BACKGROUND: Diagnostic autopsy has been in use for long to determine the cause of death. Since recently however 'Minimally Invasive Tissue Sampling' (MITS) is introduced to determine definitive cause of neonatal death. This study describes locally established facilitators to introduce MITS procedures to determine cause of neonatal death in Ethiopia. METHODS: Exploratory study was conducted in Butajira community where twenty-two key informants representing community opinion leaders' health care workers, five in depth interviews with parents who recently lost neonates and eight FGDs with community members were completed to generate evidences in line with the research question. Interviews and discussions were audio recorded, transcribed verbatim and analysed facilitated by open-code software. Thematic analysis was applied to identify and interpret patterns of the evidences RESULTS: In Butajira, ANC and delivery in health facilities was found to have improved over the years. Yet, child death remains an outstanding problem. While different factors were identified to cause the death of a child, relatively few participants choose to accept newborn death as a natural occurrence or will of the creator. Majority of the study participants expressed interest to know definitive cause of death using MITS. Yet, awareness about MITS and how it works was unanimously desired. It was found that husbands and wives are key to authorize MITS procedure while community opinion leaders including religious leaders were identified as key to influence parental decisions for the procedure CONCLUSION: Building awareness of the community members and engagement of opinion leaders is critical to introduce MITS.

Background: With a neonatal mortality rate of 33 per 1000 livebirths in 2021, Ethiopia is working hard to attain the SDG target of 12 deaths per 1,000 livebirths by 2030. A better understanding of the major causes of neonatal mortality is needed to effectively design and implement interventions to achieve this goal. Minimally Invasive Tissue Sampling (MITS), an alternative to conventional autopsy, requires fewer resources and through task-shifting of sample collection from pathologists to nurses, has the potential to support the expansion of pathology-based post-mortem examination and improve mortality data. This study assesses the feasibility of MITS task-shifting by evaluating the accuracy and adequacy of MITS performed by nurses compared with pathologists.Methods: Nurses in a tertiary hospital and a district hospital in Ethiopia were trained using standardized protocols for MITS sample collection. The adequacy and accuracy of the samples collected by nurses were compared against standard pre-set criteria. Both pathologists and nurses conducted MITS in the tertiary hospital and only nurses did MITS in the district hospital. Proportions of MITS with adequate samples were compared to assess comparability and statistical significance.Findings: One hundred thirty-nine MITS were done:125 in hospitals and 14 inside homes within rural communities. The accuracy and adequacy of MITS samples collected by nurses was equal to that of pathologists in the tertiary hospital and in the district hospital except for brain samples from extremely preterm deaths.Interpretation: We showed that MITS could be done by nurses accurately and with comparable precision as pathologists in neonatal deaths in primary health facilities and home-based deaths. We recommend further research on a larger scale within the health system and within demographic and health surveillance systems.Funding Information: This study was funded by grants from the Bill & Melinda Gates Foundation (INV-004160) and RTI international project number 0216178 (Opp-1180554).Declaration of Interests: The authors declare no conflicts of interest.Ethics Approval Statement: The study was approved by the research and publication committees of the Pediatrics and Child Health and the Pathology departments of Addis Ababa University College of Health Sciences. The proposal was approved by the Institutional review board of Addis Ababa university (IRB approval letter number AAUMF 03-008). Written consent was obtained from the parents or legal guardians. Consent was obtained in Amharic within 24 hours after death for both the hospital deaths as well as the home deaths.

Background Essential health and nutrition services for pregnant women, newborns, and children, particularly in low- and middle-income countries (LMICs), are disrupted by the COVID-19 pandemic. This formative research was conducted at five LMICs to understand the pandemic’s impact on barriers to and mitigation for strategies of care-seeking and managing possible serious bacterial infection (PSBI) in young infants. Methods We used a convergent parallel mixed-method design to explore the possible factors influencing PSBI management, barriers, and facilitators at three levels: 1) national and local policy, 2) the health systems, public and private facilities, and 3) community and caregivers. We ascertained trends in service provision and utilisation across pre-lockdown, lockdown, and post-lockdown periods by examining facility records and community health worker registers. Results The pandemic aggravated pre-existing challenges in the identification of young infants with PSBI; care-seeking, referral, and treatment due to several factors at the policy level (limited staff and resource reallocation), health facility level (staff quarantine, sub-optimal treatment in facilities, limited duration of service availability, lack of clear guidelines on the management of sick young infants, and inadequate supplies of protective kits and essential medicines) and at the community level (travel restrictions, lack of transportation, and fear of contracting the infection in hospitals). Care-seeking shifted to faith healers, traditional and informal private sources, or home remedies. However, caregivers were willing to admit their sick young infants to the hospital if advised by doctors. A review of facility records showed low attendance (<50%) of sick young infants in the OPD/emergencies during lockdowns in Bangladesh, India (both sites) and Pakistan, but it gradually increased as lockdowns eased. Stakeholders suggested aspirational and pragmatic mitigation strategies. Conclusions We obtained useful insights on health system preparedness during catastrophes and strategies to strengthen services and improve utilisation regarding PSBI management. The current pandemic provides an opportunity for implementing various mitigation strategies at the policy, health system, and community levels to improve preparedness.

