Impact of malaria diagnostic choice on monitoring of Plasmodium falciparum prevalence estimates in the Democratic Republic of the Congo and relevance to control programs in high-burden countries.

Malaria programs rely upon a variety of diagnostic assays, including rapid diagnostic tests (RDTs), microscopy, polymerase chain reaction (PCR), and bead-based immunoassays (BBA), to monitor malaria prevalence and support control and elimination efforts. Data comparing these assays are limited, especially from high-burden countries like the Democratic Republic of the Congo (DRC). Using cross-sectional and routine data, we compared diagnostic performance and Plasmodium falciparum prevalence estimates across health areas of varying transmission intensity to illustrate the relevance of assay performance to malaria control programs. Data and samples were collected between March-June 2018 during a cross-sectional household survey across three health areas with low, moderate, and high transmission intensities within Kinshasa Province, DRC. Samples from 1,431 participants were evaluated using RDT, microscopy, PCR, and BBA. P. falciparum parasite prevalence varied between diagnostic methods across all health areas, with the highest prevalence estimates observed in Bu (57.4-72.4% across assays), followed by Kimpoko (32.6-53.2%), and Voix du Peuple (3.1-8.4%). Using latent class analysis to compare these diagnostic methods against an "alloyed gold standard," the most sensitive diagnostic method was BBA in Bu (high prevalence) and Voix du Peuple (low prevalence), while PCR diagnosis was most sensitive in Kimpoko (moderate prevalence). RDTs were consistently the most specific diagnostic method in all health areas. Among 9.0 million people residing in Kinshasa Province in 2018, the estimated P. falciparum prevalence by microscopy, PCR, and BBA were nearly double that of RDT. Comparison of malaria RDT, microscopy, PCR, and BBA results confirmed differences in sensitivity and specificity that varied by endemicity, with PCR and BBA performing best for detecting any P. falciparum infection. Prevalence estimates varied widely depending on assay type for parasite detection. Inherent differences in assay performance should be carefully considered when using community survey and surveillance data to guide policy decisions.

Plasmodium falciparum with pfhrp2/3 Deletion Not Detected in a 2018-2021 Malaria Longitudinal Cohort Study in Kinshasa Province, Democratic Republic of the Congo.

Histidine-rich protein 2- (HRP2-) based rapid diagnostic tests (RDTs) are widely used to detect Plasmodium falciparum in sub-Saharan Africa. Reports of parasites with pfhrp2 and/or pfhrp3 (pfhrp2/3) gene deletions in Africa raise concerns about the long-term viability of HRP2-based RDTs. We evaluated changes in pfhrp2/3 deletion prevalence over time using a 2018-2021 longitudinal study of 1,635 enrolled individuals in Kinshasa Province, Democratic Republic of the Congo (DRC). Samples collected during biannual household visits with ≥ 100 parasites/µL by quantitative real-time polymerase chain reaction were genotyped using a multiplex real-time PCR assay. Among 2,726 P. falciparum PCR-positive samples collected from 993 participants during the study period, 1,267 (46.5%) were genotyped. No pfhrp2/3 deletions or mixed pfhrp2/3-intact and -deleted infections were identified in our study. Pfhrp2/3-deleted parasites were not detected in Kinshasa Province; ongoing use of HRP2-based RDTs is appropriate.

Extent of induced abortions and occurrence of complications in Kinshasa, Democratic Republic of the Congo.

