Browsing by Author "Musoke, Philippa"

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    Adherence To Antiretroviral Therapy In Children Attending Mulago Hospital, Kampala
    (Annals of tropical paediatrics, 2007) Barungi, Nicolette Nabukeera; Kalyesubula, Israel; Kekitiinwa, Addy; Tusiime, Jayne Byakika; Musoke, Philippa
    Non-adherence reduces the effectiveness of antiretroviral therapy in children attending the paediatric HIV/AIDS clinic at Mulago Hospital, Kampala.To determine the levels of adherence to HAART and identify factors associated with non-adherence.A cross-sectional study of 170 children aged 2–18 years. Adherence to HAART was defined as taking ≥95% of prescribed medication. It was determined using three measures: a 3-day self-report by the caregivers, clinic-based pill counts at enrolment and home-based unannounced pill counts 2–3 weeks later.The 3-day self-reported ≥95% adherence was 89.4% (n=170). Using clinic-based pill counts, 94.1% (n=170) had ≥95% adherence to treatment compared with only 72% (n=164) by unannounced pill counts. When the primary caregiver was the only one who knew the child's serostatus, he/she was three times more likely to be non-adherent (p=0.02, OR 3.34, 95% CI 1.14–9.82). Those who had been hospitalised twice or more before starting HAART were more likely to have ≥95% adherence (p=0.02, OR 0.44, 95% CI 0.20–0.92). The majority of children had good adherence levels when estimated by unannounced pill counts. Disclosing the child's HIV serostatus only to the primary caregiver and having been hospitalised only once or not at all were associated with poor adherence.
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    Adherence to antiretroviral therapy in children attending Mulago Hospital, Kampala
    (Annals of tropical Paediatrics, 2007) Nabukeera-Barungi, Nicolette; Kalyesubula, Israel; Kekitiinwa, Addy; Byakika-Tusiime, Jayne; Musoke, Philippa
    Background: Non-adherence reduces the effectiveness of antiretroviral therapy in children attending the paediatric HIV/AIDS clinic at Mulago Hospital, Kampala. Aim: To determine the levels of adherence to HAART and identify factors associated with non-adherence. Methods: A cross-sectional study of 170 children aged 2–18 years. Adherence to HAART was defined as taking >95% of prescribed medication. It was determined using three measures: a 3-day self-report by the caregivers, clinic-based pill counts at enrolment and home-based unannounced pill counts 2–3 weeks later. Results: The 3-day self-reported >95% adherence was 89.4% (n5170). Using clinic-based pill counts, 94.1% (n5170) had >95% adherence to treatment compared with only 72% (n5164) by unannounced pill counts. When the primary caregiver was the only one who knew the child’s serostatus, he/she was three times more likely to be non-adherent (p50.02, OR 3.34, 95% CI 1.14–9.82). Those who had been hospitalised twice or more before starting HAART were more likely to have >95% adherence (p50.02, OR 0.44, 95% CI 0.20–0.92). Conclusion: The majority of children had good adherence levels when estimated by unannounced pill counts. Disclosing the child’s HIV serostatus only to the primary caregiver and having been hospitalised only once or not at all were associated with poor adherence.
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    Analysis of Drug Resistance in Children Receiving Antiretroviral Therapy for Treatment of HIV-1 Infection in Uganda
    (AIDS research and human retroviruses, 2010) Towler, William I.; Barlow-Mosha, Linda; Church, Jessica D.; Bagenda, Danstan; Ajuna, Patrick; Mubiru, Micheal; Musoke, Philippa; Eshleman, Susan H.
    We analyzed drug resistance in HIV-infected Ugandan children who received antiretroviral therapy in a prospective, observational study (2004–2006); some children had prior single-dose nevirapine (sdNVP) exposure. Children received stavudine (d4T), lamivudine (3TC), and nevirapine (NVP); treatment was continued if they were clinically and immunologically stable. Samples with >1,000 copies=ml HIV RNA were analyzed by using the ViroSeq HIV Genotyping System (ViroSeq). Subtype A and D pretreatment samples also were analyzed with the LigAmp assay (for K103N, Y181C, and G190A). ViroSeq results were obtained for 74 pretreatment samples (35 from sdNVP-exposed children (median age, 19 months) and 39 from sdNVP-unexposed children (median age, 84 months). This included 39 subtype A, 22 subtype D, 1 subtype C, and 12 inter-subtype recombinant samples. One sample had nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance, one had nucleoside reverse transcriptase inhibitor (NRTI) resistance, and three had protease inhibitor (PI) resistance. Y181C was detected by using LigAmp in five pretreatment samples [four (14.8%) of 37 samples from sdNVP-exposed children, one (4.2%) of 24 samples from children without prior sdNVP exposure; p¼0.35]. Among children who were not virally suppressed at 48 weeks of treatment, all 12 tested had NNRTI resistance, as well as resistance to 3TC and emtricitibine (FTC); three had resistance to other NRTIs. Seven of those children had a ViroSeq result at 96 weeks of treatment; four of the seven acquired resistance to additional NRTIs by 96 weeks. In Uganda, clinically and immunologically stable children receiving nonsuppressive antiretroviral treatment regimens are at risk for development of drug resistance.