Background: A Skin disease, which is estimated to affect between 21 and 87% of children, are the reason for up to a third of outpatient visits to pediatricians and dermatologists. It can possibly re-sult in considerable anxiety, parental worry, and embarrassment to the child and lead to loss of confidence, disruption of social relations, and feeling of stigmatization. This study aimed to assess the pattern of skin diseases in children attending at ALERT referral hospital.Methods: The study setting is ALERT referral hospital, Addis Ababa, Ethiopia. A hospital-based, retrospective, cross-sectional descriptive study was carried out between July and August 2020. All children younger than 12 years, who were diagnosed for skin diseases from May 2018 to May 2020, were included. Four hundred twenty-three children were sampled using a random sampling method. SPSS Version 20 software was used for data analysis.Results: The results showed that 385(91%) of patients had one skin disease and the remaining 38(9%) had two or more skin diseases. Fungal infections were present in30.1% of the cases fol-lowed by eczema, which accounted for 27.4%. Among fungal infections, Tinea Capitis (106/116), 91.4% followed by Tinea Corporis and Tinea Pedis were the most common in ALERT dermatology clinic. Among eczema cases, family atopic dermatitis (82/106), 77% was the most common. The result showed seasonal variation in some diseases.Conclusion: Skin fungal infections were the most common followed by eczema, pigmentary dis-order, infestation, viral infection, urticaria, bacterial infection, and others. There was some sea-sonal variation in some diseases.

BACKGROUND:WHO does not recommend community-level health workers (CLHWs) using integrated community case management (iCCM) to treat 7-59 days old infants with fast breathing with oral amoxicillin, whereas World Health Organization (WHO) integrated management of childhood illness (IMCI) recommends it. We want to collect evidence to help harmonization of both protocols. METHODS:A cluster, randomized, open-label trial will be conducted in Africa and Asia (Ethiopia, Malawi, Bangladesh and India) using a common protocol with the same study design, inclusion criteria, intervention, comparison, and outcomes to contribute to the overall sample size. This trial will also identify hypoxaemia in young infants with fast breathing. CLHWs will assess infants for fast breathing, which will be confirmed by a study supervisor. Enrolled infants in the intervention clusters will be treated with oral amoxicillin, whereas in the control clusters they will be managed as per existing iCCM protocol. An independent outcome assessor will assess all enrolled infants on days 6 and 14 of enrolment for the study outcomes in both intervention and control clusters. Primary outcome will be clinical treatment failure by day 6. This trial will obtain approval from the WHO and site institutional ethics committees. CONCLUSIONS:If the research shows that CLHWs can effectively and safely treat fast breathing pneumonia in 7-59 days old young infants, it will increase access to pneumonia treatment substantially for infants living in communities with poor access to health facilities. Additionally, this evidence will contribute towards the review of the current iCCM protocol and its harmonization with IMCI protocol. TRIAL REGISTRATION:The trial is registered at AZNCTR International Trial Registry as ACTRN12617000857303.

Aim. To determine the risk factors for death among preterm neonates. Methods and materials. The data set used was derived from a prospective, multi-center, observational clinical study conducted in 5 tertiary hospitals in Ethiopia from July, 2016 to May, 2018. Subjects were infants admitted into neonatal intensive care unit. Results. Risk factors were determined using statistical model developed for this study. The mean gestational age was 32.87 (SD ± 2.42) weeks with a range of 20 to 36 weeks. There were 2667 (70.69%) survivors and 1106 (29.31%) deaths. The significant risk factors for preterm death were low gestational age, low birth weight, being female, feeding problem, no antenatal care visits and vaginal delivery among mothers with higher educational level. Conclusions. The study identified several risk factors for death among preterm neonates. Most of the risk factors are preventable. Thus, it is important to address neonatal and maternal factors identified in this study through appropriate ANC and optimum infant medical care and feeding practices to decrease the high rate of preterm death.

Background: Preterm birth is the leading cause of neonatal deaths. Neonatal deaths account for 46% of all under-five deaths. Just over a third of neonatal deaths are a result of preterm-related causes. With the increasing contribution of neonatal deaths to overall child mortality, urgent action is needed to determine the major causes of preterm mortality.Methods: This was a multi-centre prospective observational study in 5 tertiary hospitals in Ethiopia over a period of nearly 2 years to determine the causes of preterm mortality. An independent panel of experts determined the primary and contributory causes of preterm mortality using data on socioeconomic status, maternal/obstetric history, clinical conditions, laboratory investigations and post-mortem examinations (both complete diagnostic autopsy [CDA] and minimally invasive tissue sampling [MITS]).Findings: A total of 4,919 preterm infants were enrolled in the study. Of these 3,852 were admitted to NICU's and of these 1109 died. The main causes of death were RDS (45%), sepsis, pneumonia and meningitis (30%) and asphyxia 14%. Hypothermia was the most common contributory cause of preterm mortality.Interpretation: Three conditions were the primary causes for 89% of all deaths: RDS - 45%, infections - 30 % and asphyxia - 14%. There is a need to scale up interventions against these conditions and in particular those specific to RDS such as continuous positive airway pressure (CPAP), and blended oxygen to contribute to neonatal mortality.Funding Statement: This study was funded by grants from the Bill & Melinda Gates Foundation (OPP1136965). We would like to acknowledge the support we received from the administrative, clinical, nursing, microbiology and pathology technical staff of all study hospitals.Declaration of Interests: The authors declare no conflicts of interest.Ethics Approval Statement: The study was approved by the Institutional Review Board of each hospital and at the College of Health Sciences of the Addis Ababa University. Written consent for participation in the study was obtained, with a separate written consent for autopsy and MITS, in cases of death. Consent was obtained in English, Amharic and Oromifa languages, as appropriate. Confidentially of the information was maintained.

