OBJECTIVES:In the absence of reliable biomarkers, analytical treatment interruption (ATI) is needed to evaluate HIV-1 cure/remission strategies. Children living with HIV-1 may have high potential to achieve cure/remission due to very-early antiretroviral therapy (ART) initiation combined with early-life immunity. However, pediatric ATI safety monitoring requires frequent blood sampling for early plasma viral rebound detection to facilitate prompt ART resumption. DESIGN:We hypothesized that viral rebound during ATI would be detected earlier by point-of-care (PoC) total HIV-1 nucleic acid (TNA) measurement, which quantifies both HIV-1 RNA and DNA, than via standard laboratory assays of plasma HIV-1 RNA. Therefore, viral rebound during pediatric ATI studies could be detected earlier via a practical and user-friendly approach. METHODS:Nineteen very-early ART-treated children underwent ATI. Sixteen experienced plasma HIV-1 viral rebound. PoC TNA testing with the Cepheid GeneXpert HIV-1 Qual XC assay, requiring 100 μl of whole blood and 2 h turnaround time (TAT), was compared with standard plasma HIV-1 RNA quantification (Aptima Quant), requiring 500 μl of whole blood and 30 h TAT. RESULTS:GeneXpert TNA Ct values and plasma HIV-1 RNA were strongly negatively correlated ( r = -0.88, P < 0.0001). In all 27 instances where viral rebound was detected by plasma HIV-1 RNA testing, TNA was also detected. In 12 instances, TNA was detected prior to any plasma RNA rebound. There were no instances where plasma rebound was detected prior to TNA detection ( P = 2 x 10 -15 ). CONCLUSION:PoC HIV-1 TNA testing offers a more rapid and lower-volume method to detect viral rebound in pediatric ATI, enhancing safety monitoring and timely ART reinitiation.
MHC polymorphism is explained by natural selection driven by the MHC-dependent impact of certain infections, inflammatory conditions, autoimmune diseases, and cancers. However, examples of human disease driving this process are rare. We evaluated the impact of HIV-1 in altering HLA-I frequencies in KwaZulu-Natal, South Africa, and the influence of antiretroviral therapy (ART) on this process. In a historical mother-child cohort in the pre-ART era (1998-2005), HIV-1 survival and vertical transmission were both strongly HLA-B dependent: "disease-susceptible" HLA-B alleles (HLA-B*18/B*45:01/B*58:02) increased adult AIDS progression and vertical transmission (OR 1.6, P = 0.01), whereas "protective" HLA-B alleles (HLA-B*57/B*58:01/B*81:01) slowed AIDS progression, and decreased vertical transmission (OR 0.57, P = 0.002). By contrast, in contemporary antenatal KwaZulu-Natal cohorts in the ART era (2015-2025) the impact of HLA-B on HIV-1 disease outcome and vertical transmission is dramatically reduced. Using these and reported data, we constructed a model to estimate the impact of HIV-1 on HLA-B frequencies in KwaZulu-Natal, both in the prevailing setting of ART and in a hypothetical counterfactual scenario where ART was never rolled out. Over the 45-y period 1990-2035, in the absence of ART, the proportion of the population possessing any "protective" HLA-B allele was projected to increase from 23 to 42% (allele frequencies increasing from 0.12 to 0.24), and the proportion of the population possessing any "disease-susceptible" HLA-B allele was projected to decrease from 28 to 18% (allele frequencies declining from 0.15 to 0.092). The introduction of ART radically slows HLA-B frequency change. These data therefore demonstrate the potential for natural selection from an infectious disease to alter human population genetics within decades, and for the successful roll-out of therapy to halt this process.
