Reported Side Effects and Adherence of Daily HIV Pre-Exposure Prophylaxis Users in Ontario, Canada: An Analysis of the Ontario Pre-Exposure Prophylaxis Cohort Study.

Side effects are a common concern of current and potential HIV pre-exposure prophylaxis (PrEP) users, potentially leading to missed doses. We examined the relationship between reported side effects and adherence in the Ontario PrEP Cohort Study (ON-PrEP). In total, 600 predominantly gay (87.3%), White (65.8%), and male (95.0%) participants completed questionnaires assessing the presence and severity of five side effect categories (nausea, diarrhea, headache, abdominal pain, and "other") as well as their adherence to daily PrEP (any missed doses in the previous 4 days). In total, 175 participants (29%) ever reported experiencing side effects: most commonly diarrhea (7.5% of study visits), and most were of mild severity. Lower incomes (p = 0.01), identifying as bisexual (p = 0.04), and baseline concern about side effects (p < 0.001) were associated with ever reporting side effects. The odds of reporting any side effects decreased by a factor of 0.44 (95% confidence interval 0.25-0.80) with each additional year of PrEP use, however 1 in 10 participants still reported side effects after 1 year of use. The odds of reporting optimal adherence were 0.48 (0.28-0.83) times lower for participants reporting any side effects, 0.67 (0.51-0.89) times lower per additional side effect category reported, and 0.78 (0.65-0.97) times lower per incremental increase in side effect severity ratings. We found some evidence of interaction between side effect measures and duration of PrEP use, suggesting that these relationships were stronger for participants taking PrEP for longer. Clinicians should make efforts to ascertain patients' experience of side effects and consider risk counseling and alternative PrEP regimens to promote adherence.

Hepatitis E virus in the Kathmandu Valley: Insights from a representative longitudinal serosurvey.

BACKGROUND: Hepatitis-E virus (HEV), an etiologic agent of acute inflammatory liver disease, is a significant cause of morbidity and mortality in South Asia. HEV is considered endemic in Nepal; but data on population-level infection transmission is sparse. METHODS: We conducted a longitudinal serosurvey in central Nepal to assess HEV exposure. At each visit, capillary blood samples were collected and analyzed for the presence of anti-HEV IgG antibodies. The study took place between February 2019 and April 2021, with up to 4 visits per participant approximately 6 months apart. RESULTS: We collected 2513 samples from 923 participants aged 0-25 years, finding a seroprevalence of 4.8% and a seroincidence rate of 10.9 per 1000 person-years. Young adults and individuals consuming surface water faced the highest incidence of infection. Geospatial analysis identified potential HEV clusters, suggesting a need for targeted interventions. SIGNIFICANCE: Our findings demonstrate that HEV is endemic in Nepal and that the risk of infection increases with age.

HIV pre-exposure prophylaxis and opportunities for vaccination against hepatitis A virus, hepatitis B virus and human papillomavirus: an analysis of the Ontario PrEP cohort study.