Background: The standard 11 days IMCI (Integrated Management of Childhood Illness) training course (standard IMCI) has faced barriers such as high cost to scale up. Distance learning IMCI training program was developed as an alternative to the standard IMCI course. This article presents the evaluation results of the implementation of distance learning IMCI training program in Tanzania. Methods: From December 2012 to end of June 2015, a total of 4806 health care providers (HCP) were trained on distance learning IMCI from 1427 health facilities (HF) in 68 districts in Tanzania Clinical assessments were done at the end of each course and on follow up visits of health facilities 4 to 6 weeks after training. The results of those assessments are used to compare performance of health care providers trained in distance learning IMCI with those trained in the standard IMCI course. Statistical analysis is done by comparing proportions of those with appropriate performances using four WHO priority performance indicators as well as cost of conducting the courses in addition, the perspectives of health care providers, IMCI course facilitators, policy makers and partners were gathered using either focussed group discussions or structured questionnaires. Results: Distance learning IMCI allowed clusters of training courses to take place in parallel, allowing rapid expansion of IMCI coverage. Health care providers trained in distance learning IMCI performed equally well as those trained in the standard IMCI course in assessing Main Symptoms, treating sick children and counselling caretakers appropriately. They performed better in assessing Danger Signs. Distance learning IMCI gave a 70% reduction in cost of conducting the training courses. Conclusion: Distance learning IMCI is an alternative to scaling up IMCI as it provides an effective option with significant cost reduction in conducting training courses.

Accurate knowledge regarding cause of death (COD) for stillbirths and neonatal deaths is crucial, especially in low-income countries, in order for public health and medical officials to choose appropriate interventions likely to reduce these deaths. To date, many of the COD studies in these areas have relied only on obstetric or neonatal clinical information and the determination of COD is likely to be inaccurate. Information related to infectious COD is especially lacking. Thus, without more sophisticated testing, data as currently collected only provide a very weak approximation of the COD and may well lead to adoption of interventions of limited usefulness. In this commentary, we propose recommendations regarding the type of data needed to determine with reasonable accuracy the COD for stillbirths and neonatal deaths in low-resource settings. Using these data, and a method to determine the degree of certainty, we then propose definitions for the most common COD. Our goal is to reduce subjectivity and provide more specificity for the tests used in existing classification systems so that the methodology of COD determination is transparent and able to be replicated over time and from location to location.

Background. Skin diseases associated with Human Immunodeficiency Virus (HIV) infection are associated with significant morbidity and mortality. In resource-limited settings, nondermatologists and lay health care providers on the front line of HIV care provide much of the treatment for these conditions. Objective. To evaluate guidelines for treatment of HIV-related skin conditions and assess their accessibility, comprehensiveness, and quality of evidence employed. Methods. A review was undertaken of all national and society guidelines which included treatment information on the ten highest burden HIV-related skin conditions. The search strategy included gray and peer-reviewed literature. Results. Of 430 potential guidelines, 86 met inclusion criteria, and only 2 were written specifically to address HIV-related skin diseases as a whole. Treatment information for HIV-related skin conditions was embedded within guidelines written for other purposes, primarily HIV/AIDs treatment guidelines (49%). Development of guidelines relied either partially or completely on expert opinion (62%). Only 16% of guidelines used gradation of evidence quality and these were primarily from high-income countries (p = 0.001). Limitations. Due to the nature of gray literature, not all guidelines may have been identified. Conclusion. This review highlights the need for evidence-based summary guidelines that address treatment for HIV-related skin conditions in an accessible format.

Background. To understand regional burdens and inform delivery of health services, we conducted a systematic review and meta-analysis to evaluate the effect of antiretroviral therapy (ART) on incidence of key opportunistic infections (OIs) in human immunodeficiency virus (HIV)-infected adults in low-and middle-income countries (LMICs).Methods. Eligible studies describing the cumulative incidence of OIs and proportion on ART from 1990 to November 2013 were identified using multiple databases. Summary incident risks for the ART-naive period, and during and after the first year of ART, were calculated using random-effects meta-analyses. Summary estimates from ART subgroups were compared using meta-regression. The number of OI cases and associated costs averted if ART was initiated at a CD4 count >= 200 cells/mu L were estimated using Joint United Nations Programme on HIV/AIDS (UNAIDS) country estimates and global average OI treatment cost per case.Results. We identified 7965 citations, and included 126 studies describing 491 608 HIV-infected persons. In ART-naive patients, summary risk was highest (>5%) for oral candidiasis, tuberculosis, herpes zoster, and bacterial pneumonia. The reduction in incidence was greatest for all OIs during the first 12 months of ART (range, 57%-91%) except for tuberculosis, and was largest for oral candidiasis, Pneumocystis pneumonia, and toxoplasmosis. Earlier ART was estimated to have averted 857 828 cases in 2013 (95% confidence interval [CI], 828 032-874 853), with cost savings of $46.7 million (95% CI, $ 43.8-$49.4 million).Conclusions. There was a major reduction in risk for most OIs with ART use in LMICs, with the greatest effect seen in the first year of treatment. ART has resulted in substantial cost savings from OIs averted.

