Using viral sequence diversity to estimate time of HIV infection in infants.

Age at HIV acquisition may influence viral pathogenesis in infants, and yet infection timing (i.e. date of infection) is not always known. Adult studies have estimated infection timing using rates of HIV RNA diversification, however, it is unknown whether adult-trained models can provide accurate predictions when used for infants due to possible differences in viral dynamics. While rates of viral diversification have been well defined for adults, there are limited data characterizing these dynamics for infants. Here, we performed Illumina sequencing of gag and pol using longitudinal plasma samples from 22 Kenyan infants with well-characterized infection timing. We used these data to characterize viral diversity changes over time by designing an infant-trained Bayesian hierarchical regression model that predicts time since infection using viral diversity. We show that diversity accumulates with time for most infants (median rate within pol = 0.00079 diversity/month), and diversity accumulates much faster than in adults (compare previously-reported adult rate within pol = 0.00024 diversity/month [1]). We find that the infant rate of viral diversification varies by individual, gene region, and relative timing of infection, but not by set-point viral load or rate of CD4+ T cell decline. We compare the predictive performance of this infant-trained Bayesian hierarchical regression model with simple linear regression models trained using the same infant data, as well as existing adult-trained models [1]. Using an independent dataset from an additional 15 infants with frequent HIV testing to define infection timing, we demonstrate that infant-trained models more accurately estimate time since infection than existing adult-trained models. This work will be useful for timing HIV acquisition for infants with unknown infection timing and for refining our understanding of how viral diversity accumulates in infants, both of which may have broad implications for the future development of infant-specific therapeutic and preventive interventions.

Evidence-based service delivery interventions for testing, linking, treating, and retaining children and adolescents living with HIV in primary health care settings: Protocol for a systematic review.

BACKGROUND: At the end of 2019, there were about 2.8 million children and adolescents aged 0-19 living with HIV. In contrast to pregnant women and adults, service delivery for children and adolescents living with HIV continues to lag behind with regard to access to care, components of care delivery, treatment options, and clinical and immunologic outcomes. AIM: The aim of this systematic review is to synthesize the evidence on the most effective interventions, models, programs, and strategies to optimize the delivery of services for the testing, linkage, treatment and retention of children and adolescents living with HIV globally. METHODS: This review protocol is registered at PROSPERO with Registration number: CRD42020209553. The systematic review will be conducted in accordance with the Preferred Reporting Items for Systematic Review and Meta-analysis Protocols (PRISMA-P). We will use a comprehensive search strategy to search several bibliographic databases including MEDLINE, Embase, CINAHL, Cochrane Library, Global Health, and Psycinfo to identify relevant studies published in the last ten years (2010 to 2020). In addition, we will review cited and citing references of included studies. A pair of reviewers will independently screen titles, abstracts and full texts of articles, extract data from articles meeting inclusion criteria and perform quality assessments of the evidence collected. We will conduct a narrative synthesis of our findings, and if there are sufficient clinically similar studies available, we will conduct meta-analysis using a random-effects model. DISCUSSION: This review will provide evidence on service delivery models that have been evaluated in a range of settings to efficiently and effectively locate, link, treat and retain in care, children and adolescents living with HIV. The synthesized evidence will help guide national governments and health care providers in prioritizing and adopting evidence-based service delivery approaches for children and adolescents living with HIV. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020209553.

Eliminating mother-to-child transmission of human immunodeficiency virus, syphilis and hepatitis B in sub-Saharan Africa.

Triple elimination is an initiative supporting the elimination of mother-to-child transmission of three diseases - human immunodeficiency virus (HIV) infection, syphilis and hepatitis B. Significant progress towards triple elimination has been made in some regions, but progress has been slow in sub-Saharan Africa, the region with the highest burden of these diseases. The shared features of the three diseases, including their epidemiology, disease interactions and core interventions for tackling them, enable an integrated health-systems approach for elimination of mother-to-child transmission. Current barriers to triple elimination in sub-Saharan Africa include a lack of policies, strategies and resources to support the uptake of well established preventive and treatment interventions. While much can be achieved with existing tools, the development of new products and models of care, as well as a prioritized research agenda, are needed to accelerate progress on triple elimination in sub-Saharan Africa. In this paper we aim to show that health systems working together with communities in sub-Saharan Africa could deliver rapid and sustainable results towards the elimination of mother-to-child transmission of all three diseases. However, stronger political support, expansion of evidence-based interventions and better use of funding streams are needed to improve efficiency and build on the successes in prevention of mother-to-child transmission of HIV. Triple elimination is a strategic opportunity to reduce the morbidity and mortality from HIV infection, syphilis and hepatitis B for mothers and their infants within the context of universal health coverage.

