Integrated management of HIV, diabetes, and hypertension in sub-Saharan Africa (INTE-AFRICA): a pragmatic cluster-randomised, controlled trial.

BACKGROUND: In sub-Saharan Africa, health-care provision for chronic conditions is fragmented. The aim of this study was to determine whether integrated management of HIV, diabetes, and hypertension led to improved rates of retention in care for people with diabetes or hypertension without adversely affecting rates of HIV viral suppression among people with HIV when compared to standard vertical care in medium and large health facilities in Uganda and Tanzania. METHODS: In INTE-AFRICA, a pragmatic cluster-randomised, controlled trial, we randomly allocated primary health-care facilities in Uganda and Tanzania to provide either integrated care or standard care for HIV, diabetes, and hypertension. Random allocation (1:1) was stratified by location, infrastructure level, and by country, with a permuted block randomisation method. In the integrated care group, participants with HIV, diabetes, or hypertension were managed by the same health-care workers, used the same pharmacy, had similarly designed medical records, shared the same registration and waiting areas, and had an integrated laboratory service. In the standard care group, these services were delivered vertically for each condition. Patients were eligible to join the trial if they were living with confirmed HIV, diabetes, or hypertension, were aged 18 years or older, were living within the catchment population area of the health facility, and were likely to remain in the catchment population for 6 months. The coprimary outcomes, retention in care (attending a clinic within the last 6 months of study follow-up) for participants with either diabetes or hypertension (tested for superiority) and plasma viral load suppression for those with HIV (>1000 copies per mL; tested for non-inferiority, 10% margin), were analysed using generalised estimating equations in the intention-to-treat population. This trial is registered with ISCRTN 43896688. FINDINGS: Between June 30, 2020, and April 1, 2021 we randomly allocated 32 health facilities (17 in Uganda and 15 in Tanzania) with 7028 eligible participants to the integrated care or the standard care groups. Among participants with diabetes, hypertension, or both, 2298 (75·8%) of 3032 were female and 734 (24·2%) of 3032 were male. Of participants with HIV alone, 2365 (70·3%) of 3365 were female and 1000 (29·7%) of 3365 were male. Follow-up lasted for 12 months. Among participants with diabetes, hypertension, or both, the proportion alive and retained in care at study end was 1254 (89·0%) of 1409 in integrated care and 1457 (89·8%) of 1623 in standard care. The risk differences were -0·65% (95% CI -5·76 to 4·46; p=0·80) unadjusted and -0·60% (-5·46 to 4·26; p=0·81) adjusted. Among participants with HIV, the proportion who had a plasma viral load of less than 1000 copies per mL was 1412 (97·0%) of 1456 in integrated care and 1451 (97·3%) of 1491 in standard care. The differences were -0·37% (one-sided 95% CI -1·99 to 1·26; pnon-inferiority<0·0001 unadjusted) and -0·36% (-1·99 to 1·28; pnon-inferiority<0·0001 adjusted). INTERPRETATION: In sub-Saharan Africa, integrated chronic care services could achieve a high standard of care for people with diabetes or hypertension without adversely affecting outcomes for people with HIV. FUNDING: European Union Horizon 2020 and Global Alliance for Chronic Diseases.

Antioxidant supplementation for sickle cell disease.

