Plasmodium falciparum genetic diversity and multiplicity of infection based on msp-1, msp-2, glurp and microsatellite genetic markers in sub-Saharan Africa: a systematic review and meta-analysis.

BACKGROUND: In sub-Saharan Africa (SSA), Plasmodium falciparum causes most of the malaria cases. Despite its crucial roles in disease severity and drug resistance, comprehensive data on Plasmodium falciparum genetic diversity and multiplicity of infection (MOI) are sparse in SSA. This study summarizes available information on genetic diversity and MOI, focusing on key markers (msp-1, msp-2, glurp, and microsatellites). The systematic review aimed to evaluate their influence on malaria transmission dynamics and offer insights for enhancing malaria control measures in SSA. METHODS: The review was conducted following the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines. Two reviewers conducted article screening, assessed the risk of bias (RoB), and performed data abstraction. Meta-analysis was performed using the random-effects model in STATA version 17. RESULTS: The review included 52 articles: 39 cross-sectional studies and 13 Randomized Controlled Trial (RCT)/cohort studies, involving 11,640 genotyped parasite isolates from 23 SSA countries. The overall pooled mean expected heterozygosity was 0.65 (95% CI: 0.51-0.78). Regionally, values varied: East (0.58), Central (0.84), Southern (0.74), and West Africa (0.69). Overall pooled allele frequencies of msp-1 alleles K1, MAD20, and RO33 were 61%, 44%, and 40%, respectively, while msp-2 I/C 3D7 and FC27 alleles were 61% and 55%. Central Africa reported higher frequencies (K1: 74%, MAD20: 51%, RO33: 48%) than East Africa (K1: 46%, MAD20: 42%, RO33: 31%). For msp-2, East Africa had 60% and 55% for I/C 3D7 and FC27 alleles, while West Africa had 62% and 50%, respectively. The pooled allele frequency for glurp was 66%. The overall pooled mean MOI was 2.09 (95% CI: 1.88-2.30), with regional variations: East (2.05), Central (2.37), Southern (2.16), and West Africa (1.96). The overall prevalence of polyclonal Plasmodium falciparum infections was 63% (95% CI: 56-70), with regional prevalences as follows: East (62%), West (61%), Central (65%), and South Africa (71%). CONCLUSION: The study shows substantial regional variation in Plasmodium falciparum parasite genetic diversity and MOI in SSA. These findings suggest a need for malaria control strategies and surveillance efforts considering regional-specific factors underlying Plasmodium falciparum infection.

A randomized trial of double vs single-dose etonogestrel implant to overcome the interaction with efavirenz-based antiretroviral therapy.

BACKGROUND: Concomitant use of efavirenz-based antiretroviral therapy and a standard-dose etonogestrel contraceptive implant led to 82% lower etonogestrel exposure when compared with women who do not receive antiretroviral therapy. The clinical impact of this reduced exposure is supported by retrospective cohort evaluations that demonstrated higher rates of unintended pregnancies when contraceptive implants were combined with efavirenz. We hypothesized that placement of 2 etonogestrel implants in those taking efavirenz-based antiretroviral therapy could increase etonogestrel exposure and improve measures of contraceptive efficacy. OBJECTIVE: This study compared the rate of ovulation and etonogestrel pharmacokinetics among women on efavirenz-based antiretroviral therapy who received 2 etonogestrel implants (136 mg; double implant group) in comparison with those who received 1 etonogestrel implant (68 mg; control group). STUDY DESIGN: This randomized, open-label study enrolled Ugandan women with regular menstrual periods who were receiving efavirenz-based antiretroviral therapy for the treatment of HIV. Participants were randomized 1:1 to the double implant or control group, and the etonogestrel implant(s) were placed in the same arm at enrollment. All participants used a copper intrauterine device to prevent pregnancy. Ovulation was evaluated by weekly serum progesterone concentrations measured over 4 consecutive weeks at months 3 (weeks 9-12), 6 (weeks 21-24), and 12 (weeks 45-48). Progesterone concentrations >3 ng/mL were interpreted as ovulation. The ovulation rate in each group was compared using Fisher's exact tests for each month and generalized estimating equations over 48 weeks. Plasma was collected at day 3 and weeks 1, 4, 12, 24, 36, and 48 after implant placement and analyzed using a validated liquid chromatography-triple quadrupole mass spectrometry method for etonogestrel. Etonogestrel concentrations were summarized as median (interquartile range) and compared between groups by geometric mean ratio with 90% confidence intervals. RESULTS: All participants (n=72) were cisgender Ugandan women with a median age of 31 years (interquartile range, 29-36), and 36 participants were enrolled in each study group. Two participants in the control group discontinued the trial; 1 at week 1 because of undetected pregnancy at entry and another at week 45 because of clinically significant depression. There were 47 ovulations over 104 person-months (45%) in 25 of 34 participants in the control group, and 2 ovulations over 108 person-months (2%) in 2 of 36 participants in the double implant group (month 3: 11 [31%] vs 0 [0%]; month 6: 17 [49%] vs 0 [0%]; month 12: 19 [56%] vs 2 [6%], respectively; all P<.001). The odds of ovulation were reduced by 97.7% (95% confidence interval, 90.1-99.5) in the double implant group over 48 weeks. At each time point, etonogestrel concentration was more than 2-fold higher in the double implant group than in the controls (geometric mean ratio, 2.30-2.83) with a geometric mean ratio of 2.83 (90% confidence interval, 1.89-3.35) at week 48. There were no differences in the adverse events between groups and no participant discontinued because of adverse events. CONCLUSION: Over 48 weeks of combined use, placing 2 etonogestrel implants suppressed ovulation and increased plasma etonogestrel exposure when compared with 1 etonogestrel implant among women on efavirenz-based antiretroviral therapy. Doubling the dose of etonogestrel during efavirenz-based antiretroviral therapy could improve contraceptive effectiveness.