La triple élimination est une initiative visant à soutenir l'éradication de la transmission mère-enfant de trois maladies ­ l'infection au virus de l'immunodéficience humaine (VIH), la syphilis et l'hépatite B. Bien que des avancées considérables aient été observées en ce sens dans certaines régions, les progrès demeurent lents en Afrique subsaharienne, pourtant durement touchée par ces maladies. Les caractéristiques communes aux trois affections, notamment leur épidémiologie, les interactions entre elles et les principales interventions nécessaires à leur prise en charge permettent aux systèmes de santé d'adopter une approche intégrée pour éviter la transmission mère-enfant. Plusieurs obstacles entravent actuellement la triple élimination en Afrique subsaharienne, parmi lesquels l'absence de politiques, de stratégies et de ressources pour garantir la disponibilité de traitements préventifs et curatifs bien établis. Les outils existants offrent déjà de nombreuses solutions; mais pour accélérer la progression de cette triple élimination en Afrique subsaharienne, il est indispensable de développer de nouveaux produits et modèles de soins, ainsi qu'un programme de recherche prioritaire. Dans le présent document, nous voulons montrer que si les systèmes de santé collaborent avec les communautés en Afrique subsaharienne, ils pourront obtenir des résultats rapides et durables en vue d'éradiquer la transmission mère-enfant des trois maladies susmentionnées. Néanmoins, une telle démarche implique un soutien politique massif, l'expansion des interventions fondées sur des données scientifiques, et une meilleure utilisation des sources de financement afin d'améliorer l'efficacité et de s'appuyer sur les réussites en matière de prévention de la transmission du VIH de la mère à l'enfant. La triple élimination représente une occasion stratégique de réduire la morbidité et la mortalité liées à l'infection au VIH, à la syphilis et à l'hépatite B, tant chez les mères que chez les nourrissons, dans un contexte de couverture maladie universelle.

La triple eliminación es una iniciativa que apoya la eliminación de la transmisión maternoinfantil de tres enfermedades: la infección por el virus de la inmunodeficiencia humana (VIH), la sífilis y la hepatitis B. En algunas regiones se han logrado avances significativos hacia la triple eliminación, pero los progresos se han desarrollado con mayor lentitud en el África subsahariana, la región con la mayor carga de estas enfermedades. Las características comunes de las tres enfermedades, como su epidemiología, las interacciones entre ellas y las intervenciones básicas para combatirlas, permiten un enfoque integrado de los sistemas de salud para la eliminación de la transmisión maternoinfantil. Los obstáculos actuales para la triple eliminación en el África subsahariana incluyen la falta de políticas, estrategias y recursos para apoyar la adopción de intervenciones preventivas y de tratamiento bien establecidas. Aunque se puede lograr mucho con las herramientas existentes, se necesita el desarrollo de nuevos productos y modelos de atención, así como una agenda de investigación prioritaria, para acelerar el progreso de la triple eliminación en el África subsahariana. En este documento pretendemos demostrar que los sistemas de salud que trabajan conjuntamente con las comunidades del África subsahariana podrían obtener resultados rápidos y sostenibles hacia la eliminación de la transmisión maternoinfantil de las tres enfermedades. Sin embargo, se necesita un mayor apoyo político, la ampliación de las intervenciones basadas en la evidencia y un mejor uso de los flujos de financiación para mejorar la eficiencia y aprovechar los éxitos en la prevención de la transmisión maternoinfantil del VIH. La triple eliminación es una oportunidad estratégica para reducir la morbilidad y la mortalidad de la infección por el VIH, la sífilis y la hepatitis B para las madres y sus hijos en el contexto de la cobertura sanitaria universal.

Breast Milk Virome and Bacterial Microbiome Resilience in Kenyan Women Living with HIV.