BACKGROUND: Sickle cell disease (SCD) refers to a group of genetic disorders characterized by the presence of an abnormal haemoglobin molecule called haemoglobin S (HbS). When subjected to oxidative stress from low oxygen concentrations, HbS molecules form rigid polymers, giving the red cell the typical sickle shape. Antioxidants have been shown to reduce oxidative stress and improve outcomes in other diseases associated with oxidative stress. Therefore, it is important to review and synthesize the available evidence on the effect of antioxidants on the clinical outcomes of people with SCD. OBJECTIVES: To assess the effectiveness and safety of antioxidant supplementation for improving health outcomes in people with SCD. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was 15 August 2023. SELECTION CRITERIA: We included randomized and quasi-randomized controlled trials comparing antioxidant supplementation to placebo, other antioxidants, or different doses of antioxidants, in people with SCD. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data, assessed the risk of bias and certainty of the evidence, and reported according to Cochrane methodological procedures. MAIN RESULTS: The review included 1609 participants in 26 studies, with 17 comparisons. We rated 13 studies as having a high risk of bias overall, and 13 studies as having an unclear risk of bias overall due to study limitations. We used GRADE to rate the certainty of evidence. Only eight studies reported on our important outcomes at six months. Vitamin C (1400 mg) plus vitamin E (800 mg) versus placebo Based on evidence from one study in 83 participants, vitamin C (1400 mg) plus vitamin E (800 mg) may not be better than placebo at reducing the frequency of crisis (risk ratio (RR) 1.18, 95% confidence interval (CI) 0.64 to 2.18), the severity of pain (RR 1.33, 95% CI 0.40 to 4.37), or adverse effects (AE), of which the most common were headache, nausea, fatigue, diarrhoea, and epigastric pain (RR 0.56, 95% CI 0.31 to 1.00). Vitamin C plus vitamin E may increase the risk of SCD-related complications (acute chest syndrome: RR 2.66, 95% CI 0.77 to 9.13; 1 study, 83 participants), and increase haemoglobin level (median (interquartile range) 90 (81 to 96) g/L versus 93.5 (84 to 105) g/L) (1 study, 83 participants) compared to placebo. However, the evidence for all the above effects is very uncertain. The study did not report on quality of life (QoL) of participants and their caregivers, nor on frequency of hospitalization. Zinc versus placebo Zinc may not be better than placebo at reducing the frequency of crisis at six months (rate ratio 0.62, 95% CI 0.17 to 2.29; 1 study, 36 participants; low-certainty evidence). We are uncertain whether zinc is better than placebo at improving sickle cell-related complications (complete healing of leg ulcers at six months: RR 2.00, 95% CI 0.60 to 6.72; 1 study, 34 participants; very low-certainty evidence). Zinc may be better than placebo at increasing haemoglobin level (g/dL) (MD 1.26, 95% CI 0.44 to 1.26; 1 study, 36 participants; low-certainty evidence). The study did not report on severity of pain, QoL, AE, and frequency of hospitalization. N-acetylcysteine versus placebo N-acetylcysteine (NAC) 1200 mg may not be better than placebo at reducing the frequency of crisis in SCD, reported as pain days (rate ratio 0.99 days, 95% CI 0.53 to 1.84; 1 study, 96 participants; low-certainty evidence). Low-certainty evidence from one study (96 participants) suggests NAC (1200 mg) may not be better than placebo at reducing the severity of pain (MD 0.17, 95% CI -0.53 to 0.87). Compared to placebo, NAC (1200 mg) may not be better at improving physical QoL (MD -1.80, 95% CI -5.01 to 1.41) and mental QoL (MD 2.00, 95% CI -1.45 to 5.45; very low-certainty evidence), reducing the risk of adverse effects (gastrointestinal complaints, pruritus, or rash) (RR 0.92, 95% CI 0.75 to 1.14; low-certainty evidence), reducing the frequency of hospitalizations (rate ratio 0.98, 95% CI 0.41 to 2.38; low-certainty evidence), and sickle cell-related complications (RR 5.00, 95% CI 0.25 to 101.48; very low-certainty evidence), or increasing haemoglobin level (MD -0.18 g/dL, 95% CI -0.40 to 0.04; low-certainty evidence). L-arginine versus placebo L-arginine may not be better than placebo at reducing the frequency of crisis (monthly pain) (RR 0.71, 95% CI 0.26 to 1.95; 1 study, 50 participants; low-certainty evidence). However, L-arginine may be better than placebo at reducing the severity of pain (MD -1.41, 95% CI -1.65 to -1.18; 2 studies, 125 participants; low-certainty evidence). One participant allocated to L-arginine developed hives during infusion of L-arginine, another experienced acute clinical deterioration, and a participant in the placebo group had clinically relevant increases in liver function enzymes. The evidence is very uncertain whether L-arginine is better at reducing the mean number of days in hospital compared to placebo (MD -0.85 days, 95% CI -1.87 to 0.17; 2 studies, 125 participants; very low-certainty evidence). Also, L-arginine may not be better than placebo at increasing haemoglobin level (MD 0.4 g/dL, 95% CI -0.50 to 1.3; 2 studies, 106 participants; low-certainty evidence). No study in this comparison reported on QoL and sickle cell-related complications. Omega-3 versus placebo Very low-certainty evidence shows no evidence of a difference in the risk of adverse effects of omega-3 compared to placebo (RR 1.05, 95% CI 0.74 to 1.48; 1 study, 67 participants). Very low-certainty evidence suggests that omega-3 may not be better than placebo at increasing haemoglobin level (MD 0.36 g/L, 95% CI -0.21 to 0.93; 1 study, 67 participants). The study did not report on frequency of crisis, severity of pain, QoL, frequency of hospitalization, and sickle cell-related complications. AUTHORS' CONCLUSIONS: There was inconsistent evidence on all outcomes to draw conclusions on the beneficial and harmful effects of antioxidants. However, L-arginine may be better than placebo at reducing the severity of pain at six months, and zinc may be better than placebo at increasing haemoglobin level. We are uncertain whether other antioxidants are beneficial for SCD. Larger studies conducted on each comparison would reduce the current uncertainties.

Retention in care for type 2 diabetes management in Sub-Saharan Africa: A systematic review.

OBJECTIVE: Diabetes prevalence has risen rapidly in Sub-Saharan Africa, but rates of retention in diabetes care are poorly understood. We conducted a systematic review and meta-analysis to determine rates of retention in care of persons with type 2 diabetes. METHODS: We searched MEDLINE, Global Health and CINAHL online databases for cohort studies and randomised control trials (RCTs) published up to 12 October 2021, that reported retention in or attrition from care for patients with type 2 diabetes in Sub-Saharan Africa. Retention was defined as persons diagnosed with diabetes who were alive and in care or with a known outcome, while attrition was defined as loss from care. RESULTS: From 6559 articles identified, after title and abstract screening, 209 articles underwent full text review. Forty six papers met the inclusion criteria, comprising 22,610 participants. Twenty one articles were of RCTs of which 8 trials had 1 year or more of follow-up and 25 articles were of non-randomised studies of which 19 had 12 months or more of follow-up. A total of 11 studies (5 RCTs and 6 non-randomised) were assessed to be of good quality. Sixteen RCTs were done in secondary or tertiary care settings. Their pooled retention rate (95% CI) was 80% (77%, 84%) in the control arm. Four RCTs had been done in primary care settings and their pooled retention rate (95% CI) was 53% (45%, 62%) in the control arm. The setting of one trial was unclear. For non-randomised studies, retention rates (95% CI) were 68% (62%, 75%) among 19 studies done in secondary and tertiary care settings, and 40% (33%, 49%) among the 6 studies done in primary care settings. CONCLUSION: Rates of retention in care of people living with diabetes are poor in primary care research settings.

Asymptomatic Plasmodium falciparum carriage and clinical disease: a 5-year community-based longitudinal study in The Gambia.

