Browsing by Author "Kaleebu, Pontiano"

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    CLSI-Derived Hematology and Biochemistry Reference Intervals for Healthy Adults in Eastern and Southern Africa
    (2009-02-06) Karita, Etienne; Ketter, Nzeera; Price, Matt A; Kayitenkore, Kayitesi; Kaleebu, Pontiano; Nanvubya, Annet; Anzala, Omu; Jaoko, Walter; Mutua, Gaudensia; Ruzagira, Eugene; Mulenga, Joseph; Sanders, Eduard J.; Mwangome, Mary; Allen, Susan; Bwanika, Agnes; Bahemuka, Ubaldo; Awuondo, Ken; Omosa, Gloria; Farah, Bashir; Amornkul, Pauli; Birungi, Josephine; Yates, Sarah; Stoll-Johnson, Lisa; Gilmour, Jill; Stevens, Gwynn; Shutes, Erin; Manigart, Olivier; Hughes, Peter; Dally, Len; Scott, Janet; Stevens, Wendy; Fast, Pat; Kamali, Anatoli
    Background: Clinical laboratory reference intervals have not been established in many African countries, and non-local intervals are commonly used in clinical trials to screen and monitor adverse events (AEs) among African participants. Using laboratory reference intervals derived from other populations excludes potential trial volunteers in Africa and makes AE assessment challenging. The objective of this study was to establish clinical laboratory reference intervals for 25 hematology, immunology and biochemistry values among healthy African adults typical of those who might join a clinical trial. Methods and Findings: Equal proportions of men and women were invited to participate in a cross sectional study at seven clinical centers (Kigali, Rwanda; Masaka and Entebbe, Uganda; two in Nairobi and one in Kilifi, Kenya; and Lusaka, Zambia). All laboratories used hematology, immunology and biochemistry analyzers validated by an independent clinical laboratory. Clinical and Laboratory Standards Institute guidelines were followed to create study consensus intervals. For comparison, AE grading criteria published by the U.S. National Institute of Allergy and Infectious Diseases Division of AIDS (DAIDS) and other U.S. reference intervals were used. 2,990 potential volunteers were screened, and 2,105 (1,083 men and 1,022 women) were included in the analysis. While some significant gender and regional differences were observed, creating consensus African study intervals from the complete data was possible for 18 of the 25 analytes. Compared to reference intervals from the U.S., we found lower hematocrit and hemoglobin levels, particularly among women, lower white blood cell and neutrophil counts, and lower amylase. Both genders had elevated eosinophil counts, immunoglobulin G, total and direct bilirubin, lactate dehydrogenase and creatine phosphokinase, the latter being more pronounced among women. When graded against U.S.-derived DAIDS AE grading criteria, we observed 774 (35.3%) volunteers with grade one or higher results; 314 (14.9%) had elevated total bilirubin, and 201 (9.6%) had low neutrophil counts. These otherwise healthy volunteers would be excluded or would require special exemption to participate in many clinical trials. Conclusions: To accelerate clinical trials in Africa, and to improve their scientific validity, locally appropriate reference ranges should be used. This study provides ranges that will inform inclusion criteria and evaluation of adverse events for studies in these regions of Africa.
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    Community‑based ART distribution system can effectively facilitate long‑term program retention and low‑rates of death and virologic failure in rural Uganda
    (AIDS Research Therapy, 2015) Okoboi, Stephen; Ding, Erin; Persuad, Steven; Wangisi, Jonathan; Birungi, Josephine; Shurgold, Susan; Kato, Darius; Nyonyintono, Maureen; Egessa, Aggrey; Bakanda, Celestin; Munderi, Paula; Kaleebu, Pontiano; Moore, David M.
