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IntroductionDespite significant gains in access to early infant diagnosis (EID) over the past decade, most HIV‐exposed infants still do not get tested for HIV in the first two months of life. For those who are tested, the long turnaround time between when the sample is drawn and when the results are returned leads to a high rate of loss to follow‐up, which in turn means that few infected infants start antiretroviral treatment. Consequently, there continues to be high mortality from perinatally acquired HIV, and the ambitious goals of 90% of infected children identified, 90% of identified children treated and 90% of treated children with sustained virologic suppression by 2020 seem far beyond our reach. The objective of this commentary is to review recent advances in the field of HIV diagnosis in infants and describe how these advances may overcome long‐standing barriers to access to testing and treatment.DiscussionSeveral innovative approaches to EID have recently been described. These include point‐of‐care testing, use of SMS printers to connect the central laboratory and the health facility through a mobile phone network, expanding paediatric testing to other entry points where children access the health system and testing HIV‐exposed infants at birth as a rapid way to identify in utero infection. Each of these interventions is discussed here, together with the opportunities and challenges associated with scale‐up. Point‐of‐care testing has the potential to provide immediate results but is less cost‐effective in settings where test volumes are low. Virological testing at birth has been piloted in some countries to identify those infants who need urgent treatment, but a negative test at birth does not obviate the need for additional testing at six weeks. Routine testing of infants in child health settings is a useful strategy to identify exposed and infected children whose mothers were not enrolled in programmes for the prevention of mother‐to‐child transmission. Facility‐based SMS printers speed up the return of laboratory results and may be of value for other testing services apart from HIV infant diagnosis.ConclusionsNew tools and strategies for HIV infant diagnosis could have a significant positive impact on the identification and retention of HIV‐infected infants. In order to be most effective, national programmes should carefully consider which ideas to implement and how best to integrate novel strategies into existing systems. There is no single solution that will work everywhere. Rather, a number of approaches need to be considered and should be linked in order to achieve the greatest impact on the continuum of care from testing to treatment.

AbstractIntroductionViral load testing is essential to manage HIV disease, especially in infants and children. Early infant diagnosis (EID) is performed using nucleic‐acid testing in children under 18 months. Resource‐limited health systems face severe challenges to scale‐up both viral load and EID to unprecedented levels. Streamlining laboratory systems would be beneficial to improve access to quality testing and to increase efficiency of antiretroviral treatment programmes. We evaluated the performance of viral load testing to serve as an EID assay in children younger than 18 months.MethodsThis study was an observational, prospective study, including children between one and 18 months of age who were born to HIV‐positive mothers in 134 health facilities in Maputo City and Maputo Province, Mozambique. Dried blood spot specimens from heel or toe pricks were collected between January and April 2018, processed using SPEX buffer for both assays, and tested for routine EID and viral load testing using the Roche CAP/CTM HIV‐1 Qualitative v2 and Roche CAP/CTM HIV‐1 Quantitative v2 assays respectively. The sensitivity, specificity and positive and negative predictive values were estimated using the EID results as the reference standard.ResultsA total of 1021 infants were included in the study, of which 47% were female. Over 95% of mothers and children were on antiretroviral treatment or received antiretroviral prophylaxis respectively. The sensitivity and specificity of using the viral load assay to detect infection were 100% (95% CI: 96.2 to 100%) and 99.9% (95% CI: 99.4 to 100%). The positive and negative predictive values were 99.0% (95% CI: 94.3 to 100%) and 100% (95% CI: 99.6 to 100%). The McNemar's test was 1.000 and Cohen's kappa was 0.994.ConclusionsThe comparable performance suggests that viral load assays can be used as an infant diagnostic assay. Infants with either low levels of viraemia or high cycle threshold values should be repeat tested to ensure the result is truly positive prior to treatment initiation, regardless of assay used. Viral load assays could replace traditional EID testing, substantially streamlining molecular laboratory services for children and lowering costs, with the additional advantage of providing baseline viral load results for antiretroviral treatment management.

