Global health collaborative research: beyond mandatory collaboration to mandatory authorship.

Collaborative research between the global north and global south is common and growing in number. Due to inability of local governments to fund research, global north actors provide the bulk of research funding. While providing mutual benefits, global collaborative research projects are far from ideal. In this paper, we review the authorship discrepancies in global collaborative research, discuss preventive measures in place and their shortfalls, and recommend an intervention to address the problem. Malawi research guidelines recommend collaboration between foreign and local researchers in locally conducted research. However, there is no provision requiring joint authorship in final published papers. Journal recommendations on authorship criteria exist, but they can disadvantage low- and middle-income country researchers in collaborative projects because of exclusionary interpretations of guidelines. For example, the requirement for authors to make substantial contributions to conception or design of the work may favor research grant holders, often from the global north. Systematic and holistic changes proposed to address power asymmetries at the core of the problem have been proposed. However, these proposals may take a long time to produce change. Ad interim, local institutions can take more direct action to address inequalities by establishing offices of research integrity to enforce mandates to increase opportunities for authorship in collaborative research.

Cross-sectional health centre and community-based evaluation of the impact of pneumococcal and malaria vaccination on antibiotic prescription and usage, febrile illness and antimicrobial resistance in young children in Malawi: the IVAR study protocol.

INTRODUCTION: Vaccination is a potentially critical component of efforts to arrest development and dissemination of antimicrobial resistance (AMR), though little is known about vaccination impact within low-income and middle-income countries. This study will evaluate the impact of vaccination on reducing carriage prevalence of resistant Streptococcus pneumoniae and extended spectrum beta-lactamase-producing Escherichia coli and Klebsiella species. We will leverage two large ongoing cluster-randomised vaccine evaluations in Malawi assessing; first, adding a booster dose to the 13-valent pneumococcal conjugate vaccine (PCV13) schedule, and second, introduction of the RTS,S/AS01 malaria vaccine. METHODS AND ANALYSIS: Six cross-sectional surveys will be implemented within primary healthcare centres (n=3000 users of outpatient facilities per survey) and their local communities (n=700 healthy children per survey): three surveys in Blantyre district (PCV13 component) and three surveys in Mangochi district (RTS,S/AS01 component). We will evaluate antibiotic prescription practices and AMR carriage in children ≤3 years. For the PCV13 component, surveys will be conducted 9, 18 and 33 months following a 3+0 to 2+1 schedule change. For the RTS,S/AS01 component, surveys will be conducted 32, 44 and 56 months post-RTS,S/AS01 introduction. Six health centres in each study component will be randomly selected for study inclusion. Between intervention arms, the primary outcome will be the difference in penicillin non-susceptibility prevalence among S. pneumoniae nasopharyngeal carriage isolates in healthy children. The study is powered to detect an absolute change of 13 percentage points (ie, 35% vs 22% penicillin non-susceptibility). ETHICS AND DISSEMINATION: This study has been approved by the Kamuzu University of Health Sciences (Ref: P01-21-3249), University College London (Ref: 18331/002) and University of Liverpool (Ref: 9908) Research Ethics Committees. Parental/caregiver verbal or written informed consent will be obtained prior to inclusion or recruitment in the health centre-based and community-based activities, respectively. Results will be disseminated via the Malawi Ministry of Health, WHO, peer-reviewed publications and conference presentations.

Artemether-lumefantrine efficacy among adults on antiretroviral therapy in Malawi.

