities. The...
BACKGROUND
African animal trypanocide resistance (AATr) continues to undermine global efforts to eliminate the transmission of African trypanosomiasis in endemic communities. The continued lack of new trypanocides has precipitated drug misuse and overuse, thus contributing to the development of the AATr phenotype. In this study, we investigated the threat associated with AATr by using the major globally available chemotherapeutical agents.
METHODS
A total of seven electronic databases were screened for an article on trypanocide resistance in AATr by using keywords on preclinical and clinical trials with the number of animals with treatment relapse, days taken to relapse, and resistant gene markers using the PRISMA checklist. Data were cleaned using the SR deduplicator and covidence and analyzed using Cochrane RevMan®. Dichotomous outputs were presented using risk ratio (RR), while continuous data were presented using the standardized mean difference (SMD) at a 95% confidence interval.
RESULTS
A total of eight publications in which diminazene aceturate (DA), isometamidium chloride (ISM), and homidium chloride/bromide (HB) were identified as the major trypanocides were used. In all preclinical studies, the development of resistance was in the order of HB > ISM > DA. DA vs. ISM (SMD = 0.15, 95% CI: -0.54, 0.83; = 46%, = 0.05), DA vs. HB (SMD = 0.96, 95% CI: 0.47, 1.45; = 0%, = 0.86), and HB vs. ISM (SMD = -0.41, 95% CI: -0.96, 0.14; = 5%, = 0.38) showed multiple cross-resistance. Clinical studies also showed evidence of multi-drug resistance on DA and ISM (RR = 1.01, 95% CI: 0.71-1.43; = 46%, = 0.16). To address resistance, most preclinical studies increased the dosage and the treatment time, and this failed to improve the patient's prognosis. Major markers of resistance explored include AT1, P1/P2 transporters, folate transporters, such as F-I, F-II, F-III, and polyamine biosynthesis inhibitors. In addition, immunosuppressed hosts favor the development of AATr.
CONCLUSION
AATr is a threat that requires a shift in the current disease control strategies in most developing nations due to inter-species transmission. Multi-drug cross-resistance against the only accessible trypanocides is a major public health risk, justifying the need to revise the policy in developing countries to promote control of African trypanosomiasis.
PubMed: 36686196
DOI: 10.3389/fvets.2022.950248 -
Acta Tropica Oct 2015The control and eventual elimination of human African trypanosomiasis (HAT) requires the expansion of current control and surveillance activities. A systematic review of... (Review)
Review
The control and eventual elimination of human African trypanosomiasis (HAT) requires the expansion of current control and surveillance activities. A systematic review of the published literature on the costs of HAT prevention, treatment, and control, in addition to the economic burden, was conducted. All studies that contained primary or secondary data on costs of prevention, treatment and control were considered, resulting in the inclusion of 42 papers. The geographically focal nature of the disease and a lack of standardization in the cost data limit the usefulness of the available information for making generalizations across diverse settings. More recent information on the costs of treatment and control interventions for HAT is needed to provide accurate information for analyses and planning. The cost information contained herein can be used to inform rational decision making in control and elimination programs, and to assess potential synergies with existing vector-borne disease control programs, but programs would benefit significantly from new cost data collection.
