Towards access for all: 1st Working Group Report for the Global Gene Therapy Initiative (GGTI).

The gene and cell therapy field saw its first approved treatments in Europe in 2012 and the United States in 2017 and is projected to be at least a $10B USD industry by 2025. Despite this success, a massive gap exists between the companies, clinics, and researchers developing these therapeutic approaches, and their availability to the patients who need them. The unacceptable reality is a geographic exclusion of low-and middle-income countries (LMIC) in gene therapy development and ultimately the provision of gene therapies to patients in LMIC. This is particularly relevant for gene therapies to treat human immunodeficiency virus infection and hemoglobinopathies, global health crises impacting tens of millions of people primarily located in LMIC. Bridging this divide will require research, clinical and regulatory infrastructural development, capacity-building, training, an approval pathway and community adoption for success and sustainable affordability. In 2020, the Global Gene Therapy Initiative was formed to tackle the barriers to LMIC inclusion in gene therapy development. This working group includes diverse stakeholders from all sectors and has set a goal of introducing two gene therapy Phase I clinical trials in two LMIC, Uganda and India, by 2024. Here we report on progress to date for this initiative.

Effect of a solar lighting intervention on fuel-based lighting use and exposure to household air pollution in rural Uganda: A randomized controlled trial.

Solar lighting is an alternative to polluting kerosene and other fuel-based lighting devices relied upon by millions of families in resource-limited settings. Whether solar lighting provides sustained displacement of fuel-based lighting sources and reductions in personal exposure to fine particulate matter (PM2 .5 ) and black carbon (BC) has not been examined in randomized controlled trials. Eighty adult women living in rural Uganda who utilized fuel-based (candles and kerosene lamps) and/or clean (solar, grid, and battery-powered devices) lighting were randomized in a 1:1 ratio to receive a home solar lighting system at no cost to study participants (ClinicalTrials.gov NCT03351504). Among intervention group participants, kerosene lamps were completely displaced in 92% of households using them. The intervention led to an average exposure reduction of 36.1 µg/m3 (95% CI -70.3 to -2.0) in PM2 .5 and 10.8 µg/m3 (95% CI -17.6 to -4.1) in BC, corresponding to a reduction from baseline of 37% and 91%, respectively. Reductions were greatest among participants using kerosene lamps. Displacement of kerosene lamps and personal exposure reductions were sustained over 12 months of follow-up. Solar lighting presents an immediate opportunity for achieving sustained reductions in personal exposure to PM2.5 and BC and should be considered in household air pollution intervention packages.

Smoking cessation after engagement in HIV care in rural Uganda.

People living with HIV (PLWH) are more likely to smoke compared to HIV-uninfected counterparts, but little is known about smoking behaviors in sub-Saharan Africa. To address this gap in knowledge, we characterized smoking cessation patterns among people living with HIV (PLWH) compared to HIV-uninfected individuals in rural Uganda. PLWH were at least 40 years of age and on antiretroviral therapy for at least three years, and HIV-uninfected individuals were recruited from the clinical catchment area. Our primary outcome of interest was smoking cessation, which was assessed using an adapted WHO STEPS smoking questionnaire. We fit Cox proportional hazards models to compare time to smoking cessation between PLWH pre-care, PLWH in care, and HIV-uninfected individuals. We found that, compared to HIV-uninfected individuals, PLWH in care were less likely to have ever smoked (40% vs. 49%, p = 0.04). The combined sample of 267 ever-smokers had a median age of 56 (IQR 49-68), 56% (n = 150) were male, and 26% (n = 70) were current smokers. In time-to-event analyses, HIV-uninfected individuals and PLWH prior to clinic enrollment ceased smoking at similar rates (HR 0.8, 95% CI 0.5-1.2). However, after enrolling in HIV care, PLWH had a hazard of smoking cessation over twice that of HIV-uninfected individuals and three times that of PLWH prior to enrollment (HR 2.4, 95% CI 1.3-4.6, p = 0.005 and HR 3.0, 95% CI 1.6-5.5, p = 0.001, respectively). In summary, we observed high rates of smoking cessation among PLWH after engagement in HIV care in rural Uganda. While we hypothesize that greater access to primary care services and health counseling might contribute, future studies should better investigate the mechanism of this association.

