Publications by authors named "Henry C Mwandumba"

40 Publications

New management approaches to tuberculosis in people living with HIV.

Authors:
David V Mhango David T Mzinza Kondwani C Jambo Henry C Mwandumba

Curr Opin Infect Dis 2021 Feb;34(1):25-33

Malawi Liverpool Wellcome Trust Clinical Research Programme, University of Malawi College of Medicine, Blantyre, Malawi.

Purpose Of Review: People living with HIV (PLWH) are commonly coinfected with Mycobacterium tuberculosis, particularly in high-transmission resource-limited regions. Despite expanded access to antiretroviral therapy and tuberculosis (TB) treatment, TB remains the leading cause of death among PLWH. This review discusses recent advances in the management of TB in PLWH and examines emerging therapeutic approaches to improve outcomes of HIV-associated TB.

Recent Findings: Three recent key developments have transformed the management of HIV-associated TB. First, the scaling-up of rapid point-of-care urine-based tests for screening and diagnosis of TB in PLWH has facilitated early case detection and treatment. Second, increasing the availability of potent new and repurposed drugs to treat drug-resistant TB has generated optimism about the treatment and outcome of multidrug-resistant and extensively drug-resistant TB. Third, expanded access to the integrase inhibitor dolutegravir to treat HIV in resource-limited regions has simplified the management of TB/HIV coinfected patients and minimized serious adverse events.

Summary: While it is unequivocal that substantial progress has been made in early detection and treatment of HIV-associated TB, significant therapeutic challenges persist. To optimize the management and outcomes of TB in HIV, therapeutic approaches that target the pathogen as well as enhance the host response should be explored.
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http://dx.doi.org/10.1097/QCO.0000000000000704DOI Listing
February 2021

TZM-gfp cells: a tractable fluorescent tool for analysis of rare and early HIV-1 infection.

Authors:
David W Gludish Saikat Boliar Shannon Caldwell Dumizulu L Tembo Elizabeth T Chimbayo Kondwani C Jambo Henry C Mwandumba David G Russell

Sci Rep 2020 11 16;10(1):19900. Epub 2020 Nov 16.

Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA.

Here we describe TZM-gfp, a novel HIV-1 reporter cell derived from the same parental clone JC.53, used previously to generate the widely-utilized indicator cell line TZM-bl. We re-engineered JC.53 cells to express GFP under regulation of HIV Tat and Rev. We characterize the new reporter cell line to show that TZM-gfp cells are equally susceptible to HIV infection, exhibit minimal background signal, and can report HIV infection in rare cells from a bulk population of experimentally-infected human monocyte-derived macrophages. We demonstrate the utility and sensitivity of the cells in detection of even a single HIV-positive macrophage by fluorescence-assisted correlative electron microscopy, using the GFP signal to guide imaging of HIV virions in primary co-culture. Finally, we used TZM-gfp cells for viral capture during co-culture with human peripheral blood mononuclear cells, showing that TZM-gfp can support outgrowth and analyses of patient-derived primary HIV-1 isolates.
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http://dx.doi.org/10.1038/s41598-020-76422-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7670428PMC
November 2020

Turning Discoveries into Treatments: Immunology in Africa.

Authors:
Faith H A Osier Henry C Mwandumba Clive M Gray

Trends Immunol 2020 12 4;41(12):1051-1053. Epub 2020 Nov 4.

Division of Immunology, Institute of Infectious Disease and Molecular Medicine and Department of Pathology, University of Cape Town, Cape Town, South Africa.

An exemplar outcome of an immunology-based intervention is vaccine development; the current COVID-19 pandemic is a case in point. Can we build an immunology research ecosystem in Africa that nurtures discovery and enables translation? We see African immunologists as key agents of change and discuss obstacles and opportunities.
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http://dx.doi.org/10.1016/j.it.2020.10.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7879494PMC
December 2020

Virological failure, HIV-1 drug resistance, and early mortality in adults admitted to hospital in Malawi: an observational cohort study.

Authors:
Ankur Gupta-Wright Katherine Fielding Joep J van Oosterhout Melanie Alufandika Daniel J Grint Elizabeth Chimbayo Judith Heaney Matthew Byott Eleni Nastouli Henry C Mwandumba Elizabeth L Corbett Ravindra K Gupta

Lancet HIV 2020 09;7(9):e620-e628

Department of Medicine, University of Cambridge, Cambridge, UK; Africa Health Research Institute, Durban, KwaZulu-Natal, South Africa.

Background: Antiretroviral therapy (ART) scale-up in sub-Saharan Africa combined with weak routine virological monitoring has driven increasing HIV drug resistance. We investigated ART failure, drug resistance, and early mortality among patients with HIV admitted to hospital in Malawi.

Methods: This observational cohort study was nested within the rapid urine-based screening for tuberculosis to reduce AIDS-related mortality in hospitalised patients in Africa (STAMP) trial, which recruited unselected (ie, irrespective of clinical presentation) adult (aged ≥18 years) patients with HIV-1 at admission to medical wards. Patients were included in our observational cohort study if they were enrolled at the Malawi site (Zomba Central Hospital) and were taking ART for at least 6 months at admission. Patients who met inclusion criteria had frozen plasma samples tested for HIV-1 viral load. Those with HIV-1 RNA of at least 1000 copies per mL had drug resistance testing by ultra-deep sequencing, with drug resistance defined as intermediate or high-level resistance using the Stanford HIVDR program. Mortality risk was calculated 56 days from enrolment. Patients were censored at death, at 56 days, or at last contact if lost to follow-up. The modelling strategy addressed the causal association between HIV multidrug resistance and mortality, excluding factors on the causal pathway (most notably, CD4 cell count, clinical signs of advanced HIV, and poor functional and nutritional status).

Findings: Of 1316 patients with HIV enrolled in the STAMP trial at the Malawi site between Oct 26, 2015, and Sept 19, 2017, 786 had taken ART for at least 6 months. 252 (32%) of 786 patients had virological failure (viral load ≥1000 copies per mL). Mean age was 41·5 years (SD 11·4) and 528 (67%) of 786 were women. Of 237 patients with HIV drug resistance results available, 195 (82%) had resistance to lamivudine, 128 (54%) to tenofovir, and 219 (92%) to efavirenz. Resistance to at least two drugs was common (196, 83%), and this was associated with increased mortality (adjusted hazard ratio 1·7, 95% CI 1·2-2·4; p=0·0042).

Interpretation: Interventions are urgently needed and should target ART clinic, hospital, and post-hospital care, including differentiated care focusing on patients with advanced HIV, rapid viral load testing, and routine access to drug resistance testing. Prompt diagnosis and switching to alternative ART could reduce early mortality among inpatients with HIV.

Funding: Joint Global Health Trials Scheme of the Medical Research Council, UK Department for International Development, and Wellcome Trust.
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http://dx.doi.org/10.1016/S2352-3018(20)30172-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7487765PMC
September 2020

Intrapulmonary pharmacokinetics of first-line anti-TB drugs in Malawian tuberculosis patients.

Authors:
Andrew D McCallum Henry E Pertinez Laura J Else Sujan Dilly-Penchala Aaron P Chirambo Irene Sheha Madalitso Chasweka Alex Chitani Rose D Malamba Jamilah Z Meghji Stephen B Gordon Geraint R Davies Saye H Khoo Derek J Sloan Henry C Mwandumba

Clin Infect Dis 2020 Aug 28. Epub 2020 Aug 28.