    Background: Community-drug distribution point is a care model for stable patients in the community designed to make ART delivery more efficient for the health system and provide appropriate support to encourage long-term retention of patients. We examined program retention among ART program participants in rural Uganda, which has used a community-based distribution model of ART delivery since 2004. Methods: We analyzed data of all patients >18 years who initiated ART in Jinja, Ugandan site of The AIDS Support Organization between January 1, 2004 and July 31, 2009. Participants attended clinic or outreach visits every 2–3 months and had CD4 cell counts measured every 6 months. Retention to care was defined as any patient with at least one visit in the 6 months before June 1, 2013. We then identified participants with at least one visit in the6 months before June 1, 2013 and examined associations with mortality and lost-to-follow-up (LTFU). Participants with >4 years of follow up during August, 2012 to May, 2013 had viral load conducted, since no routine viral load testing was available. Results: A total of 3345 participants began ART during 2004–2009. The median time on ART in June 2013 was 5.69 years. A total of 1335 (40 %) were residents of Jinja district and 2005 (60 %) resided in outlying districts. Of these, 2322 (69 %) were retained in care, 577 (17 %) died, 161 (5 %) transferred out and 285 (9 %) were LTFU. Factors associated with mortality or LTFU included male gender, [Adjusted Hazard Ratio (AHR) = 1.56; 95 % CI 1.28–1.9], CD4 cell count <50 cells/μL (AHR = 4.09; 95 % CI 3.13–5.36) or 50–199 cells/μL (AHR = 1.86; 95 % CI 1.46–2.37); ART initiation and WHO stages 3 (AHR = 1.35; 95 % CI 1.1–1.66) or 4 (AHR = 1.74; 95 % CI 1.23–2.45). Residence outside of Jinja district was not associated with mortality/LTFU (p value = 0.562). Of 870 participants who had VL tests, 756 (87 %) had VLs <50 copies/mL. Conclusion: Community-based ART distribution systems can effectively mitigate the barriers to program retention and result in good rates of Virologic suppression.
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    Community‑based ART distribution system can effectively facilitate long‑term program retention and low‑rates of death and virologic failure in rural Uganda
    (BioMed Central Ltd., 2015-11-12) Okoboi, Stephen; Ding, Erin; Persuad, Steven; Wangisi, Jonathan; Birungi, Josephine; Shurgold, Susan; Kato, Darius; Nyonyintono, Maureen; Egessa, Aggrey; Bakanda, Celestin; Munderi, Paula; Kaleebu, Pontiano; Moore, David M.
    Background: Community-drug distribution point is a care model for stable patients in the community designed to make ART delivery more efficient for the health system and provide appropriate support to encourage long-term retention of patients. We examined program retention among ART program participants in rural Uganda, which has used a community-based distribution model of ART delivery since 2004. Methods: We analyzed data of all patients >18 years who initiated ART in Jinja, Ugandan site of The AIDS Support Organization between January 1, 2004 and July 31, 2009. Participants attended clinic or outreach visits every 2–3 months and had CD4 cell counts measured every 6 months. Retention to care was defined as any patient with at least one visit in the 6 months before June 1, 2013. We then identified participants with at least one visit in the 6 months before June 1, 2013 and examined associations with mortality and lost-to-follow-up (LTFU). Participants with >4 years of follow up during August, 2012 to May, 2013 had viral load conducted, since no routine viral load testing was available. Results: A total of 3345 participants began ART during 2004–2009. The median time on ART in June 2013 was 5.69 years. A total of 1335 (40 %) were residents of Jinja district and 2005 (60 %) resided in outlying districts. Of these, 2322 (69 %) were retained in care, 577 (17 %) died, 161 (5 %) transferred out and 285 (9 %) were LTFU. Factors associated with mortality or LTFU included male gender, [Adjusted Hazard Ratio (AHR) = 1.56; 95 % CI 1.28–1.9], CD4 cell count <50 cells/μL (AHR = 4.09; 95 % CI 3.13–5.36) or 50–199 cells/μL (AHR = 1.86; 95 % CI 1.46–2.37); ART initiation and WHO stages 3 (AHR = 1.35; 95 % CI 1.1–1.66) or 4 (AHR = 1.74; 95 % CI 1.23–2.45). Residence outside of Jinja district was not associated with mortality/LTFU (p value = 0.562). Of 870 participants who had VL tests, 756 (87 %) had VLs <50 copies/mL. Conclusion: Community-based ART distribution systems can effectively mitigate the barriers to program retention and result in good rates of virologic suppression.