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    Analysis of Drug Resistance in Children Receiving Antiretroviral Therapy for Treatment of HIV-1 Infection in Uganda
    (AIDS research and human retroviruses, 2010) Towler, William I.; Mosha, Linda Barlow; Church, Jessica D.; Bagenda, Danstan; Ajuna, Patrick; Mubiru, Micheal; Musoke, Philippa; Eshleman, Susan H.
    We analyzed drug resistance in HIV-infected Ugandan children who received antiretroviral therapy in a prospective, observational study (2004–2006); some children had prior single-dose nevirapine (sdNVP) exposure. Children received stavudine (d4T), lamivudine (3TC), and nevirapine (NVP); treatment was continued if they were clinically and immunologically stable. Samples with >1,000 copies/ml HIV RNA were analyzed by using the ViroSeq HIV Genotyping System (ViroSeq). Subtype A and D pretreatment samples also were analyzed with the LigAmp assay (for K103N, Y181C, and G190A). ViroSeq results were obtained for 74 pretreatment samples (35 from sdNVP-exposed children (median age, 19 months) and 39 from sdNVP-unexposed children (median age, 84 months). This included 39 subtype A, 22 subtype D, 1 subtype C, and 12 inter-subtype recombinant samples. One sample had nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance, one had nucleoside reverse transcriptase inhibitor (NRTI) resistance, and three had protease inhibitor (PI) resistance. Y181C was detected by using LigAmp in five pretreatment samples [four (14.8%) of 37 samples from sdNVP-exposed children, one (4.2%) of 24 samples from children without prior sdNVP exposure; p = 0.35]. Among children who were not virally suppressed at 48 weeks of treatment, all 12 tested had NNRTI resistance, as well as resistance to 3TC and emtricitibine (FTC); three had resistance to other NRTIs. Seven of those children had a ViroSeq result at 96 weeks of treatment; four of the seven acquired resistance to additional NRTIs by 96 weeks. In Uganda, clinically and immunologically stable children receiving nonsuppressive antiretroviral treatment regimens are at risk for development of drug resistance.
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    Analysis of HIV Diversity Using a High-Resolution Melting Assay
    (AIDS research and human retroviruses, 2010) Towler, William I.; James, Maria M.; Ray, Stuart C.; Wang, Lei; Donnell, Deborah; Mwatha, Anthony; Guay, Laura; Nakabiito, Clemensia; Musoke, Philippa; Jackson, J. Brooks; Eshleman, Susan
    HIV viruses are usually genetically homogeneous shortly after infection, and become more heterogeneous over time. We developed a high-resolution melting (HRM) assay to analyze HIV diversity without sequencing. Plasma samples from the HIVNET 012 trial were obtained from nine Ugandan mother–infant pairs. DNA amplified from the HIV gag region was analyzed to determine the number of degrees over which the DNA melted (HRM score). HRM gag DNA was also cloned and sequenced (50 clones/mother; 20 clones/infant). The median HRM score for infants (4.3, range 4.2–5.3) was higher than that for control plasmids (3.4, range 3.2–3.8, p < 0.001) and lower than that for mothers (5.7, range 4.4–7.7, p = 0.005, exact Wilcoxon rank sum test). The intraclass correlation coefficient reflecting assay reproducibility was 94% (95% CI: 89–98%). HRM scores were also compared to sequenced-based measures of HIV diversity; higher HRM scores were associated with higher genetic diversity (p < 0.001), complexity (p = 0.009), and Shannon entropy (p = 0.022), but not with length variation (p = 0.111). The HRM assay provides a novel, rapid method for assessing HIV diversity without sequencing. This assay could be applied to any region of the HIV genome or to other genetic systems that exhibit DNA diversity.
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    Analysis of HIV tropism in Ugandan infants
    (Current HIV research, 2010) Church, Jessica D.; Huang, Wei; Mwatha, Anthony; Musoke, Philippa; Jackson, J. Brooks; Bagenda, Danstan; Omer, Saad B.; Donnell, Deborah; Nakabiito, Clemensia; Eure, Chineta; Guay, Laura A.; Taylor, Allan; Bakaki, Paul M.; Matovu, Flavia; McConnell, Michelle; Fowler, Mary Glenn; Eshleman, Susan H.
    HIV-infected infants may have CXCR4-using (X4-tropic) HIV, CCR5-using (R5-tropic) HIV, or a mixture of R5-tropic and X4-tropic HIV (dual/mixed, DM HIV). The level of infectivity for R5 virus (R5-RLU) varies among HIV-infected infants. HIV tropism and R5-RLU were measured in samples from HIV-infected Ugandan infants using a commercial assay. DM HIV was detected in 7/72 (9.7%) infants at the time of HIV diagnosis (birth or 6–8 weeks of age, 4/15 (26.7%) with subtype D, 3/57 (5.3 %) with other subtypes, P=0.013). A transition from R5-tropic to DM HIV was observed in only two (6.7%) of 30 infants over 6–12 months. Six (85.7%) of seven infants with DM HIV died, compared to 21/67 (31.3%) infants with R5-tropic HIV (p=0.09). Higher R5- RLU at 6–8 weeks was not associated with decreased survival. Infants with in utero infection had a higher median R5-RLU than infants who were HIV-uninfected at birth (p=0.025).
