Last data update: Apr 22, 2024. (Total: 46599 publications since 2009)
Records 1-30 (of 51 Records) |
Query Trace: Nguyen HT [original query] |
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Increase in human immunodeficiency virus and syphilis prevalence and incidence among men who have sex with men, Vietnam 2015 - 2020
Thanh Nguyen HT , Nguyen LT , Thanh Hoang HT , Bui DH , Thu Phan HT , Van Khuu N , Hong Ngo HT , Dang DA , Mirzazadeh A , McFarland W , Pham TH . Int J STD AIDS 2024 35 (3) 197-205 INTRODUCTION: We assessed trends in HIV and syphilis prevalence, HIV incidence, related risk factors, and preventive behaviors among men who have sex with men (MSM) in Vietnam from 2015 to 2020. METHODS: Data originated from the HIV Sentinel Surveillance Plus system, which sampled MSM at venues and hotspots in seven of Vietnam's 63 provinces in 2015, 2016, 2018, and 2020 (N = 1100-1445 per year; ∼150-300 per province per year). RESULTS: HIV prevalence estimates increased from 6.6% (95% CI 4.5-9.6) in 2015 to 13.8% (95% CI 10.5-18.2, p = .001 for trend) in 2020 overall, and separately in An Giang, Can Tho, Hai Phong, and Khanh Hoa provinces but not in Ho Chi Minh City, Hanoi, or Kien Giang. Syphilis prevalence increased from 2.7% (95% CI 1.4-5.1) in 2015 to 12.6% (95% CI 8.7-18.0) in 2020 overall (p < .001 for trend), and separately in An Giang, Can Tho, and Hai Phong provinces but not in Ho Chi Minh City or Kien Giang. We calculated time-at-risk from first anal sex to first HIV-positive or last HIV-negative test to estimate HIV incidence. Estimated HIV incidence suggested increasing rates of seroconversion from 1.36 per 100 person-years experienced by participants in 2015 to 2.61 per 100 person-years among participants in 2020 (hazard ratio per year 1.13, 95% CI 1.08-1.18, p < .001). There was a statistically significant increase in HIV testing, STI testing, and receipt of free condoms over the period (p < .05 for trend), and a statistically significant decrease in amphetamine use (p = .043 for trend). CONCLUSIONS: Despite prevention efforts and improvements in some risk indicators, consecutive cross-sectional sampling results provide evidence of increasing incidence of HIV and syphilis among MSM in Vietnam, especially outside the major cities. Aggressive HIV prevention and treatment services can be expanded while conducting deeper investigations into the causes of these increases. |
Genetic diversity of G9, G3, G8 and G1 rotavirus group A strains circulating among children with acute gastroenteritis in Vietnam from 2016 to 2021
Le LKT , Chu MNT , Tate JE , Jiang B , Bowen MD , Esona MD , Gautam R , Jaimes J , Pham TPT , Nguyen HT , Anh DD , Trang NV , Parashar U . Infect Genet Evol 2024 105566 Rotavirus group A (RVA) is the most common cause of severe childhood diarrhea worldwide. The introduction of rotavirus vaccination programs has contributed to a reduction in hospitalizations and mortality caused by RVA. From 2016 to 21, we conducted surveillance to monitor RVA prevalence and genotype distribution in Nam Dinh and Thua Thien Hue (TT Hue) provinces where a pilot Rotavin-M1 vaccine (Vietnam) implementation took place from 2017 to 20. Out of 6626 stool samples, RVA was detected in 2164 (32.6%) by ELISA. RT-PCR using type-specific primers were used to determine the G and P genotypes of RVA-positive specimens. Whole genome sequences of a subset of 52 specimens randomly selected from 2016 to 21 were mapped using next-generation sequencing. From 2016 to 21, the G9, G3 and G8 strains dominated, with detected frequencies of 39%, 23%, and 19%, respectively; of which, the most common genotypes identified were G9P[8], G3P[8] and G8P[8]. G1 strains re-emerged in Nam Dinh and TT Hue (29.5% and 11.9%, respectively) from 2020 to 2021. G3 prevalence decreased from 74% to 20% in TT Hue and from 21% to 13% in Nam Dinh province between 2017 and 2021. The G3 strains consisted of 52% human typical G3 (hG3) and 47% equine-like G3 (eG3). Full genome analysis showed substantial diversity among the circulating G3 strains with different backgrounds relating to equine and feline viruses. G9 prevalence decreased sharply from 2016 to 2021 in both provinces. G8 strains peaked during 2019-2020 in Nam Dinh and TT Hue provinces (68% and 46%, respectively). Most G8 and G9 strains had no genetic differences over the surveillance period with very high nucleotide similarities of 99.2-99.9% and 99.1-99.7%, respectively. The G1 strains were not derived from the RVA vaccine. Changes in the genotype distribution and substantial diversity among circulating strains were detected throughout the surveillance period and differed between the two provinces. Determining vaccine effectiveness against circulating strains over time will be important to ensure that observed changes are due to natural secular variation and not from vaccine pressure. |
New insights into the neuraminidase-mediated hemagglutination activity of influenza A(H3N2) viruses
Gao R , Pascua PNQ , Nguyen HT , Chesnokov A , Champion C , Mishin VP , Wentworth DE , Gubareva LV . Antiviral Res 2023 218 105719 Influenza virus neuraminidase (NA) can act as a receptor-binding protein, a role commonly attributed to hemagglutinin (HA). In influenza A(H3N2) viruses, three NA amino acid residues have previously been associated with NA-mediated hemagglutination: T148, D151, and more recently, H150. These residues are part of the 150-loop of the NA monomer. Substitutions at 148 and 151 arise from virus propagation in laboratory cell cultures, whereas changes at 150 occurred during virus evolution in the human host. In this study, we examined the effect of natural amino acid polymorphism at position 150 on NA-mediated hemagglutination. Using the A/Puerto Rico/8/34 backbone, we generated a comprehensive panel of recombinant A(H3N2) viruses that have different NAs but shared an HA that displays poor binding to red blood cells (RBCs). None of the tested substitutions at 150 (C, H, L, R, and S) promoted NA-binding. However, we identified two new determinants of NA-binding, Q136K and T439R, that emerged during virus culturing. Similar to T148I, both Q136K and T439R reduced NA enzyme activity by 48-86% and inhibition (14- to 173-fold) by the NA inhibitor zanamivir. NA-binding was observed when a virus preparation contained approximately 10% of NA variants with either T148I or T439R, highlighting the benefit of using deep sequencing in virus characterization. Taken together, our findings provide new insights into the molecular mechanisms underlying the ability of NA to function as a binding protein. Information gained may aid in the design of new and improved NA-targeting antivirals. |
