Performance of a stool-based quantitative PCR assay for the diagnosis of tuberculosis in adolescents and adults: a multinational, prospective diagnostic accuracy study.

BACKGROUND: Despite increasing availability of rapid molecular tests for the diagnosis of tuberculosis in high-burden settings, many people with tuberculosis are undiagnosed. Reliance on sputum as the primary specimen for tuberculosis diagnostics contributes to this diagnostic gap. We evaluated the diagnostic accuracy and additive yield of a novel stool quantitative PCR (qPCR) assay for the diagnosis of tuberculosis in three countries in Africa with high tuberculosis burdens. METHODS: We undertook a prospective diagnostic accuracy study in Eswatini, Mozambique, and Tanzania from Sept 21, 2020, to Feb 2, 2023, to compare the diagnostic accuracy for tuberculosis of a novel stool qPCR test with the current diagnostic standard for Mycobacterium tuberculosis DNA detection from sputum and stool, Xpert-MTB/RIF Ultra (Xpert Ultra). Sputum, stool, and urine samples were provided by a cohort of participants, aged 10 years or older, diagnosed with tuberculosis. Participants with tuberculosis (cases) were enrolled within 72 h of treatment initiation for tuberculosis diagnosed clinically or following laboratory confirmation. Participants without tuberculosis (controls) consisted of household contacts of the cases who did not develop tuberculosis during a 6-month follow-up. The performance was compared with a robust composite microbiological reference standard (CMRS). FINDINGS: The cohort of adolescents and adults (n=408) included 268 participants with confirmed or clinical tuberculosis (cases), 147 (55%) of whom were living with HIV, and 140 participants (controls) without tuberculosis. The sensitivity of the novel stool qPCR was 93·7% (95% CI 87·4-97·4) compared with participants with detectable growth on M tuberculosis culture, and 88·1% (81·3-93·0) compared with sputum Xpert Ultra. The stool qPCR had an equivalent sensitivity as sputum Xpert Ultra (94·8%, 89·1-98·1) compared with culture. Compared with the CMRS, the sensitivity of the stool qPCR was higher than the current standard for tuberculosis diagnostics on stool, Xpert Ultra (80·4%, 73·4-86·2 vs 73·5%, 66·0-80·1; p=0·025 on paired comparison). The qPCR also identified 17-21% additional tuberculosis cases compared to sputum Xpert Ultra or sputum culture. In controls without tuberculosis, the specificity of the stool qPCR was 96·9% (92·2-99·1). INTERPRETATION: In this study, a novel qPCR for the diagnosis of tuberculosis from stool specimens had a higher accuracy in adolescents and adults than the current diagnostic PCR gold standard on stool, Xpert-MTB/RIF Ultra, and equivalent sensitivity to Xpert-MTB/RIF Ultra on sputum. FUNDING: National Institutes of Health (NIH) Allergy and Infectious Diseases, and NIH Fogarty International Center.

Factors Associated With Viral Suppression and Drug Resistance in Children and Adolescents Living With HIV in Care and Treatment Programs in Southern Tanzania.

BACKGROUND: Achieving viral suppression (VS) for persons living with HIV is key to reaching epidemic control. We assessed the prevalence of VS and the frequency of HIV drug resistance mutations (HIVDRM) among children and adolescents living with HIV (CALHIV) in the Southern Highland zone of Tanzania. METHODS: From 2019 to 2021, we enrolled CALHIV aged 1-19 years on ART for >6 months in a cross-sectional study. Participants had viral load (VL) testing; those with VL ≥ 1000 copies/mL underwent HIVDRM testing. VS (<1000 copies/mL) prevalence estimates were calculated and robust Poisson regression was used to estimate prevalence ratios (PRs) and 95% confidence intervals (CIs) for associations with potential predictors of VS. RESULTS: Of 707 participants, 595 had VS (PR: 0.84, 95% CI: 0.81-0.87). Use of an integrase strand transfer inhibitor-containing regimen (aPR 1.15, 95% CI: 0.99-1.34), age 5-9 years (aPR 1.16, 95% CI: 1.07-1.26), and seeking care at a referral center (aPR 1.12, 95% CI: 1.04-1.21) were associated with VS. Factors inversely associated with VS included having one (aPR 0.82, 95% CI: 0.72-0.92) or two or more (aPR 0.79, 95% CI: 0.66-0.94) referrals for adherence counselling, and self-reporting missing one to two (aPR 0.88, 95% CI: 0.78-0.99) or three or more (aPR 0.77, 95% CI: 0.63-0.92) doses of ART in the past month. Of 74 participants with PRRT and INT sequencing done, 60 (81.1%) had HIVDRMs at the following frequencies: 71.6%, 67.6%, 1.4%, and 4.1% for major NNRTI, NRTI, PI, and INSTI respectively. CONCLUSIONS: Higher rates of VS were observed in this cohort, and HIVDRMs were common in those without VS. This evidence supports ART optimization using dolutegravir-based regimens. However, better strategies to improve adherence are needed.

