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BACKGROUND Optimal care for children with HIV infection includes timely assessment of treatment failure. Using HIV viral load to define treatment failure remains a challenge in resource-limited settings. METHODS Children with HIV infection who were already on or starting first-line antiretroviral therapy were enrolled and followed over time. We examined clinical and immunologic predictors of virologic failure (VF), defined as consecutive viral load measurements > 1000 copies/mL (VF). Children were followed every 6 months with clinical assessments, immunologic assays and viral load testing until treatment failure or up to 18 months. RESULTS Of the 484 children with complete data, we observed a prevalence of 15% who had VF at enrollment, and 18 who developed VF over 10.5 person-years of follow-up for an incidence of 4.97 [95% CI: 3.04-7.70) per 100 person-years. Lower adherence, lower CD4 T-cell count, lower white blood cells count, lower platelets and a lower glomerular filtration rate were all associated with increased VF. However, in a multivariable analysis, renal function (estimated glomerular filtration rate < 90 mL/min), odds ratio: 11.5 (95% CI: 1.5-63.7), and lower adherence, odds ratio: 3.9 (95% CI: 1.1-13.4), were the only factors associated with development of VF. CONCLUSIONS We identified a significant risk of VF in children with HIV infection in a prospective cohort study in southern Ethiopia and limited predictive value of clinical variables for VF. This provides further evidence that rapid and reliable viral load testing is needed to adequately address the HIV epidemic, along with implementation of adherence interventions in sub-Saharan Africa.

Routine health information system (RHIS) data are essential in driving decision making and planning in health systems as well as health programs. However, despite their importance, these data are underutilized, and the underlying individual-level facilitators and barriers to use remain understudied. In this research, we applied the Integrated Behavior Model (IBM) to examine how attitudes toward RHIS data, perceived norms concerning RHIS data use, and the ability to use RHIS data influence the demand and use of RHIS data among stakeholders in Senegal. Using data from interviews with respondents working at national levels of malaria, HIV, and TB control programs in Senegal, we used a framework analysis approach to apply the IBM behavioral constructs and identify their linkages to RHIS data use. We found that attitudes about the quality, availability, and relevance of RHIS data for decision making were important in driving data use among respondents. Institutional expectations, organizational protocols, policies, and practices around RHIS data ultimately shape social norms around the use of the data. Although we found that perceived ability and self-efficacy to use RHIS data were not barriers to RHIS data use among stakeholders at the strategic levels of their respective organizations, these were reported to be barriers at lower levels of the health system. Low perceived control of the RHIS data production process ultimately reduced RHIS data use for decision making among the strategic-level respondents. We recommend context-specific reexamination of existing RHIS interventions with a renewed emphasis on behavioral aspects of data use. The IBM can help guide practitioners, policy makers, and academics to address multiple socioecological factors that influence data use behavior when recommending RHIS and data use solutions.

Background Increasing the performance of routine health information systems (RHIS) is an important policy priority both globally and in Senegal. As RHIS data become increasingly important in driving decision-making in Senegal, it is imperative to understand the factors that determine their use. Methods Semi-structured interviews were conducted with 18 high- and mid-level key informants active in the malaria, tuberculosis and HIV programmatic areas in Senegal. Key informants were employed in the relevant divisions of the Senegal Ministry of Health or nongovernmental / civil society organizations. We asked respondents questions related to the flow, quality and use of RHIS data in their organizations. A framework approach was used to analyze the qualitative data. Results Although the respondents worked at the strategic levels of their respective organizations, they consistently indicated that data quality and data use issues began at the operational level of the health system before the data made its way to the central level. We classify the main identified barriers and facilitators to the use of routine data into six categories and attempt to describe their interrelated nature. We find that data quality is a central and direct determinant of RHIS data use. We report that a number of upstream factors in the Senegal context interact to influence the quality of routine data produced. We identify the sociopolitical, financial and system design determinants of RHIS data collection, dissemination and use. We also discuss the organizational and infrastructural factors that influence the use of RHIS data. Conclusions We recommend specific prescriptive actions with potential to improve RHIS performance in Senegal, the quality of the data produced and their use. These actions include addressing sociopolitical factors that often interrupt RHIS functioning in Senegal, supporting and motivating staff that maintain RHIS data systems as well as ensuring RHIS data completeness and representativeness. We argue for improved coordination between the various stakeholders in order to streamline RHIS data processes and improve transparency. Finally, we recommend the promotion of a sustained culture of data quality assessment and use.

OBJECTIVES: Ethiopia is 1 of 15 countries that account for nearly 75% of all people living with HIV. Khat use, a common practice in Ethiopia and sub-Saharan Africa, has gained attention as a potential risk factor for HIV. Our objective was to evaluate associations between khat use and demographic and risk-taking characteristics (alcohol use, sexual behavior), and also associations between HIV status and these characteristics among voluntary counseling and testing clients in Addis Ababa, Ethiopia. METHODS: This cross-sectional study was conducted among Pro Pride voluntary counseling and testing center clients, aged 18 to 49 years, from November 2009 to March 2010. All clients were approached, and 98.8% of these (684) completed a self-administered questionnaire. Associations between khat use, alcohol use, multiple sexual partners, and HIV status were assessed using logistic regression models. RESULTS: Using khat in the past 90 days (current khat use) was significantly associated with being Muslim, being male, alcohol use, and having a greater number of sex partners in one's lifetime. The adjusted odds of current khat use was almost 7-fold higher in those having 4 or more sexual partners in their lifetime (adjusted odds ratio 6.89, 95% confidence interval 3.87, 12.25) as compared with those with 1 or none. HIV-positive status was significantly associated with age, employment, marital status, number of sex partners in one's lifetime, and khat use. Having used khat in one's lifetime, but not currently, past khat use, was associated with over a 2-fold increased adjusted odds (adjusted odds ratio 2.64, 95% confidence interval 1.13, 6.19) of being HIV-infected. CONCLUSIONS: Our findings highlight associations between current khat use and the modifiable factors of number of lifetime sexual partners and alcohol use. In addition, we observed the association between HIV status and past khat use after adjusting for age, marital status, and number of sex partners in one's lifetime.