Antiviral susceptibility of clade 2.3.4.4b highly pathogenic avian influenza A(H5N1) viruses isolated from birds and mammals in the United States, 2022
Nguyen HT , Chesnokov A , De La Cruz J , Pascua PNQ , Mishin VP , Jang Y , Jones J , Di H , Ivashchenko AA , Killian ML , Torchetti MK , Lantz K , Wentworth DE , Davis CT , Ivachtchenko AV , Gubareva LV . Antiviral Res 2023 217 105679 Clade 2.3.4.4 b highly pathogenic avian influenza (HPAI) A (H5N1) viruses that are responsible for devastating outbreaks in birds and mammals pose a potential threat to public health. Here, we evaluated their susceptibility to influenza antivirals. Of 1015 sequences of HPAI A (H5N1) viruses collected in the United States during 2022, eight viruses (∼0.8%) had a molecular marker of drug resistance to an FDA-approved antiviral: three adamantane-resistant (M2-V27A), four oseltamivir-resistant (NA-H275Y), and one baloxavir-resistant (PA-I38T). Additionally, 31 viruses contained mutations that may reduce susceptibility to inhibitors of neuraminidase (NA) (n = 20) or cap-dependent endonuclease (CEN) (n = 11). A panel of 22 representative viruses was tested phenotypically. Overall, clade 2.3.4.4 b A (H5N1) viruses lacking recognized resistance mutations were susceptible to FDA-approved antivirals. Oseltamivir was least potent at inhibiting NA activity, while the investigational NA inhibitor AV5080 was most potent, including against NA mutants. A novel NA substitution T438N conferred 12-fold reduced inhibition by zanamivir, and in combination with the known marker N295S, synergistically affected susceptibility to all five NA inhibitors. In cell culture-based assays HINT and IRINA, the PA-I38T virus displayed 75- to 108-fold and 37- to 78-fold reduced susceptibility to CEN inhibitors baloxavir and investigational AV5116, respectively. Viruses with PA-I38M or PA-A37T showed 5- to 10-fold reduced susceptibilities. As HPAI A (H5N1) viruses continue to circulate and evolve, close monitoring of drug susceptibility is needed for risk assessment and to inform decisions regarding antiviral stockpiling. |
Impact and effectiveness of Rotavin-M1 under conditions of routine use in two provinces in Vietnam, 20162021, an observational and casecontrol study
VanTrang N , Tate JE , PhuongMai LT , Vu TD , Quyet NT , ThiLe LK , ThiChu MN , NgocTran MP , ThiPham TP , Nguyen HT , Hien ND , Jiang B , Yen C , Tran DN , Anh DD , Parashar UD , Anh LT , Thanh VD , Sanh LV , DieuThuy DT , Trang DC , Phong NQ , Truong DH , Tai TV , Dung PV , Van DV . Lancet Reg Health West Pac 2023 Background: Half of diarrhea hospitalizations in children aged <5 years in Vietnam are due to rotavirus. Following introduction of a locally developed and licensed oral rotavirus vaccine, Rotavin-M1, into the routine immunization program in two Vietnamese provinces, Nam Dinh and TT Hue, we describe changes in rotavirus positivity among children hospitalized for diarrhea and calculate vaccine effectiveness against moderate-to-severe rotavirus hospitalizations. Methods: Active rotavirus surveillance among children <5 years began in December 2016 at sentinel hospitals in districts where rotavirus vaccine was introduced in December 2017. To estimate reductions in rotavirus detection, we calculated risk ratios comparing rotavirus positivity pre- and post-vaccine introduction. We used a test-negative casecontrol design to calculate vaccine effectiveness. Findings: From December 2016 to May 2021, 7228 children <5 years hospitalized for diarrhea were enrolled. Following introduction, Rotavin-M1 coverage was 77% (1066/1377) in Nam Dinh and 42% (203/489) in TT Hue. In Nam Dinh, rotavirus positivity among children <5 years significantly declined by 40.6% (95% CI: 34.8%45.8%) during the three-year post-vaccine introduction period. In TT Hue, no change in rotavirus positivity was observed. Among children aged 623 months, a 2-dose series of Rotavin-M1 was 57% (95% CI: 39%70%) effective against moderate-to-severe rotavirus hospitalizations. Interpretation: Higher vaccination coverage in Nam Dinh than TT Hue likely contributed to substantial declines in rotavirus positivity observed in Nam Dinh following rotavirus vaccine introduction. Robust vaccine effectiveness was observed through the second year of life. National rotavirus vaccine introduction with high coverage may have substantial impact on reducing rotavirus disease burden in Vietnam. Funding: Bill and Melinda Gates Foundation. 2023 |
Impact and effectiveness of Rotavin-M1 under conditions of routine use in two provinces in Vietnam, 2016-2021, an observational and case-control study
