Browsing by Author "Ssewanyana, Isaac"

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    Cryptococcal Antigenemia in Human Immunodeficiency Virus Antiretroviral Therapy–Experienced Ugandans With Virologic Failure
    (Clinical infectious diseases, 2020) Mpoza, Edward; Radha, Rajasingham; Tugume, Lillian; Joshua, Rhein; Nabaggala, Maria Sarah; Ssewanyana, Isaac; Nyegenye, Wilson; Kushemererwa, Grace Esther; Mulema, Vivienne; Kalamya, Julius; Kiyaga, Charles; Kabanda, Joseph; Ssali, Mina; Boulware, David R.; Meya, David B.
    Detectable serum or plasma cryptococcal antigen (CrAg) precedes symptomatic cryptococcal meningitis. The World Health Organization recommends CrAg screening for human immunodeficiency virus–positive persons with CD4 count <100 cells/μL initiating antiretroviral therapy (ART). However, an increasing proportion of patients with cryptococcosis are now ART experienced. Whether CrAg screening is cost-effective in those with virologic failure is unknown. Methods We retrospectively performed nationwide plasma CrAg testing among ART-experienced Ugandan adults with virologic failure (≥1000 copies/mL) using leftover plasma after viral load testing during September 2017–January 2018. For those who were CrAg positive, we obtained ART history, meningitis occurrence, and 6-month survival via medical records review. Results Among 1186 subjects with virologic failure, 35 (3.0%) were CrAg positive with median ART duration of 41 months (interquartile range, 10–84 months). Among 25 subjects with 6-month outcomes, 16 (64%) survived, 7 (28%) died, and 2 (8%) were lost. One survivor had suffered cryptococcal meningitis 2 years prior. Two others developed cryptococcal meningitis and survived. Five survivors were known to have received fluconazole. Thus, meningitis-free survival at 6 months was 61% (14/23). Overall, 91% (32/35) of CrAg-positive persons had viral load ≥5000 copies/mL compared with 64% (735/1151) of CrAg-negative persons (odds ratio, 6.0 [95% confidence interval, 1.8–19.8]; P = .001). CrAg prevalence was 4.2% (32/768) among those with viral loads ≥5000 copies/mL and 0.7% (3/419) among those with viral loads <5000 copies/mL. Conclusions In addition to the CD4 threshold of <100 cells/μL, reflexive CrAg screening should be considered in persons failing ART in Uganda with viral loads ≥5000 copies/mL.
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    Factors Associated with Virological Nonsuppression among HIV-Positive Patients on Antiretroviral Therapy in Uganda, August 2014–July 2015
    (BMC infectious diseases, 2017) Bulage, Lilian; Ssewanyana, Isaac; Nankabirwa, Victoria; Nsubuga, Fred; Kihembo, Christine; Pande, Gerald; Ario, Alex R.; Matovu, Joseph K. B.; Wanyenze, Rhoda K.; Kiyaga, Charles
    Despite the growing number of people on antiretroviral therapy (ART), there is limited information about virological non suppression and its determinants among HIV-positive (HIV+) individuals enrolled in HIV care in many resource-limited settings. We estimated the proportion of virologically non-suppressed patients, and identified the factors associated with virological non suppression. Methods: We conducted a descriptive cross-sectional study using routinely collected program data from viral load (VL) samples collected across the country for testing at the Central Public Health Laboratories (CPHL) in Uganda. Data were generated between August 2014 and July 2015. We extracted data on socio-demographic, clinical and VL testing results. We defined virological non-suppression as having ≥1000 copies of viral RNA/ml of blood for plasma or ≥5000 copies of viral RNA/ml of blood for dry blood spots. We used logistic regression to identify factors associated with virological non-suppression. Results: The study was composed of 100,678 patients; of these, 94,766(94%) were for routine monitoring, 3492(4%) were suspected treatment failures while 1436(1%) were repeat testers after suspected failure. The overall proportion of non suppression was 11%. Patients on routine monitoring registered the lowest (10%) proportion of nonsuppressed patients. Virological non-suppression was higher among suspected treatment failures (29%) and repeat testers after suspected failure (50%). Repeat testers after suspected failure were six times more likely to have virological non-suppression (ORadj = 6.3, 95%CI = 5.5–7.2) when compared with suspected treatment failures (ORadj = 3.3, 95%CI = 3.0–3.6). The odds of virological non-suppression decreased with increasing age, with children aged 0–4 years (ORadj = 5.3, 95%CI = 4.6–6.1) and young adolescents (ORadj = 4.1, 95%CI = 3.7–4.6) registering the highest odds. Poor adherence (ORadj = 3.4, 95%CI = 2.9–3.9) and having active TB (ORadj = 1.9, 95%CI = 1.6–2.4) increased the odds of virological non-suppression. However, being on second/third line regimens (ORadj = 0.86, 95%CI = 0.78–0.95) protected patients against virological non-suppression. Conclusion: Young age, poor adherence and having active TB increased the odds of virological non-suppression while second/third line ART regimens were protective against non-suppression. We recommend close follow up and intensified targeted adherence support for repeat testers after suspected failure, children and adolescents.