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    Analysis of Nevirapine (NVP) Resistance in Ugandan Infants Who Were HIV Infected Despite Receiving Single-Dose (SD) NVP versus SD NVP Plus Daily NVP Up to 6 Weeks of Age to Prevent HIV Vertical Transmission
    (The Journal of infectious disease, 2010) Church, Jessica D.; Omer, Saad B.; Guay, Laura A.; Huang, Wei; Lidstrom, Jessica; Musoke, Philippa; Mmiro, Francis; Jackson, J. Brooks; Eshleman, Susan H.
    Background. Single-dose nevirapine (SD NVP) at birth plus NVP prophylaxis for the infant up to 6 weeks of age is superior to SD NVPalone for prevention of vertical transmission of human immunodeficiency virus (HIV) through breastfeeding. We analyzed NVP resistance in HIV-infected Ugandan infants who received either SD NVP or extended NVP prophylaxis. Methods. We tested plasma HIV by using a genotyping assay (ViroSeq; Celera Diagnostics), a phenotypic resistance assay (PhenoSense; Monogram Biosciences), and sensitive point mutation assay (LigAmp, for K103N, Y181C, and G190A). Results. When infants were 6 weeks old, ViroSeq detected NVP resistance in a higher proportion of infants in the extended NVP arm than in the SD NVP arm (21 of 25 [84%] vs. 12 of 24 [50%]; P = .01). Similar results were obtained with LigAmp and PhenoSense. In both study arms, infants who were HIV infected at birth frequently had NVP resistance detected. In contrast, infants in the extended NVP arm who were HIV infected after birth were more likely to have resistance detected at 6 weeks, compared with infants in the SD NVP arm. The use of extended NVP prophylaxis was also associated with detection of NVP resistance by ViroSeq at 6 months (7 of 7 [100%] infants in the extended NVP arm had resistance detected, compared with 1 of 6 [16.7%] infants in the SD NVP arm; P = .005). Conclusions. The use of extended NVP prophylaxis was associated with increased selection for and persistence of NVP resistance in HIV-infected Ugandan infants.
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    Antiretroviral Treatment for Children with Peripartum Nevirapine Exposure
    (New England Journal of Medicine, 2010) Palumbo, Paul; Lindsey, Jane C.; Hughes, Michael D.; Cotton, Mark F.; Bobat, Raziya; Meyers, Tammy; Dangarembizi, Mutsawashe Bwakura; Chi, Benjamin H.; Musoke, Philippa; Kamthunzi, Portia; Schimana, Werner; Purdue, Lynette; Eshleman, Susan H.; Abrams, Elaine J.; Millar, Linda; Petzold, Elizabeth; Mofenson, Lynne M.; Philippe, Patrick Jean; Violari, Avy
    Single-dose nevirapine is the cornerstone of the regimen for prevention of mother-to-child transmission of human immunodeficiency virus (HIV) in resource-limited settings, but nevirapine frequently selects for resistant virus in mothers and children who become infected despite prophylaxis. The optimal antiretroviral treatment strategy for children who have had prior exposure to single-dose nevirapine is unknown.We conducted a randomized trial of initial therapy with zidovudine and lamivudine plus either nevirapine or ritonavir-boosted lopinavir in HIV-infected children 6 to 36 months of age, in six African countries, who qualified for treatment according to World Health Organization (WHO) criteria. Results are reported for the cohort that included children exposed to single-dose nevirapine prophylaxis. The primary end point was virologic failure or discontinuation of treatment by study week 24. Enrollment in this cohort was terminated early on the recommendation of the data and safety monitoring board. A total of 164 children were enrolled. The median percentage of CD4+ lymphocytes was 19%; a total of 56% of the children had WHO stage 3 or 4 disease. More children in the nevirapine group than in the ritonavir-boosted lopinavir group reached a primary end point (39.6% vs. 21.7%; weighted difference, 18.6 percentage-points; 95% confidence interval, 3.7 to 33.6; nominal P=0.02). Baseline resistance to nevirapine was detected in 18 of 148 children (12%) and was predictive of treatment failure. No significant between-group differences were seen in the rate of adverse events.Among children with prior exposure to single-dose nevirapine for perinatal prevention of HIV transmission, antiretroviral treatment consisting of zidovudine and lamivudine plus ritonavir-boosted lopinavir resulted in better outcomes than did treatment with zidovudine and lamivudine plus nevirapine. Since nevirapine is used for both treatment and perinatal prevention of HIV infection in resource-limited settings, alternative strategies for the prevention of HIV transmission from mother to child, as well as for the treatment of HIV infection, are urgently required. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT00307151. opens in new tab.)