Van Trang N , Tate JE , Phuong Mai LT , Vu TD , Quyet NT , Thi Le LK , Thi Chu MN , Ngoc Tran MP , Thi Pham TP , Nguyen HT , Hien ND , Jiang B , Yen C , Tran DN , Anh DD , Parashar UD , Anh LT , Thanh VD , Sanh LV , Dieu Thuy DT , Trang DC , Phong NQ , Truong DH , Tai TV , Dung PV , Van DV . Lancet Reg Health West Pac 2023 37 100789 Background: Half of diarrhea hospitalizations in children aged <5 years in Vietnam are due to rotavirus. Following introduction of a locally developed and licensed oral rotavirus vaccine, Rotavin-M1, into the routine immunization program in two Vietnamese provinces, Nam Dinh and TT Hue, we describe changes in rotavirus positivity among children hospitalized for diarrhea and calculate vaccine effectiveness against moderate-to-severe rotavirus hospitalizations. Methods: Active rotavirus surveillance among children <5 years began in December 2016 at sentinel hospitals in districts where rotavirus vaccine was introduced in December 2017. To estimate reductions in rotavirus detection, we calculated risk ratios comparing rotavirus positivity pre- and post-vaccine introduction. We used a test-negative case–control design to calculate vaccine effectiveness. Findings: From December 2016 to May 2021, 7228 children <5 years hospitalized for diarrhea were enrolled. Following introduction, Rotavin-M1 coverage was 77% (1066/1377) in Nam Dinh and 42% (203/489) in TT Hue. In Nam Dinh, rotavirus positivity among children <5 years significantly declined by 40.6% (95% CI: 34.8%–45.8%) during the three-year post-vaccine introduction period. In TT Hue, no change in rotavirus positivity was observed. Among children aged 6–23 months, a 2-dose series of Rotavin-M1 was 57% (95% CI: 39%–70%) effective against moderate-to-severe rotavirus hospitalizations. Interpretation: Higher vaccination coverage in Nam Dinh than TT Hue likely contributed to substantial declines in rotavirus positivity observed in Nam Dinh following rotavirus vaccine introduction. Robust vaccine effectiveness was observed through the second year of life. National rotavirus vaccine introduction with high coverage may have substantial impact on reducing rotavirus disease burden in Vietnam. Funding: Bill and Melinda Gates Foundation. © 2023 |
An optimized cell-based assay to assess influenza virus replication by measuring neuraminidase activity and its applications for virological surveillance
Patel MC , Flanigan D , Feng C , Chesnokov A , Nguyen HT , Elal AA , Steel J , Kondor RJ , Wentworth DE , Gubareva LV , Mishin VP . Antiviral Res 2022 208 105457 Year-round virological characterization of circulating epidemic influenza viruses is conducted worldwide to detect the emergence of viruses that may escape pre-existing immunity or acquire resistance to antivirals. High throughput phenotypic assays are needed to complement the sequence-based analysis of circulating viruses and improve pandemic preparedness. The recent entry of a polymerase inhibitor, baloxavir, into the global market further highlighted this need. Here, we optimized a cell-based assay that considerably streamlines antiviral and antigenic testing by replacing lengthy immunostaining and imaging procedures used in current assay with measuring the enzymatic activity of nascent neuraminidase (NA) molecules expressed on the surface of virus-infected cells. For convenience, this new assay was named IRINA (Influenza Replication Inhibition Neuraminidase-based Assay). IRINA was successfully validated to assess inhibitory activity of baloxavir on virus replication by testing a large set (>150) of influenza A and B viruses, including drug resistant strains and viruses collected during 2017-2022. To test its versatility, IRINA was utilized to evaluate neutralization activity of a broadly reactive human anti-HA monoclonal antibody, FI6, and post-infection ferret antisera, as well as the inhibition of NA enzyme activity by NA inhibitors. Performance of IRINA was tested in parallel using respective conventional assays. IRINA offers an attractive alternative to current phenotypic assays, while maintaining reproducibility and high throughput capacity. Additionally, the improved turnaround time may prove to be advantageous when conducting time sensitive studies, such as investigating a new virus outbreak. This assay can meet the needs of surveillance laboratories by providing a streamlined and cost-effective approach for virus characterization. |
Influenza Activity and Composition of the 2022-23 Influenza Vaccine - United States, 2021-22 Season.
Merced-Morales A , Daly P , Abd Elal AI , Ajayi N , Annan E , Budd A , Barnes J , Colon A , Cummings CN , Iuliano AD , DaSilva J , Dempster N , Garg S , Gubareva L , Hawkins D , Howa A , Huang S , Kirby M , Kniss K , Kondor R , Liddell J , Moon S , Nguyen HT , O'Halloran A , Smith C , Stark T , Tastad K , Ujamaa D , Wentworth DE , Fry AM , Dugan VG , Brammer L . MMWR Morb Mortal Wkly Rep 2022 71 (29) 913-919 Before the emergence of SARS-CoV-2, the virus that causes COVID-19, influenza activity in the United States typically began to increase in the fall and peaked in February. During the 2021-22 season, influenza activity began to increase in November and remained elevated until mid-June, featuring two distinct waves, with A(H3N2) viruses predominating for the entire season. This report summarizes influenza activity during October 3, 2021-June 11, 2022, in the United States and describes the composition of the Northern Hemisphere 2022-23 influenza vaccine. Although influenza activity is decreasing and circulation during summer is typically low, remaining vigilant for influenza infections, performing testing for seasonal influenza viruses, and monitoring for novel influenza A virus infections are important. An outbreak of highly pathogenic avian influenza A(H5N1) is ongoing; health care providers and persons with exposure to sick or infected birds should remain vigilant for onset of symptoms consistent with influenza. Receiving a seasonal influenza vaccine each year remains the best way to protect against seasonal influenza and its potentially severe consequences. |
Global update on the susceptibilities of human influenza viruses to neuraminidase inhibitors and the cap-dependent endonuclease inhibitor baloxavir, 2018-2020.