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    Field evaluation of the performance of seven Antigen Rapid diagnostic tests for the diagnosis of SARs-CoV-2 virus infection in Uganda
    (Plos one, 2022) Bwogi, Josephine; Lutalo, Tom; Tushabe, Phionah; Bukenya, Henry; Eliku, James Peter; Ssewanyana, Isaac; Nabadda, Susan; Nsereko, Christopher; Matthew, Cotten; Robert, Downing; Lutwama, Julius; Kaleebu, Pontiano
    Objective The objective of this study was to evaluate the performance of seven antigen rapid diagnostic tests (Ag RDTs) in a clinical setting to identify those that could be recommended for use in the diagnosis of SARS-CoV-2 infection in Uganda. Methods This was a cross-sectional prospective study. Nasopharyngeal swabs were collected consecutively from COVID-19 PCR positive and COVID-19 PCR negative participants at isolation centers and points of entry, and tested with the SARS-CoV-2 Ag RDTs. Test sensitivity and specificity were generated by comparing results against qRT-PCR results (Berlin Protocol) at a cycle threshold (Ct) cut-off of ≤39. Sensitivity was also calculated at Ct cut-offs ≤29 and ≤33. Results None of the Ag RDTs had a sensitivity of ≥80% at Ct cut-off values ≤33 and ≤39. Two kits, Panbio™ COVID-19 Ag and VivaDiag™ SARS-CoV-2 Ag had a sensitivity of ≥80% at a Ct cut-off value of ≤29. Four kits: BIOCREDIT COVID -19 Ag, COVID-19 Ag Respi-Strip, MEDsan® SARS-CoV-2 Antigen Rapid Test and Panbio™ COVID-19 Ag Rapid Test had a specificity of ≥97%. Conclusions This evaluation identified one Ag RDT, Panbio™ COVID-19 Ag with a performance at high viral load (Ct value ≤29) reaching that recommended by WHO. This kit was recommended for screening of patients with COVID -19-like symptoms presenting at health facilities.
