NRU :: Browsing by Author "Munderi, Paula"

Browsing by Author "Munderi, Paula"

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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.
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.
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 and 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.
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.
Cost Effectiveness Analysis of Clinically Driven versus Routine Laboratory Monitoring of Antiretroviral Therapy in Uganda and Zimbabwe
(PloS one, 2012) Lara, Antonieta Medina; Kigozi, Jesse; Amurwon, Jovita; Muchabaiwa, Lazarus; Wakaholi, Barbara Nyanzi; Mota, Ruben E. Mujica; Walker, A. Sarah; Kasirye, Ronnie; Ssali, Francis; Reid, Andrew; Grosskurth, Heiner; Babiker, Abdel G.; Kityo, Cissy; Katabira, Elly; Munderi, Paula; Mugyenyi, Peter; Hakim, James; Darbyshire, Janet; Gibb, Diana M.; Gilks, Charles F.
Despite funding constraints for treatment programmes in Africa, the costs and economic consequences of routine laboratory monitoring for efficacy and toxicity of antiretroviral therapy (ART) have rarely been evaluated.Cost-effectiveness analysis was conducted in the DART trial (ISRCTN13968779). Adults in Uganda/Zimbabwe starting ART were randomised to clinically-driven monitoring (CDM) or laboratory and clinical monitoring (LCM); individual patient data on healthcare resource utilisation and outcomes were valued with primary economic costs and utilities. Total costs of first/second-line ART, routine 12-weekly CD4 and biochemistry/haematology tests, additional diagnostic investigations, clinic visits, concomitant medications and hospitalisations were considered from the public healthcare sector perspective. A Markov model was used to extrapolate costs and benefits 20 years beyond the trial.3316 (1660LCM;1656CDM) symptomatic, immunosuppressed ART-naive adults (median (IQR) age 37 (32,42); CD4 86 (31,139) cells/mm3) were followed for median 4.9 years. LCM had a mean 0.112 year (41 days) survival benefit at an additional mean cost of $765 [95%CI:685,845], translating into an adjusted incremental cost of $7386 [3277,dominated] per life-year gained and $7793 [4442,39179] per quality-adjusted life year gained. Routine toxicity tests were prominent cost-drivers and had no benefit. With 12-weekly CD4 monitoring from year 2 on ART, low-cost second-line ART, but without toxicity monitoring, CD4 test costs need to fall below $3.78 to become cost-effective (<3xper-capita GDP, following WHO benchmarks). CD4 monitoring at current costs as undertaken in DART was not cost-effective in the long-term.There is no rationale for routine toxicity monitoring, which did not affect outcomes and was costly. Even though beneficial, there is little justification for routine 12-weekly CD4 monitoring of ART at current test costs in low-income African countries. CD4 monitoring, restricted to the second year on ART onwards, could be cost-effective with lower cost second-line therapy and development of a cheaper, ideally point-of-care, CD4 test.
Distribution of HLA-B alleles in a Ugandan HIV-infected adult population: NORA pharmacogenetic substudy of DART
(Tropical medicine & international health, 2011) Munderi, Paula; Snowden, Wendy B.; Kityo, Cissy; Kabuye, Geoffrey; Thoofer, Navdeep K.; Ssali, Francis; Gilks, Charles F.; Hughes, Arlene R.
To determine the frequencies of HLA-B alleles in Ugandan patients in the NORA substudy of the DART trial and to compare HLA-B allele frequencies in those with and without clinically diagnosed hypersensitivity reaction (HSR). DNA-based HLA-B genotyping was used to determine HLA alleles in 247 participants who received abacavir, including all six participants (‘cases’) with clinically diagnosed abacavir HSR. The incidence of clinical abacavir HSR in this double-blinded study was 2.0% (6/300) in the abacavir group. As HLA-B*5701 was absent throughout the entire cohort, including the six HSR ‘cases’, an association could not be established between HLA-B*5701 and clinically diagnosed abacavir HSR. No other HLA-B*57 alleles were present among the six ‘cases’. HLA-B*5703 was the most frequent HLA-B*57 allele among the abacavir-tolerant participants. The rate of clinical HSR was low, which may reflect the expected 2–3% clinical false-positive rate seen in previous double-blind randomized studies. The presumption that these cases may be false-positive abacavir HSR is supported by the fact that no HLA-B*5701 alleles were found in the abacavir group. Implementation of prospective HLA-B*5701 screening must be based on benefit/risk considerations within local practice. Clinical risk management remains paramount.
Distribution of HLA-B alleles in a Ugandan HIV-infected adult population: NORA pharmacogenetic substudy of DART
(Tropical medicine & international health, 2011-11-23) Munderi, Paula; Kityo, Cissy; Kabuye, Geoffrey; Hughes, Arlene R.