Realizing the Promise of Dolutegravir in Effectively Treating Children and Adolescents Living With HIV in Real-world Settings in 6 Countries in Eastern and Southern Africa.

BACKGROUND: Despite encouraging results from clinical trials and in high-income countries, large-scale data on the effectiveness and safety of dolutegravir (DTG) in children and adolescents living with HIV (CALHIV) are lacking in low- and middle-income countries (LMICs). METHODS: Retrospective analysis was performed among CALHIV 0-19 years old and weighing greater than or equal to 20 kg who received DTG from 2017 to 2020 at sites in Botswana, Eswatini, Lesotho, Malawi, Tanzania and Uganda to determine effectiveness, safety and predictors of viral load suppression (VLS) among CALHIV using DTG, including through single drug substitutions (SDS). RESULTS: Among 9419 CALHIV using DTG, 7898 had a documented post-DTG VL, and VLS post-DTG was 93.4% (7378/7898). VLS for antiretroviral therapy (ART) initiations was 92.4% (246/263), and VLS was maintained for the ART-experienced [92.9% (7026/7560) pre- vs. 93.5% (7071/7560) post-DTG; P = 0.14). Among previously unsuppressed, 79.8% (426/534) achieved VLS with DTG. Only 5 patients reported a Grade 3 or 4 adverse event (0.057 per 100 patient-years) requiring DTG discontinuation. History of protease inhibitor-based ART [odds ratio (OR) = 1.53; 95% confidence interval (CI): 1.16-2.03], care in Tanzania (OR = 5.45; 95% CI: 3.41-8.70), and being 15-19 years old (OR = 1.31; 95% CI: 1.03-1.65) were associated with gain of VLS post-DTG. Predictors of VLS on DTG included VLS before DTG (OR = 3.87; 95% CI: 3.03-4.95) and using the once-daily, single tab tenofovir-lamivudine-DTG regimen (OR = 1.78; 95% CI: 1.43-2.22). SDS maintained VLS [95.9% (2032/2120) pre- vs. 95.0% (2014/2120) post-SDS with DTG; P = 0.19], and 83.0% (73/88) of unsuppressed gained VLS using SDS with DTG. CONCLUSIONS: We found DTG to be highly effective and safe within our cohort of CALHIV in LMICs. These findings can empower clinicians to prescribe DTG confidently to eligible CALHIV.

Divergent clinical presentations and outcomes among children and adolescents with Kaposi sarcoma in Malawi and Tanzania.

