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Background: Pediatric tuberculous meningitis (TBM) commonly causes death or disability. In adults, high-dose rifampicin may reduce mortality. The role of fluoroquinolones remains unclear. There have been no antimicrobial treatment trials for pediatric TBM., Methods: TBM-KIDS was a phase 2 open-label randomized trial among children with TBM in India and Malawi. Participants received isoniazid and pyrazinamide plus: (i) high-dose rifampicin (30 mg/kg) and ethambutol (R30HZE, arm 1); (ii) high-dose rifampicin and levofloxacin (R30HZL, arm 2); or (iii) standard-dose rifampicin and ethambutol (R15HZE, arm 3) for 8 weeks, followed by 10 months of standard treatment. Functional and neurocognitive outcomes were measured longitudinally using Modified Rankin Scale (MRS) and Mullen Scales of Early Learning (MSEL)., Results: Of 2487 children prescreened, 79 were screened and 37 enrolled. Median age was 72 months; 49%, 43%, and 8% had stage I, II, and III disease, respectively. Grade 3 or higher adverse events occurred in 58%, 55%, and 36% of children in arms 1, 2, and 3, with 1 death (arm 1) and 6 early treatment discontinuations (4 in arm 1, 1 each in arms 2 and 3). By week 8, all children recovered to MRS score of 0 or 1. Average MSEL scores were significantly better in arm 1 than arm 3 in fine motor, receptive language, and expressive language domains (P < .01)., Conclusions: In a pediatric TBM trial, functional outcomes were excellent overall. The trend toward higher frequency of adverse events but better neurocognitive outcomes in children receiving high-dose rifampicin requires confirmation in a larger trial., Clinical Trials Registration: NCT02958709., Competing Interests: Potential conflicts of interest. A. G. reports funding received by her institution outside the scope of this work from NIH, Unitaid, the Centers for Disease Control and Prevention (CDC), and various foundations (Wyncote, Ujala, Todi); participation on a data safety monitoring board or advisory board for the NIH/NIAID Advisory Council and Indo US Science Technology Governing Board; and a leadership or fiduciary role on the IMPAACT Network TB Scientific Committee and the World Health Organization (WHO) multidrug-resistant tuberculosis guidelines committee. D. B. D., K. Y. K., M. V., P. G., and S. B. report support outside the scope of this work given to the ICMR-NIRT for the TBM-KIDS trial by the NICHD and funded through John Hopkins University. K. T. T. reports grants or contracts (NIH, CDC), outside the scope of this work, and consulting fees from WHO. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: Children with comorbidities or danger signs are often excluded from trials evaluating pneumonia treatment., Methods: We sought to investigate whether the percentage of children with chest-indrawing pneumonia cured at Day 14 was lower among those with HIV infection or exposure, malaria, moderate or severe acute malnutrition, or anemia enrolled in a prospective observational cohort study than among children without these comorbidities enrolled in a concurrent prospective randomized controlled trial evaluating duration of amoxicillin treatment in Lilongwe, Malawi., Results: Children with chest-indrawing pneumonia and comorbidities but without danger signs did not have statistically significant higher treatment failure rates by Day 6 than those in the chest-indrawing pneumonia clinical trial. However, children with chest-indrawing pneumonia and HIV infection or exposure, malaria, or moderate or severe acute malnutrition had higher rates of not being clinically cured at Day 14 when compared to children without these comorbidities (adjusted differences ranging from 7.7% to 17.0%). Furthermore, among children without danger signs at enrollment, but with HIV infection or HIV exposure or moderate or severe acute malnutrition, 12.5% and 15.6% respectively were not clinically cured at Day 14 even though they were without treatment failure by Day 6., Conclusions: More intensive follow-up of children with chest-indrawing pneumonia and comorbidities who do not have danger signs may be beneficial., Competing Interests: Competing interests: The authors completed the ICMJE Unified Competing Interest form (available upon request from the corresponding author), and declare no conflicts of interest., (Copyright © 2021 by the Journal of Global Health. All rights reserved.)