Building Capacity for Research Ethics Committees in Uganda.

Timely communication from Research Ethics Committees (REC) to researchers is essential to meet deadlines. We conducted a capacity building program for REC members, REC and research administrators, and researchers from seven RECs in Uganda in order to improve the research regulatory approval cycle. The training was delivered from March 2020 to July 2021. Trainees were evaluated using pre and post-training tests. There was an increase in the average score from 38% to 53% in pre and post-training test respectively for the personal effectiveness and leadership programme for REC and research administrators. There was an increase in the average score of from 53.9% to 70.1% in pre and post-training test respectively for training on emerging and complex study designs. We achieved shift in knowledge and skills in use of the National Research Information Management System. We recommend regular training of REC members and administrators for efficient review of research protocols.

Prevalence of and Factors Associated with Hypertension Among Adults on Dolutegravir-Based Antiretroviral Therapy in Uganda: A Cross Sectional Study.

Introduction: Dolutegravir-based anti-retroviral therapy (ART) regimens were rolled out as first line HIV treatment in Uganda due to their tolerability, efficacy and high resistance barrier to human immunodeficiency virus (HIV). They have however been associated with weight gain, dyslipidemia and hyperglycemia which are cardiometabolic risk factors of hypertension. We assessed the prevalence and factors associated with hypertension among adults on dolutegravir regimens. Methods: We conducted a cross-sectional study on 430 systematically sampled adults on dolutegravir-based ART for ≥ 6 months. Hypertension was defined as systolic blood pressure ≥ 140 mmHg or diastolic blood pressure ≥ 90 mmHg or history of use of antihypertensive agents. Results: The prevalence of hypertension was 27.2% (117 of 430 participants) [95% CI: 23.2-31.6]. Majority were female (70.7%), the median age 42 [34, 50] years, with body mass index (BMI) ≥ 25 kg/m3 (59.6%) and median duration on DTG-based regimens of 28 [15, 33] months. Being male [aPR: 1.496, 95% CI: 1.122-1.994, P = 0.006], age ≥ 45 years [aPR: 4.23, 95% CI: 2.206-8.108, P < 0.001] and 35-44 years [aPR: 2.455, 95% CI: 1.216-4.947, P < 0.012] as compared with age < 35 years, BMI ≥ 25 kg/m3 [aPR: 1.489, 95% CI: 1.072-2.067, P = 0.017] as compared with BMI < 25 kg/m3, duration on dolutegravir-based ART [aPR: 1.008, 95% CI: 1.001-1.015, P = 0.037], family history of hypertension [aPR: 1.457, 95% CI: 1.064-1.995, P = 0.019] and history of heart disease [aPR: 1.73, 95% CI: 1.205-2.484, P = 0.003] were associated with hypertension. Conclusion: One in every four people with HIV (PWH) on dolutegravir-based ART has hypertension. We recommend the integration of hypertension management in the HIV treatment package and policies to improve existing supply chains for low cost and high-quality hypertension medications.

Virologic Nonsuppression Among Patients With HIV Newly Diagnosed With Cancer at Uganda Cancer Institute: A Cross-Sectional Study.