Background The objective of this analysis was to assess the cost-effectiveness of TB diagnosis using microscopic observation drug susceptibility (MODS), Xpert MTB/RIF (Xpert) and empiric treatment for all patients, in addition to current clinical diagnostic practices in children less than 5 years of age in a national tuberculosis (TB) referral hospital in Uganda. Methods A decision analysis was conducted from the healthcare perspective, with a primary outcome of incremental cost-effectiveness expressed as cost per year of life gained (YLG). Results Cost-effectiveness of the algorithms depended strongly on 3 variables: the prevalence of TB, probability of death if TB was untreated and accuracy of existing diagnostic algorithms. Xpert and MODS had similar cost-effectiveness profiles and were preferred in settings where the prevalence of TB and probability of death from untreated TB were low. As the underlying probability of TB disease and death increased, treating all children with clinically suspected disease became more cost-effective. In settings where the probability that an untreated child will die of TB-whether a result of high prevalence of TB or high mortality from untreated TB-treating all children for TB is likely to be the most cost-effective approach until better diagnostic tests can be developed. Conclusions The cost-effectiveness of diagnostic tools for TB in children depends on the population, natural history of untreated TB and existing diagnostic practices. In settings where the risk of TB death is high, empiric treatment of all children for TB should be considered until a more sensitive, low-cost diagnostic test is available.

Setting Sixty-seven government health facilities providing tuberculosis (TB) and human immunodeficiency virus (HIV) services across Ethiopia. Objective To examine clinician barriers to implementing isoniazid preventive therapy (IPT) among people living with HIV. Design A cross-sectional study to evaluate the provider-related factors associated with high IPT coverage at the facility level. Results On bivariate analysis, the odds of high IPT implementation were lower when clinicians felt patients were negatively affected by the side effects of IPT (OR 0.18, 95%CI 0.04-0.81) and perceived that IPT increased multidrug-resistant TB (MDR-TB) rates (OR 0.66, 95%CI 0.44-0.98). The presence of IPT guidelines on site (OR 2.93, 95%CI 1.10-7.77) and TB-HIV training (OR 3.08, 95%CI 1.11-8.53) had a positive relationship with high IPT uptake. In the multivariate model, clinician's perception that active TB was difficult to rule out had a negative association with a high IPT rate (OR 0.93; 95%CI 0.90-0.95). Conclusions Clinician impression that ruling out active TB among HIV patients is difficult was found to be a significant barrier to IPT uptake. Continued advancement of IPT relies greatly on improving the ability of providers to determine IPT eligibility and more confidently care for patients on IPT. Improved clinician support and training as well as development of new TB diagnostic technologies could impact IPT utilization among providers.

BackgroundThere are limited data on the treatment outcomes of adolescents living with HIV. Our objective was to compare mortality and loss to follow up (LTFU) rates between adolescent and younger age groups at enrollment in care.MethodsThis was a retrospective cohort study carried out in eight health facilities in two regions of Ethiopia. Adolescents (age 10-14 and 15-19 year) and children (age 0-9 year) enrolled in chronic HIV care between 2005 and 2013 constituted the study population. We reviewed the individual patient charts between March and June 2014 and updated the data on the status of each patient through December 2015. We used death and loss-to-follow up as primary endpoints and used the Cox-regression analysis where age, categorized as adolescent versus child, was the main predictor variable.ResultsOf 2058 participants studied, 52.1% were adolescents. The cohort contributed 2422 person-years of observation (PYO) during the pre-ART follow-up, whereas 1531 patients put on ART contributed 5984 PYO. Of those put on ART, 209 (13.7%) LTFU and 92 (6%) deaths were reported. Adolescents in age group 15-19 yr had the highest risk of LTFU [adjusted hazard ratio, aHR (95% CI) = 3.1 2.1, 5.0 ] followed by those in age group 10-14 yr (aHR = 1.5 [0.9, 2.3]) compared with children aged 0-9 yr. Mortality hazard was significantly higher among younger adolescents (aHR = 2.8 [1.4, 5.4]) and older adolescents (aHR = 2.3 [1.1, 4.9]) compared with children.ConclusionsAdolescents are at higher risk of mortality and LTFU as compared to children ages 0-9. Younger adolescents and children had similar LTFU rates. Narrow age band disaggregated analysis can serve as useful guide for tailoring interventions to the specific needs of different age groups.