Factors Associated with Chronic Obstructive Pulmonary Disease: A Hospital-Based Case-Control Study.

Purpose: Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. In this paper, we determined risk factors for COPD among patients presenting to pulmonology and medical outpatients' clinics of Mbarara Regional Referral Hospital (MRRH). Methods: In this case-control study, cases were patients with COPD confirmed by spirometry and controls were those with normal spirometry. The two groups were matched by age and gender. Results: We enrolled 123 participants, of whom 41 were cases and 82 controls. A total of 51 women (41.5%) and 72 men (58.5%), of whom 25 were male cases (61%) and 47 were male controls (57%), were included. The results of our study suggest that the variables associated with the presence of COPD among participants attending MRRH were a history of having ever smoked and a prior history of atopy. This brings to our attention the fact that smoking remains a major risk factor for COPD in this setting, just as it is in developed countries. Conclusion: Our study has shown that the factors associated with COPD are smoking and a history of atopy. Patients with a history of asthma and tuberculosis are also probably more likely to develop COPD than those without similar disease conditions.

"If you have light, your heart will be at peace": A qualitative study of household lighting and social integration in southwestern Uganda.

Background: Expanding electrification and access to other clean and affordable energy, such as solar energy, is a critical component of the Sustainable Development Goals, particularly in sub-Saharan Africa where 70% of people are energy insecure. Intervention trials related to access or less polluting household energy alternatives have typically focused on air quality and biological outcomes rather than on how an intervention affects the end user's lived experiences, a key determinant of uptake and adoption outside of a research setting. We explored perceptions of and experiences with a household solar lighting intervention in rural Uganda. Methods: In 2019, we completed a one-year parallel group, randomized wait-list controlled trial of indoor solar lighting systems (ClinicalTrials.gov NCT03351504) in rural Uganda where participants are largely relying on kerosene and other fuel-based lighting received household indoor solar lighting systems. In this qualitative sub-study, we conducted one-on-one, in-depth qualitative interviews with all 80 female participants enrolled in the trial. Interviews explored how solar lighting and illumination impacted participants' lives. We applied a theoretical model linking social integration and health to analyse dynamic interactions across aspects of study participants' lived experiences. Sensors were used to measure daily lighting use before and after receipt of the intervention solar lighting system. Results: Introduction of the solar lighting system increased daily household lighting use by 6.02 (95% confidence intervals (CI) = 4.05-8.00) hours a day. The solar lighting intervention had far-reaching social implications with improved social integration and, consequently, social health. Participants felt that lighting improved their social status, mitigated the stigma of poverty, and increased the duration and frequency of social interactions. Household relationships improved with access to lighting because of reduced conflicts over light rationing. Participants also described a communal benefit of lighting due to improved feelings of safety. At the individual-level, many reported improved self-esteem, sense of well-being, and reduced stress. Conclusion: Improved access to lighting and illumination had far reaching implications for participants, including improved social integration. More empirical research, particularly in the light and household energy field, is needed that emphasizes the impacts of interventions on social health. Registration: ClinicalTrials.gov No. NCT03351504.

Use, cost-effectiveness, and end user perspectives of a home solar lighting intervention in rural Uganda: a mixed methods, randomized controlled trial.