PURPOSE: AIDS-related mortality declined markedly since the introduction of antiretroviral therapy (ART); however, cancer mortality in Africa was higher than its incidence in 2020. People living with HIV (PLWHIV) are at an increased risk of malignancy and death from malignancy compared with the general population. In Uganda, AIDS-defining malignancies (ADMs), including cervical cancer, Kaposi sarcoma, and non-Hodgkin lymphoma, are among the commonest malignancies. Virologic nonsuppression has been identified as an important predictor of mortality among PLWHIV diagnosed with cancer. This study aimed to determine the prevalence and to identify factors associated with virologic nonsuppression among PLWHIV newly diagnosed with cancer. METHODS: This was a cross-sectional study that was carried out between December 2018 and April 2019 at the Uganda Cancer Institute. PLWHIV who had been on ART for at least 6 months and were newly diagnosed with cancer were enrolled. RESULTS: A total of 167 participants were enrolled. Cervical cancer was the commonest ADM (n = 45; 50.6%) of all ADMs, while esophageal and breast cancers were the commonest non-ADMs, accounting for 17.5% (n = 14) each of all non-ADMs. The prevalence of virologic nonsuppression was 15%. Having Kaposi sarcoma (odds ratio [OR], 8.15; P = .003), being poorly adherent to ART (OR, 4.1; P = .045), and being on second-line ART (OR, 5.68; P = .011) were associated with virologic nonsuppression. CONCLUSION: The prevalence of virologic nonsuppression is high among patients with HIV newly diagnosed with cancer. These findings emphasize the need for strengthening of adherence strategies, optimizing ART regimens, and prioritization of viral load testing among PLWHIV with newly diagnosed malignancy.

Building clinical pharmacology laboratory capacity in low- and middle-income countries: Experience from Uganda.

Background: Research and clinical use of clinical pharmacology laboratories are limited in low- and middle-income countries. We describe our experience in building and sustaining laboratory capacity for clinical pharmacology at the Infectious Diseases Institute, Kampala, Uganda. Intervention: Existing laboratory infrastructure was repurposed, and new equipment was acquired. Laboratory personnel were hired and trained to optimise, validate, and develop in-house methods for testing antiretroviral, anti-tuberculosis and other drugs, including 10 high-performance liquid chromatography methods and four mass spectrometry methods. We reviewed all research collaborations and projects for which samples were assayed in the laboratory from January 2006 to November 2020. We assessed laboratory staff mentorship from collaborative relationships and the contribution of research projects towards human resource development, assay development, and equipment and maintenance costs. We further assessed the quality of testing and use of the laboratory for research and clinical care. Lessons learnt: Fourteen years post inception, the clinical pharmacology laboratory had contributed significantly to the overall research output at the institute by supporting 26 pharmacokinetic studies. The laboratory has actively participated in an international external quality assurance programme for the last four years. For clinical care, a therapeutic drug monitoring service is accessible to patients living with HIV at the Adult Infectious Diseases clinic in Kampala, Uganda. Recommendations: Driven primarily by research projects, clinical pharmacology laboratory capacity was successfully established in Uganda, resulting in sustained research output and clinical support. Strategies implemented in building capacity for this laboratory may guide similar processes in other low- and middle-income countries.

Association of fluvoxamine with mortality and symptom resolution among inpatients with COVID-19 in Uganda: a prospective interventional open-label cohort study.

Prior research suggests that fluvoxamine, a selective serotonin reuptake inhibitor (SSRI) used for the treatment of obsessive-compulsive disorder and major depressive disorder, could be repurposed against COVID-19. We undertook a prospective interventional open-label cohort study to evaluate the efficacy and tolerability of fluvoxamine among inpatients with laboratory-confirmed COVID-19 in Uganda. The main outcome was all-cause mortality. Secondary outcomes were hospital discharge and complete symptom resolution. We included 316 patients, of whom 94 received fluvoxamine in addition to standard care [median age, 60 years (IQR = 37.0); women, 52.2%]. Fluvoxamine use was significantly associated with reduced mortality [AHR = 0.32; 95% CI = 0.19-0.53; p < 0.001, NNT = 4.46] and with increased complete symptom resolution [AOR = 2.56; 95% CI = 1.53-5.51; p < 0.001, NNT = 4.44]. Sensitivity analyses yielded similar results. These effects did not significantly differ by clinical characteristic, including vaccination status. Among the 161 survivors, fluvoxamine was not significantly associated with time to hospital discharge [AHR 0.81, 95% CI (0.54-1.23), p = 0.32]. There was a trend toward greater side effects with fluvoxamine (7.45% versus 3.15%; SMD = 0.21; χ2 = 3.46, p = 0.06), most of which were light or mild in severity and none of which were serious. One hundred mg of fluvoxamine prescribed twice daily for 10 days was well tolerated and significantly associated with reduced mortality and with increased complete symptom resolution, without a significant increase in time to hospital discharge, among inpatients with COVID-19. Large-scale randomized trials are urgently needed to confirm these findings, especially for low- and middle-income countries, where access to vaccines and approved treatments against COVID-19 is limited.