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    Concordant Proficiency in Measurement of T-Cell Immunity in Human Immunodeficiency Virus Vaccine Clinical Trials by Peripheral Blood Mononuclear Cell and Enzyme-Linked Immunospot Assays in Laboratories from Three Continents
    (Clinical and vaccine immunology, 2009-02) Boaz, Mark J.; Hayes, Peter; Tarragona, Tony; Seamons, Laura; Cooper, Andrew; Birungi, Josephine; Kitandwe, Paul; Semaganda, Aloysius; Kaleebu, Pontiano; Stevens, Gwynneth; Anzala, Omu; Farah, Bashir; Ogola, Simon; Indangasi, Jackton; Mhlanga, Patrick; Eeden, Melanie Van; Thakar, Madhuri; Pujari, Ashwini; Mishra, Shadri; Goonetilleke, Nilu; Moore, Stephen; Mahmoud, Abdul; Sathyamoorthy, Pattabiraman; Mahalingam, Jayashri; Narayanan, Paranji R.; Ramanathan, Vadakkuppattu D.; Cox, Josephine H.; Dally, Len; Gill, Dilbinder K.; Gilmour, Jill
    The gamma interferon (IFN-_) enzyme-linked immunospot (ELISPOT) assay is used routinely to evaluate the potency of human immunodeficiency virus (HIV) vaccine candidates and other vaccine candidates. In order to compare candidates and pool data from multiple trial laboratories, validated standardized methods must be applied across laboratories. Proficiency panels are a key part of a comprehensive quality assurance program to monitor inter- and intralaboratory performance, as well as assay performance, over time. Seven International AIDS Vaccine Initiative-sponsored trial sites participated in the proficiency panels described in this study. At each laboratory, two operators independently processed identical sample sets consisting of frozen peripheral blood mononuclear cell (PBMC) samples from different donors by using four blind stimuli. PBMCM recovery and viability after overnight resting and the IFN-_ ELISPOT assay performance were assessed. All sites demonstrated good performance in PBMC thawing and resting, with a median recovery of 78% and median viability of 95%. The laboratories were able to detect similar antigen-specific T-cell responses, ranging from 50 to >3,000 spot-forming cells per million PBMC. An approximate range of a half log in results from operators within or across sites was seen in comparisons of antigen-specific responses. Consistently low background responses were seen in all laboratories. The results of these proficiency panels demonstrate the ability of seven laboratories, located across three continents, to process PBMC samples and to rank volunteers with differential magnitudes of IFN-_ ELISPOT responses. These findings also illustrate the ability to standardize the IFN-_ ELISPOT assay across multiple laboratories when common training methods, reagents such as fetal calf serum, and standard operating procedures are adopted. These results are encouraging for laboratories that are using cell-based immunology assays to test HIV vaccines and other vaccines.