Energy poverty is prevalent in resource-limited settings, leading households to use inefficient fuels and appliances that contribute to household air pollution. Randomized controlled trials of household energy interventions in low and middle income countries have largely focused on cooking services. Less is known about the adoption and impact of clean lighting interventions. We conducted an explanatory sequential mixed methods study as part of a randomized controlled trial of home solar lighting systems in rural Uganda in order to identify contextual factors determining the use and impact of the solar lighting intervention. We used sensors to track usage, longitudinally assessed household lighting expenditures and health-related quality of life, and performed cost-effectiveness analyses. Qualitative interviews were conducted with all 80 trial participants and coded using reflexive thematic analysis. Uptake of the intervention solar lighting system was high with daily use averaging 8.23 ± 5.30 hours per day. The intervention solar lighting system increased the EQ5D index by 0.025 [95% CI 0.002 - 0.048] and led to an average monthly reduction in household lighting costs by -1.28 [-2.52, -0.85] US dollars, with higher savings in users of fuel-based lighting. The incremental cost-effectiveness ratio for the solar lighting intervention was $2025.72 US dollars per quality adjusted life year (QALY) gained making the intervention cost-effective when benchmarked against the gross domestic product (GDP) per capita in Uganda. Thematic analysis of qualitative data from individual interviews showed that solar lighting was transformative and associated with numerous benefits that fit within a Social Determinants of Health (SDOH) framework. The benefits included improved household finances, improved educational performance of children, increased household safety, improved family and community cohesion, and improved perceived household health. Our findings suggest that household solar lighting interventions may be a cost-effective approach to improve health-related quality of life by addressing SDOH.

Correction: Gut carriage of antimicrobial resistance genes in women exposed to small-scale poultry farms in rural Uganda: A feasibility study.

[This corrects the article DOI: 10.1371/journal.pone.0229699.].

Gut carriage of antimicrobial resistance genes in women exposed to small-scale poultry farms in rural Uganda: A feasibility study.

BACKGROUND: Antibiotic use for livestock is presumed to be a contributor to the acquisition of antimicrobial resistance (AMR) genes in humans, yet studies do not capture AMR data before and after livestock introduction. METHODS: We performed a feasibility study by recruiting a subset of women in a delayed-start randomized controlled trial of small-scale chicken farming to examine the prevalence of clinically-relevant AMR genes. Stool samples were obtained at baseline and one year post-randomization from five intervention women who received chickens at the start of the study, six control women who did not receive chickens until the end of the study, and from chickens provided to the control group at the end of the study. Stool was screened for 87 clinically significant AMR genes using a commercially available qPCR array (Qiagen). RESULTS: Chickens harbored 23 AMR genes from classes found in humans as well as additional vancomycin and ß-lactamase resistance genes. AMR patterns between intervention and control women appeared more similar at baseline than one year post randomization (PERMANOVA R2 = 0.081, p = 0.61 at baseline, R2 = 0.186, p = 0.09 at 12 months) Women in the control group who had direct contact with the chickens sampled in the study had greater similarities in AMR gene patterns to chickens than those in the intervention group who did not have direct contact with chickens sampled (p = 0.01). However, at one year there was a trend towards increased similarity in AMR patterns between humans in both groups and the chickens sampled (p = 0.06). CONCLUSIONS: Studies designed to evaluate human AMR genes in the setting of animal exposure should account for high baseline AMR rates. Concomitant collection of animal, human, and environmental samples over time is recommended to determine the directionality and source of AMR genes. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02619227.

Diagnostic and Treatment Challenges of Paroxysmal Nocturnal Hemoglobinuria in Uganda.

INTRODUCTION: Paroxysmal nocturnal hemoglobinuria (PNH) is a very rare disorder of the hematopoietic stem cells which is often underdiagnosed. Its incidence is about 5 cases per million inhabitants in a year, and currently, there are only 1610 patients in the International PNH Registry. In this report, we describe a case of PNH in southwestern Uganda. CASE PRESENTATION: A 34-year-old man, subsistence farmer, with a history of multiple prior presentations with anemia, jaundice, and dark-colored urine requiring blood transfusions presented to us again in July 2018 with a week's history of palpitations, dizziness, and dark-colored urine. Investigations done suggested a direct antiglobulin test- (DAT-) negative hemolytic anemia, and subsequently, flow cytometry showed a large clone of PNH. He received many blood transfusions and hematinics on several occasions during the course of his admissions. CONCLUSIONS: Our report showed diagnostic and treatment challenges of PNH in health resource-limited setting.