AbstractIntroductionThe scale‐up of effective HIV viral load (VL) testing is an urgent public health priority. Implementation of testing is supported by the availability of accurate, nucleic acid based laboratory and point‐of‐care (POC) VL technologies and strong WHO guidance recommending routine testing to identify treatment failure. However, test implementation faces challenges related to the developing health systems in many low‐resource countries. The purpose of this commentary is to review the challenges and solutions from the large‐scale implementation of other diagnostic tests, namely nucleic‐acid based early infant HIV diagnosis (EID) and CD4 testing, and identify key lessons to inform the scale‐up of VL.DiscussionExperience with EID and CD4 testing provides many key lessons to inform VL implementation and may enable more effective and rapid scale‐up. The primary lessons from earlier implementation efforts are to strengthen linkage to clinical care after testing, and to improve the efficiency of testing. Opportunities to improve linkage include data systems to support the follow‐up of patients through the cascade of care and test delivery, rapid sample referral networks, and POC tests. Opportunities to increase testing efficiency include improvements to procurement and supply chain practices, well connected tiered laboratory networks with rational deployment of test capacity across different levels of health services, routine resource mapping and mobilization to ensure adequate resources for testing programs, and improved operational and quality management of testing services. If applied to VL testing programs, these approaches could help improve the impact of VL on ART failure management and patient outcomes, reduce overall costs and help ensure the sustainable access to reduced pricing for test commodities, as well as improve supportive health systems such as efficient, and more rigorous quality assurance. These lessons draw from traditional laboratory practices as well as fields such as logistics, operations management and business.ConclusionsThe lessons and innovations from large‐scale EID and CD4 programs described here can be adapted to inform more effective scale‐up approaches for VL. They demonstrate that an integrated approach to health system strengthening focusing on key levers for test access such as data systems, supply efficiencies and network management. They also highlight the challenges with implementation and the need for more innovative approaches and effective partnerships to achieve equitable and cost‐effective test access.

AbstractGlobally, 150,000 new paediatric human immunodeficiency virus type 1 (HIV‐1) infections occurred in 2015. There remain complex challenges to the global elimination of paediatric HIV‐1 infection. Thus, for the global community to achieve elimination of new paediatric HIV‐1 infections, innovative approaches need to be explored. Immune‐based approaches to prevention of mother‐to‐child transmission (MTCT) may help fill some of the remaining gaps and provide new opportunities to achieve an AIDS‐free generation. Immune‐based interventions to prevent MTCT of HIV‐1 may include paediatric HIV vaccines and passive immunization approaches. Recent discoveries providing evidence of robust immune responses to HIV in infants open new and exciting prospects for paediatric HIV vaccines. Moreover, successful vaccination of infants has a different set of requirements than vaccination of adults and may be easier to achieve. Proof‐of‐concept has been established over the last two decades that passively administered HIV‐1 Env‐specific monoclonal antibody (mAbs) can prevent chimeric simian human immunodeficiency virus (SHIV) transmission to newborn nonhuman primates. There has been tremendous progress in isolating and characterizing broadly neutralizing antibodies to HIV, and clinical testing of these antibodies for treatment and prevention in both infants and adults is a major effort in the field. Immune‐based interventions need to be actively explored as they can provide critically important tools to address persistent challenges in MTCT prevention. It is a pivotal time for the field with active discussions on the best strategy to further reduce HIV infection of infants and accomplish the World Health Organization Fast‐Track 2030 goals to eliminate new paediatric HIV infections.

IntroductionAcute infection with HIV in the postpartum period results in a high risk of vertical transmission through breastfeeding. A study was done to determine the HIV incidence rate and associated risk factors among postpartum women in Southern Mozambique, where HIV prevalence among pregnant women is 21%.MethodsA prospective cohort study was conducted in six rural health facilities in Gaza and Maputo provinces from March 2008 to July 2011. A total of 1221 women who were HIV‐negative on testing at delivery or within two months postpartum were recruited and followed until 18 months postpartum. HIV testing, collection of dried blood spot samples and administration of a structured questionnaire to women were performed every three months. Infant testing by DNA‐PCR was done as soon as possible after identification of a new infection in women. HIV incidence was estimated, and potential risk factors at baseline were compared using Poisson regression.ResultsData from 957 women were analyzed with follow‐up after the enrolment visit, with a median follow‐up of 18.2 months. The HIV incidence in postpartum women is estimated at 3.20/100 women‐years (95% CI: 2.30–4.46), with the highest rate among 18‐ to 19‐year‐olds (4.92 per 100 women‐years; 95% CI: 2.65–9.15). Of the new infections, 14 (34%) were identified during the first six months postpartum, 11 (27%) between 6 and 12 months and 16 (39%) between 12 and 18 months postpartum. Risk factors for incident HIV infection include young age, low number of children, higher education level of the woman's partner and having had sex with someone other than one's partner. The vertical transmission was 21% (95% CI: 5–36) among newly infected women.ConclusionsIncidence of HIV is high among breastfeeding women in Southern Mozambique, contributing to increasing numbers of HIV‐infected infants. Comprehensive primary prevention strategies targeting women of reproductive age, particularly pregnant and postpartum women and their partners, will be crucial for the elimination of paediatric AIDS in Africa.