BACKGROUND: Due to a lack of relevant data on induced abortions in the Democratic Republic of the Congo (DRC) as well as the persistence of maternal deaths in the country, this study aims to analyse the extent of induced abortions and occurrence of complications in Kinshasa. METHODOLOGY: This cross-sectional study was conducted with a sample of 460 women who were interviewed about their experiences as females, and provided information of 1444 women of childbearing age living in Kinshasa. Respondents' households were selected to represent the five types of residential quarters in Kinshasa, differentiated by cultural, socioeconomic, and infrastructural characteristics. Information was collected using a survey form and analyzed. RESULTS: Among all confidantes included in the study, 5.5% (95% CI: 4.4-6.8%) had induced abortions during 2015, a rate of 55.0 abortions per 1000 women of childbearing age. This practice was significantly performed amongst single/separated/divorced women; those without formal education, or primary-school education, and women who consumed excessive alcohol. Most abortions were induced by the administration of high doses of medication, by the women themselves or by health workers. A percentage of 51.9% (95%CI: 40.4-63.3%) of induced abortions led to complications, which were predominantly haemorrhagic. Moreover, 39% of patients had a complication for which they sought care, and of whom 12.5% had genital trauma or uterine perforation/intestinal necrosis. CONCLUSION: Induced abortion is a public health problem in Kinshasa due to its frequency of practice, the complications that occur, and the absence of major surgeries in the health care package offered by the health centres or dispensaries that also provide the treatment of some serious complications. Thus, there is a need to focus on the enhancement of the health care package offered by health centres to include appropriate measures in favour of maternal health.

African isolates show a high proportion of multiple copies of the Plasmodium falciparum plasmepsin-2 gene, a piperaquine resistance marker.

BACKGROUND: Today, the development of new and well-tolerated anti-malarial drugs is strongly justified by the emergence of Plasmodium falciparum resistance. In 2014-2015, a phase 2b clinical study was conducted to evaluate the efficacy of a single oral dose of Artefenomel (OZ439)-piperaquine (PPQ) in Asian and African patients presenting with uncomplicated falciparum malaria. METHODS: Blood samples collected before treatment offered the opportunity to investigate the proportion of multidrug resistant parasite genotypes, including P. falciparum kelch13 mutations and copy number variation of both P. falciparum plasmepsin 2 (Pfpm2) and P. falciparum multidrug resistance 1 (Pfmdr1) genes. RESULTS: Validated kelch13 resistance mutations including C580Y, I543T, P553L and V568G were only detected in parasites from Vietnamese patients. In Africa, isolates with multiple copies of the Pfmdr1 gene were shown to be more frequent than previously reported (21.1%, range from 12.4% in Burkina Faso to 27.4% in Uganda). More strikingly, high proportions of isolates with multiple copies of the Pfpm2 gene, associated with piperaquine (PPQ) resistance, were frequently observed in the African sites, especially in Burkina Faso and Uganda (> 30%). CONCLUSIONS: These findings were considered to sharply contrast with the recent description of increased sensitivity to PPQ of Ugandan parasite isolates. This emphasizes the necessity to investigate in vitro susceptibility profiles to PPQ of African isolates with multiple copies of the Pfpm2 gene and estimate the risk of development of PPQ resistance in Africa. Trial registration Clinicaltrials.gov reference: NCT02083380. Study title: Phase II efficacy study of artefenomel and piperaquine in adults and children with P. falciparum malaria. https://clinicaltrials.gov/ct2/results?cond=&term=NCT02083380&cntry=&state=&city=&dist= . FSFV: 23-Jul-2014; LSLV: 09-Oct-2015.

Analysis of induced abortion-related complications in women admitted to referral health facilities in Kinshasa, Democratic Republic of the Congo.