Govorkova EA , Takashita E , Daniels RS , Fujisaki S , Presser LD , Patel MC , Huang W , Lackenby A , Nguyen HT , Pereyaslov D , Rattigan A , Brown SK , Samaan M , Subbarao K , Wong S , Wang D , Webby RJ , Yen HL , Zhang W , Meijer A , Gubareva LV . Antiviral Res 2022 200 105281 Global analysis of the susceptibility of influenza viruses to neuraminidase (NA) inhibitors (NAIs) and the polymerase acidic (PA) inhibitor (PAI) baloxavir was conducted by five World Health Organization Collaborating Centres for Reference and Research on Influenza during two periods (May 2018-May 2019 and May 2019-May 2020). Combined phenotypic and NA sequence-based analysis revealed that the global frequency of viruses displaying reduced or highly reduced inhibition (RI or HRI) or potential to show RI/HRI by NAIs remained low, 0.5% (165/35045) and 0.6% (159/26010) for the 2018-2019 and 2019-2020 periods, respectively. The most common amino acid substitution was NA-H275Y (N1 numbering) conferring HRI by oseltamivir and peramivir in A(H1N1)pdm09 viruses. Combined phenotypic and PA sequence-based analysis showed that the global frequency of viruses showing reduced susceptibility to baloxavir or carrying substitutions associated with reduced susceptibility was low, 0.5% (72/15906) and 0.1% (18/15692) for the 2018-2019 and 2019-2020 periods, respectively. Most (n = 61) of these viruses had I38→T/F/M/S/L/V PA amino acid substitutions. In Japan, where baloxavir use was highest, the rate was 4.5% (41/919) in the 2018-2019 period and most of the viruses (n = 32) had PA-I38T. Zoonotic viruses isolated from humans (n = 32) in different countries did not contain substitutions in NA associated with NAI RI/HRI phenotypes. One A(H5N6) virus had a dual substitution PA-I38V + PA-E199G, which may reduce susceptibility to baloxavir. Therefore, NAIs and baloxavir remain appropriate choices for the treatment of influenza virus infections, but close monitoring of antiviral susceptibility is warranted. |
Cluster of Oseltamivir-Resistant and Hemagglutinin Antigenically Drifted Influenza A(H1N1)pdm09 Viruses, Texas, USA, January 2020
Mohan T , Nguyen HT , Kniss K , Mishin VP , Merced-Morales AA , Laplante J , St George K , Blevins P , Chesnokov A , De La Cruz JA , Kondor R , Wentworth DE , Gubareva LV . Emerg Infect Dis 2021 27 (7) 1953-1957 Four cases of oseltamivir-resistant influenza A(H1N1)pdm09 virus infection were detected among inhabitants of a border detention center in Texas, USA. Hemagglutinin of these viruses belongs to 6B.1A5A-156K subclade, which may enable viral escape from preexisting immunity. Our finding highlights the necessity to monitor both drug resistance and antigenic drift of circulating viruses. |
Testing early warning and response systems through a full-scale exercise in Vietnam.
Clara A , Dao ATP , Tran Q , Tran PD , Dang TQ , Nguyen HT , Tran QD , Rzeszotarski P , Talbert K , Stehling-Ariza T , Veasey F , Clemens L , Mounts AW , Lofgren H , Balajee SA , Do TT . BMC Public Health 2021 21 (1) 409 BACKGROUND: Simulation exercises can functionally validate World Health Organization (WHO) International Health Regulations (IHR 2005) core capacities. In 2018, the Vietnam Ministry of Health (MOH) conducted a full-scale exercise (FSX) in response to cases of severe viral pneumonia with subsequent laboratory confirmation for Middle East Respiratory Syndrome Coronavirus (MERS-CoV) to evaluate the country's early warning and response capabilities for high-risk events. METHODS: An exercise planning team designed a complex fictitious scenario beginning with one case of severe viral pneumonia presenting at the hospital level and developed all the materials required for the exercise. Actors, controllers and evaluators were trained. In August 2018, a 3-day exercise was conducted in Quang Ninh province and Hanoi city, with participation of public health partners at the community, district, province, regional and national levels. Immediate debriefings and an after-action review were conducted after all exercise activities. Participants assessed overall exercise design, conduction and usefulness. RESULTS: FSX findings demonstrated that the event-based surveillance component of the MOH surveillance system worked optimally at different administrative levels. Detection and reporting of signals at the community and health facility levels were appropriate. Triage, verification and risk assessment were successfully implemented to identify a high-risk event and trigger timely response. The FSX identified infection control, coordination with internal and external response partners and process documentation as response challenges. Participants positively evaluated the exercise training and design. CONCLUSIONS: This exercise documents the value of exercising surveillance capabilities as part of a real-time operational scenario before facing a true emergency. The timing of this exercise and choice of disease scenario was particularly fortuitous given the subsequent appearance of COVID-19. As a result of this exercise and subsequent improvements made by the MOH, the country may have been better able to deal with the emergence of SARS-CoV-2 and contain it. |
Susceptibility of widely diverse influenza a viruses to PB2 polymerase inhibitor pimodivir.
Patel MC , Chesnokov A , Jones J , Mishin VP , De La Cruz JA , Nguyen HT , Zanders N , Wentworth DE , Davis TC , Gubareva LV . Antiviral Res 2021 188 105035 Pimodivir exerts an antiviral effect on the early stages of influenza A virus replication by inhibiting the cap-binding function of polymerase basic protein 2 (PB2). In this study, we used a combination of sequence analysis and phenotypic methods to evaluate pimodivir susceptibility of influenza A viruses collected from humans and other hosts. Screening PB2 sequences for substitutions previously associated with reduced pimodivir susceptibility revealed a very low frequency among seasonal viruses circulating in the U.S. during 2015-2020 (<0.01%; 3/11,934) and among non-seasonal viruses collected in various countries during the same period (0.2%; 18/8971). Pimodivir potently inhibited virus replication in two assays, a single-cycle HINT and a multi-cycle FRA, with IC(50) values in a nanomolar range. Median IC(50) values determined by HINT were similar for both subtypes of seasonal viruses, A (H1N1)pdm09 and A (H3N2), across three seasons. Human seasonal viruses with PB2 substitutions S324C, S324R, or N510K displayed a 27-317-fold reduced pimodivir susceptibility. In addition, pimodivir was effective at inhibiting replication of a diverse group of animal-origin viruses that have pandemic potential, including avian viruses of A (H5N6) and A (H7N9) subtypes. A rare PB2 substitution H357N was identified in an A (H4N2) subtype poultry virus that displayed >100-fold reduced pimodivir susceptibility. Our findings demonstrate a broad inhibitory activity of pimodivir and expand the existing knowledge of amino acid substitutions that can reduce susceptibility to this investigational antiviral. |
Asians and Asian subgroups are underrepresented in medical research studies published in high-impact generalist journals
Nguyen HT , Zheng A , Gugel A , Kistin CJ . J Immigr Minor Health 2021 23 (3) 646-649 Including diverse participants in biomedical research is essential to reduce health disparities. We assessed the inclusion of Asians in original research studies conducted in North America and published from 2015-2016 in six high-impact generalist journals: New England Journal of Medicine, Journal of the American Medical Association (JAMA), JAMA Internal Medicine, JAMA Pediatrics, Annals of Internal Medicine, and Pediatrics. We determined race reporting method, participant percentage, and reporting of outcomes or implications of findings for Asians and Asian subgroups. Of 1077 studies, 263 articles (24.4%) identified Asians as a distinct race/ethnicity; the median percentage of Asians per study was 3.8%. Of the 263 articles, 28 (10.6%) studies reported outcomes for Asians; nine (3.4%) articles included information about Asian subgroups. Asians are underrepresented in high-impact medical research studies in North America. Efforts to improve study enrollment, data collection, and reporting of findings of Asians in studies remain essential to improve health outcomes for this population. |
Detection of baloxavir resistant influenza A viruses using next generation sequencing and pyrosequencing methods.
