ORF8 and ORF3b antibodies are accurate serological markers of early and late SARS-CoV-2 infection.

The SARS-CoV-2 virus emerged in December 2019 and has caused a worldwide pandemic due to the lack of any pre-existing immunity. Accurate serology testing is urgently needed to help diagnose infection, determine past exposure of populations and assess the response to a future vaccine. The landscape of antibody responses to SARS-CoV-2 is unknown. In this study, we utilized the luciferase immunoprecipitation system to assess the antibody responses to 15 different SARS-CoV-2 antigens in patients with COVID-19. We identified new targets of the immune response to SARS-CoV-2 and show that nucleocapsid, open reading frame (ORF)8 and ORF3b elicit the strongest specific antibody responses. ORF8 and ORF3b antibodies, taken together as a cluster of points, identified 96.5% of COVID-19 samples at early and late time points of disease with 99.5% specificity. Our findings could be used to develop second-generation diagnostic tests to improve serological assays for COVID-19 and are important in understanding pathogenicity.

Author Correction: ORF8 and ORF3b antibodies are accurate serological markers of early and late SARS-CoV-2 infection.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Evaluation of a SARS-CoV-2 Surrogate Virus Neutralization Test for Detection of Antibody in Human, Canine, Cat, and Hamster Sera.

Surrogate neutralization assays for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that can be done without biosafety level 3 containment and in multiple species are desirable. We evaluate a recently developed surrogate virus neutralization test (sVNT) in comparison to 90% plaque reduction neutralization tests (PRNT90) in human, canine, cat, and hamster sera. With PRNT90 as the reference, sVNT had sensitivity of 98.9% and specificity of 98.8%. Using a panel of immune sera corresponding to other coronaviruses, we confirm the lack of cross-reactivity to other coronaviruses in SARS-CoV-2 sVNT and PRNT90, except for cross-reactivity to SARS-CoV-1 in sVNT.

SARS-CoV-2 Virus Culture and Subgenomic RNA for Respiratory Specimens from Patients with Mild Coronavirus Disease.

We investigated 68 respiratory specimens from 35 coronavirus disease patients in Hong Kong, of whom 32 had mild disease. We found that severe acute respiratory syndrome coronavirus 2 and subgenomic RNA were rarely detectable beyond 8 days after onset of illness. However, virus RNA was detectable for many weeks by reverse transcription PCR.

Exhaled air dispersion during high-flow nasal cannula therapy versus CPAP via different masks.

BACKGROUND: High-flow nasal cannula (HFNC) is an emerging therapy for respiratory failure but the extent of exhaled air dispersion during treatment is unknown. We examined exhaled air dispersion during HFNC therapy versus continuous positive airway pressure (CPAP) on a human patient simulator (HPS) in an isolation room with 16 air changes·h-1. METHODS: The HPS was programmed to represent different severity of lung injury. CPAP was delivered at 5-20 cmH2O via nasal pillows (Respironics Nuance Pro Gel or ResMed Swift FX) or an oronasal mask (ResMed Quattro Air). HFNC, humidified to 37°C, was delivered at 10-60 L·min-1 to the HPS. Exhaled airflow was marked with intrapulmonary smoke for visualisation and revealed by laser light-sheet. Normalised exhaled air concentration was estimated from the light scattered by the smoke particles. Significant exposure was defined when there was ≥20% normalised smoke concentration. RESULTS: In the normal lung condition, mean±sd exhaled air dispersion, along the sagittal plane, increased from 186±34 to 264±27 mm and from 207±11 to 332±34 mm when CPAP was increased from 5 to 20 cmH2O via Respironics and ResMed nasal pillows, respectively. Leakage from the oronasal mask was negligible. Mean±sd exhaled air distances increased from 65±15 to 172±33 mm when HFNC was increased from 10 to 60 L·min-1. Air leakage to 620 mm occurred laterally when HFNC and the interface tube became loose. CONCLUSION: Exhaled air dispersion during HFNC and CPAP via different interfaces is limited provided there is good mask interface fitting.

