|Call||Career Development Fellowship (CDF)|
Neurocognitive Function among HIV Infected Infants with Severe Pneumonia Receiving Empirical Treatment for Cytomegalovirus and Tuberculosis (Neuro-Empirical)
Primary Aim To compare neurocognitive function of HIV infected children with severe pneumonia receiving intervention (empirical treatment for either CMV, TB, or both CMV and TB in addition to standard of care) to those receiving standard of care alone at one year post randomization and at two years of age Secondary Aims 1. To compare the neurocognitive function of HIV infected children with severe pneumonia receiving intervention (empirical treatment for either CMV, TB, or both CMV and TB in addition to standard of care) or standard of care alone to a cohort of HIV positive infants without pneumonia 2. To compare neurocognitive function across all the treatment groups to a cohort of HIV negative children with severe pneumonia at baseline, one year post randomization and at two years of age
This prospective longitudinal observational study will be nested under the EMPIRICAL study, a randomized open label clinical trial among HIV positive children under 1 year of age with severe pneumonia. We will additionally recruit and enroll a longitudinal cohort of HIV negative children with severe pneumonia, as well as a cross-sectional cohort of HIV positive children without pneumonia.
|China-Uganda Friendship Hospital-Naguru, Mbarara Regional Referral Hospital, Jinja Regional Referral Hospital|
|Type||Name||Title||University||Start Date||End Date|
|Makerere University, Uganda||Masters in Paediatrics and Child Health||2019-01-14|
|Makerere University, Uganda||Bachelors of Medicine and Bachelors of Surgery||2013-01-14|
Lower Respiratory Tract Infections (LRTIs)
Mortality among children under 5 years of age admitted to malnutrition units in sub-Saharan Africa remains high. The burden of HIV infection, a major risk factor for mortality among patients with severe acute malnutrition (SAM), has reduced due to concerted prevention and treatment strategies. None the less, anecdotal reports from the malnutrition unit at Uganda’s National Referral Hospital (NRH) indicate that there is high mortality among patients with severe acute malnutrition (SAM) in routine care. Uganda has recently adopted the revised World Health Organization (WHO) treatment guidelines for SAM to improve outcomes. The mortality among children with SAM in routine care has not been recently elucidated. We report the magnitude and factors associated with mortality among children under 5 years of age admitted to the NRH for routine care of SAM.
This was a cohort study of all severely malnourished children admitted to the NRH between June and October 2017. The primary outcome was two-week mortality. Mortality was calculated using simple proportions and Cox regression analysis was used to determine factors associated with time to mortality. Data was entered into Epidata and analysed using Stata v14.
Two-hundred-sixty (98.5%) children: 59.6% male; mean age 14.4 (SD 9.4) months, completed two weeks of follow-up. Of these, 25.2% (95% CI 19.9–30.4%) died. In-hospital mortality was 20.7% (95% CI15.9–25.6%). The prevalence of HIV infection was 12.2%. Factors associated with mortality included: positive HIV status (AHR 2.2, (95% CI; 1.2–4.2), p = 0.014), bacteraemia (AHR 9 (95% CI 3.4–23.0), p < 0.001, and low glomerular filtration rate (eGFR), AHR 3.2; (95% CI 1.7–6.3), p = 0.001).
A 25% mortality among children with severe malnutrition remains unacceptably high despite significant reduction in HIV prevalence. Children with SAM who are HIV infected, have eGFR below 60 mL/min/1.73m2 or have bacteraemia, are more likely to die. Further studies to explore the relationship between eGFR and mortality among children with SAM are needed. Studies to establish efficacious antibiotics are urgently required to inform treatment guidelines for children with SAM.
There is limited data available on exposure to anti-tuberculosis (TB) drugs in this region. Peloquin has described reference ranges  however some studies have demonstrated that patients actually achieve concentrations below these ranges . There is limited data about exposure to anti-TB drugs in the HIV/TB co-infected population in Sub-Saharan Africa. Our objective is to describe the concentration of anti-TB drug levels in a well characterized prospective cohort of adult patients starting treatment for pulmonary TB.
This study is an ongoing study carried out in the TB/HIV integrated clinic at the Infectious Diseases Institute in Kampala, Uganda. Sputum culture and microscopy was done for all patients. We performed pharmacokinetic blood sampling of anti-TB drugs for 1 hour, 2 hours and 4 hours post dose at 2 weeks, 8 weeks and 24 weeks after initiation of anti-TB treatment using ultraviolet high-performance liquid chromatography (UV-HPLC). We described the maximum concentration (Cmax) of isoniazid (H), rifampicin (R), ethambutol (E) and pyrazinamide (Z) and compare them with the values observed by Peloquin et al. referenced in other studies.