Malawi-Liverpool-Wellcome Clinical Research Programme, University of Malawi College of Medicine, Blantyre, Malawi.

Background: Further work is required to understand the intrapulmonary pharmacokinetics of first-line anti-tuberculosis drugs. This study aimed to describe the plasma and intrapulmonary pharmacokinetics of rifampicin, isoniazid, pyrazinamide, and ethambutol, and explore relationships with clinical treatment outcomes in patients with pulmonary tuberculosis.

Methods: Malawian adults with a first presentation of microbiologically-confirmed pulmonary tuberculosis received standard 6-month first-line therapy. Plasma and intrapulmonary samples were collected 8 and 16 weeks into treatment and drug concentrations measured in plasma, lung/airway epithelial lining fluid, and alveolar cells. Population pharmacokinetic modelling generated estimates of drug exposure (Cmax and AUC) from individual-level post-hoc Bayesian estimates of plasma and intrapulmonary pharmacokinetics.

Results: One-hundred-and-fifty-seven patients (58% HIV co-infected) participated. Despite standard weight-based dosing, peak plasma concentrations of first-line drugs were below therapeutic drug monitoring targets. Rifampicin concentrations were low in all three compartments. Isoniazid, pyrazinamide, and ethambutol achieved higher concentrations in epithelial lining fluid and alveolar cells than plasma. Isoniazid and pyrazinamide concentrations were 14.6 (95% CI: 11.2-18.0) and 49.8-fold (95% CI: 34.2-65.3) higher in lining fluid than plasma respectively. Ethambutol concentrations were highest in alveolar cells (alveolar cells:plasma ratio 15.0, 95% CI 11.4-18.6). Plasma or intrapulmonary pharmacokinetics did not predict clinical treatment response.

Conclusions: We report differential drug concentrations between plasma and the lung. While plasma concentrations were below therapeutic monitoring targets, accumulation of drugs at the site of disease may explain the success of the first-line regimen. The low rifampicin concentrations observed in all compartments lend strong support for ongoing clinical trials of high-dose rifampicin regimens.
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http://dx.doi.org/10.1093/cid/ciaa1265DOI Listing
August 2020

High SARS-CoV-2 seroprevalence in Health Care Workers but relatively low numbers of deaths in urban Malawi.

Authors:
Marah Grace Chibwana Khuzwayo Chidiwa Jere Raphael Kamng'ona Jonathan Mandolo Vincent Katunga-Phiri Dumizulu Tembo Ndaona Mitole Samantha Musasa Simon Sichone Agness Lakudzala Lusako Sibale Prisca Matambo Innocent Kadwala Rachel Louise Byrne Alice Mbewe Ben Morton Chimota Phiri Jane Mallewa Henry C Mwandumba Emily R Adams Stephen B Gordon Kondwani Charles Jambo

medRxiv 2020 Aug 1. Epub 2020 Aug 1.

Background In low-income countries, like Malawi, important public health measures including social distancing or a lockdown, have been challenging to implement owing to socioeconomic constraints, leading to predictions that the COVID-19 pandemic would progress rapidly. However, due to limited capacity to test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, there are no reliable estimates of the true burden of infection and death. We, therefore, conducted a SARS-CoV-2 serosurvey amongst health care workers (HCW) in Blantyre city to estimate the cumulative incidence of SARS-CoV-2 infection in urban Malawi. Methods Five hundred otherwise asymptomatic HCWs were recruited from Blantyre City (Malawi) from 22nd May 2020 to 19th June 2020 and serum samples were collected all participants. A commercial ELISA was used to measure SARS-CoV-2 IgG antibodies in serum. We run local negative samples (2018 - 2019) to verify the specificity of the assay. To estimate the seroprevalence of SARS CoV-2 antibodies, we adjusted the proportion of positive results based on local specificity of the assay. Results Eighty-four participants tested positive for SARS-CoV-2 antibodies. The HCW with a positive SARS-CoV-2 antibody result came from different parts of the city. The adjusted seroprevalence of SARS-CoV-2 antibodies was 12.3% [CI 9.0-15.7]. Using age-stratified infection fatality estimates reported from elsewhere, we found that at the observed adjusted seroprevalence, the number of predicted deaths was 8 times the number of reported deaths. Conclusion The high seroprevalence of SARS-CoV-2 antibodies among HCW and the discrepancy in the predicted versus reported deaths, suggests that there was early exposure but slow progression of COVID-19 epidemic in urban Malawi. This highlights the urgent need for development of locally parameterised mathematical models to more accurately predict the trajectory of the epidemic in sub-Saharan Africa for better evidence-based policy decisions and public health response planning.
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http://dx.doi.org/10.1101/2020.07.30.20164970DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402052PMC
August 2020

Longitudinal Pharmacokinetic-Pharmacodynamic Biomarkers Correlate With Treatment Outcome in Drug-Sensitive Pulmonary Tuberculosis: A Population Pharmacokinetic-Pharmacodynamic Analysis.

Authors:
Frank Kloprogge Henry C Mwandumba Gertrude Banda Mercy Kamdolozi Doris Shani Elizabeth L Corbett Nadia Kontogianni Steve Ward Saye H Khoo Geraint R Davies Derek J Sloan

Open Forum Infect Dis 2020 Jul 6;7(7):ofaa218. Epub 2020 Jun 6.

Malawi Liverpool Wellcome Trust Clinical Research Programme, Blantyre, Malawi.

Background: This study aims to explore relationships between baseline demographic covariates, plasma antibiotic exposure, sputum bacillary load, and clinical outcome data to help improve future tuberculosis (TB) treatment response predictions.

Methods: Data were available from a longitudinal cohort study in Malawian drug-sensitive TB patients on standard therapy, including steady-state plasma antibiotic exposure (154 patients), sputum bacillary load (102 patients), final outcome (95 patients), and clinical details. Population pharmacokinetic and pharmacokinetic-pharmacodynamic models were developed in the software package NONMEM. Outcome data were analyzed using univariate logistic regression and Cox proportional hazard models in R, a free software for statistical computing.

Results: Higher isoniazid exposure correlated with increased bacillary killing in sputum (.01). Bacillary killing in sputum remained fast, with later progression to biphasic decline, in patients with higher rifampicin area under the curve (AUC) (01). Serial sputum colony counting negativity at month 2 (05), isoniazid (.05), isoniazid /minimum inhibitory concentration ([MIC] 01), and isoniazid AUC/MIC (01) correlated with treatment success but not with remaining free of TB. Slower bacillary killing (05) and earlier progression to biphasic bacillary decline (01) both correlate with treatment failure. Posttreatment recurrence only correlated with slower bacillary killing (05).

Conclusions: Patterns of early bacillary clearance matter. Static measurements such as month 2 sputum conversion and pharmacokinetic parameters such as /MIC and AUC/MIC were predictive of treatment failure, but modeling of quantitative longitudinal data was required to assess the risk of recurrence. Pooled individual patient data analyses from larger datasets are needed to confirm these findings.
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http://dx.doi.org/10.1093/ofid/ofaa218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7378673PMC
July 2020

Endothelial dysfunction and carotid atherosclerosis in Malawian adults: A cross-sectional study.

Authors:
Joseph Kamtchum-Tatuene Gloria Mwangalika Kachingwe Henry C Mwandumba Tom Solomon Laura A Benjamin

eNeurologicalSci 2020 Sep 28;20:100252. Epub 2020 Jun 28.

Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom.

Background And Objective: In sub-Saharan Africa, data on prevalence, risk factors and pathobiology of carotid atherosclerosis are scarce. We aimed to investigate the relationship between biomarkers of endothelial dysfunction and carotid atherosclerosis.

Methods: Carotid ultrasound was performed in 66 patients. Plasma concentration of ICAM-1, PAI-1, VEGF, and soluble thrombomodulin were measured by ELISA. A univariable logistic regression analysis was performed to study the relationship between carotid atherosclerosis, biomarkers of endothelial dysfunction, and various demographic and clinical parameters of the participants.

Results: The mean age of the participants was 58.7 years (95% CI: 54.4-63.1). Carotid atherosclerosis was diagnosed in 39.4% (95% CI: 27.6-52.2). In the univariable logistic regression, the following factors were associated with carotid atherosclerosis: age > 45 years (OR = 12.0, 95% CI: 1.4-98.8,  = .02), hypertension (OR = 3.8, 95% CI: 1.2-12.1, p = .02), and high-level of soluble thrombomodulin (OR = 3.4, 95% CI: 1.2-10.0, p = .02).

Conclusions: There is an association between high levels of soluble thrombomodulin and carotid atherosclerosis in Malawian adults. Further studies with a larger sample size are needed to confirm our findings in other African populations.
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http://dx.doi.org/10.1016/j.ensci.2020.100252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334363PMC
September 2020

A pragmatic approach to managing antiretroviral therapy-experienced patients diagnosed with HIV-associated cryptococcal meningitis: impact of antiretroviral therapy adherence and duration.

Authors:
Melanie Alufandika David S Lawrence Timothée Boyer-Chammard Cecilia Kanyama Chiratidzo E Ndhlovu Mosepele Mosepele Lillian Tugume David Meya David R Boulware Joshua Rhein Conrad Muzoora Nabila Youssouf Síle F Molloy Charlotte Schutz Olivier Lortholary Graeme Meintjes Henry C Mwandumba Thomas S Harrison Joseph N Jarvis

AIDS 2020 07;34(9):1425-1428

Department of Clinical Research, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK.

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http://dx.doi.org/10.1097/QAD.0000000000002556DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7473821PMC
July 2020

The significant gap between international standards and stroke management practices at Queen Elizabeth Central Hospital (Malawi): An audit report.

Authors:
Yohane Gadama Joseph Kamtchum-Tatuene Laura Benjamin Tamara Phiri Henry C Mwandumba

Malawi Med J 2019 12;31(4):249-255

Malawi-Liverpool-Wellcome Trust Clinical Research Programme, College of Medicine, P.O. Box 30096, Chichiri, Blantyre 3, Malawi.

Background: The Queen Elizabeth Central Hospital (QECH) is preparing to set up the first stroke unit in Blantyre, Malawi. We conducted this audit to assess current stroke management practices and outcomes at QECH and identify priority areas for intervention.

Methods: From April to June 2018, we prospectively enrolled patients with acute stroke and collected data on clinical presentation, cardiovascular risk factors, investigations and interventions, in-hospital outcomes, and follow-up plans after discharge. The American Heart Association/American Stroke Association (AHA/ASA) guidelines were used as the standard of care for comparison.

Results: Fifty patients with acute stroke were enrolled (46% women, 54% men). The mean age was 63.1 years (95% CI: 59.7-66.6). The diagnosis of stroke was based on the World Health Organization criteria. The diagnosis was made within 24 hours of admission in 19 patients (38%). Acute revascularisation therapy was not available. Forty-eight patients (96%) had their vital signs checked at baseline and <10% had their vital signs checked more than three times within the first 24 hours. Essential blood tests including random blood sugar (RBS), full blood count (FBC), urea/creatinine, and lipid profiles were performed in 72%, 68%, 48%, and 4%, respectively. An electrocardiogram was performed on 34 patients (68%). Blood pressure on admission was >140/90 mmHg in 34 patients (68%), including 4 with values >220/120 mmHg. Nine patients had an RBS >10 mmol/L and four received insulin. Prophylaxis for deep venous thrombosis was offered to 12 patients (24%). Aspiration pneumonia was reported in 16 patients (32%) and was the most common hospital complication. The mean duration of hospitalisation was 10.4 days (95% CI: 5.6-15.2), and case fatality was 18%. The modified Rankin scale at discharge was ≤2 in 32% of patients. Only four patients (8%) were transferred to a rehabilitation centre. At the time of discharge, only 32% of patients received education on stroke.

Conclusion: Acute stroke care is less than optimal in this setting. Simple interventions such as reducing the delay in making a stroke diagnosis, early swallow assessments, and closer monitoring of vital signs could make a significant difference in stroke outcome. Furthermore, treating cardiovascular risk factors and setting up health education programmes to improve secondary prevention represent key priorities.
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http://dx.doi.org/10.4314/mmj.v31i4.6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7036432PMC
December 2019

A cross-sectional feasibility study of neurovascular ultrasound in Malawian adults with acute stroke-like syndrome.

Authors:
Joseph Kamtchum-Tatuene Henry C Mwandumba Gloria Mwangalika Kachingwe Laura J Bonnett Noel Kayange Tom Solomon Laura A Benjamin

PLoS One 2020 7;15(2):e0229033. Epub 2020 Feb 7.

Institute of Infection and Global Health, University of Liverpool, Liverpool, England, United Kingdom.

Background: In sub-Saharan Africa, there is a dearth of epidemiologic data on the burden of cerebral atherosclerosis. This is explained by the limited availability and the high cost of standard vascular imaging techniques. Neurovascular ultrasound is portable, cheaper and non-invasive and could, therefore, represent a reasonable alternative to fill this knowledge gap. We explored the feasibility of neurovascular ultrasound in Malawian adults with acute stroke-like syndrome to inform the design of future large stroke studies comparing its diagnostic performance to that of gold standard vascular imaging techniques in sub-Saharan Africa.

Methods: We enrolled consecutive patients diagnosed with acute stroke-like syndrome based on the World Health Organization definition. Clinical and demographic data were recorded, and a comprehensive neurovascular ultrasound was performed. Fisher's exact and Kruskal-Wallis tests were used to study the relationship between atherosclerosis and potential risk factors.

Results: Sixty-six patients were enrolled (mean age: 58.7 years). The frequency of extracranial atherosclerosis was 39.4% (n = 26, 95% CI: 28.6-52.2). There were 12 patients with abnormal carotid intima media thickness (18.2%, 95% CI: 9.8-29.6) and 14 patients with a carotid plaque (21.2%, 95% CI: 12.1-33.0). The frequency of intracranial atherosclerosis was 19.2% (95%CI: 6.6-39.4) in 26 patients with successful transcranial insonation. Hypertension (80.8 versus 52.5%, p = 0.03) and hypercholesterolemia (11.5 versus 0.0%, p = 0.05) were more prevalent in patients with extracranial atherosclerosis.

Conclusions: This study demonstrates the feasibility of neurovascular ultrasound to assess cervical arteries in adults with stroke-like syndrome in sub-Saharan Africa. There is a high rate of transcranial insonation failure in this setting, highlighting the need for echocontrast agents.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0229033PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7006928PMC
May 2020

Tuberculosis in Hospitalized Patients With Human Immunodeficiency Virus: Clinical Characteristics, Mortality, and Implications From the Rapid Urine-based Screening for Tuberculosis to Reduce AIDS Related Mortality in Hospitalized Patients in Africa.