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    Equivalence of ELISpot Assays Demonstrated between Major HIV Network Laboratories
    (PLOS ONE, 2010-12-14) Gill, Dilbinder K.; Huang, Yunda; Levine, Gail L.; Sambor, Anna; Carter, Donald K.; Sato, Alicia; Kopycinski, Jakub; Hayes, Peter; Hahn, Bridget; Birungi, Josephine; Tarragona-Fiol, Tony; Wan, Hong; Randles, Mark; Cooper, Andrew Raxworthy; Ssemaganda, Aloysius; Clark, Lorna; Kaleebu, Pontiano; Self, Steven G.; Koup, Richard; Wood, Blake; McElrath, M. Juliana; Cox, Josephine H.; Hural, John; Gilmour, Jill
    Background: The Comprehensive T Cell Vaccine Immune Monitoring Consortium (CTC-VIMC) was created to provide standardized immunogenicity monitoring services for HIV vaccine trials. The ex vivo interferon-gamma (IFN-c) ELISpot is used extensively as a primary immunogenicity assay to assess T cell-based vaccine candidates in trials for infectious diseases and cancer. Two independent, GCLP-accredited central laboratories of CTC-VIMC routinely use their own standard operating procedures (SOPs) for ELISpot within two major networks of HIV vaccine trials. Studies are imperatively needed to assess the comparability of ELISpot measurements across laboratories to benefit optimal advancement of vaccine candidates. Methods: We describe an equivalence study of the two independently qualified IFN-g ELISpot SOPs. The study design, data collection and subsequent analysis were managed by independent statisticians to avoid subjectivity. The equivalence of both response rates and positivity calls to a given stimulus was assessed based on pre-specified acceptance criteria derived from a separate pilot study. Findings: Detection of positive responses was found to be equivalent between both laboratories. The 95% C.I. on the difference in response rates, for CMV (21.5%, 1.5%) and CEF (20.4%, 7.8%) responses, were both contained in the prespecified equivalence margin of interval [215%, 15%]. The lower bound of the 95% C.I. on the proportion of concordant positivity calls for CMV (97.2%) and CEF (89.5%) were both greater than the pre-specified margin of 70%. A third CTC-VIMC central laboratory already using one of the two SOPs also showed comparability when tested in a smaller sub-study. Interpretation: The described study procedure provides a prototypical example for the comparison of bioanalytical methods in HIV vaccine and other disease fields. This study also provides valuable and unprecedented information for future vaccine candidate evaluations on the comparison and pooling of ELISpot results generated by the CTC-VIMC central core laboratories.
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    Feasibility and acceptability of mobile phone short message service as a support for patients receiving antiretroviral therapy in rural Uganda: a cross-sectional study
    (Wiley-Blackwell, 2015-12) Kim, Jiho; Zhang, Wendy; Nyonyitono, Maureen; Lourenco, Lillian; Nanfuka, Mastula; Okoboi, Stephen; Birungi, Josephine; Lester, Richard T.; Kaleebu, Pontiano; Munderi, Paula; Moore, David M.
    Introduction: Mobile phone technologies have been promoted to improve adherence to antiretroviral therapy (ART).We studied the receptiveness of patients in a rural Ugandan setting to the use of short messaging service (SMS) communication for such purposes. Methods: We performed a cross-sectional analysis measuring mobile phone ownership and literacy amongst patients of The AIDS Support Organisation (TASO) in Jinja, Uganda. We performed bivariate and multivariate logistic regression analyses to examine associations between explanatory variables and a composite outcome of being literate and having a mobile phone. Results: From June 2012 to August 2013, we enrolled 895 participants, of whom 684 (76%) were female. The median age was 44 years. A total of 576 (63%) were both literate and mobile phone users. Of these, 91% (527/ 576) responded favourably to the potential use of SMS for health communication, while only 38.9% (124/319) of others were favourable to the idea (pB0.001). A lower proportion of literate mobile phone users reported optimal adherence to ART (86.4% vs. 90.6%; p=0.007). Male participants (AOR=2.81; 95% CI 1.83=4.30), sub-optimal adherence (AOR=1.76; 95%CI 1.12=2.77), thosewithwaged or salaried employment (AOR=2.35; 95% CI 1.23=4.49), crafts/trade work (AOR=2.38; 95% CI 1.11=5.12), or involved in petty trade (AOR=1.85; 95% CI 1.09=3.13) (in comparison to those with no income) were more likely to report mobile phone ownership and literacy. Conclusions: In a rural Ugandan setting, we found that over 60% of patients could potentially benefit from a mobile phone-based ART adherence support. However, support for such an intervention was lower for other patients.