Effect of double-dose levonorgestrel subdermal implant in women taking efavirenz-based antiretroviral therapy: The DoubLNG pharmacokinetic study.

OBJECTIVE: We evaluated the pharmacokinetics of double-dose levonorgestrel (LNG) implants to overcome the drug-drug interaction with efavirenz-based antiretroviral therapy (ART). STUDY DESIGN: We conducted a nonrandomized, open-label, parallel-group, longitudinal pharmacokinetic study among Ugandan women ages 18-45 years. Participants with HIV on ART containing efavirenz 600 mg received 300 mg of LNG implants (Jadelle®, Bayer, New Zealand): 300LNG+ART group. We compared our outcomes with women without HIV using standard dose, 150 mg of LNG implants: 150LNG group. The implant was placed on day zero in both groups, and we quantified plasma LNG concentrations over 48 weeks post implant insertion. LNG pharmacokinetic parameters were estimated using noncompartmental techniques. Our primary outcome was the geometric mean ratio with 90% confidence intervals of LNG area under the concentration-time curve over 24 weeks (AUC0-24w) between groups. Demographic data were described as median (interquartile range). A secondary outcome compared between-group percent of LNG concentrations ≥300 pg/mL, a minimum threshold selected a priori based on observed pregnancies in Ugandan women on standard-dose LNG implants plus efavirenz. RESULTS: We enrolled 27 women in the 300LNG+ART group (34 [28.0 to 40.5] years and 61.0 [49.8-66.0] kg) and 19 women in the 150LNG group (33 [30.0 to 34.5] years and 64.9 [59.0 to 74.5] kg). LNG AUC0-24w was 34% lower for 300LNG+ART versus 150LNG (geometric mean 9998 vs. 15,231 pg*week/mL, respectively [geometric mean ratio 0.66 (90% confidence intervals, 0.54 to 0.80)]). The percentage of participants with LNG concentrations ≥300 pg/mL was not statistically different between groups at week 24 (300LNG+ART: 74.1%; 150LNG: 89.5%; p = 0.27). CONCLUSION: Double-dose LNG implant did not completely overcome the drug-drug interaction with efavirenz. IMPLICATION: In women using ART containing efavirenz, placing two implant systems (300 mg) did not normalize LNG pharmacokinetics compared with the standard-dose implant (150 mg), and some women had evidence of ovulatory activity. Alternative ART without drug-drug interactions, such as dolutegravir, is recommended with contraceptive implants.

Tracheobronchomegaly (Mounier-Kuhn Syndrome) in a 43-Year-Old Male: A Case Report.

Mounier-Kuhn syndrome (MKS) or congenital tracheobronchomegaly is a rare disorder characterized by marked dilatation of the trachea and main bronchi, bronchiectasis, and recurrent respiratory tract infections. The etiology of this disorder is uncertain and the clinical presentation is variable. The diagnosis is usually made based on the characteristic computed tomography (CT) scan findings. This report describes a case of a 43-year-old man presenting with persistent cough and recurrent lower respiratory tract infections since childhood associated with copious amounts of purulent sputum, difficulty in breathing, and weight loss. In addition, he reported palpitations, dyspnea, orthopnea, abdominal and lower limb swelling. The chest X-ray showed a dilated trachea (35mm) and bronchi (26mm (right) and 27mm (left)) with cystic bronchiectasis and reticulolinear opacities predominantly involving the middle and lower lung zones. Chest CT scan confirmed the diagnosis of MKS as evidenced by dilated trachea and bronchi complicated by diverticula formation. Electrocardiogram, echocardiography and abdominal ultrasound scan showed features of right-sided heart failure secondary to pulmonary hypertension. MKS, although rare, should be considered as a possible diagnosis in patients presenting with productive chronic cough, recurrent pneumonia, or incomplete response to appropriate antibiotic therapy for pneumonia.

Factors Associated with Medical Students' Career Choices Regarding Internal Medicine in Uganda.