Background: Costing and financing systematic implementation are recognized barriers to human immunodeficiency virus (HIV) prevention. In the absence of empiric implementation and economic data, perspectives from international stakeholders involved in developing and supporting daily oral pre-exposure prophylaxis (PrEP) policy, and programs can provide critical insights for developing costed plans to support and accelerate the rollout of novel long-acting PrEP (LA-PrEP) methods, such as the monthly dapivirine vaginal ring (PrEP ring). Methods: We interviewed stakeholders from purposively selected international organizations about anticipated PrEP-ring implementation costs, evidence gaps and key process steps for developing a costed rollout plan template (CRPT). We deductively analysed interviews. Results: The 27 stakeholders (11 donors, 10 nongovernmental, 4 academic/research, 2 multilateral) identified 10 cost-related themes: 7 for planning and implementation and 3 for financing, costing and budgeting. Planning and implementation cost considerations included: (1) actionable target setting; (2) multilevel communication strategies for awareness-raising, demand creation, client-level adherence and choice counselling; (3) human resources, encompassing task shifting and integration into non-HIV services; (4) supply chain costs, including commodities, manufacturing diversification, packaging and forecasting; (5) laboratory infrastructure and monitoring; (6) updated health information systems and metrics to monitor and evaluate multiple methods integrated into HIV, non-HIV and de-medicalized delivery settings; and (7) technical assistance and knowledge management. Themes for financing, costing and budgeting comprised: (8) cost and budget analyses, such as cost–effectiveness; (9) economic evidence gaps on service integration; and (10) innovative or co-financing for sustainable and equitable allocation of limited financial resources to support accelerated PrEP-ring delivery. We organized these themes within the CRPT. Conclusions: The CRPT could expedite planning and enhance the pace and scale of optimized, systematic and sustainable delivery of PrEP methods. Further research is needed to evaluate use cases of the CRPT. Contributions to the literature: To address recognized barriers stymieing goals to end the HIV epidemic, we introduced a process and tool to support national-level systematic implementation, costing and financing plans for the monthly dapivirine ring. International stakeholders involved in oral PrEP policy and programming highlighted priority areas for costed introduction of the monthly dapivirine ring: (1) target setting, (2) communication and demand creation, (3) human resources, (4) supply chains, (5) laboratories, (6) monitoring and evaluation, (7) technical assistance, (8) cost and effectiveness, (9) service integration and (10) financing partnerships. These priorities are relevant for LA-PrEP as well. Participants validated anonymity in reported responses, an important approach in qualitative implementation science, where stakeholder contributions may be sensitive. [ABSTRACT FROM AUTHOR]

Background: HPTN 084 compared the safety and efficacy of long-acting injectable cabotegravir (CAB) to daily oral TDF/FTC for prevention of HIV-1 in uninfected African women. Like a similar trial in MSM/TGW (HPTN 083), the trial was stopped early for efficacy, expediting the need to consider introduction strategies for different populations. We examine survey and qualitative data from a four-country sub-study to examine oral and injectable PrEP acceptability and considerations for CAB access among African women. Methods: Participants completed baseline and follow-up surveys on HIV risk perception, sexual behavior. product acceptability and adherence during the blinded trial. Additionally, up to two in-depth interviews each with 73 sub-study participants explored product use and trial-related experiences, during the blinded and unblinded study periods. Using survey data, we classified participants as: engaged in female sex work (FSW), having multiple non-transactional partners, or monogamous. A study statistician identified participants' assigned study arm. We followed a thematic analysis process to read transcripts, develop a codebook and apply codes in NVivo to transcripts with intermittent intercoder reliability checks; using Excel matrices to explore differences across risk categories and study arms. Findings: Participants overwhelmingly preferred injections to pills, appreciating the ease, convenience, and privacy of a long-acting formulation. Many participants described challenges with contraceptive and/or study pill adherence, impeded by late night work, unexpected travel, or heavy drinking. Women in the TDF/FTC arm were more likely to describe side effects, compared to those in the CAB arm. Pain also varied widely by study arm. When considering post-trial access to CAB, limited PrEP knowledge, cost and concerns around stigma and poor service quality were potential access barriers. Conclusion: Women's desire for privacy and ease of use outweighed injectable concerns, resulting in a strong preference for CAB. Cost and accessibility will need to be addressed by implementation programs. [ABSTRACT FROM AUTHOR]