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    The Association Between the Ratio of Monocytes: Lymphocytes and Risk of Tuberculosis Among HIV-Infected Postpartum Women
    (BMC medicine, 2014) Naranbhai, Vivek; Moodley, Dhayendre; Chipato, Tsungai; Chibanda, Lynda Stranix; Nakabaiito, Clemensia; Kamateeka, Moreen; Musoke, Philippa; Manji, Karim; George, Kathleen; Emel, Lynda M.; Richardson, Paul; Andrew, Philip; Fowler, MaryGlenn; Fletcher, Helen; McShane, Helen; Coovadia, Hoosen M.; Hill, Adrian V. S.; for the HPTN 046 Protocol Team
    Recent transcriptomic studies revived a hypothesis suggested by historical studies in rabbits that the ratio of peripheral blood monocytes to lymphocytes (ML) is associated with risk of tuberculosis (TB) disease. Recent data confirmed the hypothesis in cattle and in adults infected with HIV.We tested this hypothesis in 1,336 infants (540 HIV-infected, 796 HIV-exposed, uninfected (HEU)) prospectively followed in a randomized controlled trial of isoniazid prophylaxis in Southern Africa, the IMPAACT P1041 study. We modeled the relationship between ML ratio at enrollment (91 to 120 days after birth) and TB disease or death in HIV-infected children and latent Mycobacterium tuberculosis (MTB) infection, TB disease or death in HEU children within 96 weeks (with 12 week window) of randomization. Infants were followed-up prospectively and routinely assessed for MTB exposure and outcomes. Cox proportional hazards models allowing for non-linear associations were used; in all cases linear models were the most parsimonious.Increasing ML ratio at baseline was significantly associated with TB disease/death within two years (adjusted hazard ratio (HR) 1.17 per unit increase in ML ratio; 95% confidence interval (CI) 1.01 to 1.34; P = 0.03). Neither monocyte count nor lymphocyte counts alone were associated with TB disease. The association was not statistically dissimilar between HIV infected and HEU children. Baseline ML ratio was associated with composite endpoints of TB disease and death and/or TB infection. It was strongest when restricted to probable and definite TB disease (HR 1.50; 95% CI 1.19 to 1.89; P = 0.006). Therefore, per 0.1 unit increase in the ML ratio at three to four months of age, the hazard of probable or definite TB disease before two years was increased by roughly 4% (95% CI 1.7% to 6.6%).Elevated ML ratio at three- to four-months old is associated with increased hazards of TB disease before two years among children in Southern Africa. While significant, the modest effect size suggests that the ML ratio plays a modest role in predicting TB disease-free survival; its utility may, therefore, be limited to combination with existing tools to stratify TB risk, or to inform underlying pathophysiologic determinants of TB disease.
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    Association of cord blood Nevirapine concentration with reported timing of dose and HIV-1 transmission
    (Aids, 2006) Jackson, J. Brooks; Parsons, Teresa; Musoke, Philippa; Nakabiito, Clemensia; Donnell, Deborah; Fleming, Thomas; Mirochnick, Mark; Mofenson, Lynne; Fowler, Mary Glenn; Mmiro, Francis; Guay, Laura
    Background: To correlate nevirapine presence and concentration in cord bloods of infants born to HIV-1 infected women with report of timing of dose and HIV-1 transmission at 6 weeks of age. Methods: All available cord blood samples from the infants of mothers enrolled in the HIVNET 012 trial who were randomly assigned to receive either nevirapine or zidovudine at the onset of labor were tested for a nevirapine concentration. Results: Nevirapine was detected in the cord blood of 244 of 259 (94%) infants whose mothers reported they took nevirapine in labor more than 1 h before delivery and in 12 of 13 (92%) infants whose mothers reported they took nevirapine less than 1 h before delivery. The median nevirapine cord blood concentration was 1238 ng/ml [interquartile range (IQR), 905–1474 ng/ml] and 122 ng/ml (IQR, 64–321 ng/ml) for women who reported taking nevirapine more or less than 1 h before delivery, respectively (P < 0.001). The median nevirapine cord blood concentration of infants who were HIV-1 negative at birth, but positive at 6–8 weeks of age (n ¼ 11), was 916 ng/ml (IQR, 737–1245 ng/ml) compared with 1192 ng/ml (IQR, 875–1471 ng/ml) for uninfected infants (n ¼ 236). Conclusions: Cord blood nevirapine concentration correlated well with report of nevirapine administration and timing of dose before delivery. The nevirapine cord blood concentration was modestly lower in infected infants, although the number of infants infected between birth and 6–8 weeks of age was small (n ¼ 11). The high adherence rate in the HIVNET 012 study supports the efficacy, simplicity and deliverability of this regimen.
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    Association of HIV Diversity and Survival in HIV-Infected Ugandan Infants
    (PLoS One, 2011) James, Maria M.; Wang, Lei; Musoke, Philippa; Donnell, Deborah; Fogel, Jessica; Towler, William I.; Khaki, Leila; Nakabiito, Clemensia; Jackson, J. Brooks; Eshleman, Susan H.