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    High Schistosoma mansoni infection intensity is associated with distinct gut microbiome and low levels of systemic cytokines in children along the Albert-Nile, Northern Uganda
    (Research Square, 2024) Mulindwa, Julius; Lujumba, Ibra; Musiime, Caroline; Namulondo, Joyce; Magambo, Phillip Kimuda; Nyangiri, Oscar; Gloria, Cuu; Mwubaha, Caroline; Tukwasibwe, Stephen; Ssemaganda, Aloysious; Ssewanyana, Isaac; Nerima , Barbara; Baingana, Rhona; Harry, Noyes; Annette, MacLeod; Matovu, Enock
    Background Schistosomiasis is a chronic neglected disease that affects millions of people in sub Saharan Africa, with a range of impacts on both host immune responses and the gut microbiome. The gut microbiota plays a fundamental in role in the host’s nutrition, metabolism, protection against pathogens, and modulation of host immunity. There is a need to understand the role of the gut microbiome in pathophysiology of Schistosoma mansoni infection and how this influences the host’s immune response. Methodology: A cross sectional study was carried out on 140 faecal samples collected from school children aged 10-15years residing in the schistosomiasis endemic hot spots of the Albert-Nile, Pakwach district, Northern Uganda. The samples were categorised by S. mansoni infection intensity based on the Kato Katz test. Faecal DNA was isolated and microbiome composition was determined by 16S rRNA V3-V4 sequencing. Plasma Th1/Th2 profiling of 13 cytokines was carried out on the Luminex platform and compared with respect to S. mansoni infection intensities. Results The genera Phascolarctobaterium and Prevotella_7 were significantly enriched (padj < 0.05, LDA > 3.0) in the high S. mansoni infection intensity group whereas, Ruminobacter and Alloprevotella were enriched in the Low infection intensity group. We observed significantly lower systemic Th1/Th2 cytokine levels between the high intensity infection and the control samples (padj < 0.05). Linear regression analysis using all cytokines as covariates showed that the genus Alloprevotella, Streptococcus, Gastranaerophilales and Ruminobacter were associated with systemic IL6 response. Conclusion There are alterations in the gut microbiome of S. mansoni infected children with distinct genera that discriminate the high and low infection intensity that could be potentially used as biomarkers. There is an association between the gut microbiome and systemic cytokine response whose mechanism in chronic disease pathophysiology can be further investigated.
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    High T-cell immune activation and immune exhaustion among individuals with suboptimal CD4 recovery after 4 years of antiretroviral therapy in an African cohort
    (BMC infectious diseases, 2011) Nakanjako, Damalie; Ssewanyana, Isaac; Mayanja-Kizza, Harriet; Kiragga, Agnes; Manabe, Yukari C.; Nabatanzi, Rose; Kamya, Moses R.; Cao, Huyen
    Antiretroviral therapy (ART) partially corrects immune dysfunction associated with HIV infection. The levels of T-cell immune activation and exhaustion after long-term, suppressive ART and their correlation with CD4 T-cell count reconstitution among ART-treated patients in African cohorts have not been extensively evaluated.T-cell activation (CD38+HLA-DR+) and immune exhaustion (PD-1+) were measured in a prospective cohort of patients initiated on ART; 128 patient samples were evaluated and subcategorized by CD4 reconstitution after long-term suppressive treatment: Suboptimal [median CD4 count increase 129 (-43-199) cells/μl], N = 34 ], optimal [282 (200-415) cells/μl, N = 64] and super-optimal [528 (416-878) cells/μl, N = 30].Both CD4+ and CD8 T-cell activation was significantly higher among suboptimal CD4 T-cell responders compared to super-optimal responders. In a multivariate model, CD4+CD38+HLADR+ T-cells were associated with suboptimal CD4 reconstitution [AOR, 5.7 (95% CI, 1.4-23, P = 0.014)]. T-cell exhaustion (CD4+PD1+ and CD8+PD1+) was higher among suboptimal relative to optimal (P < 0.001) and super-optimal responders (P < 0.001). T-cell exhaustion was significantly associated with suboptimal responders [AOR, 1.5 (95%CI, 1.1-2.1), P = 0.022].T-cell activation and exhaustion persist among HIV-infected patients despite long-term, sustained HIV-RNA viral suppression. These immune abnormalities were associated with suboptimal CD4 reconstitution and their regulation may modify immune recovery among suboptimal responders to ART.
