How feasible or useful are timeliness metrics as a tool to optimise One Health outbreak responses?

INTRODUCTION: As timeliness metrics gain traction to assess and optimise outbreak detection and response performance, implementation and scale-up require insight into the perspectives of stakeholders adopting these tools. This study sought to characterise the feasibility and utility of tracking One Health outbreak milestones across relevant human, animal, plant, and environmental sectors to systematically quantify timeliness metrics in Uganda, a country prone to outbreaks of WHO priority diseases. METHODS: A database of outbreak events occurring in Uganda between 2018 and 2022 was compiled. Outbreak reports meeting our inclusion criteria were reviewed to quantify the frequency of milestone reporting. Key informant interviews were conducted with expert stakeholders to explore the feasibility and utility of tracking metrics using a framework analysis. Quantitative and qualitative data were collected and analysed concurrently. RESULTS: Of the 282 public health emergencies occurring between 2018 and 2022, 129 events met our inclusion criteria, and complete data were available for 82 outbreaks. For our qualitative portion, 10 informants were interviewed from 7 institutions, representing the human, animal and environmental sectors. Informants agreed most One Health milestones are feasible to track, which was supported by the frequency of milestone reporting; however, there was a demonstrated need for increased reporting of after-action reviews, as well as outbreak start and end dates. Predictive alerts signalling potential outbreaks and preventive responses to alerts are seen as challenging to routinely capture, reflecting the lack of public health action for these domains. CONCLUSION: Despite consensus among stakeholders that timeliness metrics are a beneficial tool to assess outbreak performance, not all One Health metrics are being tracked consistently, thereby missing opportunities to optimise epidemic intelligence, preparedness and prevention. The feasibility of tracking these metrics depends on the integration of reporting channels, enhanced documentation of milestones and development of guidance for early adopters, recognising country-specific on-the-ground realities and challenges to national scaling efforts.

Clinical, pharmacological, and qualitative characterization of drug-drug interactions in pregnant women initiating HIV therapy in Sub-Saharan Africa.

BACKGROUND: We investigated the impact of Drug-Drug Interactions (DDIs) on virologic control among HIV-positive pregnant women initiating antiretroviral therapy while identifying drivers for Traditional Medicine (TM) use and exploring the nature and extent of TM-related DDIs. METHODS: Employing a three-pronged approach, we examined DDIs arising from comedication, including TM, in ART. The DolPHIN-2 trial (NCT03249181) randomized 268 HIV-positive pregnant women in Uganda and South Africa to dolutegravir (DTG)-based (135) or efavirenz-based (133) regimens while systematically recording comedications and screening for DDIs. We used Cox regression models to compare time-to-virologic control between participants with and without DDIs. We conducted in-depth interviews and focus group discussions among 37 and 67 women with and without HIV, respectively, to explore reasons for TM use during pregnancy. Additionally, in-vitro and in-vivo studies evaluated the composition and impact of clay-based TM, mumbwa, on DTG plasma exposure. RESULTS: The baseline prevalence of DDIs was 67.2%, with TM use prevalent in 34% of participants, with mumbwa being the most frequent (76%, 69/91). There was no difference in virologic response between participants with and without DDIs. Fetal health and cultural norms were among the reasons cited for TM use. Analysis of mumbwa rods confirmed significant amounts of aluminium (8.4%-13.9%) and iron (4%-6%). In Balb-C mice, coadministration of mumbwa led to a reduction in DTG exposure observed in the AUC0-24 (-21%; P = 0.0271) and C24 (-53%; P = 0.0028). CONCLUSIONS: The widespread use of clay-based TM may compromise HIV treatment, necessitating medication screening and counselling to manage DDIs in pregnant women.

Cost-Effectiveness of Dolutegravir Compared With Efavirenz for Prevention of Perinatal Transmission in Women Presenting With HIV in Late Pregnancy in Uganda.

