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Summary: Background: Integrase inhibitor (INSTI) with boosted darunavir (DRV/r), a regimen with a high-resistance barrier, avoiding NRTI toxicities, might be a switching option in children living with HIV (CLWHIV). Methods: SMILE is a randomised non-inferiority trial evaluating safety and antiviral efficacy of once-daily INSTI + DRV/r vs. continuing on current standard-of-care (SOC) triple ART (2NRTI + boosted PI/NNRTI) in virologically-suppressed CLWHIV aged 6–18 years. The primary outcome is the proportion with confirmed HIV-RNA ≥50 copies/mL by week 48, estimated by Kaplan–Meier method. Non-inferiority margin was 10%. Registration number for SMILE are: ISRCTN11193709, NCT #: NCT02383108. Findings: Between 10th June 2016 and 30th August 2019, 318 participants were enrolled from Africa 53%, Europe 24%, Thailand 15% and Latin America 8%, 158 INSTI + DRV/r [153 Dolutegravir (DTG); 5 Elvitegravir (EVG)], 160 SOC. Median (range) age was 14.7 years (7.6–18.0); CD4 count 782 cells/mm3 (227–1647); 61% female. Median follow-up was 64.3 weeks with no loss to follow-up. By 48 weeks, 8 INSTI + DRV/r vs. 12 SOC had confirmed HIV-RNA ≥50 copies/mL; difference (INSTI + DRV/r-SOC) −2.5% (95% CI: −7.6, 2.5%), showing non-inferiority. No major PI or INSTI resistance mutations were observed. There were no differences in safety between arms. By week 48, difference (INSTI + DRV/r-SOC) in mean CD4 count change from baseline was −48.3 cells/mm3 (95% CI: −93.4, −3.2; p = 0.036). Difference (INSTI + DRV/r-SOC) in mean HDL change from baseline was −4.1 mg/dL (95% CI: −6.7, −1.4; p = 0.003). Weight and Body Mass Index (BMI) increased more in INSTI + DRV/r than SOC [difference: 1.97 kg (95% CI: 1.1, 2.9; p

Resumen: El objetivo del Consenso Mexicano para el Tratamiento de la Hepatitis C fue el de desarrollar un documento como guía en la práctica clínica con aplicabilidad en México. Se tomó en cuenta la opinión de expertos en el tema con especialidad en: gastroenterología, infectología y hepatología. Se realizó una revisión de la bibliografía en MEDLINE, EMBASE y CENTRAL mediante palabras claves referentes al tratamiento de la hepatitis C. Posteriormente se evaluó la calidad de la evidencia mediante el sistema GRADE y se redactaron enunciados, los cuales fueron sometidos a voto mediante un sistema modificado Delphi, y posteriormente se realizó revisión y corrección de los enunciados por un panel de 34 votantes. Finalmente se clasificó el nivel de acuerdo para cada oración. Esta guía busca dar recomendaciones con énfasis en los nuevos antivirales de acción directa y de esta manera facilitar su uso en la práctica clínica. Cada caso debe ser individualizado según sus comorbilidades y el manejo de estos pacientes siempre debe ser multidisciplinario. Abstract: The aim of the Mexican Consensus on the Treatment of Hepatitis C was to develop clinical practice guidelines applicable to Mexico. The expert opinion of specialists in the following areas was taken into account: gastroenterology, infectious diseases, and hepatology. A search of the medical literature was carried out on the MEDLINE, EMBASE, and CENTRAL databases through keywords related to hepatitis C treatment. The quality of evidence was subsequently evaluated using the GRADE system and the consensus statements were formulated. The statements were then voted upon, using the modified Delphi system, and reviewed and corrected by a panel of 34 voting participants. Finally, the level of agreement was classified for each statement. The present guidelines provide recommendations with an emphasis on the new direct-acting antivirals, to facilitate their use in clinical practice. Each case must be individualized according to the comorbidities involved and patient management must always be multidisciplinary. Palabras clave: Consenso, Agentes antivirales de acción directa, Regímenes libres de interferón, Ribavirina, Keywords: Consensus, Direct-acting antiviral agents, Interferon-free regimens, Ribavirin

Aedes mosquito-borne viruses (ABVs) place a substantial strain on public health resources in the Americas. Vector control of Aedes mosquitoes is an important public health strategy to decrease or prevent spread of ABVs. The ongoing Targeted Indoor Residual Spraying (TIRS) trial is an NIH-sponsored clinical trial to study the efficacy of a novel, proactive vector control technique to prevent dengue virus (DENV), Zika virus (ZIKV), and chikungunya virus (CHIKV) infections in the endemic city of Merida, Yucatan, Mexico. The primary outcome of the trial is laboratory-confirmed ABV infections in neighborhood clusters. Despite the difficulties caused by the COVID-19 pandemic, by early 2021 the TIRS trial completed enrollment of 4,792 children aged 2-15 years in 50 neighborhood clusters which were allocated to control or intervention arms via a covariate-constrained randomization algorithm. Here, we describe the makeup and ABV seroprevalence of participants and mosquito population characteristics in both arms before TIRS administration. Baseline surveys showed similar distribution of age, sex, and socio-economic factors between the arms. Serum samples from 1,399 children were tested by commercially available ELISAs for presence of anti-ABV antibodies. We found that 45.1% of children were seropositive for one or more flaviviruses and 24.0% were seropositive for CHIKV. Of the flavivirus-positive participants, most were positive for ZIKV-neutralizing antibodies by focus reduction neutralization testing which indicated a higher proportion of participants with previous ZIKV than DENV infections within the cohort. Both study arms had statistically similar seroprevalence for all viruses tested, similar socio-demographic compositions, similar levels of Ae. aegypti infestation, and similar observed mosquito susceptibility to insecticides. These findings describe a population with a high rate of previous exposure to ZIKV and lower titers of neutralizing antibodies against DENV serotypes, suggesting susceptibility to future outbreaks of flaviviruses is possible, but proactive vector control may mitigate these risks., Competing Interests: The authors have declared that no competing interests exist., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Since the Zika virus (ZIKV) pandemic in 2015-2017, there has been a near absence of reported cases in the Americas outside of Brazil. However, the conditions for Aedes-borne transmission persist in Latin America, and the threat of ZIKV transmission is increasing as population immunity wanes. Mexico has reported only 70 cases of laboratory-confirmed ZIKV infection since 2020, with no cases recorded in the Yucatán peninsula. Here, we provide evidence of active ZIKV transmission, despite the absence of official case reports, in the city of Mérida, Mexico, the capital of the state of Yucatán. Capitalizing on an existing cohort, we detected cases in participants with symptoms consistent with flavivirus infection from 2021 to 2022. Serum samples from suspected cases were tested for ZIKV RNA by polymerase chain reaction or ZIKV-reactive IgM by ELISA. To provide more specific evidence of exposure, focus reduction neutralization tests were performed on ELISA-positive samples. Overall, we observed 25 suspected ZIKV infections for an estimated incidence of 2.8 symptomatic cases per 1,000 persons per year. Our findings emphasize the continuing threat of ZIKV transmission in the setting of decreased surveillance and reporting.