Territory-wide population-based study of chronic hepatitis C infection and implications for hepatitis elimination in Hong Kong.

BACKGROUND: To study the epidemiology of chronic hepatitis C virus infection in Hong Kong and to estimate the service gap for achieving the WHO hepatitis elimination targets of attaining a diagnosis rate of 90%, treatment rate of 80% and 65% reduction in mortality rate by 2030. METHODS: From January 2005 to March 2017, patients who were tested positive for anti-HCV were retrospectively retrieved from all public hospitals in Hong Kong. The epidemiological data of 15 participating hospitals were analysed. RESULTS: A total of 11 309 anti-HCV+ patients were identified and the estimated diagnosis rate was 50.9%. Our HCV-infected patients were ageing (median age 59). The all-cause mortality rate increased from 26.2 to 54.8 per 1000 person-years over the last decade. Our estimated treatment rate was 12.4%. Among the treated patients, 93.6% had received pegylated interferon/ribavirin (Peg-IFN/RBV) but only 10.8% had received interferon-free direct-acting antivirals (DAAs). In a cohort of 1533 patients, 39% already had advanced liver fibrosis or cirrhosis. The sustained virological response rate for Peg-IFN/RBV and DAAs were 74.8% and 97.2% respectively. However, more than 70% of patients were not subjected to interferon treatment for various reasons. Patients who achieved SVR were associated with a significantly lower risk of HCC (4.7% vs 9.6%, P = 0.005) and death (1.7% vs 23.8%, P < 0.001). CONCLUSION: Our diagnosis rate, treatment rate and mortality rate reduction were still low, particularly the Peg-IFN outcomes, making it difficult to meet the WHO hepatitis elimination targets. A more generalized use of DAAs is urgently needed to improve the situation.

From SARS to Avian Influenza Preparedness in Hong Kong.

The first human H5N1 case was diagnosed in Hong Kong in 1997. Since then, experience in effective preparedness strategies that target novel influenza viruses has expanded. Here, we report on avian influenza preparedness in public hospitals in Hong Kong to illustrate policies and practices associated with control of emerging infectious diseases. The Hong Kong government's risk-based preparedness plan for influenza pandemics includes 3 response levels for command, control, and coordination frameworks for territory-wide responses. The tiered levels of alert, serious, and emergency response enable early detection based on epidemiological exposure followed by initiation of a care bundle. Information technology, laboratory preparedness, clinical and public health management, and infection control preparedness provide a comprehensive and generalizable preparedness plan for emerging infectious diseases.

Surrogate neutralization responses following severe acute respiratory syndrome coronavirus 2 vaccination in people with HIV: comparison between inactivated and mRNA vaccine.

OBJECTIVE: People with HIV (PWH) co-infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are at higher odds of severe diseases. Whereas the immunogenicity of mRNA vaccine and adenovirus-vectored vaccine was similar between PWH in stable condition and healthy adults, the effects of inactivated vaccines are not known. DESIGN: Prospective longitudinal observational study in real-world setting. METHODS: Adult PWH in care and planning to receive either inactivated (day 0 and day 28) or mRNA-based (day 0 and day 21) vaccine against SARS-CoV-2 were recruited, with blood samples collected over 6 months for surrogate virus neutralization test (sVNT). Demographic and clinical data including age, sex, CD4 + cell count, and suppressed viral load (SVL) status were transcribed for analyses, by simple and multivariable linear regression models, and multivariable linear generalized estimating equations (GEE). RESULTS: A total of 611 HIV patients, 91% male patients, were recruited, of whom 423 and 184 have received mRNA-based and inactivated vaccine, respectively. The seroconversion rate was 99% for mRNA-based vs, 86% for inactivated vaccine [odds ratio (OR) = 21.56, P  = 0.004]. At 6 months, mRNA-based vaccine continued to give a higher response (94 vs. 57%, P  < 0.001). The temporal pattern varied between the two vaccines. By GEE, mRNA-based vaccine ( B  = 40.59, P  < 0.001) and latest SVL status ( B  = 10.76, P  = 0.01) were positively associated with sVNT level, but not latest CD4 + cell count. CONCLUSION: In HIV patients, inactivated vaccine gave a lower peak and shorter duration of sVNT responses compared with mRNA vaccine. The results suggested that different strategies may be needed in boosting the immunity in anticipation of the emergence of variants in the community.

