149 results on '"Hannah Kibuuka"'
Search Results
2. Persistent low‐level viraemia is associated with non‐infectious comorbidities in an observational cohort in four African countries
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Allahna L. Esber, Suze Colt, Ningbo Jian, Nicole Dear, Bonnie Slike, Valentine Sing'oei, Jonah Maswai, Michael Iroezindu, Emmanuel Bahemana, Hannah Kibuuka, Christina S. Polyak, Hendrik Streeck, Neha Shah, Trevor A. Crowell, Julie A. Ake, and the AFRICOS Study Group
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cohort studies ,HIV ,low‐level viraemia ,multimorbidity ,non‐communicable diseases ,sub‐Saharan Africa ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Abstract Introduction People living with HIV (PLWH) have higher rates of non‐infectious comorbid diseases (NCDs) than individuals without HIV. We characterized the risk of NCDs among PLWH with undetectable viral load and persistent low‐level viraemia (pLLV) in the African Cohort Study (AFRICOS). We secondarily quantified the role of immune activation in the association between LLV and NCDs. Methods AFRICOS enrols participants in 12 clinics in Uganda, Kenya, Tanzania and Nigeria. Participants on antiretroviral therapy ≥ 6 months without an NCD at enrolment were included. PLLV was defined as at least two consecutive visits with a detectable viral load
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- 2024
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3. Heterologous cAd3-Ebola and MVA-EbolaZ vaccines are safe and immunogenic in US and Uganda phase 1/1b trials
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Myra Happe, Amelia R. Hofstetter, Jing Wang, Galina V. Yamshchikov, LaSonji A. Holman, Laura Novik, Larisa Strom, Francis Kiweewa, Salim Wakabi, Monica Millard, Colleen F. Kelley, Sarah Kabbani, Srilatha Edupuganti, Allison Beck, Florence Kaltovich, Tamar Murray, Susanna Tsukerman, Derick Carr, Carl Ashman, Daphne A. Stanley, Aurélie Ploquin, Robert T. Bailer, Richard Schwartz, Fatim Cham, Allan Tindikahwa, Zonghui Hu, Ingelise J. Gordon, Nadine Rouphael, Katherine V. Houser, Emily E. Coates, Barney S. Graham, Richard A. Koup, John R. Mascola, Nancy J. Sullivan, Merlin L. Robb, Julie A. Ake, Kirsten E. Lyke, Mark J. Mulligan, Julie E. Ledgerwood, Hannah Kibuuka, and the VRC 208 and RV 422 study team
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Immunologic diseases. Allergy ,RC581-607 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Ebola virus disease (EVD) is a filoviral infection caused by virus species of the Ebolavirus genus including Zaire ebolavirus (EBOV) and Sudan ebolavirus (SUDV). We investigated the safety and immunogenicity of a heterologous prime-boost regimen involving a chimpanzee adenovirus 3 vectored Ebola vaccine [either monovalent (cAd3-EBOZ) or bivalent (cAd3-EBO)] prime followed by a recombinant modified vaccinia virus Ankara EBOV vaccine (MVA-EbolaZ) boost in two phase 1/1b randomized open-label clinical trials in healthy adults in the United States (US) and Uganda (UG). Trial US (NCT02408913) enrolled 140 participants, including 26 EVD vaccine-naïve and 114 cAd3-Ebola-experienced participants (April-November 2015). Trial UG (NCT02354404) enrolled 90 participants, including 60 EVD vaccine-naïve and 30 DNA Ebola vaccine-experienced participants (February-April 2015). All tested vaccines and regimens were safe and well tolerated with no serious adverse events reported related to study products. Solicited local and systemic reactogenicity was mostly mild to moderate in severity. The heterologous prime-boost regimen was immunogenic, including induction of durable antibody responses which peaked as early as two weeks and persisted up to one year after each vaccination. Different prime-boost intervals impacted the magnitude of humoral and cellular immune responses. The results from these studies demonstrate promising implications for use of these vaccines in both prophylactic and outbreak settings.
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- 2024
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4. Implications of asymptomatic malaria infections on hematologic parameters in adults living with HIV in malaria-endemic regions with varying transmission intensities
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Edwin Kamau, Risper Maisiba, Nicole Dear, Allahna Esber, Ajay P. Parikh, Michael Iroezindu, Emmanuel Bahemana, Hannah Kibuuka, John Owuoth, Jonah Maswai, Benjamin Opot, Raphael O. Okoth, Farid Abdi, Maureen Mwalo, Dennis Juma, Ben Andagalu, Hoseah M. Akala, Neha Shah, Trevor A. Crowell, Jessica Cowden, Christina S. Polyak, and Julie A. Ake
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HIV ,Asymptomatic malaria ,Hematologic abnormalities ,Kenya ,Uganda ,Nigeria ,Infectious and parasitic diseases ,RC109-216 - Abstract
Objectives: HIV and malaria coinfection impacts disease management and clinical outcomes. This study investigated hematologic abnormalities in malaria-asymptomatic people living with HIV (PLHIV) in regions with differing malaria transmission. Methods: Study participants were enrolled in the African Cohort Study: two sites in Kenya, one in Uganda, and one in Nigeria. Data was collected at enrollment and every 6 months. Logistic regression estimated odds ratios for associations between HIV/malaria status and anemia, thrombocytopenia, and leucopenia. Results: Samples from 1587 participants with one or more visits comprising 1471 (92.7%) from PLHIV and 116 (7.3%) without HIV were analyzed. Parasite point prevalence significantly differed across the study sites (P
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- 2023
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5. Molecular characterisation of human adenoviruses associated with respiratory infections in Uganda
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Qouilazoni A. Ukuli, Bernard Erima, Andrew Mubiru, Gladys Atim, Titus Tugume, Hannah Kibuuka, Edison Mworozi, Mariette F. Ducatez, Fred Wabwire-Mangen, and Denis K. Byarugaba
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Human adenoviruses ,Respiratory infection ,Uganda ,Infectious and parasitic diseases ,RC109-216 - Abstract
Abstract Human adenoviruses (HAdV) are a diverse group of viruses causing a broad range of infections of the respiratory, urogenital and gastrointestinal tracts and keratoconjunctivitis. There are seven species of human adenoviruses with 113 genotypes which may contain multiple genetic variants. This study characterised respiratory human adenoviruses and associated factors in samples collected from selected hospitals in Uganda. A total of 2,298 nasopharyngeal samples were collected between the period of 2008 to 2016 from patients seeking health care at tertiary hospitals for influenza-like illness. They were screened by polymerase chain reaction (PCR) to determine the prevalence of HAdV. HAdV was cultured in A549 cell lines and the hexon gene was sequenced for genotyping. Of the 2,298 samples tested, 225 (9.8%) were adenovirus-positive by PCR. Age was found to be significantly associated with HAdV infections (p = 0.028) with 98% (220/225) of the positives in children aged 5 years and below and none in adults above 25 years of age. The sequenced isolates belonged to species HAdV-B and HAdV-C with most isolates identified as genotype B3. The results showed a high prevalence and genetic diversity in respiratory HAdV circulating in Ugandan population. Deeper genomic characterization based on whole genome sequencing may be necessary to further elucidate possible transmission and impact of current adenovirus-vectored vaccines in Africa.
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- 2023
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6. Long-Term Clinical Safety of the Ad26.ZEBOV and MVA-BN-Filo Ebola Vaccines: A Prospective, Multi-Country, Observational Study
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Adeep Puri, Andrew J. Pollard, Catherine Schmidt-Mutter, Fabrice Lainé, George PrayGod, Hannah Kibuuka, Houreratou Barry, Jean-François Nicolas, Jean-Daniel Lelièvre, Sodiomon Bienvenu Sirima, Beatrice Kamala, Daniela Manno, Deborah Watson-Jones, Auguste Gaddah, Babajide Keshinro, Kerstin Luhn, Cynthia Robinson, and Macaya Douoguih
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Ebola virus ,Ad26.ZEBOV ,MVA-BN-Filo ,vaccines ,clinical trials ,safety ,Medicine - Abstract
In this prospective, observational study (ClinicalTrials.gov Identifier: NCT02661464), long-term safety information was collected from participants previously exposed to the Ebola vaccines Ad26.ZEBOV and/or MVA-BN-Filo while enrolled in phase 1, 2, or 3 clinical studies. The study was conducted at 15 sites in seven countries (Burkina Faso, France, Kenya, Tanzania, Uganda, the United Kingdom, and the United States). Adult participants and offspring from vaccinated female participants who became pregnant (estimated conception ≤28 days after vaccination with MVA-BN-Filo or ≤3 months after vaccination with Ad26.ZEBOV) were enrolled. Adults were followed for 60 months after their first vaccination, and children born to female participants were followed for 60 months after birth. In the full analysis set (n = 614 adults; median age [range]: 32.0 [18–65] years), 49 (8.0%) had ≥1 serious adverse event (SAE); the incidence rate of any SAE was 27.4 per 1000 person-years (95% confidence interval: 21.0, 35.2). The unrelated SAEs of malaria were reported in the two infants in the full analysis set, aged 11 and 18 months; both episodes were resolved. No deaths or life-threatening SAEs occurred during the study. Overall, no major safety issues were identified; one related SAE was reported. These findings support the long-term clinical safety of the Ad26.ZEBOV and MVA-BN-Filo vaccines.
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- 2024
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7. Coronavirus Antibody Responses before COVID-19 Pandemic, Africa and Thailand
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Yifan Li, Mélanie Merbah, Suzanne Wollen-Roberts, Bradley Beckman, Thembi Mdluli, Isabella Swafford, Sandra V. Mayer, Jocelyn King, Courtney Corbitt, Jeffrey R. Currier, Heather Liu, Allahna Esber, Suteeraporn Pinyakorn, Ajay Parikh, Leilani V. Francisco, Nittaya Phanuphak, Jonah Maswai, John Owuoth, Hannah Kibuuka, Michael Iroezindu, Emmanuel Bahemana, Sandhya Vasan, Julie A. Ake, Kayvon Modjarrad, Gregory Gromowski, Dominic Paquin-Proulx, and Morgane Rolland
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COVID-19 ,viruses ,respiratory infections ,severe acute respiratory syndrome coronavirus 2 ,SARS-CoV-2 ,SARS ,Medicine ,Infectious and parasitic diseases ,RC109-216 - Abstract
Prior immune responses to coronaviruses might affect human SARS-CoV-2 response. We screened 2,565 serum and plasma samples collected from 2013 through early 2020, before the COVID-19 pandemic began, from 2,250 persons in 4 countries in Africa (Kenya, Nigeria, Tanzania, and Uganda) and in Thailand, including persons living with HIV-1. We detected IgG responses to SARS-CoV-2 spike (S) subunit 2 protein in 1.8% of participants. Profiling against 23 coronavirus antigens revealed that responses to S, subunit 2, or subunit 1 proteins were significantly more frequent than responses to the receptor-binding domain, S-Trimer, or nucleocapsid proteins (p
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- 2022
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8. Immune response of a two-dose heterologous Ebola vaccine regimen: summary of three African clinical trials using a single validated Filovirus Animal Nonclinical Group enzyme-linked immunosorbent assay in a single accredited laboratoryResearch in context
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Chelsea McLean, Houreratou Barry, Mark Kieh, Zacchaeus Anywaine, Baimba Tapima Rogers, Seydou Doumbia, Sodiomon B. Sirima, Alimamy Serry-Bangura, Abdoul Habib Beavogui, Auguste Gaddah, Michael Katwere, Jenny Hendriks, Babajide Keshinro, Serge Eholie, Hannah Kibuuka, Stephen B. Kennedy, Omu Anzala, Mohamed Samai, Eric D'Ortenzio, Bailah Leigh, Samba Sow, Rodolphe Thiébaut, Brian Greenwood, Deborah Watson-Jones, Macaya Douoguih, Kerstin Luhn, and Cynthia Robinson
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Ad26.ZEBOV ,MVA-BN-Filo ,Africa ,Ebola ,Vaccine ,Medicine ,Medicine (General) ,R5-920 - Abstract
Summary: Background: This analysis evaluated the immune response to the two-dose, heterologous Ad26.ZEBOV, MVA-BN-Filo Ebola virus vaccine regimen, administered 56-days apart, from multiple African sites based on results from one analytic laboratory. Methods: Immunogenicity across three trials (EBL2002, EBL2004/PREVAC, EBL3001) conducted in East and West Africa is summarised. Vaccine-induced Ebola glycoprotein-binding antibody concentrations were analysed by Q2 Solutions laboratory at baseline, 21 days (EBL2002 and EBL3001) or 28 days (EBL2004) post-dose 2 (regimen completion), and 12 months post-dose 1 using the validated Filovirus Animal Nonclinical Group Ebola glycoprotein enzyme-linked immunosorbent assay (ELISA). Responders were defined as those with a >2.5-fold increase from baseline or the lower limit of quantification (LLOQ) if
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- 2023
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9. Genome Analysis of Klebsiella pneumoniae Reveals International High-Risk Pandemic MDR Clones Emerging in Tertiary Healthcare Settings in Uganda
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Denis K. Byarugaba, Bernard Erima, Godfrey Wokorach, Stephen Alafi, Hannah Kibuuka, Edison Mworozi, Florence Najjuka, James Kiyengo, Ambrose K. Musinguzi, and Fred Wabwire-Mangen
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multidrug resistant ,hypervirulence ,virulence ,resistance genes ,Medicine - Abstract
Klebsiella pneumoniae is a threat to public health due to its continued evolution. In this study, we investigated the evolution, convergence, and transmission of hypervirulent and multi-drug resistant (MDR) clones of K. pneumoniae within healthcare facilities in Uganda. There was high resistance to piperacillin (90.91%), cefuroxime (86.96%), ceftazidime (84.62%), cefotaxime (84.00%), amoxicillin/clavulanate (75%), nalidixic acid (73.68%), and nitrofurantoin (71.43%) antibiotics among K. pneumoniae isolates. The isolates were genetically diverse, consisting of 20 different sequence types (STs) and 34 K-serotype groups. Chromosomal fosA (for fosfomycin) and oqxAB efflux pump genes were detected in all isolates. Two carbapenem resistance genes, blaNDM-5 and blaOXA-181 plus extended-spectrum beta-lactamase (blaCTX-M-15) gene (68.12%), quinolone-resistant genes qnrS1 (28.99%), qnrB1 (13.04%), and qnrB6 (13.04%) and others were found. All, except three of the isolates, harbored plasmids. While the isolates carried a repertoire of virulence genes, only two isolates carried hypervirulent genes demonstrating a low prevalence (2.90%) of hypervirulent strains. Our study demonstrated genetically diverse populations of K. pneumoniae, low levels of carbapenem resistance among the isolates, and no convergence of MDR and hypervirulence. Emerging high-risk international pandemic clones (ST11, ST14, ST147, ST 86 and ST307) were detected in these healthcare settings which are difficult to treat.