Background: There is an unmet need for internal medicine physicians in Uganda owing to the growing burden of diseases. This study aimed at evaluating the factors associated with career choices of undergraduate medical students regarding internal medicine in Uganda. Methods: We conducted a cross-sectional study in the first 3 weeks of October 2021 via WhatsApp messenger. Medical students in the 3rd to 5th year of study who had completed internal medicine clinical rotations and pursuing a Bachelor of Medicine and Bachelor of Surgery (MBChB) degree at 7 Ugandan universities (4 public and 3 private) were enrolled. Multivariable logistic regression model was constructed to determine factors associated with a career choice in internal medicine. Results: We enrolled 418 participants, median age was 24 (interquartile range (IQR): 23-26) years, 67.7% were male, and 36.1% had a family member or relative who was a doctor. Most of the students (84.0%) were interested in research. The top three most preferred specialties were internal medicine (52.6%), surgery (51.2%), and obstetrics and gynaecology (51.0%). Overall, 186 (44.5%) participants reported plans to pursue a Master of Medicine degree in internal medicine. Interest in research was the only factor independently associated with 2.5-fold higher odds of pursuing a career in internal medicine (adjusted odds ratio: 2.5, 95% CI: 1.4-4.6, p = 0.003). About 73% of the participants strongly agreed that internal medicine requires wide reading. Conclusion: There is a strong interest to pursue a career in internal medicine among Ugandan medical students. We recommend an increase in training opportunities in Internal Medicine, especially in view of the growing disease burden and increasing population growth.

Incidence, microbiological aspects and associated risk factors of catheter-related bloodstream infections in adults on chronic haemodialysis at a tertiary hospital in Uganda.

Objectives: The high burden of infectious complications among patients receiving haemodialysis (HD) via central venous catheters increases morbidity and mortality. This study determined the incidence of catheter-related bloodstream infections (CRBSIs), microbiological profile of causative organisms, and associated predictors in patients on chronic HD. Methods: A prospective single-centre cohort study of 121 adult patients with end-stage kidney disease was conducted from October 2019 to March 2020. Antibiotic susceptibility was determined by the Kirby-Bauer disk diffusion method. Cox proportional hazards model was used to determine predictors of CRBSI. Results: The mean age was 50 (standard deviation 14.9) years and the median duration of follow-up was 69 (interquartile range 23-124) days. At least one CRBSI was recorded for 41% of patients, at a rate of 5.2 infections per 1000 patient-days. Causative organisms were predominantly Gram-negative bacteria (60.3%), and 36.5% of all isolates were multi-drug resistant. Anaemia [hazard ratio (HR) 5.44, P=0.019, 95% confidence interval (CI) 1.32-22.48] and previous bloodstream infection [HR 2.47, P=0.028, 95% CI 1.10-5.54] were predictors of CRBSI. Conclusion: The high incidence of CRBSI in patients on chronic HD with predominance of Gram-negative bacteria means that catheter care bundles should include Gram-negative coverage.

Pharmacokinetics of levonorgestrel and etonogestrel contraceptive implants over 48†weeks with rilpivirine- or darunavir-based antiretroviral therapy.

BACKGROUND: Pharmacokinetic data are lacking for progestin-releasing subdermal contraceptive implants when used with either rilpivirine- or darunavir/ritonavir-based ART. OBJECTIVES: To characterize the pharmacokinetics of etonogestrel or levonorgestrel implants when administered with these ART regimens over 48 weeks. PATIENTS AND METHODS: Two separate, parallel, three-group, non-randomized, pharmacokinetic studies evaluated either etonogestrel or levonorgestrel in women receiving rilpivirine- or darunavir-based ART compared with women without HIV (control group). Participants on ART were switched to rilpivirine-based ART with a run-in period of 6 weeks or darunavir-based ART with a run-in of 2 weeks prior to implant insertion. Plasma was collected on Day 0, and 1, 4, 12, 24, 36 and 48 weeks post-insertion. Plasma progestin concentrations were compared between ART and control groups by geometric mean ratio (GMR) and 90% CI. RESULTS: At the primary endpoint of Week 24, progestin concentrations were similar between the rilpivirine and control groups [etonogestrel: 1.18 (0.99-1.37); levonorgestrel: 1.16 (0.97-1.33)]. At Week 24, progestin exposure was higher in the darunavir groups compared with the control group [etonogestrel: 2.56 (1.69-3.28); levonorgestrel: 1.89 (1.38-2.29)]. Results remained consistent through to Week 48. No differences in etonogestrel-related adverse events were observed, but both ART groups experienced more menstrual abnormalities versus the control group with levonorgestrel. CONCLUSIONS: Etonogestrel and levonorgestrel concentrations were not altered by rilpivirine-based ART. Although progestin concentrations were higher in the ART groups containing ritonavir-boosted darunavir, no implant-related serious adverse events were observed. Both progestin-releasing implants are an appropriate contraceptive option with either rilpivirine- or darunavir/ritonavir-based ART.