While residual insecticide applications have the potential to decrease pathogen transmission by reducing the density of vectors and shifting the age structure of the adult mosquito population towards younger stages of development, this double entomological impact has not been documented for Aedes aegypti. Aedes collected from households enrolled in a cluster-randomized trial evaluating the epidemiological impact of targeted indoor residual spraying (TIRS) in Merida, Mexico, were dissected and their age structure characterized by the Polovodova combined with Christopher's ovariole growth methods. In total, 813 females were dissected to characterize age structure at 1, 3, 6, and 9 months post-TIRS. Significant differences in the proportion of nulliparous Ae. aegypti females between the treatment groups was found at one-month post-TIRS (control: 35% vs. intervention: 59%), three months (20% vs. 49%) but not at six or nine months post-TIRS. TIRS significantly shiftted Ae. aegypti age structure towards younger stages and led to a non-linear reduction in survivorship compared to the control arm. Reduced survivorship also reduced the number of arbovirus transmitting females (those who survived the extrinsic incubation period). Our findings provide strong evidence of the full entomological impact of TIRS, with important implications for quantifying the epidemiological impact of vector control methods., (© 2023. The Author(s).)

Background: Integrase inhibitor (INSTI) with boosted darunavir (DRV/r), a regimen with a high-resistance barrier, avoiding NRTI toxicities, might be a switching option in children living with HIV (CLWHIV)., Methods: SMILE is a randomised non-inferiority trial evaluating safety and antiviral efficacy of once-daily INSTI + DRV/r vs. continuing on current standard-of-care (SOC) triple ART (2NRTI + boosted PI/NNRTI) in virologically-suppressed CLWHIV aged 6-18 years. The primary outcome is the proportion with confirmed HIV-RNA ≥50 copies/mL by week 48, estimated by Kaplan-Meier method. Non-inferiority margin was 10%. Registration number for SMILE are: ISRCTN11193709, NCT #: NCT02383108., Findings: Between 10th June 2016 and 30th August 2019, 318 participants were enrolled from Africa 53%, Europe 24%, Thailand 15% and Latin America 8%, 158 INSTI + DRV/r [153 Dolutegravir (DTG); 5 Elvitegravir (EVG)], 160 SOC. Median (range) age was 14.7 years (7.6-18.0); CD4 count 782 cells/mm 3 (227-1647); 61% female. Median follow-up was 64.3 weeks with no loss to follow-up. By 48 weeks, 8 INSTI + DRV/r vs. 12 SOC had confirmed HIV-RNA ≥50 copies/mL; difference (INSTI + DRV/r-SOC) -2.5% (95% CI: -7.6, 2.5%), showing non-inferiority. No major PI or INSTI resistance mutations were observed. There were no differences in safety between arms. By week 48, difference (INSTI + DRV/r-SOC) in mean CD4 count change from baseline was -48.3 cells/mm 3 (95% CI: -93.4, -3.2; p = 0.036). Difference (INSTI + DRV/r-SOC) in mean HDL change from baseline was -4.1 mg/dL (95% CI: -6.7, -1.4; p = 0.003). Weight and Body Mass Index (BMI) increased more in INSTI + DRV/r than SOC [difference: 1.97 kg (95% CI: 1.1, 2.9; p < 0.001), 0.66 kg/m 2 (95% CI: 0.3, 1.0; p < 0.001)]., Interpretation: In virologically-suppressed children, switching to INSTI + DRV/r was non-inferior virologically, with similar safety profile, to continuing SOC. Small but significant differences in CD4, HDL-cholesterol, weight and BMI were observed between INSTI + DRV/r vs. SOC although clinical relevance needs further investigation. SMILE data corroborate adult findings and provide evidence for this NRTI-sparing regimen for children and adolescents., Funding: Fondazione Penta Onlus, Gilead, Janssen, INSERM/ANRS and UK MRC. ViiV-Healthcare provided Dolutegravir., Competing Interests: ACom, YS, YR and ACoe declare that their institution Inserm received a grant for the trial through PENTA Foundation “agreement PENTA-Inserm” started 14th September 2014 and declare support for scientific meetings from PENTA Foundation. AVi declares funding given from PENTA Foundation to her institution for the conduct of the study. ABab declares a grant from Medical Research Council, UKRI to his Institution. PA and ADK declare sponsored study materials and participant recruitment costs from PENTA foundation. PA, ADK and CG declare a research grant for part of the study from Gilead and funded drug supply for the study from ViiV Healthcare. NPR declares a financial support for the research paid to her institution from PENTA Foundation and from Merck. NPR declares that her institution receives the drugs for the study from PENTA Foundation. NPR declares a support for attending ID week in 2022 from AstraZeneca. All other authors declare no competing interests., (© 2023 The Authors.)