Background: The purpose of this paper is to describe the establishment of the Advanced Clinical Monitoring of ART Project in Ethiopia for monitoring and evaluation of the longitudinal effectiveness of the ART program and to show the opportunities it presents. This cohort was established in response to the 2005 call by WHO for establishing additional mechanisms for stronger monitoring of ART and the need for creating the platform to generate evidence to guide the care given for the ever increasing number of patients on ART in Ethiopia.Method: A participatory and multi-stage process which started from a consensus building workshop and steered by a mother protocol as well as guiding documents which dictated the degree of engagement and expectations was followed. The primary and secondary aims of the study were agreed upon. A multi-site longitudinal observational clinical cohort was established by a consortium of stakeholders including seven Ethiopian medical schools and their affiliated referral hospitals, John Hopkins University, Ethiopian Public Health Institute, Ministry of Science and Technology, US Centers for Disease Prevention and Control - CDC-Ethiopia, and the Federal Ministry of Health. Adult and adolescent cohorts covering the age range of 14+ years) and pediatric cohorts covering those below age 14 years were the two main cohorts. During the initial recruitment of these cohorts information was extracted from existing documents for a total of 2,100 adult participants. In parallel, a prospective cohort of 1,400 adult and adolescent patients were enrolled for ART initiation and follow-up. Using similar recruitment procedures, a total of 120 children were enrolled in each of retrospective and prospective cohorts. Replacement of participants were made in subsequent years based on lost follow up and death rates to maintain adequacy of the sample to be followed-up.Achievements: Between January 2005 and August 2013 a total of 4,339 patients were followed for a median of 41.6 months and data on demographic characteristics, baseline and ongoing clinical features, hospitalization history, medication and laboratory information were collected. 39,762 aliquots and 25,515 specimens of plasma and dry-blood-spots respectively were obtained and stored longitudinally from October 2009 to August 2013. The project created a research platform for researchers, policy and decision makers. Moreover, it encouraged local and international investigators to identify and answer clinically and programmatically relevant research questions using the available data and specimens. Calls for concept notes paired with multiple trainings to stimulate investigators to conduct analyses further boosted the potential for doing research.Conclusions: A comprehensive and resourceful mechanism for scientific inquiry was established to support the national HIV/ART program. With meaningful involvement and defined roles, establishment of a study, which involved multiple institutions and investigators, was possible. Since ACM is the largest multi-site clinical cohort of patients on antiretroviral treatment in Ethiopia---which can be used for research and for improving clinical management---considering options to sustain the project is crucial. Key Words: Ethiopia, HIV clinical cohort, Antiretroviral therapy, Establishing Longitudinal Cohort Study, ART Monitoring and Evaluation

Purpose The Ethiopian Paediatric HIV Cohort (EPHIC) was established to identify clinical and laboratory predictors of virological treatment failure to ultimately develop a clinical–immunological prediction rule with area under the curve of >0.80 for detecting first-line antiretroviral therapy failure (ARTF). It will also assess the performance of the current WHO guidelines for detection of first-line ARTF in children. Participants Using a prospective cohort design, HIV-infected children and adolescents below the age of 18 years are followed every 6 months with a set of clinical and laboratory parameters at 6 hospitals in southern Ethiopia. For inclusion in the cohort, children should be on or are initiating first-line antiretroviral therapy (ART) and are not on second-line ART. Virological treatment failure is taken as the gold standard for the diagnosis of treatment failure. Findings to date From October 2015 through April 2016, 628 children have been enrolled from 6 different HIV treatment centres across southern Ethiopia. The mean age at enrolment was 11.1 years and 47.6% were girls. Many of the children (88.6%) were at WHO Clinical stage 1 at time of enrolment. At enrolment, the mean duration on first-line ART was 45 months. Substitution of ART drugs was performed to nearly half (42.6%) of the cohort. Adherence as assessed with the Visual Analogue Scale was high (mean, 94.4%; SD=11.9). The median CD4 count of the cohort at enrolment was 741 with 3.1% having a value consistent with ARTF. Future plans Regular data uploads from the 6 hospitals in southern Ethiopia enable this cohort to be followed prospectively. The cohort will be completed in September 2017. The successful completion of this study will allow for better targeting of viral-load testing to those at highest risk in resource-poor settings and provide clinicians and policymakers with a practical prediction rule. Ethics approval SNNPR Regional Health Bureau Institutional Review Board.

Background.Task-shifting mental health into general medical care requires more than brief provider training. Generalists need long-term support to master new skills and changes to work context are required to sustain change in the face of competing priorities. We examined program and context factors promoting sustainability of a mental health task-shifting training for hospital-based HIV providers in Ethiopia.Methods.Convergent mixed-methods quasi-experimental study. Sustained impact was measured by trained/not-trained provider differences in case detection and management 16 months following the end of formal support. Factors related to sustainability were examined through interviews with trained providers.Results.Extent of sustained impact: Trained providers demonstrated modest but better agreement with standardized screeners (greater sensitivity with similar specificity). They were more likely to request that patients with mental health problems return to see them v. making a referral. Factors promoting sustainability (reported in semi-structured interviews): provider belief that the treatments they had learned were effective. New interactions with on-site mental health staff were a source of ongoing learning and encouragement. Factors diminishing sustainability: providers feelings of isolation when mental health partners left for work elsewhere, failure to incorporate mental health indicators into administrative data, to re-stock staff education materials, and to build formal mechanisms for generalist-mental health staff interaction.Conclusions.An intervention seen as feasible and effective, and promotion of relationships across professional lines, helped generalists sustain new skills. Failure to address key system context issues made use of the skills unsustainable as external supports ended.

SETTING: Eight health facilities in two regions of Ethiopia OBJECTIVE: To determine TB incidence rates and associated factors among adolescents living with HIV in selected health facilities in Ethiopia. DESIGN: This was a retrospective cohort study. Adolescents enrolled in HIV care between January 2005-December 31 2013 constituted the study population. The main outcome variable was diagnosis of TB during follow up. Baseline WHO clinical stage, CD4 count, previous history of TB and the use of isoniazid preventive therapy (IPT) were main independent variables. We estimated TB incidence rates as incident cases per 100 person-years of observation (PYO). The Cox regression analysis was used to control for confounders. RESULTS: Of 1,221 adolescents screened, 1,072 eligible adolescents were studied; 60.1% were girls. TB incidence rate was 16.32 per 100 PYO during pre-antiretroviral therapy (pre-ART) follow up but declined to 2.25 per 100 PY after initiation of ART. Advanced WHO clinical stage (adjusted Hazard Ratio, aHR=2.71; 95% CI=1.69, 4.33) and CD4 count