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    Immune activation alters cellular and humoral responses to yellow fever 17D vaccine
    (The Journal of Clinical Investigation, 2014-07) Muyanja, Enoch; Ssemaganda, Aloysius; Ngauv, Pearline; Cubas, Rafael; Perrin, Helene; Srinivasan, Divya; Canderan, Glenda; Lawson, Benton; Kopycinski, Jakub; Graham, Amanda S.; Rowe, Dawne K.; Smith, Michaela J.; Isern, Sharon; Michael, Scott; Silvestri, Guido; Vanderford, Thomas H.; Castro, Erika; Pantaleo, Giuseppe; Singer, Joel; Gillmour, Jill; Kiwanuka, Noah; Nanvubya, Annet; Schmidt, Claudia; Birungi, Josephine; Cox, Josephine; Haddad, Elias K.; Kaleebu, Pontiano; Fast, Patricia; Sekaly, Rafick-Pierre; Trautmann, Lydie
    Background. Defining the parameters that modulate vaccine responses in African populations will be imperative to design effective vaccines for protection against HIV, malaria, tuberculosis, and dengue virus infections. This study aimed to evaluate the contribution of the patient-specific immune microenvironment to the response to the licensed yellow fever vaccine 17D (YF-17D) in an African cohort. Methods. We compared responses to YF-17D in 50 volunteers in Entebbe, Uganda, and 50 volunteers in Lausanne, Switzerland. We measured the CD8+ T cell and B cell responses induced by YF-17D and correlated them with immune parameters analyzed by flow cytometry prior to vaccination. Results. We showed that YF-17D–induced CD8+ T cell and B cell responses were substantially lower in immunized individuals from Entebbe compared with immunized individuals from Lausanne. The impaired vaccine response in the Entebbe cohort associated with reduced YF-17D replication. Prior to vaccination, we observed higher frequencies of exhausted and activated NK cells, differentiated T and B cell subsets and proinflammatory monocytes, suggesting an activated immune microenvironment in the Entebbe volunteers. Interestingly, activation of CD8+ T cells and B cells as well as proinflammatory monocytes at baseline negatively correlated with YF-17D–neutralizing antibody titers after vaccination. Additionally, memory T and B cell responses in preimmunized volunteers exhibited reduced persistence in the Entebbe cohort but were boosted by a second vaccination. Conclusion. Together, these results demonstrate that an activated immune microenvironment prior to vaccination impedes efficacy of the YF-17D vaccine in an African cohort and suggest that vaccine regimens may need to be boosted in African populations to achieve efficient immunity. Trial registration. Registration is not required for observational studies. Funding. This study was funded by Canada’s Global Health Research Initiative, Defense Threat Reduction Agency, National Institute of Allergy and Infectious Diseases, Bill & Melinda Gates Foundation, and United States Agency for International Development.
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    Lack of Effectiveness of Antiretroviral Therapy in Preventing HIV Infection in Serodiscordant Couples in Uganda: An Observational Study.
    (2015-07-14) Birungi, Josephine; Min, Jeong Eun; Muldoon, Katherine A.; Kaleebu, Pontiano; King, Rachel; Khanakwa, Sarah; Nyonyintono, Maureen; Chen, YaLin; Mills, Edward J.; Lyagoba, Fred; Ragonnet-Cronin, Manon; Wangisi, Jonathan; Lourenco, Lillian; Moore, David M.