Breast milk is nutritionally and immunologically beneficial in early life but is also a potential source of infection. Little is known about breast milk microbiota of women living with HIV (WLHIV), the impact of severe immunosuppression, and the contribution to mortality of HIV-exposed infants. Here, we performed metagenomic sequencing to characterize the bacterial microbiome and DNA virome of breast milk samples at 1 month postpartum from Kenyan WLHIV who were not receiving combination antiretroviral therapy (cART), 23 women with CD4 counts of <250 and 30 women with CD4 of >500; and additionally, 19 WLHIV with infants that lived and 26 WLHIV with infants that died during the first 2 years of life were included. We found that breast milk bacterial microbiomes in this study population were highly diverse but shared a core community composed of the Streptococcaceae, Staphylococcaceae, Moraxellaceae, and Eubacteriaceae families. The breast milk virome was dominated by human cytomegalovirus (CMV) and included the bacteriophage families Myoviridae, Siphoviridae, and Podoviridae Bacterial microbiome and virome profiles and diversity were not significantly altered by HIV immunosuppression, as defined by a CD4 of <250. CMV viral load was not associated with maternal CD4 counts or infant mortality. In conclusion, we show that the core bacterial and viral communities are resilient in breast milk despite immunosuppression in WLHIV.IMPORTANCE Breastfeeding plays an important role in seeding the infant gut microbiome and mammary health. Although most studies focus on the diverse breast milk bacterial communities, little is known about the viral communities harbored in breast milk. We performed the first breast milk virome study of an HIV population. In this study cohort of Kenyan women living with HIV from the pre-antiretroviral therapy era, we found that breast milk harbors a core bacterial microbiome and a virome dominated by human cytomegalovirus. The virome and bacterial microbiome were not substantially altered by immunosuppression or associated with infant mortality. Together, these findings indicate resilience of the microbial community in breast milk compartmentalization. These findings advance out fundamental understanding of the breast milk core microbiome and virome interactions in the context of HIV disease.

Women's Autonomy in Infant Feeding Decision-Making: A Qualitative Study in Nairobi, Kenya.

BACKGROUND: Exclusive breastfeeding (EBF) is the optimal way to feed young infants. Guidelines recommend that women living with HIV on antiretroviral therapy should EBF for 6 months and continue breastfeeding for up to 24 months or longer. Parents may face social or logistical barriers creating challenges to EBF. OBJECTIVES: To explore barriers, facilitators and community norms influencing EBF practices in Kenya. METHODS: This qualitative research was nested within a longitudinal study of intensive maternal counseling to increase EBF among HIV-positive mothers. HIV-negative and HIV-positive mothers were recruited from four public clinics in Nairobi. Women participated in focus group discussions (FGDs) that explored beliefs about and experiences with infant feeding. Conventional content analysis was used to describe and compare barriers and facilitators influencing HIV-positive and HIV-negative women's EBF experiences. RESULTS: We conducted 17 FGDs with 80 HIV-positive and 53 HIV-negative women between 2009 and 2012. Overall, women agreed that breastmilk is good for infants. However, early mixed feeding was a common cultural practice. HIV-positive women perceived that infant feeding methods and durations were their decision. In contrast, HIV-negative women reported less autonomy and more mixed feeding, citing peer pressure and lack of HIV transmission concerns. Autonomy in decision-making was facilitated by receiving EBF counseling and family support, especially from male partners. Low milk production was a barrier to EBF, regardless of HIV status, and perceived to represent poor maternal nutrition. CONCLUSIONS: Despite challenges, counseling empowered women living with HIV to advocate for EBF with spouses and family.

Accelerating progress towards the elimination of mother-to-child transmission of HIV: a narrative review.