BACKGROUND: Carriers of persistent asymptomatic Plasmodium falciparum infections constitute an infectious reservoir that maintains malaria transmission. Understanding the extent of carriage and characteristics of carriers specific to endemic areas could guide use of interventions to reduce infectious reservoir. METHODS: In eastern Gambia, an all-age cohort from four villages was followed up from 2012 to 2016. Each year, cross-sectional surveys were conducted at the end of the malaria transmission season (January) and just before the start of the next one (June) to determine asymptomatic P. falciparum carriage. Passive case detection was conducted during each transmission season (August to January) to determine incidence of clinical malaria. Association between carriage at the end of the season and at start of the next one and the risk factors for this were assessed. Effect of carriage before start of the season on risk of clinical malaria during the season was also examined. RESULTS: A total of 1403 individuals-1154 from a semi-urban village and 249 from three rural villages were enrolled; median age was 12 years (interquartile range [IQR] 6, 30) and 12 years (IQR 7, 27) respectively. In adjusted analysis, asymptomatic P. falciparum carriage at the end of a transmission season and carriage just before start of the next one were strongly associated (adjusted odds ratio [aOR] = 19.99; 95% CI 12.57-31.77, p < 0.001). The odds of persistent carriage (i.e. infected both in January and in June) were higher in rural villages (aOR = 13.0; 95% CI 6.33-26.88, p < 0.001) and in children aged 5-15 years (aOR = 5.03; 95% CI 2.47-10.23, p = < 0.001). In the rural villages, carriage before start of the season was associated with a lower risk of clinical malaria during the season (incidence risk ratio [IRR] 0.48, 95% CI 0.27-0.81, p = 0.007). CONCLUSIONS: Asymptomatic P. falciparum carriage at the end of a transmission season strongly predicted carriage just before start of the next one. Interventions that clear persistent asymptomatic infections when targeted at the subpopulation with high risk of carriage may reduce the infectious reservoir responsible for launching seasonal transmission.

"After all, we are all sick": multi-stakeholder understanding of stigma associated with integrated management of HIV, diabetes and hypertension at selected government clinics in Uganda.

BACKGROUND: Integrated care is increasingly used to manage chronic conditions. In Uganda, the integration of HIV, diabetes and hypertension care has been piloted, to leverage the advantages of well facilitated and established HIV health care provision structures. This qualitative study aimed to explore HIV stigma dynamics whilst investigating multi-stakeholder perceptions and experiences of providing and receiving integrated management of HIV, diabetes and hypertension at selected government clinics in Central Uganda.  METHODS: We adopted a qualitative-observational design. Participants were purposively selected. In-depth interviews were conducted with patients and with health care providers, clinical researchers, policy makers, and representatives from international nongovernmental organizations (NGOs). Focus group discussions were conducted with community members and leaders. Clinical procedures in the integrated care clinic were observed. Data were managed using Nvivo 12 and analyzed thematically. RESULTS: Triangulated findings revealed diverse multi-stakeholder perceptions around HIV related stigma. Integrated care reduced the frequency with which patients with combinations of HIV, diabetes, hypertension visited health facilities, reduced the associated treatment costs, increased interpersonal relationships among patients and healthcare providers, and increased the capacity of health care providers to manage multiple chronic conditions. Integration reduced stigma through creating opportunities for health education, which allayed patient fears and increased their resolve to enroll for and adhere to treatment. Patients also had an opportunity to offer and receive psycho-social support and coupled with the support they received from healthcare worker. This strengthened patient-patient and provider-patient relationships, which are building blocks of service integration and of HIV stigma reduction. Although the model significantly reduced stigma, it did not eradicate service level challenges and societal discrimination among HIV patients. CONCLUSION: The study reveals that, in a low resource setting like Uganda, integration of HIV, diabetes and hypertension care can improve patient experiences of care for multiple chronic conditions, and that integrated clinics may reduce HIV related stigma.

Implementing integrated care clinics for HIV-infection, diabetes and hypertension in Uganda (INTE-AFRICA): process evaluation of a cluster randomised controlled trial.

BACKGROUND: Sub-Saharan Africa is experiencing a dual burden of chronic human immunodeficiency virus and non-communicable diseases. A pragmatic parallel arm cluster randomised trial (INTE-AFRICA) scaled up 'one-stop' integrated care clinics for HIV-infection, diabetes and hypertension at selected facilities in Uganda. These clinics operated integrated health education and concurrent management of HIV, hypertension and diabetes. A process evaluation (PE) aimed to explore the experiences, attitudes and practices of a wide variety of stakeholders during implementation and to develop an understanding of the impact of broader structural and contextual factors on the process of service integration. METHODS: The PE was conducted in one integrated care clinic, and consisted of 48 in-depth interviews with stakeholders (patients, healthcare providers, policy-makers, international organisation, and clinical researchers); three focus group discussions with community leaders and members (n = 15); and 8 h of clinic-based observation. An inductive analytical approach collected and analysed the data using the Empirical Phenomenological Psychological five-step method. Bronfenbrenner's ecological framework was subsequently used to conceptualise integrated care across multiple contextual levels (macro, meso, micro). RESULTS: Four main themes emerged; Implementing the integrated care model within healthcare facilities enhances detection of NCDs and comprehensive co-morbid care; Challenges of NCD drug supply chains; HIV stigma reduction over time, and Health education talks as a mechanism for change. Positive aspects of integrated care centred on the avoidance of duplication of care processes; increased capacity for screening, diagnosis and treatment of previously undiagnosed comorbid conditions; and broadening of skills of health workers to manage multiple conditions. Patients were motivated to continue receiving integrated care, despite frequent NCD drug stock-outs; and development of peer initiatives to purchase NCD drugs. Initial concerns about potential disruption of HIV care were overcome, leading to staff motivation to continue delivering integrated care. CONCLUSIONS: Implementing integrated care has the potential to sustainably reduce duplication of services, improve retention in care and treatment adherence for co/multi-morbid patients, encourage knowledge-sharing between patients and providers, and reduce HIV stigma. TRIAL REGISTRATION NUMBER: ISRCTN43896688.

Efficacy of Single-Dose Primaquine With Artemisinin Combination Therapy on Plasmodium falciparum Gametocytes and Transmission: An Individual Patient Meta-Analysis.

