Humphrey Mulenga

University of Cape Town, Cape Town, Province of the Western Cape, South Africa

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Publications (10)53.51 Total impact

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    ABSTRACT: Response to treatment may be useful for diagnostic confirmation of childhood tuberculosis (TB). We aimed to evaluate time to symptom resolution in children treated for pulmonary TB.
    The Pediatric Infectious Disease Journal 08/2014; · 3.57 Impact Factor
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    ABSTRACT: Tuberculosis (TB) is a major public health problem globally. Little is known about TB incidence in adolescents who are a proposed target group for new TB vaccines. We conducted a study to determine the TB incidence rates and risk factors for TB disease in a cohort of school-going adolescents in a high TB burden area in South Africa. We recruited adolescents aged 12 to 18 years from high schools in Worcester, South Africa. Demographic and clinical information was collected, a tuberculin skin test (TST) performed and blood drawn for a QuantiFERON TB Gold assay at baseline. Screening for TB cases occurred at follow up visits and by surveillance of registers at public sector TB clinics over a period of up to 3.8 years after enrolment. A total of 6,363 adolescents were enrolled (58% of the school population targeted). During follow up, 67 cases of bacteriologically confirmed TB were detected giving an overall incidence rate of 0.45 per 100 person years (95% confidence interval 0.29-0.72). Black or mixed race, maternal education of primary school or less or unknown, a positive baseline QuantiFERON assay and a positive baseline TST were significant predictors of TB disease on adjusted analysis. The adolescent TB incidence found in a high burden setting will help TB vaccine developers plan clinical trials in this population. Latent TB infection and low socio-economic status were predictors of TB disease.
    PLoS ONE 03/2013; 8(3):e59652. · 3.53 Impact Factor
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    ABSTRACT: Screening for tuberculosis (TB) disease is important for TB control and TB vaccine efficacy trials but this has not been evaluated in adolescents. We conducted a study to determine the prevalence of active TB and performance of specific screening tests for TB in adolescents in a high burden setting. Adolescents aged 12-18 years were recruited from high schools in a rural town in South Africa. Participants were screened for active TB using symptoms, household TB contact, positive interferon gamma release assay (IGRA) and positive tuberculin skin test (TST). Of 6363 adolescents recruited, 21 were newly diagnosed with TB of whom 19 were culture positive. After exclusions, the derived prevalence of smear positive TB was 16/5682 = 3/1000 (95% confidence interval (CI) 1-4/1000). The sensitivity of TST and IGRA for active TB were 85% (95% CI 62-100%) and 94% (95% CI 79-100%) respectively. None of the methods alone or in combination had positive predictive values greater than 2%. The screening tools evaluated in this study may not be practical for routine use owing to low positive predictive values but may be useful in TB vaccine clinical trials.
    Tuberculosis (Edinburgh, Scotland) 03/2013; · 2.54 Impact Factor
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    ABSTRACT: RATIONALE: Conversions and reversions occur with interferon-gamma release assay (IGRA) serial testing as with the tuberculin skin test (TST). Recent TST conversion is associated with an established risk of developing tuberculosis (TB) disease, but the risk associated with recent IGRA conversions is unknown. OBJECTIVE: To compare the incidence rate of tuberculosis disease following recent QuantiFERON TB Gold In-Tube (QFT) conversion compared to non-converters. METHODS: Adolescents with converted IGRA status (QFT Converters [n=534]) and randomly chosen adolescents whose IGRA status had remained negative over a period of two years (QFT Non-Converters [n=629]) were identified in a cohort study of tuberculosis infection and disease. Subsequent tuberculosis disease incidence was compared between the two groups over a mean 1.9 years of follow up. MEASUREMENTS AND MAIN RESULTS: For QFT Converters, the tuberculosis incidence rate (all cases) was 1.46 cases per 100 person years (95% CI 0.82-2.39) and cumulative incidence, 2.8% (95% CI 1.58-4.59). A significantly lower tuberculosis incidence rate (0.17 cases per 100 person years [95% CI 0.02-0.62]) and cumulative incidence (0.32% [95% CI 0.03-1.14]) was observed for QFT Non-Converters.The incidence rate ratio was 8.54 (95% CI 2.51-29.13) for all cases of tuberculosis and 9.1 (95% CI 1.65-50.36) for protocol defined tuberculosis. CONCLUSION: Recent QFT conversion was indicative of approximately 8-fold higher risk of progression to tuberculosis disease (compared to non-converters) within 2 years of conversion in a cohort of adolescents in a high tuberculosis burden population.
