From policy to practice: uptake of pre-exposure prophylaxis among adolescent girls and young women in United States President's Emergency Plan for AIDS Relief-supported countries, 2017-2020.

BACKGROUND: The US President's Emergency Plan for AIDS Relief's (PEPFAR) first implemented pre-exposure prophylaxis (PrEP) for HIV prevention through the Determined, Resilient, Empowered, AIDS-Free, Mentored and Safe (DREAMS) partnership in 2016. PrEP is a critical intervention to achieve the main objective of DREAMS, reducing new HIV infections among 15-14 year old adolescent girls and young women (AGYW) in 15 high HIV burdened countries. METHODS: We describe uptake of PrEP among AGYW in PEPFAR. Most PrEP programs screened persons who tested HIV-negative for eligibility and offered PrEP as part of combination prevention with follow-up, including repeat HIV testing and counseling, at 3-month intervals. Platforms providing comprehensive services for AGYW were also leveraged. We examined two PEPFAR monitoring indicators, using the FY20Q4 Monitoring, Evaluation, Reporting (MER) indicator dataset to assess progress in PrEP uptake, and descriptive narratives to understand successes and challenges from fiscal year 2017 to 2020. To assess coverage, we calculated the PrEP to Need ratio (PnR) using a published methodology. RESULTS: From FY2017 to FY2020, 576570 total clients initiated PrEP and the number of PEPFAR countries offering PrEP doubled from 12 to 24. Of 360073 (62% of total) initiations among women, 52% were among AGYW with steady increases from year to year. Among all AGYW, 20-24-year-old women represented a significantly higher proportion of PrEP initiators than adolescents (15-19years) (64 versus 36%, P  < 0.05). Of all 186985 PrEP initiations among AGYW, 99% were in DREAMS countries. Barriers, such as low demand and adherence, were addressed through outreach efforts, including mobile sites, use of technology to educate and support AGYW, media campaigns, and engaging peers in program implementation. We saw a 2.5-fold increase in PrEP uptake among AGYW from 2018 to 2019; by 2020, all DREAMS countries were implementing PrEP. However, PrEP coverage among AGYW in DREAMS countries remains low (PnR range: 0-4.1); only two have a PnR greater than 1 where there were more PrEP users than new HIV diagnoses. CONCLUSION: PrEP uptake among AGYW has grown since 2016; however, challenges remain. Tools to improve adherence are needed to improve PrEP persistence among AGYW. National policies to facilitate greater PrEP uptake among adolescents would be beneficial. A greater need for PrEP in DREAMS countries is evident and if realized, will contribute to epidemic control.

Pre-exposure prophylaxis (PrEP) uptake and service delivery adaptations during the first wave of the COVID-19 pandemic in 21 PEPFAR-funded countries.

BACKGROUND: Mitigation measures for the first wave of the COVID-19 pandemic and burden on health systems created challenges for pre-exposure prophylaxis (PrEP) service delivery. We examined PrEP uptake in PEPFAR programs before and after the start of the COVID-19 pandemic. METHODS: We studied two PEPFAR program monitoring indicators, using routine Monitoring, Evaluation, Reporting (MER) indicators capturing uptake of PrEP (PrEP_NEW) and overall use of PrEP (PrEP_CURR). We also analyzed descriptive program narratives to understand successes and challenges field teams encountered after the start of the COVID-19 pandemic. To assess changes in coverage of PrEP across 21 countries, we calculated the "PrEP to need ratio" (PnR) using a published methodology. We defined the pre-COVID time period as April 1, 2019 -March 31, 2020 and the COVID time period as April 1, 2020 -March 31, 2021. FINDINGS: The total number of persons who initiated PrEP increased by 157% from 233,250 in the pre-COVID-19 period compared with 599,935 in the COVID-19 period. All countries, except five, noted significant increases in PrEP uptake. PrEP uptake among adolescent girls and young women (AGYW) increased by 159% from 80,452 AGYW in the pre-COVID-19 period to 208,607 AGYW in the COVID-19 period. There were 77,430 key populations (KP) initiated on PrEP in the pre-COVID-19 period and 209,114 KP initiated in the COVID-19 period (a 170% increase). The PnR increased 214% in the COVID-19 period across all PEPFAR-supported countries. Adaptations, such as multi-month dispensing (MMD) of PrEP; virtual demand creation activities; decentralized, community-based and virtual service delivery, were implemented to maintain PrEP services. CONCLUSIONS: PEPFAR programs continued to maintain and initiate new clients on PrEP despite the challenges posed by the COVID-19 pandemic. Adaptations such as MMD of PrEP and use of technology were vital in expanding service delivery and increasing PrEP coverage. FUNDING: This project has been supported by the U.S. President's Emergency Plan for AIDS Relief.

Assessing the continuum of event-based biosurveillance through an operational lens.

This research follows the Updated Guidelines for Evaluating Public Health Surveillance Systems, Recommendations from the Guidelines Working Group, published by the Centers for Disease Control and Prevention nearly a decade ago. Since then, models have been developed and complex systems have evolved with a breadth of disparate data to detect or forecast chemical, biological, and radiological events that have a significant impact on the One Health landscape. How the attributes identified in 2001 relate to the new range of event-based biosurveillance technologies is unclear. This article frames the continuum of event-based biosurveillance systems (that fuse media reports from the internet), models (ie, computational that forecast disease occurrence), and constructs (ie, descriptive analytical reports) through an operational lens (ie, aspects and attributes associated with operational considerations in the development, testing, and validation of the event-based biosurveillance methods and models and their use in an operational environment). A workshop was held in 2010 to scientifically identify, develop, and vet a set of attributes for event-based biosurveillance. Subject matter experts were invited from 7 federal government agencies and 6 different academic institutions pursuing research in biosurveillance event detection. We describe 8 attribute families for the characterization of event-based biosurveillance: event, readiness, operational aspects, geographic coverage, population coverage, input data, output, and cost. Ultimately, the analyses provide a framework from which the broad scope, complexity, and relevant issues germane to event-based biosurveillance useful in an operational environment can be characterized.

