After a decade of civil war and the 2014-2016 West African Ebola outbreak, Sierra Leone now faces the COVID-19 pandemic with a fragile health system. As was demonstrated during Ebola, preparedness is ...key to limiting a health crisis' spread and impact on health systems and ensuring continued care for vulnerable populations including people living with HIV (PLHIV). To assess COVID-19 preparedness and inform interventions to ensure continuity of HIV services at health facilities (HFs) and community service points (CSPs), we conducted site readiness assessments in Freetown, the epicenter of COVID-19 in Sierra Leone. Data were collected at nine high-volume HIV HFs and seven CSPs in April 2020, a month after COVID-19 was declared a pandemic. CSPs comprised three community drop-in centers providing HIV counseling and testing services as well as HIV prevention services (e.g., condoms and lubricants) for key and priority populations and four community-based support groups serving PLHIV. At the time of assessment, CSPs did not provide antiretroviral therapy (ART) but were considered potential sites for expansion of differentiated service delivery (DSD)-a client-centered approach to HIV care-in the context of COVID-19. Overall, 5/9 HFs had trained staff on use of personal protective equipment (PPE) and prevention of COVID-19 transmission. Most had access to masks (5/9) and gloves (7/9) for management of suspected/confirmed COVID-19 cases, and 4/9 HFs had triage procedures for isolation of suspected cases. Conversely, few CSPs had access to masks (2/7) or gloves (2/7) and no staff were trained on PPE use or COVID-19 transmission. 7/9 HFs had adequate ART stock for multi-month dispensing though few had procedures for (3/9) or had trained staff in providing DSD (2/9). Among CSPs where measures were applicable, 2/4 had procedures for DSD, 1/3 had staff trained on DSD and none had adequate ART stock. Identification of gaps in COVID-19 preparedness is a critical step in providing support for infection control and modified service delivery. Findings from this assessment highlight gaps in COVID-19 preparedness measures at sites supporting PLHIV in Sierra Leone and indicate CSPs may require intensive supervision and training to ensure HIV services are uninterrupted while minimizing COVID-19 risk, especially if used as sites to scale up DSD.
Persons with opioid use disorders who inject drugs (PWID) in the United States (US) face multiple and intertwining health risks. These include interference with consistent access, linkage, and ...retention to health care including medication for opioid use disorder (MOUD), HIV prevention using pre-exposure prophylaxis (PrEP), and testing and treatment for sexually transmitted infections (STIs). Most services, when available, including those that address substance misuse, HIV prevention, and STIs, are often provided in multiple locations that may be difficult to access, which further challenges sustained health for PWID. HPTN 094 (INTEGRA) is a study designed to test the efficacy of an integrated, "whole-person" strategy that provides integrated HIV prevention including antiretroviral therapy (ART), PrEP, MOUD, and STI testing and treatment from a mobile health delivery unit ("mobile unit") with peer navigation compared to peer navigation alone to access these services at brick and mortar locations.
HPTN 094 (INTEGRA) is a two-arm, randomized controlled trial in 5 US cities where approximately 400 PWID without HIV are assigned either to an experimental condition that delivers 26 weeks of "one-stop" integrated health services combined with peer navigation and delivered in a mobile unit or to an active control condition using peer navigation only for 26 weeks to the same set of services delivered in community settings. The primary outcomes include being alive and retained in MOUD and PrEP at 26 weeks post-randomization. Secondary outcomes measure the durability of intervention effects at 52 weeks following randomization.
This trial responds to a need for evidence on using a "whole-person" strategy for delivering integrated HIV prevention and substance use treatment, while testing the use of a mobile unit that meets out-of-treatment PWID wherever they might be and links them to care systems and/or harm reduction services. Findings will be important in guiding policy for engaging PWID in HIV prevention or care, substance use treatment, and STI testing and treatment by addressing the intertwined epidemics of addiction and HIV among those who have many physical and geographic barriers to access care.
ClinicalTrials.gov NCT04804072 . Registered on 18 March 2021.