BACKGROUND: Since the World Health Organization recommended single low-dose (0.25 mg/kg) primaquine (PQ) in combination with artemisinin-based combination therapies (ACTs) in areas of low transmission or artemisinin-resistant Plasmodium falciparum, several single-site studies have been conducted to assess efficacy. METHODS: An individual patient meta-analysis to assess gametocytocidal and transmission-blocking efficacy of PQ in combination with different ACTs was conducted. Random effects logistic regression was used to quantify PQ effect on (1) gametocyte carriage in the first 2 weeks post treatment; and (2) the probability of infecting at least 1 mosquito or of a mosquito becoming infected. RESULTS: In 2574 participants from 14 studies, PQ reduced PCR-determined gametocyte carriage on days 7 and 14, most apparently in patients presenting with gametocytemia on day 0 (odds ratio [OR], 0.22; 95% confidence interval [CI], .17-.28 and OR, 0.12; 95% CI, .08-.16, respectively). Rate of decline in gametocyte carriage was faster when PQ was combined with artemether-lumefantrine (AL) compared to dihydroartemisinin-piperaquine (DP) (P = .010 for day 7). Addition of 0.25 mg/kg PQ was associated with near complete prevention of transmission to mosquitoes. CONCLUSIONS: Transmission blocking is achieved with 0.25 mg/kg PQ. Gametocyte persistence and infectivity are lower when PQ is combined with AL compared to DP.

Safety of single-dose primaquine as a Plasmodium falciparum gametocytocide: a systematic review and meta-analysis of individual patient data.

BACKGROUND: In 2012, the World Health Organization (WHO) recommended single low-dose (SLD, 0.25 mg/kg) primaquine to be added as a Plasmodium (P.) falciparum gametocytocide to artemisinin-based combination therapy (ACT) without glucose-6-phosphate dehydrogenase (G6PD) testing, to accelerate malaria elimination efforts and avoid the spread of artemisinin resistance. Uptake of this recommendation has been relatively slow primarily due to safety concerns. METHODS: A systematic review and individual patient data (IPD) meta-analysis of single-dose (SD) primaquine studies for P. falciparum malaria were performed. Absolute and fractional changes in haemoglobin concentration within a week and adverse effects within 28 days of treatment initiation were characterised and compared between primaquine and no primaquine arms using random intercept models. RESULTS: Data comprised 20 studies that enrolled 6406 participants, of whom 5129 (80.1%) had received a single target dose of primaquine ranging between 0.0625 and 0.75 mg/kg. There was no effect of primaquine in G6PD-normal participants on haemoglobin concentrations. However, among 194 G6PD-deficient African participants, a 0.25 mg/kg primaquine target dose resulted in an additional 0.53 g/dL (95% CI 0.17-0.89) reduction in haemoglobin concentration by day 7, with a 0.27 (95% CI 0.19-0.34) g/dL haemoglobin drop estimated for every 0.1 mg/kg increase in primaquine dose. Baseline haemoglobin, young age, and hyperparasitaemia were the main determinants of becoming anaemic (Hb < 10 g/dL), with the nadir observed on ACT day 2 or 3, regardless of G6PD status and exposure to primaquine. Time to recovery from anaemia took longer in young children and those with baseline anaemia or hyperparasitaemia. Serious adverse haematological events after primaquine were few (9/3, 113, 0.3%) and transitory. One blood transfusion was reported in the primaquine arms, and there were no primaquine-related deaths. In controlled studies, the proportions with either haematological or any serious adverse event were similar between primaquine and no primaquine arms. CONCLUSIONS: Our results support the WHO recommendation to use 0.25 mg/kg of primaquine as a P. falciparum gametocytocide, including in G6PD-deficient individuals. Although primaquine is associated with a transient reduction in haemoglobin levels in G6PD-deficient individuals, haemoglobin levels at clinical presentation are the major determinants of anaemia in these patients. TRIAL REGISTRATION: PROSPERO, CRD42019128185.

Malaria rapid diagnostic tests for the case management of febrile children in Nigerian primary healthcare settings: a cross-sectional study.

BACKGROUND: Malaria has been identified as a significant public health burden, exhibiting a high risk of death and morbidity. In sub-Saharan Africa, most young children attending primary healthcare facilities are commonly diagnosed with malaria. Thus, introduction of malaria rapid diagnostic test (mRDT) kits and effective antimalarials has substantially improved the management of malaria cases. However, healthcare worker confidence and adherence to procedures dependent on malaria test results remain variable in high-burden settings due to lacking alternative point-of-care tests to diagnose other causes of fever. In this study, we compared the results of malaria screenings using mRDT and microscopy in febrile children presenting at a primary health facility. METHODS: This study was conducted at a primary health center in Owo, Ondo State, Nigeria. Children with fever were assessed for malaria by health staff and, where indicated, screened using Plasmodium falciparum histidine-rich protein-2 mRDT kits. Blood samples were collected on slides for microscopy and in hematocrit tubes for hematocrit determination simultaneously, whereas the mRDT test was done by routine health staff. Children found positive for malaria via mRDT were diagnosed as uncomplicated malaria cases and treated as outpatients using artemether-lumefantrine. Blood slides were read independently by two trained microscopists blinded to the mRDT results. The parasite densities were defined as average counts by both microscopists. We then assessed the sensitivity, specificity, and predictive value of mRDT for the diagnosis of malaria. RESULTS: We compared the test results of 250 febrile children who are under 15 years old. The test positivity rates were 93.6% (234/250) and 97.2% (243/250) using microscopy and rapid RDTs, respectively. The sensitivity and specificity of mRDT compared to microscopy were 100.0% and 43.8%, respectively, with a positive predictive value of 96.3% (95% CI 93.1-98.3). The hematocrit value was <30% in 64% of the children. CONCLUSION: As per our findings, mRDTs have correctly detected infections in febrile children. Healthcare workers and caregivers should be encouraged to act in accordance with the test results by means of regular feedback on the quality of mRDTs in use in malaria case management.