    American Journal of Respiratory and Critical Care Medicine 09/2012; · 11.04 Impact Factor
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    ABSTRACT: A high tuberculosis (TB) burden rural area in South Africa. To compare TB case yield and disease profile among bacille Calmette-Guérin (BCG) vaccinated children using two case-finding strategies from birth until 2 years of age. BCG-vaccinated infants were enrolled within 2 weeks of birth and randomised to 3-monthly home visits for questionnaire-based TB screening plus record surveillance of TB registers, hospital admission and X-ray lists at health facilities for TB suspects and cases (Group 1), or record surveillance (as above) only (Group 2). Both groups received a close-out visit after 2 years. Participants were evaluated for suspected TB disease using standardised investigations. A total of 4786 infants were enrolled: 2392 were randomised to Group 1 and 2394 to Group 2. The case-finding rate was significantly greater in Group 1 (2.2/100 py) than in Group 2 (0.8/100 py), with a case-finding rate ratio of 2.6 (95%CI 1.8-4.0, P < 0.001). Although the proportion of cases with bacteriological confirmation was lower in Group 1, this difference did not reach statistical significance. There was also no significant difference in the proportions with TB symptoms and signs. Home visits combined with record surveillance detected significantly more cases than record surveillance with a single study-end visit. The TB case profile did not differ significantly between the two groups.
    The International Journal of Tuberculosis and Lung Disease 02/2012; 16(2):185-91. · 2.76 Impact Factor
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    ABSTRACT: Novel tuberculosis (TB) vaccines should be safe and effective in populations infected with Mycobacterium tuberculosis (M.tb) and/or HIV for effective TB control. To determine the safety and immunogenicity of MVA85A, a novel TB vaccine, among M.tb- and/or HIV-infected persons in a setting where TB and HIV are endemic. An open-label, phase IIa trial was conducted in 48 adults with M.tb and/or HIV infection. Safety and immunogenicity were analyzed up to 52 weeks after intradermal vaccination with 5 × 10(7) plaque-forming units of MVA85A. Specific T-cell responses were characterized by IFN-γ enzyme-linked immunospot and whole blood intracellular cytokine staining assays. MVA85A was well tolerated and no vaccine-related serious adverse events were recorded. MVA85A induced robust and durable response of mostly polyfunctional CD4(+) T cells, coexpressing IFN-γ, tumor necrosis factor-α, and IL-2. Magnitudes of pre- and postvaccination T-cell responses were lower in HIV-infected, compared with HIV-uninfected, vaccinees. No significant effect of antiretroviral therapy on immunogenicity of MVA85A was observed. MVA85A was safe and immunogenic in persons with HIV and/or M.tb infection. These results support further evaluation of safety and efficacy of this vaccine for prevention of TB in these target populations.
    American Journal of Respiratory and Critical Care Medicine 01/2012; 185(7):769-78. · 11.04 Impact Factor
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    ABSTRACT: The Global Polio Eradication Initiative aims to eradicate wild poliovirus by the end of 2012. Therefore, more-immunogenic polio vaccines, including monovalent oral poliovirus vaccines (mOPVs), are needed for supplemental immunization activities. This trial assessed the immunogenicity of monovalent types 1 and 3, compared with that of trivalent oral poliovirus vaccine (tOPV), in South Africa. We conducted a blinded, randomized, 4-arm controlled trial comparing the immunogenicity of a single dose of mOPV1 (from 2 manufacturers) and mOPV3 (from 1 manufacturer), given at birth, with the immunogenicity of tOPV. Eight hundred newborns were enrolled; 762 (95%) were included in the analysis. At 30 days after vaccine administration, seroconversion to poliovirus type 1 was 73.4% and 76.4% in the 2 mOPV1 arms, compared with 39.1% in the tOPV arm (P < .0000001), and seroconversion to poliovirus type 3 was 58.0% in the mOPV3 arm, compared with 21.2% in the tOPV arm (P < .0000001). The vaccines were well tolerated, and no adverse events were attributed to trial interventions. A dose of mOPV1 or mOPV3 at birth was superior to that of tOPV in inducing type-specific seroconversion in this sub-Saharan African population. Our results support continued use of mOPVs in supplemental immunization activities in countries where poliovirus types 1 or 3 circulate. Clinical Trials Registration. ISRCTN18107202.