    Background: The level of viral diversity in an HIV-infected individual can change during the course of HIV infection, reflecting mutagenesis during viral replication and selection of viral variants by immune and other selective pressures. Differences in the level of viral diversity in HIV-infected infants may reflect differences in viral dynamics, immune responses, or other factors that may also influence HIV disease progression. We used a novel high resolution melting (HRM) assay to measure HIV diversity in Ugandan infants and examined the relationship between diversity and survival through 5 years of age. Methods: Plasma samples were obtained from 31 HIV-infected infants (HIVNET 012 trial). The HRM assay was used to measure diversity in two regions in the gag gene (Gag1 and Gag2) and one region in the pol gene (Pol). Results: HRM scores in all three regions increased with age from 6–8 weeks to 12–18 months (for Gag1: P = 0.005; for Gag2: P = 0.006; for Pol: P = 0.016). Higher HRM scores at 6–8 weeks of age (scores above the 75th percentile) were associated with an increased risk of death by 5 years of age (for Pol: P = 0.005; for Gag1/Gag2 (mean of two scores): P = 0.003; for Gag1/ Gag2/Pol (mean of three scores): P = 0.002). We did not find an association between HRM scores and other clinical and laboratory variables. Conclusions: Genetic diversity in HIV gag and pol measured using the HRM assay was typically low near birth and increased over time. Higher HIV diversity in these regions at 6–8 weeks of age was associated with a significantly increased risk of death by 5 years of age
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    Association of HIV Diversity and Survival in HIV-Infected Ugandan Infants
    (PLoS One, 2011) James, Maria M.; Wang, Lei; Musoke, Philippa; Donnell, Deborah; Fogel, Jessica; Towler, William I.; Khaki, Leila; Nakabiito, Clemensia; Jackson, J. Brooks; Eshleman, Susan H.
    The level of viral diversity in an HIV-infected individual can change during the course of HIV infection, reflecting mutagenesis during viral replication and selection of viral variants by immune and other selective pressures. Differences in the level of viral diversity in HIV-infected infants may reflect differences in viral dynamics, immune responses, or other factors that may also influence HIV disease progression. We used a novel high resolution melting (HRM) assay to measure HIV diversity in Ugandan infants and examined the relationship between diversity and survival through 5 years of age.Plasma samples were obtained from 31 HIV-infected infants (HIVNET 012 trial). The HRM assay was used to measure diversity in two regions in the gag gene (Gag1 and Gag2) and one region in the pol gene (Pol).HRM scores in all three regions increased with age from 6–8 weeks to 12–18 months (for Gag1: P = 0.005; for Gag2: P = 0.006; for Pol: P = 0.016). Higher HRM scores at 6–8 weeks of age (scores above the 75th percentile) were associated with an increased risk of death by 5 years of age (for Pol: P = 0.005; for Gag1/Gag2 (mean of two scores): P = 0.003; for Gag1/Gag2/Pol (mean of three scores): P = 0.002). We did not find an association between HRM scores and other clinical and laboratory variables.Genetic diversity in HIV gag and pol measured using the HRM assay was typically low near birth and increased over time. Higher HIV diversity in these regions at 6–8 weeks of age was associated with a significantly increased risk of death by 5 years of age.
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    Associations of Chemokine Receptor Polymorphisms With HIV-1 Mother-to-Child Transmission in Sub-Saharan Africa: Possible Modulation of Genetic Effects by Antiretrovirals
    (Journal of acquired immune deficiency syndromes, 1999) Singh, Kumud K.; Hughes, Michael D.; Chen, Jie; Phiri, Kelesitse; Rousseau, Christine; Kuhn, Louise; Coutsoudis, Anna; Jackson, J. Brooks; Guay, Laura A.; Musoke, Philippa; Mmiro, Francis; Semba, Richard D.; Spector, Stephen A.
    Background—HIV-1 mother-to-child transmission (MTCT) remains an important route of infection in sub-Saharan Africa. Methods—Genetic variants in CCR5 promoter, CCR2, CX3CR1, and Stromal cell-derived factor-1 (SDF-1) genes were determined in 980 infants from sub-Saharan Africa using real-time polymerase chain reaction to determine association with MTCT. Results—In antiretroviral-naive mother–infant pairs (n = 637), CCR5 promoter polymorphisms at positions 59029: A allele vs. G/G [odds ratio (OR): 1.61, 95% confidence interval (CI): 1.04 to 2.48; P = 0.032] and 59356: T allele vs. C/C (OR: 0.63, 95% CI: 0.41 to 0.96; P = 0.033) and CCR2-180: G allele vs. A/A (OR: 3.32, 95% CI: 1.13 to 9.73; P = 0.029) were associated with risk of MTCT. Treatment of HIV-1–infected mothers and infants with single-dose nevirapine or perinatal zidovudine altered but did not eliminate the association of genetic variants with MTCT. Conclusions—CCR5 promoter, CCR2, and CX3CR1 polymorphisms were associated with risk of MTCT likely through their role as an HIV-1 coreceptor or by modulating the early immune response. genetics may continue to alter MTCT when short-course interventions that only partially suppress virus are used. These findings will need to be confirmed in validation cohorts with a large number of infected infants.
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    Associations of Chemokine Receptor Polymorphisms With HIV-1 Mother-to-Child Transmission in Sub-Saharan Africa: Possible Modulation of Genetic Effects by Antiretrovirals
    (Journal of acquired immune deficiency syndromes, 2008) Singh, Kumud K.; Hughes, Michael D.; Chen, Jie; Phiri, Kelesitse; Rousseau, Christine; Kuhn, Louise; Coutsoudis, Anna; Jackson, J. Brooks; Guay, Laura A.; Musoke, Philippa; Mmiro, Francis; Semba, Richard D.; Spector, Stephen A.