OBJECTIVES: Populations who seek HIV pre-exposure prophylaxis (PrEP) are disproportionately affected by hepatitis A virus (HAV), hepatitis B virus (HBV) and human papillomavirus (HPV). We examined immunity/vaccination against these infections among participants in the Ontario PrEP cohort study (ON-PrEP). METHODS: ON-PrEP is a prospective cohort of HIV-negative PrEP users from 10 Ontario clinics. We descriptively analysed baseline immunity/vaccination against HAV (IgG reactive), HBV (hepatitis B surface antibody >10) and HPV (self-reported three-dose vaccination). We further performed multivariable logistic regression to identify characteristics associated with baseline immunity/vaccination. We used cumulative incidence functions to describe vaccine uptake among participants non-immune at baseline. RESULTS: Of 633 eligible participants, 59.1% were white, 85.8% were male and 79.6% were gay. We found baseline evidence of immunity/vaccination against HAV, HBV and HPV in 69.2%, 81.2% and 16.8% of PrEP-experienced participants and 58.9%, 70.3% and 10.4% of PrEP-naïve participants, respectively. Characteristics associated with baseline HAV immunity were greater PrEP duration (adjusted OR (aOR) 1.41/year, 95% CI 1.09 to 1.84), frequent sexually transmitted and bloodborne infection (STBBI) testing (aOR 2.38, 95% CI 1.15 to 4.92) and HBV immunity (aOR 3.53, 95% CI 2.09 to 5.98). Characteristics associated with baseline HBV immunity were living in Toronto (aOR 3.54, 95% CI 1.87 to 6.70) or Ottawa (aOR 2.76, 95% CI 1.41 to 5.40), self-identifying as racialised (aOR 2.23, 95% CI 1.19 to 4.18), greater PrEP duration (aOR 1.39/year, 95% CI 1.02 to 1.90) and HAV immunity (aOR 3.75, 95% CI 2.19 to 6.41). Characteristics associated with baseline HPV vaccination were being aged ≤26 years (aOR 9.28, 95% CI 2.11 to 40.77), annual income between CAD$60 000 and CAD$119 000 (aOR 3.42, 95% CI 1.40 to 8.34), frequent STBBI testing (aOR 7.00, 95% CI 1.38 to 35.46) and HAV immunity (aOR 6.96, 95% CI 2.00 to 24.25). Among those non-immune at baseline, overall cumulative probability of immunity/vaccination was 0.70, 0.60 and 0.53 among PrEP-experienced participants and 0.93, 0.80 and 0.70 among PrEP-naïve participants for HAV, HBV and HPV, respectively. CONCLUSIONS: Baseline immunity to HAV/HBV was common, and a sizeable proportion of non-immune participants were vaccinated during follow-up. However, HPV vaccination was uncommon. Continued efforts should be made to remove barriers to HPV vaccination such as cost, inclusion in clinical guidelines and provider recommendation.

Hybrid immunity from severe acute respiratory syndrome coronavirus 2 infection and vaccination in Canadian adults: A cohort study.

Background: Few national-level studies have evaluated the impact of 'hybrid' immunity (vaccination coupled with recovery from infection) from the Omicron variants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Methods: From May 2020 to December 2022, we conducted serial assessments (each of ~4000-9000 adults) examining SARS-CoV-2 antibodies within a mostly representative Canadian cohort drawn from a national online polling platform. Adults, most of whom were vaccinated, reported viral test-confirmed infections and mailed self-collected dried blood spots (DBSs) to a central lab. Samples underwent highly sensitive and specific antibody assays to spike and nucleocapsid protein antigens, the latter triggered only by infection. We estimated cumulative SARS-CoV-2 incidence prior to the Omicron period and during the BA.1/1.1 and BA.2/5 waves. We assessed changes in antibody levels and in age-specific active immunity levels. Results: Spike levels were higher in infected than in uninfected adults, regardless of vaccination doses. Among adults vaccinated at least thrice and infected more than 6 months earlier, spike levels fell notably and continuously for the 9-month post-vaccination. In contrast, among adults infected within 6 months, spike levels declined gradually. Declines were similar by sex, age group, and ethnicity. Recent vaccination attenuated declines in spike levels from older infections. In a convenience sample, spike antibody and cellular responses were correlated. Near the end of 2022, about 35% of adults above age 60 had their last vaccine dose more than 6 months ago, and about 25% remained uninfected. The cumulative incidence of SARS-CoV-2 infection rose from 13% (95% confidence interval 11-14%) before omicron to 78% (76-80%) by December 2022, equating to 25 million infected adults cumulatively. However, the coronavirus disease 2019 (COVID-19) weekly death rate during the BA.2/5 waves was less than half of that during the BA.1/1.1 wave, implying a protective role for hybrid immunity. Conclusions: Strategies to maintain population-level hybrid immunity require up-to-date vaccination coverage, including among those recovering from infection. Population-based, self-collected DBSs are a practicable biological surveillance platform. Funding: Funding was provided by the COVID-19 Immunity Task Force, Canadian Institutes of Health Research, Pfizer Global Medical Grants, and St. Michael's Hospital Foundation. PJ and ACG are funded by the Canada Research Chairs Program.