OBJECTIVES: The Kaposi sarcoma (KS) T0 versus T1 staging classification does not address the unique clinical features of paediatric KS in human gammaherpesvirus 8 (HHV-8) endemic regions of Africa. This study seeks to define patterns of childhood KS using a paediatric-specific approach. METHODS: The Lilongwe paediatric KS staging classification categorizes disease based on clinical phenotype: stage 1 = mild/moderate KS limited to cutaneous/oral involvement, stage 2 = primarily lymphadenopathic disease, stage 3 = woody edema KS, stage 4 = visceral and/or severe/disseminated mucocutaneous disease. Characteristics and outcomes were evaluated from paediatric referral centres in Lilongwe, Malawi, and Mbeya, Tanzania. RESULTS: Among 171 patients, the median age was 9.3 years, 37% (n = 63) were female, and 87% (n = 149) had HIV. Breakdown by stage was as follows: 18% (n = 31) stage 1, 33% (n = 56) stage 2, 19% (n = 33) stage 3, and 30% (n = 51) stage 4. Age (younger stage 2 and older stage 3), severe CD4 count suppression (lower CD4 for stages 1 and 4), and presence of severe anaemia and thrombocytopenia (worse for stages 2 and 4) differed across stages. Estimated 2-year event-free survival/progression-free survival/overall survival by stage was as follows: stage 1, 81%/81%/87%; stage 2, 50%/50%/63%; stage 3, 24%/49%/81%; and stage 4, 29%/34%/54%. Sub-analysis of stage 2 lymphadenopathic KS demonstrated superior long-term 6-year event-free survival of 70% (95% confidence interval [CI] 49-83) for younger children (aged <7 years) versus 27% (95% CI 8-51) for older children. CONCLUSIONS: This paediatric-specific staging classification categorizes patients with distinct characteristics and patterns of treatment response. This platform may guide clinicians to provide risk-stratified treatment with the hope of improving survival among children with KS.

Optimal Timing of Antiretroviral Therapy Initiation in Children and Adolescents With Human Immunodeficiency Virus-Associated Pulmonary Tuberculosis.

BACKGROUND: There is insufficient evidence in children and adolescents with human immunodeficiency virus (CAHIV) to guide the timing of antiretroviral treatment (ART) initiation after starting treatment for pulmonary tuberculosis (pTB). To address this knowledge gap, we evaluated the risk of mortality associated with timing of ART initiation in ART-naive CAHIV treated for pTB. METHODS: Data were extracted from electronic medical records of ART-naive patients, aged 0-19 years, who were treated for HIV-associated pTB at Baylor Centers of Excellence in Botswana, Eswatini, Malawi, Lesotho, Tanzania, or Uganda between 2013 and 2020. Data were analyzed against a primary outcome of all-cause mortality with unadjusted Kaplan-Meier curves and Cox proportional hazard models. RESULTS: The study population included 774 CAHIV with variable intervals to ART initiation after starting TB treatment: <2 weeks (n = 266), 2 weeks to 2 months (n = 398), >2 months (n = 66), and no ART initiated (n = 44). Adjusted Cox proportional hazards models demonstrated increased mortality 1 year from TB treatment initiation in children never starting ART (adjusted HR [aHR]: 2.67; 95% CI: 1.03, 6.94) versus children initiating ART between 2 weeks and 2 months from TB treatment initiation. Mortality risk did not differ for the <2-weeks group (aHR: 1.02; 95% CI: .55, 1.89) versus the group initiating ART between 2 weeks and 2 months. CONCLUSIONS: This retrospective study demonstrated no increase in mortality among CAHIV initiating ART <2 weeks from TB treatment initiation. Given the broad health benefits of ART, this evidence supports the recent WHO recommendation for CAHIV to initiate ART within 2 weeks of initiating TB treatment.

Achieving Antiretroviral Therapy Uptake and Viral Suppression Among Children and Adolescents Living With HIV in the UNAIDS 90-90-90 Era Across Six Countries in Eastern and Southern Africa-Lessons From the BIPAI Network.