BACKGROUND: Due to a lack of relevant data on induced abortions in the Democratic Republic of the Congo (DRC), as well as the persistence of maternal deaths in the country, this study aims to analyze the extent and characteristics of induced abortion-related complications in women who were admitted to referral health facilities in Kinshasa, including the duration of hospitalization, the mortality rate due to induced abortion complications and their characteristics, and the deaths that occurred after two days of hospitalization. METHODS: This is a cross-sectional study on 843 obstetric and gynecological patients who were admitted as emergency cases to five referral health facilities in Kinshasa during 2014. These facilities were selected as being representative of five types of districts in Kinshasa, according to their cultural, socioeconomic, and infrastructural characteristics. Patient data were collected from patient records and analyzed. RESULTS: From the 843 patients admitted to receive obstetric and gynecological emergency care services in 2014 at the health facilities surveyed, 14.7% (95% CI: 12.4-17.3%) had complications due to induced abortion. These complications were significantly diagnosed in adolescents (p = 0.003) and in single, separated, divorced, or widowed women (p = 0.03). The median duration of hospitalization was nine days, and this period of time was significantly longer for the patients who underwent surgery for pelvic peritonitis due to uterine perforation compared with the patients who underwent Caesarean section/hysterectomy. Furthermore, it was significantly longer for the patients who were treated for other induced-abortion related complications compared with patients treated for spontaneous abortion. The mortality rate related to induced abortions was 5.6% (95% CI: 2.3-11.3%), with an increase in risk of death in the presence of a postabortive pelvic peritonitis-type complication; 42.9% of deaths occurred after two days of hospitalization. CONCLUSION: The complications of induced abortions are a major public health problem due to their frequency among patients admitted to Kinshasa's referral health facilities, their mortality, and their poor medical management. Therefore, there is a need to understand the reason for its poor medical management in order to provide an adequate intervention program.

Analysis of induced abortion-related complications in women admitted to the Kinshasa reference general hospital: a tertiary health facility, Democratic Republic of the Congo.

BACKGROUND: Due to a lack of relevant data on induced abortions in the Democratic Republic of the Congo (DRC) as well as the persistence of maternal deaths in the country, this study aims to analyse the induced abortion-related complications in women who were admitted to the Kinshasa Reference General Hospital (KRGH). METHODS: This is a cross-sectional study on 368 obstetric and gynecological patients who were admitted, as emergency cases, to the KRGH during 2014. This health facility was selected because it is a tertiary health facility with an obstetric and gynecological emergency unit most used in the city of Kinshasa. Patient data were collected from patient records and analyzed. RESULTS: From the 368 patients admitted to receive obstetric and gynecological emergency care services in 2014 at the KRGH, 12.2% (95% CI: 9.1-16.1%) had complications due to induced abortion that was significantly diagnosed to adolescents (p <  0.001), single or separated or divorced women or widow(p <  0.001), and to patients with history of one or several induced abortions(p <  0.001). The median duration of hospitalization was ten days and this period of time was significantly longer for the patients who underwent surgery for pelvic peritonitis due to uterine perforation(p <  0.001) compared with the group of patients who underwent Caesarean section/hysterectomy. The mortality rate related to them is 37.8% (95% CI: 23.8-53.5%) with an increase of risk of death in the presence of a post-abortive pelvic peritonitis-type complication, 56.3% of deaths occurred after two days of hospitalization. CONCLUSION: The complications of induced abortions are a major public health problem due to its frequency among patients admitted to the KRGH, as well as the poor medical management, and mortality percentage related to them. Therefore, there is a need to understand the reason for the poor medical management to fill in and provide an adequate intervention package.

A randomised, double-blind clinical phase II trial of the efficacy, safety, tolerability and pharmacokinetics of a single dose combination treatment with artefenomel and piperaquine in adults and children with uncomplicated Plasmodium falciparum malaria.

