27 results on '"Hannah Kibuuka"'
Search Results
2. 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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3. 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
4. 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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5. 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
6. 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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7. 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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8. 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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9. 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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10. 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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11. 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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12. 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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13. 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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14. 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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15. 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
- Subjects
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
- Full Text
- View/download PDF
16. 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
- Subjects
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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17. 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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18. 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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19. 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
- Subjects
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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20. 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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Raabya Rossenkhan, Lydia Bonar, Jan P.L. Labuschagne, Meera Bose, Kultida Poltavee, Elizabeth A. Harbolick, Daniel B. Reeves, Morgane Rolland, Jerome H. Kim, Bethany L. Dearlove, Leigh Anne Eller, Merlin L. Robb, Gustavo H. Kijak, Hannah Kibuuka, Paul T. Edlefsen, Eric Lewitus, Phuc Pham, Bahar Ahani, Annemarie O'Sullivan, Shana Miller, Eric Sanders-Buell, Sorachai Nitayaphan, Fred Sawe, Jenica Lee, Christopher L. Owen, Yifan Li, Robert Gramzinski, Lucas Maganga, Nelson L. Michael, and Sodsai Tovanabutra
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Male ,RNA viruses ,Time Factors ,Human immunodeficiency virus (HIV) ,HIV Infections ,medicine.disease_cause ,Pathology and Laboratory Medicine ,Database and Informatics Methods ,Immunodeficiency Viruses ,Medicine and Health Sciences ,Medicine ,Prospective Studies ,Biology (General) ,Data Management ,0303 health sciences ,Vaccines ,Molecular dating ,030302 biochemistry & molecular biology ,Phylogenetic Analysis ,Africa, Eastern ,Viral Load ,Thailand ,Phylogenetics ,Infectious Diseases ,Method comparison ,Molecular Diagnostic Techniques ,Medical Microbiology ,Viral Pathogens ,Cohort ,Viruses ,Physical Sciences ,Female ,Pathogens ,Viral load ,Sequence Analysis ,Research Article ,Adult ,medicine.medical_specialty ,Computer and Information Sciences ,Infectious Disease Control ,Bioinformatics ,QH301-705.5 ,Immunology ,Viremia ,Genome, Viral ,Research and Analysis Methods ,Microbiology ,Drug levels ,03 medical and health sciences ,Internal medicine ,Virology ,Retroviruses ,Genetics ,East africa ,Humans ,Evolutionary Systematics ,Molecular Biology ,Microbial Pathogens ,030304 developmental biology ,Taxonomy ,Evolutionary Biology ,business.industry ,Lentivirus ,Organisms ,Biology and Life Sciences ,HIV ,Eigenvalues ,RC581-607 ,medicine.disease ,Algebra ,Linear Algebra ,HIV-1 ,Parasitology ,Immunologic diseases. Allergy ,business ,Sequence Alignment ,Viral Transmission and Infection ,Mathematics - 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., Author summary HIV-1 infected individuals rarely know when they became infected but knowing when an infection occurred provides critical information regarding HIV-1 pathogenesis and epidemiology. Using a unique cohort in which infection was known to have occurred in a narrow interval, we investigated methods to estimate the timing of infections. Several methods suggested that HIV-1 infection typically occurs a median of one week before the infection can be detected by HIV-1 RNA testing. Going forward, we provide a strategy that can be used to elucidate the origin of an acute/early infection.