The implementation of new control strategies for Aedes aegypti (Ae. Aegpyti), a vector of dengue, chikungunya, and Zika viruses, requires communities to adopt specific behaviors to achieve the success of these innovations., Aim: We evaluated the effect of an educational intervention based on the Precede-Proceed Model (PPM) and the Diffusion of Innovations Theory (DIT) for the control and prevention of diseases transmitted by Ae. aegypti through release of male mosquitoes infected with Wolbachia bacteria in a suburban town in Yucatan, Mexico., Material and Methods: From July 2019 to February 2020, a quasi-experimental study was carried out through an educational intervention (pre- and post-measurements) using quantitative-qualitative techniques, in a Yucatan suburban town where male mosquitoes with Wolbachia were released for the suppression of Ae. aegypti populations. Eleven educational workshops were attended by heads of household (n = 19) and schoolchildren (n = 11). Other 136 heads of household not attending the workshops received information individually., Results: The educational intervention had a significant effect on the mean scores of the contributing and behavioral factors for adoption of innovation (p < 0.05) in the pre- and post-intervention measurements., Conclusion: Innovative methods for the control and prevention of diseases related to Aedes aegypti can be strengthened through educational interventions supported by sound methodologies., Descriptors: Community health education, Aedes aegypti, Wolbachia, Mexico., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Insecticide-based approaches remain a key pillar for Aedes-borne virus (ABV, dengue, chikungunya, Zika) control, yet they are challenged by the limited effect of traditional outdoor insecticide campaigns responding to reported arboviral cases and by the emergence of insecticide resistance in mosquitoes. A three-arm Phase II unblinded entomological cluster randomized trial was conducted in Merida, Yucatan State, Mexico, to quantify the entomological impact of targeted indoor residual spraying (TIRS, application of residual insecticides in Ae. aegypti indoor resting sites) applied preventively 2 months before the beginning of the arbovirus transmission season. Trial arms involved the use of two insecticides with unrelated modes of action (Actellic 300CS, pirimiphos-methyl, and SumiShield 50WG, clothianidin) and a control arm where TIRS was not applied. Entomological impact was quantified by Prokopack adult collections performed indoors during 10 min per house. Regardless of the insecticide, conducting a preventive TIRS application led to significant reductions in indoor Ae. aegypti densities, which were maintained at the same levels as in the low arbovirus transmission period (Actellic 300CS reduced Ae. aegypti density up to 8 months, whereas SumiShield 50WG up to 6 months). The proportional reduction in Ae. aegypti abundance in treatment houses compared to control houses was 50-70% for Actellic 300CS and 43-63% for SumiShield 50WG. Total operational costs including insecticide ranged from US$4.2 to US$10.5 per house, depending on the insecticide cost. Conducting preventive residual insecticide applications can maintain Ae. aegypti densities at low levels year-round with important implications for preventing ABVs in the Americas and beyond., (© 2022. The Author(s).)

The prevalence of SARS-CoV-2 exposure in children during the global COVID-19 pandemic has been underestimated due to lack of testing and the relatively mild symptoms in adolescents. Understanding the exposure rates in the pediatric population is essential as children are the last to receive vaccines and can act as a source for SARS-CoV-2 mutants that may threaten vaccine escape. This cross-sectional study aims to quantify the prevalence of anti-SARS-CoV-2 serum antibodies in children in a major city in México in the Spring of 2021 and determine if there are any demographic or socioeconomic correlating factors. We obtained socioeconomic information and blood samples from 1,005 children from 50 neighborhood clusters in Mérida, Yucatán, México. We then tested the sera of these participants for anti-SARS-CoV-2 IgG and IgM antibodies using lateral flow immunochromatography. We found that 25.5% of children in our cohort were positive for anti-SARS-CoV-2 antibodies and there was no correlation between age and antibody prevalence. Children that lived with large families were statistically more likely to have antibodies against SARS-CoV-2. Spatial analyses identified two hotspots of high SARS-CoV-2 seroprevalence in the west of the city. These results indicate that a large urban population of unvaccinated children has been exposed to SARS-CoV-2 and that a major correlating factor was the number of people within the child's household with a minor correlation with particular geographical hotspots. There is also a larger population of children that may be susceptible to future infection upon easing of social distancing measures. These findings suggest that in future pandemic scenarios, limited public health resources can be best utilized on children living in large households in urban areas., Competing Interests: The authors have declared that no competing interests exist., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

We conducted a baseline characterization of the abundance and seasonality of Aedes aegypti (Linnaeus, 1762)-a vector of dengue, chikungunya, and Zika-in two suburban localities of Yucatan, Mexico, as the first step in the implementation of an integrated vector management (IVM) plan combining 'traditional Aedes control' (source reduction/truck-mounted ultra-low volume [ULV] spraying) and incompatible insect technique/sterile insect technique for population suppression in Yucatan, Mexico. Weekly entomological collections with ovitraps and BG-sentinel traps were performed in 1-ha quadrants of both localities for 1 yr. Three distinct periods/phases were identified, closely associated with precipitation: 1) a phase of low population abundance during the dry season (weekly average of Aedes eggs per ovitrap and adults per BG trap = 15.51 ± 0.71 and 10.07 ± 0.88, respectively); 2) a phase of population growth and greatest abundance of Aedes (49.03 ± 1.48 eggs and 25.69 ± 1.31 adults) during the rainy season; and finally 3) a phase of decline among populations (20.91 ± 0.97 eggs and 3.24 ± 0.21 adults) after the peak of the rainy season. Seasonal abundance and dynamics of Ae. aegypti populations suggest that it is feasible to develop and implement time-specific actions as part of an IVM approach incorporating integrating novel technologies (such as rear-and-release of Wolbachia-infected males) with classic (insecticide-based) approaches implemented routinely for vector control. In agreement with the local vector control program, we propose a pilot IVM strategy structured in a preparation phase, an attack phase with traditional vector control, and a suppression phase with inundative releases, which are described in this paper., (© The Author(s) 2021. Published by Oxford University Press on behalf of Entomological Society of America.)