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    HIV drug resistance among adults initiating antiretroviral therapy in Uganda
    (Journal of Antimicrobial Chemotherapy, 2021) Watera, Christine; Ssemwanga, Deogratius; Namayanja, Grace; Asio, Juliet; Lutalo, Tom; Namale, Alice; Sanyu, Grace; Ssewanyana, Isaac; Gonzalez-Salazar, Jesus Fidel; Nazziwa, Jamirah; Nanyonjo, Maria; Raizes, Elliot; Kabuga, Usher; Mwangi, Christina; Kirungi, Wilford; Musinguzi, Joshua; Mugagga, Kaggwa; Katongole Mbidde, Edward; Kaleebu, Pontiano
    WHO revised their HIV drug resistance (HIVDR) monitoring strategy in 2014, enabling countries to generate nationally representative HIVDR prevalence estimates from surveys conducted using this methodology. In 2016, we adopted this strategy in Uganda and conducted an HIVDR survey among adults initiating or reinitiating ART. Methods: A cross-sectional survey of adults aged 18 years initiating or reinitiating ART was conducted at 23 sites using a two-stage cluster design sampling method. Participants provided written informed consent prior to enrolment. Whole blood collected in EDTA vacutainer tubes was used for preparation of dried blood spot (DBS) specimens or plasma. Samples were shipped from the sites to the Central Public Health Laboratory (CPHL) for temporary storage before transfer to the Uganda Virus Research Institute (UVRI) for genotyping. Prevalence of HIVDR among adults initiating or reinitiating ART was determined.
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    Impact of CD8R T-cell activation on CD4R T-cell recovery and mortality in HIV-infected Ugandans initiating antiretroviral therapy
    (AIDS (London, England), 2011) Hunt, Peter W.; Caoa, Huyen L.; Muzoora, Conrad; Ssewanyana, Isaac; Bennett, John; Emenyonu, Nneka; Kembabazi, Annet; Neilands, Torsten B.; Bangsberg, David R.; Deeks, Steven G.; Martin, Jeffrey N.
    To assess whether T-cell activation independently predicts the extent of CD4þ T-cell recovery and mortality in HIV-infected Ugandans initiating antiretroviral therapy (ART). Prospective cohort study. HIV-infected adults starting ART and achieving a plasma HIV RNA level (VL) less than 400 copies/ml by month 6 were sampled from the Uganda AIDS Rural Treatment Outcomes (UARTO) cohort in Mbarara, Uganda. CD4 count, VL, and the percentage-activated (CD38þHLA-DRþ) T cells were measured every 3 months. Of 451 HIV-infected Ugandans starting ART, most were women (70%) with median pre-ART values: age, 34 years; CD4 count, 135 cells/ml; and VL, 5.1 log10 copies/ml. Of these, 93% achieved a VL less than 400 copies/ml by month 6 and were followed for a median of 24 months, with 8% lost to follow-up at 3 years. Higher pre- ART CD8þ T-cell activation was associated with diminished CD4 recovery after year 1, after adjustment for pre-ART CD4 count, VL, and sex (P¼0.017). Thirty-four participants died, 15 after month 6. Each 10% point increase in activated CD8þ T cells at month 6 of suppressive ART was associated with a 1.6-fold increased hazard of subsequent death after adjusting for pretherapy CD4 count (P¼0.048). Higher pre-ART CD8þ T-cell activation independently predicts slower CD4þ T-cell recovery and higher persistent CD8þ T-cell activation during ART mediated viral suppression independently predicts increased mortality among HIV infected Ugandans. Novel therapeutic strategies aimed at preventing or reversing immune activation during ART are needed in this setting.