Rapid and Comprehensive Screening for Urogenital and Gastrointestinal Schistosomiasis with Handheld Digital Microscopy Combined with Circulating Cathodic Antigen Testing.

Novel methods are required to aid the monitoring of schistosomiasis control and elimination initiatives through mass drug administration. Portable digital and mobile phone microscopy is a promising tool for this purpose. This cross-sectional study evaluated the diagnostic operating characteristics of a converted mobile phone microscope (the SchistoScope) for the detection of Schistosoma haematobium eggs, as determined by community-based field workers and expert microscopists, compared with a field gold standard of light microscopy. Three hundred sixty-five urine samples were evaluated by conventional light microscopy, with 49 (13.4%) positive for S. haematobium. Compared with light microscopy, the sensitivity and specificity of S. haematobium detection by field microscopists trained to use the SchistoScope were 26.5% (95% CI: 14.9-41.1%) and 98.4% (95% CI: 96.3-99.5%), respectively. The sensitivity and specificity of S. haematobium detection by expert microscopists using the SchistoScope was 74% (95% CI: 59.7-85.4%) and 98.1% (95% CI: 95.9-99.3%), respectively, compared with light microscopy. The sensitivity rose to 96.1% and 100% when evaluating for egg counts greater than five and 10 eggs per 10 mL, respectively. A point-of-care circulating cathodic anion (POC CCA) test was used to evaluate Schistosoma mansoni; however, there were too few positive samples to reliably comment on diagnostic characteristics. This study demonstrated that a "urine-only" approach to rapidly screen for schistosomiasis at the point of sample collection can be conducted with mobile phone microscopy (S. haematobium) coupled with POC CCA (S. mansoni). Such an approach may aid in streamlined schistosomiasis control and elimination initiatives.

Estimating the Seroincidence of Scrub Typhus using Antibody Dynamics after Infection.

Scrub typhus, a vector-borne bacterial infection, is an important but neglected disease globally. Accurately characterizing the burden is challenging because of nonspecific symptoms and limited diagnostics. Prior seroepidemiology studies have struggled to find consensus cutoffs that permit comparisons of estimates across contexts and time. In this study, we present a novel approach that does not require a cutoff and instead uses information about antibody kinetics after infection to estimate seroincidence. We use data from three cohorts of scrub typhus patients in Chiang Rai, Thailand, and Vellore, India, to characterize antibody kinetics after infection and two population serosurveys in the Kathmandu Valley, Nepal, and Tamil Nadu, India, to estimate seroincidence. The samples were tested for IgM and IgG responses to Orientia tsutsugamushi-derived recombinant 56-kDa antigen using commercial enzyme-linked immunosorbent assay kits. We used Bayesian hierarchical models to characterize antibody responses after scrub typhus infection and used the joint distributions of the peak antibody titers and decay rates to estimate population-level incidence rates in the cross-sectional serosurveys. Median responses persisted above an optical density (OD) of 1.8 for 23.6 months for IgG and an OD of 1 for 4.5 months for IgM. Among 18- to 29-year-olds, the seroincidence was 10 per 1,000 person-years (95% CI, 5-19) in Tamil Nadu, India, and 14 per 1,000 person-years (95% CI: 10-20) in the Kathmandu Valley, Nepal. When seroincidence was calculated with antibody decay ignored, the disease burden was underestimated by more than 50%. The approach can be deployed prospectively, coupled with existing serosurveys, or leverage banked samples to efficiently generate scrub typhus seroincidence estimates.

Human movement and environmental barriers shape the emergence of dengue.