    Background We examined the real-world effectiveness of ART as an HIV prevention tool among HIV serodiscordant couples in a programmatic setting in a low-income country. Methods We enrolled individuals from HIV serodiscordant couples aged >18 years of age in Jinja, Uganda from June 2009 – June 2011. In one group of couples the HIV positive partner was receiving ART as they met clinical eligibility criteria (a CD4 cell count >250 cells/ μL or WHO Stage III/IV disease). In the second group the infected partner was not yet ARTeligible. We measured HIV incidence by testing the uninfected partner every three months. We conducted genetic linkage studies to determine the source of new infections in seroconverting participants. Results A total of 586 couples were enrolled of which 249 (42%) of the HIV positive participants were receiving ART at enrollment, and an additional 99 (17%) initiated ART during the study. The median duration of follow-up was 1.5 years. We found 9 new infections among partners of participants who had been receiving ART for at least three months and 8 new infections in partners of participants who had not received ART or received it for less than three months, for incidence rates of 2.09 per 100 person-years (PYRs) and 2.30 per 100 PYRs, respectively. The incidence rate ratio for ART-use was 0.91 (95% confidence interval 0.31-2.70; p=0.999). The hazard ratio for HIV seroconversion associated with ART-use by the positive partner was 1.07 (95% CI 0.41-2.80). A total of 5/7 (71%) of the transmissions on ART and 6/7 (86%) of those not on ART were genetically linked. Conclusion Overall HIV incidence was low in comparison to previous studies of serodiscordant couples. However, ART-use was not associated with a reduced risk of HIV transmission in this study.
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    Pervasive and Non-random Recombination in Near Full-Length HIV Genomes From Uganda
    (Virus Evolution, 2020) Kitayimbwa, John M.; Grant, Heather E.; Hodcroft, Emma B.; Ssemwanga, Deogratius; Gonzalo, Yebra; Gomez, Luis Roger Esquivel; Frampton, Dan; Gall, Astrid; Kellam, Paul; Oliveira, Tulio de; Bbosa, Nicholas; Nsubuga, Rebecca N.; Kibengo, Freddie; Kwan, Tsz Ho; Lycett, Samantha; Kao, Rowland; Robertson, David L.; Ratmann, Oliver; Fraser, Christophe; Pillay, Deenan; Kaleebu, Pontiano; Brown, Andrew J. Leigh
    Recombination is an important feature of HIV evolution, occurring both within and between the major branches of diversity (subtypes). The Ugandan epidemic is primarily composed of two subtypes, A1 and D that have been co-circulating for 50 years frequently recombining in dually infected patients. Here, we investigate the frequency of recombinants in this population and the location of breakpoints along the genome. As part of the PANGEA-HIV consortium, 1,472 consensus genome sequences over 5 kb have been obtained from 1,857 samples collected by the MRC/UVRI & LSHTM Research unit in Uganda, 465 (31.6 per cent) of which were near full-length sequences (>8 kb). Using the subtyping tool SCUEAL, we find that of the near full-length dataset, 233 (50.1 per cent) genomes contained only one subtype, 30.8 per cent A1 (n¼143), 17.6 percent D (n¼82), and 1.7 per cent C (n¼8), while 49.9 per cent (n¼232) contained more than one subtype (including A1/D (n¼164), A1/C (n¼13), C/D (n¼9); A1/C/D (n¼13), and 33 complex types). K-means clustering of the recombinant A1/D genomes revealed a section of envelope (C2gp120-TMgp41) is often inherited intact, whilst a generalized linear model was used to demonstrate significantly fewer breakpoints in the gag–pol and envelope C2-TM regions compared with accessory gene regions. Despite similar recombination patterns in many recombinants, no clearly supported circulating recombinant form (CRF) was found, there was limited evidence of the transmission of breakpoints, and the vast majority (153/164; 93 percent) of the A1/D recombinants appear to be unique recombinant forms. Thus, recombination is pervasive with clear biases in breakpoint location, but CRFs are not a significant feature, characteristic of a complex, and diverse epidemic.
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    A Phase 2 Study to Evaluate the Safety and Immunogenicity of a Recombinant HIV Type 1 Vaccine Basedon Adeno-Associated Virus.