BACKGROUND: When people with human immunodeficiency virus (HIV) infection (PWH) develop malaria, they are at risk of poor anti-malarial treatment efficacy resulting from impairment in the immune response and/or drug-drug interactions that alter anti-malarial metabolism. The therapeutic efficacy of artemether-lumefantrine was evaluated in a cohort of PWH on antiretroviral therapy (ART) and included measurement of day 7 lumefantrine levels in a subset to evaluate for associations between lumefantrine exposure and treatment response. METHODS: Adults living with HIV (≥ 18 years), on ART for ≥ 6 months with undetectable HIV RNA viral load and CD4 count ≥ 250/mm3 were randomized to daily trimethoprim-sulfamethoxazole (TS), weekly chloroquine (CQ) or no prophylaxis. After diagnosis of uncomplicated Plasmodium falciparum malaria, a therapeutic efficacy monitoring was conducted with PCR-correction according to WHO guidelines. The plasma lumefantrine levels on day 7 in 100 episodes of uncomplicated malaria was measured. A frailty proportional hazards model with random effects models to account for clustering examined the relationship between participant characteristics and malaria treatment failure within 28 days. Pearson's Chi-squared test was used to compare lumefantrine concentrations among patients with treatment failure and adequate clinical and parasitological response (ACPR). RESULTS: 411 malaria episodes were observed among 186 participants over 5 years. The unadjusted ACPR rate was 81% (95% CI 77-86). However, after PCR correction to exclude new infections, ACPR rate was 94% (95% CI 92-97). Increasing age and living in Ndirande were associated with decreased hazard of treatment failure. In this population of adults with HIV on ART, 54% (51/94) had levels below a previously defined optimal day 7 lumefantrine level of 200 ng/ml. This occurred more commonly among participants who were receiving an efavirenz-based ART compared to other ART regimens (OR 5.09 [95% CI 1.52-7.9]). Participants who experienced treatment failure had lower day 7 median lumefantrine levels (91 ng/ml [95% CI 48-231]) than participants who experienced ACPR (190 ng/ml [95% CI 101-378], p-value < 0.008). CONCLUSION: Recurrent malaria infections are frequent in this population of PWH on ART. The PCR-adjusted efficacy of AL meets the WHO criteria for acceptable treatment efficacy. Nevertheless, lumefantrine levels tend to be low in this population, particularly in those on efavirenz-based regimens, with lower concentrations associated with more frequent malaria infections following treatment. These results highlight the importance of understanding drug-drug interactions when diseases commonly co-occur.

The prevalence of Schistosoma mansoni infection among adults with chronic non-communicable diseases in Malawi.

BACKGROUND: Schistosomiasis is a parasitic infectious disease caused by flatworms of the Schistosoma genus. The global burden of schistosomiasis is high. In Malawi, schistosomiasis is among the top 20 causes of outpatient department visits in health facilities. Schistosomiasis is among the most important but neglected causes of non-communicable diseases (NCD) peculiar to tropical endemic settings. While much is known about the contribution of S. haematobium to the NCD burden in Malawi, the role of S. mansoni remains largely unknown. METHODS: We conducted a cross-sectional study at Mangochi District Hospital. Adults over 18 years diagnosed with NCDs (n = 414), admitted or attending weekly outpatient clinics were recruited between August 2021 and February 2022. Data were collected on sociodemographic characteristics, medical history, body weight, blood pressure, and fasting blood glucose. Stool and midstream urine were collected for Kato-Katz (KK) microscopy and urine point of care-circulating cathodic antigen (POC-CCA) tests, respectively. We computed prevalence of S. mansoni as number of positive KK and CCA tests, each divided by total submitted samples. Univariate and multivariable logistic regression were done to evaluate risk factors of NCDs and association between S. mansoni infection and NCDs. RESULTS: We recruited 414 participants, mean age 57 years (SD 16), 67% of whom were female. Prevalence of S. mansoni based on urine CCA was 15% (95% CI: 11-19) and 0% on KK microscopy. Hypertension was the most common condition with a prevalence of 85% (95% CI: 81-89), followed by diabetes mellitus with a prevalence of 42% (95% CI: 37-46) and heart disease with a prevalence of 3% (95% CI: 2-5). S. mansoni infection was not significantly associated with hypertension (OR: 1.2, 95% CI: 0.5-3.1), diabetes (OR: 0.6, 95% CI: 0.3-1.10) or heart disease (OR: 2.0, 95% CI: 0.4-10). CONCLUSIONS: We observed moderate prevalence of S. mansoni infection among adults in the study per WHO classification of endemicity. This is within the range observed in children in Mangochi from 10 to 56.7%.

