Efficacy and safety of fexinidazole for treatment of chronic indeterminate Chagas disease (FEXI-12): a multicentre, randomised, double-blind, phase 2 trial.

BACKGROUND: More than six million people worldwide, particularly in vulnerable communities in Latin America, are infected with Trypanosoma cruzi, the causative agent of Chagas disease. Only a small portion have access to diagnosis and treatment. Both drugs used to treat this chronic, neglected infection, benznidazole and nifurtimox, were developed more than 50 years ago, and adverse drug reactions during treatment pose a major barrier, causing 20% of patients to discontinue therapy. Fexinidazole proved efficacious in an earlier, interrupted clinical trial, but the doses evaluated were not well tolerated. The present study evaluated fexinidazole at lower doses and for shorter treatment durations. METHODS: In this randomised, double-blind, phase 2 trial, we included adult patients (18-60 years old) with confirmed T cruzi infection by serology and PCR and without signs of organ involvement. We evaluated three regimens of fexinidazole-600 mg once daily for 10 days (6·0 g total dose), 1200 mg daily for 3 days (3·6 g), and 600 mg daily for 3 days followed by 1200 mg daily for 4 days (6·6 g)-and compared them with a historical placebo control group (n=47). The primary endpoint was sustained negative results by PCR at end of treatment and on each visit up to four months of follow-up. This study is registered with ClinicalTrials.gov, NCT03587766, and EudraCT, 2016-004905-15. FINDINGS: Between Oct 16, 2017, and Aug 7, 2018, we enrolled 45 patients (n=15 for each group), of whom 43 completed the study. Eight (19%) of 43 fexinidazole-treated patients reached the primary endpoint, compared with six (13%) of 46 in the historical control group. Mean parasite load decreased sharply following treatment but rebounded beginning 10 weeks after treatment. Five participants had seven grade 3 adverse events: carpal tunnel, sciatica, device infection, pneumonia, staphylococcal infection, and joint and device dislocation. Two participants discontinued treatment due to adverse events unrelated to fexinidazole. INTERPRETATION: The fexinidazole regimens in this study had an acceptable safety profile but did not prove effective against T cruzi infection. Development of fexinidazole monotherapy for treating T cruzi infection has been stopped. FUNDING: The Drugs for Neglected Diseases initiative.

Trends in imported malaria during the COVID-19 pandemic, Spain (+Redivi Collaborative Network).

INTRODUCTION: The COVID-19 pandemic has caused disruptions in prevention and management strategies for malaria globally. Currently, data analysing trends in travel-related infections during the pandemic years are scarce. The objective of this analysis was to describe the epidemiological and clinical characteristics of patients with imported malaria within the +Redivi network in Spain, focusing on yearly trends from pre-pandemic years to date. METHODS: Cases recorded in +Redivi from October 2009 to December 2021 were analysed and patients with a diagnosis of malaria (standard diagnostic methods using thick/thin peripheral blood smears, with/without a malaria rapid diagnostic test and/or Plasmodium spp. polymerase chain reaction) were identified. The total number of malaria cases, cases according to type of patient and severe cases, per year, were analysed. RESULTS: In total, 1751 cases of malaria (1751/26 601, 6.6%) were identified. The majority occurred in males (1041, 59.5%), median age was 36.3 (interquartile range: 27-44.7) years and most occurred in visiting friends and relatives (VFR)-immigrants (872, 49.8%). Most infections were acquired in sub-Saharan Africa (1.660, 94.8%) and were due to Plasmodium falciparum (81.3%). There were 64 cases of severe malaria (3.7%) and 4 patients died (0.2% mortality, all in pre-pandemic years). A significant increase in cases of severe malaria was observed during the study period (P < 0.001) (attributable to the increase in 2021). There were 16/93 severe cases in 2021 (17.2%), all due to Plasmodium falciparum, (compared with ≤ 5% in previous years), which mainly occurred in travellers and VFR-immigrants (10/16, 62.5% and 5/16, 31.3%, respectively). CONCLUSIONS: After an initial decline associated with travel restrictions due to the ongoing COVID-19 pandemic, an increase in imported malaria and a significant increase in cases of severe malaria was observed. Patients with imported malaria may present and/or be diagnosed late during this public health crisis and health care professionals should be alerted to the recent increase in severe cases.

Frequency and characteristics of HTLV in migrants: results from the +Redivi collaborative network in Spain.