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- 2023
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10. Routine HIV clinic visit adherence in the African Cohort Study
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Nicole Dear, Allahna Esber, Michael Iroezindu, Emmanuel Bahemana, Hannah Kibuuka, Jonah Maswai, John Owuoth, Christina S. Polyak, Julie A. Ake, Trevor A. Crowell, and the AFRICOS Study Group
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HIV ,East Africa ,West Africa ,Clinic visits ,Patient engagement ,Care retention ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Abstract Background Retention in clinical care is important for people living with HIV (PLWH). Evidence suggests that missed clinic visits are associated with interruptions in antiretroviral therapy (ART), lower CD4 counts, virologic failure, and overlooked coinfections. We identified factors associated with missed routine clinic visits in the African Cohort Study (AFRICOS). Methods In 2013, AFRICOS began enrolling people with and without HIV in Uganda, Kenya, Tanzania, and Nigeria. At enrollment and every 6 months thereafter, sociodemographic questionnaires are administered and clinical outcomes assessed. Missed clinic visits were measured as the self-reported number of clinic visits missed in the past 6 months and dichotomized into none or one or more visits missed. Logistic regression with generalized estimating equations was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for associations between risk factors and missed visits. Results Between January 2013 and March 2020, 2937 PLWH were enrolled, of whom 2807 (95.6%) had initiated ART and 2771 had complete data available for analyses. Compared to PLWH 50+, missed clinic visits were more common among those 18–29 years (aOR 2.33, 95% CI 1.65–3.29), 30–39 years (aOR 1.59, 95% CI 1.19–2.13), and 40–49 years (aOR 1.42, 95% CI 1.07–1.89). As compared to PLWH on ART for
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- 2022
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11. Resistome and virulome of high-risk pandemic clones of multidrug-resistant extra-intestinal pathogenic Escherichia coli (ExPEC) isolated from tertiary healthcare settings in Uganda.
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Denis K Byarugaba, Bernard Erima, Godfrey Wokorach, Stephen Alafi, Hannah Kibuuka, Edison Mworozi, Ambrose K Musinguzi, James Kiyengo, Florence Najjuka, and Fred Wabwire-Mangen
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Medicine ,Science - Abstract
Multi-drug resistant (MDR) globally disseminated extraintestinal pathogenic high-risk Escherichia coli (ExPEC) clones are threatening the gains in bacterial disease management. In this study, we evaluated the genomic structure including the resistome and virulome of the E. coli isolates from extraintestinal infections using whole genome sequencing (WGS). The results highlight that isolates were highly resistant (≥ 90.0%) to commonly used antibiotics (Ampicillin, Trimethoprim-Sulfamethoxazole, Nalidixic acid, and Piperacillin) and were less (
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- 2023
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12. Systematic comparison of HIV-1 Envelope-specific IgG responses induced by different vaccination regimens: Can we steer IgG recognition towards regions of viral vulnerability?
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Augusta Horvath, Lisa Rogers, Georgios Pollakis, Olga Baranov, Nora Pieroth, Sarah Joseph, Mkunde Chachage, Asli Heitzer, Lucas Maganga, Frank Msafiri, Agricola Joachim, Edna Viegas, Leigh-Anne Eller, Hannah Kibuuka, Supachai Rerks-Ngarm, Punnee Pitisuttithum, Sorachai Nitayapan, Jittima Dhitavat, Nakorn Premsri, Sarah Fidler, Robin J. Shattock, Merlin Lee Robb, Jonathan Weber, Sheena McCormack, Patricia Jane Munseri, Eligius Lyamuya, Charlotta Nilsson, Arne Kroidl, Michael Hoelscher, Ralf Wagner, Christof Geldmacher, and Kathrin Held
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HIV ,CN54rgp140 vaccine ,envelope-specific antibodies ,immunogen sequence ,V3-antibodies ,V2-antibodies ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Immunogens and vaccination regimens can influence patterns of immune-epitope recognition, steering them towards or away from epitopes of potential viral vulnerability. HIV-1 envelope (Env)-specific antibodies targeting variable region 2 (V2) or 3 (V3) correlated with protection during the RV144 trial, however, it was suggested that the immunodominant V3 region might divert antibody responses away from other relevant sites. We mapped IgG responses against linear Env epitopes in five clinical HIV vaccine trials, revealing a specific pattern of Env targeting for each regimen. Notable V2 responses were only induced in trials administering CRF01_AE based immunogens, but targeting of V3 was seen in all trials, with the soluble, trimeric CN54gp140 protein eliciting robust V3 recognition. Strong V3 targeting was linked to greater overall response, increased number of total recognised antigenic regions, and where present, stronger V2 recognition. Hence, strong induction of V3-specific antibodies did not negatively impact the targeting of other linear epitopes in this study, suggesting that the induction of antibodies against V3 and other regions of potential viral vulnerability need not be necessarily mutually exclusive.
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- 2023
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13. Perceived satisfaction with HIV care and its association with adherence to antiretroviral therapy and viral suppression in the African Cohort Study
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Nancy Somi, Nicole Dear, Domonique Reed, Ajay Parikh, Anange Lwilla, Emmanuel Bahemana, Samoel Khamadi, Michael Iroezindu, Hannah Kibuuka, Jonah Maswai, Trevor A. Crowell, John Owuoth, Lucas Maganga, Christina Polyak, Julie Ake, Allahna Esber, and the AFRICOS Study Group
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HIV/AIDS ,Quality of care ,Viral load ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Abstract Background Increased availability of HIV care over the past decade has dramatically reduced morbidity and mortality among people living with HIV (PLWH) in sub-Saharan Africa. However, perceived and experienced barriers to care, including dissatisfaction with services, may impact adherence and viral suppression. We examined the associations between satisfaction with HIV care and antiretroviral therapy (ART) adherence and viral load suppression. Methods The African Cohort Study (AFRICOS) is a prospective observational study conducted at PEPFAR-supported clinics in four African countries. At enrollment and twice-yearly study visits, participants received a clinical assessment and a socio-behavioral questionnaire was administered. Participants were classified as dissatisfied with care if they reported dissatisfaction with any of the following: waiting time, health care worker skills, health care worker attitudes, quality of clinic building, or overall quality of care received. Robust Poisson regression was used to estimate prevalence ratios and 95% confidence intervals (CIs) for associations between satisfaction with care and ART adherence and between satisfaction with care and viral suppression (viral load
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- 2021
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14. Prevalence and risk factors associated with HIV and syphilis co-infection in the African Cohort Study: a cross-sectional study
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Laura Gilbert, Nicole Dear, Allahna Esber, Michael Iroezindu, Emmanuel Bahemana, Hannah Kibuuka, John Owuoth, Jonah Maswai, Trevor A. Crowell, Christina S. Polyak, Julie A. Ake, and the AFRICOS Study Group
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Human immunodeficiency virus (HIV) ,Syphilis ,Africa ,Infectious and parasitic diseases ,RC109-216 - Abstract
Abstract Background Each year, 5.6 million new syphilis cases are diagnosed globally. Guidelines for people living with HIV (PLWH) in low-income countries (LIC) recommend STI testing for symptomatic persons and those newly diagnosed with HIV; routine STI testing is less clear. Here we provide updated syphilis prevalence and identify co-infection risk factors in PLWH in the African Cohort Study (AFRICOS) to understand these rates as they relate to syndromic treatment. Methods AFRICOS is a study enrolling PLWH and HIV-uninfected individuals in four African countries. Participant study enrollment information was used to determine syphilis prevalence and co-infection risk factors. Inclusion criteria consisted of adults 18 years or older receiving care at a participating clinic as a long-term resident who consented to data and specimen collection. Exclusion criteria consisted of pregnancy and/or imprisonment. Screen-positive syphilis was defined as a reactive rapid plasma regain (RPR) upon study enrollment whereas confirmed syphilis included a reactive RPR followed by reactive treponemal test. Multivariate analyses was performed to determine HIV and syphilis co-infection risk factors. Results Between 2013 and March 1, 2020, 2939 PLWH enrolled and 2818 were included for analysis. Screen-positive and confirmed syphilis prevalence were 5.3% (151/2818) and 3.1% (87/2818), respectively. When the analysis was restricted to PLWH with an RPR titer of greater than, or equal to, 1:8, 11/87 (12.6%) participants were included. No PLWH and confirmed syphilis had documented genital ulcers. In the multivariate model, participants with confirmed syphilis co-infection were more likely to have none or some primary education [aOR 3.29 (1.60, 6.74)] and consume alcohol [aOR 1.87 (1.16, 3.03)] compared to those without syphilis. Antiretroviral therapy (ART) with suppressed viral load (VL) was protective in the unadjusted model but not adjusted multivariate model. Conclusions Our findings show that syphilis rates in sub-Saharan Africa remain elevated where diagnosis remains challenging, and that both lower education level and alcohol consumption are significantly associated with HIV/syphilis co-infection in AFRICOS. Based on our analysis, current STI guidelines targeting testing for African individuals with either new HIV diagnosis or syndromic symptoms may be inadequate, highlighting the need for increased testing and treatment strategies in resource-limited settings.