BACKGROUND: The clinical development of a single encounter treatment for uncomplicated malaria has the potential to significantly improve the effectiveness of antimalarials. Exploratory data suggested that the combination of artefenomel and piperaquine phosphate (PQP) has the potential to achieve satisfactory cure rates as a single dose therapy. The primary objective of the study was to determine whether a single dose of artefenomel (800 mg) plus PQP in ascending doses is an efficacious treatment for uncomplicated Plasmodium falciparum malaria in the 'target' population of children ≤ 5 years of age in Africa as well as Asian patients of all ages. METHODS: Patients in six African countries and in Vietnam were randomised to treatment with follow-up for 42-63 days. Efficacy, tolerability, safety and pharmacokinetics were assessed. Additional key objectives were to characterise the exposure-response relationship for polymerase chain reaction (PCR)-adjusted adequate clinical and parasitological response at day 28 post-dose (ACPR28) and to further investigate Kelch13 mutations. Patients in Africa (n = 355) and Vietnam (n = 82) were included, with 85% of the total population being children < 5 years of age. RESULTS: ACPR28 in the per protocol population (95% confidence interval) was 70.8% (61.13-79.19), 68.4% (59.13-76.66) and 78.6% (70.09-85.67) for doses of 800 mg artefenomel with 640 mg, 960 mg and 1440 mg of PQP respectively. ACPR28 was lower in Vietnamese than in African patients (66.2%; 54.55-76.62 and 74.5%; 68.81-79.68) respectively. Within the African population, efficacy was lowest in the youngest age group of ≥ 0.5 to ≤ 2 years, 52.7% (38.80-66.35). Initial parasite clearance was twice as long in Vietnam than in Africa. Within Vietnam, the frequency of the Kelch13 mutation was 70.1% and was clearly associated with parasite clearance half-life (PCt1/2). The most significant tolerability finding was vomiting (28.8%). CONCLUSIONS: In this first clinical trial evaluating a single encounter antimalarial therapy, none of the treatment arms reached the target efficacy of > 95% PCR-adjusted ACPR at day 28. Achieving very high efficacy following single dose treatment is challenging, since > 95% of the population must have sufficient concentrations to achieve cure across a range of parasite sensitivities and baseline parasitaemia levels. While challenging, the development of tools suitable for deployment as single encounter curative treatments for adults and children in Africa and to support elimination strategies remains a key development goal. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02083380 . Registered on 7 March 2014.

Long-lasting insecticidal net (LLIN) ownership, use and cost of implementation after a mass distribution campaign in Kasaï Occidental Province, Democratic Republic of Congo.

BACKGROUND: Long-lasting insecticidal nets (LLIN) are a highly effective means for preventing malaria infection and reducing associated morbidity and mortality. Mass free distribution campaigns have been shown to rapidly increase LLIN ownership and use. Around 3.5 million LLINs were distributed free of charge in the Kasaï Occidental Province in the Democratic Republic of Congo (DRC) in September-October 2014, using two different approaches, a fixed delivery strategy and a door-to-door strategy including hang-up activities. METHODS: Repeated community-based cross-sectional surveys were conducted 2 months before and six months after the mass distribution. Descriptive statistics were used to measure changes in key malaria household indicators. LLIN ownership and use were compared between delivery strategies. Univariate and multivariate logistic regression analyses were used to identify factors associated with LLIN use before and after the mass distribution. A comparative financial cost analysis between the fixed delivery and door-to-door distribution strategies was carried out from the provider's perspective. RESULTS: Household ownership of at least one LLIN increased from 39.4% pre-campaign to 91.4% post-campaign and LLIN universal coverage, measured as the proportion of households with at least one LLIN for every two people increased from 4.1 to 41.1%. Population access to LLIN within the household increased from 22.2 to 80.7%, while overall LLIN use increased from 18.0 to 68.3%. Higher LLIN ownership was achieved with the fixed delivery strategy compared with the door-to-door (92.5% [95% CI 90.2-94.4%] versus 85.2% [95% CI 78.5-90.0%]), while distribution strategy did not have a significant impact on LLIN use (69.6% [95% CI 63.1-75.5%] versus 65.7% [95% CI 52.7-76.7%]). Malaria prevalence among children aged 6-59 months was 44.8% post-campaign. Living in a household with sufficient numbers of LLIN to cover all members was the strongest determinant of LLIN use. The total financial cost per LLIN distributed was 6.58 USD for the fixed distribution strategy and 6.61 USD for the door-to-door strategy. CONCLUSIONS: The mass distribution campaign was effective for rapidly increasing LLIN ownership and use. These gains need to be sustained for long-term reduction in malaria burden. The fixed delivery strategy achieved a higher LLIN coverage at lower delivery cost compared with the door-to-door strategy and seems to be a better distribution strategy in the context of the present study setting.

Ensuring quality in AFRINEST and SATT: clinical standardization and monitoring.