Patel MC , Mishin VP , De La Cruz JA , Chesnokov A , Nguyen HT , Wilson MM , Barnes J , Kondor RJG , Wentworth DE , Gubareva LV . Antiviral Res 2020 182 104906 Baloxavir, a new antiviral drug targeting cap-dependent endonuclease activity of polymerase acidic (PA) protein of influenza viruses, is now approved in multiple countries. Several substitutions at isoleucine 38 in PA protein (e.g., PA-I38T) have been associated with decreased baloxavir susceptibility in vitro and in vivo. In recent years, next generation sequencing (NGS) analysis and pyrosequencing have been used by CDC and U.S. Public Health Laboratories to monitor drug susceptibility of influenza viruses. Here we described an improved pyrosequencing assay for detecting influenza A viruses carrying substitutions at PA-38. Cyclic and customized orders of nucleotide dispensation were evaluated, and pyrosequencing results were compared to those generated using NGS. Our data showed that the customized nucleotide dispensation has improved the pyrosequencing assay performance in identification of double mixtures (e.g., PA-38I/T); however, identification of PA-38 variants in triple mixtures remains a challenge. While NGS analysis indicated the presence of PA-I38K in one clinical specimen and isolate, our attempts to detect this mutation by pyrosequencing or recover the virus carrying PA-I38K in cell culture were unsuccessful, raising a possibility of a rarely occurring sequencing error. Overall, pyrosequencing provides a convenient means to detect baloxavir resistant influenza viruses when NGS is unavailable or a faster turnaround time is required. |
Developing monitoring and evaluation tools for event-based surveillance: experience from Vietnam
Clara A , Dao ATP , Mounts AW , Bernadotte C , Nguyen HT , Tran QM , Tran QD , Dang TQ , Merali S , Balajee SA , Do TT . Global Health 2020 16 (1) 38 BACKGROUND: In 2016-2017, Vietnam's Ministry of Health (MoH) implemented an event-based surveillance (EBS) pilot project in six provinces as part of Global Health Security Agenda (GHSA) efforts. This manuscript describes development and design of tools for monitoring and evaluation (M&E) of EBS in Vietnam. METHODS: A strategic EBS framework was developed based on the EBS implementation pilot project's goals and objectives. The main process and outcome components were identified and included input, activities, outputs, and outcome indicators. M&E tools were developed to collect quantitative and qualitative data. The tools included a supervisory checklist, a desk review tool, a key informant interview guide, a focus group discussion guide, a timeliness form, and an online acceptability survey. An evaluation team conducted field visits for assessment of EBS 5-9 months after implementation. RESULTS: The quantitative data collected provided evidence on the number and type of events that were being reported, the timeliness of the system, and the event-to-signal ratio. The qualitative and subjective data collected helped to increase understanding of the system's field utility and acceptance by field staff, reasons for non-compliance with established guidelines, and other factors influencing implementation. CONCLUSIONS: The use of M&E tools for the EBS pilot project in Vietnam provided data on signals and events reported, timeliness of reporting and response, perceptions and opinions of implementers, and fidelity of EBS implementation. These data were valuable for Vietnam's MoH to understand the function of the EBS program, and the success and challenges of implementing this project in Vietnam. |
Global update on the susceptibilities of human influenza viruses to neuraminidase inhibitors and the cap-dependent endonuclease inhibitor baloxavir, 2017-2018.
Takashita E , Daniels RS , Fujisaki S , Gregory , Gubareva LV , Huang W , Hurt AC , Lackenby A , Nguyen HT , Pereyaslov D , Roe M , Samaan M , Subbarao K , Tse H , Wang D , Yen H-L , Zhang W , Meijer A . Antiviral Res 2020 175 104718-104718 The global analysis of neuraminidase inhibitor (NAI) susceptibility of influenza viruses has been conducted since the 2012-13 period. In 2018 a novel cap-dependent endonuclease inhibitor, baloxavir, that targets polymerase acidic subunit (PA) was approved for the treatment of influenza virus infection in Japan and the United States. For this annual report, the susceptibilities of influenza viruses to NAIs and baloxavir were analyzed. A total of 15409 viruses, collected by World Health Organization (WHO) recognized National Influenza Centers and other laboratories between May 2017 and May 2018, were assessed for phenotypic NAI susceptibility by five WHO Collaborating Centers (CCs). The 50% inhibitory concentration (IC(50)) was determined for oseltamivir, zanamivir, peramivir and laninamivir. Reduced inhibition (RI) or highly reduced inhibition (HRI) by one or more NAIs was exhibited by 0.8% of viruses tested (n = 122). The frequency of viruses with RI or HRI has remained low since this global analysis began (2012-13: 0.6%; 2013-14: 1.9%; 2014-15: 0.5%; 2015-16: 0.8%; 2016-17: 0.2%). PA gene sequence data, available from public databases (n = 13523), were screened for amino acid substitutions associated with reduced susceptibility to baloxavir (PA E23G/K/R, PA A36V, PA A37T, PA I38F/M/T/L, PA E119D, PA E199G): 11 (0.08%) viruses possessed such substitutions. Five of them were included in phenotypic baloxavir susceptibility analysis by two WHO CCs and IC(50) values were determined. The PA variant viruses showed 6-17-fold reduced susceptibility to baloxavir. Overall, in the 2017-18 period the frequency of circulating influenza viruses with reduced susceptibility to NAIs or baloxavir was low, but continued monitoring is important. |
Susceptibility of influenza A, B, C, and D viruses to Baloxavir
Mishin VP , Patel MC , Chesnokov A , De La Cruz J , Nguyen HT , Lollis L , Hodges E , Jang Y , Barnes J , Uyeki T , Davis CT , Wentworth DE , Gubareva LV . Emerg Infect Dis 2019 25 (10) 1969-1972 Baloxavir showed broad-spectrum in vitro replication inhibition of 4 types of influenza viruses (90% effective concentration range 1.2-98.3 nmol/L); susceptibility pattern was influenza A > B > C > D. This drug also inhibited influenza A viruses of avian and swine origin, including viruses that have pandemic potential and those resistant to neuraminidase inhibitors. |
Replicative fitness of seasonal influenza A viruses with decreased susceptibility to baloxavir
Chesnokov A , Patel MC , Mishin VP , De La Cruz JA , Lollis L , Nguyen HT , Dugan V , Wentworth DE , Gubareva LV . J Infect Dis 2019 221 (3) 367-371 Susceptibility of influenza A viruses to baloxavir can be affected by changes at amino acid residue 38 in polymerase acidic (PA) protein. Information on replicative fitness of PA-I38-substituted viruses remains sparse. We demonstrated that substitutions I38L/M/S/T not only had a differential effect on baloxavir susceptibility (9- to 116-fold), but also on in vitro replicative fitness. While I38L conferred undiminished growth, other substitutions led to mild attenuation. In a ferret model, control viruses outcompeted those carrying I38M or I38T substitutions, although their advantage was limited. These findings offer insights into the attributes of baloxavir resistant viruses needed for informed risk assessment. |
Detection of oseltamivir-resistant zoonotic and animal influenza A viruses using the rapid influenza antiviral resistance test.