Cara Lynn Kim,1 Ligia Maria Cruz Espinoza,1 Kirsten S Vannice,2 Birkneh Tilahun Tadesse,1,3,4 Ellis Owusu-Dabo,5 Raphaël Rakotozandrindrainy,6 Ilesh V Jani,7 Mekonnen Teferi,8 Abdramane Bassiahi Soura,9 Octavie Lunguya,10,11 A Duncan Steele,2 Florian Marks1,6,12,13 1International Vaccine Institute, Seoul, Republic of Korea; 2Enteric and Diarrheal Diseases, Bill & Melinda Gates Foundation, Seattle, WA, USA; 3Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden; 4Center for Innovative Drug Development and Therapeutic Trials for Africa, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia; 5School of Public Health, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana; 6University of Antananarivo, Antananarivo, Madagascar; 7Instituto Nacional de Saúde (INS), Maputo Province, Mozambique; 8Armauer Hansen Research Institute, Addis Ababa, Ethiopia; 9Institut Supérieur des Sciences de la Population, Université Joseph Ki-Zerbo de Ouagadougou, Ouagadougou, Burkina Faso; 10Department of Microbiology, Institut National de Recherche Biomédicale, Kinshasa, Democratic Republic of the Congo; 11Department of Medical Biology, University Teaching Hospital of Kinshasa, Kinshasa, Democratic Republic of the Congo; 12Cambridge Institute of Therapeutic Immunology and Infectious Disease, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, UK; 13Heidelberg Institute of Global Health, University of Heidelberg, Heidelberg, GermanyCorrespondence: Florian Marks, Tel +82-2-881-1133, Email fmarks@ivi.intAbstract: While typhoid fever has largely been eliminated in high-income regions which have developed modern water, sanitation, and hygiene facilities, it remains a significant public health burden resulting in morbidity and mortality among millions of individuals in resource-constrained settings. Prevention and control efforts are needed that integrate several high-impact interventions targeting facilities and infrastructure, including those addressing improvements in sanitation, access to safe water, and planned urbanization, together with parallel efforts directed at effective strategies for use of typhoid conjugate vaccines (TCV). The use of TCVs is a critical tool with the potential of having a rapid impact on typhoid fever disease burden; their introduction will also serve as an important strategy to combat evolving antimicrobial resistance to currently available typhoid fever treatments. Well-designed epidemiological surveillance studies play a critical role in establishing the need for, and monitoring the impact of, typhoid fever control and prevention strategies implemented by public health authorities. Here, we present a perspective based on a narrative review of the impact of typhoid fever on morbidity and mortality in sub-Saharan Africa and discuss ongoing surveillance activities and the role of vaccination in prevention and control efforts.Keywords: typhoid, burden, mortality, sub-Saharan Africa, conjugate-vaccine, antimicrobial resistance

OBJECTIVES: The success of National Public Health Institutes (NPHIs) in low-income and middle-income countries (LMICs) is critical to countries' ability to deliver public health services to their populations and effectively respond to public health emergencies. However, empirical data are limited on factors that promote or are barriers to the sustainability of NPHIs. This evaluation explored stakeholders' perceptions about enabling factors and barriers to the success and sustainability of NPHIs in seven countries where the U.S. Centers for Disease Control and Prevention (CDC) has supported NPHI development and strengthening. DESIGN: Qualitative study. SETTING: Cambodia, Colombia, Liberia, Mozambique, Nigeria, Rwanda and Zambia. PARTICIPANTS: NPHI staff, non-NPHI government staff, and non-governmental and international organisation staff. METHODS: We conducted semistructured, in-person interviews at a location chosen by the participants in the seven countries. We analysed data using a directed content analysis approach. RESULTS: We interviewed 43 NPHI staff, 29 non-NPHI government staff and 24 staff from non-governmental and international organisations. Participants identified five enabling factors critical to the success and sustainability of NPHIs: (1) strong leadership, (2) financial autonomy, (3) political commitment and country ownership, (4) strengthening capacity of NPHI staff and (5) forming strategic partnerships. Three themes emerged related to major barriers or threats to the sustainability of NPHIs: (1) reliance on partner funding to maintain key activities, (2) changes in NPHI leadership and (3) staff attrition and turnover. CONCLUSIONS: Our findings contribute to the scant literature on sustainability of NPHIs in LMICs by identifying essential components of sustainability and types of support needed from various stakeholders. Integrating these components into each step of NPHI development and ensuring sufficient support will be critical to strengthening public health systems and safeguarding their ...