Divergent TLR7 and TLR9 signaling and type I interferon production distinguish pathogenic and nonpathogenic AIDS virus infections.

Pathogenic HIV infections of humans and simian immunodeficiency virus (SIV) infections of rhesus macaques are characterized by generalized immune activation and progressive CD4(+) T cell depletion. In contrast, natural reservoir hosts for SIV, such as sooty mangabeys, do not progress to AIDS and show a lack of aberrant immune activation and preserved CD4(+) T cell populations, despite high levels of SIV replication. Here we show that sooty mangabeys have substantially reduced levels of innate immune system activation in vivo during acute and chronic SIV infection and that sooty mangabey plasmacytoid dendritic cells (pDCs) produce markedly less interferon-alpha in response to SIV and other Toll-like receptor 7 and 9 ligands ex vivo. We propose that chronic stimulation of pDCs by SIV and HIV in non-natural hosts may drive the unrelenting immune system activation and dysfunction underlying AIDS progression. Such a vicious cycle of continuous virus replication and immunopathology is absent in natural sooty mangabey hosts.

Severe depletion of mucosal CD4+ T cells in AIDS-free simian immunodeficiency virus-infected sooty mangabeys.

HIV-infected humans and SIV-infected rhesus macaques experience a rapid and dramatic loss of mucosal CD4+ T cells that is considered to be a key determinant of AIDS pathogenesis. In this study, we show that nonpathogenic SIV infection of sooty mangabeys (SMs), a natural host species for SIV, is also associated with an early, severe, and persistent depletion of memory CD4+ T cells from the intestinal and respiratory mucosa. Importantly, the kinetics of the loss of mucosal CD4+ T cells in SMs is similar to that of SIVmac239-infected rhesus macaques. Although the nonpathogenic SIV infection of SMs induces the same pattern of mucosal target cell depletion observed during pathogenic HIV/SIV infections, the depletion in SMs occurs in the context of limited local and systemic immune activation and can be reverted if virus replication is suppressed by antiretroviral treatment. These results indicate that a profound depletion of mucosal CD4+ T cells is not sufficient per se to induce loss of mucosal immunity and disease progression during a primate lentiviral infection. We propose that, in the disease-resistant SIV-infected SMs, evolutionary adaptation to both preserve immune function with fewer mucosal CD4+ T cells and attenuate the immune activation that follows acute viral infection protect these animals from progressing to AIDS.

Avian sarcoma and leukosis virus cytopathic effect in the absence of TVB death domain signaling.

The cytopathic effect (CPE) seen with some subgroups of avian sarcoma and leukosis virus (ASLV) is associated with viral Env activation of the death-promoting activity of TVB (a tumor necrosis factor receptor-related receptor that is most closely related to mammalian TNF-related apoptosis-inducing ligand [TRAIL] receptors) and with viral superinfection leading to unintegrated viral DNA (UVD) accumulation, which is presumed to activate a cellular DNA damage response. In this study, we employed cells that express signaling-deficient ASLV receptors to demonstrate that an ASLV CPE can be uncoupled from the death-promoting functions of the TVB receptor. However, these cell-killing events were associated with much higher levels of viral superinfection and DNA accumulation than those seen when the virus used signaling-competent TVB receptors. These findings suggest that a putative cellular DNA damage response that is activated by UVD accumulation might act in concert with the death-signaling pathways activated by Env-TVB interactions to trigger cell death. Such a model is consistent with the well-established synergy that exists between TRAIL-signaling pathways and DNA damage responses which is currently being exploited in cancer therapy regimens.

Amino acid residues Tyr-67, Asn-72, and Asp-73 of the TVB receptor are important for subgroup E avian sarcoma and leukosis virus interaction.

The chicken TVB(S1) protein serves as the cellular receptor for the cytopathic subgroups B and D avian sarcoma and leukosis viruses (ASLVs) as well as for the non-cytopathic subgroup E ASLV. Previous studies had mapped the subgroup B viral interaction determinants to a region that was located between residues 32 and 46 of TVB(S1) [J. Virol. 76 (2002) 5404]. To gain a greater insight into ASLV Env-receptor interactions and the possible role of these interactions in viral cytopathic effects, we employed a homolog-scanning mutagenesis approach to identify amino acid residues important for subgroup E viral receptor function by exchanging amino acid residues between TVB(S1) and its human homolog, DR5. These studies identified residues Tyr-67, Asn-72, and Asp-73 of TVB(S1) as important subgroup E viral interaction determinants. Intriguingly, these three residues are conserved between TVB(S1) and DR5, demonstrating that the human protein contains critical subgroup E viral interaction determinants, but in this context, they cannot support viral entry. These data confirm that the molecular determinants of the TVB receptor required for subgroup E viral entry are completely distinct from those used by subgroup B viruses.

Resistance to infection by subgroups B, D, and E avian sarcoma and leukosis viruses is explained by a premature stop codon within a resistance allele of the tvb receptor gene.

Here we present the first molecular characterization of the defect associated with an avian sarcoma and leukosis virus (ASLV) receptor resistance allele, tvb(r). We show that resistance to infection by subgroups B, D, and E ASLV is explained by the presence of a single base pair mutation that distinguishes this allele from tvb(s1), an allele which encodes a receptor for all three viral subgroups. This mutation generates an in-frame stop codon that is predicted to lead to the production of a severely truncated protein.