Hodges EN , Mishin VP , De la Cruz J , Guo Z , Nguyen HT , Fallows E , Stevens J , Wentworth DE , Davis CT , Gubareva LV . Influenza Other Respir Viruses 2019 13 (5) 522-7 Mutations in the influenza virus neuraminidase (NA) that cause reduced susceptibility to the NA inhibitor (NAI) oseltamivir may occur naturally or following antiviral treatment. Currently, detection uses either a traditional NA inhibition assay or gene sequencing to identify known markers associated with reduced inhibition by oseltamivir. Both methods are laborious and require trained personnel. The influenza antiviral resistance test (iART), a prototype system developed by Becton, Dickinson and Company for research use only, offers a rapid and simple method to identify such viruses. This study investigated application of iART to influenza A viruses isolated from non-human hosts with a variety of NA subtypes (N1-N9). |
Evaluation of Vietnam's post-exposure prophylaxis delivery system, 2017
Nguyen HT , Le ND , Pham TN , Urabe MI , Afriyie DO , Otsu S , Tran DN , Tran HG , Nguyen HV , Le HT , Tran CH . Vaccine 2019 37 Suppl 1 A20-A27 Background: Canine-mediated human rabies deaths typically occur in poor and rural populations with limited access to rabies biologics: vaccine and immunoglobulin. A critical aspect of reducing rabies deaths is understanding how these countries procure, deliver, and forecast rabies biologics. Vietnam is one of the few endemic countries where biologics is widely available. However, a formal evaluation of its current rabies biologics distribution system has not been conducted. Methods: In 2017, we conducted a formal evaluation of Vietnam's rabies biologics distribution system. Our goals were (1)to identify centers providing rabies biologics (2)identify costs to the patient and centers and (3)assess the rabies biologic procurement and delivery system at eligible district and provincial centers (provides and orders biologics for itself and other centers directly from the manufacture). To conduct the formal evaluation, we developed a standardized survey that was distributed to centers. Results: Of the 780 designated rabies biologics centers in Vietnam, 659 (84%)of them provide rabies immunoglobulin (eRIG), vaccine, or both. Of the 177 eligible centers, 90% (160)responded to the survey. The average costs to patients were $8.45 (range: 5.43–12.77)for one dose of IM injection, $13.90 (range: 11.86–16.71)for domestic eRIG, and $23 (21.11–27.11)for imported eRIG. Respondents reported experiencing delays in receiving vaccine in 50 centers and eRIG in 14 centers within the past year. Respondents stated their top three challenges in providing biologics were: delays or shortages from manufactures, lack of funds to pay for biologics, and the high cost of biologics. Conclusions and relevance: Despite the wide availability of biologics in Vietnam, more work is needed to provide affordable and reliable supply of biologics to patients. This includes the expansion of ID injection use throughout the country to lower vaccine demand, and decrease the costs to centers and patients. Furthermore, a more coordinated effort to share biologics among centers, possibly through a more centralized system at the provincial level may alleviate delays and shortages. © 2019 The Author(s) |
Insights into the antigenic advancement of influenza A(H3N2) viruses, 2011-2018.
