Pharmacokinetics and safety profile of artesunate-amodiaquine co-administered with antiretroviral therapy in malaria uninfected HIV-positive Malawian adults.

There are limited data on the pharmacokinetic and safety profiles of artesunate-amodiaquine in human immnunodeficiency virus infected (HIV+) individuals receiving antiretroviral therapy. In a two-step intensive sampling pharmacokinetic trial, we compared area under the concentration time curve from 0 to 28 days (AUC0-28 days) of an active metabolite of amodiaquine, desethylamodiaquine, and treatment-emergent adverse events between antiretroviral therapy naive HIV+ adults and those taking nevirapine and ritonavir-boosted lopinavir-based antiretroviral therapy. In step 1, malaria uninfected adults (n=6/arm) received half the standard adult treatment regimen of artesunate-amodiaquine. In step 2, another cohort (n=25/arm) received the full regimen. In step 1, there were no safety signals and significant differences in desethylamodiaquine AUC0-28 days among participants in the ritonavir-boosted lopinavir, nevirapine and antiretroviral therapy-naive arms. In step 2, compared with the antiretroviral therapy-naive arm, participants in the ritonavir-boosted lopinavir arm had 51% lower desethylamodiaquine AUC0-28 days, (geometric mean [95% CI]; 23,822 [17,458-32506] vs 48,617 [40,787-57,950] ng.hr/mL, p < 0.001). No significant differences in AUC0-28 days were observed between nevirapine and antiretroviral therapy-naïve arms. Treatment-emergent transaminitis was higher in the nevirapine (20% [5/25]) than the antiretroviral therapy naïve (0.0% [0/25]) arm (risk difference 20% [95% CI:4.3-35.7] p=0.018). Ritonavir-boosted lopinavir antiretroviral regimen was associated with reduced desethylamodiaquine exposure which may compromise artesunate-amodiaquine’s efficacy. Co-administration of nevirapine and artesunate amodiaquine may be associated with hepatoxicity

Qualitative study to develop processes and tools for the assessment and tracking of African institutions’ capacity for operational health research

Objectives Research is key to achieving global development goals. Our objectives were to develop and test an evidence-informed process for assessing health research management and support systems (RMSS) in four African universities and for tracking interventions to address capacity gaps. Setting Four African universities. Participants 83 university staff and students from 11 cadres. Intervention/methods A literature-informed ‘benchmark’ was developed and used to itemise all components of a university’s health RMSS. Data on all components were collected during site visits to four African universities using interview guides, document reviews and facilities observation guides. Gaps in RMSS capacity were identified against the benchmark and institutional action plans developed to remedy gaps. Progress against indicators was tracked over 15 months and common challenges and successes identified. Results Common gaps in operational health research capacity included no accessible research strategy, a lack of research e-tracking capability and inadequate quality checks for proposal submissions and contracts. Feedback indicated that the capacity assessment was comprehensive and generated practical actions, several of which were no-cost. Regular follow-up helped to maintain focus on activities to strengthen health research capacity in the face of challenges. Conclusions Identification of each institutions’ strengths and weaknesses against an evidence-informed benchmark enabled them to identify gaps in in their operational health research systems, to develop prioritised action plans, to justify resource requests to fulfil the plans and to track progress in strengthening RMSS. Use of a standard benchmark, approach and tools enabled comparisons across institutions which has accelerated production of evidence about the science of research capacity strengthening. The tools could be used by institutions seeking to understand their strengths and to address gaps in research capacity. Research capacity gaps that were common to several institutions could be a ‘smart’ investment for governments and health research funders

Curtailing COVID-19 on a Dollar-a-Day in Malawi: Implications for the Ongoing Pandemic

Utilizing population-based data from the COVID-19 phone survey (N=2,262$) of the Malawi Longitudinal Study of Families and Health (MLSFH) collected during June 2nd--August 17th, 2020, we investigate behavioral, economic and social responses COVID-19 and focus on the crucial role that community leadership and trust in institutions play towards shaping these responses. We argue that the effective response of Malawi to limit the spread of the virus was facilitated by the engagement of local leaders to mobilize communities to adapt and adhere to COVID-19 prevention strategies. Village heads (VHs) played pivotal role in shaping individual\u27s knowledge about the pandemic and the adaption of preventive health behaviors and were crucial for mitigating the negative economic and health consequences of the pandemic. We further show that trust in institutions is of particular importance in shaping individuals\u27 behavior during the pandemic, and these findings highlight the pivotal role of community leadership in fostering better compliance and adoption of public health measures essential to contain the virus. Overall, our findings point to distinctive patterns of pandemic response in a low-income sub-Saharan African rural population that emphasized local leadership as mediators of public health messages and policies. These lessons from the first pandemic wave remain relevant as in many low-income countries behavioral responses to COVID-19 will remain the primary prevention strategy for a foreseeable future

Provider and user acceptability of intermittent screening and treatment for the control of malaria in pregnancy in Malawi.