    HIV-1 mother-to-child transmission (MTCT) remains an important route of infection in sub-Saharan Africa.Genetic variants in CCR5 promoter, CCR2, CX3CR1, and Stromal cell-derived factor-1 (SDF-1) genes were determined in 980 infants from sub-Saharan Africa using real-time polymerase chain reaction to determine association with MTCT.In antiretroviral-naive mother–infant pairs (n = 637), CCR5 promoter polymorphisms at positions 59029: A allele vs. G/G [odds ratio (OR): 1.61, 95% confidence interval (CI): 1.04 to 2.48; P = 0.032] and 59356: T allele vs. C/C (OR: 0.63, 95% CI: 0.41 to 0.96; P = 0.033) and CCR2-180: G allele vs. A/A (OR: 3.32, 95% CI: 1.13 to 9.73; P = 0.029) were associated with risk of MTCT. Treatment of HIV-1–infected mothers and infants with single-dose nevirapine or perinatal zidovudine altered but did not eliminate the association of genetic variants with MTCT.CCR5 promoter, CCR2, and CX3CR1 polymorphisms were associated with risk of MTCT likely through their role as an HIV-1 coreceptor or by modulating the early immune response. Host genetics may continue to alter MTCT when short-course interventions that only partially suppress virus are used. These findings will need to be confirmed in validation cohorts with a large number of infected infants.
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    Bacteraemia in severely malnourished children in an HIV-endemic setting
    (Annals of tropical paediatrics, 2006) Babirekere-Iriso, Esther; Musoke, Philippa; Kekitiinwa, Adeodata
    Background: HIV infection predisposes children with malnutrition to recurrent bacterial infections and a high risk of bacteraemia. Methods: A cross-sectional descriptive study to determine the prevalence, causative organisms, antibiotic sensitivity and factors associated with bacteraemia in malnourished children was undertaken at Mulago Hospital, Kampala. The prevalence of HIV infection was also determined. A total of 134 children aged 6–59 months with severe malnutrition were recruited. Results: Sixty-one (45.5%) had oedematous malnutrition and 73 (54.5%) had severe wasting. Fifty-nine (44.0%) were HIV-infected. The prevalence of bacteraemia was 22%. The predominant organisms isolated were gramnegative enteric bacilli (77%) with Salmonella species and E. coli contributing 67% of the isolates. Hypoglycaemia was significantly associated with bacteraemia (p50.007). Most organisms were resistant to cotrimaxazole (93.3%), ampicillin (76.7%), gentamicin (66.7%) and chloramphenicol (60%). All isolates were sensitive to ceftriaxone. Sensitivity to ciprofloxacin was 97%. There was no strong association between HIV infection and bacteraemia. The relative risk of death in malnourished children with bacteraemia was ten times higher than in those without bacteraemia. Conclusions: Nearly a quarter (22%) of children admitted with severe malnutrition had bacteraemia and gram-negative organisms were the predominant cause. Forty-four per cent were HIV-infected.Most of the bacteria were sensitive to ceftriaxone and ciprofloxacin and resistant to commonly used antibiotics. In the absence of culture and sensitivity, ciprofloxacin or ceftriaxone should be considered as first-line antibiotics for severely malnourished children.
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    Bacteraemia In Severely Malnourished Children In An HIV-Endemic Setting
    (Annals of tropical paediatrics, 2006) Iriso, Esther Babirekere; Musoke, Philippa; Kekitiinwa, Adeodata
    HIV infection predisposes children with malnutrition to recurrent bacterial infections and a high risk of bacteraemia.A cross-sectional descriptive study to determine the prevalence, causative organisms, antibiotic sensitivity and factors associated with bacteraemia in malnourished children was undertaken at Mulago Hospital, Kampala. The prevalence of HIV infection was also determined. A total of 134 children aged 6–59 months with severe malnutrition were recruited.Sixty-one (45.5%) had oedematous malnutrition and 73 (54.5%) had severe wasting. Fifty-nine (44.0%) were HIV-infected. The prevalence of bacteraemia was 22%. The predominant organisms isolated were gram-negative enteric bacilli (77%) with Salmonella species and E. coli contributing 67% of the isolates. Hypoglycaemia was significantly associated with bacteraemia (p=0.007). Most organisms were resistant to cotrimaxazole (93.3%), ampicillin (76.7%), gentamicin (66.7%) and chloramphenicol (60%). All isolates were sensitive to ceftriaxone. Sensitivity to ciprofloxacin was 97%. There was no strong association between HIV infection and bacteraemia. The relative risk of death in malnourished children with bacteraemia was ten times higher than in those without bacteraemia.Nearly a quarter (22%) of children admitted with severe malnutrition had bacteraemia and gram-negative organisms were the predominant cause. Forty-four per cent were HIV-infected. Most of the bacteria were sensitive to ceftriaxone and ciprofloxacin and resistant to commonly used antibiotics. In the absence of culture and sensitivity, ciprofloxacin or ceftriaxone should be considered as first-line antibiotics for severely malnourished children.
