SUNScholar - Browsing by Author "Mills, Edward J."

Browsing by Author "Mills, Edward J."

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Accelerating clinical evaluation of repurposed combination therapies for COVID-19
(American Society of Tropical Medicine and Hygiene, 2020-08-21) Rayner, Craig R.; Dron, Louis; Park, Jay J. H.; Decloedt, Eric H.; Cotton, Mark F.; Niranjan, Vis; Smith, Patrick F.; Dodds, Michael G.; Brown, Fran; Reis, Gilmar; Wesche, David; Mills, Edward J.
As the global COVID-19 pandemic continues, unabated and clinical trials demonstrate limited effective pharmaceutical interventions, there is a pressing need to accelerate treatment evaluations. Among options for accelerated development is the evaluation of drug combinations in the absence of prior monotherapy data. This approach is appealing for a number of reasons. First, combining two or more drugs with related or complementary therapeutic effects permits a multipronged approach addressing the variable pathways of the disease. Second, if an individual component of a combination offers a therapeutic effect, then in the absence of antagonism, a trial of combination therapy should still detect individual efficacy. Third, this strategy is time saving. Rather than taking a stepwise approach to evaluating monotherapies, this strategy begins with testing all relevant therapeutic options. Finally, given the severity of the current pandemic and the absence of treatment options, the likelihood of detecting a treatment effect with combination therapy maintains scientific enthusiasm for evaluating repurposed treatments. Antiviral combination selection can be facilitated by insights regarding SARS-CoV-2 pathophysiology and cell cycle dynamics, supported by infectious disease and clinical pharmacology expert advice. We describe a clinical evaluation strategy using adaptive combination platform trials to rapidly test combination therapies to treat COVID-19.
Chloroquine and hydroxychloroquine for the prevention or treatment of Novel Coronavirus Disease (COVID-19) in Africa : caution for inappropriate off-label use in healthcare settings
(American Society of Tropical Medicine and Hygiene, 2020) Abena, Pascale M.; Decloedt, Eric H.; Bottieau, Emmanuel; Suleman, Fatima; Adejumo, Prisca; Sam-Agudu, Nadia A.; TamFum, Jean-Jacques Muyembe; Seydi, Moussa; Eholie, Serge P.; Mills, Edward J.; Kallay, Oscar; Zumla, Alimuddin; Nachega, Jean B.
ENGLISH ABSTRACT: The novel severe acute respiratory syndrome-coronavirus-2 pandemic has spread to Africa, where nearly all countries have reported laboratory-confirmed cases of novel coronavirus disease (COVID-19). Although there are ongoing clinical trials of repurposed and investigational antiviral and immune-based therapies, there are as yet no scientifically proven, clinically effective pharmacological treatments for COVID-19. Among the repurposed drugs, the commonly used antimalarials chloroquine (CQ) and hydroxychloroquine (HCQ) havebecome the focus of global scientific, media, and political attention despite a lack of randomized clinical trials supporting their efficacy. Chloroquine has been used worldwide for about 75 years and is listed by theWHOas an essential medicine to treat malaria. Hydroxychloroquine is mainly used as a therapy for autoimmune diseases. However, the efficacy and safety of CQ/HCQ for the treatment of COVID-19 remains to be defined. Indiscriminate promotion and widespread use of CQ/HCQ have led to extensive shortages, self-treatment, and fatal overdoses. Shortages and increased market prices leave all countries vulnerable to substandard and falsified medical products, and safety issues are especially concerning for Africa because of its healthcare system limitations. Much needed in Africa is a cross-continental collaborative network for coordinated production, distribution, and post-marketing surveillance aligned to low-cost distribution of any approved COVID-19 drug; this would ideally be piggybacked on existing global aid efforts. Meanwhile, African countries should strongly consider implementing prescription monitoring schemes to ensure that any off-label CQ/HCQ use is appropriate and beneficial during this pandemic.
