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Tuberculosis (TB) is a leading cause of global child mortality. Until the turn of the 21st century, Mycobacterium bovis bacille Calmette-Guerin (BCG) was the only vaccine to prevent TB. The pediatric TB vaccine pipeline has advanced in the past decade to include the evaluation of novel whole cell vaccines to replace infant BCG and investigation of subunit and whole cell vaccines to boost TB immunity during adolescence. We describe the history of BCG, current TB vaccine candidates in clinical trials, and the challenges and opportunities for future TB vaccine research in children. Children are a critical target population for TB vaccines, and expansion of the pediatric TB vaccine pipeline is urgently needed to end the TB pandemic.

Background We explored the effects of predominant breastfeeding on infection-related hospitalization (uncommon outcome), over the first year of life, using the Mother Infant Health cohort study (MIHS), and the effect of early antiretroviral treatment (ART) on viral suppression (< 400 copies/mL) (common outcome), in children aged 7 to 12 weeks, using a subset of the Children with HIV Early AntiRetroviral Treatment (CHER) clinical trial data. We assessed the sensitivity of findings to different models to account for dependency of uncommon and common binary outcome. Methods We fitted generalized linear mixed model with (1) random intercept and (2) random slope, generalized estimating equations (GEE) with 3) an exchangeable correlation structure; 4) autoregressive correlation structure of order 1 (AR1) and 5) unstructured correlation structure and 6) logistic regression model. Results Eighty four and 119 children from MIHS were non-predominantly and predominantly breastfed, respectively. There were 34 infection-related hospitalizations overall. Most infants were hospitalized once, except for four with two hospitalizations. We analysed 88 HIV-infected children from the CHER trial. On average, a child achieved viral suppression twice, range of one to four. The effect of predominant breastfeeding on infection-related hospitalization was similar across all models, except for the GEE with AR1 that had a high estimate (wider confidence intervals). The effect of early ART exposure on viral suppression varied across models. Conclusions The sensitivity of estimates to the method of analysis was driven by frequency of the outcome.

Focus of Presentation A randomized clinical trial is considered the best experimental study design for comparing the effect of an intervention against a control. Selecting a trial design depends on the trial objective, a better choice would be a design that provides optimal estimation of the intervention effect, i.e. a design that yields smaller variance for the estimated intervention effect and giving stable estimates. The choice of analysis method depends on trial design aspects, reasonable assumption on the underlying probabilistic model generating the data and the credibility of findings depend on the appropriateness of the analysis method used. Here, we describe a planned randomized standard of care-controlled trial on interactive weekly mobile text messaging added to a motivational interviewing intervention aimed at sustaining continued breastfeeding among women living with HIV in South Africa. Under the “findings” heading, we highlight some of the trial design and statistical issues for discussion at the early career workshop, to gain insights on possible approaches to address the methods issues. Methods and trial design: Women from peri-urban informal settlements and a rural setting will be invited to participate within 24 hours of giving birth at selected primary healthcare facilities. Eligible women will be individually randomized to intervention or control arm after providing written informed consent. The intervention will consist of a weekly text message encouraging women to exclusively breastfeed and inquiring if they have any problems breastfeeding their infants. In addition to text messaging, women assigned to the intervention arm must visit the research site where a research nurse or counsellor will conduct an individual motivational interview, at weeks 2, 6, and 10 post-delivery. Women assigned to the control arm will be counselled by the standard of care service, i.e. primary healthcare nurses and trained counsellors will counsel women to exclusively breastfeed for the first six months through group educational infant feeding counselling sessions. Study participation will not change standard of care of participants, so women assigned to the intervention arm will receive the standard of care service, in line with provincial guidelines applicable in the sector during the study period. The primary outcomes are 1) number of women who are exclusively breastfeeding at week 24 post-delivery and 2) number of women reporting any breastfeeding at week 24 post-delivery. Findings or trial design and statistical issues Although women are individually randomly assigned to intervention and control arms, the standard of care at the primary health care facility may induce a dependency between these participants, also called the group therapy effect. For example, promotion of exclusive breastfeeding in HIV-infected women may be enhanced through positive feedback from women who follow this practice or vice versa. The standard of care will be clustered within group infant feeding counselling session, where participants (both assigned to the control and intervention arm) will receive the standard of care in groups. Women assigned to the intervention arm will receive individual motivational interview and the text messages will be send separately, to each woman’s mobile phone. Implications The trial objective will be to determine whether at week 24 following delivery, weekly text message added to motivational interview leads to better adherence to exclusive breastfeeding and leads to extended breastfeeding than standard of care. Trial design and statistical issues to discuss during the workshop will include a discussion around: 1) the appropriateness of invoking the standard experimental design to address the study objectives, and possible alternatives 2) Sample size estimation for a trial comparing group and individual treatments? 3) Reasonable assumption on the underlying probabilistic model generating the outcome data and 4) Candidate statistical models. Key messages Use of sound statistical principles of experimental design established for clinical trials allow objective and unbiased comparisons.