BACKGROUND: Malaria in pregnancy is a major cause of adverse maternal and fetal outcomes. Intermittent preventive treatment with sulfadoxine-pyrimethamine (IPTp-SP) is one of the control strategies promoted by WHO. In response to mounting resistance to SP, intermittent screening and treatment (ISTp) has been proposed as an alternative. The objective of this study was to explore the acceptability of ISTp for health workers and pregnant women. METHODS: Semi-structured interviews of ten health workers and five focus group discussions of 38 women enrolled in an ongoing trial comparing IPTp-SP and ISTp with dihydroartemisinin-piperaquine (DP) were conducted at two antenatal clinics in rural Malawi. All transcripts were coded and themes were identified using a content analysis approach. RESULTS: Amongst health workers, there were contrasting opinions on the preference of blood sampling methods, and the influence of method on reliability of diagnosis. The perceived greater effectiveness of DP compared to SP was appreciated, however concerns of user compliance with the full dose of DP in non-trial settings were raised. Despite the discomfort of repeated finger pricks, pregnant women were generally accepting of ISTp, particularly the chance for regular blood tests to check for infections and the perceived greater effectiveness with fewer side effects of DP compared to SP. CONCLUSION: In the trial context, pregnant women tended to prefer ISTp-DP over IPTp-SP. Health workers were also accepting of ISTp-DP as an alternative to IPTp-SP in light of increasing SP resistance. However, reliability of stock, adherence to malaria test results and user adherence to the full course of DP may present barriers to successful routine implementation. Effective communication with health workers and between health workers, pregnant women and their communities will be essential for the acceptability of focused antenatal care, including the best malaria control measures available

Qualitative study to develop processes and tools for the assessment and tracking of African institutions’ capacity for operational health research

Objectives Research is key to achieving global development goals. Our objectives were to develop and test an evidence-informed process for assessing health research management and support systems (RMSS) in four African universities and for tracking interventions to address capacity gaps. Setting Four African universities. Participants 83 university staff and students from 11 cadres. Intervention/methods A literature-informed ‘benchmark’ was developed and used to itemise all components of a university’s health RMSS. Data on all components were collected during site visits to four African universities using interview guides, document reviews and facilities observation guides. Gaps in RMSS capacity were identified against the benchmark and institutional action plans developed to remedy gaps. Progress against indicators was tracked over 15 months and common challenges and successes identified. Results Common gaps in operational health research capacity included no accessible research strategy, a lack of research e-tracking capability and inadequate quality checks for proposal submissions and contracts. Feedback indicated that the capacity assessment was comprehensive and generated practical actions, several of which were no-cost. Regular follow-up helped to maintain focus on activities to strengthen health research capacity in the face of challenges. Conclusions Identification of each institutions’ strengths and weaknesses against an evidence-informed benchmark enabled them to identify gaps in in their operational health research systems, to develop prioritised action plans, to justify resource requests to fulfil the plans and to track progress in strengthening RMSS. Use of a standard benchmark, approach and tools enabled comparisons across institutions which has accelerated production of evidence about the science of research capacity strengthening. The tools could be used by institutions seeking to understand their strengths and to address gaps in research capacity. Research capacity gaps that were common to several institutions could be a ‘smart’ investment for governments and health research funders

Minority-Variant pfcrt K76T Mutations and Chloroquine Resistance, Malawi

Genotyping of the chloroquine-resistance biomarker pfcrt (Plasmodium falciparum chloroquine resistance transporter gene) suggests that, in the absence of chloroquine pressure, Plasmodium falciparum parasites in Malawi have reverted to chloroquine sensitivity. However, malaria infections in Africa are commonly polyclonal, and standard PCRs cannot detect minority genotypes if present in <20% of the parasites in an individual host. We have developed a multiple site-specific heteroduplex tracking assay (MSS-HTA) that can detect pfcrt 76T mutant parasites consisting of as little as 1% of the parasite population. In clinical samples, no pfcrt 76T was detected in 87 pregnant Malawian women by standard PCR. However, 22 (25%) contained minority-variant resistant genotypes detected by the MSS-HTA. These results were confirmed by subcloning and sequencing. This finding suggests that the chloroquine-resistant genotype remains common in Malawians and that PCR-undetectable drug-resistant genotypes may be present in disease-endemic populations. Surveillance for minority-variant drug resistant mutations may be useful in making antimalarial drug policy