Topics: Animals; Cattle; Health Care Costs; Hospitalization; Humans; Insect Control; Trypanosomiasis, African; Tsetse Flies
PubMed: 26056739
DOI: 10.1016/j.actatropica.2015.06.003 -
Journal of Medical Entomology Jul 2022African animal trypanosomiasis (AAT) a parasitic disease of livestock in sub-Saharan Africa causing tremendous loses. Sub-Saharan continental estimation of mean... (Meta-Analysis)
Meta-Analysis
African animal trypanosomiasis (AAT) a parasitic disease of livestock in sub-Saharan Africa causing tremendous loses. Sub-Saharan continental estimation of mean prevalence in both large and small domestic animals, risk factors, tsetse and non-tsetse prevalence and drug resistance is lacking. A review and meta-analysis was done to better comprehend changes in AAT prevalence and drug resistance. Publish/Perish software was used to search and extract peer-reviewed articles in Google scholar, PubMed and CrossRef. In addition, ResearchGate and African Journals Online (AJOL) were used. Screening and selection of articles from 2000-2021 was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Articles 304 were retrieved; on domestic animals 192, tsetse and non-tsetse vectors 44, risk factors 49 and trypanocidal drug resistance 30. Prevalence varied by, host animals in different countries, diagnostic methods and species of Trypanosoma. Cattle had the highest prevalence with Ethiopia and Nigeria leading, T. congolense (11.80-13.40%) and T. vivax (10.50-18.80%) being detected most. This was followed by camels and pigs. Common diagnostic method used was buffy coat microscopy. However; polymerase chain reaction (PCR), CATT and ELISA had higher detection rates. G. pallidipes caused most infections in Eastern regions while G. palpalis followed by G. mortisans in Western Africa. Eastern Africa reported more non-tsetse biting flies with Stomoxys leading. Common risk factors were, body conditions, breed type, age, sex and seasons. Ethiopia and Nigeria had the highest trypanocidal resistance 30.00-35.00% and highest AAT prevalence. Isometamidium and diminazene showed more resistance with T. congolense being most resistant species 11.00-83.00%.
Topics: Animals; Cattle; Cattle Diseases; Drug Resistance; Ethiopia; Prevalence; Risk Factors; Swine; Swine Diseases; Trypanosoma; Trypanosomiasis, African; Tsetse Flies
PubMed: 35579072
DOI: 10.1093/jme/tjac018 -
PLoS Neglected Tropical Diseases Dec 2016Control operations targeting Animal African Trypanosomiasis and its primary vector, the tsetse, were covering approximately 128,000 km2 of Africa in 2001, which is a... (Review)
Review
BACKGROUND
Control operations targeting Animal African Trypanosomiasis and its primary vector, the tsetse, were covering approximately 128,000 km2 of Africa in 2001, which is a mere 1.3% of the tsetse infested area. Although extensive trypanosomiasis and tsetse (T&T) control operations have been running since the beginning of the 20th century, Animal African Trypanosomiasis is still a major constraint of livestock production in sub-Saharan Africa.
METHODOLOGY/PRINCIPAL FINDINGS
We performed a systematic review of the existing literature describing T&T control programmes conducted in a selection of five African countries, namely Burkina Faso, Cameroon, Ethiopia, Uganda and Zambia, between 1980 and 2015. Sixty-eight documents were eventually selected from those identified by the database search. This was supplemented with information gathered through semi-structured interviews conducted with twelve key informants recruited in the study countries and selected based on their experience and knowledge of T&T control. The combined information from these two sources was used to describe the inputs, processes and outcomes from 23 major T&T control programmes implemented in the study countries. Although there were some data gaps, involvement of the target communities and sustainability of the control activities were identified as the two main issues faced by these programmes. Further, there was a lack of evaluation of these control programmes, as well as a lack of a standardised methodology to conduct such evaluations.
CONCLUSIONS/SIGNIFICANCE
Past experiences demonstrated that coordinated and sustained control activities require careful planning, and evidence of successes, failures and setbacks from past control programmes represent a mine of information. As there is a lack of evaluation of these programmes, these data have not been fully exploited for the design, analyses and justification of future control programmes.