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- 2021
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15. Whole Genome Sequencing Reveals High Genetic Diversity, Diverse Repertoire of Virulence-Associated Genes and Limited Antibiotic Resistance Genes among Commensal Escherichia coli from Food Animals in Uganda
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Denis K. Byarugaba, Godfrey Wokorach, Stephen Alafi, Bernard Erima, Florence Najjuka, Edison A. Mworozi, Hannah Kibuuka, and Fred Wabwire-Mangen
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MLST ,genetic diversity ,commensals ,virulence genes ,Shiga toxin ,Biology (General) ,QH301-705.5 - Abstract
Commensal Escherichia coli with broad repertoire of virulence and antimicrobial resistance (AMR) genes pose serious public health risks as reservoirs of AMR and virulence. This study undertook whole genome characterization of commensal E. coli from food-producing animals in Uganda to investigate their genome variability (resistome and virulome). We established that the E. coli had high genomic diversity with 38 sequence types, 24 FimH types, and 33 O-antigen serotypes randomly distributed within three phylogroups (A, B1, and E). A greater proportion (≥93.65%) of the E. coli were resistant to amoxicillin/clavulanate and ampicillin antibiotics. The isolates were AmpC beta-lactamase producers dominated by blaEC-15 (71.88%) and tet(A) (20.31%) antimicrobial resistant genes besides a diverse armory of virulence-associated genes in the class of exotoxin, adhesins, iron uptake, and serine protease autotransporters which varied by host species. Cattle were found to be the major source of E. coli carrying Shiga toxin genes, whereas swine was the main source of E. coli carrying colicin-like Usp toxin gene. The study underscores the importance of livestock as the carrier of E. coli with antimicrobial resistance and a large repertoire of virulence traits with a potential of causing disease in animals and humans by acquiring more genetic traits.
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- 2023
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16. Persons living with HIV in sero-discordant partnerships experience improved HIV care engagement compared with persons living with HIV in sero-concordant partnerships: a cross-sectional analysis of four African countries
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Domonique M. Reed, Allahna L. Esber, Trevor A. Crowell, Kavitha Ganesan, Hannah Kibuuka, Jonah Maswai, John Owuoth, Emmanuel Bahemana, Michael Iroezindu, Julie A. Ake, Christina S. Polyak, and The AFRICOS Study Team
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Sero-discordant relationship ,Viral load ,ART uptake ,HIV care continuum ,Sub-Saharan Africa ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Abstract Background Persons living with HIV (PLWH) who are members of sero-discordant and sero-concordant relationships may experience psychological stressors or motivators that affect HIV care. We assessed the association between sero-discordance status, antiretroviral therapy (ART) uptake, and viral suppression in the African Cohort Study (AFRICOS). Methods AFRICOS enrolls PLWH and HIV-uninfected individuals at 12 sites in Uganda, Kenya, Tanzania, and Nigeria. At enrollment, we determined ART use through self-report. Viral suppression was defined as HIV RNA
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- 2021
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17. Assessing the impact of HIV support groups on antiretroviral therapy adherence and viral suppression in the African cohort study
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Prudence Mbah, Michael Iroezindu, Allahna L. Esber, Nicole Dear, Domonique Reed, Yakubu Adamu, Abdulwasiu Bolaji Tiamiyu, Samirah Sani Mohammed, Hannah Kibuuka, Jonah Maswai, John Owuoth, Emmanuel Bahemana, Julie A. Ake, Christina S. Polyak, Trevor A. Crowell, and for the AFRICOS Study Group
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Africa ,ART adherence ,HIV ,Support group ,Viral suppression ,Infectious and parasitic diseases ,RC109-216 - Abstract
Abstract Background Support groups for people living with HIV (PLWH) may improve HIV care adherence and outcomes. We assessed the impact of support group attendance on antiretroviral therapy (ART) adherence and viral suppression in four African countries. Methods The ongoing African Cohort Study (AFRICOS) enrolls participants at 12 clinics in Kenya, Uganda, Tanzania, and Nigeria. Self-reported attendance of any support group meetings, self-reported ART adherence, and HIV RNA are assessed every 6 months. Logistic regression models with generalized estimating equations were used to estimate adjusted odds ratios (aORs) and 95% confidence intervals (95% CIs) for support group attendance and other factors potentially associated with ART adherence and viral suppression. Results From January 2013 to December 1, 2019, 1959 ART-experienced PLWH were enrolled and 320 (16.3%) reported any support group attendance prior to enrollment. Complete ART adherence, with no missed doses in the last 30 days, was reported by 87.8% while 92.4% had viral suppression
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- 2021
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18. Seroprevalence of human coronaviruses among patients visiting hospital-based sentinel sites in Uganda
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Elijah Nicholas Mulabbi, Robert Tweyongyere, Fred Wabwire-Mangen, Edison Mworozi, Jeff Koehlerb, Hannah Kibuuka, Monica Millard, Bernard Erima, Titus Tugume, Ukuli Qouilazoni Aquino, and Denis K. Byarugaba
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Human coronaviruses ,Febrile illnesses ,Emerging viral infections ,Seroprevalence ,Infectious and parasitic diseases ,RC109-216 - Abstract
Abstract Background Human coronaviruses are causative agents of respiratory infections with several subtypes being prevalent worldwide. They cause respiratory illnesses of varying severity and have been described to be continuously emerging but their prevalence is not well documented in Uganda. This study assessed the seroprevalence of antibodies against the previously known human coronaviruses prior 2019 in Uganda. Methods A total 377 serum samples collected from volunteers that showed influenza like illness in five hospital-based sentinel sites and archived were analyzed using a commercial Qualitative Human Coronavirus Antibody IgG ELISA kit. Although there is no single kit available that can detect the presence of all the circulating coronaviruses, this kit uses a nucleoprotein, aa 340–390 to coat the wells and since there is significant homology among the various human coronavirus strains with regards to the coded for proteins, there is significant cross reactivity beyond HCoV HKU-39849 2003. This gives the kit a qualitative ability to detect the presence of human coronavirus antibodies in a sample. Results The overall seroprevalence for all the sites was 87.53% with no significant difference in the seroprevalence between the Hospital based sentinel sites (p = 0.8). Of the seropositive, the age group 1–5 years had the highest percentage (46.97), followed by 6–10 years (16.67) and then above 20 (16.36). An odds ratio of 1.6 (CI 0.863–2.97, p = 0.136) showed that those volunteers below 5 years of age were more likely to be seropositive compared to those above 5 years. The seropositivity was generally high throughout the year with highest being recorded in March and the lowest in February and December. Conclusions The seroprevalence of Human coronaviruses is alarmingly high which calls for need to identify and characterize the circulating coronavirus strains so as to guide policy on the control strategies.
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- 2021
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19. In-vitro Immunomodulatory activity of Azadirachta indica A.Juss. Ethanol: water mixture against HIV associated chronic CD4+ T-cell activation/ exhaustion
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Omalla A. Olwenyi, Bannet Asingura, Prossy Naluyima, Godwin Upoki Anywar, Justine Nalunga, Mariam Nakabuye, Michael Semwogerere, Bernard Bagaya, Fatim Cham, Allan Tindikahwa, Francis Kiweewa, Eliezer Z. Lichter, Anthony T. Podany, Courtney V. Fletcher, Siddappa N. Byrareddy, and Hannah Kibuuka
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Immunomodulation ,CD4+ T cell activation/exhaustion ,Azadirachta indica (A. indica) ethanol: water mixture ,Staphylococcal enterotoxin B (SEB) ,Microbial translocation ,Other systems of medicine ,RZ201-999 - Abstract
Abstract Background In Sub-Saharan Africa, herbal therapy continues to be utilized for HIV-1 disease management. However, the therapeutic benefits of these substances remain ambiguous. To date, little is known about the effects of these plant extracts on chronic CD4 + T-cell activation and exhaustion which is partly driven by HIV-1 associated microbial translocation. Methods Effects of Azadirachta indica, Momordica foetida and Moringa oleifera ethanol: water mixtures on cell viability were evaluated using the Guava PCA system. Then, an in-vitro cell culture model was developed to mimic CD4+ T cell exposures to antigens following HIV-1 microbial translocation. In this, peripheral blood mononuclear cells (PBMCs) isolated from HIV negative (n = 13), viral load 1000 copies per mL (n = 6) study participants from rural Uganda were treated with Staphylococcus enterotoxin B (SEB). Then, the candidate plant extract (A. indica) was added to test the potential to inhibit corresponding CD4+ T cell activation. Following BD Facs Canto II event acquisition, variations in %CD38, %CD69, Human Leukocyte Antigen -DR (HLA-DR), Programmed cell death protein 1 (PD-1), T-cell immunoglobulin and mucin domain-containing protein 3 (Tim-3), interferon gamma (IFN γ) and interleukin 2 (IL-2) CD4 + T cell expression were evaluated. Results Following exposure to SEB, only A. indica demonstrated a concentration-dependent ability to downregulate the levels of CD4 + T cell activation. At the final concentration of 0.500 μg/mL of A. indica, a significant downregulation of CD4 + CD38 + HLA-DR+ expression was observed in HIV negative (p
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- 2021
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20. Factors associated with sexually transmitted infections among care-seeking adults in the African Cohort Study
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Michael Semwogerere, Nicole Dear, Joshua Tunnage, Domonique Reed, Hannah Kibuuka, Francis Kiweewa, Michael Iroezindu, Emmanuel Bahemana, Jonah Maswai, John Owuoth, Trevor A. Crowell, Julie A. Ake, Christina S. Polyak, Allahna Esber, and for the AFRICOS Study Group
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Sexually transmitted infections ,Sub-Saharan Africa ,People living with HIV ,Public aspects of medicine ,RA1-1270 - Abstract
Abstract Objectives Sexually transmitted infections (STIs) are a major cause of morbidity. Understanding drivers of transmission can inform effective prevention programs. We describe STI prevalence and identify factors associated with STIs in four African countries. Methods The African Cohort Study is an ongoing, prospective cohort in Kenya, Nigeria, Tanzania and Uganda. At enrollment, a physical exam was conducted and STI diagnosis made by a clinician using a syndromic management approach. Multivariable logistic regression was used to estimate adjusted odds ratios (aORs) and 95% confidence intervals (95% CIs) for factors associated with an STI diagnosis. Results As of June 2020, 3544 participants were enrolled. STI prevalence was 7.7% and did not differ by HIV status (p = 0.30). Prevalence differed by syndrome (3.5% vaginal discharge, 1.5% genital ulcer, 2.1% lower abdominal pain, 0.2% inguinal bubo). The odds of having an STI were higher at all sites compared to Kisumu West, Kenya, and among those with a primary level education or below compared to those with secondary or higher (aOR: 1.77; 95% CI: 1.32–2.38). The odds of an STI diagnosis was higher among participants 18–29 years (aOR: 2.29; 95% CI: 1.35–3.87), females (aOR: 2.64; 95% CI: 1.94–3.59), and those with depression (aOR: 1.78; 95% CI: 1.32–2.38). Among PLWH, similar factors were independently associated with an STI diagnosis. Viral suppression was protective against STIs (aOR: 2.05; 95% CI: 1.32–3.20). Conclusions Prevalence of STIs varied by site with young people and females most at risk for STIs. Mental health is a potential target area for intervention.
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- 2021
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21. HIV-1 infections with multiple founders associate with the development of neutralization breadth.
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Eric Lewitus, Samantha M Townsley, Yifan Li, Gina C Donofrio, Bethany L Dearlove, Hongjun Bai, Eric Sanders-Buell, Anne Marie O'Sullivan, Meera Bose, Hannah Kibuuka, Lucas Maganga, Sorachai Nitayaphan, Fredrick K Sawe, Leigh Anne Eller, Nelson L Michael, Victoria R Polonis, Julie A Ake, Sandhya Vasan, Merlin L Robb, Sodsai Tovanabutra, Shelly J Krebs, and Morgane Rolland
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Immunologic diseases. Allergy ,RC581-607 ,Biology (General) ,QH301-705.5 - Abstract
Eliciting broadly neutralizing antibodies (bnAbs) is a cornerstone of HIV-1 vaccine strategies. Comparing HIV-1 envelope (env) sequences from the first weeks of infection to the breadth of antibody responses observed several years after infection can help define viral features critical to vaccine design. We investigated the relationship between HIV-1 env genetics and the development of neutralization breadth in 70 individuals enrolled in a prospective acute HIV-1 cohort. Half of the individuals who developed bnAbs were infected with multiple HIV-1 founder variants, whereas all individuals with limited neutralization breadth had been infected with single HIV-1 founders. Accordingly, at HIV-1 diagnosis, env diversity was significantly higher in participants who later developed bnAbs compared to those with limited breadth (p = 0.012). This association between founder multiplicity and the subsequent development of neutralization breadth was also observed in 56 placebo recipients in the RV144 vaccine efficacy trial. In addition, we found no evidence that neutralization breath was heritable when analyzing env sequences from the 126 participants. These results demonstrate that the presence of slightly different HIV-1 variants in acute infection could promote the induction of bnAbs, suggesting a novel vaccine strategy, whereby an initial immunization with a cocktail of minimally distant antigens would be able to initiate bnAb development towards breadth.