OBJECTIVES: Dolutegravir (DTG) has proved to be more efficacious, tolerable, and safer than efavirenz (EFV) among mothers living with HIV and their infants in Uganda. This study assessed the cost-effectiveness of the DTG-based antiretroviral therapy (ART) compared with the standard of care for preventing perinatal transmissions among pregnant women initiating ART in late pregnancy in Uganda. METHODS: We used data from a randomized open-label trial (DolPHIN-2) and a 2-part cost-effectiveness model composed of a short-term decision tree to estimate the perinatal transmission rate and costs and an individual-based 3-state Markov model (HIV, advanced HIV, dead) to estimate the long-term costs and health outcomes from the Ugandan payer perspective using a lifetime horizon and a 1-year Markov cycle. The main outcomes were the mean annual costs in US dollars ($), disability-adjusted life-years (DALYs), and incremental cost-effectiveness ratio. Both the deterministic and probabilistic sensitivity analyses were conducted to assess the effect of parameter uncertainties on the ultimate results and the model's robustness. RESULTS: Compared with the EFV-based ART, the DTG-based ART was associated with fewer mean annual costs ($43.58 vs $68.44) and DALYs (0.33 vs 0.56), leading to cost savings of $110 per DALY averted. In the incremental analysis, the DTG-based ART dominated the EFV-based ART; that is, it was less costly and more effective. These results were robust to deterministic and probabilistic sensitivity analyses. CONCLUSION: The DTG-based ART is a highly cost-effective strategy compared with the EFV-based ART among women initiating treatment in the third trimester of pregnancy in a low-income setting.

Strategies to Enhance COVID-19 Vaccine Uptake among Prioritized Groups, Uganda-Lessons Learned and Recommendations for Future Pandemics.

COVID-19 vaccination was launched in March 2021 in Uganda and initially prioritized persons >50 years of age, persons with underlying conditions, healthcare workers, teachers, and security forces. However, uptake remained low 5 months after the program launch. Makerere University's Infectious Diseases Institute supported Uganda's Ministry of Health in optimizing COVID-19 vaccination uptake models by using point-of-care, place of worship, and place of work engagement and the Social Assistance Grant for Empowerment model in 47 of 135 districts in Uganda, where we trained influencers to support mobilization for vaccination outreach under each model. During July-December, vaccination rates increased significantly in targeted regions, from 92% to 130% for healthcare workers, 40% to 90% for teachers, 25% to 33% for security personnel, 6% to 15% for persons >50 years of age, and 6% to 11% for persons with underlying conditions. Our approach could be adopted in other targeted vaccination campaigns for future pandemics.

Evidence of Orientia spp. Endemicity among Severe Infectious Disease Cohorts, Uganda.

At 3 severe infection cohort sites in Uganda, Orientia seropositivity was common. We identified 4 seroconversion cases and 1 PCR-positive case. These results provide serologic and molecular support for Orientia spp. circulating in sub-Saharan Africa, possibly expanding its endemic range. Orientia infections could cause severe illness and hospitalizations in this region.

Characterization of Antibiotic Resistance in Select Tertiary Hospitals in Uganda: An Evaluation of 2020 to 2023 Routine Surveillance Data.