SARS-CoV-2 accessory proteins reveal distinct serological signatures in children.

The antibody response magnitude and kinetics may impact clinical severity, serological diagnosis and long-term protection of COVID-19, which may play a role in why children experience lower morbidity. We therefore tested samples from 122 children in Hong Kong with symptomatic (n = 78) and asymptomatic (n = 44) SARS-CoV-2 infections up to 200 days post infection, relative to 71 infected adults (symptomatic n = 61, and asymptomatic n = 10), and negative controls (n = 48). We assessed serum IgG antibodies to a 14-wide antigen panel of structural and accessory proteins by Luciferase Immuno-Precipitation System (LIPS) assay and circulating cytokines. Infected children have lower levels of Spike, Membrane, ORF3a, ORF7a, ORF7b antibodies, comparable ORF8 and elevated E-specific antibodies than adults. Combination of two unique antibody targets, ORF3d and ORF8, can accurately discriminate SARS-CoV-2 infection in children. Principal component analysis reveals distinct pediatric serological signatures, and the highest contribution to variance from adults are antibody responses to non-structural proteins ORF3d, NSP1, ORF3a and ORF8. From a diverse panel of cytokines that can modulate immune priming and relative inflammation, IL-8, MCP-1 and IL-6 correlate with the magnitude of pediatric antibody specificity and severity. Antibodies to SARS-CoV-2 internal proteins may become an important sero surveillance tool of infection with the roll-out of vaccines in the pediatric population.

Neutralizing antibody titres in SARS-CoV-2 infections.

The SARS-CoV-2 pandemic poses the greatest global public health challenge in a century. Neutralizing antibody is a correlate of protection and data on kinetics of virus neutralizing antibody responses are needed. We tested 293 sera from an observational cohort of 195 reverse transcription polymerase chain reaction (RT-PCR) confirmed SARS-CoV-2 infections collected from 0 to 209 days after onset of symptoms. Of 115 sera collected ≥61 days after onset of illness tested using plaque reduction neutralization (PRNT) assays, 99.1% remained seropositive for both 90% (PRNT90) and 50% (PRNT50) neutralization endpoints. We estimate that it takes at least 372, 416 and 133 days for PRNT50 titres to drop to the detection limit of a titre of 1:10 for severe, mild and asymptomatic patients, respectively. At day 90 after onset of symptoms (or initial RT-PCR detection in asymptomatic infections), it took 69, 87 and 31 days for PRNT50 antibody titres to decrease by half (T1/2) in severe, mild and asymptomatic infections, respectively. Patients with severe disease had higher peak PRNT90 and PRNT50 antibody titres than patients with mild or asymptomatic infections. Age did not appear to compromise antibody responses, even after accounting for severity. We conclude that SARS-CoV-2 infection elicits robust neutralizing antibody titres in most individuals.

SARS-CoV-2 specific T cell responses are lower in children and increase with age and time after infection.

SARS-CoV-2 infection of children leads to a mild illness and the immunological differences with adults are unclear. Here, we report SARS-CoV-2 specific T cell responses in infected adults and children and find that the acute and memory CD4+ T cell responses to structural SARS-CoV-2 proteins increase with age, whereas CD8+ T cell responses increase with time post-infection. Infected children have lower CD4+ and CD8+ T cell responses to SARS-CoV-2 structural and ORF1ab proteins when compared with infected adults, comparable T cell polyfunctionality and reduced CD4+ T cell effector memory. Compared with adults, children have lower levels of antibodies to ß-coronaviruses, indicating differing baseline immunity. Total T follicular helper responses are increased, whilst monocyte numbers are reduced, indicating rapid adaptive co-ordination of the T and B cell responses and differing levels of inflammation. Therefore, reduced prior ß-coronavirus immunity and reduced T cell activation in children might drive milder COVID-19 pathogenesis.