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- 2022
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22. Dynamic MAIT cell response with progressively enhanced innateness during acute HIV-1 infection
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Kerri G. Lal, Dohoon Kim, Margaret C. Costanzo, Matthew Creegan, Edwin Leeansyah, Joana Dias, Dominic Paquin-Proulx, Leigh Anne Eller, Alexandra Schuetz, Yuwadee Phuang-ngern, Shelly J. Krebs, Bonnie M. Slike, Hannah Kibuuka, Lucas Maganga, Sorachai Nitayaphan, Josphat Kosgei, Carlo Sacdalan, Jintanat Ananworanich, Diane L. Bolton, Nelson L. Michael, Barbara L. Shacklett, Merlin L. Robb, Michael A. Eller, and Johan K. Sandberg
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Science - Abstract
Here, using longitudinal pre- and post-infection samples from the RV217 Early Capture HIV Cohort Study, the authors show that mucosa-associated invariant T (MAIT) cells become activated and expand during the early acute phase of HIV infection, with subsequent reprogramming towards innate-like functionality.
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- 2020
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23. Safety and immunogenicity of 2-dose heterologous Ad26.ZEBOV, MVA-BN-Filo Ebola vaccination in children and adolescents in Africa: A randomised, placebo-controlled, multicentre Phase II clinical trial
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Zacchaeus Anywaine, Houreratou Barry, Omu Anzala, Gaudensia Mutua, Sodiomon B. Sirima, Serge Eholie, Hannah Kibuuka, Christine Bétard, Laura Richert, Christine Lacabaratz, M. Juliana McElrath, Stephen C. De Rosa, Kristen W. Cohen, Georgi Shukarev, Michael Katwere, Cynthia Robinson, Auguste Gaddah, Dirk Heerwegh, Viki Bockstal, Kerstin Luhn, Maarten Leyssen, Rodolphe Thiébaut, Macaya Douoguih, and on behalf of the EBL2002 Study group
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Medicine - Abstract
Background Reoccurring Ebola outbreaks in West and Central Africa have led to serious illness and death in thousands of adults and children. The objective of this study was to assess safety, tolerability, and immunogenicity of the heterologous 2-dose Ad26.ZEBOV, MVA-BN-Filo vaccination regimen in adolescents and children in Africa. Methods and findings In this multicentre, randomised, observer-blind, placebo-controlled Phase II study, 131 adolescents (12 to 17 years old) and 132 children (4 to 11 years old) were enrolled from Eastern and Western Africa and randomised 5:1 to receive study vaccines or placebo. Vaccine groups received intramuscular injections of Ad26.ZEBOV (5 × 1010 viral particles) and MVA-BN-Filo (1 × 108 infectious units) 28 or 56 days apart; placebo recipients received saline. Primary outcomes were safety and tolerability. Solicited adverse events (AEs) were recorded until 7 days after each vaccination and serious AEs (SAEs) throughout the study. Secondary and exploratory outcomes were humoral immune responses (binding and neutralising Ebola virus [EBOV] glycoprotein [GP]-specific antibodies), up to 1 year after the first dose. Enrolment began on February 26, 2016, and the date of last participant last visit was November 28, 2018. Of the 263 participants enrolled, 217 (109 adolescents, 108 children) received the 2-dose regimen, and 43 (20 adolescents, 23 children) received 2 placebo doses. Median age was 14.0 (range 11 to 17) and 7.0 (range 4 to 11) years for adolescents and children, respectively. Fifty-four percent of the adolescents and 51% of the children were male. All participants were Africans, and, although there was a slight male preponderance overall, the groups were well balanced. No vaccine-related SAEs were reported; solicited AEs were mostly mild/moderate. Twenty-one days post-MVA-BN-Filo vaccination, binding antibody responses against EBOV GP were observed in 100% of vaccinees (106 adolescents, 104 children). Geometric mean concentrations tended to be higher after the 56-day interval (adolescents 13,532 ELISA units [EU]/mL, children 17,388 EU/mL) than the 28-day interval (adolescents 6,993 EU/mL, children 8,007 EU/mL). Humoral responses persisted at least up to Day 365. A limitation of the study is that the follow-up period was limited to 365 days for the majority of the participants, and so it was not possible to determine whether immune responses persisted beyond this time period. Additionally, formal statistical comparisons were not preplanned but were only performed post hoc. Conclusions The heterologous 2-dose vaccination was well tolerated in African adolescents and children with no vaccine-related SAEs. All vaccinees displayed anti-EBOV GP antibodies after the 2-dose regimen, with higher responses in the 56-day interval groups. The frequency of pyrexia after vaccine or placebo was higher in children than in adolescents. These data supported the prophylactic indication against EBOV disease in a paediatric population, as licenced in the EU. Trial registration ClinicalTrials.govNCT02564523. Zacchaeus Anywaine and co-workers study safety and immunogenicity of an Ebola vaccine among children and adolescents across four African countries. Author summary Why was the study done? There have been larger and more extensive Ebola virus disease (EVD) outbreaks in Africa in the past decade with no licenced treatments available. As such, there is an unmet medical need for prophylactic Ebola vaccines. This study was performed to evaluate whether a 2-dose heterologous Ad26.ZEBOV, MVA-BN-Filo Ebola vaccination was safe and immunogenic in healthy African children. What did the researchers do and find? In this randomised, placebo-controlled, Phase II clinical trial, the Ad26.ZEBOV, MVA-BN-Filo Ebola vaccination regimen was administered to African participants in 2 age cohorts (12 to 17 and 4 to 11 years). No vaccine-related serious adverse events were reported, and robust immune responses were induced in both adolescents and children after receiving the active 2-dose regimen. What do these findings mean? These data support the use of the Ad26.ZEBOV, MVA-BN-Filo vaccination regimen in African adolescents and children at risk of Ebola infection. Although vaccination according to a 28-day regimen may lead to protection against EVD in a shorter time frame, vaccination according to a 56-day regimen results in higher EBOV GP binding and neutralising antibody responses. The observation that Ad26 preexisting immunity in the majority of participants does not affect the EBOV GP-specific antibody responses postvaccination augurs well for the use of this vaccine regimen even in regions with a high prevalence of preexisting Ad26 seropositivity.
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- 2022
24. Clinical similarities and differences between two large HIV cohorts in the United States and Africa.
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Anne K Monroe, Christina S Polyak, Amanda D Castel, Allahna L Esber, Morgan E Byrne, Jonah Maswai, John Owuoth, Lucas Maganga, Emmanuel Bahemana, Yakubu Adamu, Michael Iroezindu, Hannah Kibuuka, Francis Kiweewa, Alan E Greenberg, Trevor A Crowell, Julie A Ake, and DC Cohort Executive Committee and AFRICOS Study Group
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Medicine ,Science - Abstract
BackgroundWashington, DC, and sub-Saharan Africa are both affected by generalized HIV epidemics. However, care for persons living with HIV (PLWH) and clinical outcomes may differ in these geographically and culturally diverse areas. We compared patient and clinical site characteristics among adult persons living with HIV (PLWH) enrolled in two longitudinal HIV cohort studies-the African Cohort Study (AFRICOS) and the DC Cohort.MethodsThe DC Cohort is a clinic-based city-wide longitudinal cohort comprised of PLWH attending 15 HIV clinics in Washington, DC. Patients' socio-demographic characteristics, clinical evaluations, and laboratory data are retrospectively collected from electronic medical records and limited manual chart abstraction. AFRICOS is a prospective observational cohort of PLWH and uninfected volunteers attending 12 select HIV care and treatment facilities in Nigeria, Kenya, Uganda and Tanzania. AFRICOS study participants are a subset of clinic patients who complete protocol-specific visits every 6 months with history and physical examination, questionnaire administration, and blood/sputum collection for ascertainment of HIV outcomes and comorbidities, and neurocognitive and functional assessments. Among participants aged ≥ 18 years, we generated descriptive statistics for demographic and clinical characteristics at enrollment and follow up and compared them using bivariable analyses.ResultsThe study sample included 2,774 AFRICOS and 8,420 DC Cohort participants who enrolled from January 2013 (AFRICOS)/January 2011 (DC Cohort) through March 2018. AFRICOS participants were significantly more likely to be women (58.8% vs 27.1%) and younger (83.3% vs 61.1% aged < 50 years old) and significantly less likely to be MSM (only 0.1% of AFRICOS population reported MSM risk factor) than DC Cohort. Similar rates of current viral suppression (about 75% of both samples), hypertension, hepatitis B coinfection and alcohol use were observed. However, AFRICOS participants had significantly higher rates of CD4ConclusionsWith similar viral suppression outcomes, but many differences between our cohorts noted, the combined sample provides unique opportunities to assess and compare HIV care and treatment outcomes in the U.S. and sub-Saharan Africa. Comparing these two cohorts may inform care and treatment practices and may pave the way for future pathophysiologic analyses.
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- 2022
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25. Safety and immunogenicity of 2-dose heterologous Ad26.ZEBOV, MVA-BN-Filo Ebola vaccination in healthy and HIV-infected adults: A randomised, placebo-controlled Phase II clinical trial in Africa
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Houreratou Barry, Gaudensia Mutua, Hannah Kibuuka, Zacchaeus Anywaine, Sodiomon B. Sirima, Nicolas Meda, Omu Anzala, Serge Eholie, Christine Bétard, Laura Richert, Christine Lacabaratz, M. Juliana McElrath, Stephen De Rosa, Kristen W. Cohen, Georgi Shukarev, Cynthia Robinson, Auguste Gaddah, Dirk Heerwegh, Viki Bockstal, Kerstin Luhn, Maarten Leyssen, Macaya Douoguih, Rodolphe Thiébaut, and the EBL2002 Study group
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Medicine - Abstract
Background We investigated safety, tolerability, and immunogenicity of the heterologous 2-dose Ebola vaccination regimen in healthy and HIV-infected adults with different intervals between Ebola vaccinations. Methods and findings In this randomised, observer-blind, placebo-controlled Phase II trial, 668 healthy 18- to 70-year-olds and 142 HIV-infected 18- to 50-year-olds were enrolled from 1 site in Kenya and 2 sites each in Burkina Faso, Cote d’Ivoire, and Uganda. Participants received intramuscular Ad26.ZEBOV followed by MVA-BN-Filo at 28-, 56-, or 84-day intervals, or saline. Females represented 31.4% of the healthy adult cohort in contrast to 69.7% of the HIV-infected cohort. A subset of healthy adults received booster vaccination with Ad26.ZEBOV or saline at Day 365. Following vaccinations, adverse events (AEs) were collected until 42 days post last vaccination and serious AEs (SAEs) were recorded from signing of the ICF until the end of the study. The primary endpoint was safety, and the secondary endpoint was immunogenicity. Anti-Ebola virus glycoprotein (EBOV GP) binding and neutralising antibodies were measured at baseline and at predefined time points throughout the study. The first participant was enrolled on 9 November 2015, and the date of last participant’s last visit was 12 February 2019. No vaccine-related SAEs and mainly mild-to-moderate AEs were observed among the participants. The most frequent solicited AEs were injection-site pain (local), and fatigue, headache, and myalgia (systemic), respectively. Twenty-one days post-MVA-BN-Filo vaccination, geometric mean concentrations (GMCs) with 95% confidence intervals (CIs) of EBOV GP binding antibodies in healthy adults in 28-, 56-, and 84-day interval groups were 3,085 EU/mL (2,648 to 3,594), 7,518 EU/mL (6,468 to 8,740), and 7,300 EU/mL (5,116 to 10,417), respectively. In HIV-infected adults in 28- and 56-day interval groups, GMCs were 4,207 EU/mL (3,233 to 5,474) and 5,283 EU/mL (4,094 to 6,817), respectively. Antibody responses were observed until Day 365. Ad26.ZEBOV booster vaccination after 1 year induced an anamnestic response. Study limitations include that some healthy adult participants either did not receive dose 2 or received dose 2 outside of their protocol-defined interval and that the follow-up period was limited to 365 days for most participants. Conclusions Ad26.ZEBOV, MVA-BN-Filo vaccination was well tolerated and immunogenic in healthy and HIV-infected African adults. Increasing the interval between vaccinations from 28 to 56 days improved the magnitude of humoral immune responses. Antibody levels persisted to at least 1 year, and Ad26.ZEBOV booster vaccination demonstrated the presence of vaccination-induced immune memory. These data supported the approval by the European Union for prophylaxis against EBOV disease in adults and children ≥1 year of age. Trial registration ClinicalTrials.govNCT02564523 Houreratou Barry and co-workers report on safety and immunogenicity of an Ebola vaccine in adults across four African countries. Author summary Why was this study done? With Ebola outbreaks increasing, there is an unmet medical need for a prophylactic vaccine to prevent and mitigate Ebola outbreaks. To address the urgent medical need during the 2014 to 2016 outbreak, the clinical development of the 2-dose vaccine regimen comprising of Ad26.ZEBOV and MVA-BN-Filo was accelerated. This Phase II study was part of this accelerated program, evaluating the safety and immunogenicity of the 2-dose vaccine regimen in healthy and HIV-infected African adults, with 28-, 56-, and 84-day intervals between doses. The study was amended to evaluate safety and immunogenicity of a booster vaccination with Ad26.ZEBOV, administered approximately 1 year after the first vaccination, in healthy adults. What did the researchers do and find? We conducted a randomised trial to assess the safety and the immunogenicity of the Ad26.ZEBOV, MVA-BN-Filo vaccine regimen in 3 different vaccination intervals in healthy and HIV-infected adults. The vaccine regimen was well tolerated and induced marked immune responses; the highest humoral responses were observed after vaccination with 56-day and 84-day intervals. Anamnestic responses were observed in all healthy participants receiving Ad26.ZEBOV as booster at 1 year after the first dose. What do these findings mean? Our results demonstrate that the Ad26.ZEBOV, MVA-BN-Filo vaccine regimen is safe and immunogenic in healthy and HIV-infected adults and induces immune memory that can rapidly be reactivated. Our findings support the prophylactic use of the 2-dose Ad26.ZEBOV, MVA-BN-Filo vaccine regimen against Ebola infection in African adult populations. The 2-dose vaccine regimen comprising of Ad26.ZEBOV and MVA-BN-Filo has received marketing authorisation under exceptional circumstances for prophylactic use against EVD in adults and children ≥1 year old within the European Union.