Background Integrating mental health with general medical care can increase access to mental health services, but requires helping generalists acquire a range of unfamiliar knowledge and master potentially complex diagnostic and treatment processes.Method We describe a model for integrating complex specialty care with generalist/primary care, using as an illustration the integration of mental health into hospital-based HIV treatment services in Ethiopia. Generalists and specialists collaboratively developed mental health treatments to fit the knowledge, skills and resources of the generalists. The model recognizes commonalities between mental health and general medical care, focusing on practical interventions acceptable to patients. It was developed through a process of literature review, interviews, observing clinical practice, pilot trainings and expert consultation. Preliminary evaluation results were obtained by debriefing generalist trainees after their return to their clinical sites.Results In planning interviews, generalists reported discomfort making mental health diagnoses but recognition of symptom groups including low mood, anxiety, thought problems, poor child behaviour, seizures and substance use. Diagnostic and treatment algorithms were developed for these groups and tailored to the setting by including possible medical causes and burdens of living with HIV. First-line treatment included modalities familiar to generalists: empathetic patient–provider interactions, psychoeducation, cognitive reframing, referral to community supports and elements of symptom-specific evidence-informed counselling. Training introduced basic skills, with evolving expertise supported by job aides and ongoing support from mental health nurses cross-trained in HIV testing. Feedback from trainees suggested the programme fit well with generalists’ settings and clinical goals.Conclusions An integration model based on collaboratively developing processes that fit the generalist setting shows promise as a method for incorporating complex, multi-faceted interventions into general medical settings. Formal evaluations will be needed to compare the quality of care provided with more traditional approaches and to determine the resources required to sustain quality over time.

Background. In resource-limited settings, mothers infected with human immunodeficiency virus type 1 (HIV-1) face a difficult choice: breastfeed their infants but risk transmitting HIV-1 or not breastfeed their infants and risk the infants dying of other infectious diseases or malnutrition. Recent results from observational studies and randomized clinical trials indicate daily administration of nevirapine to the infant can prevent breast-milk HIV-1 transmission. Methods. Data from 5396 mother-infant pairs who participated in 5 randomized trials where the infant was HIV-1 negative at birth were pooled to estimate the efficacy of infant nevirapine prophylaxis to prevent breast-milk HIV-1 transmission. Four daily regimens were compared: nevirapine for 6 weeks, 14 weeks, or 28 weeks, or nevirapine plus zidovudine for 14 weeks. Results. The estimated 28-week risk of HIV-1 transmission was 5.8% (95% confidence interval [CI], 4.3%–7.9%) for the 6-week nevirapine regimen, 3.7% (95% CI, 2.5%–5.4%) for the 14-week nevirapine regimen, 4.8% (95% CI, 3.5%–6.7%) for the 14-week nevirapine plus zidovudine regimen, and 1.8% (95% CI, 1.0%–3.1%) for the 28-week nevirapine regimen (log-rank test for trend, P

HIV/AIDS has had a profound impact on children around the world since the start of the epidemic. There are currently 3.4 million children under the age of 15 years living with HIV globally, and more than 450,000 children currently receiving lifesaving antiretroviral treatment. This article describes efforts supported by the President’s Emergency Plan for AIDS Relief (PEPFAR) to expand access to treatment for children living with HIV in high-burden countries. The article also highlights a series of case studies that illustrate the impact that the PEPFAR initiative has had on the pediatric HIV epidemic. Through its support of host governments and partner organizations, the PEPFAR initiative has expanded HIV testing and treatment for pregnant women to reduce vertical transmission of HIV, increased access to early infant diagnosis for HIV-exposed infants, improved training and resources for clinicians who provide pediatric care and antiretroviral treatment, and, through public–private partnerships with pharmaceutical manufacturers, helped increase the number of medications available for the treatment of HIV-infected children in resource-limited settings.

Nevirapine resistance mutations arise commonly following single or extended-dose nevirapine (ED-NVP) prophylaxis to prevent mother-to-child transmission (PMTCT) of human immunodeficiency virus (HIV), but decay within 6–12 months of single-dose exposure. Use of ED-NVP prophylaxis in infants is expected to rise, but data on decay of nevirapine resistance mutations in infants in whom ED-NVP failed remain limited. We assessed, in Ethiopian infants participating in the Six-Week Extended Nevirapine (SWEN) Trial, the prevalence and persistence of nevirapine resistance mutations at 6 and 12 months following single-dose or up to 6 weeks of ED-NVP, and correlated their presence with the timing of infection and the type of resistance mutations. Standard population genotyping followed by high-throughput cloning were done on dried blood spot samples collected during the trial. More infants who received ED-NVP had nevirapine resistance detected by standard population genotyping (high frequencies) at age 6 months compared with those who received single-dose nevirapine (SD-NVP) (58% of 24 vs. 26% of 19, respectively; p = 0.06). Moreover, 56% of ED-NVP-exposed infants with nevirapine resistance at age 6 months still had nevirapine resistance mutations present at high frequencies at age 1 year. Infants infected before 6 weeks of age who received either SD- or ED-NVP were more likely to have Y181C or K103N; these mutations were also more likely to persist at high frequencies through 1 year of age. HIV-infected infants in whom ED-NVP prophylaxis fails are likely to experience delayed clearance of nevirapine-resistant virus in the first year of life, which in turn places them at risk for early selection of multidrug-resistant HIV after initial therapy with nonnucleoside reverse transcriptase inhibitor-based regimens.

Human immunodeficiency virus (HIV) remains a major cause of pediatric morbidity in Africa. In addition, HIV-exposed, but uninfected (HEU) infants can comprise a substantial proportion of all infants born in high prevalence countries and may also be a vulnerable group with special health problems.A total of 14,110 infants were recruited within 96 hours of birth between November 1996 and January 2000. Rates and causes of sick clinic visits and hospitalizations during infancy were investigated according to infant HIV infection group: infected-intrauterine, infected-intrapartum, postnatally-infected, HEU, and not-exposed (born to HIV-negative mother).A total of 382 infected-intrauterine, 499 infected-intrapartum, 188 postnatally-infected, 2849 HEU, and 9207 not-exposed infants were included in the analysis. Compared with not-exposed infants, HIV-infected infants made 2.8 times more all-cause sick clinic visits and required 13.3 times more hospitalizations; they had 7.2 times more clinic visits and 23.5 times more hospitalizations for lower respiratory tract infection after the neonatal period and were 159.9 times more likely to be hospitalized for malnutrition during the second half of infancy. Compared with not-exposed infants, sick clinic visits were 1.2 times more common among HEU infants, were inversely associated with maternal CD4 cell count, and were significantly higher for all HEU infants except those whose mothers had a CD4 count ≥ 800 cells/μL, which was the mean value of HIV-negative women enrolled in the trial.Morbidity is extremely high among HIV-infected infants. Compared with not-exposed infants, morbidity is higher among HEU infants and increases with severity of maternal disease, but is significantly higher for all mothers with CD4 cell count800 cells/μL.