HIV, tuberculosis, diabetes mellitus and hypertension admissions and premature mortality among adults in Uganda from 2011 to 2019: is the tide turning?

BACKGROUND: The growing burden of diabetes mellitus (DM) and hypertension (HTN) on the background of endemic Human Immuno-deficiency Virus (HIV) and tuberculosis (TB) is a concern in low- and middle-income countries. We aimed to describe annual trends in admissions, mortality rates and premature mortality (years of potential life lost-YPLLs) due to HIV, tuberculosis (TB), diabetes mellitus (DM) and hypertension (HTN) in Uganda. METHODS: We conducted a retrospective cohort study, retrieving electronic records of adults admitted to Mulago and Kiruddu national referral hospitals medical wards between 1st January 2011 and 31st December 2019. We used STATA BE 17.0 and GraphPad Prism 8.0.2 to compute total admissions, inpatient crude mortality rates, and YPLLs; and demonstrate trends using Mann-Kendall test. RESULTS: Of 108,357 admissions, 55,620 (51.3%) were female, 15,300 (14.1%) were recorded in 2012, and 22,997 (21.2%) were aged 21-30 years. HIV, TB, DM and HTN accounted for 26,021 (24.0%); 9537 (8.8%); 13,708 (12.7) and 13,252 (12.2%) of all admissions, respectively. Overall inpatient mortality was 16.7% (18,099/108,357), 53.5% (9674/18,099) were male, 21.5% (3898) were aged 31-40 years and 2597 (14.4%) were registered in 2013. HIV, TB, DM and HTN accounted for 35.6% (6444), 14.6% (2646), 9.1% (1648) and 11.8% (2142) of all deaths, respectively. Total admissions (Kendall's tau-B = - 0.833, p < 0.001) and deaths declined (Kendall's tau-B = - 0.611, p = 0.029). A total of 355,514 (mean = 20.8 years, SD 30.0) YPLLs were recorded, of which 54.6% (191,869) were in males; 36.2% (128,755) were among those aged 21-30 years and were recorded in 2012 (54,717; 15.4%). HIV, TB, DM and HTN accounted for 46.5% (165,352); 19.5% (69,347); 4.8% (16,991) and 4.5% (16,167) of YPLLs, respectively. Proportionate contribution of HIV to deaths and YPLLs declined, remained stagnant for TB; and increased for both DM and HTN. CONCLUSION: TB and HIV account for higher though declining, while DM and HTN account for lower albeit rising morbidity and premature mortality among adult medical patients in Uganda. TB prevention and treatment; and DM/HTN service integration in HIV care should be optimized and scaled up.

Safety and efficacy of hydroxychloroquine for treatment of non-severe COVID-19 among adults in Uganda: a randomized open label phase II clinical trial.

BACKGROUND: Several repurposed drugs such as hydroxychloroquine (HCQ) have been investigated for treatment of COVID-19, but none was confirmed to be efficacious. While in vitro studies have demonstrated antiviral properties of HCQ, data from clinical trials were conflicting regarding its benefit for COVID-19 treatment. Drugs that limit viral replication may be beneficial in the earlier course of the disease thus slowing progression to severe and critical illness. DESIGN: We conducted a randomized open label Phase II clinical trial from October-December 2020. METHODS: Patients diagnosed with COVID-19 using RT-PCR were included in the study if they were 18 years and above and had a diagnosis of COVID-19 made in the last 3 days. Patients were randomized in blocks, to receive either HCQ 400 mg twice a day for the first day followed by 200 mg twice daily for the next 4 days plus standard of care (SOC) treatment or SOC treatment alone. SARS COV-2 viral load (CT values) from RT-PCR testing of samples collected using nasal/orapharyngeal swabs was performed at baseline, day 2, 4, 6, 8 and 10. The primary outcome was median time from randomization to SARS COV-2 viral clearance by day 6. RESULTS: Of the 105 participants enrolled, 55 were assigned to the intervention group (HCQ plus SOC) and 50 to the control group (SOC only). Baseline characteristics were similar across treatment arms. Viral clearance did not differ by treatment arm, 20 and 19 participants respectively had SARS COV-2 viral load clearance by day 6 with no significant difference, median (IQR) number of days to viral load clearance between the two groups was 4(3-4) vs 4(2-4): p = 0.457. There were no significant differences in secondary outcomes (symptom resolution and adverse events) between the intervention group and the control group. There were no significant differences in specific adverse events such as elevated alkaline phosphatase, prolonged QTc interval on ECG, among patients in the intervention group as compared to the control group. CONCLUSION: Our results show that HCQ 400 mg twice a day for the first day followed by 200 mg twice daily for the next 4 days was safe but not associated with reduction in viral clearance or symptom resolution among adults with COVID-19 in Uganda. TRIAL REGISTRATION:  NCT04860284.

