Prediction of HIV transmission cluster growth with statewide surveillance data

Background:Prediction of HIV transmission cluster growth may help guide public health action. We developed a predictive model for cluster growth in North Carolina (NC) using routine HIV surveillance data.Methods:We identified putative transmission clusters with ≥2 members through pairwise genetic distances ≤1.5% from HIV-1 pol sequences sampled November 2010-December 2017 in NC. Clusters established by a baseline of January 2015 with any sequences sampled within 2 years before baseline were assessed for growth (new diagnoses) over 18 months. We developed a predictive model for cluster growth incorporating demographic, clinical, temporal, and contact tracing characteristics of baseline cluster members. We internally and temporally externally validated the final model in the periods January 2015-June 2016 and July 2016-December 2017.Results:Cluster growth was predicted by larger baseline cluster size, shorter time between diagnosis and HIV care entry, younger age, shorter time since the most recent HIV diagnosis, higher proportion with no named contacts, and higher proportion with HIV viremia. The model showed areas under the receiver-operating characteristic curves of 0.82 and 0.83 in the internal and temporal external validation samples.Conclusions:The predictive model developed and validated here is a novel means of identifying HIV transmission clusters that may benefit from targeted HIV control resources. © 2018 Wolters Kluwer Health, Inc. All rights reserved

Sustained Sexual Behavior Change after Acute HIV Diagnosis in Malawi

Background Identification of acute HIV infection (AHI) allows for important opportunities for HIV prevention through behavior change and biomedical intervention. Here, we evaluate changes in sexual risk behaviors among persons with AHI enrolled in a combined behavioral and biomedical intervention designed to reduce onward transmission of HIV. Methods Participants were randomized to standard HIV counseling, a multisession behavioral intervention, or a multisession behavioral intervention plus antiretrovirals. Sexual behaviors were assessed periodically over 1 year. Results Four weeks after diagnosis, the predicted probability of reporting multiple sexual partners decreased from 24% to 9%, and the probability of reporting unprotected sex decreased from 71% to 27%. These declines in sexual risk behaviors were sustained over follow-up irrespective of study arm. Conclusions Diagnosis of AHI alone may be sufficient to achieve immediate and sustained behavior change during this highly infectious period

Multicenter evaluation of the Xpert Norovirus assay for detection of norovirus genogroups I and II in fecal specimens

Norovirus is the most common cause of sporadic gastroenteritis and outbreaks worldwide. The rapid identification of norovirus has important implications for infection prevention measures and may reduce the need for additional diagnostic testing. The Xpert Norovirus assay recently received FDA clearance for the detection and differentiation of norovirus genogroups I and II (GI and GII), which account for the vast majority of infections. In this study, we evaluated the performance of the Xpert Norovirus assay with both fresh, prospectively collected ( n = 914) and frozen, archived ( n = 489) fecal specimens. A Centers for Disease Control and Prevention (CDC) composite reference method was used as the gold standard for comparison. For both prospective and frozen specimens, the Xpert Norovirus assay showed positive percent agreement (PPA) and negative percent agreement (NPA) values of 98.3% and 98.1% for GI and of 99.4% and 98.2% for GII, respectively. Norovirus prevalence in the prospective specimens (collected from March to May of 2014) was 9.9% ( n = 90), with the majority of positives caused by genogroup II (82%, n = 74). The positive predictive value (PPV) of the Xpert Norovirus assay was 75% for GI-positive specimens, whereas it was 86.5% for GII-positive specimens. The negative predictive values (NPV) for GI and GII were 100% and 99.9%, respectively

Human Immunodeficiency Virus (HIV)-1 Transmission among Persons with Acute HIV-1 Infection in Malawi: Demographic, Behavioral, and Phylogenetic Relationships

Background: Understanding sexual networks involving acute human immunodeficiency virus (HIV)-1 infections (AHI) may lead to prevention opportunities to mitigate high rates of onward transmission. We evaluated HIV-1 phylogenetic and behavioral characteristics among persons with AHI and their referred partners. Methods: Between 2012 and 2014, 46 persons with AHI in Malawi participated in a combined behavioral and biomedical intervention. Participants referred sexual partners by passive referral. Demographics and sexual behaviors were collected through interviews and HIV-1 genetic relationships were assessed with phylogenetics. Results: Among 45 AHI participants with HIV-1 sequences, none was phylogenetically-linked with another AHI index. There were 19 (42%) AHI participants who referred a single partner that returned for testing. Most partners (n = 17) were HIV-infected, with 15 (88%) presenting with an established infection. There were 14 index-partner pairs that had sequences available; 13 (93%) pairs were phylogenetically-linked dyads. The AHI index was female in 7/13 (54%) dyads. Age-disparate relationships among dyads were common (≥5-year age difference in 67% of dyads), including 3/6 dyads involving a male index and a younger woman. Index participants with a referred partner were more likely to report no casual partners and to be living with their current partner than participants not in dyads. Conclusions: Passive-partner referral successfully identified partners with genetically-similar HIV infections - the likely source of infection - but only 40% of index cases referred partners who presented for HIV-1 testing. Future work evaluating assisted partner notification may help reach susceptible partners or more people with untreated HIV-1 infections connected to acute transmission. Clinical Trials Registration: NCT01450189