Clinical characteristics and outcomes of patients hospitalized for COVID-19 in Africa : early insights from the Democratic Republic of the Congo
(American Society of Tropical Medicine and Hygiene, 2020) Nachega, Jean B.; Ishoso, Daniel Katuashi; Otokoye, John Otshudiema; Hermans, Michel P.; Machekano, Rhoderick Neri; Sam-Agudu, Nadia A.; Nswe, Christian Bongo-Pasi; Mbala-Kingebeni, Placide; Madinga, Joule Ntwan; Mukendi, Stephane; Koli, Marie Claire; Nkwembe, Edith N.; Mbuyi, Gisele M.; Nsio, Justus M.; Tshialala, Didier Mukeba; Pipo, Michel Tshiasuma; Ahuka-Mundeke, Steve; Muyembe-Tamfum, Jean-Jacques; Mofenson, Lynne; Smith, Gerald; Mills, Edward J.; Mellors, John W.; Zumla, Alimuddin; Landu, Don Jethro Mavungu; Kayembe, Jean-Marie
ENGLISH ABSTRACT: Little is known about the clinical features and outcomes of SARS-CoV-2 infection in Africa. We conducted a retrospective cohort study of patients hospitalized for COVID-19 between March 10, 2020 and July 31, 2020 at seven hospitals in Kinshasa, Democratic Republic of the Congo (DRC). Outcomes included clinical improvement within 30 days (primary) and in-hospital mortality (secondary). Of 766 confirmed COVID-19 cases, 500 (65.6%) were male, with a median (interquartile range [IQR]) age of 46 (34–58) years. One hundred ninety-one (25%) patients had severe/critical disease requiring admission in the intensive care unit (ICU). Six hundred twenty patients (80.9%) improved and were discharged within 30 days of admission. Overall in-hospital mortality was 13.2% (95% CI: 10.9–15.8), and almost 50% among those in the ICU. Independent risk factors for death were age < 20 years (adjusted hazard ratio [aHR] = 6.62, 95% CI: 1.85–23.64), 40–59 years (aHR = 4.45, 95% CI: 1.83–10.79), and ³ 60 years (aHR = 13.63, 95% CI: 5.70–32.60) compared with those aged 20–39 years, with obesity (aHR = 2.30, 95% CI: 1.24–4.27), and with chronic kidney disease (aHR = 5.33, 95% CI: 1.85–15.35). In marginal structural model analysis, there was no statistically significant difference in odds of clinical improvement (adjusted odds ratio [aOR] = 1.53, 95% CI: 0.88–2.67, P = 0.132) nor risk of death (aOR = 0.65, 95% CI: 0.35–1.20) when comparing the use of chloroquine/azithromycin versus other treatments. In this DRC study, the high mortality among patients aged < 20 years and with severe/critical disease is of great concern, and requires further research for confirmation and targeted interventions.
Clinical trials of disease stages in COVID 19 : complicated and often misinterpreted
(Elsevier, 2020-08-20) Park, Jay J. H.; Decloedt, Eric H.; Rayner, Craig R.; Cotton, Mark; Mills, Edward J.
As of July 28, 2020, 1840 clinical trials were registered globally, with 1001 clinical trials recruiting patients for COVID-19 management.1 Despite this large number, only 30 trials have been published as peer-reviewed or preprint publications.2 Media reports and prepublications on medRxiv and bioRxiv represent the most frequent mechanism for data sharing, with wide public reach and usually with little detail. However, with inadequate details on the trials and only superficial scrutiny by the public and scientific decision makers, the consequences have had disastrous effects on other clinical trial funding, permissions, recruitment, and interpretation.
Global health : the importance of evidence-based medicine
(BioMed Central, 2013-10) Birbeck, Gretchen L.; Wiysonge, Charles S.; Mills, Edward J.; Frenk, Julio J.; Zhou, Xiao-Nong; Jha, Prabhat
ENGLISH ABSTRACT: Global health is a varied field that comprises research, evaluation and policy that, by its definition, also occurs in disparate locations across the world. This forum article is introduced by our guest editor of the Medicine for Global Health article collection, Gretchen Birbeck. Here, experts based across different settings describe their personal experiences of global health, discussing how evidence-based medicine in resource-limited settings can be translated into improved health outcomes.