High Mortality During the Second Wave of the Coronavirus Disease 2019 (COVID-19) Pandemic in Uganda: Experience From a National Referral COVID-19 Treatment Unit.

BACKGROUND: We evaluated clinical outcomes of patients hospitalized with coronavirus disease 2019 (COVID-19) in the second wave of the pandemic in a national COVID-19 treatment unit (CTU) in Uganda. METHODS: We conducted a retrospective cohort study of COVID-19 patients hospitalized at the Mulago National Referral Hospital CTU between May 1 and July 11, 2021. We performed Kaplan-Meier analysis to evaluate all-cause in-hospital mortality. RESULTS: Of the 477 participants, 247 (52%) were female, 15 (3%) had received at least 1 dose of the COVID-19 vaccine, and 223 (46%) had at least 1 comorbidity. The median age was 52 (interquartile range, 41-65) years. More than 80% of the patients presented with severe (19%, n=91) or critical (66%, n=315) COVID-19 illness. Overall, 174 (37%) patients died. Predictors of all-cause in-hospital mortality were as follows; age ≥50 years (adjusted odds ratio [aOR], 1.9; 95% confidence interval [CI], 1.2-3.2; P=.011), oxygen saturation at admission of ≥92% (aOR, 0.97; 95% CI, 0.91-0.95; P<.001), and admission pulse rate of ≥100 beats per minute (aOR, 1.01; 95% CI, 1.00-1.02; P=.042). The risk of death was 1.4-fold higher in female participants compared with their male counterparts (hazards ratio, 1.4; 95% CI, 1.0-2.0; P=.025). CONCLUSIONS: In this cohort, where the majority of the patients presented with severe or critical illness, more than one third of the patients hospitalized with COVID-19 at a national CTU died of the illness.

An open-label, randomized, single intravenous dosing study to investigate the effect of fixed-dose combinations of tenofovir/lamivudine or atazanavir/ritonavir on the pharmacokinetics of remdesivir in Ugandan healthy volunteers (RemTLAR).

BACKGROUND: Remdesivir is a novel broad-spectrum antiviral therapeutic with activity against several viruses that cause emerging infectious diseases. The purpose of this study is to explore how commonly utilized antiretroviral therapy (tenofovir disoproxil fumarate/lamivudine [TDF/3TC] and atazanavir/ritonavir [ATV/r]) influence plasma and intracellular concentrations of remdesivir. METHODS: This is an open-label, randomized, fixed sequence single intravenous dosing study to assess pharmacokinetic interactions between remdesivir and TDF/3TC (Study A, crossover design) or TDF/3TC plus ATV/r (Study B). Healthy volunteers satisfying study entry criteria will be enrolled in the study and randomized to either Study A; N=16 (Sequence 1 or Sequence 2) or Study B; N=8. Participants will receive standard adult doses of antiretroviral therapy for 7 days and a single 200mg remdesivir infusion administered over 60 min. Pharmacokinetic blood sampling will be performed relative to the start of remdesivir infusion; predose (before the start of remdesivir infusion) and 30 min after the start of remdesivir infusion. Additional blood samples will be taken at 2, 4, 6, 12, and 24 h after the end of remdesivir infusion. DISCUSSION: This study will characterize the pharmacokinetics of remdesivir from a typical African population in whom clinical use is anticipated. Furthermore, this study will deliver pharmacokinetic datasets for remdesivir drug concentrations and demographic characteristics which could support pharmacometric approaches for simulation of remdesivir treatment regimens in patients concurrently using tenofovir/lamivudine and/or atazanavir/ritonavir. TRIAL REGISTRATION: ClinicalTrials.gov NCT04385719 . Registered 13 May 2020.

Antibiotic Prevalence Study and Factors Influencing Prescription of WHO Watch Category Antibiotic Ceftriaxone in a Tertiary Care Private Not for Profit Hospital in Uganda.