BACKGROUND:The International Maternal, Pediatric, and Adolescent Clinical Trials P1060 trial demonstrated superior outcomes for HIV-infected children less than 3 years old initiating antiretroviral therapy (ART) with lopinavir/ritonavir compared to nevirapine, but lopinavir/ritonavir is four-fold costlier.DESIGN/METHODS:We used the Cost-Effectiveness of Preventing AIDS Complications (CEPAC)-Pediatric model, with published and P1060 data, to project outcomes under three strategies: no ART; first-line nevirapine (with second-line lopinavir/ritonavir); and first-line lopinavir/ritonavir (second-line nevirapine). The base-case examined South African children initiating ART at age 12 months; sensitivity analyses varied all key model parameters. Outcomes included life expectancy, lifetime costs, and incremental cost-effectiveness ratios [ICERs; dollars/year of life saved ($/YLS)]. We considered interventions with ICERs less than 1× per-capita gross domestic product (South Africa: $7500)/YLS as 'very cost-effective,' interventions with ICERs below 3× gross domestic product/YLS as 'cost-effective,' and interventions leading to longer life expectancy and lower lifetime costs as 'cost-saving'.RESULTS:Projected life expectancy was 2.8 years with no ART. Both ART regimens markedly improved life expectancy and were very cost-effective, compared to no ART. First-line lopinavir/ritonavir led to longer life expectancy (28.8 years) and lower lifetime costs ($41 350/person, from lower second-line costs) than first-line nevirapine (27.6 years, $44 030). First-line lopinavir/ritonavir remained cost-saving or very cost-effective compared to first-line nevirapine unless: liquid lopinavir/ritonavir led to two-fold higher virologic failure rates or 15-fold greater costs than in the base-case, or second-line ART following first-line lopinavir/ritonavir was very ineffective.CONCLUSIONS:On the basis of P1060 data, first-line lopinavir/ritonavir leads to longer life expectancy and is cost-saving or very cost-effective compared to first-line nevirapine. This supports WHO guidelines, but increasing access to pediatric ART is critical regardless of the regimen used.

Background: Treatment of young HIV-infected children is challenging because of rapid disease progression, high viral loads and few drug options. This review was undertaken to update evidence on the management of young HIV-infected children and to inform the development of the 2013 WHO guidelines for antiretroviral therapy (ART) in low and middle-income countries. Design: A systematic review and meta-analysis. Methods: We identified and critically assessed randomized controlled trials that evaluated treatment strategies in perinatally HIV-infected infants and young children (aged <3 years). Results: Eight studies were included. Antiretroviral therapy (ART) initiation in asymptomatic infants led to 74% reduction in mortality or disease progression [hazard ratio 0.36, 95% confidence interval (CI) 0.18–0.74, P = 0.0002]. Regardless of previous exposure to prevention of mother to child transmission (PMTCT), treatment failure at 24 weeks was more likely in children starting nevirapine-based than in those starting lopinavir/ritonavir (lopinavir/r)-based ART (hazard ratio 1.79, 95% CI 1.33–2.41, P = 0.0001). Infants starting lopinavir/r-based ART and substituting lopinavir/r with nevirapine once virologic suppression was achieved were less likely to experience viral load more than 50 copies/ml (hazard ratio 0.62, 95% CI 0.41–0.92, P = 0.02) but more likely to have confirmed virologic failure (>1000 copies/ml) than those remaining on lopinavir/r (hazard ratio 10.19, 95% CI 2.36–43.94, P = 0.002). Children receiving induction-maintenance ART (four-drug NNRTI-based regimen for 36 weeks followed by three-drug ART) showed better short-term immunologic and virologic responses, but no long-term benefits. The only trial comparing continuous ART from infancy with interrupted ART beyond infancy was terminated early because the duration of treatment interruption was less than 3 months in most infants. Conclusion: ART initiation in asymptomatic infants reduces morbidity and mortality. Lopinavir/r-based first-line ART is superior to nevirapine-based regimens in young children, regardless of PMTCT exposure, but lopinavir/r use is challenging. Substituting lopinavir/r with nevirapine following virologic suppression may be feasible where viral load testing is available. Considering current evidence, induction-maintenance and treatment interruption strategies are not recommended. This review contributed to the evidence base for the 2013 WHO guidelines on antiretroviral therapy, which recommend that all children below 3 years start lopinavir/r-based ART and that lopinavir/r can be substituted with nevirapine once sustained virologic suppression is achieved.

Abstract Objective To investigate the clinical characteristics of children who died from diarrhoea in low- and middle-income countries, such as the duration of diarrhoea, comorbid conditions, care-seeking behaviour and oral rehydration therapy use. Methods The study included verbal autopsy data on children who died from diarrhoea between 2000 and 2012 at seven sites in Bangladesh, Ethiopia, Ghana, India, Pakistan, Uganda and the United Republic of Tanzania, respectively. Data came from demographic surveillance sites, randomized trials and an extended Demographic and Health Survey. The type of diarrhoea was classified as acute watery, acute bloody or persistent and risk factors were identified. Deaths in children aged 1 to 11 months and 1 to 4 years were analysed separately. Findings The proportion of childhood deaths due to diarrhoea varied considerably across the seven sites from less than 3% to 30%. Among children aged 1–4 years, acute watery diarrhoea accounted for 31–69% of diarrhoeal deaths, acute bloody diarrhoea for 12–28%, and persistent diarrhoea for 12–56%. Among infants aged 1–11 months, persistent diarrhoea accounted for over 30% of diarrhoeal deaths in Ethiopia, India, Pakistan, Uganda and the United Republic of Tanzania. At most sites, more than 40% of children who died from persistent diarrhoea were malnourished. Conclusion Persistent diarrhoea remains an important cause of diarrhoeal death in young children in low- and middle-income countries. Research is needed on the public health burden of persistent diarrhoea and current treatment practices to understand why children are still dying from the condition.