Patient and health provider costs of integrated HIV, diabetes and hypertension ambulatory health services in low-income settings - an empirical socio-economic cohort study in Tanzania and Uganda.

BACKGROUND: Integration of health services might be an efficient strategy for managing multiple chronic conditions in sub-Saharan Africa, considering the scope of treatments and synergies in service delivery. Proven to promote compliance, integration may lead to increased economies-of-scale. However, evidence on the socio-economic consequences of integration for providers and patients is lacking. We assessed the clinical resource use, staff time, relative service efficiency and overall societal costs associated with integrating HIV, diabetes and hypertension services in single one-stop clinics where persons with one or more of these conditions were managed. METHODS: 2273 participants living with HIV infection, diabetes, or hypertension or combinations of these conditions were enrolled in 10 primary health facilities in Tanzania and Uganda and followed-up for up to 12 months. We collected data on resources used from all participants and on out-of-pocket costs in a sub-sample of 1531 participants, while a facility-level costing study was conducted at each facility. Health worker time per participant was assessed in a time-motion morbidity-stratified study among 228 participants. The mean health service cost per month and out-of-pocket costs per participant visit were calculated in 2020 US$ prices. Nested bootstrapping from these samples accounted for uncertainties. A data envelopment approach was used to benchmark the efficiency of the integrated services. Last, we estimated the budgetary consequences of integration, based on prevalence-based projections until 2025, for both country populations. RESULTS: Their average retention after 1 year service follow-up was 1911/2273 (84.1%). Five hundred and eighty-two of 2273 (25.6%) participants had two or all three chronic conditions and 1691/2273 (74.4%) had a single condition. During the study, 84/2239 (3.8%) participants acquired a second or third condition. The mean service costs per month of managing two conditions in a single participant were $39.11 (95% CI 33.99, 44.33), $32.18 (95% CI 30.35, 34.07) and $22.65 (95% CI 21.86, 23.43) for the combinations of HIV and diabetes and of HIV and hypertension, diabetes and hypertension, respectively. These costs were 34.4% (95% CI 17.9%, 41.9%) lower as compared to managing any two conditions separately in two different participants. The cost of managing an individual with all three conditions was 48.8% (95% CI 42.1%, 55.3%) lower as compared to managing these conditions separately. Out-of-pocket healthcare expenditure per participant per visit was $7.33 (95% CI 3.70, 15.86). This constituted 23.4% (95% CI 9.9, 54.3) of the total monthly service expenditure per patient and 11.7% (95% CI 7.3, 22.1) of their individual total household income. The integrated clinics' mean efficiency benchmark score was 0.86 (range 0.30-1.00) suggesting undercapacity that could serve more participants without compromising quality of care. The estimated budgetary consequences of managing multi-morbidity in these types of integrated clinics is likely to increase by 21.5% (range 19.2-23.4%) in the next 5 years, including substantial savings of 21.6% on the provision of integrated care for vulnerable patients with multi-morbidities. CONCLUSION: Integration of HIV services with diabetes and hypertension control reduces both health service and household costs, substantially. It is likely an efficient and equitable way to address the increasing burden of financially vulnerable households among Africa's ageing populations. Additional economic evidence is needed from longer-term larger-scale implementation studies to compare extended integrated care packages directly simultaneously with evidence on sustained clinical outcomes.

Reactive, self-administered malaria treatment against asymptomatic malaria infection: results of a cluster randomized controlled trial in The Gambia.

BACKGROUND: Selectively targeting and treating malaria-infected individuals may further decrease parasite carriage in low-burden settings. Using a trans-disciplinary approach, a reactive treatment strategy to reduce Plasmodium falciparum prevalence in participating communities was co-developed and tested. METHODS: This is a 2-arm, open-label, cluster-randomized trial involving villages in Central Gambia during the 2017 and 2018 malaria transmission season. Villages were randomized in a 1:1 ratio using a minimizing algorithm. In the intervention arm, trained village health workers delivered a full course of pre-packed dihydroartemisinin-piperaquine to all residents of compounds where clinical cases were reported while in the control arm, compound residents were screened for infection at the time of the index case reporting. All index cases were treated following national guidelines. The primary endpoint was malaria prevalence, determined by molecular methods, at the end of the intervention period. RESULTS: The trial was carried out in 50 villages: 34 in 2017 and 16 additional villages in 2018. At the end of the 2018 transmission season, malaria prevalence was 0.8% (16/1924, range 0-4%) and 1.1% (20/1814, range 0-17%) in the intervention and control arms, respectively. The odds of malaria infection were 29% lower in the intervention than in the control arm after adjustment for age (OR 0.71, 95% CI 0.27-1.84, p = 0.48). Adherence to treatment was high, with 98% (964/979) of those treated completing the 3-day treatment. Over the course of the study, only 37 villages, 20 in the intervention and 17 in the control arm, reported at least one clinical case. The distribution of clinical cases by month in both transmission seasons was similar and the odds of new clinical malaria cases during the trial period did not vary between arms (OR 1.04, 95% CI 0.57-1.91, p = 0.893). All adverse events were classified as mild to moderate and resolved completely. CONCLUSION: The systematic and timely administration of an anti-malarial treatment to residents of compounds with confirmed malaria cases did not significantly decrease malaria prevalence and incidence in communities where malaria prevalence was already low. Treatment coverage and adherence was very high. Results were strongly influenced by the lower-than-expected malaria prevalence, and by no clinical cases in villages with asymptomatic malaria-infected individuals. TRIAL REGISTRATION: This study is registered with ClinicalTrials.gov, NCT02878200. Registered 25 August 2016. https://clinicaltrials.gov/ct2/show/NCT02878200 .

Ivermectin treatment in humans for reducing malaria transmission.