Background. This systematic review aimed to assess the safety and efficacy of antiretroviral options for postexposure prophylaxis (PEP). Recognizing the limited data on the safety and efficacy of antiretroviral drugs for PEP in children, this review was extended to include consideration of data on the use of antiretroviral drugs for treatment of infants and children living with human immunodeficiency virus. Methods. The PEP literature was assessed to identify studies reporting safety and completion rates for children given PEP, and this information was complemented by safety and efficacy data for drugs used in antiretroviral therapy. The proportion of patients experiencing each outcome was calculated and data were pooled using randomeffects meta-analysis. Results. Three prospective cohort studies reported outcomes of children given zidovudine (ZDV) plus lamivudine (3TC) as a 2-drug PEP regimen. The proportion of children completing the full 28-day course of PEP was 64.0% (95% confidence interval [CI], 41.2%–86.8%), whereas the proportion discontinuing due to adverse events was 4.5% (95% CI, .4%–8.6%). One randomized trial compared abacavir (ABC) plus lamivudine (3TC) and ZDV+3TC as part of a dual or triple first-line antiretroviral therapy regimen; this study showed better efficacy in the ABC-containing combinations and no difference in the time to first serious adverse event. Three randomized trials compared lopinavir/ritonavir (LPV/r) to nevirapine (NVP) for antiretroviral therapy and showed a lower risk of treatment discontinuations associated with LPV/r vs NVP (hazard ratio, 0.56 [95% CI, .41–.75]) but no difference in drug-related adverse events. The overall quality of the evidence was rated as very low. Conclusions. This review supports ZDV+3TC+LPV/r as the preferred 3-drug regimen for PEP in children.

To investigate the effect of trimethoprim/sulfamethoxazole on the survival of Mycobacterium tuberculosis and trimethoprim and sulfamethoxazole individually and combined with the first-line tuberculosis drugs (isoniazid, rifampicin and ethambutol).M. tuberculosis strains were exposed to either trimethoprim/sulfamethoxazole combination or sulfamethoxazole and trimethoprim alone at various concentrations. The strains were also exposed to sulfamethoxazole in combination with existing antibiotics to assess the combined effect on the growth of M. tuberculosis in the BACTEC 460TB system. The effect of the drugs was compared with vehicle-treated controls. Drug interactions were interpreted using quotient values obtained from the growth index of cultures treated with a single drug or the combination.Trimethoprim showed a negligible effect on the growth of M. tuberculosis while sulfamethoxazole inhibited 80% of the growth of M. tuberculosis at 4.75 mg/L. There was no synergistic activity between sulfamethoxazole and trimethoprim, although an additive effect was observed. A statistically significant synergistic effect was observed between sulfamethoxazole and rifampicin. Sulfamethoxazole also had an additive effect with ethambutol, but there was no interaction with isoniazid.Sulfamethoxazole is the main active compound against M. tuberculosis in the combination trimethoprim/sulfamethoxazole and has a synergistic effect with rifampicin. These findings suggest that sulfamethoxazole has potential in the multidrug regimen against M. tuberculosis.

Confirming the diagnosis of childhood tuberculosis is a major challenge. However, research on childhood tuberculosis as it relates to better diagnostics is often neglected because of technical difficulties, such as the slow growth in culture, the difficulty of obtaining specimens, and the diverse and relatively nonspecific clinical presentation of tuberculosis in this age group. Researchers often use individually designed criteria for enrollment, diagnostic classifications, and reference standards, thereby hindering the interpretation and comparability of their findings. The development of standardized research approaches and definitions is therefore needed to strengthen the evaluation of new diagnostics for detection and confirmation of tuberculosis in children. In this article we present consensus statements on methodological issues for conducting research of Tuberculosis diagnostics among children, with a focus on intrathoracic tuberculosis. The statements are complementary to a clinical research case definition presented in an accompanying publication and suggest a phased approach to diagnostics evaluation; entry criteria for enrollment; methods for classification of disease certainty, including the rational use of culture within the case definition; age categories and comorbidities for reporting results; and the need to use standard operating procedures. Special consideration is given to the performance of microbiological culture in children and we also recommend for alternative methodological approaches to report findings in a standardized manner to overcome these limitations are made. This consensus statement is an important step toward ensuring greater rigor and comparability of pediatric tuberculosis diagnostic research, with the aim of realizing the full potential of better tests for children.