Isolation of SARS-CoV-2 in viral cell culture in immunocompromised patients with persistently positive RT-PCR results

Immunocompromised adults can have prolonged acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive RT-PCR results, long after the initial diagnosis of coronavirus disease 2019 (COVID-19). This study aimed to determine if SARS-CoV-2 virus can be recovered in viral cell culture from immunocompromised adults with persistently positive SARS-CoV-2 RT-PCR tests. We obtained 20 remnant SARS-CoV-2 PCR positive nasopharyngeal swabs from 20 immunocompromised adults with a positive RT-PCR test ≥14 days after the initial positive test. The patients\u27

Randomized Controlled Pilot Study of Antiretrovirals and a Behavioral Intervention for Persons with Acute HIV Infection: Opportunity for Interrupting Transmission

Background. Persons with acute HIV infection (AHI) have heightened transmission risk. We evaluated potential transmission reduction using behavioral and biomedical interventions in a randomized controlled pilot study in Malawi. Methods. Persons were randomized 1:2:2 to standard counseling (SC), 5-session behavioral intervention (BI), or behavioral intervention plus 12 weeks of antiretrovirals (ARVs; BIA). All were followed for 26-52 weeks and, regardless of arm, referred for treatment according to Malawi-ARV guidelines. Participants were asked to refer partners for testing. Results. Among 46 persons (9 SC, 18 BI, 19 BIA), the average age was 28; 61% were male. The median viral load (VL) was 5.9 log copies/mL at enrollment. 67% (10/15) of BIA participants were suppressed (<1000 copies/mL) at week 12 vs 25% BI and 50% SC (P = .07). Although the mean number of reported condomless sexual acts in the past week decreased from baseline across all arms (1.5 vs 0.3 acts), 36% experienced incident sexually transmitted infection by 52 weeks (12% SC, 28% BI, 18% BIA). Forty-one percent (19/46) of participants referred partners (44% SC, 44% BI, 37% BIA); 15 of the partners were HIV-infected. Conclusions. Diagnosis of AHI facilitates behavioral and biomedical risk reduction strategies during a high-transmission period that begins years before people are typically identified and started on ARVs. Sexually transmitted infection incidence in this cohort suggests ongoing risk behaviors, reinforcing the importance of early intervention with ARVs to reduce transmission. Early diagnosis coupled with standard AHI counseling and early ARV referral quickly suppresses viremia, may effectively change behavior, and could have tremendous public health benefit in reducing onward transmission

Csnk1a1 inhibition has p53-dependent therapeutic efficacy in acute myeloid leukemia

Despite extensive insights into the underlying genetics and biology of acute myeloid leukemia (AML), overall survival remains poor and new therapies are needed. We found that casein kinase 1 α (Csnk1a1), a serine-threonine kinase, is essential for AML cell survival in vivo. Normal hematopoietic stem and progenitor cells (HSPCs) were relatively less affected by shRNA-mediated knockdown of Csnk1a1. To identify downstream mediators of Csnk1a1 critical for leukemia cells, we performed an in vivo pooled shRNA screen and gene expression profiling. We found that Csnk1a1 knockdown results in decreased Rps6 phosphorylation, increased p53 activity, and myeloid differentiation. Consistent with these observations, p53-null leukemias were insensitive to Csnk1a1 knockdown. We further evaluated whether D4476, a casein kinase 1 inhibitor, would exhibit selective antileukemic effects. Treatment of leukemia stem cells (LSCs) with D4476 showed highly selective killing of LSCs over normal HSPCs. In summary, these findings demonstrate that Csnk1a1 inhibition causes reduced Rps6 phosphorylation and activation of p53, resulting in selective elimination of leukemia cells, revealing Csnk1a1 as a potential therapeutic target for the treatment of AML