    The Journal of Infectious Diseases 12/2011; 205(2):228-36. · 5.85 Impact Factor
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    ABSTRACT: To identify diagnostic features associated with culture of Mycobacterium tuberculosis (MTB), the standard for tuberculosis (TB) diagnosis, to inform clinical end point definitions for new TB vaccine trials. Children <2 years of age (n = 1445) were screened and investigated for TB during a Bacille Calmette Guerin vaccine trial in South Africa. Standardized clinical, radiologic, and microbiologic data were collected, including paired gastric lavage and induced sputum for MTB liquid culture. Adjusted odds ratios (AORs) were calculated using a multivariate logistic regression model. Adjusted odds of positive MTB culture increased by 90% with history of wheezing (AOR, 1.9) and by 4% with each 1-mm increase in Mantoux diameter (AOR, 1.04). Odds of positive MTB culture doubled if the chest radiograph was suggestive of pulmonary TB (AOR, 2.16) and more than tripled if lower chest retraction was observed clinically (AOR, 3.37). Fever, night sweats, and presence of lymphadenopathy were negatively associated with MTB culture (AOR: 0.5, 0.62, and 0.2, respectively). Persistent cough, weight loss, and failure to thrive were not significantly associated with MTB culture in this study population. Wheezing and lower chest retraction, consistent with intrathoracic airway obstruction; chest radiography suggestive of pulmonary tuberculosis; and Mantoux diameter were predictive of positive MTB culture. These variables should be considered for inclusion in composite clinical end point definitions for infant TB vaccine trials. Several clinical features, commonly used for TB diagnosis in older children, were not associated with positive MTB culture among children younger than 2 years.
    The Pediatric Infectious Disease Journal 11/2011; 31(1):42-6. · 3.57 Impact Factor
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    ABSTRACT: The endpoint definition for infant tuberculosis (TB) vaccine trials should match the TB disease phenotype expected in the control arm of the study population. Our aim was to analyse selected combinations of the clinical, radiological, and microbiological features of pulmonary TB among children investigated under vaccine trial conditions, in order to estimate case frequency for a range of expected TB phenotypes. Two thousand one hundred and eighty five South African children were investigated over a nine-year period (2001-2009). Evidence of TB exposure and classical symptoms were several times more common than chest radiography (CXR) compatible with TB, or positive Mycobacterium tuberculosis culture. Discordance between clinical, radiological, and microbiological features was common in individual children. Up to one third of children with compatible CXR, and up to half the children who were M. tuberculosis culture positive, were asymptomatic. The culture positive rate fell over time, although rates of TB exposure and compatible chest radiography increased. Consequently, the annual incidence of diagnostic combinations that included M. tuberculosis culture fell to <0.2%. However, in this study population (children <2 years of age), annual incidence of the TB disease phenotype that included the triad of TB exposure, symptoms, and compatible CXR, approached 1% (n=848 per 100,000). These findings allow modelling of expected TB case frequency in multi-centre infant TB vaccine trials, based upon benchmarking of diagnostic data against the key indicator variables that constitute the building blocks of a trial endpoint.
    Vaccine 06/2011; 29(26):4316-21. · 3.77 Impact Factor
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    ABSTRACT: BCG, the only licensed tuberculosis vaccine, affords poor protection against lung tuberculosis in infants and children. A new tuberculosis vaccine, which may enhance the BCG-induced immune response, is urgently needed. We assessed the safety of and characterized the T cell response induced by 3 doses of the candidate vaccine, MVA85A, in BCG-vaccinated infants from a setting where tuberculosis is endemic.  Infants aged 5-12 months were vaccinated intradermally with either 2.5 × 10(7), 5 × 10(7), or 10 × 10(7) plaque-forming units of MVA85A, or placebo. Adverse events were documented, and T-cell responses were assessed by interferon γ (IFN-γ) enzyme-linked immunospot assay and intracellular cytokine staining. The 3 MVA85A doses were well tolerated, and no vaccine-related serious adverse events were recorded. MVA85A induced potent, durable T-cell responses, which exceeded prevaccination responses up to 168 d after vaccination. No dose-related differences in response magnitude were observed. Multiple CD4 T cell subsets were induced; polyfunctional CD4 T cells co-expressing T-helper cell 1 cytokines with or without granulocyte-macrophage colony-stimulating factor predominated. IFN-γ-expressing CD8 T cells, which peaked later than CD4 T cells, were also detectable. MVA85A was safe and induced robust, polyfunctional, durable CD4 and CD8 T-cell responses in infants. These data support efficacy evaluation of MVA85A to prevent tuberculosis in infancy. Clinical Trials Registration. NCT00679159.
    The Journal of Infectious Diseases 06/2011; 203(12):1832-43. · 5.85 Impact Factor