Background: Effective Aedes aegypti control is limited, in part, by the difficulty in achieving sufficient intervention coverage. To maximise the effect of vector control, areas with persistently high numbers of Aedes-borne disease cases could be identified and prioritised for preventive interventions. We aimed to identify persistent Aedes-borne disease hotspots in cities across southern Mexico., Methods: In this spatial analysis, geocoded cases of dengue, chikungunya, and Zika from nine endemic Mexican cities were aggregated at the census-tract level. We included cities that were located in southern Mexico (the arbovirus endemic region of Mexico), with a high burden of dengue cases (ie, more than 5000 cases reported during a 10-year period), and listed as high priority for the Mexican dengue control and prevention programme. The Getis-Ord Gi*(d) statistic was applied to yearly slices of the dataset to identify spatial hotspots of each disease in each city. We used Kendall's W coefficient to quantify the agreement in the distribution of each virus., Findings: 128 507 dengue, 4752 chikungunya and 25 755 Zika clinical cases were reported between Jan 1, 2008, and Dec 31, 2016. All cities showed evidence of transmission heterogeneity, with a mean of 17·6% (SD 4·7) of their total area identified as persistent disease hotspots. Hotspots accounted for 25·6% (SD 9·7; range 12·8-43·0) of the population and 32·1% (10·5; 19·6-50·5) of all Aedes-borne disease cases reported. We found an overlap between hotspots of 61·7% for dengue and Zika and 53·3% for dengue and chikungunya. Dengue hotspots in 2008-16 were significantly associated with dengue hotspots detected during 2017-20 in five of the nine cities. Heads of vector control confirmed hotspot areas as problem zones for arbovirus transmission., Interpretation: This study provides evidence of the overlap of Aedes-borne diseases within geographical hotspots and a methodological framework for the stratification of arbovirus transmission risk within urban areas, which can guide the implementation of surveillance and vector control., Funding: USAID, the US Centers for Disease Control and Prevention, the Canadian Institutes of Health Research, International Development Research Centre, Fondo Mixto CONACyT (Mexico)-Gobierno del Estado de Yucatan, and the US National Institutes of Health., Translation: For the Spanish translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: In the absence of vaccines or drugs, insecticides are the mainstay of Aedes-borne disease control. Their utility is challenged by the slow deployment of resources, poor community compliance and inadequate household coverage. Novel application methods are required., Methodology and Principal Findings: A 10% w/w metofluthrin "emanator" that passively disseminates insecticide from an impregnated net was evaluated in a randomized trial of 200 houses in Mexico. The devices were introduced at a rate of 1 per room and replaced at 3-week intervals. During each of 7 consecutive deployment cycles, indoor resting mosquitoes were sampled using aspirator collections. Assessments of mosquito landing behaviours were made in a subset of houses. Pre-treatment, there were no differences in Aedes aegypti indices between houses recruited to the control and treatment arms. Immediately after metofluthrin deployment, the entomological indices between the trial arms diverged. Averaged across the trial, there were significant reductions in Abundance Rate Ratios for total Ae. aegypti, female abundance and females that contained blood meals (2.5, 2.4 and 2.3-times fewer mosquitoes respectively; P<0.001). Average efficacy was 60.2% for total adults, 58.3% for females, and 57.2% for blood-fed females. The emanators also reduced mosquito landings by 90% from 12.5 to 1.2 per 10-minute sampling period (P<0.05). Homozygous forms of the pyrethroid resistant kdr alleles V410L, V1016L and F1534C were common in the target mosquito population; found in 39%, 24% and 95% of mosquitoes collected during the trial., Conclusions/significance: This is the first randomized control trial to evaluate the entomological impact of any volatile pyrethroid on urban Ae. aegypti. It demonstrates that volatile pyrethroids can have a sustained impact on Ae. aegypti population densities and human-vector contact indoors. These effects occur despite the presence of pyrethroid-resistant alleles in the target population. Formulations like these may have considerable utility for public health vector control responses., Competing Interests: The authors have declared that no competing interests exist.

Arbovirus infection in Aedes aegypti has historically been quantified from a sample of the adult population by pooling collected mosquitoes to increase detectability. However, there is a significant knowledge gap about the magnitude of natural arbovirus infection within areas of active transmission, as well as the sensitivity of detection of such an approach. We used indoor Ae. aegypti sequential sampling with Prokopack aspirators to collect all mosquitoes inside 200 houses with suspected active ABV transmission from the city of Mérida, Mexico, and tested all collected specimens by RT-PCR to quantify: a) the absolute arbovirus infection rate in individually tested Ae. aegypti females; b) the sensitivity of using Prokopack aspirators in detecting ABV-infected mosquitoes; and c) the sensitivity of entomological inoculation rate (EIR) and vectorial capacity (VC), two measures ABV transmission potential, to different estimates of indoor Ae. aegypti abundance. The total number of Ae. aegypti (total catch, the sum of all Ae. aegypti across all collection intervals) as well as the number on the first 10-min of collection (sample, equivalent to a routine adult aspiration session) were calculated. We individually tested by RT-PCR 2,161 Aedes aegypti females and found that 7.7% of them were positive to any ABV. Most infections were CHIKV (77.7%), followed by DENV (11.4%) and ZIKV (9.0%). The distribution of infected Aedes aegypti was overdispersed; 33% houses contributed 81% of the infected mosquitoes. A significant association between ABV infection and Ae. aegypti total catch indoors was found (binomial GLMM, Odds Ratio > 1). A 10-min indoor Prokopack collection led to a low sensitivity of detecting ABV infection (16.3% for detecting infected mosquitoes and 23.4% for detecting infected houses). When averaged across all infested houses, mean EIR ranged between 0.04 and 0.06 infective bites per person per day, and mean VC was 0.6 infectious vectors generated from a population feeding on a single infected host per house/day. Both measures were significantly and positively associated with Ae. aegypti total catch indoors. Our findings provide evidence that the accurate estimation and quantification of arbovirus infection rate and transmission risk is a function of the sampling effort, the local abundance of Aedes aegypti and the intensity of arbovirus circulation., Competing Interests: The authors have declared that no competing interests exist.