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- 2021
26. Genetic Evolution of Avian Influenza A (H9N2) Viruses Isolated from Domestic Poultry in Uganda Reveals Evidence of Mammalian Host Adaptation, Increased Virulence and Reduced Sensitivity to Baloxavir
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Gladys Atim, Titus Tugume, Qouilazoni A. Ukuli, Bernard Erima, Andrew Mubiru, Hannah Kibuuka, Edison Mworozi, Pamela McKenzie, Jasmine C. M. Turner, David Walker, Trushar Jeevan, Robert G. Webster, Jeremy Jones, Richard J. Webby, Mariette F. Ducatez, Fred Wabwire-Mangen, and Denis K. Byarugaba
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influenza ,phylogenetics ,molecular markers ,reassortment ,Microbiology ,QR1-502 - Abstract
A (H9N2) avian influenza A viruses were first detected in Uganda in 2017 and have since established themselves in live bird markets. The aim of this study was to establish the subsequent genetic evolution of H9N2 viruses in Uganda. Cloacal samples collected from live bird market stalls in Kampala from 2017 to 2019 were screened by RT-PCR for influenza A virus and H9N2 viruses were isolated in embryonated eggs. One hundred and fifty H9N2 isolates were subjected to whole genome sequencing on the Illumina MiSeq platform. The sequence data analysis and comparison with contemporary isolates revealed that the virus was first introduced into Uganda in 2014 from ancestors in the Middle East. There has since been an increase in nucleotide substitutions and reassortments among the viruses within and between live bird markets, leading to variations in phylogeny of the different segments, although overall diversity remained low. The isolates had several mutations such as HA-Q226L and NS-I106M that enable mammalian host adaptation, NP-M105V, PB1-D3V, and M1-T215A known for increased virulence/pathogenicity and replication, and PA-E199D, NS-P42S, and M2-S31N that promote drug resistance. The PA-E199D substitution in particular confers resistance to the endonuclease inhibitor Baloxavir acid, which is one of the new anti-influenza drugs. Higher EC50 was observed in isolates with a double F105L+E199D substitution that may suggest a possible synergistic effect. These H9N2 viruses have established an endemic situation in live bird markets in Uganda because of poor biosecurity practices and therefore pose a zoonotic threat. Regular surveillance is necessary to further generate the needed evidence for effective control strategies and to minimize the threats.
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- 2022
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27. Associations Between Antibody Fc-Mediated Effector Functions and Long-Term Sequelae in Ebola Virus Survivors
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Dominic Paquin-Proulx, Bronwyn M. Gunn, Aljawharah Alrubayyi, Danielle V. Clark, Matthew Creegan, Dohoon Kim, Hannah Kibuuka, Monica Millard, Salim Wakabi, Leigh Anne Eller, Nelson L. Michael, Randal J. Schoepp, Matthew J. Hepburn, Lisa E. Hensley, Merlin L. Robb, Galit Alter, and Michael A. Eller
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antibodies ,Ebola ,Fc-mediated antibody functions ,inflammation ,long term sequelae ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Antibodies that mediate non-neutralizing functions play an important role in the immune response to Ebola virus (EBOV) and are thought to impact disease outcome. EBOV has also been associated with long term sequelae in survivors, however, the extent to which antibodies that mediate non-neutralizing functions are associated with the development of these sequelae is unknown. Here, the presence of antibodies mediating different effector functions and how they relate to long-term sequelae two years after the 2007 Bundibugyo Ebola virus (BDBV) outbreak was investigated. The majority of survivors demonstrated robust antibody effector functional activity and demonstrated persistent polyfunctional antibody profiles to the EBOV glycoprotein (GP) two years after infection. These functions were strongly associated with the levels of GP-specific IgG1. The odds of developing hearing loss, one of the more common sequelae to BDBV was reduced when antibodies mediating antibody dependent cellular phagocytosis (ADCP), antibody dependent complement deposition (ADCD), or activating NK cells (ADNKA) were observed. In addition, hearing loss was associated with increased levels of several pro-inflammatory cytokines and levels of these pro-inflammatory cytokines were associated with lower ADCP. These results are indicating that a skewed antibody profile and persistent inflammation may contribute to long term outcome in survivors of BDBV infection
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- 2021
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28. NK Cell Subset Redistribution and Antibody Dependent Activation after Ebola Vaccination in Africans
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Helen R. Wagstaffe, Omu Anzala, Hannah Kibuuka, Zacchaeus Anywaine, Sodiomon B. Sirima, Rodolphe Thiébaut, Laura Richert, Yves Levy, Christine Lacabaratz, Viki Bockstal, Kerstin Luhn, Macaya Douoguih, and Martin R. Goodier
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Ebola ,vaccine ,natural killer cell ,antibody ,Africa ,Medicine - Abstract
Natural killer cells play an important role in the control of viral infections both by regulating acquired immune responses and as potent innate or antibody-mediated cytotoxic effector cells. NK cells have been implicated in control of Ebola virus infections and our previous studies in European trial participants have demonstrated durable activation, proliferation and antibody-dependent NK cell activation after heterologous two-dose Ebola vaccination with adenovirus type 26.ZEBOV followed by modified vaccinia Ankara-BN-Filo. Regional variation in immunity and environmental exposure to pathogens, in particular human cytomegalovirus, have profound impacts on NK cell functional capacity. We therefore assessed the NK cell phenotype and function in African trial participants with universal exposure to HCMV. We demonstrate a significant redistribution of NK cell subsets after vaccine dose two, involving the enrichment of less differentiated CD56dimCD57− and CD56dimFcεR1γ+ (canonical) cells and the increased proliferation of these subsets. Sera taken after vaccine dose two support robust antibody-dependent NK cell activation in a standard NK cell readout; these responses correlate strongly with the concentration of anti-Ebola glycoprotein specific antibodies. These sera also promote comparable IFN-γ production in autologous NK cells taken at baseline and post-vaccine dose two. However, degranulation responses of post-vaccination NK cells were reduced compared to baseline NK cells and these effects could not be directly attributed to alterations in NK cell phenotype after vaccination. These studies demonstrate consistent changes in NK cell phenotypic composition and robust antibody-dependent NK cell function and reveal novel characteristics of these responses after heterologous two dose Ebola vaccination in African individuals.
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- 2022
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29. Factors influencing estimates of HIV-1 infection timing using BEAST.
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Bethany Dearlove, Sodsai Tovanabutra, Christopher L Owen, Eric Lewitus, Yifan Li, Eric Sanders-Buell, Meera Bose, Anne-Marie O'Sullivan, Gustavo Kijak, Shana Miller, Kultida Poltavee, Jenica Lee, Lydia Bonar, Elizabeth Harbolick, Bahar Ahani, Phuc Pham, Hannah Kibuuka, Lucas Maganga, Sorachai Nitayaphan, Fred K Sawe, Jerome H Kim, Leigh Anne Eller, Sandhya Vasan, Robert Gramzinski, Nelson L Michael, Merlin L Robb, Morgane Rolland, and RV217 Study Team
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Biology (General) ,QH301-705.5 - Abstract
While large datasets of HIV-1 sequences are increasingly being generated, many studies rely on a single gene or fragment of the genome and few comparative studies across genes have been done. We performed genome-based and gene-specific Bayesian phylogenetic analyses to investigate how certain factors impact estimates of the infection dates in an acute HIV-1 infection cohort, RV217. In this cohort, HIV-1 diagnosis corresponded to the first RNA positive test and occurred a median of four days after the last negative test, allowing us to compare timing estimates using BEAST to a narrow window of infection. We analyzed HIV-1 sequences sampled one week, one month and six months after HIV-1 diagnosis in 39 individuals. We found that shared diversity and temporal signal was limited in acute infection, and insufficient to allow timing inferences in the shortest HIV-1 genes, thus dated phylogenies were primarily analyzed for env, gag, pol and near full-length genomes. There was no one best-fitting model across participants and genes, though relaxed molecular clocks (73% of best-fitting models) and the Bayesian skyline (49%) tended to be favored. For infections with single founders, the infection date was estimated to be around one week pre-diagnosis for env (IQR: 3-9 days) and gag (IQR: 5-9 days), whilst the genome placed it at a median of 10 days (IQR: 4-19). Multiply-founded infections proved problematic to date. Our ability to compare timing inferences to precise estimates of HIV-1 infection (within a week) highlights that molecular dating methods can be applied to within-host datasets from early infection. Nonetheless, our results also suggest caution when using uniform clock and population models or short genes with limited information content.
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- 2021
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30. Molecular dating and viral load growth rates suggested that the eclipse phase lasted about a week in HIV-1 infected adults in East Africa and Thailand.
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Morgane Rolland, Sodsai Tovanabutra, Bethany Dearlove, Yifan Li, Christopher L Owen, Eric Lewitus, Eric Sanders-Buell, Meera Bose, AnneMarie O'Sullivan, Raabya Rossenkhan, Jan Phillipus Lourens Labuschagne, Paul T Edlefsen, Daniel B Reeves, Gustavo Kijak, Shana Miller, Kultida Poltavee, Jenica Lee, Lydia Bonar, Elizabeth Harbolick, Bahar Ahani, Phuc Pham, Hannah Kibuuka, Lucas Maganga, Sorachai Nitayaphan, Fred K Sawe, Leigh Anne Eller, Robert Gramzinski, Jerome H Kim, Nelson L Michael, Merlin L Robb, and RV217 Study Team
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Immunologic diseases. Allergy ,RC581-607 ,Biology (General) ,QH301-705.5 - Abstract
Most HIV-1 infected individuals do not know their infection dates. Precise infection timing is crucial information for studies that document transmission networks or drug levels at infection. To improve infection timing, we used the prospective RV217 cohort where the window when plasma viremia becomes detectable is narrow: the last negative visit occurred a median of four days before the first detectable HIV-1 viremia with an RNA test, referred below as diagnosis. We sequenced 1,280 HIV-1 genomes from 39 participants at a median of 4, 32 and 170 days post-diagnosis. HIV-1 infections were dated by using sequence-based methods and a viral load regression method. Bayesian coalescent and viral load regression estimated that infections occurred a median of 6 days prior to diagnosis (IQR: 9-3 and 11-4 days prior, respectively). Poisson-Fitter, which analyzes the distribution of hamming distances among sequences, estimated a median of 7 days prior to diagnosis (IQR: 15-4 days) based on sequences sampled 4 days post-diagnosis, but it did not yield plausible results using sequences sampled at 32 days. Fourteen participants reported a high-risk exposure event at a median of 8 days prior to diagnosis (IQR: 12 to 6 days prior). These different methods concurred that HIV-1 infection occurred about a week before detectable viremia, corresponding to 20 days (IQR: 34-15 days) before peak viral load. Together, our methods comparison helps define a framework for future dating studies in early HIV-1 infection.