Jorquera PA , Mishin VP , Chesnokov A , Nguyen HT , Mann B , Garten R , Barnes J , Hodges E , De La Cruz J , Xu X , Katz J , Wentworth DE , Gubareva LV . Sci Rep 2019 9 (1) 2676 Influenza A(H3N2) viruses evade human immunity primarily by acquiring antigenic changes in the haemagglutinin (HA). HA receptor-binding features of contemporary A(H3N2) viruses hinder traditional antigenic characterization using haemagglutination inhibition and promote selection of HA mutants. Thus, alternative approaches are needed to reliably assess antigenic relatedness between circulating viruses and vaccines. We developed a high content imaging-based neutralization test (HINT) to reduce antigenic mischaracterization resulting from virus adaptation to cell culture. Ferret reference antisera were raised using clinical specimens containing viruses representing recent vaccine strains. Analysis of viruses circulating during 2011-2018 showed that gain of an N158-linked glycosylation in HA was a molecular determinant of antigenic distancing between A/Hong Kong/4801/2014-like (clade 3C.2a) and A/Texas/50/2012-like viruses (clade 3C.1), while multiple evolutionary HA F193S substitution were linked to antigenic distancing from A/Switzerland/97152963/2013-like (clade 3C.3a) and further antigenic distancing from A/Texas/50/2012-like viruses. Additionally, a few viruses carrying HA T135K and/or I192T showed reduced neutralization by A/Hong Kong/4801/2014-like antiserum. Notably, this technique elucidated the antigenic characteristics of clinical specimens, enabling direct characterization of viruses produced in vivo, and eliminating in vitro culture, which rapidly alters the genotype/phenotype. HINT is a valuable new antigenic analysis tool for vaccine strain selection. |
Assessing baloxavir susceptibility of influenza viruses circulating in the United States during the 2016/17 and 2017/18 seasons
Gubareva LV , Mishin VP , Patel MC , Chesnokov A , Nguyen HT , De La Cruz J , Spencer S , Campbell AP , Sinner M , Reid H , Garten R , Katz JM , Fry AM , Barnes J , Wentworth DE . Euro Surveill 2019 24 (3) The anti-influenza therapeutic baloxavir targets cap-dependent endonuclease activity of polymerase acidic (PA) protein. We monitored baloxavir susceptibility in the United States with next generation sequencing analysis supplemented by phenotypic one-cycle infection assay. Analysis of PA sequences of 6,891 influenza A and B viruses collected during 2016/17 and 2017/18 seasons showed amino acid substitutions: I38L (two A(H1N1)pdm09 viruses), E23G (two A(H1N1)pdm09 viruses) and I38M (one A(H3N2) virus); conferring 4-10-fold reduced susceptibility to baloxavir. |
Factors influencing community event-based surveillance: Lessons learned from pilot implementation in Vietnam
Clara A , Dao ATP , Do TT , Tran PD , Tran QD , Ngu ND , Ngo TH , Phan HC , Nguyen TTP , Bernadotte-Schmidt C , Nguyen HT , Alroy KA , Balajee SA , Mounts AW . Health Secur 2018 16 S66-s75 Community event-based surveillance aims to enhance the early detection of emerging public health threats and thus build health security. The Ministry of Health of Vietnam launched a community event-based surveillance pilot program in 6 provinces to improve the early warning functions of the existing surveillance system. An evaluation of the pilot program took place in 2017 and 2018. Data from this evaluation were analyzed to determine which factors were associated with increased detection and reporting. Results show that a number of small, local events were detected and reported through community event-based surveillance, supporting the notion that it would also facilitate the rapid detection and reporting of potentially larger events or outbreaks. The study showed the value of supportive supervision and monitoring to sustain community health worker reporting and the importance of conducting evaluations for community event-based surveillance programs to identify barriers to effective implementation. |
Event-based surveillance at community and healthcare facilities, Vietnam, 2016-2017
Clara A , Do TT , Dao ATP , Tran PD , Dang TQ , Tran QD , Ngu ND , Ngo TH , Phan HC , Nguyen TTP , Lai AT , Nguyen DT , Nguyen MK , Nguyen HTM , Becknell S , Bernadotte C , Nguyen HT , Nguyen QC , Mounts AW , Balajee SA . Emerg Infect Dis 2018 24 (9) 1649-1658 Surveillance and outbreak reporting systems in Vietnam required improvements to function effectively as early warning and response systems. Accordingly, the Ministry of Health of Vietnam, in collaboration with the US Centers for Disease Control and Prevention, launched a pilot project in 2016 focusing on community and hospital event-based surveillance. The pilot was implemented in 4 of Vietnam's 63 provinces. The pilot demonstrated that event-based surveillance resulted in early detection and reporting of outbreaks, improved collaboration between the healthcare facilities and preventive sectors of the ministry, and increased community participation in surveillance and reporting. |
Highly Pathogenic Avian Influenza A(H5N1) Viruses at the Animal-Human Interface in Vietnam, 2003-2010.
Creanga A , Hang NLK , Cuong VD , Nguyen HT , Phuong HVM , Thanh LT , Thach NC , Hien PT , Tung N , Jang Y , Balish A , Dang NH , Duong MT , Huong NT , Hoa DN , Tho ND , Klimov A , Kapella BK , Gubareva L , Kile JC , Hien NT , Mai LQ , Davis CT . J Infect Dis 2017 216 S529-s538 Mutation and reassortment of highly pathogenic avian influenza A(H5N1) viruses at the animal-human interface remain a major concern for emergence of viruses with pandemic potential. To understand the relationship of H5N1 viruses circulating in poultry and those isolated from humans, comprehensive phylogenetic and molecular analyses of viruses collected from both hosts in Vietnam between 2003 and 2010 were performed. We examined the temporal and spatial distribution of human cases relative to H5N1 poultry outbreaks and characterized the genetic lineages and amino acid substitutions in each gene segment identified in humans relative to closely related viruses from avian hosts. Six hemagglutinin clades and 8 genotypes were identified in humans, all of which were initially identified in poultry. Several amino acid mutations throughout the genomes of viruses isolated from humans were identified, indicating the potential for poultry viruses infecting humans to rapidly acquire molecular markers associated with mammalian adaptation and antiviral resistance. |
Antiviral drug-resistant influenza B viruses carrying H134N substitution in neuraminidase, Laos, February 2016
Baranovich T , Vongphrachanh P , Ketmayoon P , Sisouk T , Chomlasack K , Khanthamaly V , Nguyen HT , Mishin VP , Marjuki H , Barnes JR , Garten RJ , Stevens J , Wentworth DE , Gubareva LV . Emerg Infect Dis 2017 23 (4) 686-690 In February 2016, three influenza B/Victoria/2/87 lineage viruses exhibiting 4- to 158-fold reduced inhibition by neuraminidase inhibitors were detected in Laos. These viruses had an H134N substitution in the neuraminidase and replicated efficiently in vitro and in ferrets. Current antiviral drugs may be ineffective in controlling infections caused by viruses harboring this mutation. |