INTRODUCTION: Findings from biomedical, behavioural and implementation studies provide a rich foundation to guide programmatic efforts for the prevention of mother-to-child HIV transmission (PMTCT). METHODS: We summarized the current evidence base to support policy makers, programme managers, funding agencies and other stakeholders in designing and optimizing PMTCT programmes. We searched the scientific literature for PMTCT interventions in the era of universal antiretroviral therapy for pregnant and breastfeeding women (i.e. 2013 onward). Where evidence was sparse, relevant studies from the general HIV treatment literature or from prior eras of PMTCT programme implementation were also considered. Studies were organized into six categories: HIV prevention services for women, timely access to HIV testing, timely access to ART, programme retention and adherence support, timely engagement in antenatal care and services for infants at highest risk of HIV acquisition. These were mapped to specific missed opportunities identified by the UNAIDS Spectrum model and embedded in UNICEF operational guidance to optimize PMTCT services. RESULTS AND DISCUSSION: From May to November 2019, we identified numerous promising, evidence-based strategies that, properly tailored and adopted, could contribute to population reductions in vertical HIV transmission. These spanned the HIV and maternal and child health literature, emphasizing the importance of continued alignment and integration of services. We observed overlap between several intervention domains, suggesting potential for synergies and increased downstream impact. Common themes included integration of facility-based healthcare; decentralization of health services from facilities to communities; and engagement of partners, peers and lay workers for social support. Approaches to ensure early HIV diagnosis and treatment prior to pregnancy would strengthen care across the maternal lifespan and should be promoted in the context of PMTCT. CONCLUSIONS: A wide range of effective strategies exist to improve PMTCT access, uptake and retention. Programmes should carefully consider, prioritize and plan those that are most appropriate for the local setting and best address existing gaps in PMTCT health services.

Examining the relationship between diarrhea and linear growth in Kenyan HIV-exposed, uninfected infants.

BACKGROUND: Diarrhea in infancy can compromise linear growth and this relationship is likely influenced by diarrhea severity, number of episodes, and the timing of those episodes. HIV exposed, uninfected infants (HEU) have higher risk of growth faltering, infectious morbidity and mortality than HIV-unexposed infants and may be representative of children particularly vulnerable to diarrhea-associated linear growth faltering. METHODOLOGY/PRINCIPAL FINDINGS: We utilized data from a cohort of Kenyan HEU infants followed from birth to 12 months of age. Infant length and morbidity were ascertained at monthly study visits and sick visits. Longitudinal models estimated the association between diarrhea severity and length-for-age Z-score (LAZ) in the following month, at 12 months of age, and in 6-month intervals. The 372 enrolled infants experienced an average of 2.15 episodes (range: 0-8) of diarrhea and 0.54 episodes (0-4) of moderate-to-severe diarrhea (MSD) between birth and 12 months. Surviving infants had a mean LAZ of -0.97 (standard deviation: 1.2) at 12 months. MSD was significantly associated with an average loss of 0.14 (95% Confidence Interval [CI]: -0.24, -0.05, p = 0.003) in LAZ one month after the episode. Linear growth outcomes were not predicted by cumulative episodes of diarrhea, or timing of diarrhea during infancy. CONCLUSIONS/SIGNIFICANCE: Diarrhea severity influenced the relationship between diarrhea and subsequent linear growth. HEU infants with MSD may benefit from nutritional interventions following severe diarrhea to protect against linear growth faltering.

Maternal Diarrhea and Antibiotic Use are Associated with Increased Risk of Diarrhea among HIV-Exposed, Uninfected Infants in Kenya.

HIV-exposed, uninfected (HEU) children are a growing population at particularly high risk of infection-related death in whom preventing diarrhea may significantly reduce under-5 morbidity and mortality in sub-Saharan Africa. A historic cohort (1999-2002) of Kenyan HEU infants followed from birth to 12 months was used. Maternal and infant morbidity were ascertained at monthly clinic visits and unscheduled sick visits. The Andersen-Gill Cox model was used to assess maternal, environmental, and infant correlates of diarrhea, moderate-to-severe diarrhea (MSD; diarrhea with dehydration, dysentery, or related hospital admission), and prolonged/persistent diarrhea (> 7 days) in infants. HIV-exposed, uninfected infants (n = 373) experienced a mean 2.09 (95% CI: 1.93, 2.25) episodes of diarrhea, 0.47 (95% CI: 0.40, 0.55) episodes of MSD, and 0.34 (95% CI: 0.29, 0.42) episodes of prolonged/persistent diarrhea in their first year. Postpartum maternal diarrhea was associated with increased risk of infant diarrhea (Hazard ratio [HR]: 2.09; 95% CI: 1.43, 3.06) and MSD (HR: 2.89; 95% CI: 1.10, 7.59). Maternal antibiotic use was a risk factor for prolonged/persistent diarrhea (HR: 1.63; 95% CI: 1.04, 2.55). Infants living in households with a pit latrine were 1.44 (95% CI: 1.19, 1.74) and 1.49 (95% CI: 1.04, 2.14) times more likely to experience diarrhea and MSD, respectively, relative to those with a flush toilet. Current exclusive breastfeeding was protective against MSD (HR: 0.30; 95% CI: 0.15, 0.58) relative to infants receiving no breast milk. Reductions in maternal diarrhea may result in substantial reductions in diarrhea morbidity among HEU children, in addition to standard diarrhea prevention interventions.