This work was supported by the European and Developing Countries Clinical Trials Partnership (EDCTP), [SP.2011.41304.008] and PreDiCT-TB consortium R [IMI Joint undertaking grant agreement number 115337], resources of which are composed of financial contribution from the European Union's Seventh Framework Programme [FP7/2007-2013] and EFPIA companies' in-kind contribution. ; In this comparative biomarker study, we analysed 1768 serial sputum samples from 178 patients at 4 sites in Southeast Africa. We show that tuberculosis Molecular Bacterial Load Assay (TB-MBLA) reduces time-to-TB-bacillary-load-result from days/weeks by culture to hours and detects early patient treatment response. By day 14 of treatment, 5% of patients had cleared bacillary load to zero, rising to 58% by 12th week of treatment. Fall in bacillary load correlated with mycobacterial growth indicator tube culture time-to-positivity (Spearmans r=−0.51, 95% CI (−0.56 to −0.46), p<0.0001). Patients with high pretreatment bacillary burdens (above the cohort bacillary load average of 5.5log10eCFU/ml) were less likely to convert-to-negative by 8th week of treatment than those with a low burden (below cohort bacillary load average), p=0.0005, HR 3.1, 95% CI (1.6 to 5.6) irrespective of treatment regimen. TB-MBLA distinguished the bactericidal effect of regimens revealing the moxifloxacin—20 mg rifampicin regimen produced a shorter time to bacillary clearance compared with standard-of-care regimen, p=0.008, HR 2.9, 95% CI (1.3 to 6.7). Our data show that the TB-MBLA could inform clinical decision making in real-time and expedite drug TB clinical trials. ; Publisher PDF ; Peer reviewed

AbstractIntroductionAs prevalence of undiagnosed HIV declines, it is unclear whether testing programmes will be cost‐effective. To guide their HIV testing programmes, countries require appropriate metrics that can be measured. The cost‐per‐diagnosis is potentially a useful metric.MethodsWe simulated a series of setting‐scenarios for adult HIV epidemics and ART programmes typical of settings in southern Africa using an individual‐based model and projected forward from 2018 under two policies: (i) a minimum package of "core" testing (i.e. testing in pregnant women, for diagnosis of symptoms, in sex workers, and in men coming forward for circumcision) is conducted, and (ii) core‐testing as above plus additional testing beyond this ("additional‐testing"), for which we specify different rates of testing and various degrees to which those with HIV are more likely to test than those without HIV. We also considered a plausible range of unit test costs. The aim was to assess the relationship between cost‐per‐diagnosis and the incremental cost‐effectiveness ratio (ICER) of the additional‐testing policy. The discount rate used in the base case was 3% per annum (costs in 2018 U.S. dollars).ResultsThere was a strong graded relationship between the cost‐per‐diagnosis and the ICER. Overall, the ICER was below $500 per‐DALY‐averted (the cost‐effectiveness threshold used in primary analysis) so long as the cost‐per‐diagnosis was below $315. This threshold cost‐per‐diagnosis was similar according to epidemic and programmatic features including the prevalence of undiagnosed HIV, the HIV incidence and a measure of HIV programme quality (the proportion of HIV diagnosed people having a viral load <1000 copies/mL). However, restricting to women, additional‐testing did not appear cost‐effective even at a cost‐per‐diagnosis of below $50, while restricting to men additional‐testing was cost‐effective up to a cost‐per‐diagnosis of $585. The threshold cost per diagnosis for testing in men to be cost‐effective fell to $256 when the cost‐effectiveness threshold was $300 instead of $500, and to $81 when considering a discount rate of 10% per annum.ConclusionsFor testing programmes in low‐income settings in southern African there is an extremely strong relationship between the cost‐per‐diagnosis and the cost‐per‐DALY averted, indicating that the cost‐per‐diagnosis can be used to monitor the cost‐effectiveness of testing programmes.