Glycated haemoglobin threshold for dysglycaemia screening, and application to metabolic syndrome diagnosis in HIV-infected Africans
(Public Library of Science, 2019) Nguyen, Kim A.; Peer, Nasheeta; De Villiers, Anniza; Mukasa, Barbara; Matsha, Tandi E.; Mills, Edward J.; Kengne, Andre P.
Background: Glycated haemoglobin (HbA1c) test has been increasingly promoted as an alternative to fasting plasma glucose (FPG) or oral glucose tolerance test (OGTT) to diagnose dysglycaemia but its performance in HIV-infected Africans has yet to be established. This study aimed to assess the diagnostic accuracy of HbA1c for dysglycaemia including FPG-defined and OGTT-defined dysglycaemia, and OGTT-defined diabetes in HIV-infected Africans, and the effect of HbA1c-predicted dysglycaemia on Joint Interim Statement (JIS)-based prevalent metabolic syndrome (MS). Methods: A cross-sectional study included HIV-positive patients recruited across public healthcare facilities in the Western Cape. The recommended HbA1c cut-points were tested alongside the optimal cut-points obtained from receiver operating characteristic curve analyses, while the agreement between the MS criteria were assessed using kappa statistic. Results: 748 participants (157 men), median age 38 years, 93% on anti-retroviral drugs were included. The optimal HbA1c cut-points of 5.75% (39.3 mmol/mol) showed 54% sensitivity, 84% specificity for FPG-defined dysglycaemia, and 52% sensitivity, 85% specificity for OGTT-defined dysglycaemia. The HbA1c value of 5.85% (40.4 mmol/mol) (63% sensitivity, 99% specificity) was optimal for diabetes. The internationally advocated cut-point of 6.5% (48 mmol/mol) had 37% sensitivity and 99% specificity for diabetes, while HbA1c ≥5.7% (≥39 mmol/mol) yielded similar performance with the study-specific cut-point for any dysglycaemia. MS prevalence by the JIS criteria (28.2%) increased to 29.7% when using HbA1c ≥5.75% (≥39.3 mmol/mol) and to 32.9% with HbA1c ≥5.7% (≥39 mmol/mol); agreement between the original and modified criteria was generally good. Conclusions: This study agrees with the internationally recommended HbA1c cut-point for detecting dysglycaemia, but not for diabetes in HIV-infected Africans. In line with previous studies in general African populations, our findings suggest that similar factors interfere with HbA1c values regardless of HIV infection status. Replacing FPG-based with HbA1c-predicted dysglycaemia in the JIS criteria to diagnose MS is feasible in HIV-infected Africans.
Impact of tuberculosis on mortality among HIV-infected patients receiving antiretroviral therapy in Uganda : a prospective cohort analysis
(BioMed Central, 2013-07-13) Chu, Rong; Mills, Edward J.; Beyene, Joseph; Pullenayegum, Eleanor; Bakanda, Celestin; Nachega, Jean B.; Devereaux, P. J.; Thabane, Lehana
Background: Tuberculosis (TB) disease affects survival among HIV co-infected patients on antiretroviral therapy (ART). Yet, the magnitude of TB disease on mortality is poorly understood. Methods: Using a prospective cohort of 22,477 adult patients who initiated ART between August 2000 and June 2009 in Uganda, we assessed the effect of active pulmonary TB disease at the initiation of ART on all-cause mortality using a Cox proportional hazards model. Propensity score (PS) matching was used to control for potential confounding. Stratification and covariate adjustment for PS and not PS-based multivariable Cox models were also performed. Results: A total of 1,609 (7.52%) patients had active pulmonary TB at the start of ART. TB patients had higher proportions of being male, suffering from AIDS-defining illnesses, having World Health Organization (WHO) disease stage III or IV, and having lower CD4 cell counts at baseline (p < 0.001). The percentages of death during follow-up were 10.47% and 6.38% for patients with and without TB, respectively. The hazard ratio (HR) for mortality comparing TB to non-TB patients using 1,686 PS-matched pairs was 1.37 (95% confidence interval [CI]: 1.08 – 1.75), less marked than the crude estimate (HR = 1.74, 95% CI: 1.49 – 2.04). The other PS-based methods and not PS-based multivariable Cox model produced similar results. Conclusions: After controlling for important confounding variables, HIV patients who had TB at the initiation of ART in Uganda had an approximate 37% increased hazard of overall mortality relative to non-TB patients.