High burden of malaria among Malawian adults on antiretroviral therapy after discontinuing prophylaxis.

OBJECTIVE: Many individuals living with the human immunodeficiency virus (HIV) infection and receiving antiretroviral therapy (ART) reside in areas at high risk for malaria but how malaria affects clinical outcomes is not well described in this population. We evaluated the burden of malaria infection and clinical malaria, and impact on HIV viral load and CD4 + cell count among adults on ART. DESIGN: We recruited Malawian adults on ART who had an undetectable viral load and ≥250 CD4 +  cells/µl to participate in this randomized trial to continue daily trimethoprim-sulfamethoxazole (TS), discontinue daily co-trimoxazole, or switch to weekly chloroquine (CQ). METHODS: We defined clinical malaria as symptoms consistent with malaria and positive blood smear, and malaria infection as Plasmodium falciparum DNA detected from dried blood spots (collected every 4-12 weeks). CD4 + cell count and viral load were measured every 24 weeks. We used Poisson regression and survival analysis to compare the incidence of malaria infection and clinical malaria. Clinicaltrials.gov NCT01650558. RESULTS: Among 1499 participants enrolled, clinical malaria incidence was 21.4/100 person-years of observation (PYO), 2.4/100 PYO and 1.9/100 PYO in the no prophylaxis, TS, and CQ arms, respectively. We identified twelve cases of malaria that led to hospitalization and all individuals recovered. The preventive effect of staying on prophylaxis was approximately 90% compared to no prophylaxis (TS: incidence rate ratio [IRR] 0.11, 95% confidence interval [CI] 0.08, 0.15 and CQ: IRR 0.09, 95% CI 0.06, 0.13). P. falciparum infection prevalence among all visits was 187/1475 (12.7%), 48/1563 (3.1%), and 29/1561 (1.9%) in the no prophylaxis, TS, and CQ arms, respectively. Malaria infection and clinical malaria were not associated with changes in CD4 + cell count or viral load. CONCLUSION: In clinically stable adults living with HIV on ART, clinical malaria was common after chemoprophylaxis stopped. However, neither malaria infection nor clinical illness appeared to affect HIV disease progression.

Performance and safety of the induced sputum procedure in young children in Malawi: a prospective study.

BACKGROUND: Collecting sputum specimens is a challenge in infants and young children. We assessed the performance and safety of induced sputum (IS) collection in this population, embedded in a prospective study evaluating respiratory cryptosporidiosis in Malawian children with diarrheal disease. METHODS: We assessed the sputum quality and correlation with detection of Cryptosporidium spp. and evaluated safety and adverse events in 162 children. RESULTS: Among 159 stool specimens tested, 34 (21%, 95% CI 15.0 to 28%) were positive for Cryptosporidium spp. There were 160 IS and 161 nasopharyngeal (NP) specimens collected. IS and NP specimen collection was performed for each patient. The majority of IS specimens (122/147; 83%) were clear in appearance and 132/147 (90%) were of good quality. Among the respiratory specimens tested, 10 (6.3%, 95% CI 2.5 to 10%) IS and 4 (3%, 95% CI 0 to 5%) NP were positive for Cryptosporidium spp. When stool cryptosporidium PCR was the gold standard, IS PCR sensitivity was higher (29%, 95% CI 22 to 37%) compared with NP PCR (12%, 95% CI 7 to 17%) for detection of Cryptosporidium spp. One (0.4%) adverse event occurred, consisting of a drop in oxygen saturations at the 30-min postprocedure evaluation. Consciousness level, median respiratory rate and oxygen saturations were unchanged, before or after IS. CONCLUSIONS: IS provides good quality specimens, is more sensitive than NP specimens for diagnosis of respiratory cryptosporidiosis, and collection can be performed safely in children hospitalized with diarrheal disease.