Limited data are available regarding adults age ≥50 at initial HIV diagnosis. Improved understanding of this group is critical in designing interventions to facilitate earlier diagnosis and linkage ...to HIV care. We characterize individuals newly diagnosed with HIV, particularly those ≥50 years old, and examine the relationship between age and late diagnosis defined as concurrent HIV and AIDS diagnoses. This is a retrospective study of individuals newly diagnosed with HIV from 2006-2011 at an academic medical center in New York City. Multivariable logistic regression was performed to evaluate the effect of age, gender, race/ethnicity, risk factor, and prior medical visits on late diagnosis. Adults age ≥50 comprised 21.3% of all newly diagnosed individuals. Among these older adults, 70.0% were diagnosed as inpatients and 68.9% concurrent with AIDS, compared to 41.7% and 38.9% of younger adults, respectively. On adjusted analyses, age ≥50 (OR 3.13, 95% CI 1.63, 5.98) and injection drug use (OR 4.4, 95% CI 1.31, 14.75) were positively associated with late diagnosis, whereas female gender was negatively associated with late diagnosis (OR 0.52, 95% CI 0.28, 0.98). Our data suggest that HIV testing efforts targeting older adults are essential to address the unmet needs of this population, including implementation of HIV screening guidelines in primary care settings.
Oral metronomic topotecan represents a novel approach to chemotherapy delivery which, in preclinical models, may work synergistically with pazopanib in targeting angiogenesis. A phase I and ...pharmacokinetic (PK) study of this combination was performed in children with relapsed/refractory solid tumors. Oral topotecan and pazopanib were each administered daily without interruption in 28-day cycles at five dose levels (0.12 to 0.3 mg/m2 topotecan and 125 to 160 mg/m2 pazopanib powder for oral suspension (PfOS)), with dose escalation in accordance with the rolling-six design. PK studies were performed on day 1 and at steady state. Thirty patients were enrolled, with 26 evaluable for dose-limiting toxicity (DLT), with median age 12 years (3–20). Toxicities were generally mild; the most common grade 3/4 adverse events related to protocol therapy were neutropenia (18%), thrombocytopenia (11%), lymphopenia (11%), AST elevation (11%), and lipase elevation (11%). Only two cycle 1 DLTs were observed on study, both at the 0.3/160 mg/m2 dose level comprising persistent grade 3 thrombocytopenia and grade 3 ALT elevation. No AEs experienced beyond cycle 1 required treatment discontinuation. The best response was stable disease in 10/25 patients (40%) for a median duration of 6.4 (1.7–45.1) months. The combination of oral metronomic topotecan and pazopanib is safe and tolerable in pediatric patients with solid tumors, with a recommended phase 2 dose of 0.22 mg/m2 topotecan and 160 mg/m2 pazopanib. No objective responses were observed in this heavily pre-treated patient population, although 40% did achieve stable disease for a median of 6 months. While this combination is likely of limited benefit for relapsed disease, it may play a role in the maintenance setting.
Abstract Background Ondansetron is often used in the emergency department (ED) to promote oral rehydration in children with acute gastroenteritis (AGE), yet medication solutions administered orally ...may be poorly tolerated in this population. Objectives We compared the tolerability of ondansetron oral dissolve tab (ODT) to oral solution (OS) in children presenting to the ED with AGE. Methods Using alternate-day controlled clinical trial design, children aged 3 months to 10 years received either ondansetron ODT or OS. Our primary outcome was early vomiting (within 15 min of drug administration). The secondary outcome was intravenous (i.v.) fluid administration. Results There were 462/534 eligible children who met study criteria. Demographics, severity, and duration of illness were similar between groups. Using intention-to-treat analysis, early vomiting occurred in 8/209 ODT vs. 19/253 OS children (3.8% vs. 7.5%; odds ratio OR 0.49; 95% confidence interval CI 0.18–1.21). Using as-treated analysis, 6/222 (2.7%) children receiving ODT experienced early vomiting, compared with 21/221 (9.5%) of the OS group (OR 0.26; 95% CI 0.09–0.70). The proportion of children discharged without i.v. fluids was not different ( intention-to-treat : ODT = 91.4% (191/209), OS = 94.1% (238/253), OR 1.49, 95% CI 0.69–3.28; as-treated: ODT = 92.3% (205/222), OS = 93.2% (206/221), OR 0.88, 95% CI 0.40–1.93). Conclusions Using a conservative intention-to-treat analysis, we found that children presenting to an ED with AGE did not have statistically less early vomiting with ondansetron ODT as compared with OS. However, our as-treated analysis demonstrates that children receiving ondansetron ODT experienced early vomiting approximately one-third as often as those receiving OS. The rate of i.v. fluid administration was no different between groups regardless of the type of analysis used.