Mycoplasma genitalium infection among HIV-infected pregnant African women and implications for mother-to-child transmission of HIV.

OBJECTIVE: Many sexually transmitted infections increase risk of mother-to-child transmission (MTCT) of HIV, but the effect of Mycoplasma genitalium is not known. We hypothesized that M. genitalium infection would be common among HIV-infected pregnant women and could be associated with in-utero and intrapartum MTCT. DESIGN: Observational case-cohort study. METHODS: The current study used specimens from a Kenyan perinatal MTCT cohort (1999-2005) involving HIV-infected women and their infants, who received short-course zidovudine for prevention of MTCT. Vaginal swabs collected at 32 weeks gestation were tested for M. genitalium using a transcription-mediated amplification assay. Infant perinatal HIV infection was determined at birth and 4 weeks of age by DNA PCR. Using a case-cohort design, a random sample was generated with 3 : 1 control : case ratio; prevalence and correlates of M. genitalium were assessed with chi-squared and t tests; predictors of infant outcomes were analyzed using logistic regression. RESULTS: Among 220 HIV-infected pregnant women evaluated, 47 women (21.4%) had M. genitalium. Antenatal M. genitalium infection was associated with higher HIV RNA in plasma (5.0 vs. 4.6 log10 copies/ml in M. genitalium-positive vs. M. genitalium-negative women, P = 0.02) at 32 weeks. Women with M. genitalium were less likely to report prior sexually transmitted infections and genital ulcers (both P = 0.05). There was no association found between exposure to M. genitalium and perinatal MTCT (odds ratio = 0.72, 95% confidence interval 0.35, 1.51, P = 0.39). CONCLUSION: Vaginal M. genitalium infection was frequently detected among Kenyan HIV-infected pregnant women and was associated with higher plasma HIV levels, but was not associated with perinatal transmission of HIV.

Birth size and early pneumonia predict linear growth among HIV-exposed uninfected infants.

Stunting remains a global health priority, particularly in sub-Saharan Africa. Identifying determinants of linear growth in HIV-exposed uninfected (HEU) infants can inform interventions to prevent stunting in this vulnerable population. HIV-infected mothers and their uninfected infants were followed monthly from pregnancy to 12-month post-partum in Nairobi, Kenya. Mixed-effects models estimated the change in length-for-age z-score (LAZ) from birth to 12 months by environmental, maternal, and infant characteristics. Multivariable models included factors univariately associated with LAZ. Among 372 HEU infants, mean LAZ decreased from -0.54 (95% confidence interval [CI] [-0.67, -0.41]) to -1.09 (95% CI [-1.23, -0.96]) between 0 and 12 months. Declines in LAZ were associated with crowding (≥2 persons per room; adjusted difference [AD] in 0-12 month change: -0.46; 95% CI [-0.87, -0.05]), use of a pit latrine versus a flush toilet (AD: -0.29; 95% CI [-0.57, -0.02]), and early infant pneumonia (AD: -1.14; 95% CI [-1.99, -0.29]). Infants with low birthweight (<2,500 g; AD: 1.08; 95% CI [0.40, 1.76]) and birth stunting (AD: 1.11; 95% CI [0.45, 1.78]) experienced improved linear growth. By 12 months of age, 46 infants were stunted, of whom 11 (24%) were stunted at birth. Of the 34 infants stunted at birth with an available 12-month LAZ, 68% were not stunted at 12 months. Some low birthweight and birth-stunted HEU infants had significant linear growth recovery. Early infant pneumonia and household environment predicted poor linear growth and may identify a subgroup of HEU infants for whom to provide growth-promoting interventions.

