Growth patterns and their contributing factors among HIV-exposed uninfected infants.

With expanded HIV treatment and prevention programmes, most infants born to HIV-positive women are uninfected, but the patterns and determinants of their growth are not well described. This study aimed to assess growth patterns in a cohort of HIV-exposed uninfected (HEU) infants who participated in an experimental HIV vaccine trial and to test for associations with maternal and infant factors, including in-utero exposure to antiretroviral therapy (ART), mode of delivery, exclusive breastfeeding, mother's education and receipt of the vaccine. Infants in the trial were seen at regular clinic visits from birth to 48 weeks of age. From the anthropometric measurements at these visits, weight-for-age z-scores (WAZ), weight-for-length z-scores (WLZ) and length-for-age z-scores (LAZ) were computed using World Health Organization (WHO) software and reference tables. Growth patterns were investigated with respect to maternal and infant factors, using linear mixed regression models. From 94 infants included at birth, growth data were available for 75.5% at 48 weeks. The determinants of infant growth in this population are multifactorial: infant LAZ during the first year was significantly lower among infants delivered by caesarean section (p = 0.043); both WAZ and LAZ were depressed among infants with longer exposure to maternal ART (WAZ: p = 0.015; LAZ: p < 0.0001) and among infants of mothers with lower educational level (WAZ: p = 0.038; LAZ: p < 0.0001); the effect of maternal education was modified by breastfeeding practice, with no differences seen in exclusively breastfed infants. These findings inform intervention strategies to preserve growth in this vulnerable infant population.

Methods for conducting a double-blind randomized controlled clinical trial of three days versus five days of amoxicillin dispersible tablets for chest indrawing childhood pneumonia among children two to 59 months of age in Lilongwe, Malawi: a study protocol.

BACKGROUND: Pneumonia is the leading infectious cause of death in children under 5 years of age around the globe. In addition to preventing pneumonia, there is a critical need to provide greater access to appropriate and effective treatment. Studies in Asia have evaluated the effectiveness of 3 days of oral amoxicillin for the treatment of fast-breathing pneumonia; however, further evidence is needed to determine if 3 days of oral amoxicillin is also effective for the treatment of chest indrawing pneumonia. METHODS: This is a double-blind, randomized, non-inferiority trial with the objective to assess the effectiveness of shorter duration amoxicillin dispersible tablet (DT) treatment of chest indrawing childhood pneumonia in a malaria-endemic region of Malawi. The primary objective of this study is to determine whether 3 days of treatment with oral amoxicillin DT in HIV-uninfected Malawian children two to 59 months of age with chest indrawing pneumonia is as effective as 5 days of treatment. The study will enroll 2000 children presenting to Kamuzu Central or Bwaila District Hospitals in Lilongwe, Malawi. Each child will be randomized to either 3 days of amoxicillin DT followed by 2 days of placebo DT or 5 days of amoxicillin DT. Children in the study will be hospitalized for 48 h after enrollment and will have scheduled study visits at Days 2, 4, 6 and 14. Treatment failure by Day 6 is the primary outcome. We hypothesize that the rates of treatment failure will be similar in both arms and that 3 days of treatment will be non-inferior to 5 days of amoxicillin DT for chest indrawing pneumonia using a relative non-inferiority margin of 1.5. This trial was approved by the Western Institutional Review Board and Malawi College of Medicine Research and Ethics Committee. DISCUSSION: Given the paucity of data from Africa, African-based research is necessary to establish appropriate duration of treatment with amoxicillin DT for chest indrawing childhood pneumonia in malaria-endemic settings in the region. An expanded evidence base will contribute to future iterations of World Health Organization Integrated Management of Childhood Illness guidelines. TRIAL REGISTRATION: NCT02678195 : Pre-results. Date registered February 9, 2016.

A double blind community-based randomized trial of amoxicillin versus placebo for fast breathing pneumonia in children aged 2-59 months in Karachi, Pakistan (RETAPP).