Background: Current urban vector control strategies have failed to contain dengue epidemics and to prevent the global expansion of Aedes-borne viruses (ABVs: dengue, chikungunya, Zika). Part of the challenge in sustaining effective ABV control emerges from the paucity of evidence regarding the epidemiological impact of any Aedes control method. A strategy for which there is limited epidemiological evidence is targeted indoor residual spraying (TIRS). TIRS is a modification of classic malaria indoor residual spraying that accounts for Aedes aegypti resting behavior by applying residual insecticides on exposed lower sections of walls (< 1.5 m), under furniture, and on dark surfaces., Methods/design: We are pursuing a two-arm, parallel, unblinded, cluster randomized controlled trial to quantify the overall efficacy of TIRS in reducing the burden of laboratory-confirmed ABV clinical disease (primary endpoint). The trial will be conducted in the city of Merida, Yucatan State, Mexico (population ~ 1million), where we will prospectively follow 4600 children aged 2-15 years at enrollment, distributed in 50 clusters of 5 × 5 city blocks each. Clusters will be randomly allocated (n = 25 per arm) using covariate-constrained randomization. A "fried egg" design will be followed, in which all blocks of the 5 × 5 cluster receive the intervention, but all sampling to evaluate the epidemiological and entomological endpoints will occur in the "yolk," the center 3 × 3 city blocks of each cluster. TIRS will be implemented as a preventive application (~ 1-2 months prior to the beginning of the ABV season). Active monitoring for symptomatic ABV illness will occur through weekly household visits and enhanced surveillance. Annual sero-surveys will be performed after each transmission season and entomological evaluations of Ae. aegypti indoor abundance and ABV infection rates monthly during the period of active surveillance. Epidemiological and entomological evaluation will continue for up to three transmission seasons., Discussion: The findings from this study will provide robust epidemiological evidence of the efficacy of TIRS in reducing ABV illness and infection. If efficacious, TIRS could drive a paradigm shift in Aedes control by considering Ae. aegypti behavior to guide residual insecticide applications and changing deployment to preemptive control (rather than in response to symptomatic cases), two major enhancements to existing practice., Trial Registration: ClinicalTrials.gov NCT04343521 . Registered on 13 April 2020. The protocol also complies with the WHO International Clinical Trials Registry Platform (ICTRP) (Additional file 1)., Primary Sponsor: National Institutes of Health, National Institute of Allergy and Infectious Diseases (NIH/NIAID).

We report demographic, epidemiologic, and clinical findings for a prospective cohort of pregnant women during the initial phase of Zika virus introduction into Yucatan, Mexico. We monitored 115 pregnant women for signs of active or recent Zika virus infection. The estimated cumulative incidence of Zika virus infection was 0.31 and the ratio of symptomatic to asymptomatic cases was 1.7 (range 1.3-4.0 depending on age group). Exanthema was the most sensitive clinical sign but also the least specific. Conjunctival hyperemia, joint edema, and exanthema were the combination of signs that had the highest specificity but low sensitivity. We did not find evidence of vertical transmission or fetal anomalies, likely because of the low number of pregnant women tested. We also did not find evidence of congenital disease. Our findings emphasize the limited predictive value of clinical features in areas where Zika virus cocirculates with other flaviviruses.

Dengue is the most prevalent mosquito-borne viral disease of humans and is caused by the four serotypes of dengue virus. To estimate the incidence of dengue and other arboviruses, we analyzed the baseline and first year follow-up of a prospective school-based cohort study and their families in three cities in the state of Yucatan, Mexico. Through enhanced surveillance activities, acute febrile illnesses in the participants were detected and yearly blood samples were collected to evaluate dengue infection incidence. A Cox model was fitted to identify hazard ratios of arboviral infections in the first year of follow-up of the cohort. The incidence of dengue symptomatic infections observed during the first year of follow-up (2015-2016) was 3.5 cases per 1,000 person-years (95% CI: 1.9, 5.9). The incidence of dengue infections was 33.9 infections per 1,000 person-years (95% CI: 31.7, 48.0). The majority of dengue infections and seroconversions were observed in the younger age groups (≤ 14 years old). Other arboviruses were circulating in the state of Yucatan during the study period. The incidence of symptomatic chikungunya infections was 8.6 per 1,000 person-years (95% CI: 5.8, 12.3) and the incidence of symptomatic Zika infections was 2.3 per 1,000 person-years (95% CI: 0.9, 4.5). Our model shows that having a dengue infection during the first year of follow-up was significantly associated with being female, living in Ticul or Progreso, and being dengue naïve at baseline. Age was not significantly associated with the outcome, it was confounded by prior immunity to dengue that increases with age. This is the first report of a cohort in Latin America that provides incidence estimates of the three arboviruses co-circulating in all age groups. This study provides important information for understanding the epidemiology of dengue and other arboviruses and better informing public health policies., Competing Interests: The authors have declared that no competing interests exist.

The aim of the Mexican Consensus on the Treatment of HepatitisC was to develop clinical practice guidelines applicable to Mexico. The expert opinion of specialists in the following areas was taken into account: gastroenterology, infectious diseases, and hepatology. A search of the medical literature was carried out on the MEDLINE, EMBASE, and CENTRAL databases through keywords related to hepatitisC treatment. The quality of evidence was subsequently evaluated using the GRADE system and the consensus statements were formulated. The statements were then voted upon, using the modified Delphi system, and reviewed and corrected by a panel of 34 voting participants. Finally, the level of agreement was classified for each statement. The present guidelines provide recommendations with an emphasis on the new direct-acting antivirals, to facilitate their use in clinical practice. Each case must be individualized according to the comorbidities involved and patient management must always be multidisciplinary., (Copyright © 2018 Asociación Mexicana de Gastroenterología. Publicado por Masson Doyma México S.A. All rights reserved.)

