Efficacy of artemether-lumefantrine and dihydroartemisinin-piperaquine and prevalence of molecular markers of anti-malarial drug resistance in children in Togo in 2021.

BACKGROUND: Artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DP) are the currently recommended first- and second-line therapies for uncomplicated Plasmodium falciparum infections in Togo. This study assessed the efficacy of these combinations, the proportion of Day3-positive patients (D3 +), the proportion of molecular markers associated with P. falciparum resistance to anti-malarial drugs, and the variable performance of HRP2-based malaria rapid diagnostic tests (RDTs). METHODS: A single arm prospective study evaluating the efficacy of AL and DP was conducted at two sites (Kouvé and Anié) from September 2021 to January 2022. Eligible children were enrolled, randomly assigned to treatment at each site and followed up for 42 days after treatment initiation. The primary endpoint was polymerase chain reaction (PCR) adjusted adequate clinical and parasitological response (ACPR). At day 0, samples were analysed for mutations in the Pfkelch13, Pfcrt, Pfmdr-1, dhfr, dhps, and deletions in the hrp2/hrp3 genes. RESULTS: A total of 179 and 178 children were included in the AL and DP groups, respectively. After PCR correction, cure rates of patients treated with AL were 97.5% (91.4-99.7) at day 28 in Kouvé and 98.6% (92.4-100) in Anié, whereas 96.4% (CI 95%: 89.1-98.8) and 97.3% (CI 95%: 89.5-99.3) were observed at day 42 in Kouvé and Anié, respectively. The cure rates of patients treated with DP at day 42 were 98.9% (CI 95%: 92.1-99.8) in Kouvé and 100% in Anié. The proportion of patients with parasites on day 3 (D3 +) was 8.5% in AL and 2.6% in DP groups in Anié and 4.3% in AL and 2.1% DP groups in Kouvé. Of the 357 day 0 samples, 99.2% carried the Pfkelch13 wild-type allele. Two isolates carried nonsynonymous mutations not known to be associated with artemisinin partial resistance (ART-R) (A578S and A557S). Most samples carried the Pfcrt wild-type allele (97.2%). The most common Pfmdr-1 allele was the single mutant 184F (75.6%). Among dhfr/dhps mutations, the quintuple mutant haplotype N51I/C59R/S108N + 437G/540E, which is responsible for SP treatment failure in adults and children, was not detected. Single deletions in hrp2 and hrp3 genes were detected in 1/357 (0.3%) and 1/357 (0.3%), respectively. Dual hrp2/hrp3 deletions, which could affect the performances of HRP2-based RDTs, were not observed. CONCLUSION: The results of this study confirm that the AL and DP treatments are highly effective. The absence of the validated Pfkelch13 mutants in the study areas suggests the absence of ART -R, although a significant proportion of D3 + cases were found. The absence of dhfr/dhps quintuple or sextuple mutants (quintuple + 581G) supports the continued use of SP for IPTp during pregnancy and in combination with amodiaquine for seasonal malaria chemoprevention. TRIAL REGISTRATION: ACTRN12623000344695.

Estimated burden of serious fungal infections in Togo.

BACKGROUND: Over the years, the focus of infectious diseases in many African countries has been mainly on viral, bacterial and parasitic infections. Serious fungal infections (SFIs) with comparable morbidity rate in these countries remain neglected. OBJECTIVES: To estimate the burden of SFI in Togo and to stimulate efforts for improved attention. METHODS: Literature was thoroughly searched for epidemiological data on SFI in Togo. Incidence and/or prevalence of SFI was estimated using socio-demographics, health system's information, risk-groups data and SFI rates obtained from national and international studies. RESULTS: About 5.29% of the 7,265,286 Togolese population is estimated to suffer from SFI annually. Among HIV patients, 1,342, 1,650 and 330 may develop cryptococcal meningitis, Pneumocystis pneumonia and disseminated histoplasmosis respectively per year. Oral and oesophageal candidiasis may annually affect 19,800 and 7,535 persons, respectively, living with HIV. Estimated incidence of invasive aspergillosis (IA) was 283 cases. Prevalence of chronic pulmonary aspergillosis (CPA) was estimated at 191 cases. The annual incidence of allergic bronchopulmonary aspergillosis (ABPA) and severe asthma with fungal sensitization (SAFS) was 4,577 and 6,042 cases, respectively. Tinea capitis and recurrent Candida vaginitis presumably affect 232,271 children and 108,979 women respectively. Candidaemia incidence is estimated at 5 cases per 100, 000 inhabitants and fungal keratitis may affect 981 persons annually. CONCLUSIONS: SFIs in Togo are probably more significant than expected. These findings underscore the need to increase awareness among healthcare professionals, enhance diagnostic and therapeutic capacities and intensify epidemiological studies for effective management of fungal infections in Togo.

Therapeutic efficacy trial of artemisinin-based combination therapy for the treatment of uncomplicated malaria and investigation of mutations in k13 propeller domain in Togo, 2012-2013.