INTRODUCTION: The objective of this study was to describe the main characteristics of migrants diagnosed with human T-lymphotropic virus (HTLV) infection within the +Redivi Spanish network. METHODS: Patients with a diagnosis of HTLV type 1 or 2 in +Redivi from October 2009 to December 2020 were included. Diagnosis was based on positive HTLV serology (enzyme-linked immunosorbent assay (ELISA)/chemiluminescent immunoassay (CLIA)) with line immunoassay (LIA)/Western blot with/without polymerase chain reaction (PCR). RESULTS: A total of 107/17 007 cases (0.6%) had a final diagnosis of HTLV infection: 83 (77.67%) HTLV-1 infections, 6 (5.6%) HTLV-2 infections and 18 (16.8%) non-specified. The majority (76, 71%) were female, median age was 42 years and median time from arrival to Spain until consultation was 10 years. The group included 100 (93.5%) immigrants and 7 (6.6%) visiting friends and relatives (VFR)-immigrants. Most patients were from South America (71, 66.4%), followed by Sub-Saharan Africa (15, 14%) and Central America-Caribbean (13, 12.1%). Around 90% of patients were asymptomatic at presentation and diagnosed as part of screening programs. Median duration of follow-up was 5 years (IQR 2-7). Regarding HTLV-associated conditions, 90 patients (84.2%) had none, 7 (6.5%) had tropical spastic paraparesis , 5 (4.7%) had other associated conditions (dermatitis, uveitis, pulmonary disease), 3 (2.8%) had other neurological symptoms and 2 (1.9%) had adult T-cell leukaemia/lymphoma. No patients with HTLV-2 had HTLV-associated conditions. Four patients (3.7%) died. Concomitant diagnoses were found in 41 (38.3%) patients, including strongyloidiasis in 15 (14%) and HIV co-infection in 4 (3.7%). In 70% of patients, screening of potential contacts was not performed/recorded. CONCLUSIONS: HTLV infections (the majority due to HTLV-1) were mainly diagnosed in asymptomatic migrants from Latin America (generally long-settled immigrants and the majority female with the consequent implications for screening/prevention). A high rate of association with strongyloidiasis was found. In the majority, screening of potential contacts was not performed, representing a missed opportunity for decreasing the under diagnosis of this infection.

Effectiveness and Safety of a Single-Dose Ivermectin Treatment for Uncomplicated Strongyloidiasis in Immunosuppressed Patients (ImmunoStrong Study): The Study Protocol.

Strongyloidiasis affects an estimated 600 million people worldwide, especially in tropical and subtropical areas. Single-dose ivermectin treatment has shown to be effective among immunocompetent patients with uncomplicated strongyloidiasis. Here, we present the protocol of the ImmunoStrong study, a prospective observational study aiming to evaluate the effectiveness and safety of a single-dose ivermectin for treatment of uncomplicated strongyloidiasis in immunosuppressed patients. The secondary objectives are to assess accuracy of molecular techniques for the follow-up of these patients and to determine the population pharmacokinetics of ivermectin. The information retrieved by this study will cover relevant information gaps in the strongyloidiasis management among immunosuppressed patients.

Prospective comparative multi-centre study on imported Plasmodium ovale wallikeri and Plasmodium ovale curtisi infections.

BACKGROUND: Few previous retrospective studies suggest that Plasmodium ovale wallikeri seems to have a longer latency period and produces deeper thrombocytopaenia than Plasmodium ovale curtisi. Prospective studies were warranted to better assess interspecies differences. METHODS: Patients with imported P. ovale spp. infection diagnosed by thick or thin film, rapid diagnostic test (RDT) or polymerase chain reaction (PCR) were recruited between March 2014 and May 2017. All were confirmed by DNA isolation and classified as P. o. curtisi or P. o. wallikeri using partial sequencing of the ssrRNA gene. Epidemiological, analytical and clinical differences were analysed by statistical methods. RESULTS: A total of 79 samples (35 P. o. curtisi and 44 P. o. wallikeri) were correctly genotyped. Males predominate in wallikeri group (72.7%), whereas were 48.6% in curtisi group. Conversely, 74.3% of curtisi group were from patients of African ethnicity, whilst 52.3% of Caucasians were infected by P. o. wallikeri. After performing a multivariate analysis, more thrombocytopaenic patients (p = 0.022), a lower number of platelets (p = 0.015), a higher INR value (p = 0.041), and shorter latency in Caucasians (p = 0.034) were significantly seen in P. o. wallikeri. RDT sensitivity was 26.1% in P. o. curtisi and 42.4% in P. o. wallikeri. Nearly 20% of both species were diagnosed only by PCR. Total bilirubin over 3 mg/dL was found in three wallikeri cases. Two patients with curtisi infection had haemoglobin under 7 g/dL, one of them also with icterus. A wallikeri patient suffered from haemophagocytosis. Chemoprophylaxis failed in 14.8% and 35% of curtisi and wallikeri patients, respectively. All treated patients with various anti-malarials which included artesunate recovered. Diabetes mellitus was described in 5 patients (6.32%), 4 patients of wallikeri group and 1 curtisi. CONCLUSIONS: Imported P. o. wallikeri infection may be more frequent in males and Caucasians. Malaria caused by P. o. wallikeri produces more thrombocytopaenia, a higher INR and shorter latency in Caucasians and suggests a more pathogenic species. Severe cases can be seen in both species. Chemoprophylaxis seems less effective in P. ovale spp. infection than in P. falciparum, but any anti-malarial drug is effective as initial treatment. Diabetes mellitus could be a risk factor for P. ovale spp. infection.