BACKGROUND: Although achievements have been made globally since the UNAIDS 90-90-90 targets were announced, paediatric data remain sparse. We describe achievements toward antiretroviral therapy (ART) uptake and viral load (VL) suppression, existing gaps, and potential best practices among children and adolescents living with HIV (CALHIV) across 6 Eastern and Southern African countries. SETTING: Baylor College of Medicine International Paediatric AIDS Initiative Network sites in Botswana, Eswatini, Lesotho, Malawi, Tanzania, and Uganda. METHODS: We performed retrospective data analysis among CALHIV ages 0-19 years between 2014 and 2019. RESULTS: A total of 25,370 CALHIV received care, 85.8% (21,773/25,370) received ART, 84.4% (18,376/21,773) had documented VL results, and 74.6% (13,715/18,376) had VL < 1000 cps/mL. By 2019, the pooled proportion of CALHIV receiving ART and having viral suppression increased to 99.8% [95% confidence interval (CI): 98.1 to 100.0] and 89.8% (95 CI: 88.2 to 91.5) respectively. Lower rates of viral suppression and higher lost to follow-up (LTFU) were seen in the 0-4-year and 15-19-year cohorts. CALHIV on ART not achieving viral suppression were younger, received care in Malawi or Mbeya, had a history of tuberculosis, lower rates of integrase-strand inhibitor-based ART, and were on ART for shorter durations. Best practices reported included adopting universal ART, ART optimization with protease inhibitor-based and/or dolutegravir-based regimens, peer-supported activities, child/adolescent friendly services, community-supported activities, and technology-driven quality improvement activities and digital solutions. CONCLUSIONS: High rates of CALHIV receiving ART and having viral suppression can be achieved in settings in Eastern and Southern Africa through using pediatric best practices. Increased efforts must be made to address LTFU and to support under-fives and adolescents.

Successful Use of Multidisciplinary Palliative Care in the Outpatient Treatment of Disseminated Histoplasmosis in an HIV Positive Child.

Histoplasmosis is an uncommon opportunistic infection in human immunodeficiency virus (HIV) positive children. The most common form is primary disseminated histoplasmosis, characterized by persistent fever and failure to thrive. A 10-year-old HIV positive girl presented to the Baylor College of Medicine Children's Foundation-Tanzania Mbeya Center of Excellence (COE) with ulcerated skin lesions and a violaceous facial rash. She also had persistent fevers, severe acute malnutrition, and severe anemia. At diagnosis, the patient was failing first line antiretroviral therapy (ART) with a cluster of differentiation 4 immune cells (CD4) of 24 cells/µL and an HIV viral load (VL) of 196,658 cp/mL. The patient was changed to a second line ART regimen (abacavir, lamivudine, and ritonavir-boosted lopinavir) and received nutritional support, blood transfusions, multiple antibiotics, and meticulous wound care. She also received comprehensive symptom management, psychosocial support, and emergency housing through the COE's palliative care program. Biopsy of a lesion showed intracytoplasmic organisms consistent with Histoplasmosis capsulatum var capsulatum. The patient was treated with conventional amphotericin B and oral itraconazole and she achieved wound healing as well as immune reconstitution and HIV viral suppression. Amphotericin infusions were given as an outpatient despite the resource constraints of the setting in southwestern Tanzania. Histoplasmosis should be considered in the differential diagnosis of the immunocompromised host with unusual skin manifestations and persistent fever.

Use of Paclitaxel to Successfully Treat Children, Adolescents, and Young Adults with Kaposi Sarcoma in Southwestern Tanzania.

Treating Kaposi sarcoma (KS) in children, adolescents, and young adults (AYA) remains a challenge in low- and middle-income countries (LMIC) where chemotherapy options and availability are limited. We describe a retrospective cohort review of pediatric patients with KS treated with paclitaxel in Mbeya, Tanzania, between 1 March 2011 and 31 December 2019. Paclitaxel was given to patients who had KS relapse, a contraindication to bleomycin, vincristine, and doxorubicin (ABV), special circumstances in which a clinician determined that paclitaxel was preferable to ABV, or experienced treatment failure, defined as persistent KS symptoms at the completion of treatment. All patients also received multidisciplinary palliative care. Seventeen patients aged 5.1-21.3 years received paclitaxel, of whom 47.1% (8/17) had treatment failure, 29.4% (5/17) received paclitaxel as initial treatment, and 23.5% (4/17) had relapsed. All HIV positive patients (16/17) were given anti-retroviral therapy (ART) and 87.5% (14/16) achieved viral load <1000 cp/mL. At censure, 82.3% (14/17) of patients were alive-71.4% (10/14) achieved complete clinical remission and 28.6% (4/14) achieved a partial response. The median follow up was 37.3 months (range 8.0-83.5, IQR 19.7-41.6), and no patients were lost to follow up. In this cohort, high rates of long-term survival and favorable outcomes were possible with paclitaxel treatment.