Authors:
Ankur Gupta-Wright Katherine Fielding Douglas Wilson Joep J van Oosterhout Daniel Grint Henry C Mwandumba Melanie Alufandika-Moyo Jurgens A Peters Lingstone Chiume Stephen D Lawn Elizabeth L Corbett

Clin Infect Dis 2020 Dec;71(10):2618-2626

Tuberculosis Centre, London School of Hygiene and Tropical Medicine, London, United Kingdom.

Background: Tuberculosis (TB) is the major killer of people living with human immunodeficiency virus (HIV) globally, with suboptimal diagnostics and management contributing to high case-fatality rates.

Methods: A prospective cohort of patients with confirmed TB (Xpert MTB/RIF and/or Determine TB-LAM Ag positive) identified through screening HIV-positive inpatients with sputum and urine diagnostics in Malawi and South Africa (Rapid urine-based Screening for Tuberculosis to reduce AIDS Related Mortality in hospitalized Patients in Africa [STAMP] trial). Urine was tested prospectively (intervention) or retrospectively (standard of care arm). We defined baseline clinical phenotypes using hierarchical cluster analysis, and also used Cox regression analysis to identify associations with early mortality (≤56 days).

Results: Of 322 patients with TB confirmed between October 2015 and September 2018, 78.0% had ≥1 positive urine test. Antiretroviral therapy (ART) coverage was 80.2% among those not newly diagnosed, but with median CD4 count 75 cells/µL and high HIV viral loads. Early mortality was 30.7% (99/322), despite near-universal prompt TB treatment. Older age, male sex, ART before admission, poor nutritional status, lower hemoglobin, and positive urine tests (TB-LAM and/or Xpert MTB/RIF) were associated with increased mortality in multivariate analyses. Cluster analysis (on baseline variables) defined 4 patient subgroups with early mortality ranging from 9.8% to 52.5%. Although unadjusted mortality was 9.3% lower in South Africa than Malawi, in adjusted models mortality was similar in both countries (hazard ratio, 0.9; P = .729).

Conclusions: Mortality following prompt inpatient diagnosis of HIV-associated TB remained unacceptably high, even in South Africa. Intensified management strategies are urgently needed, for which prognostic indicators could potentially guide both development and subsequent use.
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http://dx.doi.org/10.1093/cid/ciz1133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744971PMC
December 2020

Airway CD8CD161TCRvα7.2 T Cell Depletion During Untreated HIV Infection Targets CD103 Expressing Cells.

Authors:
Leonard Mvaya Andrew Mwale Annemarie Hummel Joseph Phiri Raphael Kamng'ona David Mzinza Elizabeth Chimbayo Rose Malamba Anstead Kankwatira Henry C Mwandumba Kondwani C Jambo

Front Immunol 2019 21;10:2003. Epub 2019 Aug 21.

Malawi-Liverpool-Wellcome Trust Clinical Research Programme, University of Malawi College of Medicine, Blantyre, Malawi.

HIV-infected adults are at an increased risk to lower respiratory tract infections (LRTIs). CD8CD161TCRvα7.2 T cells are an innate-like T cell subset that are thought to play an important role in early defense against pathogens in the respiratory tract. HIV infection leads to irreversible depletion of these cells in peripheral blood, however, its impact on this subset in the human airway is still unclear. Here, we show presence of CD103 expressing CD8CD161TCRvα7.2 T cells in the airway that exhibited a distinct cytokine functional profile compared to their CD103 airway counterparts and those from peripheral blood. These CD103 expressing airway CD8CD161TCRvα7.2 T cells were selectively depleted in untreated HIV-infected adults compared to healthy controls. Their frequency was positively correlated with frequency of airway CD4 T cells. Furthermore, the frequency of airway CD8CD161TCRvα7.2 T cells was also inversely correlated with HIV plasma viral load, while suppressive antiretroviral therapy (ART) resulted in restoration of airway CD8CD161TCRvα7.2 T cells. Our findings show that CD103 expressing airway CD8CD161TCRvα7.2 T cells are functionally distinct and are preferentially depleted during untreated asymptomatic HIV infection. Depletion of CD103 expressing airway CD8CD161TCRvα7.2 T cells, at a major portal of pathogen entry, could partly contribute to the increased propensity for opportunistic LRTIs observed in untreated HIV-infected adults.
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http://dx.doi.org/10.3389/fimmu.2019.02003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6713019PMC
October 2020

Inhibition of the lncRNA SAF drives activation of apoptotic effector caspases in HIV-1-infected human macrophages.

Authors:
Saikat Boliar David W Gludish Kondwani C Jambo Raphael Kamng'ona Leonard Mvaya Henry C Mwandumba David G Russell

Proc Natl Acad Sci U S A 2019 04 27;116(15):7431-7438. Epub 2019 Mar 27.

Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853;

Long noncoding RNAs (lncRNAs) impart significant regulatory functions in a diverse array of biological pathways and manipulation of these RNAs provides an important avenue to modulate such pathways, particularly in disease. Our knowledge about lncRNAs' role in determination of cellular fate during HIV-1 infection remains sparse. Here, we have identified the impact of the lncRNA SAF in regulating apoptotic effector caspases in macrophages, a long-lived cellular reservoir of HIV-1, that are largely immune to virus-induced cell death. Expression of SAF is significantly up-regulated in HIV-1-infected human monocyte-derived macrophages (MDM) compared with bystander and virus-nonexposed cells. A similar enhancement in SAF RNA expression is also detected in the HIV-1-infected airway macrophages obtained by bronchoalveolar lavage of HIV-1-infected individuals. Down-regulation of SAF with siRNA treatment increases caspase-3/7 activity levels in virus-infected MDMs. This induction of apoptotic caspases occurs exclusively in HIV-1-infected macrophages and not in bystander cells, leading to a significant reduction in HIV-1 replication and overall viral burden in the macrophage culture. This study identifies targeting of the lncRNA SAF as a potential means to specifically induce cell death in HIV-1-infected macrophages.
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http://dx.doi.org/10.1073/pnas.1818662116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6462110PMC
April 2019

Correction to: AMBIsome Therapy Induction OptimisatioN (AMBITION): High Dose AmBisome for Cryptococcal Meningitis Induction Therapy in sub-Saharan Africa: Study Protocol for a Phase 3 Randomised Controlled Non-Inferiority Trial.

Authors:
David S Lawrence Nabila Youssouf Síle F Molloy Alexandre Alanio Melanie Alufandika David R Boulware Timothée Boyer-Chammard Tao Chen Francoise Dromer Admire Hlupeni William Hope Mina C Hosseinipour Cecilia Kanyama Oliver Lortholary Angela Loyse David B Meya Mosepele Mosepele Conrad Muzoora Henry C Mwandumba Chiratidzo E Ndhlovu Louis Niessen Charlotte Schutz Katharine E Stott Duolao Wang David G Lalloo Graeme Meintjes Shabbar Jaffar Thomas S Harrison Joseph N Jarvis

Trials 2019 01 14;20(1):48. Epub 2019 Jan 14.

Department of Clinical Research, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK.

Following publication of the original article [1], we have been notified that one of the author names was listed incorrectly. Both incorrect and correct author names are presented below. The original publication has been corrected.
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http://dx.doi.org/10.1186/s13063-018-3155-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6332521PMC
January 2019

HIV-Related Arterial Stiffness in Malawian Adults Is Associated With the Proportion of PD-1-Expressing CD8+ T Cells and Reverses With Antiretroviral Therapy.