CD4 counts increase during the postpartum period and may not correctly identify HAART-eligible HIV-positive women. HAART eligibility when defined by two CD4 cutoffs (200 and350 cells/microl) measured at two time points (within 96 h of delivery and 6 weeks) in postpartum HIV-positive women was compared. Among HIV-positive women who had CD4 at delivery and 6 weeks (n = 423), time to Stage 3 or 4 opportunistic infection or death was compared using Cox regression between three groups of women: (1) CD4200 cells/microl at delivery and 6 weeks, (2) CD4200 cells/microl at delivery butor=200 cells/microl at 6 weeks, and (3) CD4or=200 cells/microl at delivery and at 6 weeks. The analysis was repeated using the CD4350 cells/microl cut-off. CD4 counts increased by a median (IQR) of 70 (1-178) cells/microl between delivery and 6 weeks and decreased thereafter to approximately delivery levels at 12 months. Only 60% and 61% who had CD4200 cells/microl and CD4350 cells/microl, respectively, at delivery also had those levels at 6 weeks. Among those with CD4350 cells/microl at both delivery and 6 weeks, the risk of death or Stage 3 or 4 disease was 5.27 (95% CI 1.85-14.96) times higher than those with CD4350 at delivery butor=350 cells/microl at 6 weeks. The use of CD4 counts immediately postpartum to define HAART eligibility may lead to substantial misclassification.

Background Early infant diagnosis among human immunodeficiency virus (HIV)-exposed infants is a critical component of prevention of mother-to-child transmission programs. Barriers to early infant diagnosis include poor uptake, low retention at designated re-testing intervals, delayed test results, passive systems of communication, and poor linkage to treatment. This study will evaluate the HIV Infant Tracking System (HITSystem), an eHealth intervention that streamlines communication and accountability between the key early infant diagnosis stakeholders: HIV+ mothers and their HIV-exposed infants, healthcare providers, and central laboratory personnel. It is hypothesized that the HITSystem will significantly improve early infant diagnosis retention at 9 and 18 months postnatal and the timely provision of services. Methods/design Using a phased cluster-randomized controlled trial design, we will evaluate the impact of the HITSystem on eight primary benchmarks in the 18-month long cascade of care for early infant diagnosis. Study sites are six government hospitals in Kenya matched on geographic region, resource level, and patient volume. Early infant diagnosis outcomes of mother-infant dyads (n = 120 per site) at intervention hospitals (n = 3) where the HITSystem is deployed at baseline will be compared to the matched control sites providing standard care. After allowing for sufficient time for enrollment and 18-month follow-up of dyads, the HITSystem will be deployed at the control sites in the end of Year 3. Primary outcomes are retention among mother-infant dyads, initiation of antiretroviral therapy among HIV-infected infants, and the proportion of services delivered within the optimal time window indicated by national and study guidelines. Satisfaction interviews with participants and providers will inform intervention improvements. Cost-effectiveness analyses will be conducted to inform the sustainability of the HITSystem. Hypothesized outcomes include significantly higher retention throughout the 18-month early infant diagnosis process, significantly more services provided on-time at intervention sites, and a potential savings to the healthcare system. Discussion This study will evaluate the public health impact of the HITSystem to improve critical early infant diagnosis outcomes in low-resource settings. Cost-effectiveness analyses will inform the feasibility of scale-up in other settings. Trial registration ClinicalTrials.gov: NCT02072603

The importance of zinc in normal immune function - and of its deficiency in immune dysfunction - has led to increased interest in its role in nutrition and immunity in human immunodeficiency virus type 1 (HIV) infection. Zinc deficiency produces reversible immune dysfunction, particularly of T-lymphocyte cell-mediated immunity. In developing countries where zinc deficiency is prevalent, zinc supplementation has been shown to reduce morbidity from respiratory and diarrheal illnesses. The relationship between zinc and HIV infection has not been well delineated. Malabsorption, repeated concurrent infections and increased losses probably increase zinc requirements in HIV infection. In some studies, low plasma zinc levels occur frequently in HIV infection and have predicted disease progression and mortality, suggesting supplementation might be beneficial. However, the finding that zinc binding to specific HIV proteins is essential for HIV function and replication and the association in one observational study of zinc intake with higher rates of HIV progression have raised questions regarding the safety of zinc supplementation among HIV-infected individuals. To date, no randomized, placebo-controlled study of moderate zinc supplementation in HIV infection has been published. We believe that available evidence supports the need for and acceptability of such a trial.