Background: Perinatally HIV-infected (PHIV) children are at risk for under-vaccination and poor vaccine response at 4 years of age. Childhood vaccine coverage and immune response were compared between PHIV and HIV-exposed uninfected (HEU) children in Latin America and the Caribbean., Methods: PHIV and HEU children were enrolled prospectively at 15 sites from 2002 to 2009. Full vaccination by age 4 years was defined as: 3 hepatitis B virus vaccine doses; 4 tetanus toxoid-containing vaccine doses; 3 doses of Haemophilus influenzae type b vaccine by age 12 months or ≥1 dose given after age 12 months; one measles-containing vaccine dose; one rubella-containing vaccine dose. Immunity was defined by serum antibody titer. Fisher exact test (for categorical measures) and t test (for continuous measures) were used for comparisons., Results: Among 519 children seen at age 4 years, 191 had serum specimens available (137 PHIV, 54 HEU). Among those with specimens available, 29.3% initiated combination antiretroviral therapy (cART) <12 months of age, 30.9% initiated at ≥12 months of age, and 39.8% had not received cART by the time they were seen at 4 years of age. At 4 years of age, 59.9% were on PI-containing cART (cART/PI), and 20.4% were on no ART. PHIV children were less likely than HEU children to be fully vaccinated for tetanus (55.5% vs. 77.8%, P = 0.005) and measles and rubella (both 70.1% vs. 94.4%, P < 0.001). Among those fully vaccinated, immunity was significantly lower among PHIV than HEU for all vaccines examined: 20.9% versus 37.8% for hepatitis B virus (P = 0.04), 72.0% versus 90.5% for tetanus (P = 0.02), 51.4% versus 68.8% for H. influenzae type b (P = 0.05), 80.2% versus 100% for measles (P < 0.001) and 72.9% versus 98.0% for rubella (P < 0.001) vaccine, respectively., Conclusions: Compared with HEU, PHIV children were significantly less likely to be immune to vaccine-preventable diseases when fully vaccinated. Strategies to increase immunity against vaccine-preventable diseases among PHIV require further study.

Response to Zika virus (ZIKV) invasion in Brazil lagged a year from its estimated February 2014 introduction, and was triggered by the occurrence of severe congenital malformations. Dengue (DENV) and chikungunya (CHIKV) invasions tend to show similar response lags. We analyzed geo-coded symptomatic case reports from the city of Merida, Mexico, with the goal of assessing the utility of historical DENV data to infer CHIKV and ZIKV introduction and propagation. About 42% of the 40,028 DENV cases reported during 2008-2015 clustered in 27% of the city, and these clustering areas were where the first CHIKV and ZIKV cases were reported in 2015 and 2016, respectively. Furthermore, the three viruses had significant agreement in their spatio-temporal distribution (Kendall W>0.63; p<0.01). Longitudinal DENV data generated patterns indicative of the resulting introduction and transmission patterns of CHIKV and ZIKV, leading to important insights for the surveillance and targeted control to emerging Aedes-borne viruses.

Background: AI266-922 was an open-label, dose-ranging study that assessed the pharmacokinetics, safety and efficacy of efavirenz (EFV) in children (3 months to 6 years)., Methods: Antiretroviral-naïve and antiretroviral-experienced HIV-1-infected children received once-daily EFV as oral solution or capsule sprinkle plus didanosine and emtricitabine (FTC). Pharmacokinetic analyses were undertaken at week 2 and repeated at weeks 10 and 18 after an EFV dose change or switch from oral solution to capsule sprinkle., Results: Thirty-seven subjects were treated. EFV area under the plasma concentration-time curve over 1 dosing interval from time 0 to 24 hours postdose values were generally suboptimal (<110 μM × h) in subjects younger than 3 years treated with oral solution; these subjects switched to capsule sprinkle. Twenty of 21 subjects younger than 3 years treated with capsule sprinkle achieved an EFV area under the plasma concentration-time curve over 1 dosing interval from time 0 to 24 hours postdose value >110 μM × h, although higher initial doses were administered in this age group. Interpatient variability in EFV exposure was high. By week 48, 77.8% and 63.0% of subjects achieved HIV-RNA <400 and <50 copies/mL, respectively. Median changes in log10 HIV-RNA and CD4 percentage from baseline were -3.18 copies/mL and +6%, respectively. Two (5.4%) patients discontinued because of adverse events (AEs). Serious AEs occurred in 20 (54.1%) subjects. Common AEs were diarrhea (49%), nasopharyngitis (35%) and pneumonia (30%). Overall, 43% of subjects with suboptimal EFV exposure at week 2 developed resistance., Conclusions: Once-daily EFV, given as capsule sprinkle, achieved target exposures in this study although doses were 2-3 times higher than Food and Drug Administration-approved doses for children younger than 3 years. These data are useful for dose selection modeling and simulation; however, Food and Drug Administration-approved doses should be used clinically. EFV + didanosine + FTC was efficacious with no new pediatric safety findings reported.