Respiratory cryptosporidiosis in Malawian children with diarrheal disease.

BACKGROUND: Respiratory cryptosporidiosis has been documented in children with diarrhea. We sought to describe the dynamics of respiratory involvement in children hospitalized with gastrointestinal (GI) diarrheal disease. METHODS: We conducted a prospective, observational longitudinal study of Malawian children 2-24 months hospitalized with diarrhea. Nasopharyngeal (NP) swabs, induced sputum and stool specimens were collected. Participants that were positive by Cryptosporidium PCR in any of the three compartments were followed up with fortnightly visits up to 8 weeks post-enrollment. RESULTS: Of the 162 children recruited, participants had mild-moderate malnutrition (mean HAZ -1.6 (SD 2.1)), 37 (21%) were PCR-positive for Cryptosporidium at enrollment (37 stool, 11 sputum, and 4 NP) and 27 completed the majority of follow-up visits (73%). Cryptosporidium was detected in all compartments over the 4 post-enrollment visits, most commonly in stool (100% at enrollment with mean cycle thresholds (Ct) of 28.8±4.3 to 44% at 8 weeks with Ct 29.9±4.1), followed by sputum (31% at enrollment with mean Ct 31.1±4.4 to 20% at 8 weeks with Ct 35.7±2.6), then NP (11% with mean Ct 33.5±1.0 to 8% with Ct 36.6±0.7). Participants with Cryptosporidium detection in both the respiratory and GI tract over the study period reported respiratory and GI symptoms in 81% and 62% of study visits, respectively, compared to 68% and 27%, respectively, for those with only GI detection, and had longer GI shedding (17.5±6.6 v. 15.9±2.9 days). CONCLUSION: Cryptosporidium was detected in both respiratory and GI tracts throughout the 8 weeks post-enrollment. The development of therapeutics for Cryptosporidium in children should target the respiratory as well as GI tract.

Revisiting Co-trimoxazole Prophylaxis for African Adults in the Era of Antiretroviral Therapy: A Randomized Controlled Clinical Trial.

BACKGROUND: Daily co-trimoxazole is recommended for African adults living with human immunodeficiency virus (HIV) irrespective of antiretroviral treatment, immune status, or disease stage. Benefits of continued prophylaxis and whether co-trimoxazole can be stopped following immune reconstitution are unknown. METHODS: We conducted a randomized controlled trial at 2 sites in Malawi that enrolled adults with HIV with undetectable viral load and CD4 count of >250/mm3 and randomized them to continue daily co-trimoxazole, discontinue daily co-trimoxazole and begin weekly chloroquine, or discontinue daily co-trimoxazole. The primary endpoint was the preventive effect of co-trimoxazole prophylaxis against death or World Health Organization (WHO) HIV/AIDS stage 3-4 events, using Cox proportional hazards modeling, in an intention-to-treat population. RESULTS: 1499 adults were enrolled. The preventive effect of co-trimoxazole on the primary endpoint was 22% (95% CI: -14%-47%; P = .20) versus no prophylaxis and 25% (-10%-48%; P = .14) versus chloroquine. When WHO HIV/AIDS stage 2 events were added to the primary endpoint, preventive effect increased to 31% (3-51%; P = .032) and 32% (4-51%; P = .026), respectively. Co-trimoxazole and chloroquine prophylaxis effectively prevented clinical malaria episodes (3.8 and 3.0, respectively, vs 28/100 person-years; P < .001). CONCLUSIONS: Malawian adults with HIV who immune reconstituted on ART and continued co-trimoxazole prophylaxis experienced fewer deaths and WHO HIV/AIDS stage 3-4 events compared with prophylaxis discontinuation, although statistical significance was not achieved. Co-trimoxazole prevented a composite of death plus WHO HIV/AIDS stage 2-4 events. Given poor healthcare access and lack of routine viral load monitoring, co-trimoxazole prophylaxis should continue in adults on ART after immune reconstitution in sub-Saharan Africa. Clinical Trials Registration. NCT01650558.