Association between Antiretroviral Therapy and Cancers among Children Living with HIV in Sub-Saharan Africa.

Approximately 91% of the world's children living with HIV (CLWH) are in sub-Saharan Africa (SSA). Living with HIV confers a risk of developing HIV-associated cancers. To determine the incidence and risk factors for cancer among CLWH, we conducted a nested case-control study of children 0-18 years from 2004-2014 at five centers in four SSA countries. Incident cases of cancer and HIV were frequency-matched to controls with HIV and no cancer. We calculated the incidence density by cancer type, logistic regression, and relative risk to evaluate risk factors of cancer. The adjusted incidence density of all cancers, Kaposi sarcoma, and lymphoma were 47.6, 36.6, and 8.94 per 100,000 person-years, respectively. Delayed ART until after 2 years of age was associated with cancer (OR = 2.71, 95% CI 1.51, 4.89) even after adjusting for World Health Organization clinical stage at the time of enrolment for HIV care (OR = 2.85, 95% CI 1.57, 5.13). The relative risk of cancer associated with severe CD4 suppression was 6.19 (p = 0.0002), 2.33 (p = 0.0042), and 1.77 (p = 0.0305) at 1, 5, and 10 years of ART, respectively. The study demonstrates the high risk of cancers in CLWH and the potential benefit of reducing this risk by the early initiation of ART.

Tuberculosis symptom screening for children and adolescents living with HIV in six high HIV/TB burden countries in Africa.

OBJECTIVES: The WHO recommends that children and adolescents living with HIV (CALHIV) complete TB symptom screening at every clinical encounter but evidence supporting this recommendation is limited. We evaluated the performance of the recommended TB symptom screening in six high-burden TB/HIV countries. DESIGN: Retrospective longitudinal cohort. METHODS: We extracted data from electronic medical records of CALHIV receiving care from clinics in Botswana, Eswatini, Lesotho, Malawi, Tanzania, and Uganda from January 2014 to June 2017. We defined incident TB cases as those prescribed TB treatment within 30 days of TB diagnosis. We analyzed the most recent symptom screen preceding a TB diagnosis. In accordance with WHO guidelines, positive screens were defined as current fever, cough, poor weight gain, or recent TB contact. Odds of TB disease was modeled by screen result and age at which screening was conducted. RESULTS: Twenty thousand seven hundred and six patients collectively had 316 740 clinic visits, of which 240 161 (75.8%) had documented TB symptom screens. There were 35 701 (14.9%) positive TB symptom screens, and 1212 incident TB diagnoses. Sensitivity and specificity of the TB symptom screen to diagnose TB were 61.2% (95% CI 58.4--64.0) and 88.8% (95% CI 88.7--88.9), respectively. Log odds of documented TB for positive or negative screens was statistically different only for screens conducted at ages 7--17. CONCLUSION: Although specificity was high, the sensitivity of the TB symptom screen to detect TB in CALHIV was low. More accurate screening approaches are needed to optimally identify TB disease in CALHIV.

Recommendations for treating life-threatening Kaposi sarcoma during pregnancy in HIV-positive women in low income countries.

In areas of high HIV and human herpes virus 8 prevalence, life-threatening forms of Kaposi sarcoma (KS) can occur in HIV-positive women during pregnancy. Treating KS in pregnancy must balance both the well-being of the mother with the health of the fetus, yet data and recommendations on the best treatment approach for KS during pregnancy are limited. Without effective treatment, which can be difficult to obtain in low income countries (LICs), the mother and infant are at risk for poor outcomes. A successful case report is used as teaching example, followed by a detailed review of the literature that culminates in recommendations for treating KS during pregnancy among HIV-positive women in LICs. A 31-year-old HIV-positive woman presented for care in April 2016 at 28 weeks gestation with extensive KS skin lesions, KS lymphadenopathy, and a large oropharynx KS lesion causing partial airway obstruction. She had initiated antiretroviral therapy (ART) months prior and was virally suppressed, suggesting KS-immune reconstitution inflammatory syndrome. Due to the severity of KS and her third trimester status, combination chemotherapy was initiated using bleomycin, vincristine, and doxorubicin followed by maintenance therapy with paclitaxel. She showed remarkable response to the chemotherapy and had a normal vaginal delivery of a healthy baby at full term. Full clinical remission was achieved, and her baby was HIV-negative with no negative health effects of the KS or the chemotherapy. Review of the sparse existing literature demonstrates the importance, safety, and effectiveness of treating KS during pregnancy. We offer simple adaptable treatment recommendations for use in treating HIV-positive women with KS during pregnancy in LICs. Life-threatening KS can be treated using chemotherapy and ART in resource-limited settings, allowing for good outcomes in mother and infant. While monotherapy with liposomal doxorubicin or paclitaxel is preferred, these are often not available in LICs. As alternatives, bleomycin, vincristine, and doxorubicin can be safely used during the second and/or third trimesters for treating KS. Following a simple treatment approach can be an effective way to treat KS in pregnancy for pregnant women living with HIV in an LIC setting.