We started 113 HIV infected adults on a fixed dose combination of HREZ. The median age of our population was 33 years, of which 52% were male with a median BMI of 19 kg/m2 and a median CD4 cell count of 142 cells/µL. In 90% of the participants, the diagnosis of TB was based on microscopy and or cultures. The boxplot graph shows the median Cmax and IQR of H and R.
Levels of H were found to be below the reference ranges (3–6 µg/mL) in 54/77(70.1%), 38/59(64.4%) and 15/24(62.5%) participants at weeks 2, 8 and 24. Rif levels were also found to be below the reference ranges (8–24 µg/mL) in 41/66(62.1%), 26/48(54.2%) and 8/10(8%) participants at weeks 2, 8 and 24, respectively. The mean Cmax of E and Z were within the reference range at week 2 and 8; mean Cmax of 3.2±SD2.1 µg/mL and 4.0±SD3.1 µg/mL for E and 41.6±SD13.1 µg/mL and 42.6±SD16.4 µg/mL for Z.
We observed lower concentrations of isoniazid and rifampicin in our study population of HIV/TB co-infected patients. The implications of these findings are not yet clear. We therefore need to correlate our findings with the response to TB treatment.
In 2011 Uganda recommended boosted atazanavir (ATV/r) as the preferred PI for second line due to once daily dosing, replacing aluvia (LPV/r) [1, 2]. The evidence was based on the BMS O45 trial, of LPV/r vs ATV/r was performed in a high‐income setting, on patients with prior PI use and resistance testing [2, 3]. There are no RCTs or observational studies comparing use of ATV/r with LPV/r in patients failing NNRTI first line antiretroviral therapy in sub‐Saharan Africa [3, 4]. The Infectious Diseases Institute (IDI) has a large second line cohort (>1838). This aims to compare clinical, immunologic and virologic response of LPV/r versus ATV/r at IDI.
Retrospective cohort analysis on routinely collected data of patients switched to second line with NRTI backbones TDF/3TC or FTC, AZT/3TC, ABC/3TC from January 2009 to December 2013. Students T‐tests and Chi‐square tests were used in this analysis.
A total of 1286 (73.5% female) patients were switched to LPV/r 991 (77%) and ATV/r 295 (23%) (p<0.001). NRTI backbones were 760 on TDF/3TC (66.8% LPV/r vs 33.2% on ATV/r), 504 on AZT/3TC (93.3% vs 6.7%), and 22 on ABC/3TC (59% vs 41%). Median (IQR) time on first line for LPV/r was 21 (1–44) months and for ATV/r was 41 months (22–68). Median CD4 (IQR) at switch to LPV/r was 181 cells/uL (66–424) and to ATV/r was 122 (57–238) (p≤0.001). A total of 366 patients had CD4 done at six months after switch and the mean (IQR) CD4 increase was 153 (54–241) for LPV/r versus 116 (52–171) for ATV/r (p=0.232). Additionally, 304 had a CD4 at 12 months and the means were 172 (45–272) for LPV/r vs 179 (60–271) for ATV/r (p=0.426). There was no significant difference in the mean increment by NRTI backbone or by stratifying to viral load (VL) at time of switch to VL <100,000 and ≥100,000. Median (IQR) VL at switch was 61,000 (13,000–2,030,000) LPV/r and 51,000 (14,000_151,000) ATV/r. 269 had a VL done in the first 12 months and 178/250 (71.2%) on LPV/r versus 16/19 (84.2%) on ATV/r were undetectable (p=0.228). 259 (26%) LPV/r versus 33(11%) ATV/r had ≥1 opportunistic infections on second line (p<0.001).
This is an observational study based on our experience at IDI. Like elsewhere in Africa, there is no routine viral load testing, making it difficult to get sensitive analysis of data on ART efficacy within routine clinical practice. Nevertheless, this observational study is reassuring in terms of efficacy of both ATV/r and LPV/r for patients failing first line therapy in our setting.
HIV infection is associated with significant neurocognitive deficits making maximization of cognitive function among children receiving antiretroviral therapy (ART) a public health imperative. Non-protease inhibitors (non-PIs) achieve higher drug levels in the cerebral spinal fluid (CSF) compared to PIs, potentially leading to better neurocognitive function by reducing CSF viral load and inflammation. ART that maximises children’s neurodevelopment and school achievement could result in improved quality of life and productivity as adults, but little research to date has examined whether non-PI ART is associated with better neurocognitive outcomes. We compared the neurocognitive function between children living with HIV receiving PI-based and non PI-based ART.