Compensation of subjects for participation in biomedical research in resource - limited settings: a discussion of practices in Malawi.

BACKGROUND: Compensating participants of biomedical research is a common practice. However, its proximity with ethical concerns of coercion, undue influence, and exploitation, demand that participant compensation be regulated. The objective of this paper is to discuss the current regulations for compensation of research participants in Malawi and how they can be improved in relation to ethical concerns of coercion, undue influence, and exploitation. MAIN TEXT: In Malawi, national regulations recommend that research subjects be compensated with a stipend of US$10 per study visit. However, no guidance is provided on how this figure was determined and how it should be implemented. While necessary to prevent exploitation, the stipend may expose the very poor to undue influence. The stipend may also raise the cost of doing research disadvantaging local researchers and may have implications on studies where income stipend is the intervention under investigation. We recommend that development and implementation of guidelines of this importance involve interested parties such as the research community and patient groups. CONCLUSION: Compensating human research subjects is important but can also act as a barrier to voluntary participation and good research efforts. Deliberate measures need to be put in place to ensure fair compensation of research participants, avoid their exploitation and level the field for locally funded research.

Evaluating respiratory cryptosporidiosis in pediatric diarrheal disease: protocol for a prospective, observational study in Malawi.

BACKGROUND: Cryptosporidium is among the most common causes of severe diarrhea in African children 0-23 months old. It is associated with excess mortality, stunting and malnutrition. The most common manifestation of cryptosporidium is intestinal diarrheal disease. However, respiratory cryptosporidiosis has been documented in up to a third of children presenting with diarrhea. It is unclear whether respiratory involvement is a transient phenomenon or a reservoir for gastrointestinal (GI) disease. This study aims to evaluate the role of respiratory cryptosporidiosis in pediatric diarrheal disease. METHODS: This is a prospective, observational study conducted at Queen Elizabeth Central Hospital (QECH) in Blantyre, Malawi. Young children aged 2-24 months hospitalized with diarrhea will be enrolled. Enrolled children will have induced sputum, nasopharyngeal (NP) swab and stool samples collected. All participants positive for cryptosporidium on sputum/NP/stool PCR testing will be followed up fortnightly after discharge from the hospital up to 8 weeks post-discharge. Sputum/NP/stool sample collection will be done at each visit. The primary outcomes will be presence of Cryptosporidium spp. in sputum/NP/stool. The secondary outcome will be presence of respiratory and GI symptoms, mortality and stunting. Ethical approval was obtained from the University of Malawi College of Medicine Research Ethics Committee (COMREC) and the Liverpool School of Tropical Medicine (LSTM) research ethics committee. DISCUSSION: The study began recruitment activities at QECH in February 2019. The protocol allows for expansion of recruitment to secondary sites within Blantyre and Chikwawa districts in the event that targets are not met at QECH. Study recruitment is expected to continue until early 2020.

Frequent malaria illness episodes in two Malawian patients on antiretroviral therapy soon after stopping cotrimoxazole preventive therapy.

We describe two Malawian adults on successful antiretroviral therapy who experienced frequent malaria episodes after stopping cotrimoxazole prophylaxis. We argue that, in addition to stopping cotrimoxazole, diminished malaria immunity and drug interactions between efavirenz and artemether-lumefantrine may have played a causative role in the recurrent malaria our patients experienced.

TSCQ study: a randomized, controlled, open-label trial of daily trimethoprim-sulfamethoxazole or weekly chloroquine among adults on antiretroviral therapy in Malawi: study protocol for a randomized controlled trial.