Brief Report: Systemic Inflammation, Immune Activation, and Impaired Lung Function Among People Living With HIV in Rural Uganda.

BACKGROUND: Although both chronic lung disease and HIV are inflammatory diseases common in sub-Saharan Africa, the relationship between systemic inflammation and lung function among people living with HIV (PLWH) in sub-Saharan Africa is not well described. METHODS: We measured lung function (using spirometry) and serum high sensitivity C-reactive protein, interleukin 6 (IL-6), soluble CD14 (sCD14), and soluble CD163 (sCD163) in 125 PLWH on stable antiretroviral therapy (ART) and 109 age- and sex-similar HIV-uninfected control subjects in rural Uganda. We modeled the relationship between lung function and systemic inflammation using linear regression, stratified by HIV serostatus, controlled for age, sex, height, tobacco, and biomass exposure. RESULTS: Half of subjects [46% (107/234)] were women, and the median age was 52 years (interquartile range: 48-55). Most PLWH [92% (115/125)] were virologically suppressed on first-line ART. Median CD4 count was 472 cells/mm. In multivariable linear regression models stratified by HIV serostatus, an interquartile range increase in IL-6 and sCD163 were each inversely associated with lung function (mL, 95% confidence interval) among PLWH [IL-6: forced expiratory volume in 1 second (FEV1) -18.1 (-29.1 to -7.1), forced vital capacity (FVC) -17.1 (-28.2 to -5.9); sCD163: FVC -14.3 (-26.9 to -1.7)]. High sensitivity C-reactive protein (>3 vs. <1 mg/L) was inversely associated with lung function among both PLWH and HIV-uninfected control subjects [PLWH: FEV1 -39.3 (-61.7 to -16.9), FVC -44.0 (-48.4 to -6.4); HIV-uninfected: FEV1 -37.9 (-63.2 to -12.6), FVC -58.0 (-88.4 to -27.5)]. sCD14 was not associated with lung function, and all interaction terms were insignificant. CONCLUSIONS: Macrophage activation and systemic inflammation are associated with lower lung function among PLWH on stable ART in rural Uganda. Future work should focus on underlying mechanisms and public health implications.

High Prevalence of Metabolic Syndrome and Cardiovascular Disease Risk Among People with HIV on Stable ART in Southwestern Uganda.

The objectives of this study were to determine the epidemiology and correlates of cardiovascular disease (CVD) risk among Ugandans on first-line antiretroviral therapy (ART). We conducted a cross-sectional study at an HIV clinic in southwestern Uganda. We enrolled adult patients on non-nucleoside-based ART regimens for a minimum of 2 years. We collected anthropometric and clinical measurements, smoking history, and blood for fasting lipid profile and blood sugar (FBS). Outcomes of interest were (1) presence of metabolic syndrome (at least two of the following: FBS >100 mg/dL, blood pressure of ≥130/85 mmHg, triglycerides ≥150 mg/dL, HDL <40 mg/DL, or waist circumference ≥94 cm in males or ≥80 cm in females); and (2) a Framingham score correlating to >5% 10-year CVD risk. Of the 250 participants enrolled, metabolic syndrome was detected in 145/250 (58%) of participants (62% in females and 50% in males). Forty-three participants (17%) had a Framingham risk correlating to a 5% or greater risk for CVD within 10 years (26% in males and 13% in females). In multivariate analyses, being female (AOR 3.13; 95% CI: 1.0-9.70; p = 0.04) and over 40 years of age (AOR 1.78; 95% CI: 1.00-3.17; p = 0.05) was independently associated with having metabolic syndrome. We found no independent risk factors for a Framingham risk score 10-year risk exceeding 5%, or associations between ART regimen and CVD risk profiles. We conclude that metabolic abnormalities are common among patients on first-line ART in rural Uganda, and appear to be more common in women than men.