Authors:
Christine Kelly Henry C Mwandumba Robert S Heyderman Kondwani Jambo Raphael Kamng'ona Mishek Chammudzi Irene Sheha Ingrid Peterson Alicja Rapala Jane Mallewa A Sarah Walker Nigel Klein Saye Khoo

J Infect Dis 2019 05;219(12):1948-1958

Insitute of Translational Medicine, University of Liverpool.

Background: The contribution of immune activation to arterial stiffness and its reversibility in human immunodeficiency virus (HIV)-infected adults in sub-Saharan Africa is unknown.

Methods: HIV-uninfected and HIV-infected Malawian adults initiating antiretroviral therapy (ART) with a CD4+ T-cell count of <100 cells/μL were enrolled and followed for 44 weeks; enrollment of infected adults occurred 2 weeks after ART initiation. We evaluated the relationship between carotid femoral pulse wave velocity (cfPWV) and T-cell activation (defined as HLA-DR+CD38+ T cells), exhaustion (define as PD-1+ T cells), and senescence (defined as CD57+ T cells) and monocyte subsets, using normal regression.

Results: In 279 HIV-infected and 110 HIV-uninfected adults, 142 (37%) had hypertension. HIV was independently associated with a 12% higher cfPWV (P = .02) at baseline and a 14% higher cfPWV at week 10 (P = .02), but the increases resolved by week 22. CD4+ and CD8+ T-cell exhaustion were independently associated with a higher cfPWV at baseline (P = .02). At 44 weeks, arterial stiffness improved more in those with greater decreases in the percentage of CD8+ T cells and the percentage of PD-1+CD8+ T cells (P = .01 and P = .03, respectively). When considering HIV-infected participants alone, the adjusted arterial stiffness at week 44 tended to be lower in those with higher baseline percentage of PD-1+CD8+ T cells (P = .054).

Conclusions: PD-1+CD8+ T-cells are associated with HIV-related arterial stiffness, which remains elevated during the first 3 months of ART. Resources to prevent cardiovascular disease in sub-Saharan Africa should focus on blood pressure reduction and individuals with a low CD4+ T-cell count during early ART.
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http://dx.doi.org/10.1093/infdis/jiz015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6534190PMC
May 2019

Etiology and Risk Factors for Mortality in an Adult Community-acquired Pneumonia Cohort in Malawi.

Authors:
Stephen J Aston Antonia Ho Hannah Jary Jacqueline Huwa Tamara Mitchell Sarah Ibitoye Simon Greenwood Elizabeth Joekes Arthur Daire Jane Mallewa Dean Everett Mulinda Nyirenda Brian Faragher Henry C Mwandumba Robert S Heyderman Stephen B Gordon

Am J Respir Crit Care Med 2019 08;200(3):359-369

2Malawi-Liverpool-Wellcome Trust Clinical Research Programme, College of Medicine, Blantyre, Malawi.

In the context of rapid antiretroviral therapy rollout and an increasing burden of noncommunicable diseases, there are few contemporary data describing the etiology and outcome of community-acquired pneumonia (CAP) in sub-Saharan Africa. To describe the current etiology of CAP in Malawi and identify risk factors for mortality. We conducted a prospective observational study of adults hospitalized with CAP to a teaching hospital in Blantyre, Malawi. Etiology was defined by blood culture, urinary antigen detection, sputum mycobacterial culture and Xpert MTB/RIF, and nasopharyngeal aspirate multiplex PCR. In 459 patients (285 [62.1%] males; median age, 34.7 [interquartile range, 29.4-41.9] yr), 30-day mortality was 14.6% (64/439) and associated with male sex (adjusted odds ratio, 2.60 [95% confidence interval, 1.17-5.78]), symptom duration greater than 7 days (2.78 [1.40-5.54]), tachycardia (2.99 [1.48-6.06]), hypoxemia (4.40 [2.03-9.51]), and inability to stand (3.59 [1.72-7.50]). HIV was common (355/453; 78.4%), frequently newly diagnosed (124/355; 34.9%), but not associated with mortality. (98/458; 21.4%) and (75/326; 23.0%) were the most frequently identified pathogens. Viral infection occurred in 32.6% (148/454) with influenza (40/454; 8.8%) most common. Bacterial-viral coinfection occurred in 9.1% (28/307). Detection of was associated with mortality (adjusted odds ratio, 2.44 [1.19-5.01]). In the antiretroviral therapy era, CAP in Malawi remains predominantly HIV associated, with a large proportion attributable to potentially vaccine-preventable pathogens. Strategies to increase early detection and treatment of tuberculosis and improve supportive care, in particular the correction of hypoxemia, should be evaluated in clinical trials to address CAP-associated mortality.
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http://dx.doi.org/10.1164/rccm.201807-1333OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6680311PMC
August 2019

AMBIsome Therapy Induction OptimisatioN (AMBITION): High Dose AmBisome for Cryptococcal Meningitis Induction Therapy in sub-Saharan Africa: Study Protocol for a Phase 3 Randomised Controlled Non-Inferiority Trial.

Authors:
David S Lawrence Nabila Youssouf Síle F Molloy Alexandre Alanio Melanie Alufandika David R Boulware Timothée Boyer-Chammard Tao Chen Francoise Dromer Admire Hlupeni William Hope Mina C Hosseinipour Cecilia Kanyama Oliver Lortholary Angela Loyse David B Meya Mosepele Mosepele Conrad Muzoora Henry C Mwandumba Chiratidzo E Ndhlovu Louis Niessen Charlotte Schutz Katharine E Stott Duolao Wang David G Lalloo Graeme Meintjes Shabbar Jaffar Thomas S Harrison Joseph N Jarvis

Trials 2018 Nov 23;19(1):649. Epub 2018 Nov 23.

Department of Clinical Research, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK.

Background: Cryptococcal meningitis (CM) is a major cause of mortality in HIV programmes in Africa despite increasing access to antiretroviral therapy (ART). Mortality is driven in part by limited availability of amphotericin-based treatment, drug-induced toxicities of amphotericin B deoxycholate and prolonged hospital admissions. A single, high-dose of liposomal amphotericin (L-AmB, Ambisome) on a fluconazole backbone has been reported as non-inferior to 14 days of standard dose L-AmB in reducing fungal burden. This trial examines whether single, high-dose L-AmB given with high-dose fluconazole and flucytosine is non-inferior to a seven-day course of amphotericin B deoxycholate plus flucytosine (the current World Health Organization [WHO] recommended treatment regimen).

Methods: An open-label phase III randomised controlled non-inferiority trial conducted in five countries in sub-Saharan Africa: Botswana, Malawi, South Africa, Uganda and Zimbabwe. The trial will compare CM induction therapy with (1) a single dose (10 mg/kg) of L-AmB given with 14 days of fluconazole (1200 mg/day) and flucytosine (100 mg/kg/day) to (2) seven days amphotericin B deoxycholate (1 mg/kg/day) given alongside seven days of flucytosine (100 mg/kg/day) followed by seven days of fluconazole (1200 mg/day). The primary endpoint is all-cause mortality at ten weeks with a non-inferiority margin of 10% and 90% power. Secondary endpoints are early fungicidal activity, proportion of grade III/IV adverse events, pharmacokinetic parameters and pharmacokinetic/pharmacodynamic associations, health service costs, all-cause mortality within the first two and four weeks, all-cause mortality within the first ten weeks (superiority analysis) and rates of CM relapse, immune reconstitution inflammatory syndrome and disability at ten weeks. A total of 850 patients aged ≥ 18 years with a first episode of HIV-associated CM will be enrolled (425 randomised to each arm). All patients will be followed for 16 weeks. All patients will receive consolidation therapy with fluconazole 800 mg/day to complete ten weeks of treatment, followed by fluconazole maintenance and ART as per local guidance.