BACKGROUND: Before antiretroviral therapy (ART) became widely available in sub-Saharan Africa, several studies demonstrated that daily trimethoprim-sulfamethoxazole (TS) prophylaxis reduced morbidity and mortality among HIV-infected adults. As a result, the World Health Organization (WHO) recommended administering TS prophylaxis to this group. However, the applicability of the results to individuals taking ART and living in sub-Saharan Africa has not been definitively evaluated. This study aims to determine if TS prophylaxis benefits HIV-infected Malawian adults after a good response to ART. If TS prophylaxis does indeed show benefit, it is important to determine if this is due to its antibacterial and/or antimalarial properties. METHODS/DESIGN: A randomized, controlled, open-label, phase III trial of continued standard of care prophylaxis with daily trimethoprim-sulfamethoxazole (TS) compared to discontinuation of standard of care TS prophylaxis and starting weekly chloroquine (CQ) prophylaxis or discontinuation of standard of care TS prophylaxis. The study will randomize 1400-1500 HIV-infected adults (equally divided over the three study arms) with a nondetectable viral load and a CD4 count of 250/mm(3) or more from antiretroviral therapy clinics in Blantyre and Zomba. The expected rate of primary endpoint events of death and WHO stage 3 and 4 events is 6.8 per 100 person-years of follow-up in all participants. Assuming the number of events follows a Poisson distribution and average participant follow-up after 10 % loss to follow-up is 41.6 months, the study will have approximately 85 % power to rule out a reduction of 35 % or more in primary endpoint events in the TS or CQ arms compared to discontinuation of TS prophylaxis-i.e., to show that discontinuation of TS prophylaxis is noninferior to either TS or CQ, with a noninferiority margin of 35 %. Ethical and regulatory approvals were obtained from the University of Malawi College of Medicine Research Ethics Committee; the Malawi Pharmacy, Medicines and Poisons Board; and the University of Maryland Baltimore Institutional Review Board. DISCUSSION: The study began recruitment activities at the Ndirande site in November 2012. The sponsor agreed to extend and expand the study in early 2015, and a second site, Zomba, was added for recruitment and follow-up in mid-2015. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01650558 (registered on 6 July 2012). PROTOCOL VERSION: Letter of amendment #1 to the DAIDS-ES 10822 TSCQ Malawi Protocol, Version 4.0, 16 December 2014.

Is it ethical to prevent secondary use of stored biological samples and data derived from consenting research participants? The case of Malawi.

BACKGROUND: This paper discusses the contentious issue of reuse of stored biological samples and data obtained from research participants in past clinical research to answer future ethical and scientifically valid research questions. Many countries have regulations and guidelines that guide the use and exportation of stored biological samples and data. However, there are variations in regulations and guidelines governing the reuse of stored biological samples and data in Sub-Saharan Africa including Malawi. DISCUSSION: The current research ethics regulations and guidelines in Malawi do not allow indefinite storage and reuse of biological samples and data for future unspecified research. This comes even though the country has managed to answer pertinent research questions using stored biological samples and data. We acknowledge the limited technical expertise and equipment unavailable in Malawi that necessitates exportation of biological samples and data and the genuine concern raised by the regulatory authorities about the possible exploitation of biological samples and data by researchers. We also acknowledge that Malawi does not have bio-banks for storing biological samples and data for future research purposes. This creates room for possible exploitation of biological samples and data collected from research participants in primary research projects in Malawi. However, research ethics committees require completion and approval of material transfer agreements and data transfer agreements for biological samples and data collected for research purposes respectively and this requirement may partly address the concern raised by the regulatory authorities. Our concern though is that there is no such requirement for biological samples and data collected from patients for clinical or diagnostic purposes. In conclusion, we propose developing a medical data and material transfer agreement for biological samples and data collected from patients for clinical or diagnostic purposes in both public and private health facilities that may end up in research centers outside Malawi. We also propose revision of the current research ethics regulations and guidelines in Malawi in order to allow secondary use of biological samples and data collected from primary research projects as a way of maximizing the use of collected samples and data. Finally, we call for consultation of all stakeholders within the Malawi research community when regulatory authorities are developing policies that govern research in Malawi.