Background: IPT with or without concomitant administration of ART is a proven intervention to prevent tuberculosis among PLHIV. However, there are few data on the routine implementation of this intervention and its effectiveness in settings with limited resources. Objectives: To measure the level of uptake and effectiveness of IPT in reducing tuberculosis incidence in a cohort of PLHIV enrolled into HIV care between 2007 and 2010 in five hospitals in southern Ethiopia. Methods: A retrospective cohort analysis of electronic patient database was done. The independent effects of no intervention, ‘‘IPT-only,’’ ‘‘IPT-before-ART,’’ ‘‘IPT-and-ART started simultaneously,’’ ‘‘ART-only,’’ and ‘‘IPT-after-ART’’ on TB incidence were measured. Cox-proportional hazards regression was used to assess association of treatment categories with TB incidence. Results: Of 7,097 patients, 867 were excluded because they were transferred-in; a further 823 (12%) were excluded from the study because they were either identified to have TB through screening (292 patients) or were on TB treatment (531). Among the remaining 5,407 patients observed, IPT had been initiated for 39% of eligible patients. Children, male sex, advanced disease, and those in Pre-ART were less likely to be initiated on IPT. The overall TB incidence was 2.6 per 100 person-years. As compared to those with no intervention, use of ‘‘IPT-only’’ (aHR=0.36, 95% CI=0.19–0.66) and ‘‘ART-only’’ (aHR=0.32, 95% CI=0.24–0.43) were associated with significant reduction in TB incidence rate. Combining ART and IPT had a more profound effect. Starting IPT-before-ART (aHR=0.18, 95% CI=0.08–0.42) or simultaneously with ART (aHR=0.20, 95% CI=0.10–0.42) provided further reduction of TB at ,80%. Conclusions: IPT was found to be effective in reducing TB incidence, independently and with concomitant ART, under programme conditions in resource-limited settings. The level of IPT provision and effectiveness in reducing TB was encouraging in the study setting. Scaling up and strengthening IPT service in addition to ART can have beneficial effect in reducing TB burden among PLHIV in settings with high TB/HIV burden.

The human p55 tumor necrosis factor (TNF) receptor (TR55) initiates at least two independent signaling cascades. The acidic sphingomyelinase (A-SMase) pathway involves a phosphatidylcholine-specific phospholipase C, an endosomal A-SMase, and controls expression of multiple TNF-responsive genes through induction of transcription factors such as NF-kappaB. The neutral sphingomyelinase (N-SMase) pathway comprises a membrane-bound N-SMase, proline-directed protein kinases, as well as phospholipase A2 and appears critical for the inflammatory responses induced by TNF. While the domain of TR55 that induces A-SMase is probably identical to the death domain, the exact location and extent of a putative N-SMase activation domain are still unknown. Structure-function analysis of TR55 deletion mutants revealed a novel region of 11 amino acids at position 309-319 that is both necessary and sufficient for activation of N-SMase. The N-SMase activation domain is distinct from the death domain and incapable of induction of A-SMase, NF-kappaB, and cytotoxicity. Taken together, our results suggest that a functionally independent region of TR55 is responsible for selectively initiating the N-SMase pathway that couples to an important inflammatory signaling cascade.

In the last part of this three-part review of parasitic infections of the central nervous system in children, we consider parasites which due to their size, distribution, or the nature of the host response, tend to cause focal lesions in the brain and spinal cord and therefore present as space-occupying lesions which occasionally mimic malignant tumors. As in Parts I and II, infections are grouped according to their predominant geographic area. Such infections include cysticercosis, one of the more common and important infections of the central nervous system. (J Child Neurol 1995; 10:177-190).

In the second segment of this three-part review of parasitic infections of the central nervous system in children, we consider parasitic infections which typically involve various tissues and organs in addition to the brain and spinal cord. Parasites capable of dissemination in immunocompetent hosts are discussed first, and, as in Part I, organisms are grouped according to their predominant geographic location. This is followed by a discussion of the unique aspects of toxoplasmosis, strongyloidiasis and infection with microsporidia in immunocompromised patients, with an emphasis on the central nervous system. (J Child Neurol 1995;10:77-87).

Khat (Catha edulis, a natural stimulant), has been used in Ethiopia for centuries. Over the past few decades, however, its use has dramatically increased, with recent research linking khat use to HIV status. Using qualitative methods, we explored the individual and micro-environmental characteristics of khat use and the social and physical contexts influencing type, acceptability and consequences of khat use. Among khat chewers attending an HIV voluntary counselling and testing centre in Addis Ababa, Ethiopia, we found that chewing typically starts at an early age (15-18 years). The majority of users are young (aged 18-35) and chew for pleasure, primarily in social settings. Over 25 types of khat, with varying effects were reported. Approximately half of the participants perceived khat to enhance sexual desire, while the rest claimed the effect on sexual desire to be the opposite. Alcohol use among chewers was high. Our findings suggest the need for culturally appropriate interventions that highlight the factors associated with khat use and the potential interplay between khat, alcohol and risky sexual behaviour.

Social networks and daily activities of children and adolescents living and/or working on the streets of a large Brazilian city were examined. Drawing on data collected through structured surveys, in-depth interviews, focus group discussions, and field observations, we described street youths' family situation, social resources, institutional experiences, survival activities, and problem behaviors and investigated differences attributable to age, gender, and living situation (at home or on the street). Youngsters who lived at home and worked on the street appeared to be experiencing orderly development despite their impoverished circumstances. Youngsters who lived on the street showed hallmarks of psychological and physical risk, including parental loss, diminished social support, substance abuse, and early onset of sexual activity. Possible implications of these contextual differences for development are discussed, and directions for future research are suggested.

Methods: From June 1989 to April 1991, 394 adolescents aged 10–18 years randomly selected upon admission at a state shelter in Belo Horizonte, Brazil underwent health history interview, physical examination, serology for HIV, hepatitis B, and syphilis, and stool examination. Participants were classified as street-based youths (n = 195) or home-based youths (n = 199). The age distribution was similar in both groups, although males were overrepresented among street-based youths (79.5% versus 62.3%). Results: Compared with home-based youths, street-based youths reported earlier onset ( p = 0.009) and higher rates of sexual activity (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.4–3.3), sexual abuse (OR, 3.7; 95% CI, 1.2–10.1), and sexually transmitted diseases (OR, 2.9; 95% CI, 1.3–6.6). Overall condom use was low in both groups. Street-based youths were 7.8 times more likely to use drugs than home-based youths (95%CI, 4.9–12.7). Inhalants and marijuana were the more commonly used drugs. Intravenous drug use was low. Conclusions: Although chronic malnutrition and multiple parasitosis were common findings in both groups, street-based youths were more likely to present disorders related to trauma and poor hygienic conditions. Antibodies to HIV were detected in four (2%) street-based youths and in none of the home-based youths. This study confirms that street youths are at higher risk for HIV infection than their home-based peers and indicates a need for HIV prevention programs targeting this population.