    (Mary Ann Liebert, Inc., 2010-08-12) Vardas, Eftyhia; Kaleebu, Pontiano; Bekker, Linda-Gail; Hoosen, Anwar; Chomba, Elwyn; Johnson, Philip R.; Anklesaria, Pervin; Birungi, Josephine; Barin, Burc; Boaz, Mark; Cox, Josephine; Lehrman, Jennifer; Stevens, Gwynn; Gilmour, Jill; Tarragona, Tony; Hayes, Peter; Lowenbein, Sarah; Kizito, Eva; Fast, Patricia; Heald, Alison E.; Schmidt, Claudia
    The recombinant vaccine, tgAAC09, based on an adeno-associated virus serotype 2 (AAV2) vector encoding HIV-1 subtype C Gag, protease, and part of reverse transcriptase, induced robust T cell and antibody responses in nonhuman primates. In a previous phase I study in 80 healthy HIV-seronegative European and Indian adults, the vaccine was generally safe, well tolerated, and modestly immunogenic when administered once at doses up to 3x10 11 DRP. This phase II double-blind, randomized, placebo-controlled trial tested two administrations and a higher dosage of tgAAC009. Ninety-one healthy HIV-seronegative adults from three African countries were given one of three dosage levels of tgAAC09 (3x1010, 3x10 11, or 3x10 12 DRP) intramuscularly, either at a 6- or 12-month interval; follow-up was 18 months. Overall, 65% and 57% of vaccine recipients experienced local and systemic signs and symptoms, respectively, most being mild. Frequency and severity were not dose related and were similar to those in placebo recipients. No vaccine-related serious adverse events were reported. Overall, HIV-specific T cell responses were detected by IFN-g ELISPOT in 17/69 (25%) vaccine recipients with 38% (10/26) responders in the highest dosage group. The response rate improved significantly with boosting at 6, but not 12 months, in the 3x10 11 and 3x10 12 dosage groups only. Neutralizing antibody titers to the AAV2 did not alter the frequency of immune responses to HIV. Two doses of tgAAC09 were well tolerated at the dosage levels given. Fewer than half the recipients of the highest vaccine dosage, 3x10 12 DRP, had T cell responses to HIV.
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    Phylogenetic Networks and Parameters Inferred from HIV Nucleotide Sequences of High-Risk and General Population Groups in Uganda: Implications for Epidemic Control
    (Viruses, 2021) Kitayimbwa, John M.; Bbosa, Nicholas; Ssemwanga, Deogratius; Nsubuga, Rebecca N.; Kiwanuka, Noah; Bagaya, Bernard S.; Ssekagiri, Alfred; Gonzalo, Yebra; Kaleebu, Pontiano; Leigh-Brown, Andrew
    Phylogenetic inference is useful in characterising HIV transmission networks and assessing where prevention is likely to have the greatest impact. However, estimating parameters that influence the network structure is still scarce, but important in evaluating determinants of HIV spread. We analyzed 2017 HIV pol sequences (728 Lake Victoria fisherfolk communities (FFCs), 592 female sex workers (FSWs) and 697 general population (GP)) to identify transmission networks on Maximum Likelihood (ML) phylogenetic trees and refined them using time-resolved phylogenies. Network generative models were fitted to the observed degree distributions and network parameters, and corrected Akaike Information Criteria and Bayesian Information Criteria values were estimated. 347 (17.2%) HIV sequences were linked on ML trees (maximum genetic distance _4.5%, _95% bootstrap support) and, of these, 303 (86.7%) that consisted of pure A1 (n = 168) and D (n = 135) subtypes were analyzed in BEAST v1.8.4. The majority of networks (at least 40%) were found at a time depth of _5 years. The waring and yule models fitted best networks of FFCs and FSWs respectively while the negative binomial model fitted best networks in the GP. The network structure in the HIV-hyperendemic FFCs is likely to be scale-free and shaped by preferential attachment, in contrast to the GP. The findings support the targeting of interventions for FFCs in a timely manner for effective epidemic control. Interventions ought to be tailored according to the dynamics of the HIV epidemic in the target population and understanding the network structure is critical in ensuring the success of HIV prevention programs.
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    Setting up a Standardized Peripheral Blood Mononuclear Cells Processing Laboratory to Support Multi-center HIV/AIDS Vaccine and Intervention Trials.