Antimicrobial resistance (AMR) is a public health concern in Uganda. We sought to conduct an extended profiling of AMR burden at selected Ugandan tertiary hospitals. We analyzed routine surveillance data collected between October 2020 and March 2023 from 10 tertiary hospitals. The analysis was stratified according to the hospital unit, age, gender, specimen type, and time. Up to 2754 isolates were recovered, primarily from pus: 1443 (52.4%); urine: 1035 (37.6%); and blood: 245 (8.9%). Most pathogens were Staphylococcus aureus, 1020 (37%), Escherichia coli, 808 (29.3%), and Klebsiella spp., 200 (7.3%). Only 28% of Escherichia coli and 42% of the other Enterobacterales were susceptible to ceftriaxone, while only 44% of Staphylococcus aureus were susceptible to methicillin (56% were MRSA). Enterococcus spp. susceptibility to vancomycin was 72%. The 5-24-year-old had 8% lower ampicillin susceptibility than the >65-year-old, while the 25-44-year-old had 8% lower ciprofloxacin susceptibility than the >65-year-old. The 0-4-year-old had 8% higher ciprofloxacin susceptibility. Only erythromycin susceptibility varied by sex, being higher in males. Escherichia coli ciprofloxacin susceptibility in blood (57%) was higher than in urine (39%) or pus (28%), as was ceftriaxone susceptibility in blood (44%) versus urine (34%) or pus (14%). Klebsiella spp. susceptibility to ciprofloxacin and meropenem decreased by 55% and 47%, respectively, during the evaluation period. During the same period, Escherichia coli ciprofloxacin susceptibility decreased by 40%, while Staphylococcus aureus gentamicin susceptibility decreased by 37%. Resistance was high across the Access and Watch antibiotic categories, varying with time, age, sex, specimen type, and hospital unit. Effective antimicrobial stewardship targeted at the critical AMR drivers is urgently needed.

Support, not blame: safe partner disclosure among women diagnosed with HIV late in pregnancy in South Africa and Uganda.

BACKGROUND: HIV partner disclosure rates remain low among pregnant women living with HIV in many African countries despite potential benefits for women and their families. Partner disclosure can trigger negative responses like blame, violence, and separation. Women diagnosed with HIV late in pregnancy have limited time to prepare for partner disclosure. We sought to understand challenges around partner disclosure and non-disclosure faced by women diagnosed with HIV late in pregnancy in South Africa and Uganda and to explore pathways to safe partner disclosure. METHODS: We conducted in-depth interviews and focus group discussions with pregnant women and lactating mothers living with HIV (n = 109), disaggregated by antenatal care (ANC) initiation before and after 20 weeks of gestation, male partners (n = 87), and health workers (n = 53). All participants were recruited from DolPHIN2 trial sites in Kampala (Uganda) and Gugulethu (South Africa). Topic guides explored barriers to partner disclosure, effects of non-disclosure, strategies for safe disclosure. Using the framework analysis approach, we coded and summarised data based on a socio-ecological model, topic guides, and emerging issues from the data. Data was analysed in NVivo software. RESULTS: Our findings illustrate pregnant women who initiate ANC late experience many difficulties which are compounded by the late HIV diagnosis. Various individual, interpersonal, community, and health system factors complicate partner disclosure among these women. They postpone or decide against partner disclosure mainly for own and baby's safety. Women experience stress and poor mental health because of non-disclosure while demonstrating agency and resilience. We found many similarities and some differences around preferred approaches to safe partner disclosure among female and male participants across countries. Women and male partners preferred healthcare workers to assist with disclosure by identifying the 'right' time to disclose, mentoring women to enhance their confidence and communication skills, and providing professional mediation for partner disclosure and couple testing. Increasing the number of counsellors and training them on safe partner disclosure was deemed necessary for strengthening local health services to improve safe partner disclosure. CONCLUSION: HIV diagnosis late in pregnancy amplifies existing difficulties among pregnant women. Late ANC initiation is an indicator for the likelihood that a pregnant woman is highly vulnerable and needs safeguarding. Respective health programmes should be prepared to offer women initiating ANC late in pregnancy additional support and referral to complementary programmes to achieve safe partner disclosure and good health.

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.

Comparison of dolutegravir and efavirenz on depression, anxiety and sleep disorders in pregnant and postpartum women living with HIV.