To determine the frequencies of HLA-B alleles in Ugandan patients in the NORA substudy of the DART trial and to compare HLA-B allele frequencies in those with and without clinically diagnosed hypersensitivity reaction (HSR). DNA-based HLA-B genotyping was used to determine HLA alleles in 247 participants who received abacavir, including all six participants (‘cases’) with clinically diagnosed abacavir HSR. The incidence of clinical abacavir HSR in this double-blinded study was 2.0% (6/300) in the abacavir group. As HLA-B*5701 was absent throughout the entire cohort, including the six HSR ‘cases’, an association could not be established between HLA-B*5701 and clinically diagnosed abacavir HSR. No other HLA-B*57 alleles were present among the six ‘cases’. HLA-B*5703 was the most frequent HLA-B*57 allele among the abacavir-tolerant participants. The rate of clinical HSR was low, which may reflect the expected 2–3% clinical false-positive rate seen in previous double-blind randomized studies. The presumption that these cases may be false-positive abacavir HSR is supported by the fact that no HLA-B*5701 alleles were found in the abacavir group. Implementation of prospective HLA-B*5701 screening must be based on benefit/risk considerations within local practice. Clinical risk management remains paramount.
High Rate of HIV Resuppression After Viral Failure on First-line Antiretroviral Therapy in the Absence of Switch to Second-line Therapy
(Clinical infectious diseases, 2014) Gupta, Ravindra K.; Goodall, Ruth L.; Kityo, Cissy; Munderi, Paula; Lyagoba, Fred; Mugarura, Lincoln; Kaleebu, Pontiano; Pillay, Deenan
In a randomized comparison of nevirapine or abacavir with zidovudine plus lamivudine, routine viral load monitoring was not performed, yet 27% of individuals with viral failure at week 48 experienced resuppression by week 96 without switching. This supports World Health Organization recommendations that suspected viral failure should trigger adherence counseling and repeat measurement before a treatment switch is considered.
Pregnancy and Infant Outcomes among HIV-Infected Women Taking Long-Term ART with and without Tenofovir in the DART Trial
(PLoS Med, 2012) Gibb, Diana M.; Kizito, Hilda; Russell, Elizabeth C.; Chidziva, Ennie; Zalwango, Eva; Nalumenya, Ruth; Spyer, Moira; Tumukunde, Dinah; Nathoo, Kusum; Munderi, Paula; Kyomugisha, Hope; Hakim, James; Grosskurth, Heiner; Gilks, Charles F.; Walker, Sarah; Musoke, Phillipa
Few data have described long-term outcomes for infants born to HIV-infected African women taking antiretroviral therapy (ART) in pregnancy. This is particularly true for World Health Organization (WHO)–recommended tenofovir-containing first-line regimens, which are increasingly used and known to cause renal and bone toxicities; concerns have been raised about potential toxicity in babies due to in utero tenofovir exposure. Methods and Findings: Pregnancy outcome and maternal/infant ART were collected in Ugandan/Zimbabwean HIV-infected women initiating ART during The Development of AntiRetroviral Therapy in Africa (DART) trial, which compared routine laboratory monitoring (CD4; toxicity) versus clinically driven monitoring. Women were followed 15 January 2003 to 28 September 2009. Infant feeding, clinical status, and biochemistry/haematology results were collected in a separate infant study. Effect of in utero ART exposure on infant growth was analysed using random effects models. 382 pregnancies occurred in 302/1,867 (16%) women (4.4/100 woman-years [95% CI 4.0–4.9]). 226/390 (58%) outcomes were live-births, 27 (7%) stillbirths ($22 wk), and 137 (35%) terminations/miscarriages (,22 wk). Of 226 live-births, seven (3%) infants died ,2 wk from perinatal causes and there were seven (3%) congenital abnormalities, with no effect of in utero tenofovir exposure (p.0.4). Of 219 surviving infants, 182 (83%) enrolled in the follow-up study; median (interquartile range [IQR]) age at last visit was 25 (12–38) months. From mothers’ ART, 62/9/111 infants had no/20%–89%/$90% in utero tenofovir exposure; most were also zidovudine/lamivudine exposed. All 172 infants tested were HIV-negative (ten untested). Only 73/ 182(40%) infants were breast-fed for median 94 (IQR 75–212) days. Overall, 14 infants died at median (IQR) age 9 (3–23) months, giving 5% 12-month mortality; six of 14 were HIV-uninfected; eight untested infants died of respiratory infection (three), sepsis (two), burns (one), measles (one), unknown (one). During follow-up, no bone fractures were reported to have occurred; 12/368 creatinines and seven out of 305 phosphates were grade one (16) or two (three) in 14 children with no effect of in utero tenofovir (p.0.1). There was no evidence that in utero tenofovir affected growth after 2 years (p = 0.38). Attained height- and weight for age were similar to general (HIV-uninfected) Ugandan populations. Study limitations included relatively small size and lack of randomisation to maternal ART regimens. Conclusions: Overall 1-year 5% infant mortality was similar to the 2%–4% post-neonatal mortality observed in this region. No increase in congenital, renal, or growth abnormalities was observed with in utero tenofovir exposure. Although some infants died untested, absence of recorded HIV infection with combination ART in pregnancy is encouraging. Detailed safety of tenofovir for pre-exposure prophylaxis will need confirmation from longer term follow-up of larger numbers of exposed children.