Topics: Animals; Burkina Faso; Cameroon; Ethiopia; Insect Control; Trypanosomiasis, African; Tsetse Flies; Uganda; Zambia
PubMed: 28027299
DOI: 10.1371/journal.pntd.0005247 -
Acta Tropica Dec 2018The appraisal of the disease burden of African animal trypanosomiasis (AAT) in some livestock at country level could invite a re-evaluation of trypanosomiasis-control... (Meta-Analysis)
Meta-Analysis Review
The appraisal of the disease burden of African animal trypanosomiasis (AAT) in some livestock at country level could invite a re-evaluation of trypanosomiasis-control strategy. This study thus estimates small ruminant and porcine trypanosomiasis prevalence in sub-Saharan African countries. It also describes Trypanosoma species prevalence in small ruminants and pigs and attempts identification of factors explaining between-study variations in prevalence. Articles reporting animal trypanosomiasis prevalence in sheep, goats, and pigs in countries within sub-Saharan Africa were retrieved from different databases (PubMed, Science Direct, Google Scholar, and African Journal Online) and reference lists of relevant literatures. A total of 85 articles from 13 countries published between 1986 and 2018 were included in the analysis. Overall random-effects meta-analytic mean prevalence estimates were: 7.67% (95% CI: 5.22-10.49), 5.84% (95% CI: 3.81-8.23), and 19.46% (95% CI: 14.61-24.80) respectively, for sheep, goats, and pigs with substantial heterogeneity (I = >95.00%. p < 0.0001) noted between studies. Ovine, caprine, and porcine prevalence were highest in Tanzania (91.67%. 95% CI: 76.50-99.84), Equatorial Guinea (27%. 95% CI: 0-81.09), and Cameroon (47%. 95% CI: 29.67-66.06), respectively. Trypanosoma brucei s. l., T. vivax, and T. congolense were the most prevalent in the livestock. Trypanosoma brucei subspecies (T. b. gambiense and T. b. rhodesiense) occurred in all three livestock being mostly prevalent in pigs. Country of study was a significant predictor of trypanosomiasis prevalence in each livestock in addition to time and sample size for caprine hosts, diagnostic technique for both caprine and ovine hosts, and sample size for porcine hosts. The pattern of animal trypanosomiasis prevalence in the studied livestock reflects their susceptibility to trypanosomal infections and tsetse fly host feeding preferences. In conclusion, sheep, goats, and especially pigs are reservoirs of human infective trypanosomes in sub-Saharan Africa; consequently, their inclusion in sleeping sickness control programmes could enhance the goal of the disease elimination.
Topics: Animal Diseases; Animals; Humans; Prevalence; Ruminants; Swine; Swine Diseases; Trypanosomiasis
PubMed: 30179607
DOI: 10.1016/j.actatropica.2018.08.034 -
Cureus Aug 2021Human African trypanosomiasis (HAT), or sleeping sickness disease, is an infection caused mainly by human African trypanosomiasis (g-HAT) and is transmitted by tsetse... (Review)
Review
Human African trypanosomiasis (HAT), or sleeping sickness disease, is an infection caused mainly by human African trypanosomiasis (g-HAT) and is transmitted by tsetse flies. The disease goes through two stages: hemolymphatic and meningo-encephalic phases. The treatment for the second stage has changed from melarsoprol or eflornithine to nifurtimox-eflornithine combination therapy (NECT) and fexinidazole. We aimed to systematically review the literature on the efficacy and toxicity of fexinidazole and NECT. We used PubMed advanced strategy and Google Scholar databases, including clinical trials and observational studies on humans in the last 20 years in the English literature. Applying the inclusion/exclusion criteria, we reviewed eight studies. We used Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) and Meta-analysis of Observational Studies in Epidemiology (MOOSE) protocol. For assessing bias, we used the Cochrane Collaboration's tool for risk assessment of the clinical trials and the Robins-I tool for the observational studies. Overall, the clinical trials showed that NECT was non-inferior to eflornithine. The proportion of patients discharged alive is higher in patients treated with NECT vs. patients treated with eflornithine. Gastrointestinal complaints are a common side effect of NECT therapy, while fearful but relatively rare convulsions can also occur. The main limitation among the studies of NECT was the lack of blinding because most of them were open-label. Fexinidazole, the new oral medication showed is effective and safe for the treatment of g-HAT infection. Because of their convenience, fexinidazole is preferred over NECT therapy, oral vs. IV infusion in the first and second stages of the disease. Compared to older therapies, fexinidazole and NECT are more effective and safer than eflornithine and melarsoprol monotherapy.