Disseminated cysticercosis and Kaposi sarcoma in a child with HIV/AIDS: A case report.

BACKGROUND: Clinical manifestations of extraneural infection with the pork tapeworm Taenia solium typically affect the muscles, eyes, alimentary canal, and/or subcutaneous tissues. Children living with HIV are at increased risk for more widespread and severe manifestations of food-borne opportunistic infections, including T. solium, due to fluctuating levels of immunosuppression. We present a case of disseminated T. solium in a HIV-positive child with Kaposi sarcoma living in Tanzania with cysticercosis presenting as widespread subcutaneous nodules. CASE PRESENTATION: A 4-year-old HIV-positive boy in Southern Tanzania presented for evaluation of > 30 violaceous skin lesions, few subcutaneous nodules, and a circumferential violaceous penile lesion which rapidly grew after initiation of ART. The patient was clinically diagnosed with Kaposi sarcoma and started on chemotherapy with bleomycin, vincristine, and doxorubicin. He completed 10 cycles of chemotherapy, with full resolution of the violaceous skin and penile lesions but persistence of his subcutaneous nodules, thus paclitaxel was added. After 12 additional cycles of paclitaxel, his subcutaneous nodules enlarged, and biopsy of a scapular subcutaneous nodule was performed. Histopathology revealed a cystic structure with a central larval scolex and serrated spiral canal consistent with T. solium, which confirmed a diagnosis of disseminated cysticercosis. He completed a 10-day course of praziquantel and albendazole with resolution of the subcutaneous nodules. CONCLUSIONS: Disseminated cysticercosis is an unusual opportunistic infection which can present as subcutaneous nodules without other typical cysticercosis symptoms. Immunosuppression - from HIV and/or chemotherapy - may unmask cysticercosis in children in endemic regions and result in more severe manifestations of this disease. Cysticercosis should remain on a clinician's differential for subcutaneous nodules, especially in children living with HIV. Cysticercosis can mimic Kaposi sarcoma, and histopathology is essential to accurately diagnose and manage patients with concerning skin lesions.

Quality matters: Redefining child TB care with an emphasis on quality.

Children have been neglected in the fight against tuberculosis (TB) for decades. Despite being the number one infectious disease killer, TB does not feature on the child survival agendas partly due to absent and inaccurate data. Quality is a missing ingredient in TB care in children, yet high rates of unfavorable TB outcomes highlight its importance in this age group. Quality care is particularly important for TB affected children in the absence of a point of care sensitive and specific diagnostic test. Using the current models of child TB care, it will take another 200 years to end TB. Without focusing on the quality of child TB care, the ambitious country specific United Nations High Level Meeting for TB targets will carry minimal impact. High TB burden countries must also adopt Universal Health Care (UHC) and ensure that quality TB care is made free and equitable for all children, adolescents and their affected families. We advocate for the importance of evaluating the quality of child TB care, and provide a basic framework for quality in child TB with special attention given to creating differentiated service delivery models for children and families affected by TB.

The Standardized Pediatric Expedited Encounters for ART Drugs Initiative (SPEEDI): description and evaluation of an innovative pediatric, adolescent, and young adult antiretroviral service delivery model in Tanzania.