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- 2020
21. Factors influencing estimates of HIV-1 infection timing using BEAST
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Elizabeth A. Harbolick, Hannah Kibuuka, Leigh Anne Eller, Bethany L. Dearlove, Lydia Bonar, Yifan Li, Sodsai Tovanabutra, Robert Gramzinski, Phuc Pham, Eric Lewitus, Merlin L. Robb, Jerome H. Kim, Meera Bose, Sandhya Vasan, Annemarie O'Sullivan, Lucas Maganga, Shana Miller, Sorachai Nitayaphan, Morgane Rolland, Gustavo H. Kijak, Jenica Lee, Fred Sawe, Christopher L. Owen, Nelson L. Michael, Eric Sanders-Buell, Kultida Poltavee, Bahar Ahani, and Global Health
- Subjects
RNA viruses ,Male ,0106 biological sciences ,0301 basic medicine ,Time Factors ,Genes, Viral ,HIV Infections ,Pathology and Laboratory Medicine ,Spectrum analysis techniques ,01 natural sciences ,Genome ,Cohort Studies ,Immunodeficiency Viruses ,Cell Signaling ,Medicine and Health Sciences ,Longitudinal Studies ,Biology (General) ,Molecular clock ,Phylogeny ,Data Management ,Likelihood Functions ,Ecology ,Phylogenetic tree ,Phylogenetic Analysis ,Genomics ,Phylogenetics ,Computational Theory and Mathematics ,Medical Microbiology ,Viral Pathogens ,Modeling and Simulation ,Viruses ,Physical Sciences ,Cohort ,Female ,Pathogens ,Genomic Signal Processing ,Research Article ,Signal Transduction ,Computer and Information Sciences ,QH301-705.5 ,Bayesian probability ,Biology ,Microbiology ,Models, Biological ,010603 evolutionary biology ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,NMR spectroscopy ,Retroviruses ,Genetics ,Humans ,Evolutionary Systematics ,Microbial Pathogens ,Molecular Biology ,Gene ,Ecology, Evolution, Behavior and Systematics ,Taxonomy ,Evolutionary Biology ,Models, Genetic ,Lentivirus ,Organisms ,Biology and Life Sciences ,HIV ,Computational Biology ,Genetic Variation ,Eigenvalues ,Bayes Theorem ,Cell Biology ,Genome Analysis ,Research and analysis methods ,Algebra ,030104 developmental biology ,Linear Algebra ,Evolutionary biology ,NMR relaxation ,HIV-1 ,Mathematics ,Software - 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., Author summary Molecular dating using phylogenetics allows us to estimate the date of an infection from time-stamped within-host sequences alone. There are large datasets of HIV-1 sequences, but genome and gene analyses are not often performed in parallel and rarely with the possibility to compare results against a known narrow window of infection. We showed that all but the longest genes are near-clonal in acute infection, with little information for dating purposes. For infections with single founders, we estimated the eclipse phase—the time between HIV-1 exposure and the first positive diagnostic test—to last between one and two weeks using env, gag, pol and near full-length genomes. This approach could be used to narrow the date of suspected infection in ongoing clinical trials for the prevention of HIV-1 infection.
- Published
- 2021
22. HIV virologic failure and its predictors among HIV-infected adults on antiretroviral therapy in the African Cohort Study
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Babajide Keshinro, Christina S Polyak, John Owuoth, Lucas Maganga, Domonique Reed, Ezra Musingye, Leigh Anne Eller, Huub C. Gelderblom, Trevor A Crowell, Rosemary Namagembe, Hannah Kibuuka, Samoel Khamadi, Fatim Cham, Monica Millard, Michael Semwogerere, Jonah Maswai, Emmanuel Bahemana, Alice Nambuya, Julie A Ake, Yakubu Adamu, Cate Kafeero, Valentine Singoei, Merlin L. Robb, Allan Tindikahwa, Francis Kiweewa, and Allahna Esber
- Subjects
RNA viruses ,Male ,0301 basic medicine ,Viral Diseases ,Multivariate analysis ,Fevers ,HIV Infections ,Pathology and Laboratory Medicine ,Cohort Studies ,0302 clinical medicine ,Immunodeficiency Viruses ,Medicine and Health Sciences ,Public and Occupational Health ,Treatment Failure ,030212 general & internal medicine ,Young adult ,Multidisciplinary ,virus diseases ,Viral Load ,Middle Aged ,Vaccination and Immunization ,Viral Persistence and Latency ,3. Good health ,Infectious Diseases ,Anti-Retroviral Agents ,Medical Microbiology ,Research Design ,Viral Pathogens ,Viruses ,Medicine ,RNA, Viral ,Female ,Pathogens ,Viral load ,Research Article ,Cohort study ,Adult ,Risk ,medicine.medical_specialty ,Adolescent ,Science ,Immunology ,030106 microbiology ,Antiretroviral Therapy ,Research and Analysis Methods ,Microbiology ,Young Adult ,03 medical and health sciences ,Signs and Symptoms ,Pharmacotherapy ,Antiviral Therapy ,Diagnostic Medicine ,Predictive Value of Tests ,Virology ,Internal medicine ,Retroviruses ,medicine ,Humans ,Viremia ,Microbial Pathogens ,business.industry ,Lentivirus ,Organisms ,Biology and Life Sciences ,HIV ,Confidence interval ,CD4 Lymphocyte Count ,Regimen ,Relative risk ,Africa ,Multivariate Analysis ,HIV-1 ,Linear Models ,Preventive Medicine ,business ,Viral Transmission and Infection - Abstract
Introduction The 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 methods We 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. Results 2054 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. Conclusion In 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.