BACKGROUND: Malaria is transmitted through the bite of Plasmodium-infected adult female Anopheles mosquitoes. Ivermectin, an anti-parasitic drug, acts by killing mosquitoes that are exposed to the drug while feeding on the blood of people (known as blood feeds) who have ingested the drug. This effect on mosquitoes has been demonstrated by individual randomized trials. This effect has generated interest in using ivermectin as a tool for malaria control. OBJECTIVES: To assess the effect of community administration of ivermectin on malaria transmission. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group (CIDG) Specialized Register, CENTRAL, MEDLINE, Embase, LILACS, Science Citation index - expanded, the World Health Organization (WHO) International Clinical Trials Registry Platform, ClinicalTrials.gov, and the National Institutes of Health (NIH) RePORTER database to 14 January 2021. We checked the reference lists of included studies for other potentially relevant studies, and contacted researchers working in the field for unpublished and ongoing trials. SELECTION CRITERIA: We included cluster-randomized controlled trials (cRCTs) that compared ivermectin, as single or multiple doses, with a control treatment or placebo given to populations living in malaria-endemic areas, in the context of mass drug administration. Primary outcomes were prevalence of malaria parasite infection and incidence of clinical malaria in the community. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data on the number of events and the number of participants in each trial arm at the time of assessment. For rate data, we noted the total time at risk in each trial arm. To assess risk of bias, we used Cochrane's RoB 2 tool for cRCTs. We documented the method of data analysis, any adjustments for clustering or other covariates, and recorded the estimate of the intra-cluster correlation (ICC) coefficient. We re-analysed the trial data provided by the trial authors to adjust for cluster effects. We used a Poisson mixed-effect model with small sample size correction, and a cluster-level analysis using the linear weighted model to adequately adjust for clustering.  MAIN RESULTS: We included one cRCT and identified six ongoing trials.  The included cRCT examined the incidence of malaria in eight villages in Burkina Faso, randomized to two arms. Both trial arms received a single dose of ivermectin 150 µg/kg to 200 µg/kg, together with a dose of albendazole. The villages in the intervention arm received an additional five doses of ivermectin, once every three weeks. Children were enrolled into an active cohort, in which they were repeatedly screened for malaria infection.  The primary outcome was the cumulative incidence of uncomplicated malaria in a cohort of children aged five years and younger, over the 18-week study. We judged the study to be at high risk of bias, as the analysis did not account for clustering or correlation between participants in the same village. The study did not demonstrate an effect of Ivermectin on the cumulative incidence of uncomplicated malaria in the cohort of children over the 18-week study (risk ratio 0.86, 95% confidence interval (CI) 0.62 to 1.17; P = 0.2607; very low-certainty evidence). AUTHORS' CONCLUSIONS: We are uncertain whether community administration of ivermectin has an effect on malaria transmission, based on one trial published to date.

Tolerance of Gambian Plasmodium falciparum to Dihydroartemisinin and Lumefantrine Detected by Ex Vivo Parasite Survival Rate Assay.

Monitoring of Plasmodium falciparum sensitivity to antimalarial drugs in Africa is vital for malaria elimination. However, the commonly used ex vivo/in vitro 50% inhibitory concentration (IC50) test gives inconsistent results for several antimalarials, while the alternative ring-stage survival assay (RSA) for artemisinin derivatives has not been widely adopted. Here, we applied an alternative two-color flow cytometry-based parasite survival rate assay (PSRA) to detect ex vivo antimalarial tolerance in P. falciparum isolates from The Gambia. The PSRA infers parasite viability by quantifying reinvasion of uninfected cells following 3 consecutive days of drug exposure (10-fold the IC50 of drug for field isolates). The drug survival rate is obtained for each isolate from the slope of the growth/death curve. We obtained parasite survival rates of 41 isolates for dihydroartemisinin (DHA) and lumefantrine (LUM) out of 51 infections tested by ring-stage survival assay (RSA) against DHA. We also determined the genotypes for known drug resistance genetic loci in the P. falciparum genes Pfdhfr, Pfdhps, Pfmdr, Pfcrt, and Pfk13 The PSRA results determined for 41 Gambian isolates showed faster killing and lower variance after treatment with DHA than after treatment with LUM, despite a strong correlation between the two drugs. Four and three isolates were tolerant to DHA and LUM, respectively, with continuous growth during drug exposure. Isolates with the PfMDR1-Y184F mutant variant showed increased LUM survival, though the results were not statistically significant. Sulfadoxine/pyrimethamine (SP) resistance markers were fixed, while all other antimalarial variants were prevalent in more than 50% of the population. The PSRA detected ex vivo antimalarial tolerance in Gambian P. falciparum This calls for its wider application and for increased vigilance against resistance to artemisinin combination therapies (ACTs) in this population.

CYP2D6 Polymorphisms and the Safety and Gametocytocidal Activity of Single-Dose Primaquine for Plasmodium falciparum.

Single-dose primaquine (PQ) clears mature gametocytes and reduces the transmission of Plasmodium falciparum after artemisinin combination therapy. Genetic variation in CYP2D6, the gene producing the drug-metabolizing enzyme cytochrome P450 2D6 (CYP2D6), influences plasma concentrations of PQ and its metabolites and is associated with PQ treatment failure in Plasmodium vivax malaria. Using blood and saliva samples of varying quantity and quality from 8 clinical trials across Africa (n = 1,076), we were able to genotype CYP2D6 for 774 samples (72%). We determined whether genetic variation in CYP2D6 has implications for PQ efficacy in individuals with gametocytes at the time of PQ administration (n = 554) and for safety in glucose-6-phosphate dehydrogenase (G6PD)-deficient individuals treated with PQ (n = 110). Individuals with a genetically inferred CYP2D6 poor/intermediate metabolizer status had a higher gametocyte prevalence on day 7 or 10 after PQ than those with an extensive/ultrarapid CYP2D6 metabolizer status (odds ratio [OR] = 1.79 [95% confidence interval {CI}, 1.10, 2.90]; P = 0.018). The mean minimum hemoglobin concentrations during follow-up for G6PD-deficient individuals were 11.8 g/dl for CYP2D6 extensive/ultrarapid metabolizers and 12.1 g/dl for CYP2D6 poor/intermediate metabolizers (P = 0. 803). CYP2D6 genetically inferred metabolizer status was also not associated with anemia following PQ treatment (P = 0.331). We conclude that CYP2D6 poor/intermediate metabolizer status may be associated with prolonged gametocyte carriage after treatment with single-low-dose PQ but not with treatment safety.