Estimating false-recent classification for the limiting-antigen avidity EIA and BED-capture enzyme immunoassay in Vietnam: Implications for HIV-1 incidence estimates
Shah NS , Duong YT , Le LV , Tuan NA , Parekh B , Ha HT , Pham QD , Cuc CT , Dobbs T , Tram TH , Lien TT , Wagar N , Yang C , Martin A , Wolfe MI , Nguyen HT , Kim AA . AIDS Res Hum Retroviruses 2017 33 (6) 546-554 BACKGROUND: Laboratory tests that can distinguish recent from long-term HIV infection are used to estimate HIV incidence in a population but can potentially misclassify a proportion of long-term HIV infections as recent. Correct application of an assay requires determination of the proportion false recents (PFR) as part of the assay characterization and for calculating HIV incidence in a local population using a HIV incidence assay. METHODS: From April 2009 to December 2010, blood specimens were collected from HIV-infected individuals attending 9 outpatient clinics (OPCs) in Vietnam (4 from northern and 5 from southern Vietnam). Participants were living with HIV for ≥1 year and reported no antiretroviral drug (ARV) treatment. Basic demographic data and clinical information were collected. Specimens were tested with the BED capture enzyme immunoassay (BED-CEIA) and the Limiting-antigen (LAg)-Avidity EIA. PFR was estimated by dividing the number of specimens classified as recent by the total number of specimens; 95% confidence intervals (CI) were calculated. Specimens that tested recent had viral load testing performed. RESULTS: Among 1,813 specimens (north, n= 942 and south, n = 871), the LAg-Avidity EIA PFR was 1.7% (CI 1.2-2.4) and differed by region [north 2.7% (CI 1.8, 3.9) versus south 0.7% (CI 0.3, 1.5); p=0.002]. The BED-CEIA PFR was 2.3% (CI 1.7, 3.0) and varied by region [north 3.4% (CI: 2.4, 4.7) versus south 1.0% (CI 0.5, 1.2), p<0.001]. Excluding specimens with an undetectable VL, the LAg-Avidity EIA PFR was 1.2% (CI: 0.8, 1.9) and the BED-CEIA PFR was 1.7% (CI: 1.2, 2.4). CONCLUSIONS: The LAg-Avidity EIA PFR was lower than the BED-CEIA PFR. After excluding specimens with an undetectable VL, the PFR for both assays was similar. A low PFR should facilitate the implementation of the LAg-Avidity EIA for cross-sectional incidence estimates in Vietnam. |
Global update on the susceptibility of human influenza viruses to neuraminidase inhibitors, 2014-2015
Hurt AC , Besselaar TG , Daniels RS , Ermetal B , Fry A , Gubareva L , Huang W , Lackenby A , Lee RT , Lo J , Maurer-Stroh S , Nguyen HT , Pereyaslov D , Rebelo-de-Andrade H , Siqueira MM , Takashita E , Tashiro M , Tilmanis D , Wang D , Zhang W , Meijer A . Antiviral Res 2016 132 178-85 The World Health Organization (WHO) Collaborating Centres for Reference and Research on Influenza (WHO CCs) tested 13,312 viruses collected by WHO recognized National Influenza Centres between May 2014 and May 2015 to determine 50% inhibitory concentration (IC50) data for neuraminidase inhibitors (NAIs) oseltamivir, zanamivir, peramivir and laninamivir. Ninety-four per cent of the viruses tested by the WHO CCs were from three WHO regions: Western Pacific, the Americas and Europe. Approximately 0.5% (n = 68) of viruses showed either highly reduced inhibition (HRI) or reduced inhibition (RI) (n = 56) against at least one of the four NAIs. Of the twelve viruses with HRI, six were A(H1N1)pdm09 viruses, three were A(H3N2) viruses and three were B/Yamagata-lineage viruses. The overall frequency of viruses with RI or HRI by the NAIs was lower than that observed in 2013-14 (1.9%), but similar to the 2012-13 period (0.6%). Based on the current analysis, the NAIs remain an appropriate choice for the treatment and prophylaxis of influenza virus infections. |
Detecting spread of avian influenza A(H7N9) virus beyond China
Millman AJ , Havers F , Iuliano AD , Davis CT , Sar B , Sovann L , Chin S , Corwin AL , Vongphrachanh P , Douangngeun B , Lindblade KA , Chittaganpitch M , Kaewthong V , Kile JC , Nguyen HT , Pham DV , Donis RO , Widdowson MA . Emerg Infect Dis 2015 21 (5) 741-9 During February 2013-March 2015, a total of 602 human cases of low pathogenic avian influenza A(H7N9) were reported; no autochthonous cases were reported outside mainland China. In contrast, since highly pathogenic avian influenza A(H5N1) reemerged during 2003 in China, 784 human cases in 16 countries and poultry outbreaks in 53 countries have been reported. Whether the absence of reported A(H7N9) outside mainland China represents lack of spread or lack of detection remains unclear. We compared epidemiologic and virologic features of A(H5N1) and A(H7N9) and used human and animal influenza surveillance data collected during April 2013-May 2014 from 4 Southeast Asia countries to assess the likelihood that A(H7N9) would have gone undetected during 2014. Surveillance in Vietnam and Cambodia detected human A(H5N1) cases; no A(H7N9) cases were detected in humans or poultry in Southeast Asia. Although we cannot rule out the possible spread of A(H7N9), substantial spread causing severe disease in humans is unlikely. |
Structural and functional analysis of surface proteins from an A(H3N8) influenza virus isolated from New England harbor seals
Yang H , Nguyen HT , Carney PJ , Guo Z , Chang JC , Jones J , Davis CT , Villanueva JM , Gubareva LV , Stevens J . J Virol 2014 89 (5) 2801-12 In late 2011, an A(H3N8) influenza virus infection resulted in the deaths of 162 New England harbor seals. Virus sequence analysis and virus receptor binding studies highlighted potential markers responsible for mammalian adaptation and a mixed receptor binding preference (Anthony et al. ; MBio 3: e00166-00112). Here we present a detailed structural and biochemical analysis of the surface antigens of this virus. Results obtained with recombinant proteins for both the hemagglutinin and neuraminidase, indicate a true avian receptor binding preference. Although the detection of this virus in new species highlights an increased potential for cross-species transmission with these viruses, our results indicate that the A(H3N8) virus currently poses a low risk to humans. IMPORTANCE: Cross-species transmission of zoonotic influenza viruses increases public health concerns. Here we report a molecular and structural study of the major surface proteins from an A(H3N8) influenza virus isolated from New England harbor seals. Results improve our understanding of these viruses as they evolve and provide important information to aid ongoing risk assessment analyses, as these zoonotic influenza viruses continue to circulate and adapt to new hosts. |
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