Effectiveness of the WC/rBS oral cholera vaccine in the prevention of traveler's diarrhea: a prospective cohort study.

OBJECTIVE: Traveler's diarrhea (TD) is the most frequent disease among people from industrialized countries who travel to less developed ones, especially sub-Saharan Africa, Southern Asia and South America. The most common bacteria causing TD is enterotoxigenic Escherichia coli (ETEC). The WC/rBS cholera vaccine (Dukoral) has been shown to induce cross-protection against ETEC by means of the B subunit of the cholera toxin. The aim of the study was to evaluate the effectiveness of the WC/rBS cholera vaccine in preventing TD. METHODS: Between May 1 and September 30 (2007), people seeking pre-travel advice in ten Spanish international vaccination centers were included in a prospective cohort study of travelers to cholera risk countries. The incidence rates of TD were adjusted for variables whose frequencies were statistically different (entry point 0.10) between the vaccinated and non-vaccinated cohorts. FINDINGS: The vaccinated cohort (n = 544 travelers) included people vaccinated with the WC/rBS cholera vaccine, and the non-vaccinated cohort (n = 530 travelers) by people not vaccinated. The cumulative incidence rate of TD was 1.69 in vaccinated and 2.14 in non-vaccinated subjects. The adjusted relative risk of TD in vaccinated travelers was 0.72 (95% CI: 0.58-0.88) and the adjusted vaccination effectiveness was 28% (95% CI: 12-42). CONCLUSIONS: The WC/rBS cholera vaccine prevents TD in 2 out of 7 travelers (preventive fraction: 28%). The number needed to vaccinate (NNV) to prevent 1 case of TD is 10.

Guidelines on the treatment of chronic coinfection by Trypanosoma cruzi and HIV outside endemic areas.

As a result of population migration, Chagas disease is no longer limited to the North and South American continents. In HIV-infected patients, chronic infection by Trypanosoma cruzi behaves as an opportunistic infection in severely immunosuppressed patients and is responsible for high morbidity and mortality. Unlike other opportunistic infections, information on the natural history, diagnosis, treatment, and prevention of Chagas disease is scarce. Spain has the highest number of cases of Chagas disease outside the North and South American continents, and coinfection with HIV is increasingly prevalent. In this article, the Spanish Society for Tropical Medicine and International Health (Sociedad Española de Medicina Tropical y Salud Internacional) reviews the current situation of coinfection with HIV and T. cruzi infection and provides guidelines on the diagnosis, treatment, and prevention in areas where Chagas disease is not endemic. It also identifies areas of uncertainty where additional research is necessary.

Recommendations for management of Chagas disease in organ and hematopoietic tissue transplantation programs in nonendemic areas.

The substantial immigration into Spain from endemic areas of Chagas disease such as Latin America has increased the number of potential donors of organs and tissues. In addition, an increasing number of patients with advanced Chagas heart disease may eventually be eligible to receive a heart transplant, a universally accepted therapeutic strategy for the advanced stages of this disease. Therefore, it is necessary to establish protocols for disease management. This document is intended to establish the guidelines to be followed when a potential donor or a tissue or organ recipient is potentially affected by Chagas disease and summarizes the action criteria against the possibility of Chagas disease transmission through the donation of organs, tissues, or hematopoietic stem cells and aims to help professionals working in this field. A single registry of transplants in Trypanosoma cruzi infected donors and/or recipients will provide and disseminate experience in this area, which has shown a low recorded incidence to date.