BACKGROUND: Both dolutegravir and efavirenz are known to be effective in pregnancy and postpartum to prevent vertical transmission of HIV and to maintain maternal health. Both drugs have also been associated with neuropsychiatric symptoms. To what extent, these symptoms occur in pregnant and postpartum women, however, is not yet known. METHODS: This was a secondary analysis of the DolPHIN2 study, a multicentre randomized trial among women presenting late in pregnancy with untreated HIV - who received either a dolutegravir-containing or efavirenz-containing regimen. Longitudinal measures of depression, anxiety and sleep quality were analysed during pregnancy and up to 48 weeks postpartum. RESULTS: Among 268 women, median (IQR) Edinburgh Post Natal Depression Score (EPDS) scores were 8 (3-11) and highest at enrolment. In the dolutegravir and efavirenz arm, respectively, 23.7 and 25.6% had an EPDS score above 9, indicating possible or probable depression. Abnormal Hospital Anxiety Depression scores (HADS) (above 11) were seen at least once during follow-up in 42 of patients (15.7%), although no differences were seen between treatment arms. No association was found between EPDS, suicidality and HADS scores and the assigned regimen ( P  = 0.93, 0.97 and 0.18 respectively). Median (IQR) Pittsburgh Sleep Quality index (PSQI) scores for dolutegravir and efavirenz were 6 (5-7) and 5 (5-6.5), respectively, P  = 0.70. CONCLUSION: No statistically significant differences were observed between efavirenz-containing or dolutegravir-containing regimens. Rates of depression were high, but decreased over the course of time and confirm the need for psychological support after initial HIV diagnosis in pregnancy.

Public perceptions of Ebola vaccines and confidence in health services to treat Ebola, malaria, and tuberculosis: Findings from a cross-sectional household survey in Uganda, 2020.

Uganda used Ebola vaccines as part of its preparedness and response during the 2018-2020 10th Ebola virus disease (EVD) outbreak in neighboring Democratic Republic of the Congo (DRC). We evaluated the public's perceptions of Ebola vaccines and compared their confidence in health services to treat Ebola versus malaria and tuberculosis as part of a survey on Ebola knowledge, attitudes, and practices (KAP) conducted in March 2020. A cross-sectional household survey was implemented in six districts in Uganda using multi-stage cluster sampling to randomly select participants. The districts were purposively selected from districts classified by the government as at high- or low-risk for an EVD outbreak. We describe perceptions of Ebola vaccines and confidence in health services to treat Ebola, tuberculosis, and malaria. Modified Poisson regression modeling was used to identify the demographic correlates of these outcomes. Among 3,485 respondents, 18% were aware of Ebola vaccines. Of those, 92% agreed that the vaccines were needed to prevent Ebola. Participants aged 15-24 years were 4% more likely to perceive such need compared to those 60 years and older (adjusted prevalence ratio [aPR] 1.04, 95% confidence interval [CI] 1.0-1.08). The perceived need was 5% lower among participants with at least some secondary education compared to uneducated participants (aPR 0.95; 0.92-0.99). Overall, 81% of those aware of the vaccines believed that everyone or most people in their community would get vaccinated if offered, and 94% said they would likely get vaccinated if offered. Confidence in health services to treat Ebola was lower compared to treating malaria or tuberculosis (55% versus 93% and 77%, respectively). However, participants from the EVD high-risk districts were 22% more likely to be confident in health services to treat Ebola compared to those in low-risk districts (aPR: 1.22; 95% CI: 1.08, 1.38). Our findings suggest that intent to take an Ebola vaccine during an outbreak was strong, but more work needs to be done to increase public awareness of these vaccines. The public's high confidence in health services to treat other health threats, such as malaria and tuberculosis, offer building blocks for strengthening their confidence in health services to treat EVD in the event of an outbreak.

Pharmacokinetics and safety of twice-daily ritonavir-boosted atazanavir with rifampicin.