OAA0304 Hypoxic adaptation uncovers a glycolytic dependence of HIV-1 latency reversal Y.I. Kayode SP 1 sp , D.C. Clemmer SP 1 sp , A.A. Owolabi SP 1 sp , L.M. Clark SP 1 sp , H.E. Taylor SP 1 sp SP 1 sp SUNY Upstate Medical University, Microbiology and Immunology, Syracuse, United States B Background b : The main barrier to HIV-1 curative strategies is the persistence of latently infected CD4 T cells in lymphoid tissue compartments which readily fuel viral rebound following antiretroviral therapy (ART) interruption in people living with HIV (PLWH). Mamba SP 1 sp , V. Williams SP 1 sp , A. Mafukidze SP 1 sp , P. Bongomin SP 1 sp , P. Dlamini SP 1 sp , G. Mchunu SP 1 sp , S. Mhlanga SP 1 sp , H. Byarugaba SP 1 sp , J. Opoku SP 2 sp , S. Kibwana SP 3 sp , S. Ojoo SP 2 sp , D. Bazira SP 2 sp , S. Haumba SP 1 sp SP 1 sp Center for Global Health Practice and Impact, Georgetown University, Mbabane, Eswatini, SP 2 sp Center for Global Health Practice and Impact, Georgetown University Medical Center, Washington DC, United States, SP 3 sp Center for Global Health Practice and Impact, Georgetown University Medical Center, Washington, United States B Background b : Pill count is widely used as an adherence measure among clients taking antiretroviral therapy (ART). OAA0102 Resident microbiota enhance HIV acquisition, replication and pathogenesis in vivo A. Wahl SP 1 sp , W. Yao SP 1 sp , B. Liao SP 1 sp , M. Chateau SP 1 sp , C. Richardson SP 1 sp , L. Ling SP 1 sp , J. Tucker SP 1 sp , I. McGowan SP 2 sp , R.B. Sartor SP 1 sp , J.V. Garcia SP 1 sp SP 1 sp University of North Carolina at Chapel Hill, Chapel Hill, United States, SP 2 sp University of Pittsburgh Medical School, Pittsburgh, United States B Background b : Resident microbiota maintain intestinal homeostasis by regulating digestion, metabolism, immune development and providing protection from infection. [Extracted from the article]

Introduction: The proven effectiveness of injectable cabotegravir (CAB-LA) is higher than that of any other HIV prevention intervention ever trialled or implemented, surpassing medical male circumcision, condoms and combination antiretroviral treatment. Based on our own analyses and experience with the South African oral pre-exposure prophylaxis (PrEP) programme, we review the supply and demand side factors that would need to be in place for a successful rollout of CAB-LA, and delineate lessons for the launch of other long-acting and extended delivery (LAED) antiretroviral drugs. Discussion: On the supply side, CAB-LA will have to be offered at a price that makes the drug affordable and cost-effective to low- and middle-income countries, especially those with high HIV prevalence. An important factor in lowering prices is a guaranteed market volume, which in turn necessitates the involvement of large funders, such as PEPFAR and the Global Fund, and a fairly rapid scale-up of the drug. Such a scale-up would have to involve speedy regulatory approval and WHO pre-qualification, swift integration of CAB-LA into national guidelines and planning for large enough manufacturing capacity, including the enabling of local manufacture. On the demand side, existing demand for HIV prevention products has to be harnessed and additional demand created, which will be aided by designing CAB-LA programmes at the primary healthcare or community level, and involving non-traditional outlets, such as private pharmacies and doctors' practices. Conclusions: CAB-LA could be the game changer for HIV prevention that we have been hoping for, and serve as a useful pilot for other LAEDs. A successful rollout would involve building markets of a guaranteed size; lowering the drug's price to a level possibly below the cost of production, while also lowering the cost of production altogether; harnessing, creating and sustaining demand for the product over the long term, wherever possible, in national programmes rather than single demonstration sites; and establishing and maintaining manufacturing capacity and supply chains. For this, all parties have to work together--including originator and generic manufacturers, donor organizations and other large funders, and the governments of low- and middle-income countries, in particular those with high HIV prevalence. [ABSTRACT FROM AUTHOR]

Background: The evaluation of seroprotection rates against vaccine-preventable infectious diseases allows for the identification of risk populations. HIV-exposed infants, even if not infected with HIV, have higher morbidity and mortality in comparison to unexposed counterparts. The aim of this study was to compare the specific IgG levels against Haemophilus influenzae type-B (HiB), Hepatitis-B (HBV), and Streptococcus pneumoniae (Spn) in two groups of infants (HIV-exposed and HIV-unexposed) living in Malawi. Methods: Blood samples from 62 infants, 49 HIV-exposed, uninfected (HEU), and born to women living with HIV and 13 HIV-unexposed and uninfected (HUU), were collected at 6 months, and specific IgG levels were determined using ELISA tests. Results: The antibody levels against HiB, HBV, and Spn were similar in the two groups. At six months, all HUU infants and 81.6% of HEU infants showed seroprotective levels against HiB, while a percentage of protection varying from 80.6 to 84.6% was observed for HBV and Spn regardless of HIV exposure. Only 59.2% of HEU and 69.2% of HUU infants showed antibody protection against all three pathogens. Conclusions: These results indicate similar rates of seroprotection among HEU and HUU infants but also suggest that a consistent fraction of infants received incomplete vaccinations. Strategies to enforce participation in immunization programs in Malawi should be a health priority. [ABSTRACT FROM AUTHOR]