We recruited a consecutive sample of clinically stable Ugandan children living with HIV aged 5–12 years who received PI-based or non PI-based ART for ≥ 1 year (viral load < 1000 copies). Neurocognitive function was assessed using the Kaufman Assessment Battery for Children, the Test of Variables of Attention, and Bruininks-Oseretsky Test of Motor Proficiency. Age-adjusted neurocognitive z-scores for the two groups were compared using linear regression models in STATA version 13. The Hommel’s method was used to adjust for multiple testing.
We enrolled 76 children living with HIV; 34 on PI ART and 42 on non-PI ART. Mean (±SD) age was greater in the non-PI vs. PI group (9.5 ± 1.9 vs. 8.5 ± 2.0) years (p = 0.03). Children in the non-PI group had lower socioeconomic scores (5.7 ± 3.3 vs. 7.4 ± 2.8, p = 0.02). There was no difference in neurocognitive function between the groups (adjusted p > 0.05) for KABC and TOVA. Children in the PI group had better total BOT scores than their counterparts (46.07 ± 1.40) vs. 40.51 (1.24), p = 0.03).
We detected no difference in neurocognitive function among children on PI and non PI-based ART therapy based on KABC and TOVA tests. Children on PI based ART had better motor function than their counterparts. We recommend a prospective study with a larger sample size.
Early diagnosis of HIV associated lymphoma is challenging because the definitive diagnostic procedure of biopsy, requires skills and equipment that are not readily available. As a consequence, diagnosis may be delayed increasing the risk of mortality. We set out to determine the frequency and risk factors associated with the misdiagnosis of HIV associated lymphoma as tuberculosis (TB) among patients attending the Uganda Cancer Institute (UCI).
A retrospective cohort study design was used among HIV patients with associated lymphoma patients attending the UCI, Kampala, Uganda between February and March 2015. Eligible patient charts were reviewed for information on TB treatment, socio-demographics, laboratory parameters (Hemoglobin, CD4cells count and lactate dehydrogenase) and clinical presentation using a semi structured data extraction form.
A total of 183 charts were reviewed; 106/183 were males (57.9%), the median age was 35 (IQR, 28–45). Fifty six (30.6%) patients had a possible misdiagnosis as TB and their median time on TB treatment was 3.5 (1–5.3) months. In multivariate analysis the presence of chest pain had an odd ratio (OR) of 4.4 (95% CI 1.89–10.58, p < 0.001) and stage III and IV lymphoma disease had an OR of 3.22 (95% CI 1.08–9.63, p < 0.037) for possible misdiagnosis of lymphoma as TB.
A high proportion of patients with HIV associated lymphoma attending UCI are misdiagnosed and treated as TB. Chest pain and stage III and IV of lymphoma were associated with an increased risk of a possible misdiagnosis of lymphoma as TB.
Background: To prevent poor long-term outcomes (deaths and readmissions) the integrated global action plan for pneumonia and diarrhoea recommends under the ‘Treat’ element of Protect, Prevent and Treat interventions the importance of continued feeding but gives no specific recommendations for nutritional support. Early nutritional support has been practiced in a wide variety of critically ill patients to provide vital cell substrates, antioxidants, vitamins, and minerals essential for normal cell function and decreasing hypermetabolism. We hypothesise that the excess post-discharge mortality associated with pneumonia may relate to the catabolic response and muscle wasting induced by severe infection and inadequacy of the diet to aid recovery. We suggest that providing additional energy-rich, protein, fat and micronutrient ready-to-use therapeutic feeds (RUTF) to help meet additional nutritional requirements may improve outcome.
Methods: COAST-Nutrition is an open, multicentre, Phase II randomised controlled trial in children aged 6 months to 12 years hospitalised with suspected severe pneumonia (and hypoxaemia, SpO 2 <92%) to establish whether supplementary feeds with RUTF given in addition to usual diet for 56-days (experimental) improves outcomes at 90-days compared to usual diet alone (control). Primary endpoint is change in mid-upper arm circumference (MUAC) at 90 days and/or as a composite with 90-day mortality. Secondary outcomes include anthropometric status, mortality, readmission at days 28 and 180. The trial will be conducted in four sites in two countries (Uganda and Kenya) enrolling 840 children followed up to 180 days. Ancillary studies include cost-economic analysis, molecular characterisation of bacterial and viral pathogens, evaluation of putative biomarkers of pneumonia, assessment of muscle and fat mass and host genetic studies.
Discussion: This study is the first step in providing an option for nutritional support following severe pneumonia and will help in the design of a large Phase III trial.
|Damalie Nalwanga||Uganda||Makerere University|