Introduction The 2013 'Consolidated guidelines on the use of antiretroviral (ARV) drugs for treating and preventing HIV infection' [1], released in July 2013, are the latest and most comprehensive of a series of important guidelines on antiretroviral therapy (ART) over the last decade from the World Health Organization (WHO). They were developed in response to important advances in the science and practice of HIV care since publication of the 2010 WHO guidance for adults and adolescents [2], pregnant women [3] and children [4]. This includes evolving evidence on the preventive and individual clinical benefits of earlier ART, innovations in service delivery such as the progressive decentralization of HIV testing and care, and the more widespread availability and affordability of once-daily fixed-dose combinations (FDCs) ART regimens [5]. In this special supplement of AIDS, we present a series of thirteen articles and five commentaries covering key aspects of the consolidated guidelines: the process, evidence base, recommendations and guidelines implementation. In this first article, we describe the WHO process and methodology of developing these guidelines. This is followed by seven selected systematic reviews [6–12] that provided the evidence base for specific recommendations. They are presented under the section heading of the relevant guidelines population or topic: Adults and adolescents (when to start ART) [6]; Pregnant women (safety of efavirenz in pregnant and breastfeeding women) [7]; Children (what ART regimen to use in children under 3 years) [8]; ART monitoring (how to monitor treatment response in adults and children) [9,10]; Service delivery (evaluation of effectiveness of service delivery innovations of decentralization and integration) [11]; and different strategies to improve treatment adherence [12]. The systematic reviews in each section are prefaced by commentaries written by the co-chairs and/or members of the Guideline Development Groups (GDGs) that highlight key recommendations and their rationale, and provide additional context for guidance [13–17]. The International HIV/AIDS Alliance and the Global Network of People Living with HIV (GNP+) report on the findings (and lessons learnt) from their consultation on community values and preferences that also informed many of the recommendations [18]. The three concluding articles all address different aspects of the critical phase of country-level adaptation and implementation of the guidelines. This includes what is known about the current status of national adoption of the recommendations in WHO ARV guidelines [19], projections of the global impact and cost of implementation of new recommendations [20] and country-level implications of implementing these guidelines for policy makers, such as diversification of service delivery models, generation and use of data, healthcare financing, human resource capacity and supply chains for drugs and diagnostics [21]. This supplement is not intended to be an exhaustive collation of all the evidence that informed the consolidated guidelines. Several of the commissioned systematic reviews as well as modelling studies have already been published in the peer reviewed literature or are in development [22–28], and a companion AIDS supplement published in January 2014 has already collated other modelling work that contributed to the guidelines process [29]. A comprehensive summary of all supporting evidence is provided as Web Annexes in the guidelines website (http://www.who.int/hiv/pub/guidelines/arv2013/annexes/en/index.html). Distinctive features of the 2013 WHO consolidated guidelines The 2013 consolidated guidelines were distinctive from previous WHO ART guidelines, or other international ART guidelines in several ways. Providing guidance across the entire continuum of HIV care More than fifty new recommendations are provided across the cascade of HIV care, from HIV testing and diagnosis, linkage to care, using ART for prevention, ART initiation, monitoring for treatment failure and ART toxicity, and retention in care. This comprehensive approach responds to the needs of programme managers who are responsible for delivery of care across all of these steps. Expanding guidance: clinical, operational and programmatic In addition to the usual clinical recommendations, there is operational guidance on how to improve delivery of HIV care (with recommendations on task shifting, decentralization, integration and adherence and improving retention in care). The guidelines also provide a framework and tools for programme managers to consider in prioritizing implementation of recommendations according to their national context, including HIV epidemiology, levels of ART uptake, health workforce capacity and available financial resources. This integrated approach better reflects the complex interplay between clinical recommendations and implementation at facility and programme level. Addressing all ages and populations Instead of separate ART guidelines for adults, pregnant women, adolescents and children, as in previous years, guidance is provided across all age groups and populations of adults, pregnant and breastfeeding women, adolescents, and children, as well as those coinfected with tuberculosis (TB), hepatitis B and/or hepatitis C. This enables a more harmonized approach to ART regimen choice, simplifying both the role of healthcare providers, and procurement and supply chain management. Target audience: programme managers in low-income and middle-income countries As for other WHO guidelines, the primary target users are country policy makers and programme managers responsible for national and regional policy and planning decisions on ART scale-up, and in settings with limited resources. Incorporating the key guiding principles of the public health approach and health equity in ART scale-up The 2013 guidelines, as with previous WHO ART guidance, are based on a public health approach to ART scale-up that promotes simplified and standardized approaches to treatment and monitoring that facilitates the widest possible access to high-quality care at the population level [30]. This in turn requires innovations in service delivery to maximize the efficiency of HIV programmes such as through integration of HIV care with other services (e.g. maternal and child health, TB and drug dependence), improved treatment adherence and retention in care, harmonized ART regimens and more affordable diagnostics. Another key guiding principle underpinning implementation of the guidelines is promotion of human rights and health equity in national HIV policies and programmes, so that expanded access is fair and equitable; priority for ART initiation is given to those most in need; and care is provided in a supportive and responsive environment, free of stigma and discrimination. Linking new recommendations with existing guidance New recommendations on the use of ART for treatment and prevention have been harmonized with relevant selected recommendations from existing WHO guidance on HIV testing, prevention and management of coinfections. WHO guidelines development process and the GRADE approach The revision process for the 2013 guidelines was initiated in early 2012, and conducted in accordance with procedures established by the WHO Guidelines Review Committee, to ensure that WHO guidelines are developed using a transparent, evidence-based, decision-making process [31]. Since 2008, WHO has used the internationally agreed standard of the GRADE approach (Grading of Recommendations, Assessment, Development and Evaluation) to assess the quality of a body of evidence, formulate recommendations and rate their strength [32–38] (GRADE working group: http://www.gradeworkingroup.org). Quality of evidence and strength of recommendation GRADE classifies the quality of evidence into one of four levels: high, moderate, low and very low. The rating of quality of evidence from randomized controlled trials starts as high, but may be decreased because of risk of bias, inconsistency in results across studies, indirectness of evidence, imprecision and publication bias [34–36]. The rating of evidence based on observational studies starts as low, but may be increased if the magnitude of the treatment effect is very large, there is evidence of a dose–response relationship, or if residual biases would underestimate the effect size [37]. In addition to the quality of the evidence, other considerations in formulating recommendations and rating their strength include the overall balance of benefits and harms to the individual and at a population level, community values and preferences, resource use, cost-effectiveness, feasibility and constraints to implementation in multiple settings, equity and human rights implications [38] (Table 1).Table 1: Key domains considered in formulating recommendations and determining their strength (strong or conditional).GRADE also