Serotype-specific antibody concentration and opsonophagocytic activity (OPA) were evaluated after 3 doses of pneumococcal conjugate vaccine. Groups included human immunodeficiency virus (HIV)-positive infants with CD4(+) cell percentagesor =25% who initiated immediate antiretroviral treatment (the HIV+/ART+ group) or whose antiretroviral treatment was deferred until clinically or immunologically indicated (the HIV+/ART- group). Immune responses were also evaluated in HIV-noninfected infants born to HIV-seronegative (M-/I-) or HIV-positive mothers (M+/I-). Antibody concentrations were similar between HIV+/ART+ and HIV+/ART- infants. However, antibody concentrations were lower in M-/I- infants than in M+/I- infants. Nevertheless, M-/I- infants had superior OPA responses, compared with those in HIV+/ART+ infants, who in turn had better OPA responses, compared with those in HIV+/ART- infants.

We report a case of hepatitis B immune reconstitution inflammatory syndrome in an 8-month-old girl with Mycobacterium tuberculosis complex and human immunodeficiency virus (HIV) co-infection. In resource-constrained countries, HIV-hepatitis B co-infections are often difficult to diagnose and to treat. We highlight on the importance of hepatitis B and HIV screening in pregnant women, to implement efficient preventive measures.

We present a case of tuberculosis (TB) paradoxical immune reconstitution inflammatory syndrome (IRIS) complicated by chylous ascites and chylothorax in a HIV-infected child. There are few descriptions of TB IRIS in children. This case extends the clinical spectrum of TB IRIS.

OBJECTIVE: To determine the prevalence of attention deficit-hyperactivity disorder (ADHD) and oppositional defiance disorder (ODD) in HIV-infected South African children. METHODS: Swanson Nolan and Pelham (SNAP-IV) questionnaires were used to determine ADHD and ODD severity and a draw-a-person (DAP) test was used to screen for developmental disorders. Associations between behavioural subtypes psychological functioning demographic and health variables were investigated. RESULTS: The SNAP-IV caregiver questionnaires showed a 26% prevalence of ADHD inattentive type; 38% hyperactive type and 24% combined type. The prevalence of ODD was 12% on parent questionnaires and 9.5% on teachers questionnaires. CONCLUSIONS: Parents/caregiver-only SNAP-IV questionnaires indicate a high prevalence of significant ADHD (all subtypes) and ODD in HIV-infected children. No significant differences were found between the severity of HIV disease and the presence of a behavioural disorder. The SNAP IV questionnaires and DAP test may prove valuable screening tools in HIV children with behavioural problems.

We describe the clinical and basic immunological findings of eight HIV-exposed uninfected infants hospitalized with serious infectious morbidity and referred for immunological evaluation. The median age at presentation was 5.5 (1.5-15) months. Infections included Pneumocystis jiroveci pneumonia (three), cytomegalovirus colitis with perforation (one), Pseudomonas sepsis (two), hemorrhagic varicella (one) and Group A streptococcal meningitis and endocarditis (one). Five required intensive care, four for assisted ventilation and one for post-surgical care. Follow-up to 36 months suggested resolution of a transient immunodeficiency in two infants, one of whom had CD4 and the other B-cell depletion. Further studies are indicated in HIV-exposed uninfected infants.