Understanding how emerging infectious diseases spread within and between countries is essential to contain future pandemics. Spread to new areas requires connectivity between one or more sources and a suitable local environment, but how these two factors interact at different stages of disease emergence remains largely unknown. Further, no analytical framework exists to examine their roles. Here we develop a dynamic modelling approach for infectious diseases that explicitly models both connectivity via human movement and environmental suitability interactions. We apply it to better understand recently observed (1995-2019) patterns as well as predict past unobserved (1983-2000) and future (2020-2039) spread of dengue in Mexico and Brazil. We find that these models can accurately reconstruct long-term spread pathways, determine historical origins, and identify specific routes of invasion. We find early dengue invasion is more heavily influenced by environmental factors, resulting in patchy non-contiguous spread, while short and long-distance connectivity becomes more important in later stages. Our results have immediate practical applications for forecasting and containing the spread of dengue and emergence of new serotypes. Given current and future trends in human mobility, climate, and zoonotic spillover, understanding the interplay between connectivity and environmental suitability will be increasingly necessary to contain emerging and re-emerging pathogens.

Detection of Salmonella Typhi bacteriophages in surface waters as a scalable approach to environmental surveillance.

BACKGROUND: Environmental surveillance, using detection of Salmonella Typhi DNA, has emerged as a potentially useful tool to identify typhoid-endemic settings; however, it is relatively costly and requires molecular diagnostic capacity. We sought to determine whether S. Typhi bacteriophages are abundant in water sources in a typhoid-endemic setting, using low-cost assays. METHODOLOGY: We collected drinking and surface water samples from urban, peri-urban and rural areas in 4 regions of Nepal. We performed a double agar overlay with S. Typhi to assess the presence of bacteriophages. We isolated and tested phages against multiple strains to assess their host range. We performed whole genome sequencing of isolated phages, and generated phylogenies using conserved genes. FINDINGS: S. Typhi-specific bacteriophages were detected in 54.9% (198/361) of river and 6.3% (1/16) drinking water samples from the Kathmandu Valley and Kavrepalanchok. Water samples collected within or downstream of population-dense areas were more likely to be positive (72.6%, 193/266) than those collected upstream from population centers (5.3%, 5/95) (p=0.005). In urban Biratnagar and rural Dolakha, where typhoid incidence is low, only 6.7% (1/15, Biratnagar) and 0% (0/16, Dolakha) river water samples contained phages. All S. Typhi phages were unable to infect other Salmonella and non-Salmonella strains, nor a Vi-knockout S. Typhi strain. Representative strains from S. Typhi lineages were variably susceptible to the isolated phages. Phylogenetic analysis showed that S. Typhi phages belonged to the class Caudoviricetes and clustered in three distinct groups. CONCLUSIONS: S. Typhi bacteriophages were highly abundant in surface waters of typhoid-endemic communities but rarely detected in low typhoid burden communities. Bacteriophages recovered were specific for S. Typhi and required Vi polysaccharide for infection. Screening small volumes of water with simple, low-cost (~$2) plaque assays enables detection of S. Typhi phages and should be further evaluated as a scalable tool for typhoid environmental surveillance.

Development of prediction models to identify hotspots of schistosomiasis in endemic regions to guide mass drug administration.

Schistosomiasis is a neglected tropical disease affecting over 150 million people. Hotspots of Schistosoma transmission-communities where infection prevalence does not decline adequately with mass drug administration-present a key challenge in eliminating schistosomiasis. Current approaches to identify hotspots require evaluation 2-5 y after a baseline survey and subsequent mass drug administration. Here, we develop statistical models to predict hotspots at baseline prior to treatment comparing three common hotspot definitions, using epidemiologic, survey-based, and remote sensing data. In a reanalysis of randomized trials in 589 communities in five endemic countries, a regression model predicts whether Schistosoma mansoni infection prevalence will exceed the WHO threshold of 10% in year 5 ("prevalence hotspot") with 86% sensitivity, 74% specificity, and 93% negative predictive value (NPV; assuming 30% hotspot prevalence), and a regression model for Schistosoma haematobium achieves 90% sensitivity, 90% specificity, and 96% NPV. A random forest model predicts whether S. mansoni moderate and heavy infection prevalence will exceed a public health goal of 1% in year 5 ("intensity hotspot") with 92% sensitivity, 79% specificity, and 96% NPV, and a boosted trees model for S. haematobium achieves 77% sensitivity, 95% specificity, and 91% NPV. Baseline prevalence is a top predictor in all models. Prediction is less accurate in countries not represented in training data and for a third hotspot definition based on relative prevalence reduction over time ("persistent hotspot"). These models may be a tool to prioritize high-risk communities for more frequent surveillance or intervention against schistosomiasis, but prediction of hotspots remains a challenge.