BACKGROUND: Three randomized open-label clinical trials [Simplified Antibiotic Therapy Trial (SATT) Bangladesh, SATT Pakistan and African Neonatal Sepsis Trial (AFRINEST)] were developed to test the equivalence of simplified antibiotic regimens compared with the standard regimen of 7 days of parenteral antibiotics. These trials were originally conceived and designed separately; subsequently, significant efforts were made to develop and implement a common protocol and approach. Previous articles in this supplement briefly describe the specific quality control methods used in the individual trials; this article presents additional information about the systematic approaches used to minimize threats to validity and ensure quality across the trials. METHODS: A critical component of quality control for AFRINEST and SATT was striving to eliminate variation in clinical assessments and decisions regarding eligibility, enrollment and treatment outcomes. Ensuring appropriate and consistent clinical judgment was accomplished through standardized approaches applied across the trials, including training, assessment of clinical skills and refresher training. Standardized monitoring procedures were also applied across the trials, including routine (day-to-day) internal monitoring of performance and adherence to protocols, systematic external monitoring by funding agencies and external monitoring by experienced, independent trial monitors. A group of independent experts (Technical Steering Committee/Technical Advisory Group) provided regular monitoring and technical oversight for the trials. CONCLUSIONS: Harmonization of AFRINEST and SATT have helped to ensure consistency and quality of implementation, both internally and across the trials as a whole, thereby minimizing potential threats to the validity of the trials' results.

Ongoing trials of simplified antibiotic regimens for the treatment of serious infections in young infants in South Asia and sub-Saharan Africa: implications for policy.

BACKGROUND: The current World Health Organization (WHO) recommendation for treatment of severe infection in young infants is hospitalization and parenteral antibiotic therapy. Hospital care is generally not available outside large cities in low- and middle-income countries and even when available is not acceptable or affordable for many families. Previous research in Bangladesh and India demonstrated that treatment outside hospitals may be possible. RESEARCH: A set of research studies with common protocols testing simplified antibiotic regimens that can be provided at the lowest-level health-care facility or at home are nearing completion. The studies are large individually randomized controlled trials that are set up in the context of a program, which provides home visits by community health workers to detect serious illness in young infants with assessment and treatment at an outpatient health facility near home. This article summarizes the policy implications of the research studies. POLICY IMPLICATIONS: The studies are expected to result in information that would inform WHO guidelines on simple, safe and effective regimens for the treatment of clinical severe infection and pneumonia in newborns and young infants in settings where referral is not possible. The studies will also inform the inputs and process required to establish outpatient treatment of newborn and young infant infections at health facilities near the home. We expect that the information from research and the resulting WHO guidelines will form the basis of policy dialogue by a large number of stakeholders at the country level to implement outpatient treatment of neonatal infections and thereby reduce neonatal and infant mortality resulting from infection.

Scientific rationale for study design of community-based simplified antibiotic therapy trials in newborns and young infants with clinically diagnosed severe infections or fast breathing in South Asia and sub-Saharan Africa.

BACKGROUND: Newborns and young infants suffer high rates of infections in South Asia and sub-Saharan Africa. Timely access to appropriate antibiotic therapy is essential for reducing mortality. In an effort to develop community case management guidelines for young infants, 0-59 days old, with clinically diagnosed severe infections, or with fast breathing, 4 trials of simplified antibiotic therapy delivered in primary care clinics (Pakistan, Democratic Republic of Congo, Kenya and Nigeria) or at home (Bangladesh and Nigeria) are being conducted. METHODS: This article describes the scientific rationale for these trials, which share major elements of trial design. All the trials are in settings of high neonatal mortality, where hospitalization is not feasible or frequently refused. All use procaine penicillin and gentamicin intramuscular injections for 7 days as reference therapy and compare this to various experimental arms utilizing comparatively simpler combination regimens with fewer injections and oral amoxicillin. CONCLUSION: The results of these trials will inform World Health Organization policy regarding community case management of young infants with clinical severe infections or with fast breathing.