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- 2020
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31. The Joint Mobile Emerging Disease Clinical Capability (JMEDICC) laboratory approach: Capabilities for high-consequence pathogen clinical research.
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Prossy Naluyima, Willy Kayondo, Chi Ritchie, Joseph Wandege, Sharon Kagabane, Lydia Tumubeere, Brenda Kusiima, Daniel Kibombo, Sharon Atukunda, Christine Nanteza, Harriet Nabirye, Francis Bunjo Mugabi, Sarah Namuyanja, Christopher Hatcher, Hypaitia Rauch, Moses Mukembo, Patrick Musinguzi, JMEDICC Consortium, Nathan Sanders, Elizabeth Turesson, Christian Cando, Richard Walwema, Derrick Mimbe, Janice Hepburn, Danielle Clark, Mohammed Lamorde, Hannah Kibuuka, Saima Zaman, Anthony P Cardile, and Karen A Martins
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Arctic medicine. Tropical medicine ,RC955-962 ,Public aspects of medicine ,RA1-1270 - Abstract
Following the 2013-2016 Ebola virus outbreak in West Africa, numerous groups advocated for the importance of executing clinical trials in outbreak settings. The difficulties associated with obtaining reliable data to support regulatory approval of investigational vaccines and therapeutics during that outbreak were a disappointment on a research and product development level, as well as on a humanitarian level. In response to lessons learned from the outbreak, the United States Department of Defense established a multi-institute project called the Joint Mobile Emerging Disease Intervention Clinical Capability (JMEDICC). JMEDICC's primary objective is to establish the technical capability in western Uganda to execute clinical trials during outbreaks of high-consequence pathogens such as the Ebola virus. A critical component of clinical trial execution is the establishment of laboratory operations. Technical, logistical, and political challenges complicate laboratory operations, and these challenges have been mitigated by JMEDICC to enable readiness for laboratory outbreak response operations.
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- 2019
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32. HIV virologic failure and its predictors among HIV-infected adults on antiretroviral therapy in the African Cohort Study.
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Francis Kiweewa, Allahna Esber, Ezra Musingye, Domonique Reed, Trevor A Crowell, Fatim Cham, Michael Semwogerere, Rosemary Namagembe, Alice Nambuya, Cate Kafeero, Allan Tindikahwa, Leigh Anne Eller, Monica Millard, Huub C Gelderblom, Babajide Keshinro, Yakubu Adamu, Jonah Maswai, John Owuoth, Valentine Chepkorir Sing'oei, Lucas Maganga, Emmanuel Bahemana, Samoel Khamadi, Merlin L Robb, Julie A Ake, Christina S Polyak, and Hannah Kibuuka
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Medicine ,Science - Abstract
IntroductionThe 2016 WHO consolidated guidelines on the use of antiretroviral drugs defines HIV virologic failure for low and middle income countries (LMIC) as plasma HIV-RNA ≥ 1000 copies/mL. We evaluated virologic failure and predictors in four African countries.Materials and methodsWe included HIV-infected participants on a WHO recommended antiretroviral therapy (ART) regimen and enrolled in the African Cohort Study between January 2013 and October 2017. Studied outcomes were virologic failure (plasma HIV-RNA ≥ 1000 copies/mL at the most recent visit), viraemia (plasma HIV-RNA ≥ 50 copies/mL at the most recent visit); and persistent viraemia (plasma HIV-RNA ≥ 50 copies/mL at two consecutive visits). Generalized linear models were used to estimate relative risks with their 95% confidence intervals.Results2054 participants were included in this analysis. Viraemia, persistent viraemia and virologic failure were observed in 396 (19.3%), 160 (7.8%) and 184 (9%) participants respectively. Of the participants with persistent viraemia, only 57.5% (92/160) had confirmed virologic failure. In the multivariate analysis, attending clinical care site other than the Uganda sitebeing on 2nd line ART (aRR 1.8, 95% CI 1·28-2·66); other ART combinations not first line and not second line (aRR 3.8, 95% CI 1.18-11.9), a history of fever in the past week (aRR 3.7, 95% CI 1.69-8.05), low CD4 count (aRR 6.9, 95% CI 4.7-10.2) and missing any day of ART (aRR 1·8, 95% CI 1·27-2.57) increased the risk of virologic failure. Being on 2nd line therapy, the site where one receives care and CD4 count < 500 predicted viraemia, persistent viraemia and virologic failure.ConclusionIn conclusion, these findings demonstrate that HIV-infected patients established on ART for more than six months in the African setting frequently experienced viraemia while continuing to be on ART. The findings also show that being on second line, low CD4 count, missing any day of ART and history of fever in the past week remain important predictors of virologic failure that should trigger intensified adherence counselling especially in the absence of reliable or readily available viral load monitoring. Finally, clinical care sites are different calling for further analyses to elucidate on the unique features of these sites.
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- 2019
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33. Correction: Rare HIV-1 transmitted/founder lineages identified by deep viral sequencing contribute to rapid shifts in dominant quasispecies during acute and early infection.
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Gustavo H Kijak, Eric Sanders-Buell, Agnes-Laurence Chenine, Michael A Eller, Nilu Goonetilleke, Rasmi Thomas, Sivan Leviyang, Elizabeth A Harbolick, Meera Bose, Phuc Pham, Celina Oropeza, Kultida Poltavee, Anne Marie O'Sullivan, Erik Billings, Melanie Merbah, Margaret C Costanzo, Joanna A Warren, Bonnie Slike, Hui Li, Kristina K Peachman, Will Fischer, Feng Gao, Claudia Cicala, James Arthos, Leigh A Eller, Robert J O'Connell, Samuel Sinei, Lucas Maganga, Hannah Kibuuka, Sorachai Nitayaphan, Mangala Rao, Mary A Marovich, Shelly J Krebs, Morgane Rolland, Bette T Korber, George M Shaw, Nelson L Michael, Merlin L Robb, Sodsai Tovanabutra, and Jerome H Kim
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Immunologic diseases. Allergy ,RC581-607 ,Biology (General) ,QH301-705.5 - Abstract
[This corrects the article DOI: 10.1371/journal.ppat.1006510.].
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- 2017
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34. Rare HIV-1 transmitted/founder lineages identified by deep viral sequencing contribute to rapid shifts in dominant quasispecies during acute and early infection.
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Gustavo H Kijak, Eric Sanders-Buell, Agnes-Laurence Chenine, Michael A Eller, Nilu Goonetilleke, Rasmi Thomas, Sivan Leviyang, Elizabeth A Harbolick, Meera Bose, Phuc Pham, Celina Oropeza, Kultida Poltavee, Anne Marie O'Sullivan, Erik Billings, Melanie Merbah, Margaret C Costanzo, Joanna A Warren, Bonnie Slike, Hui Li, Kristina K Peachman, Will Fischer, Feng Gao, Claudia Cicala, James Arthos, Leigh A Eller, Robert J O'Connell, Samuel Sinei, Lucas Maganga, Hannah Kibuuka, Sorachai Nitayaphan, Mangala Rao, Mary A Marovich, Shelly J Krebs, Morgane Rolland, Bette T Korber, George M Shaw, Nelson L Michael, Merlin L Robb, Sodsai Tovanabutra, and Jerome H Kim
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Immunologic diseases. Allergy ,RC581-607 ,Biology (General) ,QH301-705.5 - Abstract
In order to inform the rational design of HIV-1 preventive and cure interventions it is critical to understand the events occurring during acute HIV-1 infection (AHI). Using viral deep sequencing on six participants from the early capture acute infection RV217 cohort, we have studied HIV-1 evolution in plasma collected twice weekly during the first weeks following the advent of viremia. The analysis of infections established by multiple transmitted/founder (T/F) viruses revealed novel viral profiles that included: a) the low-level persistence of minor T/F variants, b) the rapid replacement of the major T/F by a minor T/F, and c) an initial expansion of the minor T/F followed by a quick collapse of the same minor T/F to low frequency. In most participants, cytotoxic T-lymphocyte (CTL) escape was first detected at the end of peak viremia downslope, proceeded at higher rates than previously measured in HIV-1 infection, and usually occurred through the exploration of multiple mutational pathways within an epitope. The rapid emergence of CTL escape variants suggests a strong and early CTL response. Minor T/F viral strains can contribute to rapid and varied profiles of HIV-1 quasispecies evolution during AHI. Overall, our results demonstrate that early, deep, and frequent sampling is needed to investigate viral/host interaction during AHI, which could help identify prerequisites for prevention and cure of HIV-1 infection.
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- 2017
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35. HIV-1 sequences with more predicted glycans in acute infection were associated with the development of higher neutralization breadth
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Melanie Merbah, Eric Sanders-Buell, Gina Donofrio, Yifan Li, Meera Bose, Anne-Marie O’Sullivan, Samantha Townsley, Bonnie Slike, Hannah Kibuuka, Lucas Maganga, Sorachai Nitayaphan, Leigh-Ann Eller, Shelly Krebs, Sodsai Tovanabutra, Nelson Michael, Merlin Robb, and Morgane Rolland
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Microbiology ,QR1-502 ,Public aspects of medicine ,RA1-1270 - Published
- 2018
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36. Combining Viral Genetics and Statistical Modeling to Improve HIV-1 Time-of-infection Estimation towards Enhanced Vaccine Efficacy Assessment
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Raabya Rossenkhan, Morgane Rolland, Jan P.L. Labuschagne, Roux-Cil Ferreira, Craig A. Magaret, Lindsay N. Carpp, Frederick A. Matsen IV, Yunda Huang, Erika E. Rudnicki, Yuanyuan Zhang, Nonkululeko Ndabambi, Murray Logan, Ted Holzman, Melissa-Rose Abrahams, Colin Anthony, Sodsai Tovanabutra, Christopher Warth, Gordon Botha, David Matten, Sorachai Nitayaphan, Hannah Kibuuka, Fred K. Sawe, Denis Chopera, Leigh Anne Eller, Simon Travers, Merlin L. Robb, Carolyn Williamson, Peter B. Gilbert, and Paul T. Edlefsen
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HIV-1 ,infection time ,founder multiplicity ,leave-one-out-cross-validation (LOOCV) ,HIV-1 primary infection ,sequence analysis ,vaccine efficacy assessment ,acute and early HIV-1 infection ,Microbiology ,QR1-502 - Abstract
Knowledge of the time of HIV-1 infection and the multiplicity of viruses that establish HIV-1 infection is crucial for the in-depth analysis of clinical prevention efficacy trial outcomes. Better estimation methods would improve the ability to characterize immunological and genetic sequence correlates of efficacy within preventive efficacy trials of HIV-1 vaccines and monoclonal antibodies. We developed new methods for infection timing and multiplicity estimation using maximum likelihood estimators that shift and scale (calibrate) estimates by fitting true infection times and founder virus multiplicities to a linear regression model with independent variables defined by data on HIV-1 sequences, viral load, diagnostics, and sequence alignment statistics. Using Poisson models of measured mutation counts and phylogenetic trees, we analyzed longitudinal HIV-1 sequence data together with diagnostic and viral load data from the RV217 and CAPRISA 002 acute HIV-1 infection cohort studies. We used leave-one-out cross validation to evaluate the prediction error of these calibrated estimators versus that of existing estimators and found that both infection time and founder multiplicity can be estimated with improved accuracy and precision by calibration. Calibration considerably improved all estimators of time since HIV-1 infection, in terms of reducing bias to near zero and reducing root mean squared error (RMSE) to 5–10 days for sequences collected 1–2 months after infection. The calibration of multiplicity assessments yielded strong improvements with accurate predictions (ROC-AUC above 0.85) in all cases. These results have not yet been validated on external data, and the best-fitting models are likely to be less robust than simpler models to variation in sequencing conditions. For all evaluated models, these results demonstrate the value of calibration for improved estimation of founder multiplicity and of time since HIV-1 infection.
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- 2019
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37. Temporal Dynamics of CD8+ T Cell Effector Responses during Primary HIV Infection.