Higher Transplacental Pathogen-Specific Antibody Transfer Among Pregnant Women Randomized to Triple Antiretroviral Treatment Versus Short Course Zidovudine.

BACKGROUND: HIV-1 infection may impair transplacental antibody transfer to infants. The impact of highly active antiretroviral treatment (ART) given during pregnancy on transplacental antibody transport is unknown. METHODS: HIV-1 infected pregnant women with CD4 counts between 200 - 500 were randomized to short-course zidovudine (ZDV) or triple ART at 32 weeks gestation for prevention of mother-to-child HIV-1 transmission. Levels of maternal antibody against measles, pneumococcus and rotavirus at delivery, and antibody transfer to the baby through cord blood, were compared between trial arms. RESULTS: Overall, 141 and 148 women were randomized to triple ART and ZDV, respectively; cord blood was available for a subset (n = 20 in triple ART and n = 22 in ZDV). Maternal antibody levels to all pathogens during pregnancy and at delivery were not significantly different between arms. Within each arm, antibody levels at delivery were lower than at enrolment. For all antibodies, a woman's levels before delivery were an important predictor of amount transferred to her infant. Women on triple ART transferred higher levels of pathogen-specific antibodies when compared with women on short course ZDV. CONCLUSIONS: Women on triple ART transferred higher levels of pathogen-specific antibodies compared with women on ZDV alone.

Lessons Learned From Option B+ in the Evolution Toward "Test and Start" From Malawi, Cameroon, and the United Republic of Tanzania.

The acceleration of prevention of mother-to-child transmission (PMTCT) activities, coupled with the rollout of 2010 World Health Organization (WHO) guidelines, led to important discussions and innovations at global and country levels. One paradigm-shifting innovation was Option B+ in Malawi. It was later included in WHO guidelines and eventually adopted by all 22 Global Plan priority countries. This article presents Malawi's experience with designing and implementing Option B+ and provides complementary narratives from Cameroon and Tanzania. Malawi's HIV program started in 2002, but by 2009, the PMTCT program was lagging far behind the antiretroviral therapy (ART) program because of numerous health system challenges. When WHO recommended Option A and Option B for PMTCT in 2010, it was clear that Malawi's HIV program would not be able to successfully implement either option without increasing existing barriers to PMTCT services and potentially decreasing women's access to care. Subsequent stakeholder discussions led to the development of Option B+. Operationalizing Option B+ required several critical considerations, including the complete integration of ART and PMTCT programs, systematic reduction of barriers to facilitate doubling the number of ART sites in less than a year, building consensus with stakeholders, and securing additional resources for the new program. During the planning and implementation process, several lessons were learned which are considerations for countries transitioning to "treat-all": Comprehensive change requires effective government leadership and coordination; national clinical guidelines must accommodate health system limitations; ART services and commodities should be decentralized within facilities; the general public should be well informed about major changes in the national HIV program; and patients should be educated on clinic processes to improve program monitoring.

Pediatric Treatment Scale-Up: The Unfinished Agenda of the Global Plan.

Five million children have died of AIDS-related causes since the beginning of the epidemic. In 2011, the Global Plan Towards the Elimination of New HIV Infections Among Children by 2015 and Keeping Their Mothers Alive (Global Plan) created the political environment to catalyze both the resources and commitment to end pediatric AIDS. Implementation and scale-up have encountered substantial hurdles, however, which have resulted in slow progress. Reasons include a lack of emphasis on testing outside of prevention of mother-to-child transmission services, an overall lack of integration and coordination with other services, a lack of training among providers, low confidence in caring for children living with HIV, and a lack of appropriate formulations for pediatric antiretrovirals. During the Global Plan period, we have learned that simplification is essential to successful decentralization, integration, and task shifting of services; that innovations require careful planning; and that the family is an important unit for delivering HIV care and treatment services. The post-Global Plan phase presents a number of noteworthy challenges that all stakeholders, national programs, and communities must tackle to guarantee universal treatment for children living with HIV. Accelerated action is essential in ensuring that HIV diagnosis and linkage to treatment happen as quickly and effectively as possible. As fewer infants are infected because of effective prevention of mother-to-child transmission interventions and the population of children living with HIV will age into adolescence adapting service delivery models to the epidemic context, and engaging the community will be critical to finding new efficiencies and allowing us to realize a true HIV-free generation-and to end AIDS by 2030.