BACKGROUND: Fast breathing pneumonia is characterized by tachypnoea in the absence of danger signs and is mostly viral in etiology. Current guidelines recommend antibiotic therapy for all children with fast breathing pneumonia in resource limited settings, presuming that most pneumonia is bacterial. High quality clinical trial evidence to challenge or support the continued use of antibiotics, as recommended by the World Health Organization is lacking. METHODS/DESIGN: This is a randomized double blinded placebo-controlled non-inferiority trial using parallel assignment with 1:1 allocation ratio, to be conducted in low income squatter settlements of urban Karachi, Pakistan. Children 2-59 months old with fast breathing, without any WHO-defined danger signs and seeking care at the primary health care center are randomized to receive either three days of placebo or amoxicillin. From prior studies, a sample size of 2430 children is required over a period of 28 months. Primary outcome is the difference in cumulative treatment failure between the two groups, defined as a new clinical sign based on preset definitions indicating illness progression or mortality and confirmed by two independent primary health care physicians on day 0, 1, 2 or 3 of therapy. Secondary outcomes include relapse measured between days 5-14. Modified per protocol analysis comparing hazards of treatment failure with 95% confidence intervals in the placebo arm with hazards in the amoxicillin arm will be done. DISCUSSION: This study will provide evidence to support or refute the use of antibiotics for fast breathing pneumonia paving a way for guideline change. TRIAL REGISTRATION: Clinical Trials (NIH) Register NCT02372461.

Correlates and outcomes of preterm birth, low birth weight, and small for gestational age in HIV-exposed uninfected infants.

BACKGROUND: Preterm birth (PTB), low birth weight (LBW) and small for gestational age (SGA) contribute to neonatal mortality. Maternal HIV-1 infection has been associated with an increased risk of PTB, but mechanisms underlying this association are undefined. We describe correlates and outcomes of PTB, LBW, and SGA in HIV-exposed uninfected infants. METHODS: This was a retrospective analysis of cohort study. Between 1999-2002, pregnant, HIV-infected women were enrolled into an HIV-1 transmission study. Logistic regression was used to identify correlates of PTB, LBW and SGA in HIV-negative, spontaneous singleton deliveries. Associations between birth outcomes and mortality were measured using survival analyses. RESULTS: In multivariable models, maternal plasma (OR = 2.1, 95% CI = 1.1-3.8) and cervical HIV-1 RNA levels (OR = 1.6, 95% CI = 1.1-2.4), and CD4 < 15% (OR = 2.4, 95% CI = 1.0-5.6) were associated with increased odds of PTB. Abnormal vaginal discharge and cervical polymorphonuclear leukocytes were also associated with PTB. Cervical HIV-1 RNA level (OR = 2.4, 95% CI = 1.5-6.7) was associated with an increased odds of LBW, while increasing parity (OR = 0.46, 95% CI = 0.24-0.88) was associated with reduced odds. Higher maternal body mass index (OR = 0.75, 95% CI = 0.61-0.92) was associated with a reduced odds of SGA, while bacterial vaginosis was associated with >3-fold increased odds (OR = 3.2, 95% CI = 1.4-7.4). PTB, LBW, and SGA were each associated with a >6-fold increased risk of neonatal death, and a >2-fold increased rate of infant mortality within the first year. CONCLUSIONS: Maternal plasma and cervical HIV-1 RNA load, and genital infections may be important risk factors for PTB in HIV-exposed uninfected infants. PTB, LBW, and SGA are associated with increased neonatal and infant mortality in HIV-exposed uninfected infants.

A Phase 2a randomized, single-center, double-blind, placebo-controlled study to evaluate the safety and preliminary efficacy of oral iOWH032 against cholera diarrhea in a controlled human infection model.

Cholera remains a major cause of infectious diarrhea globally. Despite the increased availability of cholera vaccines, there is still an urgent need for other effective interventions to reduce morbidity and mortality. Furthermore, increased prevalence of antibiotic-resistant Vibrio cholerae threatens the use of many drugs commonly used to treat cholera. We developed iOWH032, a synthetic small molecule inhibitor of the cystic fibrosis transmembrane conductance regulator chloride channel, as an antisecretory, host-directed therapeutic for cholera. In the study reported here, we tested iOWH032 in a Phase 2a cholera controlled human infection model. Forty-seven subjects were experimentally infected with V. cholerae El Tor Inaba strain N16961 in an inpatient setting and randomized to receive 500 mg iOWH032 or placebo by mouth every 8 hours for 3 days to determine the safety and efficacy of the compound as a potential treatment for cholera. We found that iOWH032 was generally safe and achieved a mean (± standard deviation) plasma level of 4,270 ng/mL (±2,170) after 3 days of oral dosing. However, the median (95% confidence interval) diarrheal stool output rate for the iOWH032 group was 25.4 mL/hour (8.9, 58.3), compared to 32.6 mL/hour (15.8, 48.2) for the placebo group, a reduction of 23%, which was not statistically significant. There was also no significant decrease in diarrhea severity and number or frequency of stools associated with iOWH032 treatment. We conclude that iOWH032 does not merit future development for treatment of cholera and offer lessons learned for others developing antisecretory therapeutic candidates that seek to demonstrate proof of principle in a cholera controlled human infection model study. Trial registration: This study is registered with ClinicalTrials.gov as NCT04150250.