Community perspectives on treating asymptomatic infections for malaria elimination in The Gambia.

BACKGROUND: Innovative and cost-effective strategies that clear asymptomatic malaria infections are required to reach malaria elimination goals, but remain a challenge. This mixed methods study explored people's attitudes towards the reactive treatment of compound contacts of malaria cases with a 3-day course of dihydroartemisinin-piperaquine (DHAP), the socio-cultural representations of asymptomatic infections, and more specifically their treatment. METHODS: Prior to the start of the intervention, a sequential mixed method study was carried out. Qualitative data collection involved in-depth interviews and participant observations (including informal conversations) with key informants from the trial communities and the trial staff. Quantitative data were derived from a pre-trial cross-sectional survey on health literacy and health-seeking behaviour among randomly selected members of the study communities. RESULTS: In the pre-trial cross-sectional survey, 73% of respondents reported that malaria could be hidden in the body without symptoms. Whilst this may be interpreted as people's comprehension of asymptomatic malaria, qualitative data indicated that informants had different interpretations of asymptomatic disease than the biomedical model. It was described as: (i) a minor illness that does not prevent people carrying out daily activities; (ii) an illness that oscillates between symptomatic and asymptomatic phases; and, (iii) a condition where disease agents are present in the body but remain hidden, without signs and symptoms, until something triggers their manifestation. Furthermore, this form of hidden malaria was reported to be most present in those living in the same compound with a malaria case (71%). CONCLUSION: Treating asymptomatic malaria with pharmaceuticals was considered acceptable. However, people felt uncertain to take treatment without screening for malaria first, largely due to the lack of symptoms. Knowledge of asymptomatic malaria was not a strong re-inforcement for treatment adherence. In this study, the pre-intervention active engagement of communities existed of having people co-design accurate information messages about their personal risk of malaria, which increased their trust in expert knowledge and thus proved essential for the successful implementation of the community-based intervention.

Bead-based assays to simultaneously detect multiple human inherited blood disorders associated with malaria.

BACKGROUND: Glucose-6-phosphate dehydrogenase deficiency (G6PDd), haemoglobin C (HbC) and S (HbS) are inherited blood disorders (IBD) common in populations in malaria endemic areas. All are associated to some degree with protection against clinical malaria whilst additionally G6PDd is associated with haemolysis following treatment with 8-aminoquinolines. Measuring the prevalence of these inherited blood disorders in affected populations can improve understanding of disease epidemiology. Current methodologies in epidemiological studies commonly rely on individual target amplification and visualization; here a method is presented to simultaneously detect the polymorphisms and that can be expanded to include other single nucleotide polymorphisms (SNPs) of interest. METHODS: Human DNA from whole blood samples was amplified in a novel, multiplex PCR reaction and extended with SNP-specific probes in an allele specific primer extension (ASPE) to simultaneously detect four epidemiologically important human markers including G6PD SNPs (G202A and A376G) and common haemoglobin mutations (HbS and HbC). The products were hybridized to magnetic beads and the median fluorescence intensity (MFI) was read on MAGPIX® (Luminex corp.). Genotyping data was compared to phenotypical data generated by flow cytometry and to established genotyping methods. RESULTS: Seventy-five samples from Burkina Faso (n = 75/78, 96.2%) and 58 samples from The Gambia (n = 58/61, 95.1%) had a G6PD and a HBB genotype successfully assigned by the bead-based assay. Flow cytometry data available for n = 61 samples further supported the concordance between % G6PD normal/deficient cells and genotype. CONCLUSIONS: The bead based assay compares well to alternative measures of genotyping and phenotyping for G6PD. The screening is high throughput, adaptable to inclusion of multiple targets of interest and easily standardized.

Single low-dose primaquine for blocking transmission of Plasmodium falciparum malaria - a proposed model-derived age-based regimen for sub-Saharan Africa.

BACKGROUND: In 2012, the World Health Organization recommended blocking the transmission of Plasmodium falciparum with single low-dose primaquine (SLDPQ, target dose 0.25 mg base/kg body weight), without testing for glucose-6-phosphate dehydrogenase deficiency (G6PDd), when treating patients with uncomplicated falciparum malaria. We sought to develop an age-based SLDPQ regimen that would be suitable for sub-Saharan Africa. METHODS: Using data on the anti-infectivity efficacy and tolerability of primaquine (PQ), the epidemiology of anaemia, and the risks of PQ-induced acute haemolytic anaemia (AHA) and clinically significant anaemia (CSA), we prospectively defined therapeutic-dose ranges of 0.15-0.4 mg PQ base/kg for children aged 1-5 years and 0.15-0.5 mg PQ base/kg for individuals aged ≥6 years (therapeutic indices 2.7 and 3.3, respectively). We chose 1.25 mg PQ base for infants aged 6-11 months because they have the highest rate of baseline anaemia and the highest risks of AHA and CSA. We modelled an anthropometric database of 661,979 African individuals aged ≥6 months (549,127 healthy individuals, 28,466 malaria patients and 84,386 individuals with other infections/illnesses) by the Box-Cox transformation power exponential and tested PQ doses of 1-15 mg base, selecting dosing groups based on calculated mg/kg PQ doses. RESULTS: From the Box-Cox transformation power exponential model, five age categories were selected: (i) 6-11 months (n = 39,886, 6.03%), (ii) 1-5 years (n = 261,036, 45.46%), (iii) 6-9 years (n = 20,770, 3.14%), (iv) 10-14 years (n = 12,155, 1.84%) and (v) ≥15 years (n = 328,132, 49.57%) to receive 1.25, 2.5, 5, 7.5 and 15 mg PQ base for corresponding median (1st and 99th centiles) mg/kg PQ base of: (i) 0.16 (0.12-0.25), (ii) 0.21 (0.13-0.37), (iii) 0.25 (0.16-0.38), (iv) 0.26 (0.15-0.38) and (v) 0.27 (0.17-0.40). The proportions of individuals predicted to receive optimal therapeutic PQ doses were: 73.2 (29,180/39,886), 93.7 (244,537/261,036), 99.6 (20,690/20,770), 99.4 (12,086/12,155) and 99.8% (327,620/328,132), respectively. CONCLUSIONS: We plan to test the safety of this age-based dosing regimen in a large randomised placebo-controlled trial (ISRCTN11594437) of uncomplicated falciparum malaria in G6PDd African children aged 0.5 - 11 years. If the regimen is safe and demonstrates adequate pharmacokinetics, it should be used to support malaria elimination.