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    Short-Term Risk of HIV-Disease Progression and Death in Ugandan Children Not Eligible for Antiretroviral Therapy
    (Journal of acquired immune deficiency syndromes, 2010) Charlebois, Edwin D; Ruel, Theodore D; Gasasira, Anne F.; Achan, Jane; Kateera, Frederick; Akello, Caroline; Cao, Huyen; Dorsey, Grant; Rosenthal, Philip J; Ssewanyana, Isaac; Kamya, Moses R; Havlir, Diane V
    Background—Increasing numbers of HIV-infected children not yet eligible for antiretroviral therapy (ART) are entering health care in Africa. We sought to characterize the risk of short-term disease progression in this population. Methods—In a cohort of HIV-infected ART-naive and -ineligible Ugandan children >1 year old, the rates of clinical/immunologic progression within 2 years were assessed using Kaplan–Meier survival analysis and multivariate Cox proportional-hazards modeling. Results—Among 192 children (mean age: 6.4 years, CD4%:25), 19% progressed within 2 years by WHO-stage 3/4 event(n=22), death (n=3), or WHO-defined CD4 threshold for ARTinitiation( n=12). Significant univariate predictors were CD4%(HR=2.0 per 10% decrease, p=0.005), HIV-RNA level(HR=2.4 per log10 increase, p=0.002), male gender (HR:2.0, p=0.04), age < 3 years (HR=3.7, p=0.001), CD4-activation [%CD4+CD38+HLADR+] (HR=1.6 per 10% increase, p=0.05) and CD8-activation [%CD8+CD38+HLADR+](HR=1.3 per 10% increase, p=0.05] (HR=1.3, p=0.5). In multivariate analysis, CD4%(HR=2.0, p=0.034), HIV-RNA level(HR=1.8, p=0.013) and age < 3 years (HR:3.0, p=0.008) were independently predictive. Children with HIV-RNA >105 copies/ml and CD4% <25 had progression rates of 29% (1 year) and 34% (2 years). Conclusions—Even with frequent CD4 monitoring, HIV-infected Ugandan children experienced significant clinical events while ineligible for ART. Alternate strategies for monitoring or ART-initiation may be needed to improve outcomes
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    Trends and distribution of Vibrio cholerae isolates at the National Microbiology Reference Laboratory, Ministry of Health, Uganda, 2014 –2023
    (Uganda Public Health, 2018) Baliruno, Leah Naluwagga; Namusoosa, Rita; Gidudu, Samuel; Okello, Paul Edward; Nakigozi, Harriet; Okiria, Chris; Ssewanyana, Isaac; Nabadda, Suzan; Najjuka, Grace; Ario, Alex Riolexus
    Background: As per the World Health Organization, countries including Uganda are to end cholera by 2030 through prevention and treatment. This achievement can be hindered due to rapid changes in antimicrobial response patterns and serotype among other factors. We described confirmed cholera cases by person, place, time, serotype, antimicrobial resistance, and multi-antimicrobial-resistant phenotype patterns, Uganda, 2014–2023. Methods: We conducted a descriptive study using the 2014 – 2023 data on confirmed cholera cases abstracted from the National Microbiology Reference Laboratory (NMRL) register. We described the cases by age group, sex, district, serotype, reporting period, antimicrobial resistance (resistant and intermediate)(rates), and multi-antimicrobialresistant phenotype patterns. We described the confirmed cases and the antimicrobial resistance patterns over time. Mann-Kendall tests for trends were used to test the significance of AMR trends. Results: We identified 489 confirmed cholera cases between January 2014 to December 2023 whose V. cholerae isolates were referred by 35 districts in Uganda. The majority of the identified confirmed cholera cases were male (239, 49%), aged 21- 40 years (170, 38%), had V. cholerae 01 Ogawa (256, 52%) and were from Kampala District (138, 28%). We observed a gradual decline in confirmed cholera cases over time with peaks in 2015, 2018 and 2023. Vibro cholerae 01 ogawa was observed to dominate throughout the period. We observed consistent resistance by V. cholerae to 6 antimicrobials from 2014 to 2023. 194 (39.7%) isolates showed multiple antimicrobialresistant with 90 (18.6%) resistant to more than one class of antimicrobials. Conclusion: We observed males, persons aged 21-40 years, and Kampala District as being most affected with cholera in Uganda with peaks in 2015, 2018, and 2023 and Vibro cholerae 01 Ogawa as the predominate serotype. Consistent antimicrobial resistance was exhibited over time between 2014 and 2023. Intensifying cholera disease prevention by the Ministry of Health targeting males, persons aged 21-40 years, and Kampala District is critical. Routine antimicrobial surveillance to guide informed antimicrobial use and prevent the spread of AMR, especially during cholera outbreaks is important.