BACKGROUND: There are limited population-based estimates of tuberculosis incidence among human immunodeficiency virus (HIV)-infected and HIV-uninfected infants aged < or =12 months. We aimed to estimate the population-based incidence of culture-confirmed tuberculosis among HIV-infected and HIV-uninfected infants in the Western Cape Province South Africa. METHODS: The incidences of pulmonary extrapulmonary and disseminated tuberculosis were estimated over a 3-year period (2004-2006) with use of prospective representative hospital surveillance data of the annual number of culture-confirmed tuberculosis cases among infants. The total number of HIV-infected and HIV-uninfected infants was calculated using population-based estimates of the total number of live infants and the annual maternal HIV prevalence and vertical HIV transmission rates. RESULTS: There were 245 infants with culture-confirmed tuberculosis. The overall incidences of tuberculosis were 1596 cases per 100000 population among HIV-infected infants (95% confidence interval [CI] 1151-2132 cases per 100000 population) and 65.9 cases per 100000 population among HIV-uninfected infants (95% CI 56-75 cases per 100000 population). The relative risk of culture-confirmed tuberculosis among HIV-infected infants was 24.2 (95% CI 17-34). The incidences of disseminated tuberculosis were 240.9 cases per 100000 population (95% CI 89-433 cases per 100000 population) among HIV-infected infants and 14.1 cases per 100000 population (95% CI 10-18 cases per 100000 population) among HIV-uninfected infants (relative risk 17.1; 95% CI 6-34). CONCLUSIONS: This study indicates the magnitude of the tuberculosis disease burden among HIV-infected infants and provides population-based comparative incidence rates of tuberculosis among HIV-infected infants. This high risk of tuberculosis among HIV-infected infants is of great concern and may be attributable to an increased risk of tuberculosis exposure increased immune-mediated tuberculosis susceptibility and/or possible limited protective effect of bacille Calmette-Guerin vaccination. Improved tuberculosis control strategies including maternal tuberculosis screening contact tracing of tuberculosis-exposed infants coupled with preventive chemotherapy and effective vaccine strategies are needed for infants in settings where HIV infection and tuberculosis are highly endemic.

It is estimated that almost 300,000 children in South Africa have human immunodeficiency virus (HIV) infection. The disease is responsible for reversing decreases in child mortality. Few data exist evaluating the outcomes of the prevention of mother-to-child transmission of HIV (PMTCT) program, although PMTCT coverage appears to be low. Hospitals are still witnessing large numbers of admissions of HIV-infected children. Postnatal transmission of HIV is high, reflecting poor education of and support for women in their infant feeding choices. Too few infants and children are entering care through early diagnosis, which should be widely available. Cotrimoxazole prophylaxis coverage is inadequate, contributing to high morbidity and mortality in infants. The number of children receiving antiretroviral therapy (ART) is increasing steadily. However, significant inequalities in access to ART exist between and within provinces. Challenges for pediatric ART include a lack of sufficiently trained health care personnel and inadequate facilities, as well as the complexity of drug regimens and formulations. The compartmentalization of the ART rollout program hinders PMTCT and makes it difficult for children to be identified and referred into appropriate services. This article delineates the challenges to pediatric HIV care in South Africa and provides some practical recommendations to improve it.

The diagnosis and management of childhood tuberculosis (TB) pose substantial challenges in the era of the human immunodeficiency virus (HIV) epidemic. The highest TB incidences and HIV infection prevalences are recorded in sub-Saharan Africa, and, as a consequence, children in this region bear the greatest burden of TB/HIV infection. The tuberculin skin test (TST), which is the standard marker of Mycobacterium tuberculosis infection in immunocompetent children, has poor sensitivity when used in HIV-infected children. Novel T cell assays may offer higher sensitivity and specificity than the TST, but these tests still fail to make the crucial distinction between latent M. tuberculosis infection and active disease and are limited by cost considerations. Symptom-based diagnostic approaches are less helpful in HIV-infected children, because of the difficulty of differentiating TB-related symptoms from those caused by other HIV-associated conditions. Knowing the HIV infection status of all children with suspected TB is helpful because it improves clinical management. HIV-infected children are at increased risk of developing active disease after TB exposure/infection, which justifies the use of isoniazid preventive therapy once active TB has been excluded. The higher mortality and relapse rates noted among HIV-infected children with active TB who are receiving standard TB treatment highlight the need for further research to define optimal treatment regimens. HIV-infected children should also receive appropriate supportive care, including cotrimoxazole prophylaxis, and antiretroviral therapy, if indicated. Despite the difficulties experienced in resource-limited countries, the management of children with TB/HIV infection could be vastly improved by better implementation of readily available interventions.