- Published
- 2019
23. Epidemiology and Surveillance of Influenza Viruses in Uganda between 2008 and 2014
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Jocelyn Kiconco, Hannah Kibuuka, Denis K. Byarugaba, Sophia Mulei, Simon Kasasa, Luswa Lukwago, Christine Ikomera, Edison Mworozi, Stephen Malinzi, Bernard Erima, Derrick Mimbe, Josephine Bwogi, Sharon Tsui, Titus Tugume, Fred Wabwire-Mangen, Monica Millard, and Rodney L. Coldren
- Subjects
RNA viruses ,Male ,0301 basic medicine ,Viral Diseases ,Veterinary medicine ,Epidemiology ,Rain ,Oropharynx ,lcsh:Medicine ,medicine.disease_cause ,Animal Diseases ,Geographical Locations ,Seasonal influenza ,Influenza A Virus, H1N1 Subtype ,0302 clinical medicine ,Zoonoses ,Nasopharynx ,Medicine and Health Sciences ,Prevalence ,Influenza A virus ,Uganda ,030212 general & internal medicine ,Child ,lcsh:Science ,Pathology and laboratory medicine ,Multidisciplinary ,Temperature ,virus diseases ,Medical microbiology ,Infectious Diseases ,Child, Preschool ,Viruses ,Human mortality from H5N1 ,RNA, Viral ,Swine Influenza ,Female ,Seasons ,Pathogens ,Research Article ,medicine.medical_specialty ,Infectious Disease Control ,Disease Surveillance ,Real-Time Polymerase Chain Reaction ,Microbiology ,Virus ,Animal Influenza ,03 medical and health sciences ,Influenza, Human ,Influenza prevention ,medicine ,Influenza viruses ,Humans ,Biology and life sciences ,business.industry ,lcsh:R ,Organisms ,Viral pathogens ,Infant ,Outbreak ,Humidity ,030112 virology ,Virology ,Influenza ,Influenza A virus subtype H5N1 ,Microbial pathogens ,Influenza B virus ,Infectious Disease Surveillance ,People and Places ,Africa ,Earth Sciences ,lcsh:Q ,business ,Zoology ,Orthomyxoviruses - Abstract
Introduction 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. Methodology 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. Results 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. Conclusion 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.
- Published
- 2016
24. How much does it cost to improve access to voluntary medical male circumcision among high-risk, low-income communities in Uganda?
- Author
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Hannah Kibuuka, Bruce A. Larson, George Mwidu, Fred Magala, and Allan Tindikahwa
- Subjects
Program evaluation ,Male ,Cost estimate ,Cost-Benefit Analysis ,Developing country ,lcsh:Medicine ,HIV Infections ,Health Services Accessibility ,Nursing ,Medicine ,Humans ,Operations management ,Uganda ,lcsh:Science ,Poverty ,Average cost ,health care economics and organizations ,Multidisciplinary ,Cost–benefit analysis ,business.industry ,lcsh:R ,Community mobilization ,Circumcision, Male ,Mobile clinic ,lcsh:Q ,Health Facilities ,business ,Research Article - Abstract
Background 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. Methods 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. Results 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. Conclusion 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.