Background: Excessive use of ceftriaxone contributes to the emergence and spread of antimicrobial resistance (AMR). In low and middle-income countries, antibiotics are overused but data on consumption are scarcely available. We aimed to determine the prevalence and factors influencing ceftriaxone prescription in a tertiary care private not-for-profit hospital in Uganda. Methods: A cross-sectional study was carried out from October 2019 through May 2020 at Mengo Hospital in Uganda. Patients admitted to the medical ward and who had been prescribed antibiotics were enrolled. Sociodemographic and clinical data were recorded in a structured questionnaire. Bivariate and adjusted logistic regression analyses were performed to determine factors associated with ceftriaxone prescription. Results: Study participants were mostly female (54.7%). The mean age was 56.2 years (SD: 21.42). The majority (187, 73.3%) presented with fever. Out of the 255 participants included in this study, 129 (50.6%) participants were prescribed ceftriaxone. Sixty-five (25.5%) and forty-one (16.0%) participants had a prescription of levofloxacin and metronidazole, respectively. Seven participants (2.7%) had a prescription of meropenem. Out of 129 ceftriaxone prescriptions, 31 (24.0%) were in combination with other antibiotics. Overall, broad-spectrum antibiotic prescriptions accounted for 216 (84.7%) of all prescriptions. Ceftriaxone was commonly prescribed for pneumonia (40/129, 31%) and sepsis (38/129, 29.5%). Dysuria [OR = 0.233, 95% CI (0.07-0.77), p = 0.017] and prophylactic indication [OR = 7.171, 95% CI (1.36-37.83), p = 0.020] were significantly associated with ceftriaxone prescription. Conclusions: Overall, we observed a high prevalence of prescriptions of ceftriaxone at the medical ward of Mengo Hospital. We recommend an antibiotic stewardship program (ASP) to monitor antibiotic prescription and sensitivity patterns in a bid to curb AMR.

A situation analysis of competences of research ethics committee members regarding review of research protocols with complex and emerging study designs in Uganda.

BACKGROUND: Over the past two decades, Uganda has experienced a significant increase in clinical research driven by both academia and industry. This has been combined with a broader spectrum of research proposals, with respect to methodologies and types of intervention that need evaluation by Research Ethics Committees (RECs) with associated increased requirement for expertise. We assessed the competencies of REC members regarding review of research protocols with complex and emerging research study designs. The aim was to guide development of a training curriculum to improve the quality of scientific and ethical review. METHODS: This was a cross-sectional study design, with quantitative data collection methods. Research Ethics Committee members completed a structured pre-coded questionnaire on current competence with complex and emerging study design. REC members were asked to outline a list of additional topics for which they needed training. Data from coded questions were entered into Epidata Version 3.1 and then exported to STATA Version14.1 for analysis. Descriptive analysis was performed and findings are presented using percentages and frequencies. RESULTS: We enrolled 55 REC members from 6 RECs who have a total of 97 members. The majority of whom were males (56.4%, n = 31/55). The level of competence for review of selected study design was lowest for Controlled Human Infection Model (10.9%, n = 6) and reverse pharmacology design (10.9%, n = 6), and highest for cluster randomized study design (52.7%, n = 29) and implementation science research (52.7%, n = 29). CONCLUSION: Competence for review of research protocols with complex and emerging study design was low among participating REC members. We recommend prioritising training of REC members on complex and emerging study designs to enhance quality of research protocol review.

Efficacy of convalescent plasma for treatment of COVID-19 in Uganda.

RATIONALE: Convalescent plasma (CCP) has been studied as a potential therapy for COVID-19, but data on its efficacy in Africa are limited. OBJECTIVE: In this trial we set out to determine the efficacy of CCP for treatment of COVID-19 in Uganda. MEASUREMENTS: Patients with a positive SARS-CoV-2 reverse transcriptase (RT)-PCR test irrespective of disease severity were hospitalised and randomised to receive either COVID-19 CCP plus standard of care (SOC) or SOC alone. The primary outcome was time to viral clearance, defined as having two consecutive RT-PCR-negative tests by day 28. Secondary outcomes included time to symptom resolution, clinical status on the modified WHO Ordinal Clinical Scale (≥1-point increase), progression to severe/critical condition (defined as oxygen saturation <93% or needing oxygen), mortality and safety. MAIN RESULTS: A total of 136 patients were randomised, 69 to CCP+SOC and 67 to SOC only. The median age was 50 years (IQR: 38.5-62.0), 71.3% were male and the median duration of symptom was 7 days (IQR=4-8). Time to viral clearance was not different between the CCP+SOC and SOC arms (median of 6 days (IQR=4-11) vs 4 (IQR=4-6), p=0.196). There were no statistically significant differences in secondary outcomes in CCP+SOC versus SOC: time to symptom resolution (median=7 (IQR=5-7) vs 7 (IQR=5-10) days, p=0.450), disease progression (9 (22.0%) vs 7 (24.0%) patients, p=0.830) and mortality (10 (14.5%) vs 8 (11.9%) deaths, p=0.476). CONCLUSION: In this African trial, CCP therapy did not result in beneficial virological or clinical improvements. Further trials are needed to determine subgroups of patients who may benefit from CCP in Africa.Trial registration number NCT04542941.