Monitoring HIV drug resistance is an important component of the World Health Organization's global HIV program. HIV drug resistance testing is optimal with commercially available clinically validated test kits using plasma; however, that type of testing may not be feasible or affordable in resource-constrained settings. HIV genotyping from dried blood spots (DBS) with noncommercial (in-house) assays may facilitate the capture of HIV drug resistance outcomes in resource-constrained settings but has had varying rates of success. With in-house assays for HIV reverse transcriptase, we evaluated the yield of genotyping DBS samples collected from HIV-infected children who were enrolled in two clinical trials conducted in sub-Saharan Africa (median HIV viral load, 5.88 log 10 HIV RNA copies/ml; range, 4.04 to 6.99). Overall, HIV genotypes were obtained for 94 (89.5%) of 105 samples tested (95% and 84% from clinical trials #1 and #2, respectively); however, successful analysis of 15 (16.1%) of the 94 samples required repeat testing using a different set of primers on previously synthesized cDNA. The yield of genotyping was lower on the DBS that were stored suboptimally from clinical trial #2 (56% versus 88% for optimally stored). Concordance with plasma genotypes derived using a clinically validated, commercial kit-based assay (ViroSeq HIV-1 genotyping system) was also assessed in a subset of children with paired testing. For 34 samples with paired DBS and plasma genotypes, there was 100% concordance for major drug resistance mutations. DBS genotyping using in-house assays provides an alternative for antiretroviral drug resistance testing in children in resource-constrained regions but may require region-specific optimization before widespread use.

This study evaluated the safety, tolerability, and pharmacokinetics of zidovudine administered intravenously and orally to infants born to women infected with the human immunodeficiency virus. Thirty-two symptom-free infants were enrolled before 3 months of age. The pharmacokinetics of zidovudine were evaluated in each infant after single intravenously and orally administered doses of zidovudine on consecutive days, and during long-term oral administration of the drug for 4 to 6 weeks. As new patients were enrolled, doses of zidovudine were progressively increased from 2 to 4 mg/kg. Therapy was continued for up to 12 months in 7 of the infants proved to be infected with human immunodeficiency virus. Zidovudine was generally well tolerated; 20 children (62.5%) had anemia (hemoglobin level10.0 gm/dl) during therapy and 9 (28.1%) had neutropenia (neutrophil countor = 750 cells/mm3); these hematologic abnormalities usually resolved spontaneously. The total body clearance of zidovudine increased significantly with age, from an average of 10.9 ml/min per kilogram in infantsor = 14 days of age to 19.0 ml/min per kilogram in older infants (p0.0001). Concurrently, there was a significant decrease in serum half-life from 3.12 hours in infantsor = 14 days to 1.87 hours in older infants (p = 0.0002). Oral absorption was satisfactory and bioavailability decreased significantly with age, from 89% in infantsor = 14 days to 61% in those14 days of age (p = 0.0002). Plasma concentrations of zidovudine were calculated to be in excess of 1 mumol/L (0.267 micrograms/ml) for 4.12 +/- 1.86 hours and 2.25 +/- 0.78 hours after oral doses of 2 mg/kg in infants younger than 2 weeks and 3 mg/kg in older infants, respectively. We conclude that zidovudine administered at oral doses of 2 mg/kg every 6 hours to infants aged less than 2 weeks and 3 mg/kg every 6 hours to infants older than 2 weeks resulted in plasma concentrations that are considered virustatic against human immunodeficiency virus. Zidovudine was well tolerated by infants at these doses.

As of January 1990 the World Health Organization (WHO) estimates that 8-10 million persons are infected with human immunodeficiency virus (HIV) worldwide. Approximately 3 million women mostly of reproductive age and more than 500000 infants and children are infected. Eighty percent these infected women and children reside in sub-Saharan Africa where the estimated prevalence of HIV infection is 2500/100000 women aged 15-49. In some African cities HIV prevalence rates of up to 30% have been documented. As heterosexual transmission of HIV increases other areas of the world the numbers of infected women and consequently their children also increase. In Latin America an estimated 200000 women are infected with a prevalence of 200/100000 women aged 15-49 years. There is a rapid increase in HIV infection among drug users and prostitutes in some Asian countries. In the United States women comprise 10% of the 171865 adult cases of AIDS reported to the Centers for Disease Control as of May 1 1991. In 1991 AIDS was the fifth leading cause of premature death in women aged 15-49; in New York City AIDS was the leading cause of death for women aged 20-40. The World Health Organization estimates that the HIV pandemic will kill 3 million or more women and 2.7 million children worldwide during the 1990s. AIDS will become the leading cause of death for women aged 15-49 in major cities throughout the Americas western Europe and sub-Saharan Africa with infant and child mortality rates as much as 30% greater than previously projected. In addition it is estimated that up to 5.5 million children under 15 will be orphaned because of the premature death of their HIV-infected mothers and fathers from AIDS. (excerpt)