Discussion: A safe, sustainable and easy to administer regimen of L-AmB that is non-inferior to seven days of daily amphotericin B deoxycholate therapy may reduce the number of adverse events seen in patients treated with amphotericin B deoxycholate and shorten hospital admissions, providing a highly favourable and implementable alternative to the current WHO recommended first-line treatment.

Trial Registration: ISRCTN, ISRCTN72509687 . Registered on 13 July 2017.
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http://dx.doi.org/10.1186/s13063-018-3026-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6251219PMC
November 2018

B cell, CD8  T cell and gamma delta T cell infiltration alters alveolar immune cell homeostasis in HIV-infected Malawian adults.

Authors:
Andrew Mwale Annemarie Hummel Leonard Mvaya Raphael Kamng'ona Elizabeth Chimbayo Joseph Phiri Rose Malamba Anstead Kankwatira Henry C Mwandumba Kondwani C Jambo

Wellcome Open Res 2017 6;2:105. Epub 2018 Apr 6.

Malawi-Liverpool-Wellcome Trust Clinical Research Programme, University of Malawi College of Medicine, Blantyre, Malawi.

: HIV infection is associated with increased risk to lower respiratory tract infections (LRTI). However, the impact of HIV infection on immune cell populations in the lung is not well defined. We sought to comprehensively characterise the impact of HIV infection on immune cell populations in the lung. : Twenty HIV-uninfected controls and 17 HIV-1 infected ART-naïve adults were recruited from Queen Elizabeth Central Hospital, Malawi. Immunophenotyping of lymphocyte and myeloid cell populations was done on bronchoalveolar lavage fluid and peripheral blood cells. : We found that the numbers of CD8 T cells, B cells and gamma delta T cells were higher in BAL fluid of HIV-infected adults compared to HIV-uninfected controls (all p<0.05). In contrast, there was no difference in the numbers of alveolar CD4 T cells in HIV-infected adults compared to HIV-uninfected controls (p=0.7065). Intermediate monocytes were the predominant monocyte subset in BAL fluid (HIV-, 63%; HIV+ 81%), while the numbers of classical monocytes was lower in HIV-infected individuals compared to HIV-uninfected adults (1 × 10 vs. 2.8 × 10 cells/100ml of BAL fluid, p=0.0001). The proportions of alveolar macrophages and myeloid dendritic cells was lower in HIV-infected adults compared to HIV-uninfected controls (all p<0.05). : Chronic HIV infection is associated with broad alteration of immune cell populations in the lung, but does not lead to massive depletion of alveolar CD4 T cells. Disruption of alveolar immune cell homeostasis likely explains in part the susceptibility for LRTIs in HIV-infected adults.
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http://dx.doi.org/10.12688/wellcomeopenres.12869.3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5872007PMC
April 2018

Human alveolar macrophages predominately express combined classical M1 and M2 surface markers in steady state.

Authors:
Elena Mitsi Raphael Kamng'ona Jamie Rylance Carla Solórzano J Jesus Reiné Henry C Mwandumba Daniela M Ferreira Kondwani C Jambo

Respir Res 2018 04 18;19(1):66. Epub 2018 Apr 18.

Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, UK.

Alveolar macrophages (AM) are critical to the homeostasis of the inflammatory environment in the lung. Differential expression of surface markers classifies macrophages to either classically (M1) or alternatively activated (M2). We investigated the phenotype of human alveolar macrophages (AM) in adults living in two different geographical locations: UK and Malawi. We show that the majority of AM express high levels of M1 and M2 markers simultaneously, with the M1/M2 phenotype being stable in individuals from different geographical locations. The combined M1/M2 features confer to AM a hybrid phenotype, which does not fit the classic macrophage classification. This hybrid phenotype may confer to alveolar macrophages an ability to quickly switch between M1 or M2 associated functions allowing for appropriate responses to stimuli and tissue environment.
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http://dx.doi.org/10.1186/s12931-018-0777-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5907303PMC
April 2018

HIV-associated disruption of lung cytokine networks is incompletely restored in asymptomatic HIV-infected Malawian adults on antiretroviral therapy.

Authors:
Kondwani C Jambo Dumizulu L Tembo Arox W Kamng'ona Patrick Musicha Dominic H Banda Anstead M Kankwatira Rose D Malamba Theresa J Allain Robert S Heyderman David G Russell Henry C Mwandumba

ERJ Open Res 2017 10 14;3(4). Epub 2017 Dec 14.

Malawi-Liverpool-Wellcome Trust Clinical Research Programme, University of Malawi College of Medicine, Blantyre, Malawi.

Disruption of lung cytokine networks during chronic HIV infection is incompletely restored in individuals on antiretroviral therapy.
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http://dx.doi.org/10.1183/23120541.00097-2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5731235PMC
October 2017

Alveolar T-helper 17 responses to streptococcus pneumoniae are preserved in ART-untreated and treated HIV-infected Malawian adults.

Authors:
Chikondi Peno Dominic H Banda Ndaru Jambo Anstead M Kankwatira Rose D Malamba Theresa J Allain Daniela M Ferreira Robert S Heyderman David G Russell Henry C Mwandumba Kondwani C Jambo

J Infect 2018 02 29;76(2):168-176. Epub 2017 Nov 29.

Malawi-Liverpool-Wellcome Trust Clinical Research Programme, University of Malawi College of Medicine, Blantyre, Malawi; Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, UK. Electronic address:

Objective: We explored if HIV infection is associated with impaired T-Helper 17 responses against Streptococcus pneumoniae in the lung.

Methods: We recruited 30 HIV-uninfected healthy controls, 23 asymptomatic HIV-infected adults not on ART, and 40 asymptomatic HIV-infected adults on ART (Median time 3.5yrs), in whom we collected bronchoalveolar lavage fluid. We measured alveolar CD4 T cell immune responses following stimulation with pneumococcal cell culture supernatant using flow cytometry-based intracellular cytokine staining.

Results: We found that the proportion of alveolar CD4 T cells producing IL-17A following stimulation with pneumococcal cell culture supernatant (CCS) was similar between HIV-uninfected controls and ART-naïve HIV-infected adults (0.10% vs. 0.14%; p = 0.9273). In contrast, the proportion and relative absolute counts of CD4 T cells producing IL-17A in response to pneumococcal CCS were higher in ART-treated HIV-infected adults compared HIV-uninfected controls (0.22% vs. 0.10%, p = 0.0166; 5420 vs. 1902 cells/100 ml BAL fluid; p = 0.0519). The increase in relative absolute numbers of IL-17A-producing alveolar CD4 T cells in ART-treated individuals was not correlated with the peripheral blood CD4 T cell count (r=-0.1876, p = 0.1785).