Reference and point-of-care testing for G6PD deficiency: Blood disorder interference, contrived specimens, and fingerstick equivalence and precision.

Certain clinical indications and treatments such as the use of rasburicase in cancer therapy and 8-aminoquinolines for Plasmodium vivax malaria treatment would benefit from a point-of-care test for glucose-6-phosphate dehydrogenase (G6PD) deficiency. Three studies were conducted to evaluate the performance of one such test: the STANDARD™ G6PD Test (SD BIOSENSOR, South Korea). First, biological interference on the test performance was evaluated in specimens with common blood disorders, including high white blood cell (WBC) counts. Second, the test precision on fingerstick specimens was evaluated against five individuals of each, deficient, intermediate, and normal G6PD activity status. Third, clinical performance of the test was evaluated at three point-of-care settings in the United States. The test performed equivalently to the reference assay in specimens with common blood disorders. High WBC count blood samples resulted in overestimation of G6PD activity in both the reference assay and the STANDARD G6PD Test. The STANDARD G6PD Test showed good precision on multiple fingerstick specimens from the same individual. The same G6PD threshold values (U/g Hb) were applied for a semiquantitative interpretation for fingerstick- and venous-derived results. The sensitivity/specificity values (95% confidence intervals) for the test for G6PD deficiency were 100 (92.3-100.0)/97 (95.2-98.2) and 100 (95.7-100.0)/97.4 (95.7-98.5) for venous and capillary specimens, respectively. The same values for females with intermediate (> 30% to ≤ 70%) G6PD activity were 94.1 (71.3-99.9)/88.2 (83.9-91.7) and 82.4 (56.6-96.2)/87.6(83.3-91.2) for venous and capillary specimens, respectively. The STANDARD G6PD Test enables point-of-care testing for G6PD deficiency.

Should fast breathing pneumonia cases be treated with antibiotics? The scientific rationale for revisiting management in Low and Middle income countries.

BACKGROUND: Pneumonia is the largest single contributor to child mortality and the problem is more acute in low and middle income countries. The World Health Organization (WHO) currently recommends oral antibiotic treatment for all children with fast breathing pneumonia without danger signs. It is, however, widely acknowledged that most such infections are viral and self-limiting and that the evidence for the guidance is weak. RATIONALE: Overuse of antibiotics exposes children to adverse events, increases cost for families, burdens already stretched health care resources and may contribute to development of antibiotic resistance. CONCLUSION: There is equipoise regarding utility of antibiotic in case of fast breathing pneumonia and no high quality trial evidence exists. This paper provides further information behind the rationale for conducting non-inferiority trials to test the hypothesis that antibiotics may not be necessary for children with fast breathing as the sole symptomatology.

Title Correction: Clinical Outcomes of Pneumonia and Other Comorbidities in Children Aged 2-59 Months in Lilongwe, Malawi: Protocol for the Prospective Observational Study "Innovative Treatments in Pneumonia".

[This corrects the article DOI: 10.2196/13377.].

Clinical Outcomes of Pneumonia and Other Comorbidities in Children Aged 2-59 Months in Lilongwe, Malawi: Protocol for the Prospective Observational Study "Innovative Treatments in Pneumonia".