Alveolar Echinococcus in a 70-year-old man in Ontario.

Background: Alveolar echinococcus, caused by the tapeworm Echinococcus multilocularis, mimics hepatic malignancy, and carries a mortality rate exceeding 90% in untreated patients. Methods: Diagnosis of E. multilocularis infection is established through clinical, radiographic, and microbiological assessments. Currently available laboratory diagnostics in Ontario are fresh tissue microscopy and histopathology. However, genus-specific Echinococcus enzyme-linked immunosorbent assay (ELISA) serology as well as confirmatory testing with species-specific serology and E. multilocularis polymerase chain reaction (PCR) can be obtained from external reference laboratories. Results: The article presents the first case report of human alveolar echinococcus in Ontario. We outline the multidisciplinary approach of diagnosis as well as surgical and medical management of E. multilocularis infection in a 70-year-old man in Ontario. We describe prior literature of alveolar echinococcus in Canadian settings and highlight its emerging nature with recent human case clusters in the Prairies and reports of E. multilocularis in recent veterinary literature in Ontario. Conclusion: E. multilocularis is an emerging parasitic infection in Canadian settings including Ontario. Clinicians should be aware of the emergence of this invasive infection, especially in those with close contact to canids.

Historique: Causée par le ténia Echinococcus multilocularis, l'échinococcose alvéolaire, qui imite le cancer du foie, est associée à un taux de décès de plus de 90 % chez les patients non traités. Méthodologie: Le diagnostic d'infection par l'E multilocularis est posé par une évaluation clinique, radiographique et microbiologique. La microscopie sur tissus frais et l'histopathologie sont les diagnostics microbiologiques actuellement offerts en Ontario. Cependant, il est possible d'obtenir une analyse sérologique par la méthode d'immunoabsorption enzymatique (ELISA) spécifique du genre Echinococcus ainsi que des tests de confirmation par analyse sérologique spécifique à l'espèce et par amplification en chaîne par polymérase (PCR) de l'E multilocularis auprès de laboratoires de référence externes. Résultats: L'article présente le premier rapport de cas d'échinococcose alvéolaire humaine en Ontario. Les chercheurs soulignent l'approche multidisciplinaire du diagnostic, de même que la prise en charge chirurgicale et médicale de l'infection à E multilocularis chez un homme de 70 ans de l'Ontario. Ils décrivent les publications scientifiques antérieures sur l'échinococcose alvéolaire au Canada et soulignent l'émergence de cette maladie parasitaire dans une récente grappe de cas humains des Prairies, de même que les comptes rendus de cas d'E multilocularis dans les récentes publications vétérinaires de l'Ontario. Conclusion: L'E multilocularis est une infection parasitaire en émergence au Canada, y compris en Ontario. Les cliniciens devraient être informés de l'émergence de cette infection invasive, notamment chez les personnes en contact étroit avec des canidés.

Clade I-Associated Mpox Cases Associated with Sexual Contact, the Democratic Republic of the Congo.

We report a cluster of clade I monkeypox virus infections linked to sexual contact in the Democratic Republic of the Congo. Case investigations resulted in 5 reverse transcription PCR-confirmed infections; genome sequencing suggest they belonged to the same transmission chain. This finding demonstrates that mpox transmission through sexual contact extends beyond clade IIb.