Mobile health technology for enhancing the COVID-19 response in Africa : a potential game changer?
(American Society of Tropical Medicine and Hygiene, 2020) Nachega, Jean B.; Leisegang, Rory; Kallay, Oscar; Mills, Edward J.; Zumla, Alimuddin; Lester, Richard T.
The WHO Africa Region is experiencing an increase in the number of novel COVID-19 cases. As of May 20, 2020, 63,521 cases with 1,796 deaths (2.8% case fatality) have been reported from 45 countries.1 Although these numbers are small compared with those in United States or Europe, the WHO recently estimated that up to 190,000 people could die of COVID-19 in Africa if the pandemic is not controlled.2 These projections are threatening the already overstretched health services in Africa, where governments have been implementing mitigating strategies to flatten epidemic curves at manageable levels. These include education, personal hygiene practices, social distancing, travel bans, and partial or total lockdowns.3 However, as lockdowns and social distancing measures are currently being lifted in stages by most African countries, governments will need to ensure that public health infrastructure and needed resources are put in place for community surveillance to identify cases and clusters of new infections through active case finding, large-scale testing, and contact tracing.
Patient-reported barriers to adherence to antiretroviral therapy : a systematic review and meta-analysis
(Public Library of Science, 2016) Shubber, Zara; Mills, Edward J.; Nachega, Jean B.; Vreeman, Rachel; Freitas, Marcelo; Bock, Peter; Nsanzimana, Sabin; Penazzato, Martina; Appolo, Tsitsi; Doherty, Meg; Ford, Nathan
ENGLISH SUMMARY : Background: Maintaining high levels of adherence to antiretroviral therapy (ART) is a challenge across settings and populations. Understanding the relative importance of different barriers to adherence will help inform the targeting of different interventions and future research priorities. Methods and Findings: We searched MEDLINE via PubMed, Embase, Web of Science, and PsychINFO from 01 January 1997 to 31 March 2016 for studies reporting barriers to adherence to ART. We calculated pooled proportions of reported barriers to adherence per age group (adults, adolescents, and children). We included data from 125 studies that provided information about adherence barriers for 17,061 adults, 1,099 children, and 856 adolescents. We assessed differences according to geographical location and level of economic development. The most frequently reported individual barriers included forgetting (adults 41.4%, 95% CI 37.3%–45.4%; adolescents 63.1%, 95% CI 46.3%–80.0%; children/caregivers 29.2%, 95% CI 20.1%–38.4%), being away from home (adults 30.4%, 95% CI 25.5%–35.2%; adolescents 40.7%, 95% CI 25.7%–55.6%; children/caregivers 18.5%, 95% CI 10.3%–26.8%), and a change to daily routine (adults 28.0%, 95% CI 20.9%–35.0%; adolescents 32.4%, 95% CI 0%–75.0%; children/caregivers 26.3%, 95% CI 15.3%–37.4%). Depression was reported as a barrier to adherence by more than 15% of patients across all age categories (adults 15.5%, 95% CI 12.8%–18.3%; adolescents 25.7%, 95% CI 17.7%–33.6%; children 15.1%, 95% CI 3.9%–26.3%), while alcohol/substance misuse was commonly reported by adults (12.9%, 95% CI 9.7%–16.1%) and adolescents (28.8%, 95% CI 11.8%–45.8%). Secrecy/stigma was a commonly cited barrier to adherence, reported by more than 10% of adults and children across all regions (adults 13.6%, 95% CI 11.9%–15.3%; children/caregivers 22.3%, 95% CI 10.2%–34.5%). Among adults, feeling sick (15.9%, 95% CI 13.0%–18.8%) was a more commonly cited barrier to adherence than feeling well (9.3%, 95% CI 7.2%–11.4%). Health service–related barriers, including distance to clinic (adults 17.5%, 95% CI 13.0%–21.9%) and stock outs (adults 16.1%, 95% CI 11.7%–20.4%), were also frequently reported. Limitations of this review relate to the fact that included studies differed in approaches to assessing adherence barriers and included variable durations of follow up. Studies that report self-reported adherence will likely underestimate the frequency of non-adherence. For children, barriers were mainly reported by caregivers, which may not correspond to the most important barriers faced by children. Conclusions: Patients on ART face multiple barriers to adherence, and no single intervention will be sufficient to ensure that high levels of adherence to treatment and virological suppression are sustained. For maximum efficacy, health providers should consider a more triaged approach that first identifies patients at risk of poor adherence and then seeks to establish the support that is needed to overcome the most important barriers to adherence.