Viral Evolution and Cytotoxic T Cell Restricted Selection in Acute Infant HIV-1 Infection.

Antiretroviral therapy-naive HIV-1 infected infants experience poor viral containment and rapid disease progression compared to adults. Viral factors (e.g. transmitted cytotoxic T- lymphocyte (CTL) escape mutations) or infant factors (e.g. reduced CTL functional capacity) may explain this observation. We assessed CTL functionality by analysing selection in CTL-targeted HIV-1 epitopes following perinatal infection. HIV-1 gag, pol and nef sequences were generated from a historical repository of longitudinal specimens from 19 vertically infected infants. Evolutionary rate and selection were estimated for each gene and in CTL-restricted and non-restricted epitopes. Evolutionary rate was higher in nef and gag vs. pol, and lower in infants with non-severe immunosuppression vs. severe immunosuppression across gag and nef. Selection pressure was stronger in infants with non-severe immunosuppression vs. severe immunosuppression across gag. The analysis also showed that infants with non-severe immunosuppression had stronger selection in CTL-restricted vs. non-restricted epitopes in gag and nef. Evidence of stronger CTL selection was absent in infants with severe immunosuppression. These data indicate that infant CTLs can exert selection pressure on gag and nef epitopes in early infection and that stronger selection across CTL epitopes is associated with favourable clinical outcomes. These results have implications for the development of paediatric HIV-1 vaccines.

Co-trimoxazole prophylaxis in adults, including pregnant women, with HIV: a systematic review and meta-analysis.

INTRODUCTION: Co-trimoxazole prophylaxis is used to reduce morbidity and mortality in people with HIV. We systematically reviewed three topics related to co-trimoxazole prophylaxis to update WHO guidelines: initiation, discontinuation, and dose. METHODS: We searched PubMed, Embase, WHO Global Index Medicus, and clinical trial registries in November, 2013, for randomised controlled trials and observational studies including co-trimoxazole prophylaxis and a comparator group. Studies were eligible if they reported death, WHO clinical stage 3 or 4 events, admittance to hospital, severe bacterial infections, tuberculosis, pneumonia, diarrhoea, malaria, or treatment-limiting adverse events. Infant mortality, low birthweight, and placental malaria were additional outcomes for the comparison of co-trimoxazole prophylaxis and intermittent preventive treatment for malaria in pregnant women (IPTp). We compared a dose of 480 mg co-trimoxazole once a day with one of 960 mg co-trimoxazole once a day. We used a 10% margin for non-inferiority and equivalence analyses. We used random-effects models for all meta-analyses. This study is registered with PROSPERO, number CRD42014007163. FINDINGS: 19 articles, published from 1995 to 2014 and including 35 328 participants, met the inclusion criteria. Co-trimoxazole prophylaxis reduced rates of death (hazard ratio [HR] 0·40, 95% CI 0·26-0·64) when started at CD4 counts of 350 cells per µL or lower with antiretroviral therapy (ART) worldwide. Co-trimoxazole prophylaxis started at higher than 350 cells per µL without ART reduced rates of death (0·50, 0·30-0·83) and malaria (0·25, 0·10-0·57) in Africa. Co-trimoxazole prophylaxis was non-inferior to IPTp with respect to infant mortality (risk difference [RD] -0·05, 95% CI -0·12 to 0·02), low birthweight (0·00, -0·07 to 0·07), and placental malaria (0·00, -0·10 to 0·10). Co-trimoxazole prophylaxis continuation after ART-induced recovery with CD4 counts higher than 350 cells per µL reduced admittances to hospital (HR 0·42, 95% CI 0·22-0·80), pneumonia (0·73, 0·61-0·88), malaria (0·03, 0·01-0·10), and diarrhoea (0·61, 0·48-0·78) in Africa. A dose of 480 mg co-trimoxazole prophylaxis once a day did not reduce treatment-limiting adverse events compared with 960 mg once a day (RD -0·07, 95% CI -0·52 to 0·39). INTERPRETATION: Co-trimoxazole prophylaxis should be given with ART in people with CD4 counts of 350 cells per µL or lower in low-income and middle-income countries. Co-trimoxazole prophylaxis should be provided irrespective of CD4 count in settings with a high burden of infectious diseases. Pregnant women with HIV in Africa should use co-trimoxazole rather than IPTp to prevent malaria complications in infants. Further research is needed to inform dose optimisation and co-trimoxazole use in the context of expanded ART in different epidemiological settings. FUNDING: None.