BACKGROUND: Critical drug-drug interactions (DDI) and hepatotoxicity complicate concurrent use of rifampicin and protease inhibitors. We investigated whether dose escalation of atazanavir/ritonavir could safely overcome the DDI with rifampicin. METHODS: DERIVE (NCT04121195, EDCTP) was a dose-escalation trial in people with HIV on atazanavir/ritonavir-based ART in Uganda. Four intensive pharmacokinetic (PK) visits were performed: PK1 300/100 mg OD (baseline); PK2 300/100 mg OD with rifampicin 600 mg; PK3 300/100 mg BID with rifampicin 600 mg OD; PK4 300/100 mg BID with rifampicin 1200 mg OD. Dolutegravir 50 mg BID throughout the study period ensured participants remained protected from subtherapeutic atazanavir concentrations. The data was interpreted with noncompartmental analysis. The target minimum concentration was atazanavir's protein-adjusted IC90 (PA-IC90), 0.014 mg/L. RESULTS: We enrolled 26 participants (23 female) with median (range) age 44 (28-61) years and weight 67 (50-75) kg. Compared with PK1, atazanavir Ctau, and AUC were significantly reduced at PK2 by 96% and 85%, respectively. The escalation to BID dosing (PK3) reduced this difference in Ctau, and AUC24 to 18% lower and 8% higher, respectively. Comparable exposures were maintained with double doses of rifampicin. Lowest Ctau during PK1, PK3, and PK4 were 12.7-, 4.8-, and 8.6-fold higher than PA-IC90, respectively, while 65% of PK2 Ctau were below the limit of quantification (0.03 mg/L), hence likely below PA-IC90. No participant developed significant elevation of liver enzymes, reported an SAE, or experienced rebound viraemia. CONCLUSIONS: Twice daily atazanavir/ritonavir during rifampicin co-administration was well-tolerated and achieved plasma concentrations above the target.

Unexpectedly low drug exposures among Ugandan patients with TB and HIV receiving high-dose rifampicin.

We characterized the pharmacokinetics of standard- and high-dose rifampicin in Ugandan adults with tuberculosis and HIV taking dolutegravir- or efavirenz-based antiretroviral therapy. A liver model with saturable hepatic extraction adequately described the data, and the increase in exposure between high and standard doses was 4.7-fold. This was lower than what previous reports of dose-exposure nonlinearity would predict and was ascribed to 38% lower bioavailability of the rifampicin-only top-up formulation compared to the fixed-dose combination.

Dolutegravir pharmacokinetics in Ugandan patients with TB and HIV receiving standard- versus high-dose rifampicin.

Higher rifampicin doses may improve tuberculosis treatment outcomes. This could however exacerbate the existing drug interaction with dolutegravir. Moreover, the metabolism of dolutegravir may also be affected by polymorphism of UGT1A1, a gene that codes for uridine diphosphate glucuronosyltransferase. We used population pharmacokinetic modeling to compare the pharmacokinetics of dolutegravir when coadministered with standard- versus high-dose rifampicin in adults with tuberculosis and HIV, and investigated the effect of genetic polymorphisms. Data from the SAEFRIF trial, where participants were randomized to receive first-line tuberculosis treatment with either standard- 10 mg/kg or high-dose 35 mg/kg rifampicin alongside antiretroviral therapy, were used. The dolutegravir model was developed with 211 plasma concentrations from 44 participants. The median (interquartile range) rifampicin area under the curve (AUC) in the standard- and high-dose arms were 32.3 (28.7-36.7) and 153 (138-175) mg·h/L, respectively. A one-compartment model with first-order elimination and absorption through transit compartments best described dolutegravir pharmacokinetics. For a typical 56 kg participant, we estimated a clearance, absorption rate constant, and volume of distribution of 1.87 L/h, 1.42 h-1, and 12.4 L, respectively. Each 10 mg·h/L increase in the AUC of coadministered rifampicin from 32.3 mg·h/L led to a 2.3 (3.1-1.4) % decrease in dolutegravir bioavailability. Genetic polymorphism of UGT1A1 did not significantly affect dolutegravir pharmacokinetics. Simulations of trough dolutegravir concentrations show that the 50 mg twice-daily regimen attains both the primary and secondary therapeutic targets of 0.064 and 0.3 mg/L, respectively, regardless of the dose of coadministered rifampicin, unlike the once-daily regimen.