The rise and fall of hydroxychloroquine for the treatment and prevention of COVID-19
(American Society of Tropical Medicine and Hygiene, 2021) Lee, Zelyn; Rayner, Craig R.; Forrest, Jamie I.; Nachega, Jean B.; Senchaudhuri, Esha; Mills, Edward J.
ENGLISH ABSTRACT: The efficacy and safety of hydroxychloroquine (HCQ) for the prevention and treatment of COVID-19 has received great attention, and most notably, the enthusiasm for HCQ has been one of politicization rather than science. Laboratory studies and case series published early in the pandemic supported its efficacy. The scientific community raced to conduct observational and randomized evaluations of the drug in all stages of the disease, including prophylaxis, early treatment, and advanced disease. Yet a divisive media response affected recruitment, funding, and subsequent enthusiasm for continuing scientific investigations. Of the more than 300 HCQ trials registered, fewer than 50% report having recruited any patients, and most trials might fail to achieve any useful portions of their intended sample size. Multiple observational studies and two large randomized trials have demonstrated HCQ does not offer efficacy against COVID-19 in hospitalized patients. Prophylaxis studies and early treatment studies provided heterogeneous results and are plagued by low event rates and poor study outcome monitoring. Emerging high-quality evaluations of prophylaxis and early treatment do not support a role for HCQ in these populations. The story of HCQ for COVID-19 has followed a pattern of initial enthusiasm supported by poor quality evidence, followed by disappointment based on more rigorous evaluations. The experience of HCQ in the COVID-19 era calls for the depoliticization of science away from media glare.
Survival of HIV-infected adolescents on antiretroviral therapy in Uganda : findings from a nationally representative cohort in Uganda
(Public Library of Science, 2011-04-29) Bakanda, Celestin; Birungi, Josephine; Mwesigwa, Robert; Nachega, Jean B.; Chan, Keith; Palmer, Alexis; Ford, Nathan; Mills, Edward J.
Background: Adolescents have been identified as a high-risk group for poor adherence to and defaulting from combination antiretroviral therapy (cART) care. However, data on outcomes for adolescents on cART in resource-limited settings remain scarce. Methods: We developed an observational study of patients who started cART at The AIDS Service Organization (TASO) in Uganda between 2004 and 2009. Age was stratified into three groups: children (≤10 years), adolescents (11-19 years), and adults (≥20 years). Kaplan-Meier survival curves were generated to describe time to mortality and loss to follow-up, and Cox regression used to model associations between age and mortality and loss to follow-up. To address loss to follow up, we applied a weighted analysis that assumes 50% of lost patients had died. Findings: A total of 23,367 patients were included in this analysis, including 810 (3.5%) children, 575 (2.5%) adolescents, and 21 982 (94.0%) adults. A lower percentage of children (5.4%) died during their cART treatment compared to adolescents (8.5%) and adults (10%). After adjusting for confounding, other features predicted mortality than age alone. Mortality was higher among males (p<0.001), patients with a low initial CD4 cell count (p<0.001), patients with advanced WHO clinical disease stage (p<0.001), and shorter duration of time receiving cART (p<0.001). The crude mortality rate was lower for children (22.8 per 1000 person-years; 95% CI: 16.1, 29.5), than adolescents (36.5 per 1000 person-years; 95% CI: 26.3, 46.8) and adults (37.5 per 1000 person-years; 95% CI: 35.9, 39.1). Interpretation: This study is the largest assessment of adolescents receiving cART in Africa. Adolescents did not have cART mortality outcomes different from adults or children. © 2011 Bakanda et al.

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