Molecular Evolution of Human Coronavirus 229E in Hong Kong and a Fatal COVID-19 Case Involving Coinfection with a Novel Human Coronavirus 229E Genogroup.

Compared to other human coronaviruses, the genetic diversity and evolution of human coronavirus 229E (HCoV-229E) are relatively understudied. We report a fatal case of COVID-19 pneumonia coinfected with HCoV-229E in Hong Kong. Genome sequencing of SARS-CoV-2 and HCoV-229E from a nasopharyngeal sample of the patient showed that the SARS-CoV-2 strain HK13 was most closely related to SARS-CoV-2 type strain Wuhan-Hu-1 (99.99% nucleotide identity), compatible with his recent history of travel to Wuhan. The HCoV-229E strain HK20-42 was most closely related to HCoV-229E strain SC0865 from the United States (99.86% nucleotide identity). To investigate if it may represent a newly emerged HCoV-229E genotype in Hong Kong, we retrieved 41 archived respiratory samples that tested positive for HCoV-229E from 2004 to 2019. Pneumonia and exacerbations of chronic airway diseases were common among infected patients. Complete RdRp, S, and N gene sequencing of the 41 HCoV-229E strains revealed that our contemporary HCoV-229E strains have undergone significant genetic drift with clustering of strains in chronological order. Two novel genogroups were identified, in addition to previously described genogroups 1 to 4, with recent circulating strains including strain HK20-42 belonging to novel genogroup 6. Positive selection was detected in the spike protein and receptor-binding domain, which may be important for viral evolution at the receptor-binding interphase. Molecular dating analysis showed that HCoV-229E shared the most recent common ancestor with bat and camel/alpaca 229E-related viruses at ∼1884, while camel/alpaca viruses had a relatively recent common ancestor at ∼1999. Further studies are required to ascertain the evolutionary origin and path of HCoV-229E.IMPORTANCE Since its first appearance in the 1960s, the genetic diversity and evolution of human coronavirus 229E (HCoV-229E) have been relatively understudied. In this study, we report a fatal case of COVID-19 coinfected with HCoV-229E in Hong Kong. Genome sequencing revealed that our SARS-CoV-2 strain is highly identical to the SARS-CoV-2 strain from Wuhan, compatible with the patient's recent travel history, whereas our HCoV-229E strain in this study is highly identical to a recent strain in the United States. We also retrieved 41 archived HCoV-229E strains from 2004 to 2019 in Hong Kong for sequence analysis. Pneumonia and exacerbations of chronic airway diseases were common diagnoses among the 41 patients. The results showed that HCoV-229E was evolving in chronological order. Two novel genogroups were identified in addition to the four preexisting HCoV-229E genogroups, with recent circulating strains belonging to novel genogroup 6. Molecular clock analysis dated bat-to-human and bat-to-camelid transmission to as early as 1884.

Chronic hepatitis C genotype 6 responds better to pegylated interferon and ribavirin combination therapy than genotype 1.

BACKGROUND AND AIMS: Chronic hepatitis C genotype 6 is common in Hong Kong, especially among i.v. drug abusers. Responses of these patients to combination of pegylated interferon and ribavirin treatment were inconsistent and the numbers of patients involved in previous studies were small. We performed a retrospective study to compare the therapeutic responses of this regimen in patients infected with genotype 6 and genotype 1. METHODS: Seventy patients with either genotype 6 or genotype 1 were recruited. Both groups received 800-1200 mg of ribavirin daily plus either 180 mg of pegylated alpha-interferon-2a or 1.5 mg/kg pegylated alpha-interferon-2b weekly for 48 weeks. Their responses to treatments were compared. RESULTS: The early virological response to combination therapy of patients with genotype 6 was significantly better than that of genotype 1 (88.6% vs 74.3%, P = 0.03). Significant difference was also identified in the end of treatment response of the two genotypes (60% vs 81.4% for genotype 1 and 6, respectively; P = 0.005). The sustained virological response (SVR) to treatment in patients with genotype 6 was also significantly superior to that of patients with genotype 1 (75.7% vs 57.1%, P = 0.02). Multiple logistic regression analysis demonstrated that age of 55 years or less, genotypes of hepatitis C virus, liver biopsy staging and baseline hepatitis C virus RNA of 200,000 IU/mL or less were independent predictors for better SVR in this cohort. CONCLUSION: Patients with chronic hepatitis C genotype 6 respond better to pegylated interferon and ribavirin combination treatment than patients with genotype 1.