classifies strength of recommendations as either 'strong' or 'conditional' [38]. A strong recommendation is one for which the GDG was confident that the desirable effects of the recommendation outweigh the undesirable effects, while a conditional recommendation is used when it is concluded that the desirable effects probably outweigh the undesirable effects, but there is uncertainty about these trade-offs. The higher the quality of evidence, the more likely a strong recommendation can be made. A conditional recommendation is more likely when high-quality evidence is absent, the estimates of effect are imprecise, there is uncertainty or variability in how individuals value the outcomes, or the benefits are either small or not considered worth the costs. The implications of a conditional recommendation are that, although most people or settings would adopt the recommendation, some would do so only under certain conditions. The following sources of evidence and supporting material were used to inform the development of the new recommendations. Systematic reviews Systematic reviews were commissioned on forty-six topics across the continuum of HIV care, including nine on when to start ART; eleven on what ART to start; four on monitoring the response to ART; six on monitoring toxicity; and eleven on operational aspects of service delivery. The questions were framed using the Population, Intervention, Comparison and Outcome (PICO) format [33], and outsourced to seven different research teams and organizations through a process of competitive tendering. These groups then developed search protocols and conducted reviews of the available scientific evidence. A standardized GRADE evidence table was used to present quantitative summaries of the evidence and assessment of its quality for each PICO question by outcome [32]. The full list of review questions, search protocols, GRADE tables and evidence summaries for each topic are available at http://www.who.int/hiv/pub/guidelines/arv2013/annexes/en/index.html. Seven systematic reviews are included in this supplement [6–12], and others have been published elsewhere [22–28], or are in development. Consultations on community values and preferences An assessment of community values and preferences on key ARV guideline topics was coordinated by the International HIV/AIDS Alliance and the Global Network of People Living with HIV (GNP+) through both an online e-survey (n = 1088), and moderated e-forum discussions with civil society networks (n = 955) [18,39] in six languages (Arabic, Chinese, English, French, Russian and Spanish). Key topics included community preferences regarding possible recommendations (e.g. which ART regimens to use and when to initiate ART for adults, adolescents, pregnant and breastfeeding women, and children), as well as ART service delivery considerations. Four focus group discussions were also held in Uganda and Malawi on the experiences of pregnant women with lifelong ART (option B+). Finally, two e-surveys of health workers caring for HIV-infected adults (n = 98) and children (n = 342) were undertaken on similar topics covered in the community consultation through clinical networks of eight global implementing partner organizations. In addition to the report in this supplement [18], a full consultation document is available [39]. Mathematical modelling of impact and cost effectiveness We commissioned two key modelling projects on health impact (measured using disability-adjusted-life-years (DALYs)) and cost-effectiveness from the HIV Modelling Consortium (http://www.hivmodelling.org) to support the 2013 guidelines. The first examined various HIV testing strategies and criteria for ART initiation in different populations (adults, pregnant women and HIV serodiscordant couples) on the basis of data from countries representative of different HIV epidemic types (generalized, concentrated and mixed) and level of ART coverage [26]. A second project examined different strategies for monitoring treatment response (clinical, CD4+ T-cell count and viral load) and switching to second-line ART [27]. A key strength of these analyses was their use of multiple independently developed models to compare different scenarios, for which there were limited data in the literature. Additional modelling work commissioned included a causal modelling analysis of the impact of starting ART at different ages in children, based on data from the IeDEA South African collaboration [28]. A recent article has highlighted some of the challenges in using modelling data in guidelines development, including the lack of standardized criteria for rating the quality of modelling, and clarity on the positioning of modelling within the GRADE framework for decision-making [40]. It concludes with some key considerations to guide the future use of modelling in guidelines development. Feasibility surveys Reports were commissioned on country implementation experiences, including adoption of lifelong ART in pregnant and breastfeeding women (option B+) in Malawi; introducing tenofovir (TDF) in first-line ART regimens in Zambia; phasing out stavudine (d4T) in Zimbabwe; and scaling up viral load monitoring in Médecins Sans Frontières programmes in southern Africa. These are summarized in the consolidated guidelines web annexes (http://www.who.int/hiv/pub/guidelines/arv2013/annexes/en/index.html). Impact assessment of implementation of recommendations An impact assessment was undertaken using the AIDS Impact Model (AIM) and Goals model within the Spectrum modelling system [41] to estimate the number of adults and children newly eligible for ART, based on the new treatment recommendations [20]. It also examined the cost and impact that would result if ART coverage expanded to 80% of those eligible for ART. End-user survey to inform guidelines presentation and dissemination strategies An additional preparatory activity was the conduct of an internet-based survey of country-level end-users of recent WHO HIV-related guidelines. This was undertaken to understand better how WHO ART guidelines are used, and identify areas for improvement in format, presentation and dissemination of the new guidelines. The survey targeted WHO National Program Officers and Ministry of Health HIV focal persons, and was administered in English, French, Russian and Spanish between June and September 2012. Overall, there were 78 respondents from 44 countries across all regions (28% South East Asia and Western Pacific, 26% from Central and Eastern Europe, 10% Latin America and Caribbean, 28% Sub-Saharan Africa, 8% Middle East). All respondents had used at least one of twelve WHO HIV guidelines, and the majority (75%) had used them primarily in the development of national guidelines. Although the response rate was limited, and not fully representative of all end-users, there was a good geographic spread of respondents, and several consistent observations emerged. There was a broad agreement that the most critical guideline components were clearly stated recommendations with brief evidence summaries and a clear rationale supporting the recommendation (with inclusion of GRADE tables only as part of web annexes). The value of best practice examples from a wide range of different settings to support implementation was also highlighted. Specific suggestions to enhance readability included reduced length, larger font size, and greater use of colour, summary tables and algorithms. Accessibility and user engagement in dissemination of new WHO HIV guidelines were highlighted as critical factors influencing effective country-level adaptation and implementation. Specific activities to facilitate regional and country-level dissemination of the guidelines activities were in-country workshops and webinars; the availability of guidelines in all UN languages, particularly Arabic, Chinese and Russian; the continued need for printed in addition to electronic versions of the guidelines; and an improved notification system for new guidelines using e-mail together with conference and website announcements. Guideline development groups (GDGs) and process of formulating recommendations The development of recommendations was undertaken by four separate, external technical GDGs: Adult; Maternal and Child Health; Operational and Service Delivery; and Programmatic, but managed as a unified process to ensure an integrated guidelines document for adults, pregnant and breastfeeding women and children. There were more than 112 GDG members across the four groups, comprising HIV clinicians, researchers, country HIV programme managers, guideline methodologists, partners from United Nations or other development agencies, and nominated representatives of civil society and/or networks of people living with HIV (selected on the basis of four criteria: technical knowledge, constituency and regional representation, previous experience with guidelines development). We ensured a