The retinoid (10mM) increased viral reactivation mediated by IL-15 to a similar extent as HODHBt (100mM) but unlike HODHBt, specifically promoted cell death of latently infected cells compared to controls when combined with IL-15. This indicates that the retinoid is able to reactivate latent HIV through a mechanism mediated by IL-15 but not directly dependent on STAT5 phosphorylation. Among the clinically relevant latency reversing agents (LRA) under investigation, IL-15 or the IL-15 superagonist N-803 have been shown to reactivate latent HIV I ex vivo i and I in vivo i . [Extracted from the article]

Data are limited on the prevalence and outcome of anemia and its risk on mortality among children under five years of age hospitalized for pneumonia/severe pneumonia. Thus, we conducted a secondary analysis of data extracted from Dhaka Hospital of International Centre for Diarrhoeal Disease Research, Bangladesh to address the evidence gap. Among 3468 children fulfilling the study criteria,1712 (49.4%) had anemia. If children aged ≤ 1.0, > 1.0 to 2.0, > 2.0 to < 6.0, and ≥ 6.0 to 59 months had blood hemoglobin (Hb) value of ≤ 10.7 g/dL, ≤ 9.4 g/dL, ≤ 9.5 g/dL, and ≤ 11 g/dl respectively; we considered them anemic. The trend of prevalence of anemia was found to be inversely related to increasing age (Chi-square for linear trend analysis was done to understand the relation of anemia with increasing age, which was = 6.96; p = 0.008). During hospitalization anemic children more often developed respiratory failure (7.2% vs. 4.4%, p < 0.001) and fatal outcome (7.1.0% vs. 4.2%, p < 0.001) than the children who did not have anemia. After adjusting for potential confounders, such as female sex, lack of immunization, abnormal mental status, severe acute malnutrition, dehydration, hypoxemia, severe sepsis, and bacteremia using multivariable logistic regression analysis, anemia was found to be independently associated with fatal outcome (OR = 1.88, 95% CI 1.23–2.89, p = 0.004). Thus, future interventional studies on the early management of anemia may be warranted to understand whether the intervention reduces the morbidity and deaths in such children. [ABSTRACT FROM AUTHOR]

The Edinburgh Malawi Breast Cancer Project, a collaborative partnership project between the Queen Elizabeth Central Hospital (QECH) Oncology Unit, Blantyre, Malawi and the Edinburgh Cancer Centre, UK, was established in 2015. The principal objective of the project is to help to develop high quality multi-disciplinary breast cancer care in Malawi. A needs assessment identified three priority areas for further improvement of breast cancer services: multi-disciplinary working, development of oestrogen receptor (ER) testing and management of clinical data. A 3-year project plan was implemented which has been conducted through a series of reciprocal training visits. Key achievements to date have been: (1) Development of a new specialist breast care nursing role; (2) Development of multi-disciplinary meetings; (3) Completion of a programme of oncology nursing education; (4) Development of a clinical database that enables prospective collection of data of all new patients with breast cancer; (5) Training of local staff in molecular and conventional approaches to ER testing. The Edinburgh Malawi Breast Cancer Project is supporting nursing education, data use and cross-specialty collaboration that we are confident will improve cancer care in Malawi. Future work will include the development of a breast cancer diagnostic clinic and a breast cancer registry. [ABSTRACT FROM AUTHOR]

ORAL ABSTRACT Resident microbiota enhance HIV acquisition, replication and pathogenesis in vivo A. Wahl[sup.1] , W. Yao[sup.1] , B. Liao[sup.1] , M. Chateau[sup.1] , C. Richardson[sup.1] , L. Ling[sup.1] , [...]

ORAL ABSTRACT Pharmacological enhancement of IL?15 signaling to improve ?shock?and?kill? strategies against latent HIV J.N. Howard[sup.1] , A. Bosque[sup.1] [sup.1] George Washington University, Microbiology, Immunology, and Tropical Medicine, Washington DC, [...]