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Korey R Demers, George Makedonas, Marcus Buggert, Michael A Eller, Sarah J Ratcliffe, Nilu Goonetilleke, Chris K Li, Leigh Anne Eller, Kathleen Rono, Lucas Maganga, Sorachai Nitayaphan, Hannah Kibuuka, Jean-Pierre Routy, Mark K Slifka, Barton F Haynes, Andrew J McMichael, Nicole F Bernard, Merlin L Robb, and Michael R Betts
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Immunologic diseases. Allergy ,RC581-607 ,Biology (General) ,QH301-705.5 - Abstract
The loss of HIV-specific CD8+ T cell cytolytic function is a primary factor underlying progressive HIV infection, but whether HIV-specific CD8+ T cells initially possess cytolytic effector capacity, and when and why this may be lost during infection, is unclear. Here, we assessed CD8+ T cell functional evolution from primary to chronic HIV infection. We observed a profound expansion of perforin+ CD8+ T cells immediately following HIV infection that quickly waned after acute viremia resolution. Selective expression of the effector-associated transcription factors T-bet and eomesodermin in cytokine-producing HIV-specific CD8+ T cells differentiated HIV-specific from bulk memory CD8+ T cell effector expansion. As infection progressed expression of perforin was maintained in HIV-specific CD8+ T cells with high levels of T-bet, but not necessarily in the population of T-betLo HIV-specific CD8+ T cells that expand as infection progresses. Together, these data demonstrate that while HIV-specific CD8+ T cells in acute HIV infection initially possess cytolytic potential, progressive transcriptional dysregulation leads to the reduced CD8+ T cell perforin expression characteristic of chronic HIV infection.
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- 2016
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38. Sex and Urbanicity Contribute to Variation in Lymphocyte Distribution across Ugandan Populations.
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Prossy Naluyima, Leigh Anne Eller, Benson J Ouma, Denis Kyabaggu, Peter Kataaha, David Guwatudde, Hannah Kibuuka, Fred Wabwire-Mangen, Merlin L Robb, Nelson L Michael, Mark S de Souza, Johan K Sandberg, and Michael A Eller
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Medicine ,Science - Abstract
Management of patient care and interpretation of research data require evaluation of laboratory results in the context of reference data from populations with known health status to adequately diagnose disease or make a physiological assessment. Few studies have addressed the diversity of lymphocyte subsets in rural and urban Ugandan populations. Here, 663 healthy blood bank donors from semi-urban centers of Kampala consented to participate in a study to define lymphocyte reference ranges. Whole blood immunophenotyping was performed to determine the frequency and absolute counts of T, B, and NK cells using clinical flow cytometry. Results from blood bank donors were compared to a rural cohort from the district of Kayunga and more urban clinical trial participants from the capital city, Kampala. Relationships between hematological and lymphocyte parameters were also explored. In the semi-urban blood donors, females were significantly different from males in all parameters except the frequency of CD8 T and B cells. Females had higher absolute counts of CD4 T, CD8 T and B cells, whereas males had higher NK cell counts. NK cell frequency and counts were significantly higher in semi-urban blood donors, regardless of sex, compared to more urban study participants. CD8 T cell frequency and counts were significantly higher in the blood donors compared to the rural participants, irrespective of sex. Interestingly, basophil counts were positively associated with overall T cell counts. These findings suggest that both sex and level of cohort urbanicity may influence lymphocyte subset distributions in Ugandans.
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- 2016
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39. Epidemiology and Surveillance of Influenza Viruses in Uganda between 2008 and 2014.
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Fred Wabwire-Mangen, Derrick E Mimbe, Bernard Erima, Edison A Mworozi, Monica Millard, Hannah Kibuuka, Luswa Lukwago, Josephine Bwogi, Jocelyn Kiconco, Titus Tugume, Sophia Mulei, Christine Ikomera, Sharon Tsui, Stephen Malinzi, Simon Kasasa, Rodney Coldren, and Denis K Byarugaba
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Medicine ,Science - Abstract
Influenza surveillance was conducted in Uganda from October 2008 to December 2014 to identify and understand the epidemiology of circulating influenza strains in out-patient clinic attendees with influenza-like illness and inform control strategies.Surveillance was conducted at five hospital-based sentinel sites. Nasopharyngeal and/or oropharyngeal samples, epidemiological and clinical data were collected from enrolled patients. Real-time reverse transcription polymerase chain reaction (RT-PCR) was performed to identify and subtype influenza strains. Data were double-entered into an Epi Info 3.5.3 database and exported to STATA 13.0 software for analysis.Of the 6,628 patient samples tested, influenza virus infection was detected in 10.4% (n = 687/6,628) of the specimens. Several trends were observed: influenza circulates throughout the year with two peaks; the major one from September to November and a minor one from March to June. The predominant strains of influenza varied over the years: Seasonal Influenza A(H3) virus was predominant from 2008 to 2009 and from 2012 to 2014; Influenza A(H1N1)pdm01 was dominant in 2010; and Influenza B virus was dominant in 2011. The peaks generally coincided with times of higher humidity, lower temperature, and higher rainfall.Influenza circulated throughout the year in Uganda with two major peaks of outbreaks with similar strains circulating elsewhere in the region. Data on the circulating strains of influenza and its patterns of occurrence provided critical insights to informing the design and timing of influenza vaccines for influenza prevention in tropical regions of sub-Saharan Africa.
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- 2016
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40. How much does it cost to improve access to voluntary medical male circumcision among high-risk, low-income communities in Uganda?
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Bruce Larson, Allan Tindikahwa, George Mwidu, Hannah Kibuuka, and Fred Magala
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Medicine ,Science - Abstract
The Ugandan Ministry of Health has endorsed voluntary medical male circumcision as an HIV prevention strategy and has set ambitious goals (e.g., 4.2 million circumcisions by 2015). Innovative strategies to improve access for hard to reach, high risk, and poor populations are essential for reaching such goals. In 2009, the Makerere University Walter Reed Project began the first facility-based VMMC program in Uganda in a non-research setting. In addition, a mobile clinic began providing VMMC services to more remote, rural locations in 2011. The primary objective of this study was to estimate the average cost of performing VMMCs in the mobile clinic compared to those performed in health facilities (fixed sites). The difference between such costs is the cost of improving access to VMMC.A micro-costing approach was used to estimate costs from the service provider's perspective of a circumcision. Supply chain and higher-level program support costs are not included.The average cost (US$2012) of resources used per circumcision was $61 in the mobile program ($72 for more remote locations) compared to $34 at the fixed site. Costs for community mobilization, HIV testing, the initial medical exam, and staff for performing VMMC operations were similar for both programs. The cost of disposable surgical kits, the additional upfront cost for the mobile clinic, and additional costs for staff drive the differences in costs between the two programs. Cost estimates are relatively insensitive to patient flow over time.The MUWRP VMMC program improves access for hard to reach, relatively poor, and high-risk rural populations for a cost of $27-$38 per VMMC. Costs to patients to access services are almost certainly less in the mobile program, by reducing out-of-pocket travel expenses and lost time and associated income, all of which have been shown to be barriers for accessing treatment.
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- 2015
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41. Molecular epidemiology of influenza A/H3N2 viruses circulating in Uganda.
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Denis K Byarugaba, Mariette F Ducatez, Bernard Erima, Edison A Mworozi, Monica Millard, Hannah Kibuuka, Luswa Lukwago, Josephine Bwogi, Blanche B Kaira, Derrick Mimbe, David C Schnabel, Scott Krauss, Daniel Darnell, Richard J Webby, Robert G Webster, and Fred Wabwire-Mangen
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Medicine ,Science - Abstract
The increasing availability of complete influenza virus genomes is deepening our understanding of influenza evolutionary dynamics and facilitating the selection of vaccine strains. However, only one complete African influenza virus sequence is available in the public domain. Here we present a complete genome analysis of 59 influenza A/H3N2 viruses isolated from humans in Uganda during the 2008 and 2009 season. Isolates were recovered from hospital-based sentinel surveillance for influenza-like illnesses and their whole genome sequenced. The viruses circulating during these two seasons clearly differed from each other phylogenetically. They showed a slow evolution away from the 2009/10 recommended vaccine strain (A/Brisbane/10/07), instead clustering with the 2010/11 recommended vaccine strain (A/Perth/16/09) in the A/Victoria/208/09 clade, as observed in other global regions. All of the isolates carried the adamantane resistance marker S31N in the M2 gene and carried several markers of enhanced transmission; as expected, none carried any marker of neuraminidase inhibitor resistance. The hemagglutinin gene of the 2009 isolates differed from that of the 2008 isolates in antigenic sites A, B, D, and to a lesser extent, C and E indicating evidence of an early phylogenetic shift from the 2008 to 2009 viruses. The internal genes of the 2009 isolates were similar to those of one 2008 isolate, A/Uganda/MUWRP-050/2008. Another 2008 isolate had a truncated PB1-F2 protein. Whole genome sequencing can enhance surveillance of future seasonal changes in the viral genome which is crucial to ensure that selected vaccine strains are protective against the strains circulating in Eastern Africa. This data provides an important baseline for this surveillance. Overall the influenza virus activity in Uganda appears to mirror that observed in other regions of the southern hemisphere.
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- 2011
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42. Relatively low HIV infection rates in rural Uganda, but with high potential for a rise: a cohort study in Kayunga District, Uganda.
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David Guwatudde, Fred Wabwire-Mangen, Leigh Anne Eller, Michael Eller, Francine McCutchan, Hannah Kibuuka, Monica Millard, Nelson Sewankambo, David Serwadda, Nelson Michael, Merlin Robb, and Kayunga Cohort Research Team
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Medicine ,Science - Abstract
BACKGROUND: Few studies have been conducted in Uganda to identify and quantify the determinants of HIV-1 infection. We report results from a community-based cohort study, whose primary objectives were to determine HIV-1 prevalence, incidence, and determinants of these infections, among other objectives. METHODOLOGY: Consenting volunteers from the rural district of Kayunga in Uganda aged 15-49 years were enrolled between March and July 2006. Participants were evaluated every six months. A questionnaire that collected information on behavioral and other HIV-1 risk factors was administered, and a blood sample obtained for laboratory analysis at each study visit. PRINCIPAL FINDINGS: HIV-1 prevalence among the 2025 participants was 9.9% (95% CI = 8.6%-11.2%). By the end of 12 months of follow-up, 1689.7 person-years had been accumulated, with a median follow-up time of 11.97 months. Thirteen HIV-1 incident cases were detected giving an annual HIV-1 incidence of 0.77% (95% CI = 0.35-1.19). Prevalence of HSV-2 infection was 57% and was strongly associated with prevalent HIV-1 infection (adjusted Odds Ratio = 3.9, 95% CI = 2.50-6.17); as well as incident HIV-1 infection (adjusted Rate Ratio (RR) = 8.7, 95% CI = 1.11-67.2). The single most important behavioral characteristic associated with incident HIV infection was the number of times in the past 6 months, a participant had sex with person(s) they suspected/knew were having sex with others; attaining statistical significance at 10 times and higher (adjusted RR = 6.3, 95% CI = 1.73-23.1). By the end of 12 months of follow-up, 259 participants (13%) were lost to follow-up, 13 (0.6%) had died, and 2 (0.1%) had withdrawn consent. CONCLUSIONS: Despite relatively low HIV-1 incidence observed in this community, prevalence remains relatively high. In the presence of high prevalence of HSV-2 infection and the behavioral characteristic of having sex with more than one partner, there is potential for increase in HIV-1 incidence.
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- 2009
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43. Contraceptive use in women enrolled into preventive HIV vaccine trials: experience from a phase I/II trial in East Africa.
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Hannah Kibuuka, David Guwatudde, Robert Kimutai, Lucas Maganga, Leonard Maboko, Cecilia Watyema, Fredrick Sawe, Douglas Shaffer, Dickson Matsiko, Monica Millard, Nelson Michael, Fred Wabwire-Mangen, and Merlin Robb
- Subjects
Medicine ,Science - Abstract
HIV vaccine trials generally require that pregnant women are excluded from participation, and contraceptive methods must be used to prevent pregnancy during the trial. However, access to quality services and misconceptions associated with contraceptive methods may impact on their effective use in developing countries. We describe the pattern of contraceptive use in a multi-site phase I/IIa HIV Vaccine trial in East Africa (Uganda, Kenya and Tanzania) and factors that may have influenced their use during the trial.Pregnancy prevention counseling was provided to female participants during informed consent process and at each study visit. Participants' methods of contraception used were documented. Methods of contraceptives were provided on site. Pregnancy testing was done at designated visits during the trial. Obstacles to contraceptive use were identified and addressed at each visit.Overall, 103 (31.8%) of a total of 324 enrolled volunteers were females. Female participants were generally young with a mean age of 29(+/-7.2), married (49.5%) and had less than high school education (62.1%). Hormonal contraceptives were the most common method of contraception (58.3%) followed by condom use (22.3%). The distribution of methods of contraception among the three sites was similar except for more condom use and less abstinence in Uganda. The majority of women (85.4%) reported to contraceptive use prior to screening. The reasons for not using contraception included access to quality services, insufficient knowledge of certain methods, and misconceptions.Although hormonal contraceptives were frequently used by females participating in the vaccine trial, misconceptions and their incorrect use might have led to inconsistent use resulting in undesired pregnancies. The study underscores the need for an integrated approach to pregnancy prevention counseling during HIV vaccine trials.ClinicalTrials.gov NCT00123968.