BACKGROUND: Pneumonia is the leading infectious cause of death worldwide among children below 5 years of age. Clinical trials are conducted to determine optimal treatment; however, these trials often exclude children with comorbidities and severe illness. CONCLUSIONS: Given the paucity of data from Africa, African-based research is necessary to establish optimal management of childhood pneumonia in malaria-endemic settings in the region. An expanded evidence base that includes children with pneumonia and other comorbidities, who are at high risk for mortality or have other complications and are therefore typically excluded from childhood pneumonia clinical trials, can contribute to future iterations of the World Health Organization Integrated Management of Childhood Illness guidelines. METHODS: The study enrolled 1000 children with pneumonia presenting to the outpatient departments of Kamuzu Central or Bwaila District Hospitals in Lilongwe, Malawi, who were excluded from concurrent randomized controlled clinical trials investigating fast breathing and chest indrawing pneumonia and who met the inclusion criteria for this prospective observational study. Each child received standard care for their illnesses per Malawian guidelines and hospital protocol and was prospectively followed up with scheduled study visits on days 1, 2 (if hospitalized), 6, 14 (in person), and 30 (by phone). Our primary objectives are to describe the clinical outcomes of children who meet the inclusion criteria for this study and to investigate whether the percentages of children cured at day 14 among those with either fast breathing or chest indrawing pneumonia and comorbidities such as severe malaria, anemia, severe acute malnutrition, or HIV are lower than those in children without these comorbidities in the standard care groups in concurrent clinical trials. This study was approved by the Western Institutional Review Board, Malawi College of Medicine Research and Ethics Committee, and the Malawi Pharmacy, Medicines and Poisons Board. OBJECTIVE: This prospective observational study aimed to assess the clinical outcomes of children aged 2-59 months with both pneumonia and other comorbidities in a malaria-endemic region of Malawi. RESULTS: The Innovative Treatments in Pneumonia project was funded by the Bill and Melinda Gates Foundation (OPP1105080) in April 2014. Enrollment in this study began in 2016, and the primary results are expected in 2019. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/13377.

mPneumonia, an Innovation for Diagnosing and Treating Childhood Pneumonia in Low-Resource Settings: A Feasibility, Usability and Acceptability Study in Ghana.

Pneumonia is the leading cause of infectious disease mortality in children. Currently, health care providers (HCPs) are trained to use World Health Organization Integrated Management of Childhood Illness (IMCI) paper-based protocols and manually assess respiratory rate to diagnose pneumonia in low-resource settings (LRS). However, this approach of relying on clinical signs alone has proven problematic. Hypoxemia, a diagnostic indicator of pneumonia severity associated with an increased risk of death, is not assessed because pulse oximetry is often not available in LRS. To improve HCPs' ability to diagnose, classify, and manage pneumonia and other childhood illnesses, "mPneumonia" was developed. mPneumonia is a mobile health application that integrates a digital version of the IMCI algorithm with a software-based breath counter and a pulse oximeter. A design-stage qualitative pilot study was conducted to assess feasibility, usability, and acceptability of mPneumonia in six health centers and five community-based health planning and services centers in Ghana. Nine health administrators, 30 HCPs, and 30 caregivers were interviewed. Transcribed interview audio recordings were coded and analyzed for common themes. Health administrators reported mPneumonia would be feasible to implement with approval and buy-in from national and regional decision makers. HCPs felt using the mPneumonia application would be feasible to integrate into their work with the potential to improve accurate patient care. They reported it was "easy to use" and provided confidence in diagnosis and treatment recommendations. HCPs and caregivers viewed the pulse oximeter and breath counter favorably. Challenges included electricity requirements for charging and the time needed to complete the application. Some caregivers saw mPneumonia as a sign of modernity, increasing their trust in the care received. Other caregivers were hesitant or confused about the new technology. Overall, this technology was valued by users and is a promising innovation for improving quality of care in frontline health facilities.

Infant Neutropenia Associated with Breastfeeding During Maternal Antiretroviral Treatment for Prevention of Mother-to-Child Transmission of HIV.

Maternal antiretroviral treatment (ART) is recommended for prevention of mother-to-child HIV-1 transmission (PMTCT), including in women with high CD4+ cell counts. Within a pediatric HIV-1 vaccine trial PedVacc 002, we assessed hematologic profiles of infants born to mothers receiving ART. All mothers had CD4+ cell counts of >350 mm-3; 93% received zidovudine-containing ART; infants received nevirapine up to 6 weeks and cotrimoxazole after 6 weeks. Among 84 infants at 19 weeks, 58% had hematologic toxicity; 44% had neutropenia and 23% had anemia. Breastfeeding was associated with 3.8-fold higher risk of neutropenia (RR 3.8, 95% CI 1.03-14.1, p = 0.008). Hematologic monitoring and PMTCT regimen selection are important for optimizing infant outcomes.