The differential impacts of non-locally acquired infections and treatment interventions on heterosexual HIV transmission in Hong Kong.

INTRODUCTION: Heterosexual infections have contributed to a high proportion of the HIV burden in Asia and Eastern Europe. Human mobility and non-local infections are important features in some cities/countries. An understanding of the determinants of the sustained growth of the heterosexual HIV epidemics would enable the potential impacts of treatment-based interventions to be assessed. METHODS: We developed a compartmental model for heterosexual HIV transmissions, parameterized by clinical and surveillance data (1984-2014) in Hong Kong. HIV sequence data were included for examining genetic linkages and clustering pattern. We performed sensitivity analyses to evaluate effects of high-risk sexual partnership and proportions of non-locally acquired infections. Four hypothetical interventions (a) immediate treatment, (b) enhancement of retention in care, (c) HIV testing campaigns, and (d) test-and-treat strategy, were examined. RESULTS: Data of 2174 patients (723 female and 1451 male) diagnosed with HIV between 1984 and 2012 in Hong Kong were collected for model parameterization. Among 1229 sequences of non-MSM (men who have sex with men) patients, 70% were isolates and 17% were either dyads or triads. In base-case scenario, the total estimated number of new infections in 2012-2023 would be 672 for male and 452 for female. Following 100% retention in care intervention, the total proportion of averted new infections in 2012-2023 would be 7% for male and 10% for female. HIV testing campaign in 2012 and 2017 followed by 100% immediate treatment strategy would avert 5% and 9% of male and female new infections, respectively. In the epidemic model, an increase of high-risk sexual partnership from 6% to 9% would increase the epidemic growth (annual number of newly diagnosed and newly infected cases) by about 10%. If no non-locally acquired infection occurred as from 2012, the epidemic growth would slump. To control the heterosexual epidemic, periodic HIV testing at 5-year intervals with immediate treatment would avert 5-13% of annual new infections in 2013-2023. CONCLUSIONS: Enhanced HIV testing with immediate treatment is most effective in controlling the heterosexual epidemic, the impacts of which might however be attenuated by any increase of non-locally acquired infection, assuming little variations of high risk partnership over time.

Escalating infection control response to the rapidly evolving epidemiology of the coronavirus disease 2019 (COVID-19) due to SARS-CoV-2 in Hong Kong.

OBJECTIVE: To describe the infection control preparedness measures undertaken for coronavirus disease (COVID-19) due to SARS-CoV-2 (previously known as 2019 novel coronavirus) in the first 42 days after announcement of a cluster of pneumonia in China, on December 31, 2019 (day 1) in Hong Kong. METHODS: A bundled approach of active and enhanced laboratory surveillance, early airborne infection isolation, rapid molecular diagnostic testing, and contact tracing for healthcare workers (HCWs) with unprotected exposure in the hospitals was implemented. Epidemiological characteristics of confirmed cases, environmental samples, and air samples were collected and analyzed. RESULTS: From day 1 to day 42, 42 of 1,275 patients (3.3%) fulfilling active (n = 29) and enhanced laboratory surveillance (n = 13) were confirmed to have the SARS-CoV-2 infection. The number of locally acquired case significantly increased from 1 of 13 confirmed cases (7.7%, day 22 to day 32) to 27 of 29 confirmed cases (93.1%, day 33 to day 42; P < .001). Among them, 28 patients (66.6%) came from 8 family clusters. Of 413 HCWs caring for these confirmed cases, 11 (2.7%) had unprotected exposure requiring quarantine for 14 days. None of these was infected, and nosocomial transmission of SARS-CoV-2 was not observed. Environmental surveillance was performed in the room of a patient with viral load of 3.3 × 106 copies/mL (pooled nasopharyngeal and throat swabs) and 5.9 × 106 copies/mL (saliva), respectively. SARS-CoV-2 was identified in 1 of 13 environmental samples (7.7%) but not in 8 air samples collected at a distance of 10 cm from the patient's chin with or without wearing a surgical mask. CONCLUSION: Appropriate hospital infection control measures was able to prevent nosocomial transmission of SARS-CoV-2.