balance of representation by region and sex. All external members of the GDGs and external peer review group completed WHO declaration of interest forms that included participation in consulting and advisory panels, research support and financial investment. There was also a further declaration at the GDG meeting of major roles by members within completed, ongoing or planned clinical trials on either the timing of ART, or evaluation of specific ART regimens. Overall, the WHO secretariat and cochairs of each GDG were satisfied that there had been a transparent declaration of interests, and that no case necessitated exclusion from the discussions. Four face-to-face GDG meetings were held in Geneva, Switzerland, between November 2012 and January 2013. The decision-making process and formulation of recommendations involved first a critical review of the evidence based mainly on systematic reviews of randomized clinical trials and, where appropriate, observational studies. It also considered of the overall balance of benefits and harms to the individual and at a population level, community values and health worker preferences, resource use, cost-effectiveness, feasibility and constraints to implementation in multiple settings, and issues of equity and human rights. The GDGs discussed both the proposed wording of the recommendations and the rating of its strength (strong or conditional). All decisions were reached by discussion and consensus on the recommendations, including their strength and, if appropriate, the conditions to be attached to the recommendations. Disagreements were resolved through e-mail discussions, teleconferences and redrafting recommendations and rationale. Early drafts of sections of the guidelines were circulated to GDG members, and a full draft of the guidelines was circulated to GDG members and peer reviewers for comment. A core coordinating group meeting including cochairs of the four GDGs was held in February 2013 to ensure coherence and consistency of recommendations across the guidelines. Key recommendations: strength of recommendations and quality of evidence In July 2013, the guidelines were launched at the International AIDS Society conference held in Kuala Lumpur, Malaysia, and subsequently disseminated as a printed and electronic version, including a shorter policy brief in seven languages (Arabic, Chinese, English, French, Portuguese, Russian, Spanish), with an additional web version, that includes user-friendly navigation and all supporting documentation and evidence as annexes. There were a total of 56 new recommendations in the 2013 WHO 'Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection' [1]: twenty-four were recommendations focused on adults (including pregnant women), and eighteen on children; ten were on service delivery and four on HIV testing. The most important new clinical recommendations were earlier ART initiation, starting ART in all adults with a CD4+ T-cell count of 500 cells/mm3 or less (but prioritizing those with advanced clinical disease or a CD4+ count less than 350 cells/mm3); ART initiation regardless of CD4+ cell count in pregnant and breastfeeding women, children under 5 years of age, HIV-infected partners in serodiscordant couples and those coinfected with TB, or severe hepatitis B infection; a preferred first-line ART regimen of TDF + lamivudine or emtricitabine + efavirenz (EVF) as a once-daily fixed-dose combination for adults, pregnant women and children aged 3 years and older; and the use of viral load testing as the preferred approach to monitoring ART response and diagnosing treatment failure. There were four recommendations on expansion of community-level testing, and also ten recommendations on improving the efficiency of HIV services, through decentralizing ART delivery to primary healthcare and community levels, integrating ART services within antenatal, child health and other services, task-shifting to address gaps in health staff capacity; and strategies to improve retention in care, and adherence to ART. Table 2 summarizes the strength of recommendation and quality of evidence for all recommendations, and then according to population and topic. Forty-five of the 56 recommendations (83%) were ranked as strong, and based respectively on high [two (4.4%)]; moderate [22 (48.9%)]; low [16 (35.6%)] or very low [5 (11.1%)] quality of evidence. The remaining 11 recommendations (19.6%) were conditional, of which 63.6% were based on low and 36.4% on very low quality evidence. Some trends were apparent according to population and topic. All of the fourteen service delivery and HIV testing recommendations were categorized as strong, compared with 79% of the twenty-four adult and 66.7% of the eighteen paediatric recommendations. While all fourteen strong service delivery/testing recommendations were based on low or very low quality evidence, this was 50% for the twelve strong paediatric recommendations, and only 25% of the twenty-four strong recommendations in adults. The weaker evidence base in paediatric HIV care and for service delivery interventions is well recognised, and these were identified as priority areas for operational and implementation research during the guidelines process. More importantly, there are key challenges in ensuring consistent adherence to the GRADE guidance on appropriate rating of recommendations as strong rather than conditional. There is also a need to address a perception and concern among some guideline group members that a conditional recommendation may not be taken seriously and adopted by countries. Where strong recommendations are made based on low quality evidence, it is critical that a clear rationale is provided. A recent evaluation of 456 recommendations from forty-three different WHO guidelines that had used the GRADE approach also observed that strong recommendations based on low or very low quality evidence were frequently made (55.2% of 290 strong recommendations) [42], so this phenomenon is not specific to HIV care guidelines.Table 2: Summary of strength of recommendations and rating of quality of evidence of 56 recommendations in 2013 consolidated guidelines.Guidelines dissemination and next steps Following the release of the guidelines, WHO headquarters and regional offices have worked with national ministries of health and in-country stakeholders to support national evaluation and adaptation through a series of regional dissemination workshops (Yogjakarta, Indonesia; Bejiing, China; Casablanca, Morocco; Pretoria, South Africa; Accra, Ghana; Buenos Aires, Argentina; and Istanbul, Turkey) held between July and November 2013. The consolidated guidelines will be comprehensively reviewed and updated every two years as new evidence emerges and practice evolves in the use of ART. In addition, there will be regular updates through technical and programmatic supplementary guidance, with one in early 2014 (technical updates on early infant diagnosis, scale-up of viral load monitoring and drug toxicity monitoring) and another in July 2014 (guidance on management of important co-infections, including Cryptococcus, HIV-related oral and skin conditions, hepatitis C, use of cotrimoxazole prophylaxis, linkage and retention in care, and community ART delivery). An Implementation science meeting was held with key partners in February 2014, and involved mapping of key research gaps in the 2013 consolidated guidelines and the research agenda to inform development of future ART-related guidance. WHO will also release consolidated guidelines in 2014 in two other areas: Key populations; and Strategic Information, which will provide a minimum set of quality indicators for HIV prevention and treatment programmes. Acknowledgements The authors acknowledge the excellent contributions of all members of the Guidelines Development Group (GDG), and in particular the cochairs of the four GDGs: Adult: Serge Eholie (ANEPA/Treichville Hospital, Abidjan, Côte d'Ivoire) and Stefano Vella (Istituto Superiore di Sanità, Italy); Maternal and Child Health: Elaine Abrams (International Center for AIDS Care and Treatment Programs, Mailman School of Public Health, Columbia University, USA) and Denis Tindyebwa (African Network for the Care of Children Affected by AIDS, Uganda); Operational and Service Delivery: Kevin De Cock (United States Centers for Disease Control and Prevention, USA) and Yogan Pillay (National Department of Health, South Africa); Programmatic: Adeeba Kamarulzaman (University of Malaya, Malaysia) and Tsitsi Apollo (Ministry of Health and Child Welfare, Zimbabwe). The WHO facilitators of the GDGs were: Marco Vitoria (Adults); Nathan Shaffer and Lulu Muhe (Maternal and Child Health); Eyrusalem Negussie (Operational); and Jos Perriens (Programmatic). We also thank Jonathan Edwin and Tunga Namjilsuren for assistance with the conduct of the WHO guidelines end-user survey. Conflicts of interest There are no conflicts of interest.