Conclusion: Alveolar Th17 responses against S. pneumoniae are preserved in HIV-infected adults. This suggests that there are other alternative mechanisms that are altered in HIV-infected individuals that render them more susceptible to pneumococcal pneumonia.
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http://dx.doi.org/10.1016/j.jinf.2017.10.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5792245PMC
February 2018

Functional Analysis of Phagocyte Activity in Whole Blood from HIV/Tuberculosis-Infected Individuals Using a Novel Flow Cytometry-Based Assay.

Authors:
Ankur Gupta-Wright Dumizulu Tembo Kondwani C Jambo Elizabeth Chimbayo Leonard Mvaya Shannon Caldwell David G Russell Henry C Mwandumba

Front Immunol 2017 28;8:1222. Epub 2017 Sep 28.

College of Medicine, Malawi-Liverpool-Wellcome Trust Clinical Research Programme, Blantyre, Malawi.

The accurate assessment of immune competence through analysis is paramount to our understanding of those immune mechanisms that lead to protection or susceptibility against a broad range of human pathogens. We have developed a flow cytometry-based, whole blood phagocyte functional assay that utilizes the inflammatory inducer zymosan, coupled to OxyBURST-SE, a fluorescent reporter of phagosomal oxidase activity. The assay measures both phagocytic uptake and the superoxide burst in the phagocyte populations in whole blood. We utilized this assay to demonstrate impaired superoxide burst activity in the phagocytes of hospitalized HIV-positive patients with laboratory-confirmed tuberculosis. These data validate the use of the assay to assess the immune competence of patients in a clinical setting. The method is highly reproducible with minimal intraindividual variation and opens opportunities for the rapid assessment of cellular immune competence in peripheral blood in a disease setting.
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http://dx.doi.org/10.3389/fimmu.2017.01222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5624998PMC
September 2017

Challenges of stroke management in resource-limited settings: A case-based reflection.

Authors:
Yohane G Gadama Gloria Mwangalika Louis B Kinley Beth Jackson Henry C Mwandumba Jane Mallewa Tom Solomon Rob Simister Laura A Benjamin Maria I Vargas Joseph Kamtchum-Tatuene Tamara Phiri

Malawi Med J 2017 06;29(2):189-193

Department of Medicine, College of Medicine, University of Malawi, Blantyre, Malawi.

A 19-year-old man presented with a 1-year history of headache, generalised body weakness, progressive memory loss, and disorientation. One month prior to admission, there was aggravation of the weakness of the right upper limb, with new-onset difficulty with mastication, speech impairment, apathy, and urinary incontinence. On clinical examination, the patient had a motor aphasia and a right-sided hemiparesis with increased muscle tone and hyperreflexia. A noncontrast computed tomography (CT) scan of the brain revealed large ischaemic strokes extending beyond the classical vascular territories. Cerebrospinal fluid analysis showed a mildly increased protein level. The electrocardiogram revealed an irregular sinus bradycardia. The remainder of the cardiovascular and laboratory workup was unremarkable. Considering a working diagnosis of central nervous system vasculitis, the patient was treated with aspirin, prednisolone, and physiotherapy. However, he died suddenly a few weeks later. Based on this case, we discuss the challenges of stroke management in resource-limited settings, provide practical tips for general practitioners, reflect on the potential avenues for short- and long-term action, and introduce the budding collaboration platform between the University College London, the University of Liverpool, the Queen Elizabeth Central Hospital, and the Malawi-Liverpool-Wellcome Trust Clinical Research Programme.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5610294PMC
http://dx.doi.org/10.4314/mmj.v29i2.21DOI Listing
June 2017

Loss of Humoral and Cellular Immunity to Invasive Nontyphoidal Salmonella during Current or Convalescent Plasmodium falciparum Infection in Malawian Children.

Authors:
Tonney S Nyirenda James T Nyirenda Dumizulu L Tembo Janet Storm Queen Dube Chisomo L Msefula Kondwani C Jambo Henry C Mwandumba Robert S Heyderman Melita A Gordon Wilson L Mandala

Clin Vaccine Immunol 2017 Jul 5;24(7). Epub 2017 Jul 5.

Malawi Liverpool Wellcome Trust Clinical Research Programme, Blantyre, Malawi

Invasive nontyphoidal (iNTS) infections are commonly associated with infections, but the immunologic basis for this linkage is poorly understood. We hypothesized that infection compromises the humoral and cellular immunity of the host to NTS, which increases the susceptibility of the host to iNTS infection. We prospectively recruited children aged between 6 and 60 months at a Community Health Centre in Blantyre, Malawi, and allocated them to the following groups; febrile with uncomplicated malaria, febrile malaria negative, and nonfebrile malaria negative. Levels of serovar Typhimurium-specific serum bactericidal activity (SBA) and whole-blood bactericidal activity (WBBA), complement C3 deposition, and neutrophil respiratory burst activity (NRBA) were measured. Levels of SBA with respect to Typhimurium were reduced in febrile -infected children (median, -0.20 log10 [interquartile range {IQR}, -1.85, 0.32]) compared to nonfebrile malaria-negative children (median, -1.42 log10 [IQR, -2.0, -0.47], = 0.052). In relation to SBA, C3 deposition on Typhimurium was significantly reduced in febrile -infected children (median, 7.5% [IQR, 4.1, 15.0]) compared to nonfebrile malaria-negative children (median, 29% [IQR, 11.8, 48.0], = 0.048). WBBA with respect to Typhimurium was significantly reduced in febrile -infected children (median, 0.25 log10 [IQR, -0.73, 1.13], = 0.0001) compared to nonfebrile malaria-negative children (median, -1.0 log10 [IQR, -1.68, -0.16]). In relation to WBBA, Typhimurium-specific NRBA was reduced in febrile -infected children (median, 8.8% [IQR, 3.7, 20], = 0.0001) compared to nonfebrile malaria-negative children (median, 40.5% [IQR, 33, 65.8]). infection impairs humoral and cellular immunity to Typhimurium in children during malaria episodes, which may explain the increased risk of iNTS observed in children from settings of malaria endemicity. The mechanisms underlying humoral immunity impairment are incompletely understood and should be explored further.
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http://dx.doi.org/10.1128/CVI.00057-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5498726PMC
July 2017

Genetic Determinants of the Pharmacokinetic Variability of Rifampin in Malawian Adults with Pulmonary Tuberculosis.

Authors:
Derek J Sloan Andrew D McCallum Alessandro Schipani Deirdre Egan Henry C Mwandumba Steve A Ward David Waterhouse Gertrude Banda Theresa J Allain Andrew Owen Saye H Khoo Geraint R Davies

Antimicrob Agents Chemother 2017 07 27;61(7). Epub 2017 Jun 27.

Royal Liverpool University Hospital, Liverpool, United Kingdom

Variable exposure to antituberculosis (TB) drugs, partially driven by genetic factors, may be associated with poor clinical outcomes. Previous studies have suggested an influence of the locus on the plasma area under the concentration-time curve (AUC) of rifampin. We evaluated the contribution of single nucleotide polymorphisms (SNPs) in and other candidate genes ( and ) to interindividual pharmacokinetic variability in Malawi. A total of 174 adults with pulmonary TB underwent sampling of plasma rifampin concentrations at 2 and 6 h postdose. Data from a prior cohort of 47 intensively sampled, similar patients from the same setting were available to support population pharmacokinetic model development in NONMEM v7.2, using a two-stage strategy to improve information during the absorption phase. In contrast to recent studies in South Africa and Uganda, SNPs in did not explain variability in AUC of rifampin. No pharmacokinetic associations were identified with or SNPs, which were rare in the Malawian population. Pharmacogenetic determinants of rifampin exposure may vary between African populations. and other novel candidate genes, as well as nongenetic sources of interindividual variability, should be further explored in geographically diverse, adequately powered cohorts.
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http://dx.doi.org/10.1128/AAC.00210-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5487625PMC
July 2017

Perceptions of Research Bronchoscopy in Malawian Adults with Pulmonary Tuberculosis: A Cross-Sectional Study.