PedVacc 002: a phase I/II randomized clinical trial of MVA.HIVA vaccine administered to infants born to human immunodeficiency virus type 1-positive mothers in Nairobi.

BACKGROUND: A safe, effective vaccine for breastfeeding infants born to HIV-1-positive mothers could complement antiretroviral therapy (ART) for prevention of mother-to-child transmission of HIV-1. To date, only a few HIV-1 vaccine candidates have been tested in infants. TRIAL DESIGN: A phase I/II randomized controlled trial PedVacc 002 was conducted to determine the safety and immunogenicity of a single, low dose of MVA.HIVA vaccine delivered intramuscularly to healthy 20-week-old infants born to HIV-1-positive mothers in Nairobi, Kenya. METHODS: Pregnant HIV-1-positive women in the 2nd/3rd trimester of gestation were enrolled, provided with ART and self-selected their infant-feeding modality. Infants received nevirapine and cotrimoxazole prophylaxis. At 20 weeks of age, eligible HIV-1-negative infants were randomized to vaccine versus no-treatment arms and followed to 48 weeks of age for assessments of vaccine safety, HIV-1-specific T-cell responses and antibodies to routine childhood vaccines. RESULTS: Between February and November 2010, 182 mothers were screened, 104 were eligible and followed on ART during pregnancy/postpartum, of whom 73 had eligible infants at 20 weeks postpartum. Thirty-six infants were randomized to vaccine and 37 to no treatment. Eighty-four percent of infants breastfed, and retention at 48 weeks was 99%. Adverse events were rare and similar between the two arms. HIV-1-specific T-cell frequencies in interferon-γ ELISPOT assay were transiently higher in the MVA.HIVA arm (p=0.002), but not above the threshold for a positive assay. Protective antibody levels were adequate and similar between arms for all routine childhood vaccines except HBV, where 71% of MVA.HIVA subjects compared to 92% of control subjects were protected (p=0.05). CONCLUSIONS: This trial tested for the first time an MVA-vectored candidate HIV-1 vaccine in HIV-1-exposed infants in Africa, demonstrating trial feasibility and vaccine safety, low immunogenicity, and compatibility with routine childhood vaccinations. These results are reassuring for use of the MVA vector in more potent prime-boost regimens.

A phase I randomized clinical trial of candidate human immunodeficiency virus type 1 vaccine MVA.HIVA administered to Gambian infants.

BACKGROUND: A vaccine to decrease transmission of human immunodeficiency virus type 1 (HIV-1) during breast-feeding would complement efforts to eliminate infant HIV-1 infection by antiretroviral therapy. Relative to adults, infants have distinct immune development, potentially high-risk of transmission when exposed to HIV-1 and rapid progression to AIDS when infected. To date, there have been only three published HIV-1 vaccine trials in infants. TRIAL DESIGN: We conducted a randomized phase I clinical trial PedVacc 001 assessing the feasibility, safety and immunogenicity of a single dose of candidate vaccine MVA.HIVA administered intramuscularly to 20-week-old infants born to HIV-1-negative mothers in The Gambia. METHODS: Infants were followed to 9 months of age with assessment of safety, immunogenicity and interference with Expanded Program on Immunization (EPI) vaccines. The trial is the first stage of developing more complex prime-boost vaccination strategies against breast milk transmission of HIV-1. RESULTS: From March to October 2010, 48 infants (24 vaccine and 24 no-treatment) were enrolled with 100% retention. The MVA.HIVA vaccine was safe with no difference in adverse events between vaccinees and untreated infants. Two vaccine recipients (9%) and no controls had positive ex vivo interferon-γ ELISPOT assay responses. Antibody levels elicited to the EPI vaccines, which included diphtheria, tetanus, whole-cell pertussis, hepatitis B virus, Haemophilus influenzae type b and oral poliovirus, reached protective levels for the vast majority and were similar between the two arms. CONCLUSIONS: A single low-dose of MVA.HIVA administered to 20-week-old infants in The Gambia was found to be safe and without interference with the induction of protective antibody levels by EPI vaccines, but did not alone induce sufficient HIV-1-specific responses. These data support the use of MVA carrying other transgenes as a boosting vector within more complex prime-boost vaccine strategies against transmission of HIV-1 and/or other infections in this age group. TRIAL REGISTRATION: ClinicalTrials.gov NCT00982579. The Pan African Clinical Trials Registry PACTR2008120000904116.