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- 2009
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44. Reference intervals in healthy adult Ugandan blood donors and their impact on conducting international vaccine trials.
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Leigh Anne Eller, Michael A Eller, Benson Ouma, Peter Kataaha, Denis Kyabaggu, Richard Tumusiime, Joseph Wandege, Ronald Sanya, Warren B Sateren, Fred Wabwire-Mangen, Hannah Kibuuka, Merlin L Robb, Nelson L Michael, and Mark S de Souza
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Medicine ,Science - Abstract
BACKGROUND: Clinical trials are increasingly being conducted internationally. In order to ensure enrollment of healthy participants and proper safety evaluation of vaccine candidates, established reference intervals for clinical tests are required in the target population. METHODOLOGY/PRINCIPAL FINDINGS: We report a reference range study conducted in Ugandan adult blood bank donors establishing reference intervals for hematology and clinical chemistry parameters. Several differences were observed when compared to previously established values from the United States, most notably in neutrophils and eosinophils. CONCLUSIONS/SIGNIFICANCE: In a recently conducted vaccine trial in Uganda, 31 percent (n = 69) of volunteers screened (n = 223) were excluded due to hematologic abnormalities. If local reference ranges had been employed, 83% of those screened out due to these abnormalities could have been included in the study, drastically reducing workload and cost associated with the screening process. In addition, toxicity tables used in vaccine and drug trial safety evaluations may need adjustment as some clinical reference ranges determined in this study overlap with grade 1 and grade 2 adverse events.
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- 2008
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45. Epidemiology of Tuberculosis Among People Living With HIV in the African Cohort Study From 2013 to 2021
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Kavitha Ganesan, Ronald Mwesigwa, Nicole Dear, Allahna L. Esber, Domonique Reed, Hannah Kibuuka, Michael Iroezindu, Emmanuel Bahemana, John Owuoth, Valentine Singoei, Jonah Maswai, Ajay P. Parikh, Trevor A. Crowell, Julie A. Ake, Christina S. Polyak, Neha Shah, and Joseph S. Cavanaugh
- Subjects
Infectious Diseases ,Pharmacology (medical) - Published
- 2023
46. High-risk human papillomavirus genotype distribution among women living with and at risk for HIV in Africa
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Mkunde Chachage, Ajay P. Parikh, Anifrid Mahenge, Emmanuel Bahemana, Jonathan Mnkai, Wilbert Mbuya, Ruby Mcharo, Lucas Maganga, Jaqueline Mwamwaja, Reginald Gervas, Hannah Kibuuka, Jonah Maswai, Valentine Singoei, Michael Iroezindu, Abiola Fasina, Allahna Esber, Nicole Dear, Michelle Imbach, Trevor A. Crowell, Jaclyn Hern, Xiaofang Song, Michael Hoelscher, Christina S. Polyak, Julie A. Ake, and Christof Geldmacher
- Subjects
Infectious Diseases ,Immunology ,Immunology and Allergy - Published
- 2022
47. Perinatal Depressive Symptoms and Viral Non-suppression Among a Prospective Cohort of Pregnant Women Living with HIV in Nigeria, Kenya, Uganda, and Tanzania
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Tessa Concepcion, Jennifer Velloza, Christopher G. Kemp, Amritha Bhat, Ian M. Bennett, Deepa Rao, Christina S. Polyak, Julie A. Ake, Allahna Esber, Nicole Dear, Jonah Maswai, John Owuoth, Valentine Sing’oei, Emmanuel Bahemana, Michael Iroezindu, Hannah Kibuuka, and Pamela Y. Collins
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Social Work ,Social Psychology ,Nigeria ,HIV Infections ,Reproductive health and childbirth ,Perinatal ,Tanzania ,Viral non-suppression ,Cohort Studies ,Pregnancy ,Clinical Research ,Behavioral and Social Science ,Humans ,Uganda ,Prospective Studies ,Pediatric ,Depression ,Prevention ,Public Health, Environmental and Occupational Health ,HIV ,Kenya ,Brain Disorders ,AIDS ,Mental Health ,Good Health and Well Being ,Infectious Diseases ,Africa ,Public Health and Health Services ,HIV/AIDS ,Female ,Pregnant Women ,Public Health ,Infection - Abstract
Depression is common during pregnancy and is associated with reduced adherence to HIV-related care, though little is known about perinatal trajectories of depression and viral suppression among women living with HIV (WLHV) in sub-Saharan Africa. We sought to assess any association between perinatal depressive symptoms and viral non-suppression among WLWH. Depressive symptomatology and viral load data were collected every 6 months from WLWH enrolled in the African Cohort Study (AFRICOS; January 2013–February 2020). Generalized estimating equations modeled associations between depressive symptoms [Center for Epidemiological Studies Depression (CES-D) ≥ 16] and viral non-suppression. Of 1722 WLWH, 248 (14.4%) had at least one pregnancy (291 total) and for 61 pregnancies (21.0%), women reported depressive symptoms (13.4% pre-conception, 7.6% pregnancy, 5.5% one-year postpartum). Depressive symptomatology was associated with increased odds of viral non-suppression (aOR 2.2; 95% CI 1.2–4.0, p = 0.011). Identification and treatment of depression among women with HIV may improve HIV outcomes for mothers.
- Published
- 2022
48. Genome Sequence Analysis of a Wohlfahrtiimonas chitiniclastica Strain Isolated from a Septic Wound of a Hospitalized Patient in Uganda
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Denis K. Byarugaba, Bernard Erima, Godfrey Wokorach, Florence Najjuka, James Kiyengo, Yoon I. Kwak, Ana Ong, Rosslyn Maybank, Lan Preston, Emma Mills, Patrick McGann, Hannah Kibuuka, Ambrose K. Musinguzi, and Fred Wabwire-Mangen
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Immunology and Microbiology (miscellaneous) ,Genetics ,Molecular Biology - Abstract
We report a genome sequence of Wohlfahrtiimonas chitiniclastica strain MUWRP0946, isolated from a hospitalized patient in Uganda. The genome size was 2.08 million bases, and the genome completeness was 94.22%. The strain carries tetracycline, folate pathway antagonist, β-lactam, and aminoglycoside antibiotic resistance genes.
- Published
- 2023
49. Wide distribution of Mediterranean and African Spotted fever agents and the first identification of Israeli Spotted Fever agent in ticks in Uganda
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Wilfred Eneku, Bernard Erima, Anatoli Maranda Byaruhanga, Gladys Atim, Titus Tugume, Qouilazoni A. Ukuli, Hannah Kibuuka, Edison Mworozi, Christina Burrows, Jeffrey W. Koehler, Nora G. Cleary, Michael E. von Fricken, Robert Tweyongyere, Fred Wabwire-Mangen, and Denis K. Byarugaba
- Abstract
Rickettsiamicroorganisms are causative agents of several neglected emerging infectious diseases transmitted to humans by ticks among other arthropod vectors. In this study, ticks were collected from four geographical regions of Uganda, pooled in sizes of 1-179 ticks based on location, tick species, life stage, host, and time of collection, and were tested by real time PCR forRickettsiaspecies harboured. The tick pools were tested with primers targetinggltA, 17kDaandompA genes, followed by Sanger sequencing of17kDaandompAgenes. Of the 471 tick pools tested, 116 (24.6%) were positive forRickettsiaspp. by thegltAprimers. The prevalence ofRickettsiavaried by district with Gulu recording the highest (30.1%) followed by Luwero (28.1%) and Kasese had the lowest (14%). Tick pools with highest positivity rates were from livestock (cattle, goats, sheep, and pigs), 26.9%, followed by vegetation 23.1% and pets (dogs and cats) 19.7%. Of 116gltA-positive tick pools, 86 pools were positive using17kDaprimers of which 48 purified PCR products were successfully sequenced. The predominantRickettsiaspp. identified wasR. africae(n=15) in four tick species, followed byR. conorii(n=5) in three tick species (Haemaphysalis elliptica, Rhipicephalus appendiculatus, andRh. decoloratus).Rickettsia conoriisubsp.israelensiswas detected in one tick pool. These findings indicate that multipleRickettsiaspp. capable of causing human illness are circulating in the four diverse geographical regions of Uganda including new strains previously known to occur in the Mediterranean region. Physicians should be informed aboutRickettsiaspp. infections as potential causes for acute febrile illnesses in these regions. Continued and expanded surveillance is essential to further identify and locate potential hotspots withRickettsiaspp. of concern.Author SummaryTick-borne rickettsioses are emerging infectious diseases of public health importance worldwide. Spotted fever rickettsioses transmitted by ticks can cause mild to severe human illness depending on theRickettsiaspp. and co-morbidities. Their diagnosis is challenging due to non-specific symptoms particularly in limited resource settings. Little is known about their prevalence in Uganda. Using entomological and molecular tools, we surveyed and studied tick-borne spotted fever rickettsioses in five districts from four diverse eco-regions of Uganda. Overall, 24.6% (116/471) tick pools were positive forRickettsiaspecies. By sequencing the17kDaandompAgenes ofRickettsia, we identifiedR. africaeas the most common agent, followed byR. conoriiandR. conoriisubsp.israelensis. The findings indicate multipleRickettsiaspp. that can cause febrile illness in humans are circulating in the four geographically diverse regions of Uganda. Physicians should be aware these agents are potential causes of febrile illness in these areas, particularly in individuals who encounter livestock or their grazing areas.
- Published
- 2023
50. Predictors of All-Cause Mortality Among People With Human Immunodeficiency Virus (HIV) in a Prospective Cohort Study in East Africa and Nigeria
- Author
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Hannah, Kibuuka, Ezra, Musingye, Betty, Mwesigwa, Michael, Semwogerere, Michael, Iroezindu, Emmanuel, Bahemana, Jonah, Maswai, John, Owuoth, Allahna, Esber, Nicole, Dear, Trevor A, Crowell, Christina S, Polyak, Julie A, Ake, and Willyhelmina, Olomi
- Subjects
Cohort Studies ,Male ,Microbiology (medical) ,Infectious Diseases ,Anti-HIV Agents ,HIV ,Humans ,Nigeria ,Female ,HIV Infections ,Prospective Studies ,Tanzania - Abstract
Background Introduction of antiretroviral therapy (ART) has been associated with a decline in human immunodeficiency virus (HIV)-related mortality, although HIV remains a leading cause of death in sub-Saharan Africa. We describe all-cause mortality and its predictors in people living with HIV (PLWH) in the African Cohort Study (AFRICOS). Methods AFRICOS enrolls participants with or without HIV at 12 sites in Kenya, Uganda, Tanzania, and Nigeria. Evaluations every 6 months include sociobehavioral questionnaires, medical history, physical examination, and laboratory tests. Mortality data are collected from medical records and survivor interviews. Multivariable Cox proportional hazards models were used to calculate adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for factors associated with mortality. Results From 2013 through 2020, 2724 PLWH completed at least 1 follow-up visit or experienced death. Of these 58.4% were females, 25.8% were aged ≥ 50 years, and 98.3% were ART-experienced. We observed 11.42 deaths per 1000 person-years (95% CI: 9.53–13.68) with causes ascertained in 54% of participants. Deaths were caused by malignancy (28.1%), infections (29.7%), and other non-HIV related conditions. Predictors of mortality included CD4 ≤ 350 cells/µL (aHR 2.01 [95% CI: 1.31–3.08]), a log10copies/mL increase of viral load (aHR 1.36 [95% CI: 1.22–1.51]), recent fever (aHR 1.85[95% CI: 1.22–2.81]), body mass index Conclusions The mortality rate was low in this cohort of mostly virally suppressed PLWH. Patterns of deaths and identified predictors suggest multiple targets for interventions to reduce mortality.
- Published
- 2021
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