Access to and Use of Hand Hygiene Resources during the COVID-19 Pandemic in Two Districts in Uganda, January-April 2021.

To understand access to and use of hand hygiene in healthcare facilities (HCFs) and community locations during the COVID-19 pandemic, we evaluated factors associated with hand hygiene in 60 priority HCFs and community locations in two border districts in Uganda. We assessed water and hand hygiene resource availability and observed hand hygiene practice by staff or patrons. Regression modeling estimated factors associated with the availability or use of hand hygiene. In HCFs, most inpatient (61%), outpatient (71%), and laboratory or staff (90%) rooms contained hand hygiene materials. Only 38% of community locations had hand hygiene materials at all entrances and exits, 35% of congregation areas had hand hygiene materials. Overall, 38% of healthcare staff, 48% of patrons post-latrine use, and 21% of patrons entering or exiting community locations practiced hand hygiene. HCF hand hygiene access was lower in inpatient rooms (odds ratio [OR] = 0.17, 95% CI: 0.06-0.45) and outpatient rooms (OR = 0.23, 95% CI: 0.07-0.70) compared with laboratory/staff rooms. HCF hand hygiene practice was higher for doctors than nurses (OR = 3.58, 95% CI: 1.15-11.14) and with new versus existing patient encounters (OR = 2.27, 95% CI: 1.20-4.27); it was lower before versus after patient contact for both invasive (OR = 0.03, 95% CI: 0.00-0.20) and noninvasive (OR = 0.66, 95% CI: 0.45-0.95) procedures. In community settings, hand hygiene practice after using the latrine was higher than at an entrances/exits (OR = 3.39, 95% CI: 2.08-5.52). Hand hygiene rates were relatively low in healthcare and community settings. Greater emphasis on hand hygiene before patient interactions (at HCFs) and at community entrances/exits for patrons is also needed.

Contribution of the one health approach to strengthening health security in Uganda: a case study.

BACKGROUND: The One Health approach is key in implementing International Health Regulations (IHR, 2005) and the Global Health Security Agenda (GHSA). Uganda is signatory to the IHR 2005 and in 2017, the country conducted a Joint External Evaluation (JEE) that guided development of the National Action Plan for Health Security (NAPHS) 2019-2023. AIM: This study assessed the contribution of the One Health approach to strengthening health security in Uganda. METHODS: A process evaluation between 25th September and 5th October 2020, using a mixed-methods case study. Participants were Subject Matter Experts (SMEs) from government ministries, departments, agencies and implementing partners. Focus group discussions were conducted for five technical areas (workforce development, real-time surveillance, zoonotic diseases, national laboratory systems and emergency response operations), spanning 18 indicators and 96 activities. Funding and implementation status from the NAPHS launch in August 2019 to October 2020 was assessed with a One Health lens. RESULTS: Full funding was available for 36.5% of activities while 40.6% were partially funded and 22.9% were not funded at all. Majority (65%) of the activities were still in progress, whereas 8.6% were fully implemented and14.2% were not yet done. In workforce development, several multisectoral trainings were conducted including the frontline public health fellowship program, the One Health fellowship and residency program, advanced field epidemiology training program, in-service veterinary trainings and 21 district One Health teams' trainings. Real Time Surveillance was achieved through incorporating animal health events reporting in the electronic integrated disease surveillance and response platform. The national and ten regional veterinary laboratories were assessed for capacity to conduct zoonotic disease diagnostics, two of which were integrated into the national specimen referral and transportation network. Multisectoral planning for emergency response and the actual response to prioritized zoonotic disease outbreaks was done jointly. CONCLUSIONS: This study demonstrates the contribution of 'One Health' implementation in strengthening Uganda's health security. Investment in the funding gaps will reinforce Uganda's health security to achieve the IHR 2005. Future studies could examine the impacts and cost-effectiveness of One Health in curbing prioritized zoonotic disease outbreaks.