PubMed: 34513456
DOI: 10.7759/cureus.16881 -
The Cochrane Database of Systematic... Dec 2021Human African trypanosomiasis, or sleeping sickness, is a severe disease affecting people in the poorest parts of Africa. It is usually fatal without... (Review)
Review
BACKGROUND
Human African trypanosomiasis, or sleeping sickness, is a severe disease affecting people in the poorest parts of Africa. It is usually fatal without treatment. Conventional treatments require days of intravenous infusion, but a recently developed drug, fexinidazole, can be given orally. Another oral drug candidate, acoziborole, is undergoing clinical development and will be considered in subsequent editions. OBJECTIVES: To evaluate the effectiveness and safety of currently used drugs for treating second-stage Trypanosoma brucei gambiense trypanosomiasis (gambiense human African trypanosomiasis, g-HAT).
SEARCH METHODS
On 14 May 2021, we searched the Cochrane Infectious Diseases Group Specialized Register, the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, Latin American and Caribbean Health Science Information database, BIOSIS, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform. We also searched reference lists of included studies, contacted researchers working in the field, and contacted relevant organizations.
SELECTION CRITERIA
Eligible studies were randomized controlled trials that included adults and children with second-stage g-HAT, treated with anti-trypanosomal drugs currently in use.
DATA COLLECTION AND ANALYSIS
Two review authors extracted data and assessed risk of bias; a third review author acted as an arbitrator if needed. The included trial only reported dichotomous outcomes, which we presented as risk ratio (RR) or risk difference (RD) with 95% confidence intervals (CI). MAIN RESULTS: We included one trial comparing fexinidazole to nifurtimox combined with eflornithine (NECT). This trial was conducted between October 2012 and November 2016 in the Democratic Republic of the Congo and the Central African Republic, and included 394 participants. The study reported on efficacy and safety, with up to 24 months' follow-up. We judged the study to be at low risk of bias in all domains except blinding; as the route of administration and dosing regimens differed between treatment groups, participants and personnel were not blinded, resulting in a high risk of performance bias. Mortality with fexinidazole may be higher at 24 months compared to NECT. There were 9/264 deaths in the fexinidazole group and 2/130 deaths in the NECT group (RR 2.22, 95% CI 0.49 to 10.11; 394 participants; low-certainty evidence). None of the deaths were related to treatment. Fexinidazole likely results in an increase in the number of people relapsing during follow-up, with 14 participants in the fexinidazole group (14/264) and none in the NECT group (0/130) relapsing at 24 months (RD 0.05, 95% CI 0.02 to 0.08; 394 participants; moderate-certainty evidence). We are uncertain whether there is any difference between the drugs regarding the incidence of serious adverse events at 24 months. (31/264 with fexinidazole and 13/130 with NECT group at 24 months). Adverse events were common with both drugs (247/264 with fexinidazole versus 121/130 with NECT), with no difference between groups (RR 1.01, 95% CI 0.95 to 1.06; 394 participants; moderate-certainty evidence). AUTHORS' CONCLUSIONS: Oral treatment with fexinidazole is much easier to administer than conventional treatment, but deaths and relapse appear to be more common. However, the advantages or an oral option are considerable, in terms of convenience, avoiding hospitalisation and multiple intravenous infusions, thus increasing adherence.
Topics: Animals; Antiprotozoal Agents; Humans; Nifurtimox; Pharmaceutical Preparations; Randomized Controlled Trials as Topic; Trypanosoma brucei gambiense; Trypanosomiasis, African
PubMed: 34882307
DOI: 10.1002/14651858.CD015374