Community sensitization and decision-making for trial participation: A mixed-methods study from The Gambia.

BACKGROUND: Ensuring individual free and informed decision-making for research participation is challenging. It is thought that preliminarily informing communities through 'community sensitization' procedures may improve individual decision-making. This study set out to assess the relevance of community sensitization for individual decision-making in research participation in rural Gambia. METHODS: This anthropological mixed-methods study triangulated qualitative methods and quantitative survey methods in the context of an observational study and a clinical trial on malaria carried out by the Medical Research Council Unit Gambia. RESULTS/DISCUSSION: Although 38.7% of the respondents were present during sensitization sessions, 91.1% of the respondents were inclined to participate in the trial when surveyed after the sensitization and prior to the informed consent process. This difference can be explained by the informal transmission of information within the community after the community sensitization, expectations such as the benefits of participation based on previous research experiences, and the positive reputation of the research institute. Commonly mentioned barriers to participation were blood sampling and the potential disapproval of the household head. CONCLUSION: Community sensitization is effective in providing first-hand, reliable information to communities as the information is cascaded to those who could not attend the sessions. However, further research is needed to assess how the informal spread of information further shapes people's expectations, how the process engages with existing social relations and hierarchies (e.g. local political power structures; permissions of heads of households) and how this influences or changes individual consent.

Sustained Ex Vivo Susceptibility of Plasmodium falciparum to Artemisinin Derivatives but Increasing Tolerance to Artemisinin Combination Therapy Partner Quinolines in The Gambia.

Antimalarial interventions have yielded a significant decline in malaria prevalence in The Gambia, where artemether-lumefantrine (AL) has been used as a first-line antimalarial for a decade. Clinical Plasmodium falciparum isolates collected from 2012 to 2015 were analyzed ex vivo for antimalarial susceptibility and genotyped for drug resistance markers (pfcrt K76T, pfmdr1 codons 86, 184, and 1246, and pfk13) and microsatellite variation. Additionally, allele frequencies of single nucleotide polymorphisms (SNPs) from other drug resistance-associated genes were compared from genomic sequence data sets from 2008 (n = 79) and 2014 (n = 168). No artemisinin resistance-associated pfk13 mutation was found, and only 4% of the isolates tested in 2015 showed significant growth after exposure to dihydroartemisinin. Conversely, the 50% inhibitory concentrations (IC50s) of amodiaquine and lumefantrine increased within this period. pfcrt 76T and pfmdr1 184F mutants remained at a prevalence above 80%. pfcrt 76T was positively associated with higher IC50s to chloroquine. pfmdr1 NYD increased in frequency between 2012 and 2015 due to lumefantrine selection. The TNYD (pfcrt 76T and pfmdr1 NYD wild-type haplotype) also increased in frequency following AL implementation in 2008. These results suggest selection for pfcrt and pfmdr1 genotypes that enable tolerance to lumefantrine. Increased tolerance to lumefantrine calls for sustained chemotherapeutic monitoring in The Gambia to minimize complete artemisinin combination therapy (ACT) failure in the future.

Plasmodium Infection Is Associated with Impaired Hepatic Dimethylarginine Dimethylaminohydrolase Activity and Disruption of Nitric Oxide Synthase Inhibitor/Substrate Homeostasis.

Inhibition of nitric oxide (NO) signaling may contribute to pathological activation of the vascular endothelium during severe malaria infection. Dimethylarginine dimethylaminohydrolase (DDAH) regulates endothelial NO synthesis by maintaining homeostasis between asymmetric dimethylarginine (ADMA), an endogenous NO synthase (NOS) inhibitor, and arginine, the NOS substrate. We carried out a community-based case-control study of Gambian children to determine whether ADMA and arginine homeostasis is disrupted during severe or uncomplicated malaria infections. Circulating plasma levels of ADMA and arginine were determined at initial presentation and 28 days later. Plasma ADMA/arginine ratios were elevated in children with acute severe malaria compared to 28-day follow-up values and compared to children with uncomplicated malaria or healthy children (p<0.0001 for each comparison). To test the hypothesis that DDAH1 is inactivated during Plasmodium infection, we examined DDAH1 in a mouse model of severe malaria. Plasmodium berghei ANKA infection inactivated hepatic DDAH1 via a post-transcriptional mechanism as evidenced by stable mRNA transcript number, decreased DDAH1 protein concentration, decreased enzyme activity, elevated tissue ADMA, elevated ADMA/arginine ratio in plasma, and decreased whole blood nitrite concentration. Loss of hepatic DDAH1 activity and disruption of ADMA/arginine homeostasis may contribute to severe malaria pathogenesis by inhibiting NO synthesis.