After sporadic reports of post-treatment control of HIV in children who initiated combination anti-retroviral therapy (cART) early, we prospectively studied 284 very-early-cART-treated children from KwaZulu-Natal, South Africa, after vertical HIV transmission to assess control of viremia. Eighty-four percent of the children achieved aviremia on cART, but aviremia persisting to 36 or more months was observed in only 32%. We observed that male infants have lower baseline plasma viral loads (P = 0.01). Unexpectedly, a subset (n = 5) of males maintained aviremia despite unscheduled complete discontinuation of cART lasting 3-10 months (n = 4) or intermittent cART adherence during 17-month loss to follow-up (n = 1). We further observed, in vertically transmitted viruses, a negative correlation between type I interferon (IFN-I) resistance and viral replication capacity (VRC) (P < 0.0001) that was markedly stronger for males than for females (r = -0.51 versus r = -0.07 for IFN-alpha). Although viruses transmitted to male fetuses were more IFN-I sensitive and of higher VRC than those transmitted to females in the full cohort (P < 0.0001 and P = 0.0003, respectively), the viruses transmitted to the five males maintaining cART-free aviremia had significantly lower replication capacity (P < 0.0001). These data suggest that viremic control can occur in some infants with in utero-acquired HIV infection after early cART initiation and may be associated with innate immune sex differences.
Background: There is a paucity of literature on knowledge translation (KT) interventions for occupational therapists (OTs) in assessing and caring for the neonate and at-risk infant. Care at this stage of life is paramount, requiring a shift from the survival of the neonate, to the quality of survival. Consequently, clinicians working with neonates have a crucial role in ensuring optimal development and preventing long-term adverse developmental outcomes. Aim: This study aimed to explore experts’ opinions on KT interventions for OTs working with neonates and at-risk infants in South Africa. Setting: This study was located in South Africa. Due to the virtual nature of data collection, no geographical limitations within the country were imposed. Method: A two-round Delphi study with a multidisciplinary expert panel ( n = 20; n = 18) was conducted. The round one survey was developed based on a literature review, findings from a preceding focus group, and a pilot study. The subsequent round was based on the data and comments generated from the first round. Results were pooled and presented to participants following both rounds. Results: Consensus on 127 items out of 130 was achieved. These included consensus on the definition of KT in neonatal care, the knowledge that OTs should possess, professional competencies, skills required, professional values, and characteristics. Further agreement was reached on the KT process, the usefulness of KT modalities, recommended courses in neonatal care, barriers to KT, best-practice and requirements for undergraduate training. Conclusion: Knowledge translation required for OTs working with neonates and at-risk infants were established in this study. Contribution: This study may be useful for consideration in contextually relevant KT interventions for clinicians working in neonatal care.
Background Chronic obstructive pulmonary disease (COPD) is a major cause of years of life lost globally. Acute exacerbations of COPD (AECOPD) drive disease progression, reduce quality of life and are a source of mortality in COPD. Approximately 50% of AECOPD are due to bacterial infections. Diagnosing bacterial infection as the aetiology of AECOPD however remains challenging as investigations are limited by practicality, accuracy and expense. Clinicians have traditionally used sputum colour as a marker of bacterial infection in AECOPD, despite the lack of high-quality evidence for this practice. The aim of this systematic review and meta-analysis is to determine the diagnostic accuracy of sputum colour in the diagnosis of bacterial causes of AECOPD. Methods Articles will be searched for in electronic databases (MEDLINE, Google Scholar Scopus, Web of Science, Africa-Wide, CINAHL and Health Source Nursing Academy) and we will conduct a review of citation indexes and the grey literature. Two reviewers will independently conduct study selection, against pre-defined eligibility criteria, data extraction and quality assessment of included articles using the QUADAS-2 tool. We will perform a meta-analysis using a bivariate logistic regression model with random effects. We will explore heterogeneity through the visual examination of the forest plots of sensitivities and specificities and through the inclusion of possible sources of heterogeneity as covariates in a meta-regression model if sufficient studies are included in the analysis. We also perform a sensitivity analysis to explore the effect of study quality on our findings. The results of this review will be reported according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis statement and will be submitted for peer-review and publication. Discussion The findings of this review will assist clinicians in diagnosing the aetiology of AECOPD and may have important implications for decision making in resource-limited settings, as well as for antimicrobial stewardship. Systematic review registration PROSPERO CRD42019141498