BACKGROUND: Since 2005, the Togo National Malaria Control Programme has recommended two different formulations of artemisinin-based combination therapy (ACT), artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL), for the treatment of uncomplicated malaria. Regular efficacy monitoring of these two combinations is conducted every 2 or 3 years. This paper reports the latest efficacy assessment results and the investigation of mutations in the k13 propeller domain. METHODS: The study was conducted in 2012-2013 on three sentinel sites of Togo (Lomé, Sokodé and Niamtougou). Children aged 6-59 months, who were symptomatically infected with Plasmodium falciparum, were treated with either AL (Coartem(®), Novartis Pharma, Switzerland) or ASAQ (Co-Arsucam(®), Sanofi Aventis, France). The WHO standard protocol for anti-malarial treatment evaluation was used. The primary end-point was 28-day adequate clinical and parasitological response (ACPR), corrected to exclude reinfection using polymerase-chain reaction (PCR) genotyping. RESULTS: A total of 523 children were included in the study. PCR-corrected ACPR was 96.3-100 % for ASAQ and 97-100 % for AL across the three study sites. Adverse events were negligible: 0-4.8 % across all sites, for both artemisinin-based combinations. Upon investigation of mutations in the k13 propeller domain, only 9 (1.8 %) mutations were reported, three in each site. All mutant parasites were cleared before day 3. All day 3 positive patients were infected with k13 wild type parasites. CONCLUSIONS: The efficacy of AL and ASAQ remains high in Togo, and both drugs are well tolerated. ASAQ and AL would be recommended for the treatment of uncomplicated malaria in Togo.

Performance of ParaHIT® HRP2-Based Rapid Diagnostic Test and Proportions of Plasmodium falciparum Histidine-Rich Protein 2/3 Gene Deletions in Togo.

In areas where malaria is endemic and microscopes are unavailable, rapid diagnostic tests (RDTs) are essential tools for early diagnosis and prompt and effective treatment. However, HRP2-based RDTs are threatened by the emergence of Plasmodium falciparum parasites that do not carry the pfhrp2 or pfhrp3 gene, leading to false-negative results. Therefore, the aim of this study was to evaluate the performance of the ParaHIT RDT together with the proportion of pfhrp2/3 gene-deleted P. falciparum parasites in Togo. The performance of RDTs compared with microscopy and polymerase chain reaction (PCR) was determined using capillary blood collected by finger prick during a cross-sectional study conducted from September 2021 to January 2022 in children aged 6-59 months at two sentinel sites. Blood spots were collected for molecular analysis. Amplicons from the target regions (exon 2 of hrp2 and hrp3 genes) were generated by multiplex nested PCR and sequenced using Illumina's MiSeq protocol. A total of 278 samples were analyzed for ParaHIT RDT evaluation. The sensitivity and specificity of the RDT test compared with microscopy were 96.4% and 85.7%, respectively, which increased to 97.9% and 90.7%, respectively, when compared with PCR. Of the microscopically and PCR-positive P. falciparum samples, 138 were sequenced to detect pfhrp2/3 deletions. None of the parasites had a single pfhrp2 deletion or a single pfhrp3 deletion. The ParaHIT RDT demonstrated an acceptable level of performance in this evaluation, confirming the use of HRP2-based RDTs for the detection of P. falciparum infection in areas where microscopy is not available in Togo.

Progress from morbidity control to elimination as a public health problem of schistosomiasis and the status of soil-transmitted helminth infection in Togo: a second impact assessment after ten rounds of mass drug administration.

BACKGROUND: Due to the burden of schistosomiasis (SCH) and soil-transmitted helminths (STH), Togo Ministry of Health launched a program for Preventive Chemotherapy Neglected Tropical Diseases (PC-NTDs) in 2009, initiating integrated mass drug administration (MDA) the following year for the three PC-NTDs: SCH, STH and onchocerciasis. Significant reduction of infection across the country was noted in 2015 during the first impact assessment, following 5 years of high-coverage MDA implemented at the sub-district level for SCH and district level for STH. After another 5 years of effective MDA, a second survey was conducted in 2021 to re-evaluate the situation of SCH and STH. METHODS: A cross-section of school-aged children was taken across ten districts of Togo. A total of 302 schools in 92 sub-districts were sampled, with 24 school-aged children per school resulting in 7248 children surveyed. Urine samples were tested by haemastix® for Schistosoma haematobium, with urine filtration for the presence of eggs conducted on haematuria-positive samples. Stool samples were collected in a subset of 34 sub-districts in seven out of the ten surveyed districts, where STH and Schistosoma mansoni endemicity was high during the 2015 impact assessment. Duplicate (two) Kato-Katz analysis was performed for each stool sample. Sociodemographic and school-level water, sanitation and hygiene information was also collected. RESULTS: Overall, SCH prevalence was 5.90% (95% CI: 5.4-6.5), with 5.09% (95% CI: 4.64-5.67) for S. haematobium and 2.56% (95% CI: 1.98-3.29) for S. mansoni. STH prevalence was 19.7% (95% CI: 18.2-21.4), with 19.6% (95% CI: 18.1-21.3) hookworm, 0.08% (95% CI: 2.2-5.8) Trichuris trichiura and 0.04% (95% CI: 0.01-0.33) Ascaris lumbricoides. Compared to baseline, a significant reduction in both SCH (22.2% to 5.90%) and STH (29.2% t0 19.7%) prevalence was observed. Children aged 5-9 years were less infected than older peers aged 10-14 years: 4.76% vs. 7.53% (P < 0.01) for SCH and 17.2% vs. 23.0% (P < 0.01) for STH. CONCLUSIONS: After 10 years of high coverage integrated MDA, Togo has achieved low prevalence SCH infection through the sub-district MDA implementation with considerable infection heterogeneity within sub-districts. As STH infection has not reached a level where the infections are not a public health problem, the sub-district treatment strategy could also be adopted in addition to improvement of treatment coverage among preschool age children and hygiene and sanitation practices.