    (Labmedicine, 2011) Njai, Harr Freeya; Gombe, Ben; Khamis, Tomusange; Birungi, Josephine; Ruzagira, Eugene; Admassu, Dareskedar; Tarragona-Fiol, Tony; Porter, Kholoud; Stevens, Gwynneth; Mugisha, Joseph; Gilmour, Jill; Kamali, Anatoli; Kaleebu, Pontiano
    Despite infrastructure and capacity challenges in Africa, significant development has been made in the number of laboratories supporting immunological and safety studies required for large-scale HIV/AIDS vaccine or intervention trials. In Uganda, cohorts participating in HIV intervention trials are often recruited from rural areas. To avoid transporting samples from intervention trial areas over long distances (120 km) to central laboratories in Entebbe, we set up a standardized peripheral blood mononuclear cells (PBMCs) processing laboratory at a field station in Masaka, southwest Uganda. The laboratory was well equipped and enrolled into the International AIDS Vaccine Initiative (IAVI) Quality Assurance (QA) program. Staff was trained in laboratory techniques and Good Clinical Laboratory Practice (GCLP). The laboratory received IAVI and GCLP accreditation in 2008. In this paper we describe the process and achievements of measures taken to overcome challenges, to build staff capacity, and to optimize the quality of the cells yielded.
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    Short Communication HIV Type 1 Transmitted Drug Resistance and Evidence of Transmission Clusters among Recently Infected Antiretroviral-Naive Individuals from Ugandan Fishing Communities of Lake Victoria
    (Aids Research and Human Retroviruses, 2013) Nazziwa, Jamirah; Njai, Harr Freeya; Ndembi, Nicaise; Birungi, Josephine; Lyagoba, Fred; Gershim, Asiki; Nakiyingi-Miiro, Jessica; Nielsen, Leslie; Mpendo, Juliet; Nanvubya, Annet; Debont, Jan; Grosskurth, Heiner; Kamali, Anatoli; Seeley, Janet; Kaleebu, Pontiano
    Human immunodeficiency virus type 1 (HIV-1) prevalence and incidence in the fishing communities on Lake Victoria in Uganda are high. This population may play a role in driving the HIV epidemic in Uganda including the spread of transmitted drug resistance (TDR). We report data on TDR in this population among antiretroviral (ARV)-naive, recently infected individuals about 5 years after ARV scaling-up in Uganda. We identified phylogenetic transmission clusters and combined these with volunteer life histories in order to understand the sexual networks within this population. From a prospective cohort of 1,000 HIV-negative individuals recruited from five communities, 51 seroconverters were identified over a period of 2 years. From these, whole blood was collected and population sequencing of the HIV-1 pol gene (protease/reverse transcriptase) was performed from plasma. Drug resistance mutations (DRMs) were scored using the 2009 WHO list for surveillance of TDR. TDR prevalence categories were estimated using the WHO recommended truncated sampling technique for the surveillance of TDR for use in resource-limited settings (RLS). Of the samples 92% (47/51) were successfully genotyped. HIV-1 subtype frequencies were 15/47 (32%) A1, 20/47 (43%) D, 1/47 (2%) C, 1/47 (2%) G, and 10/ 47 (21%) unique recombinant forms. Nonnucleoside reverse transcriptase inhibitor (NNRTI) drug resistance mutation K103N was identified in two individuals and V106A in one (6%) suggesting that the level of TDR was moderate in this population. No nucleoside/tide reverse transcriptase inhibitor (NRTI) or protease inhibitor (PI) DRMs were detected. In this study, we identified five transmission clusters supported by high bootstrap values and low genetic distances. Of these, one pair included the two individuals with K103N. Two of the genotypic clusters corresponded with reported sexual partnerships as detected through prior in-depth interviews. The level of TDR to NNRTIs in these ARV-naive individuals was moderate by WHO threshold survey categorization. The transmission clusters suggest a high degree of sexual partner mixing between members of these communities.