Measles outbreak from Hong Kong International Airport to the hospital due to secondary vaccine failure in healthcare workers.

OBJECTIVE: To report an outbreak of measles with epidemiological link between Hong Kong International Airport (HKIA) and a hospital. METHODS: Epidemiological investigations, patients' measles serology, and phylogenetic analysis of the hemagglutinin (H) and nucleoprotein (N) genes of measles virus isolates were conducted. RESULTS: In total, 29 HKIA staff of diverse ranks and working locations were infected with measles within 1 month. Significantly fewer affected staff had history of travel than non-HKIA-related measles patients [10 of 29 (34.5%) vs 28 of 35 (80%); P < .01]. Of 9 airport staff who could recall detailed exposure history, 6 (66.7%) had visited self-service food premises at HKIA during the incubation period, where food trays, as observed during the epidemiological field investigation, were not washed after use. Furthermore, 1 airport baggage handler who was admitted to hospital A before rash onset infected 2 healthcare workers (HCWs) known to have 2 doses of MMR vaccination with positive measles IgG and lower viral loads in respiratory specimens. Infections in these 2 HCWs warranted contact tracing of another 168 persons (97 patients and 71 HCWs). Phylogenetic comparison of H and N gene sequences confirmed the clonality of outbreak strains. CONCLUSION: Despite good herd immunity with overall seroprevalence of >95% against measles, major outbreaks of measles occurred among HKIA staff having daily contact with many international pssengers. Lessons from severe acute respiratory syndrome (SARS) and measles outbreaks suggested that an airport can be a strategic epidemic center. Pre-exanthem transmission of measles from airport staff to HCWs with secondary vaccine failure poses a grave challenge to hospital infection control.

Review of dengue fever cases in Hong Kong during 1998 to 2005.

OBJECTIVE: To describe the epidemiology, clinical and laboratory findings, and outcomes of patients presenting locally with dengue. DESIGN: Retrospective review of case records. SETTING: Public hospitals, Hong Kong. PATIENTS: Medical records of all laboratory-confirmed dengue patients admitted to public hospitals during 1998 to 2005 were reviewed retrospectively. RESULTS: A total of 126 cases were identified, 123 (98%) being dengue fever and three (2%) dengue haemorrhagic fever. One patient who had blood transfusion-acquired dengue fever was highlighted. A total of 116 (92%) cases were 'imported', while 10 (8%) were local. Among the 56 dengue cases confirmed by reverse transcription-polymerase chain reaction, dengue virus type 1 was the most common accounting for 48% of them, followed by type 2, type 3, and type 4 responsible for 23%, 16%, and 13%, respectively. Only type 1 and type 2 were present in locally acquired infections. The median age of the patients was 38 years and the mean duration of hospitalisation was 6 days. There was no mortality, and nearly all patients (98%) presented with fever. Other symptoms at presentation included: myalgia (83%), headache (65%), fatigue (59%), and skin rash (60%). More than one third of patients had gastro-intestinal and upper respiratory complaints. Maculopapular skin rash was the most common physical finding. Thrombocytopenia, neutropenia, and lymphopenia were present in 86%, 78%, and 69% of the patients, respectively. In only 29% of the patients was dengue fever included in the initial differential diagnosis. The demographic, clinical, and laboratory findings as well as outcomes did not differ significantly among the four dengue serotypes, but the lowest lymphocyte counts of type 3 was lower than the other serotypes (P=0.004). CONCLUSION: When physicians encounter patients with a relevant travel history, presenting with fever and skin rash, and having compatible haematological findings, dengue fever should be included in the differential diagnosis.