Monitoring migrant groups as a post-validation surveillance approach to contain the potential reemergence of lymphatic filariasis in Togo.

BACKGROUND: In March 2017, Togo was declared the first country in sub-Saharan Africa to eliminate lymphatic filariasis as a public health problem, but post-validation surveillance has been lacking. In some areas of the country, migrant groups from neighboring countries that are still endemic for LF pose a risk of reintroduction of LF to Togo. The objective of this study was to identify the risk posed by migrant groups by measuring their prevalence of LF infection and investigating any positive case using Togo's case investigation algorithm to prevent resurgence of LF and sustain Togo's elimination success. METHOD: A cross-sectional study was conducted in 2018 in the northernmost region of the country. Three migrant populations were identified: (i) nomadic Peuhls, (ii) Togolese members of local communities who migrate annually to neighboring countries for seasonal labor, and (iii) refugees from Ghana who came to Togo because of a communal conflict in Ghana. A questionnaire was designed to collect data on demographics and history of LF and MDA; all participants were tested for circulating filariasis antigen (CFA) using the filariasis test strip (FTS). Any CFA-positive case was confirmed with nocturnal microfilaremia. RESULTS: Refugees, seasonal economic migrants and nomadic Peuhls represented 42.1%, 31.4% and 26.5% of the study participants, respectively. The overall prevalence of CFA was 4.2% (58/1391) with the highest prevalence in the nomadic Peuhl group (11.9%), but only one of them (0.07%) was confirmed positive with nocturnal microfilaremia. Using the case investigation algorithm, no other positive case was identified in the positive case's surroundings. CONCLUSION: This study demonstrates that nomadic Peuhls, with a CFA prevalence of 11.9%, pose a potential risk for reintroduction of LF into Togo while Ghanaian refugees and seasonal economic migrants do not appear to pose a significant risk. Periodic monitoring of migrants, especially the nomadic Peuhl population, is a potential post-validation surveillance approach that could be used to promptly detect any LF cluster that may arise.

Impact of community-based integrated mass drug administration on schistosomiasis and soil-transmitted helminth prevalence in Togo.

BACKGROUND: Togo has conducted annual, integrated, community-based mass drug administration (MDA) for soil-transmitted helminths (STH) and schistosomiasis since 2010. Treatment frequency and target populations are determined by disease prevalence, as measured by baseline surveys in 2007 and 2009, and WHO guidelines. Reported programmatic treatment coverage has averaged over 94%. Togo conducted a cross-sectional survey in 2015 to assess the impact of four to five years of MDA on these diseases. METHODOLOGY/PRINCIPAL FINDINGS: In every sub-district in the country outside the capital, the same schools were visited as at baseline and a sample of fifteen children age 6 to 9 years old was drawn. Each child submitted urine and a stool sample. Urine samples were tested by dipstick for the presence of blood as a proxy measure of Schistosoma haematobium infection. Stool samples were analyzed by the Kato-Katz method for STH and Schistosoma mansoni. At baseline, 17,100 children were enrolled at 1,129 schools in 562 sub-districts; in 2015, 16,890 children were enrolled at the same schools. The overall prevalence of both STH and schistosomiasis declined significantly, from 31.5% to 11.6% for STH and from 23.5% to 5.0% for schistosomiasis (p<0.001 in both instances). Egg counts from both years were available only for hookworm and S. mansoni; intensity of infection decreased significantly for both infections from 2009 to 2015 (p<0.001 for both infections). In areas with high baseline prevalence, rebound of hookworm infection was noted in children who had not received albendazole in the past 6 months. CONCLUSIONS/SIGNIFICANCE: After four to five years of MDA in Togo, the prevalence and intensity of STH and schistosomiasis infection were significantly reduced compared to baseline. Data on STH indicate that stopping MDA in areas with high baseline prevalence may result in significant rebound of infection. Togo's findings may help refine treatment recommendations for these diseases.