BACKGROUND: As countries scale up antiretroviral therapy (ART) for children, innovative strategies to deliver quality services to children are needed. Differentiated ART delivery models have been successful in adults, but no such program has been described in children. We describe the Standardized Pediatric Expedited Encounters for ART Drugs Initiative (SPEEDI). METHODS: Descriptive analysis of patients eligible for SPEEDI was done via retrospective review of children, adolescents, and young adults on ART at the Baylor Centre of Excellence (COE) in Mbeya, Tanzania between January 2013 and December 2015. Eligibility for SPEEDI visits included the following: stable children, adolescents, and young adults on ART for approximately 3 months or longer, no medical or social complications, good adherence to ART, and presence of reliable caregiver. During a SPEEDI visit, patients were fast tracked in triage to collect medications directly without physically seeing a clinician. SPEEDI patients came to clinic every two months, and alternated SPEEDI visits with standard visits. Baseline characteristics, mortality, and lost-to-follow up rates of SPEEDI patients were analyzed. RESULTS: One thousand one hundred sixty-four patients utilized SPEEDI, totaling 3493 SPEEDI visits. SPEEDI reached 51.3% (1164/2269) of pediatric ART patients, accounting for 7.7% (3493/44489) of total patient encounters. SPEEDI patients were 52% (605/1164) female, median age of 11.7 years (range 1.2-25.5 yr), median time on ART of 21 months (range 4-130 months) and 83.5% (964/1155) categorized as no or mild HIV-associated immunodeficiency. SPEEDI patients had good outcomes (98.8%), low LTFU (0.1%) and low mortality rates (0.61 deaths per 100 patient-years). CONCLUSION: SPEEDI was an effective model for delivering ART to children, adolescents, and young adults in our setting, leading to good clinical outcomes, low mortality, and low LTFU. The SPEEDI program safely and effectively expedited and spaced out ART visits for children, adolescents, and young adults, and can serve as an adaptable ART delivery model for other resource limited settings.

Why being an expert - despite xpert -remains crucial for children in high TB burden settings.

BACKGROUND: As access to Xpert expands in high TB-burden settings, its performance against clinically diagnosed TB as a reference standard provides important insight as the majority of childhood TB is bacteriologically unconfirmed. We aim to describe the characteristics and outcomes of children with presumptive TB and TB disease, and assess performance of Xpert under programmatic conditions against a clinical diagnosis of TB as a reference standard. METHODS: Retrospective review of children evaluated for presumptive TB in Mbeya, Tanzania. Baseline characteristics were compared by TB disease status and, for patients diagnosed with TB, by TB confirmation status using Wilcoxon rank sum test for continuous variables and the Chi-square test for categorical variables. Sensitivity and specificity were calculated to assess the performance of Xpert, smear, and culture against clinical TB. Kappa statistics were calculated to assess agreement between Xpert and smear to culture. RESULTS: Among children (N = 455) evaluated for presumptive TB, 70.3% (320/455) had Xpert and 62.8% (286/455) had culture performed on sputa. 34.5% (157/455) were diagnosed with TB: 80.3% (126/157) pulmonary TB, 13.4% (21/157) bacteriologically confirmed, 53.5% (84/157) HIV positive, and 48.4% (76/157) inpatients. Compared to the reference standard of clinical diagnosis, sensitivity of Xpert was 8% (95% CI 4-15), smear 6% (95% CI 3-12) and culture 16% (95% CI 9-24), and did not differ based on patient disposition, nutrition or HIV status. CONCLUSION: Despite access to Xpert, the majority of children with presumptive TB were treated based on clinical diagnosis. Reflecting the reality of clinical practice in resource limited settings, new diagnostics such as Xpert serve as important adjunctive tests but will not obviate the need for astute clinicians and comprehensive diagnostic algorithms.

Culture is an imperfect and heterogeneous reference standard in pediatric tuberculosis.