A "Bundle of Care" to Improve Anticoagulation Control in Patients Receiving Warfarin in Uganda and South Africa: Protocol for an Implementation Study.

BACKGROUND: The quality of warfarin anticoagulation among Sub-Saharan African patients is suboptimal. This is due to several factors, including a lack of standardized dosing algorithms, difficulty in providing timely international normalized ratio (INR) results, a lack of patient feedback on their experiences with treatment, a lack of education on adherence, and inadequate knowledge and training of health care workers. Low quality of warfarin anticoagulation, expressed as time in therapeutic range (TTR), is associated with higher adverse event rates, including bleeding and thrombosis, and ultimately, increased morbidity and mortality. Processes and interventions that improve this situation are urgently needed. OBJECTIVE: This study aims to evaluate the implementation of the "warfarin bundle," a package of interventions to improve the quality of anticoagulation and thereby clinical outcomes. The primary outcome for this study is TTR over the initial 3 months of warfarin therapy. METHODS: Patients aged 18 years or older who are newly initiated on warfarin for venous thromboembolism, atrial fibrillation, or valvular heart disease will be enrolled and followed up for 3 months at clinics in Cape Town, South Africa, and Kampala, Uganda, where the warfarin bundle is implemented. A retrospective review of the clinical records of patients on warfarin treatment before implementation (controls) will be used for comparison. This study uses a mixed methods approach of the implementation of patient- and process-centered activities to improve the quality of anticoagulation. Patient-centered activities include the use of clinical dosing algorithms, adherence support, and root cause analysis, whereas process-centered activities include point-of-care INR testing, staff training, and patient education and training. We will assess the impact of these interventions by comparing the TTR and safety outcomes across the 2 groups, as well as the cost-effectiveness and acceptability of the package. RESULTS: We started recruitment in June 2021 and stopped in August 2022, having recruited 167 participants. We obtained ethics approval from the University of Cape Town Faculty of Health Sciences Human Research Ethics Committee, the Provincial Health Research Committees in South Africa, the Joint Clinical Research Centre Institutional Review Board, Kampala, and the University of Liverpool Research Ethics Committee. As of February 2023, data cleaning and formal analysis are underway. We expect to publish the full results by December 2023. CONCLUSIONS: We anticipate that the "bundle of care," which includes a clinical algorithm to guide individualized dosing of warfarin, will improve INR control and TTR of patients in Uganda and South Africa. We will use these findings to design a larger, multisite clinical trial across several Sub-Saharan African countries. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/46710.

Genomic surveillance and antimicrobial resistance determinants in Neisseria gonorrhoeae isolates from Uganda, Malawi and South Africa, 2015-20.