UNICEF/WHO recommends that infants born to HIV-infected mothers who do not have access to acceptable, feasible, affordable, sustainable, and safe replacement feeding should be exclusively breastfed for at least 6 months. The aim of three trials in Ethiopia, India, and Uganda was to assess whether daily nevirapine given to breastfed infants through 6 weeks of age can decrease HIV transmission via breastfeeding.HIV-infected women breastfeeding their infants were eligible for participation. Participants were randomly assigned to receive either single-dose nevirapine (nevirapine 200 mg to women in labour and nevirapine 2 mg/kg to newborns after birth) or 6 week extended-dose nevirapine (nevirapine 200 mg to women in labour and nevirapine 2 mg/kg to newborn babies after birth plus nevirapine 5 mg daily from days 8-42 for the infant). The randomisation sequences were generated by computer at a central data coordinating centre. The primary endpoint was HIV infection at 6 months of age in infants who were HIV PCR negative at birth. Analyses were by modified intention to treat, excluding infants with missing specimens and those with indeterminate or confirmed HIV infection at birth. These studies are registered with ClinicalTrials.gov, numbers NCT00074399, NCT00061321, and NCT00639938.2024 liveborn infants randomised in the study had at least one specimen tested before 6 months of age (1047 infants in the single-dose group and 977 infants in the extended-dose group). The modified intention-to-treat population included 986 infants in the single-dose group and 901 in the extended-dose group. At 6 months, 87 children in the single-dose group and 62 in the extended-dose group were infected with HIV (relative risk 0.80, 95% CI 0.58-1.10; p=0.16). At 6 weeks of age, 54 children in the single-dose group and 25 in the extended-dose group were HIV positive (0.54, 0.34-0.85; p=0.009). 393 infants in the single-dose group and 346 in the extended-dose group experienced grade 3 or 4 serious adverse events during the study (p=0.54).Although a 6-week regimen of daily nevirapine might be associated with a reduction in the risk of HIV transmission at 6 weeks of age, the lack of a significant reduction in the primary endpoint-risk of HIV transmission at 6 months-suggests that a longer course of daily infant nevirapine to prevent HIV transmission via breast milk might be more effective where access to affordable and safe replacement feeding is not yet available and where the risks of replacement feeding are high.US National Institutes of Health; US National Institute of Allergy and Infectious Diseases; Fogarty International Center.

The major remaining challenge in the prevention of mother-to-child transmission is the reduction of the risk in settings where breast-feeding is common. This review gives an update on ongoing or planned antiretroviral intervention studies in resource-limited settings that are aimed at reducing the risk of mother-to-infant HIV transmission during lactation. These strategies include antiretroviral therapy given to the mother to reduce viral load in plasma and breast milk as well as antiretroviral regimens providing prophylaxis to uninfected infants during the period of breast-feeding. The rationale for the interventions based on animal models and human studies is described as well as the study designs of clinical trials. Potential risks and benefits of these interventions to mothers and infants are also highlighted. Laboratory studies nested within several of these trials will provide a better understanding of the pathogenesis of postnatal HIV transmission and its potential prevention using antiretroviral drugs.

Antibodies to herpes simplex virus type 2 (HSV-2), antibodies to hepatitis B virus (HBV) core antigen (anti-HBc), and VDRL antibodies (serologic evidence of syphilis) were evaluated in women known to be infected with human immunodeficiency virus type 1 (HIV-1) (n = 95) or human T lymphotropic virus type I (HTLV-I) (n = 45) and controls (n = 89). HIV-1-seropositive women were more likely than controls to have antibodies to HSV-2 (88% vs. 54%; P less than .001), anti-HBc (67% vs. 43%; P = .008), and VDRL antibodies (21% vs. 8%; P = .02). Similarly, HTLV-I-seropositive women were more likely than controls to have antibodies to HSV-2 (82% vs. 54%; P = .003) and anti-HBc (67% vs. 43%; P = .008). There was no evidence that HIV-1 or HTLV-I predisposed to chronic hepatitis B virus infection. The stronger associations between HIV-1 and HTLV-I with HSV-2 than the associations with syphilis or HBV are consistent with the hypothesis that recurrent disruptions of mucous membranes caused by HSV-2 infections predispose to sexual transmission of HIV-1 and HTLV-I.

HIV-1 persists in a latent state in resting CD4(+) T lymphocytes of infected adults despite prolonged highly active antiretroviral therapy (HAART). To determine whether a latent reservoir for HIV-1 exists in infected children, we performed a quantitative viral culture assay on highly purified resting CD4(+) T cells from 21 children with perinatally acquired infection. Replication-competent HIV-1 was recovered from all 18 children from whom sufficient cells were obtained. The frequency of latently infected resting CD4(+) T cells directly correlated with plasma virus levels, suggesting that in children with ongoing viral replication, most latently infected cells are in the labile preintegration state of latency. However, in each of 7 children who had suppression of viral replication to undetectable levels for 1-3 years on HAART, latent replication-competent HIV-1 persisted with little decay, owing to a stable reservoir of infected cells in the postintegration stage of latency. Drug-resistance mutations generated by previous nonsuppressive regimens persisted in this compartment despite more than 1 year of fully suppressive HAART, rendering untenable the idea of recycling drugs that were part of failed regimens. Thus the latent reservoir for HIV-1 in resting CD4(+) T cells will be a major obstacle to HIV-1 eradication in children.

Vitamin A supplementation has been suggested for treatment and prevention of HIV infection. However, some in vitro data indicate that vitamin A may activate HIV. Randomly, 40 HIV-seropositive women of reproductive age were allocated to receive a single oral dose of 9900 micromol (300,000 IU) vitamin A or placebo. Plasma HIV-1 RNA concentration, total lymphocytes, selected lymphocyte subsets and activation markers, and in vitro lymphocyte proliferation to phytohemagglutinin (PHA) and Candida were measured before dosing and at various time points over an 8-week follow-up period. No differences were found between treatment groups in the frequency of signs or symptoms of acute vitamin A toxicity, nor were differences evident in any lymphocyte subset or activation marker at any time during follow-up. Mean and median viral load concentration at each time point and change in viral load from baseline to each follow-up point did not differ between treatment groups. No difference was measured between treatment groups in the proportion of women who responded to PHA or Candida. This study provides no evidence that high dose vitamin A supplementation of HIV-infected women is associated with significant clinical or immunologic adverse effects.