Pre-exposure prophylaxis (PrEP) for MSM in low HIV incidence places: should high risk individuals be targeted?

Pre-exposure prophylaxis (PrEP) targeting high-risk men who have sex with men (MSM) has been shown to be a cost-effective HIV control measure. However, the approach could be a challenge in low HIV incidence places with a low proportion of high-risk MSM. To examine the impact of PrEP in such setting in Asia, we developed an epidemic model and conducted cost-effectiveness analysis using empirical multicentre clinical and HIV sequence data from HIV-infected MSM in Hong Kong, in conjunction with behavioural data of local MSM. Without PrEP, the HIV incidence (per 100 person-years) would increase from 1.1 to 1.6 between 2011 and 2021. PrEP could avert 3-63% of total new infections in a five-year period (2017-2021), the variability of which depends on the implementation strategies and combination with test-and-treat. However, under current market drug price in 2016, the incremental cost per quality-adjusted life-year gained (QALYG) of PrEP (USD1583136/QALYG) is almost 3 times higher than test-and-treat intervention alone (USD396874/QALYG). Assuming 93% fall of PrEP drug price and in combination with test-and-treat, putting 30% of MSM on non-targeting PrEP would be more feasible, cost-effective (USD268915/QALYG), and could avert more new infections (40%). PrEP could contribute to HIV epidemic control in a low incidence place.

Anti-inflammatory effects of adjunctive macrolide treatment in adults hospitalized with influenza: A randomized controlled trial.

INTRODUCTION: - Macrolides can ameliorate inflammation in respiratory diseases, providing clinical benefits. Data in influenza is lacking. METHOD: - A randomized, open-label, multicenter trial among adults hospitalized for laboratory-confirmed influenza was conducted. Study treatments of oseltamivir and azithromycin (500 mg/day), or oseltamivir alone, both for 5 days, were allocated at 1:1 ratio. The primary outcome was plasma cytokine/chemokine concentration change over time (Day 0-10); secondary outcomes were viral load and symptom score changes. Generalized Estimating Equation (GEE) models were used to analyze longitudinal data. RESULTS: - Fifty patients were randomized to the oseltamivir-azithromycin or oseltamivir groups, with comparable baseline characteristics (age, 57 ± 18 years; A/H3N2, 70%), complications (72%), and viral load. Pro-inflammatory cytokines IL-6 (GEE: ß -0.037, 95%CI-0.067,-0.007, P = 0.016; reduction from baseline -83.4% vs -59.5%), CXCL8/IL-8 (ß -0.018, 95%CI-0.037,0.000, P = 0.056; -80.5% vs -58.0%), IL-17 (ß -0.064, 95%CI-0.117,-0.012, P = 0.015; -74.0% vs -34.3%), CXCL9/MIG (ß -0.010, 95%CI-0.020,0.000, P = 0.043; -71.3% vs -56.0%), sTNFR-1, IL-18, and CRP declined faster in the oseltamivir-azithromycin group. There was a trend toward faster symptom resolution (ß -0.463, 95%CI-1.297,0.371). Viral RNA decline (P = 0.777) and culture-negativity rates were unaffected. Additional ex vivo studies confirmed reduced induction of IL-6 (P = 0.017) and CXCL8/IL-8 (P = 0.005) with azithromycin. CONCLUSION: - We found significant anti-inflammatory effects with adjunctive macrolide treatment in adults with severe influenza infections. Virus control was unimpaired. Clinical benefits of a macrolide-containing regimen deserve further study. [ClinicalTrials.gov NCT01779570].