- Published
- 2015
25. B cell depletion in HIV-1 subtype A infected Ugandan adults: relationship to CD4 T cell count, viral load and humoral immune responses
- Author
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Hannah Kibuuka, Benson J. Ouma, Britta Flach, Mark de Souza, Peter O. Oballah, Fred Wabwire-Mangen, Merlin L. Robb, Leigh Anne Eller, Victoria R. Polonis, David C. Montefiori, Bruce K. Brown, Michael A. Eller, and Nelson L. Michael
- Subjects
lcsh:Medicine ,HIV Infections ,HIV Envelope Protein gp120 ,Immunodeficiency Viruses ,Uganda ,Neutralizing antibody ,lcsh:Science ,Recombination, Genetic ,B-Lymphocytes ,Multidisciplinary ,biology ,Antibody titer ,virus diseases ,T-Lymphocytes, Helper-Inducer ,Middle Aged ,Viral Load ,Titer ,medicine.anatomical_structure ,Medicine ,Infectious diseases ,Antibody ,Viral load ,Research Article ,Adult ,Adolescent ,T cell ,Retrovirology and HIV immunopathogenesis ,Viral diseases ,Microbiology ,Lymphocyte Depletion ,Young Adult ,Immune system ,Neutralization Tests ,Virology ,medicine ,Humans ,Biology ,B cell ,lcsh:R ,Antibody-Dependent Cell Cytotoxicity ,HIV ,Antibodies, Neutralizing ,CD4 Lymphocyte Count ,Immunity, Humoral ,Case-Control Studies ,Immunology ,biology.protein ,HIV-1 ,lcsh:Q - Abstract
To better understand the nature of B cell dysfunctions in subjects infected with HIV-1 subtype A, a rural cohort of 50 treatment-naive Ugandan patients chronically infected with HIV-1 subtype A was studied, and the relationship between B cell depletion and HIV disease was assessed. B cell absolute counts were found to be significantly lower in HIV-1+ patients, when compared to community matched negative controls (p
- Published
- 2011
26. Contraceptive Use in Women Enrolled into Preventive HIV Vaccine Trials: Experience from a Phase I/II Trial in East Africa
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Fred Wabwire-Mangen, Monica Millard, David Guwatudde, Hannah Kibuuka, Leonard Maboko, Nelson L. Michael, Fredrick Sawe, Robert Kimutai, Cecilia Watyema, Douglas Shaffer, Dickson Matsiko, Lucas Maganga, and Merlin L. Robb
- Subjects
Infectious Diseases/Epidemiology and Control of Infectious Diseases ,Adult ,medicine.medical_specialty ,Contraceptive Prevalence Surveys ,lcsh:Medicine ,Public Health and Epidemiology/Infectious Diseases ,HIV Infections ,Tanzania ,Women in development ,law.invention ,Clinical Trials, Phase II as Topic ,Condom ,law ,Informed consent ,Contraceptive Agents, Female ,medicine ,Humans ,Uganda ,HIV vaccine ,lcsh:Science ,AIDS Vaccines ,Gynecology ,Multidisciplinary ,Clinical Trials, Phase I as Topic ,business.industry ,lcsh:R ,Vaccine trial ,Middle Aged ,Kenya ,Clinical trial ,Family planning ,Data Interpretation, Statistical ,Family medicine ,Public Health and Epidemiology/Preventive Medicine ,lcsh:Q ,Female ,business ,Research Article - Abstract
Background: 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. Methods: 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. Results: Overall, 103 (31.8%) of a total of 324 enrolled volunteers were females. Female participants were generally young with a mean age of 29(67.2), 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. Conclusion: 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. Trial Registration: ClinicalTrials.gov NCT00123968
- Published
- 2009
27. Reference Intervals in Healthy Adult Ugandan Blood Donors and Their Impact on Conducting International Vaccine Trials
- Author
-
Mark de Souza, Leigh Anne Eller, Richard Tumusiime, Nelson L. Michael, Benson J. Ouma, Denis Kyabaggu, Joseph Wandege, Hannah Kibuuka, Fred Wabwire-Mangen, Michael A. Eller, Merlin L. Robb, Ronald Sanya, Peter Kataaha, and Warren B. Sateren
- Subjects
Adult ,Male ,Clinical tests ,medicine.medical_specialty ,Adolescent ,International Cooperation ,Public Health and Epidemiology ,Black People ,lcsh:Medicine ,Blood Donors ,Reference range ,Reference Values ,Internal medicine ,Humans ,Medicine ,Uganda ,lcsh:Science ,Adverse effect ,Virology/Vaccines ,Blood Specimen Collection ,Clinical Trials as Topic ,Vaccines ,Multidisciplinary ,Hematology ,business.industry ,Evidence-Based Healthcare/Clinical Decision-Making ,lcsh:R ,Vaccine trial ,Workload ,Middle Aged ,Reference intervals ,Clinical trial ,Chemistry ,Health ,Immunology ,Female ,lcsh:Q ,business ,Blood Chemical Analysis ,Research Article - 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.
- Published
- 2008
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