BACKGROUND: In pediatric tuberculosis (pTB), culture is the accepted reference standard for assessing new diagnostic tests despite culture only confirming 10-50% of clinically diagnosed cases. METHODS: Using the studies previously included in the systematic review of Gene Xpert, we evaluated the diagnostic yield of culture. Children with symptoms and signs suggestive of TB were considered to have a clinical diagnosis if they were 1) culture positive or 2) followed clinically for at least one month and started on Anti-Tuberculosis Therapy (ATT). RESULTS: Of 1989 children with presumptive pTB, 229 (11.5%) had culture-confirmation. Of the remaining 1760 culture negative children, 710 (24.4) were classified as culture-negative clinical TB and 821 were classified as "not TB". Diagnostic yield of culture was 24.4% (median 28.7% IQR 15.6%-42.4%; range 1.5%-65%). CONCLUSION: Culture, the accepted reference standard for pediatric TB diagnostics, has a low and variable yield that impacts how diagnostic studies should be reported as well as everyday clinical care.

Antiretroviral Therapy in Children Less Than 24 Months of Age at Pediatric HIV Centers in Tanzania: 12-Month Clinical Outcomes and Survival.

BACKGROUND: Without antiretroviral therapy (ART), approximately one-half of HIV-infected infants will die by two years. In 2010, the World Health Organization (WHO) recommended that all HIV-infected infants < 24 months be initiated on ART regardless of their clinical/immunologic status. However, there remains little published data detailing cohorts of infants on ART in Sub-Saharan Africa. This study describes baseline characteristics and 12 month outcomes of a cohort of HIV-infected children < 24 months of age at pediatric HIV centers in Mwanza and Mbeya, Tanzania. MATERIALS AND METHODS: Retrospective chart review. INCLUSION CRITERIA: children < 24 months of age, initiated on ART at Baylor Children s Foundation Tanzania clinics, between March-December 2011. RESULTS: Baseline: Ninety-three children were initiated on ART at a median age of 13.4 months. Sixty-seven percent had severe immunosuppression and 31.5% had severe malnutrition. OUTCOME: Seventy-three patients were still in care at 12 month follow-up, there were four (4.3%) deaths, five (5.4%) patients transferred, and 11 (11.8%) loss to follow-up. Average CD4% was 32.7 (p < 0.001). Ninety percent of patients were WHO treatment stage I (p < 0.001). Eighty-six percent had normal nutritional status (p < 0.001). CONCLUSION: Our cohort of HIV infected children < 24 months initiated on ART did well clinically at 12 month outcomes despite being severely immunocompromised and malnourished at baseline. Nevirapine based regimens had good 12 month clinical outcomes, regardless of maternal exposure. Loss to follow-up rate was high for our cohort, demonstrating the need to develop strong mechanisms to counteract this.

Maternal perception of neighborhood safety as a predictor of child weight status: The moderating effect of gender and assessment of potential mediators.

OBJECTIVE: To determine if there is a relationship between maternal perception of neighborhood safety in 3(rd) grade and weight status in 5(th) grade children, to test if gender moderates this relationship, and to identify potential mediators. METHOD: Data from 868 children and their mothers involved in the National Institute of Child Health and Human Development Study of Early Child Care and Youth Development (NICHD-SECCYD) were used to examine the relationship between maternal perception of neighborhood safety in the 3(rd) grade and child body mass index (BMI) z-score in the 5(th) grade. Multiple regression models tested this relationship, the effect of gender, and potential mediating variables (time outdoors in neighborhood, television viewing, child behavior problems and puberty status). RESULTS: Neighborhood safety ratings in the least safe tertile, compared with the safest tertile, were associated with an increased risk of obesity independent of gender, race and income-to-needs ratio (OR=1.59; 95% confidence interval [CI]: 1.03, 2.46), and higher child BMI z-scores among girls, but not boys, compared with the safest tertile (beta=0.33; 95% CI: 0.09, 0.57). Neither amount of time spent outdoors in the neighborhood, television viewing, child behavior problems (internalizing or externalizing), nor puberty status altered the relationship. CONCLUSIONS: Maternal perception of the neighborhood as unsafe in 3(rd) grade independently predicted a higher risk of obesity, and a higher BMI z-score among girls, but not boys, in the 5(th) grade. The relationship was not explained by several potential mediators. Further investigation is needed to explore these gender differences and potential mediators.