Short Report: Detection of the Dihydrofolate Reductase–164L Mutation in Plasmodium falciparum Infections from Malawi by Heteroduplex Tracking Assay

Standard polymerase chain reaction methods often cannot detect drug-resistance mutations in Plasmodium falciparum infections if the mutation is present in ≤ 20% of the parasites. A heteroduplex tracking assay was developed that can detect dihydrofolate reductase 164-L mutations in variants representing 1% of the parasites in an individual host. Using this assay, we confirmed the presence of the mutation in P. falciparum infections in Malawi

A whole genome association study of mother-to-child transmission of HIV in Malawi

Abstract: Background: More than 300,000 children are newly infected with HIV each year, predominantly through mother-to-child transmission (HIV MTCT). Identification of host genetic traits associated with transmission may more clearly explain the mechanisms of HIV MTCT and further the development of a vaccine to protect infants from infection. Associations between transmission and a selection of genes or single nucleotide polymorphisms (SNP)s may give an incomplete picture of HIV MTCT etiology. Thus, this study employed a genome-wide association approach to identify novel variants associated with HIV MTCT. Methods: We conducted a nested case-control study of HIV MTCT using infants of HIV(+) mothers, drawn from a cohort study of malaria and HIV in pregnancy in Blantyre, Malawi. Whole genome scans (650,000 SNPs genotyped using Illumina genotyping assays) were obtained for each infant. Logistic regression was used to evaluate the association between each SNP and HIV MTCT. Results: Genotype results were available for 100 HIV(+) infants (at birth, 6, or 12 weeks) and 126 HIV(-) infants (at birth, 6, and 12 weeks). We identified 9 SNPs within 6 genes with a P-value <5 × 10-5 associated with the risk of transmission, in either unadjusted or adjusted by maternal HIV viral load analyses. Carriers of the rs8069770 variant allele were associated with a lower risk of HIV MTCT (odds ratio = 0.27, 95% confidence interval = 0.14, 0.51), where rs8069770 is located within HS3ST3A1, a gene involved in heparan sulfate biosynthesis. Interesting associations for SNPs located within or near genes involved in pregnancy and development, innate immunological response, or HIV protein interactions were also observed. Conclusions: This study used a genome-wide approach to identify novel variants associated with the risk of HIV MTCT in order to gain new insights into HIV MTCT etiology. Replication of this work using a larger sample size will help us to differentiate true positive findings

Correction: A whole genome association study of mother-to-child transmission of HIV in Malawi

A correction to: Bonnie R Joubert, Ethan M Lange, Nora Franceschini, Victor Mwapasa, Kari E North, Steven R Meshnick andthe NIAID Center for HIV/AIDS Vaccine Immunology. A whole genome association study of mother-to-child transmission of HIV in Malawi. Genome Medicine 2010, 2:17

Sex, power, marginalisation and HIV amongst young fishermen in Malawi: Exploring intersecting inequalities

Through scale-up of effective treatment and prevention, HIV incidence rates are falling across Southern and Eastern Africa. However, key population groups, including people living in fishing communities, continue to face an elevated risk of infection and have high rates of undiagnosed disease. We set out to investigate how intersecting inequalities make young fishermen working on the southern shores of Lake Malawi particularly vulnerable to HIV-infection. We used qualitative research methods including observations (over a 15-month period), in-depth interviews (59) and focus group discussions (16) with a range of male and female participants living and working in two fishing villages. We found that the roles that men occupied in the fishing industry depended on several factors, including their age, socio-economic position and the amount of experience they had in the industry. In turn these roles shaped their lives, including exposure to occupational risks, mobility, living conditions, economic remuneration and social standing within the community. In this context, younger and poorer men occupied roles with the lowest social standing in the industry. Nevertheless, in these communities where poverty was pervasive, young fishermen were able to exert the power they gained through access to money and fish over poorer younger women – pressuring them into sex and increasing the risk of HIV for both men and women. Drawing on an intersectionality framework, we contextualised these findings to consider how young men’s social location, relationships and experiences of both privilege and marginalisation were shaped by broader economic and political processes. We conclude that interventions to prevent HIV in fishing communities need to address how power plays out in the broader social and economic environment