Reduced-antigen-content diphtheria-tetanus-acellular pertussis (dTpa) vaccine, Boostrix™, is indicated for booster vaccination of children, adolescents and adults. The original prefilled disposable dTpa syringe presentation was recently replaced by another prefilled-syringe presentation with latex-free tip-caps and plunger-stoppers. 671 healthy adolescents aged 10-15 years who had previously received 5 or 6 previous DT(P)/dT(pa) vaccine doses, were randomized (1:1) to receive dTpa booster, injected using the new (dTpa-new) or previous syringe (dTpa-previous) presentations. Immunogenicity was assessed before and 1-month post-booster vaccination; safety/reactogenicity were assessed during 31-days post-vaccination. Non-inferiority of dTpa-new versus dTpa-previous was demonstrated for all antigens (ULs 95% CIs for GMC ratios ranged between 1.03-1.13). 1-month post-booster, immune responses were in similar ranges for all antigens with both syringe presentations. dTpa delivered using either syringe presentation was well-tolerated. These clinical results complement the technical data and support the use of the new syringe presentation to deliver the dTpa vaccine.

Background: Two influenza B lineages have been co-circulating since the 1980s, and because inactivated trivalent influenza vaccine (TIV) contains only one B strain, it provides little/no protection against the alternate B-lineage. We assessed a candidate inactivated quadrivalent influenza vaccine (QIV) containing both B lineages versus TIV in healthy adults., Methods: Subjects received one dose of QIV (lot 1, 2, or 3) or one of two TIVs (B strain from Victoria or Yamagata lineage); randomization was 2:2:2:1:1. Hemagglutination-inhibition assays were performed 21-days post-vaccination; superiority of QIV versus TIV for the alternate B-lineage was demonstrated if the 95% confidence interval (CI) lower limit for the GMT ratio was ≥1.5, and non-inferiority against the shared strains was demonstrated if the 95% CI upper limit for the GMT ratio was ≤1.5. Reactogenicity and safety were assessed during the post-vaccination period. NCT01196975., Results: Immunogenicity of QIV lots was consistent, QIV was superior to TIV for the alternate B-lineage strain, and QIV was non-inferior versus TIVs for shared strains (A/H1N1, A/H3N2, B-strain). Reactogenicity and safety profile of the QIV was consistent with seasonal influenza vaccines., Conclusion: QIV provided superior immunogenicity for the added B strain without affecting the antibody response to the TIV strains, and without compromising safety., (Copyright © 2014. Published by Elsevier Ltd.)

The trivalent inactivated influenza vaccine Fluarix™ is licensed in the US for adults and children from 3 years old. This randomized observer-blind study (NCT00764790) evaluated Fluarix™ at two doses; 0.25 ml (Flu-25) and 0.5 ml (Flu-50) in children aged 6-35 months. The primary objective was to demonstrate immunogenic non-inferiority vs. a control vaccine (Fluzone®; 0.25 ml). Children received Flu-25 (n = 1107), Flu-50 (n = 1106) or control vaccine (n = 1104) at Day 0 and for un-primed children, also on Day 28. Serum hemagglutination-inhibition titers were determined pre-vaccination and at Day 28 (primed) or Day 56 (un-primed). Non-inferiority was assessed by post-vaccination geometric mean titer (GMT) ratio, (upper 95% confidence interval [CI] ≤ 1.5) and difference in seroconversion rate (upper 95% CI ≤ 10%). Reactogenicity/safety was monitored. The immune response to Flu-50 met all regulatory criteria. Indicated by adjusted GMT ratios [with 95% CI], the criteria for non-inferiority of Flu-50 vs. control vaccine were reached for the B/Florida strain (1.13 [1.01-1.25]) but not for the A/Brisbane/H1N1 (1.74 [1.54-1.98]) or A/Uruguay/H3N2 (1.72 [1.57-1.89]) strains. In children aged 18-35 months similar immune responses were observed for Flu-50 and the control vaccine. Flu-50 induced a higher response than Flu-25 for all strains. Temperature (≥ 37.5°C) was reported in 6.2%, 6.4%, and 6.6% of the Flu-25, Flu-50, and control group, respectively. Reactogenicity/safety endpoints were within the same range for all vaccines. In children aged 6-35 months, immune responses with Flu-50 fulfilled regulatory criteria but did not meet the pre-defined criteria for non-inferiority vs. control. This appeared to be due to differences in immunogenicity in children aged<18 months.

The safety profile of HibMenCY was compared with licensed Hib conjugate vaccines in a pooled analysis that included more than 8,500 subjects who were administered a four-dose series of HibMenCY or commercially available Hib vaccines at 2, 4, 6 and 12-15 mo of age in two primary vaccination and two fourth dose phase 3 studies. In all studies, HibMenCY or Hib vaccine was co-administered with age-appropriate, routinely recommended vaccines. In one primary and one fourth dose study (n = 4180), local and general symptoms were solicited using diary cards for 4 d after each dose. Serious adverse events (SAEs) and the occurrence of adverse events (AEs) indicating new onset of chronic disease (NOCD), rash, and conditions prompting Emergency Room (ER) visits were reported from dose 1 until 6 mo after dose 4. The incidences of solicited local and general symptoms were similar following HibMenCY and commercially available Hib vaccines. For some solicited symptoms (pain at the injection site and irritability), rates were lower in the HibMenCY group compared with the Hib control group (p value < 0.05). There were no statistically significant differences between groups in the incidences of SAEs, NOCDs, rash, or AEs leading to ER visits, with the exceptions of anemia and viral gastroenteritis, which occurred significantly less frequently in those receiving HibMenCY than those receiving commercially available Hib vaccines. In this pooled safety analysis, the safety profile of HibMenCY was similar to the safety profile of licensed monovalent Hib vaccines, despite the addition of meningococcal antigens. These studies are registered at www.clinicaltrials.gov NCT00345579 (primary vaccination study), NCT00345683 (fourth dose vaccination study) and NCT00289783 (primary and fourth dose vaccination studies).