To meet the first aim of the UNAIDS 90-90-90 targets, to help end the global HIV epidemic, 90% of people living with HIV should know their status by 2020. In the Democratic Republic of the Congo ...(DRC), however, UNAIDS estimates that less than 60% of people living with HIV know their status. To improve targeted HIV testing in Kinshasa and Haut-Katanga provinces of DRC, ICAP at Columbia University, New York, USA, launched an intensive index-testing programme in October, 2017. Here, we describe the programme and report testing yields before and after the intervention.
Our programme increased efforts to elicit information on sexual partners from people who newly test HIV positive or who were receiving antiretroviral therapy (index clients). All index clients were counselled on options for partner notification and tracing, including using peer counsellors who can anonymously notify and test past sexual partners in the community or provide referral to health facilities. We recorded the number of people referred by index clients and describe HIV testing yield (the proportion of people referred by index clients who tested HIV positive) for both male and female clients older than 15 years. We used χ2 tests to compare the testing yield at the start of the intervention to that 10 months after the start of programme implementation.
Between Oct 1, 2017, and Sept 30, 2018, 2167 male index clients referred 2624 adult female partners (1·2 contacts per index client) of whom 770 (29·3%) tested HIV-positive; 5135 adult female index clients referred 2593 male partners (0·5 contacts per client) of whom 866 (33·4%) were HIV positive. HIV testing yield increased over the course of implementation. At the start of implementation (Oct 1 to Nov 30, 2017, a total of 60 days), 507 adult female partners of index clients were tested for HIV with a testing yield of 12% and 386 adult male partners were tested with a yield of 15%. Between August 1 and Sept 30, 2018 (a total of 60 days), 396 adult female partners were tested with a yield of 38·4% (pre vs post, p<0·0001) and 547 adult male partners were tested with a yield of 41·7% (p<0·0001).
These results show the importance of index testing and partner notification in finding people who are living with HIV but unaware of their status. Identification of a client's sexual partners in the HIV testing service and conducting tracking and community-based HIV testing can improve HIV testing yield.
CDC and PEPFAR
Prevention of preterm delivery Morrison, Ellen A B; Cushman, Linda F
The New England journal of medicine,
2007-Nov-08, Volume:
357, Issue:
19
Journal Article
In humans, the SLC28 concentrative nucleoside transporter (CNT) protein family is represented by three Na+-coupled members; human CNT1 (hCNT1) and hCNT2 are pyrimidine and purine ...nucleoside-selective, respectively, whereas hCNT3 transports both purine and pyrimidine nucleosides and nucleoside drugs. Belonging to a phylogenetic CNT subfamily distinct from hCNT1/2, hCNT3 also mediates H+/nucleoside cotransport. Using heterologous expression in Xenopus oocytes, we have characterized a cysteineless version of hCNT3 (hCNT3C-). Processed normally to the cell surface, hCNT3C-exhibited hCNT3-like transport properties, but displayed a decrease in apparent affinity specific for Na+ and not H+. Site-directed mutagenesis experiments in wild-type and hCNT3C-backgrounds identified intramembranous Cys-561 as the residue responsible for this altered Na+-binding phenotype. Alanine at this position restored Na+ binding affinity, whereas substitution with larger neutral amino acids (threonine, valine, and isoleucine) abolished hCNT3 H+-dependent nucleoside transport activity. Independent of these findings, we have established that Cys-561 is located in a mobile region of the hCNT3 translocation pore adjacent to the nucleoside binding pocket and that access of p-chloromercuribenzene sulfonate to this residue reports a specific H+-induced conformational state of the protein (Slugoski, M. D., Ng, A. M. L., Yao, S. Y. M., Smith, K. M., Lin, C. C., Zhang, J., Karpinski, E., Cass, C. E., Baldwin, S. A., and Young, J. D. (2008) J. Biol. Chem. 283, 8496-8507). The present investigation validates hCNT3C- as a template for substituted cysteine accessibility method studies of CNTs and reveals a pivotal functional role for Cys-561 in Na+- as well as H+-coupled modes of hCNT3 nucleoside transport.
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