Authors:
Andrew D McCallum Deborah Nyirenda Wezzie Lora Saye H Khoo Derek J Sloan Henry C Mwandumba Nicola Desmond Geraint R Davies

PLoS One 2016 28;11(10):e0165734. Epub 2016 Oct 28.

Malawi-Liverpool-Wellcome Trust Clinical Research Programme, College of Medicine, University of Malawi, Blantyre, Malawi.

Bronchoscopy is an established research tool in Malawi, enabling collection of pulmonary samples for immunological, pharmacological, and microbiological studies. It is, however, an invasive clinical procedure that offers no direct benefit to volunteering participants when used in a research capacity alone, and thus informed consent is essential. This study aimed to explore TB patients' understanding of research bronchoscopy, what would motivate them to participate in research bronchoscopy, and their concerns, in order to inform consenting processes for future clinical studies. We used a qualitative research design. Two focus group discussions were conducted with community members and TB patients to understand their perceptions of bronchoscopy. Transcripts were coded by multiple co-authors and thematic content analysis was used to analyse main findings. We found that Malawian patients with pulmonary TB were willing to participate in a study using research bronchoscopy for health assessment and access to improved healthcare. We identified information of value to potential participants when consenting to that may lessen some of the anxieties expressed by participants. Patient and public involvement is essential to improve informed consent and institutional trust.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0165734PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5085028PMC
June 2017

Heterogeneous loss of HIV transcription and proviral DNA from 8E5/LAV lymphoblastic leukemia cells revealed by RNA FISH:FLOW analyses.

Authors:
Kaley M Wilburn Henry C Mwandumba Kondwani C Jambo Saikat Boliar Sabrina Solouki David G Russell David W Gludish

Retrovirology 2016 08 11;13(1):55. Epub 2016 Aug 11.

Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA.

8E5/LAV cells harbor a single HIV provirus, and are used frequently to generate standards for HIV genome quantification. Using flow cytometry-based in situ mRNA hybridization validated by qPCR, we find that different batches of 8E5 cells contain varying numbers of cells lacking viral mRNA and/or viral genomes. These findings raise concerns for studies employing 8E5 cells for quantitation, and highlight the value of mRNA FISH and flow cytometry in the detection and enumeration of HIV-positive cells.
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http://dx.doi.org/10.1186/s12977-016-0289-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4982266PMC
August 2016

Unstructured treatment interruption: an important risk factor for arterial stiffness in adult Malawian patients with antiretroviral treatment.

Authors:
Ingrid Peterson Damien Ming Christine Kelly Kennedy Malisita J Mallewa Henry C Mwandumba David G Lalloo Robert S Heyderman

AIDS 2016 09;30(15):2373-8

Liverpool School of Tropical Medicine, Blantyre, Malawi.

Objectives: The aim of the study was to evaluate the impact of unstructured antiretroviral treatment (ART) interruption on arterial stiffness in adult Malawians who are on ART for at least 35 years.

Design: The number of treatment interruption events for at least 60 days during ART treatment was quantified in patients for at least 35 years using retrospective routinely collected clinic data. Treatment interruption data were linked to patient carotid-femoral pulse wave velocity (PWV); PWV more than 10 m/s was set as the threshold for clinically significant cardiovascular disease risk.

Methods: PWV was measured in patients (on ART ≥ 18 months), during routine ART clinic visits in Blantyre, Malawi, between November 2014 and July 2015. Multivariable linear regression was used to estimate the change in PWV m/s associated with treatment interruption. Multivariable logistic regression was used to estimate risk of PWV more than 10 m/s. All models were controlled for demographic and cardiometabolic risk factors.

Results: In 220 patients (median age 45 years, range 37-80 years), 86 (37.4%) patients had at least one treatment interruption event. Median length of treatment interruption events was 75 days (range 31 days to 8 years). Overall, 31 (14%) patients had a PWV more than 10 m/s. In multivariable analysis, we found a 0.2 increase in PWV m/s per treatment interruption event (0.2, 95% confidence interval 0.1-0.4) and a two-fold increased risk of PWV more than 10 m/s per treatment interruption event (adjusted odds ratio 2.2, 95% confidence interval 1.2-4.0).

Conclusion: Treatment interruption in patients with ART for at least 35 years is a common and important risk factor for arterial stiffness. Therefore, the link between treatment interruption and cardiovascular disease in this setting in which traditional risks factors are less prevalent needs to be explored further.
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http://dx.doi.org/10.1097/QAD.0000000000001198DOI Listing
September 2016

Kinetics of Mycobacterium tuberculosis-specific IFN-γ responses and sputum bacillary clearance in HIV-infected adults during treatment of pulmonary tuberculosis.

Authors:
David T Mzinza Derek J Sloan Kondwani C Jambo Doris Shani Mercy Kamdolozi Katalin A Wilkinson Robert J Wilkinson Geraint R Davies Robert S Heyderman Henry C Mwandumba

Tuberculosis (Edinb) 2015 Jul 28;95(4):463-9. Epub 2015 May 28.

Malawi-Liverpool-Wellcome Trust Clinical Research Programme, University of Malawi College of Medicine, P.O. Box 30096, Chichiri, Blantyre 3, Malawi; Department of Medicine, College of Medicine, Private Bag 360, Chichiri, Blantyre 3, Malawi; Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool L3 5QA, UK. Electronic address:

In HIV-uninfected adults with pulmonary tuberculosis (TB), anti-TB treatment is associated with changes in Mycobacterium tuberculosis (Mtb)-specific immune responses, which correlate with sputum bacillary load. It is unclear if this occurs in HIV-infected TB patients. We investigated changes in Mtb-specific immune responses and sputum bacillary clearance during anti-TB treatment in HIV-infected and HIV-uninfected adults with pulmonary TB. Sputum bacillary load was assessed by smear microscopy and culture. Mtb-specific IFN-γ secreting peripheral blood mononuclear cells were enumerated using an ELISPOT assay following stimulation with PPD, ESAT-6 and CFP-10. The baseline frequency of Mtb-specific IFN-γ secreting cells was lower in HIV-infected than HIV-uninfected patients (median PPD 32 vs. 104 Spot Forming Units (SFU), p = 0.05; CFP-10 19 vs. 74 SFU, p = 0.01). ESAT-6-specific IFN-γ secreting cells and sputum bacillary load declined progressively during treatment in both HIV-infected and HIV-uninfected patients. HIV infection did not influence the 2-month sputum culture conversion rate (Odds Ratio 0.89, p = 0.95). These findings suggest that changes in ESAT-6-specific immune responses during anti-TB treatment correspond with changes in sputum bacillary load irrespective of host HIV infection status. The utility of Mtb-specific IFN-γ responses as a proxy measure of treatment response in HIV-infected TB patients warrants further evaluation in other settings.
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http://dx.doi.org/10.1016/j.tube.2015.05.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4503815PMC
July 2015