We sought to determine the efficacy of a 4-6 week course of zidovudine (ZDV) in a group of infants exposed to HIV-1. A retrospective chart review was conducted on HIV-1-exposed neonates identified from February 1998 to August 1999. These infants received ZDV and their mothers were counselled regarding the risks and benefits of breastfeeding. After informed consent was obtained, the HIV-1-status of the infant was determined by RNA-PCR after 1 month of age. Thirty-three HIV-1-exposed neonates were identified; seven infants were excluded, five because of insufficient data and two because of maternal ZDV administration. In all but three, the diagnosis was suspected because of maternal illness, 19 of 26 mothers having either stage 3 or 4 disease. The transmission rate was 15.4 per cent (4 of 26). Errors in ZDV administration were detected in 20 neonates of whom four were infected (p = 1; Fischer's exact test). Antenatal diagnosis of HIV-1 status was associated with fewer medication errors in HIV-1-exposed neonates (p = 0.017, Fisher's exact test). It was concluded that a transmission rate of 15.4 per cent in symptomatic mothers suggests efficacy. Under similar circumstances, transmission rates varying between 37 and 67 per cent have been reported. Antenatal diagnosis is significantly associated with compliance to the regimen. Early identification of at-risk neonates and familiarity with the regimen may improve the outcome.

The disclosure of HIV status to infected children has received relatively little attention to date in sub-Saharan Africa. We conducted 40 semi-structured interviews with healthcare providers working in a large paediatric HIV clinic in Cape Town, South Africa regarding attitudes and experiences around discussing HIV with infected children. Most providers felt that the optimal age for general discussions about an HIV-infected child's health should happen around age 6, but that specific discussions regarding HIV infection should be delayed to a median of 10 years. Though most providers said that primary caregivers were the most appropriate individuals to lead disclosure discussions, there were strong views that caregivers require support from healthcare providers. These findings indicate the complexities involved in the disclosure of HIV status to infected children, and point to the need for interventions to support caregivers and providers in disclosure discussions.

Thrombocytopoenia is a well-described marker of human immunedeficiency virus type 1 (HIV) infection of children. After documenting thrombocytopoenia in a HIV-exposed neonate, who was subsequently shown not to be infected, we evaluated thrombocytopoenia (platelets < 150 x 10(9)/l) as a marker for HIV exposure in newborns. This is, to our knowledge, the first study of thrombocytopoenia in HIV-exposed neonates. A retrospective hospital-based descriptive study was performed over an 18-month period (July 1997-December 1998). Patients were recruited either through identification of known HIV-positive mothers or neonates with thrombocytopoenia who were then screened for HIV exposure. For eligibility, neonates with either HIV antibodies or direct evidence of infection (p24 antigenaemia or HIV RNA detected by polymerase chain reaction after 1 month of age) were included. Thirty-four HIV-exposed (HIV-ELISA positive) neonates were identified, of whom 16 (47 per cent) had thrombocytopenia. In 12 (35 per cent), no underlying cause other than HIV was identified. Nine thrombocytopoenic babies were infected and seven uninfected. Unexplained thrombocytopoenia, while an imperfect marker, should alert the physician to the possibility of HIV exposure. It does not necessarily imply HIV infection. A prospective study is recommended to evaluate further the sensitivity and specificity of this marker.

We report a 9-month-old HIV-1 infected child who presented with severe upper airway obstruction (UAO) and obstructive sleep apnoea (OSA) probably as a result of co-infection with Epstein--Barr virus (EBV). EBV infection is usually asymptomatic in children from developing countries in contrast to developed countries where UAO is a recognized complication. Other features on physical examination were failure to thrive oral thrush a purulent nasal discharge hepatosplenomegaly and generalized lymphadenopathy. A lateral X-ray of the neck showed adenoidotonsillar hypertrophy and enlargement of the prevertebral space probably due to lymphadenopathy. The white cell count was 11:9 x 10/9/l with activated lymphocytes noted. The t-globulin level was elevated at 55 g/l (normal value 18-- 36 g/l). The Mantoux test was non-reactive and two gastric aspirates were negative for Mycobacterium tuberculosis culture. An echocardiogram was normal. Both the patient and his mother were HIV seropositive by three enzyme immunoassays (EIA) (Murex Diagnostics Kent UK; Organon-Technika Boxtel Netherlands; and Abbott IL USA). The CD4+ T-lymphocyte count was 233 x 10/9/l (normal 1700--2800 ´ 109/l) and CD4/8 ratio 0.32 (normal 1.5--2.9). (excerpt)