OBJECTIVES: Global antimicrobial resistance (AMR) surveillance in Neisseria gonorrhoeae is essential. In 2017-18, only five (10.6%) countries in the WHO African Region reported to the WHO Global Gonococcal Antimicrobial Surveillance Programme (WHO GASP). Genomics enhances our understanding of gonococcal populations nationally and internationally, including AMR strain transmission; however, genomic studies from Africa are extremely scarce. We describe the gonococcal genomic lineages/sublineages, including AMR determinants, and baseline genomic diversity among strains in Uganda, Malawi and South Africa, 2015-20, and compare with sequences from Kenya and Burkina Faso. METHODS: Gonococcal isolates cultured in Uganda (n = 433), Malawi (n = 154) and South Africa (n = 99) in 2015-20 were genome-sequenced. MICs were determined using ETEST. Sequences of isolates from Kenya (n = 159), Burkina Faso (n = 52) and the 2016 WHO reference strains (n = 14) were included in the analysis. RESULTS: Resistance to ciprofloxacin was high in all countries (57.1%-100%). All isolates were susceptible to ceftriaxone, cefixime and spectinomycin, and 99.9% were susceptible to azithromycin. AMR determinants for ciprofloxacin, benzylpenicillin and tetracycline were common, but rare for cephalosporins and azithromycin. Most isolates belonged to the more antimicrobial-susceptible lineage B (n = 780) compared with the AMR lineage A (n = 141), and limited geographical phylogenomic signal was observed. CONCLUSIONS: We report the first multi-country gonococcal genomic comparison from Africa, which will support the WHO GASP and WHO enhanced GASP (EGASP). The high prevalence of resistance to ciprofloxacin (and empirical use continues), tetracycline and benzylpenicillin, and the emerging resistance determinants for azithromycin show it is imperative to strengthen the gonococcal AMR surveillance, ideally including genomics, in African countries.

Improving Access to WHO Formulations of Alcohol-Based Hand Rub in Healthcare Facilities: A District-Wide Approach.

Alcohol-based hand rub (ABHR) is an effective hand hygiene measure to mitigate and prevent infectious disease transmission in healthcare facilities (HCFs); however, availability and affordability in low- and middle-income countries are limited. We sought to establish centralized local production of ABHR using a district-wide approach to increase provider access at all public HCFs in Kabarole and Kasese Districts in Western Uganda. Partner organizations worked with district governments to adapt and implement the WHO protocol for local ABHR production at the district scale. These groups identified and upgraded sites for ABHR production and storage to ensure recommended security, ventilation, and air conditioning. District governments selected technicians for training on ABHR production. Raw materials were sourced within Uganda. Alcohol-based hand rub underwent internal quality control by the production officer and external quality control (EQC) by a trained district health inspector before distribution to HCFs. We assessed ABHR production and demand from March 2019 to December 2020. All ABHR batches (N = 316) met protocol standards (alcohol concentration: 75.0-85.0%) with a mean of 79.9% (range: 78.5-80.5%). Internal quality control measurements (mean alcohol concentration: 80.0%, range: 79.5-81.0%) matched EQC measurements (mean: 79.8%, range: 78.0-80.0%). Production units supplied ABHR to 127 HCFs in Kasese District (100%) and 31 HCFs in Kabarole District (56%); 94% of HCFs were small (dispensary or next higher level). This district-wide production met quality standards and supplied ABHR to many HCFs where facility-level production would be unfeasible. Low- and middle-income countries may consider district models to expand ABHR production and supply to smaller HCFs.

Relating CYP2B6 genotype and efavirenz resistance among post-partum women living with HIV with high viremia in Uganda: a nested cross-sectional study.

BACKGROUND: We investigated the association between CYP2B6 polymorphisms and efavirenz drug resistance among women living with HIV who started on antiretroviral therapy during pregnancy and with high viremia during post-partum. METHODS: This was a cross-sectional study of women with viral loads greater than 1000 copies/ml who were at least 6 weeks postpartum. Sanger sequencing was used to detect resistant mutations, as well as host genotyping, and efavirenz resistance was compared among the metabolizer genotypes. RESULTS: Over the course of one year (July 2017-July 2018), 322 women were screened, with 110 (34.2%) having viral loads of 1000 copies/ml and 62 having whole blood available for genotyping. Fifty-nine of these women had both viral resistance and human host genotypic results. Efavirenz resistance according to metabolizer genotype was; 47% in slow, 34% in extensive and 28% in intermediate metabolizers, but the difference was not statistically significant due to the small sample size. CONCLUSIONS: There was no statistically significant difference in EFV resistance between EFV metabolizer genotypes in women who started antiretroviral therapy during pregnancy and had high viremia in the postpartum period. However, a numerical trend was discovered, which calls for confirmation in a large, well-designed, statistically powered study.