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    Bacteremia, Causative Agents and Antimicrobial Susceptibility Among HIV-1–infected Children on Antiretroviral Therapy in Uganda and Zimbabwe
    (The Pediatric infectious disease journal, 2013) Musiime, Victor; Cook, Adrian; Bakeera-Kitaka, Sabrina; Vhembo, Tichaona; Lutakome, Joseph; Keishanyu, Rosette; Prendergast, Andrew J.; Lubwama, Sam; Robertson, Val; Hughes, Peter; Nathoo, Kusum; Munderi, Paula; Klein, Nigel; Musoke, Philippa; Gibb, Diana M.
    Bacteremia is common in HIV-infected children in Africa, including after start of antiretroviral therapy (ART), but there are limited data on causative pathogens and their antimicrobial sensitivity patterns in this population. Methods: We analyzed data on blood cultures taken from HIV-infected children developing acute febrile illness after enrollment to the Antiretroviral Research for Watoto (ARROW) clinical trial in Uganda and Zimbabwe. Patterns of bacterial pathogens and their antimicrobial susceptibilities were determined and bacteremia rates calculated over time from ART initiation. Results: A total of 848 blood cultures were obtained from 461 children, of which 123 (14.5%) from 105 children (median age 3.5 years, 51% girls) were culture positive, including 75 (8.8%) with clearly pathogenic organisms. The event rates for positive cultures with clearly pathogenic organisms after 0–1, 2–3, 4–11 and ≥12 months on ART were 13.3, 11.4, 2.1 and 0.3 per 1000 person-months of follow-up, respectively. The pathogens isolated (n; %) were Streptococcus pneumoniae (36; 28.3%), Staphylococcus aureus (11; 8.7%), Klebsiella pneumoniae (6; 4.7%), Pseudomonas aeruginosa (6; 4.7%), Salmonella spp (6; 4.7%), Escherichia coli (5; 3.9%), Haemophilus influenzae (1; 0.8%) and fungal spp (4; 3.1%). Other bacteria of doubtful pathogenicity (n = 52; 42%) were also isolated. Most isolates tested were highly (80–100%) susceptible to ceftriaxone, cefotaxime and ciprofloxacin; very few (~5%) were susceptible to cotrimoxazole; S. pneumoniae had high susceptibility to amoxicillin/ampicillin (80%). Conclusions: Rates of proven bacteremia were >20-fold higher immediately after starting ART compared with 12 months later in African HIV-infected children. S. pneumoniae was most commonly isolated, suggesting need for pneumococcal vaccination and effective prophylactic antibiotics.
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    Barriers and facilitators for transitioning of young people from adolescent clinics to adult ART clinics in Uganda: unintended consequences of successful adolescent ART clinics
    (BMC Health Services Research, 2020) Mbalinda, Scovia Nalugo; Bakeera-Kitaka, Sabrina; Lusota, Derrick Amooti; Magongo, Eleanor Namusoke; Musoke, Philippa; Kaye, Dan Kabonge
    Background: There is a growing number of adolescents and young adults living with HIV (YPLHIV) who require the transfer of care from pediatric/ adolescent clinics to adult Antiretroviral therapy (ART) clinics. A successful transition is critical for optimum health outcomes, yet facilities may lack infrastructure, human resources (with appropriate knowledge and skills), and a supportive environment, as only 3% of clinics in Uganda caring for YPLHIV have a process for supporting this critical transition from pediatric to adult care, and, facilitators and barriers of a successful transition are not well documented. The purpose of this study was to explore the facilitators and barriers of transitioning among adolescents from adolescent clinics to adult ART clinics. Method: Eighteen focus group discussions were held in nine health facilities with 174 adolescents and YPLHIV to assess barriers and facilitators regarding transitioning to adult clinics. The focus group discussions were audiorecorded and transcribed. The Silences Framework using a thematic approach guided the analysis. Results: The key emerging issues were: Unfriendly adults in adult clinics, Care provided in the adolescent clinics, fear of stigma from health care providers, Congestion and long waiting time, fear to lose friends were barriers to transitioning. Transitioning preparation is key to a successful transition, moving as a cohort facilitates transition, and care in adult clinics offers new opportunities, could facilitate readiness and transition Conclusion: YPLHIV expressed fear to transition to adult clinics mainly because of the perceived better care provided in the adolescent clinic, thus constituting a barrier to smooth transition A range of individual, social and health system and services-related factors hindered transitioning. The expectation of transitioning as a group, assurance of similar care as in the adolescent clinic, and guarantees of confidentiality, privacy, and autonomy in decision-making for care was perceived as facilitators. Understanding barriers and facilitators can enable the Ministry of Health to improve the quality of life of YPLHIV through linkage to care, adherence, retention, and viral suppression. There is a need to better planning and preparation for clinical providers and YPLHIV with a focus on age-appropriate and individualized case management transition as well as focus on improving both clinical and psychosocial support throughout the process.