Objective: Determine the frequency of candida in the oral cavity of children with a risk of developing opportunistic infections, and establish if there is an association between the frequency of this oral colonization and three categories of at-risk populations., Methods: Four infant population groups in Mexico were studied: an HIV/AIDS group undergoing highly active antiretroviral therapy (35 girls and 25 boys); a malnourished group (26 girls and 29 boys); a group from the Tarahumara indigenous people, one of the poorest ethnic populations in the country (37 girls and 20 boys); and a control group (8 girls and 21 boys in apparently good health). The children with HIV/AIDS were immunologically and virologically classified according to the EC Clearinghouse criteria, while malnutrition was determined through the World Health Organization's weight/height index. A sample of oral mucosa was taken with a sterile swab, which was incubated in Sabouraud dextrose agar and in Candida CHROMagar®. The species of candida were confirmed through the API ID32C test., Results: The HIV/AIDS and malnutrition groups showed the higher frequency of Candida spps (51.7% and 38.2%, respectively), while the frequency level in the Tarahumara group was similar to that of the control group (17.5% versus 10.3%). With regard to the species of candida, the malnutrition group had the greatest diversity: C. albicans, C. tropical, C. krusei, and C. glabrata., Conclusions: The children with HIV/AIDS and malnutrition require strategies designed to reduce oral candidal colonization and reduce the risk of opportunistic infections.

In order to describe the prevalence of hypercholesterolemia and hypertriglyceridemia in a cohort of HIV-infected children and adolescents in Latin America and to determine associations with highly active antiretroviral therapy (HAART), we performed this cross-sectional analysis within the NICHD International Site Development Initiative pediatric cohort study. Eligible children had to be at least 2 years of age and be on HAART. Among the 477 eligible HIV-infected youth, 98 (20.5%) had hypercholesterolemia and 140 (29.4%) had hypertriglyceridemia. In multivariable analyses, children receiving protease inhibitor (PI)-containing HAART were at increased risk for hypercholesterolemia [adjusted odds ratio (AOR) =  2.7, 95% confidence interval (CI) 1.3-5.6] and hypertriglyceridemia (AOR = 3.5, 95% CI 1.9-6.4) compared with children receiving non-nucleoside reverse transcriptase inhibitor (NNRTI)-containing HAART. In conclusion, HIV-infected youth receiving PI-containing HAART in this Latin American cohort were at increased risk for hypercholesterolemia and hypertriglyceridemia compared with those receiving NNRTI-containing HAART.

We evaluated a commercially available immunochromatographic dipstick test to detect Trypanosoma cruzi infection in 366 human serum samples with known serological results from Argentina, Ecuador, Mexico, and Venezuela. One hundred forty-nine of 366 (40.7%) and 171/366 (46.7%) samples tested positive by dipstick and serology, respectively. Dipstick sensitivity was calculated to be 84.8% (range between countries, 77.5 to 95%), and specificity was 97.9% (95.9 to 100%).

Infection with HTLV-II is endemic in Amerindians, with prevalence ranging from 0.89% - 33%. To determine the prevalence of HTLV-II among indigenous Mayans in the Yucatan Peninsula of Mexico, 440 indigenous Mayans were recruited, all native to and residents of one of six Mayan communities in the Yucatan Peninsula, (Xohuayan n=144, Yaxachen n=101, Kanxoc n=84, Xocen n=40, Nabalan n=46 and X'calot n=25) between May, 1992 and June, 1993. All of the above are pre-Hispanic settlements located in tropical forest with no immigrations for over 50 years. Of the 440 indigenous Mayans, only one woman from the X'calot tribe (0.23%) was shown to be infected with HTLV-II. A high percentage of indeterminate results was found (22/439, 5%), three of which were accounted for by the husband and two children of the positive female case. PCR analysis followed by specific restriction digestion demonstrated the virus to be of the HTLV-IIb subtype, similar to that described in the Guaymi Indians from Panama. The presence of HTLV-II in the Mayan ethnos, and in other Amerindian populations supports the idea that HTLV-II is an ancestral virus in America and that it has been sustained in "closed" communities.

Pneumocystis carinii, an extracellular parasite thriving in the lungs of immunosuppressed mammals, is a major cause of death in AIDS patients in the USA. As a prelude to growth, the parasite adheres mostly to type I pneumocytes lining the alveolar spaces. The mechanism of adherence remains unknown, largely because of difficulties in isolating type I pneumocytes and maintaining them in vitro. As a first step to understand P. carinii adherence to its natural substrate, we developed an in situ method to directly study parasite binding to lung alveolar cells. We used formaldehyde-fixed paraffin-embedded sections of normal rat lung as substrate for adhesion. As in its binding to the lungs in vivo, P. carinii adhered preferentially to type I pneumocytes. Adherence was saturable, time and dose dependent, and selectively blocked by glycoconjugates, in particular bovine submaxillary mucin, fetuin, and asialofetuin, suggesting that it may be mediated by a lectin type of interaction. Further, IgG of rats with P. carinii pneumonia inhibited adherence, suggesting that it may react with parasite ligands involved in the recognition of type I cell receptors. Our results demonstrate the usefulness of the in situ model for studying the mechanisms of P. carinii adherence to alveolar cells. In addition, this method may be valuable for identifying neutralizing antibodies and drugs potentially useful for controlling the infection in vivo.

The antibodies to human T-lymphotropic virus type I/II (HTLV-I/II) were determined in non-intravenous drug-using female prostitutes from Merida Yucatan, Mexico. Serum specimens from 282 female prostitutes collected during 1990 were tested initially by enzyme immunoassay and further confirmed by western blot assays. Of these, 5 (1.8%, 95% confidence interval 0.2 to 3.3) were shown to be HTLV-I/II positive (reactivity to p24gag and gp68/r21eenv). All five specimens were shown to be infected with HTLV-II by immunoassays using type-specific synthetic peptides and recombinant proteins. Long-term cell lines developed from two individuals demonstrated active viral replication and were of CD8 phenotype. Polymerase chain reaction analysis from four of these five prostitutes demonstrated HTLV-II-specific amplification of all four specimens, of which one was subtype a (HTLV-IIa) and three were subtype b (HTLV-IIb). These data show that HTLV-II is the predominant HTLV type among female prostitutes from the Yucatan.