Objective: Although antiretroviral treatment (ART) has reduced the incidence of HIV-related opportunistic infections among children living with HIV, access to ART remains limited for children, especially in resource-limited settings. This paper reviews current knowledge on the contribution of opportunistic infections and common childhood illnesses to morbidity and mortality in children living with HIV, highlights interventions known to improve the health of children, and identifies research gaps for further exploration. Design and Methods: Literature review of peer-reviewed articles and abstracts combined with expert opinion and operational experience. Results: Morbidity and mortality due to opportunistic infections has decreased in both developed and resource-limited countries. However, the burden of HIV-related infections remains high, especially in sub-Saharan Africa, where the majority of HIV-infected children live. Limitations in diagnostic capacity in resource-limited settings have resulted in a relative paucity of data on opportunistic infections in children. Additionally, the reliance on clinical diagnosis means that opportunistic infections are often confused with common childhood illnesseswhich also contribute to excess morbidity and mortality in these children. Although several preventive interventions have been shown to decrease opportunistic infection-related mortality, implementation of many of these interventions remains inconsistent. Conclusions: In order to reduce opportunistic infection-related mortality, early ART must be expanded, training for front-line clinicians must be improved, and additional research is needed to improve screening and diagnostic algorithms.

Michael Schomaker and colleagues estimate the mortality associated with starting ART at different CD4 thresholds among children aged 2–5 years using observational data collected in cohort studies in Southern Africa. Please see later in the article for the Editors' Summary