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    Baseline Inflammatory Biomarkers Identify Subgroups of HIV-Infected African Children With Differing Responses to Antiretroviral Therapy
    (The Journal of infectious diseases, 2016) Prendergast, Andrew J.; Szubert, Alexander J.; Berejena, Chipo; Pimundu, Godfrey; Pala, Pietro; Shonhai, Annie; Musiime, Victor; Bwakura-Dangarembizi, Mutsa; Poulsom, Hannah; Hunter, Patricia; Musoke, Philippa; Kihembo, Macklyn; Munderi, Paula; Gibb, Diana M.; Spyer, Moira; Walker, A. Sarah; Klein, Nigel
    Background. Identifying determinants of morbidity and mortality may help target future interventions for human immunodeficiency virus (HIV)–infected children. Methods. CD4+ T-cell count, HIV viral load, and levels of biomarkers (C-reactive protein, tumor necrosis factor α [TNF-α], interleukin 6 [IL-6], and soluble CD14) and interleukin 7 were measured at antiretroviral therapy (ART) initiation in the ARROW trial (case-cohort design). Cases were individuals who died, had new or recurrent World Health Organization clinical stage 4 events, or had poor immunological response to ART. Results. There were 115 cases (54 died, 45 had World Health Organization clinical stage 4 events, and 49 had poor immunologicalresponse) and 485 controls. Before ART initiation, the median ages of cases and controls were 8.2 years (interquartile range [IQR], 4.4–11.4 years) and 5.8 years (IQR, 2.3–9.3 years), respectively, and the median percentages of lymphocytes expressing CD4were 4% (IQR, 1%–9%) and 13% (IQR, 8%–18%), respectively. In multivariable logistic regression, cases had lower age-associatedCD4+ T-cell count ratio (calculated as the ratio of the subject’s CD4+ T-cell count to the count expected in healthy individuals of thesame age; P < .0001) and higher IL-6 level (P = .002) than controls. Clustering biomarkers and age-associated CD4+ and CD8+ T-cellcount ratios identified 4 groups of children. Group 1 had the highest frequency of cases (41% cases; 16% died) and profoundimmunosuppression; group 2 had similar mortality (23% cases; 15% died), but children were younger, with less profound immunosuppression and high levels of inflammatory biomarkers and malnutrition; group 3 comprised young children with moderate immunosuppression, high TNF-α levels, and high age-associated CD8+ T-cell count ratios but lower frequencies of events (12% cases; 7% died); and group 4 comprised older children with low inflammatory biomarker levels, lower HIV viral loads, and good clinical outcomes (11% cases; 5% died). Conclusions. While immunosuppression is the major determinant of poor outcomes during ART, baseline inflammation is an additional important factor, identifying a subgroup of young children with similar mortality. Antiinflammatory interventions may help improve outcomes.
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    Bone Mineral Density in Antiretroviral Therapy-Naïve HIV-1–Infected Young Adult -Women Using Depot Medroxyprogesterone Acetate or Nonhormonal Contraceptives in Uganda
    (JBMR plus, 2021) Matovu, Flavia Kiweewa; Nabwana, Martin; Kiwanuka, Noah; Scholes, Delia; Isingel, Esther; Nolan, Monica L; Fowler, Mary G; Musoke, Philippa; Pettifor, John M; Brown, Todd T; Beksinska, Mags E
    Most studies evaluating BMD in human immunodeficiency virus (HIV)-infected populations have focused on antiretroviral therapy (ART)-experienced patients. In this study, the association between HIV-1 and/or depot medroxyprogesterone acetate (DMPA) and BMD among untreated HIV-1–infected women in a resource-limited setting was assessed before long-term exposure to ART. The data were then compared with that of the 2005–2008 United States National Health and Nutrition Examination Survey data for non-Hispanic White and Black women. Women aged 18–35 years, recruited from health facilities in Kampala, Uganda, were classified based on their combination of HIV-1 status and DMPA use: (i) HIV-1–infected current DMPA users, (ii) HIV-1–infected previous DMPA users, (iii) HIV-1–infected nonhormonal-contraceptive users, and (iv) HIV-uninfected nonhormonal-contraceptive users. All HIV-1– infected women reported being ART-naïve at baseline. BMD was measured at the lumbar spine, total hip, and femoral neck using DXA. Multivariate linear regression was used to assess the association between HIV-1 and/or DMPA and BMD Z-scores. Baseline data were analyzed for 452 HIV-1–infected (220 nonhormonal users, and 177 current and 55 previous DMPA users) and 69 HIV-1– uninfected nonhormonal-contraceptive users. The mean age was 26.1 years (SD, 4.2) with a median duration of DMPA use among current users of 24.0 months [medians (interquartile range), 12-48]. A higher proportion of HIV-1–infected previous (12.7%) or current DMPA users (20.3%) and nonhormonal users (15.0%) had low BMD (Z-score ≤−2 at any of the three sites) compared with agematched HIV-1–uninfected women (2.9%). HIV-1 infection and DMPA use were independently associated with significantly lower mean BMD Z-scores at all sites, with the greatest difference being among HIV-1–infected current DMPA users (5.6%–8.0%) versus uninfected nonhormonal users. Compared with non-Hispanic White and Black women, the Ugandan local reference population had generally lower mean BMD at all sites. Newer treatment interventions are needed to mitigate BMD loss in HIV-1–infected women in resource-limited settings.