Prevalence, Incidence and Predictors of Severe Anaemia with Zidovudine-Containing Regimens in African Adults With HIV Infection within the DART trial
(Antiviral therapy, 2006) Ssali, Francis; Munderi, Paula; Walker, Sarah; Mugyenyi, Peter
To describe the prevalence, incidence and predictors of severe anaemia in previously untreated symptomatic HIV-infected adults with CD4+ T-cells <200 cells/mm3 initiating zidovudine-containing regimens in Africa. DART is a randomized trial comparing two strategies for HIV/AIDS management in Uganda and Zimbabwe.We analysed the occurrence of anaemia at weeks 4 and 12, and then every 12 weeks. We also evaluated sex, age, WHO stage, body mass index (BMI), baseline laboratory measurements and first regimen aspredictors of developing grade 4 anaemia (<6.5 mg/dl) by week 48 using logistic regression. To May 2005, 3,314 participants (65% women, 23% at WHO stage 4, median age=37 years, baseline CD4+ T-cell=86 cells/mm3 and median baseline haemoglobin=11.4 g/dl) had a median 72 weeks follow-up. Prevalence of grade 4 anaemia was 0.7%, 2.0%, 0.5% and <0.5% at weeks 4, 12, 24 and ≥36, respectively. Overall, 219 (6.6%) participants developed grade 4 anaemia by week 48; women and those with lower haemoglobin, CD4+ T-cell count and BMI at baseline were at significantly higher risk (P<0.05), but not those with lower neutrophils or receiving cotrimoxazole at baseline. We observed a higher incidence of grade 4 anaemia than in studies from industrialized countries, which is likely to be due in part to population characteristics and in part to a higher rate of concurrent HIV-related clinical events. Clinical vigilance and haemoglobin measurements 4, 8 and 12 weeks after starting zidovudine could help to manage serious anaemia.
Reduced morbidity and mortality in the first year after initiating highly active anti-retroviral therapy (HAART) among Ugandan adults
(Tropical Medicine & International Health, 2009) Miiro, George; Todd, Jim; Mpendo, Juliet; Watera, Christine; Munderi, Paula; Nakubulwa, Susan; Kaddu, Ismael; Rutebarika, Diana; Grosskurth, Heiner
To evaluate the effect of highly active anti-retroviral therapy (HAART) and cotrimoxazole prophylaxis on morbidity after HAART eligibility. methods Between 1999 and 2006, we collected morbidity data from a community-based cohort of HAART-eligible patients, comparing patients initiating HAART and those non-HAART. Patients aged 15 years or older visited the clinic every 6 months and when ill. Baseline data on patients’ characteristics, WHO stage, haemoglobin and CD4+ T-cell counts, along with follow-up data on morbidity (new, recurrent and drug-related), were collected for the first year after initiating HAART or becoming HAART-eligible. We estimated the overall effect of HAART on morbidity; adjusted for the effect of cotrimoxazole prophylaxis by Mantel–Haenszel methods. A negative binomial regression model was used to assess rate ratios (RR) after adjustment for other confounders, including cotrimoxazole. results A total of 219 HAART patients (median age 37 years; 73% women; 82% using cotrimoxazole prophylaxis, median haemoglobin 11.7 g ⁄ dl and median CD4+ 131 cells ⁄ ll) experienced 94 events in 127 person-years. 616 non-HAART patients (median age 33 years; 70% women; 26% using cotrimoxazole prophylaxis, median haemoglobin 11.2 g ⁄ dl and median CD4+ 130 cells ⁄ ll) experienced 862 events in 474 person-years. The overall morbidity during the first year of HAART was 80% lower than among non-HAART patients (adjusted RR = 0.20, 95% CI: 0.12–0.34). Cotrimoxazole prophylaxis also reduced morbidity (adjusted RR = 0.65, 95% CI: 0.45–0.94). conclusion These results confirm the reduction in morbidity due to HAART, and the additional protection of cotrimoxazole prophylaxis.

Browsing by Author "Munderi, Paula"

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