Explaining the uptake of paediatric guidelines in a Kenyan tertiary hospital--mixed methods research.

BACKGROUND: Evidence-based standards for management of the seriously sick child have existed for decades, yet their translation in clinical practice is a challenge. The context and organization of institutions are known determinants of successful translation, however, research using adequate methodologies to explain the dynamic nature of these determinants in the quality-of-care improvement process is rarely performed. METHODS: We conducted mixed methods research in a tertiary hospital in a low-income country to explore the uptake of locally adapted paediatric guidelines. The quantitative component was an uncontrolled before and after intervention study that included an exploration of the intervention dose-effect relationship. The qualitative component was an ethnographic research based on the theoretical perspective of participatory action research. Interpretive integration was employed to derive meta-inferences that provided a more complete picture of the overall study results that reflect the complexity and the multifaceted ontology of the phenomenon studied. RESULTS: The improvement in health workers' performance in relation to the intensity of the intervention was not linear and was characterized by improved and occasionally declining performance. Possible root causes of this performance variability included challenges in keeping knowledge and clinical skills updated, inadequate commitment of the staff to continued improvement, limited exposure to positive professional role models, poor teamwork, failure to maintain professional integrity and mal-adaptation to institutional pressures. CONCLUSION: Implementation of best-practices is a complex process that is largely unpredictable, attributed to the complexity of contextual factors operating predominantly at professional and organizational levels. There is no simple solution to implementation of best-practices. Tackling root causes of inadequate knowledge translation in this tertiary care setting will require long-term planning, with emphasis on promotion of professional ethics and values and establishing an organizational framework that enhances positive aspects of professionalism. This study has significant implications for the quality of training in medical institutions and the development of hospital leadership.

Factors influencing performance of health workers in the management of seriously sick children at a Kenyan tertiary hospital--participatory action research.

BACKGROUND: Implementation of World Health Organization case management guidelines for serious childhood illnesses remains a challenge in hospitals in low-income countries. Facilitators of and barriers to implementation of locally adapted clinical practice guidelines (CPGs) have not been explored. METHODS: This ethnographic study based on the theory of participatory action research (PAR) was conducted in Kenyatta National Hospital, Kenya's largest teaching hospital. The primary intervention consisted of dissemination of locally adapted CPGs. The PRECEDE-PROCEED health education model was used as the conceptual framework to guide and examine further reinforcement activities to improve the uptake of the CPGs. Activities focussed on introduction of routine clinical audits and tailored educational sessions. Data were collected by a participant observer who also facilitated the PAR over an eighteen-month period. Naturalistic inquiry was utilized to obtain information from all hospital staff encountered while theoretical sampling allowed in-depth exploration of emerging issues. Data were analysed using interpretive description. RESULTS: Relevance of the CPGs to routine work and emergence of a champion of change facilitated uptake of best-practices. Mobilization of basic resources was relatively easily undertaken while activities that required real intellectual and professional engagement of the senior staff were a challenge. Accomplishments of the PAR were largely with the passive rather than active involvement of the hospital management. Barriers to implementation of best-practices included i) mismatch between the hospital's vision and reality, ii) poor communication, iii) lack of objective mechanisms for monitoring and evaluating quality of clinical care, iv) limited capacity for planning strategic change, v) limited management skills to introduce and manage change, vi) hierarchical relationships, and vii) inadequate adaptation of the interventions to the local context. CONCLUSIONS: Educational interventions, often regarded as 'quick-fixes' to improve care in low-income countries, may be necessary but are unlikely to be sufficient to deliver improved services. We propose that an understanding of organizational issues that influence the behaviour of individual health professionals should guide and inform the implementation of best-practices.

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

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