Efficacy and safety of ivermectin in patients with mild COVID-19 in Japan and Thailand.

BACKGROUND: Ivermectin is an antiparasitic drug administered to hundreds of millions of people worldwide. Fundamental research suggests that ivermectin is effective against coronavirus disease 2019 (COVID-19); therefore, we investigated the efficacy and safety of ivermectin as a COVID-19 treatment option. METHODS: This multi-regional (Japan and Thailand), multicenter, placebo-controlled, randomized, double-blind, parallel-group, Phase III study evaluated the efficacy and safety of ivermectin in patients with mild COVID-19 (IVERMILCO Study). The participants took a specified number of the investigational product (ivermectin or placebo) tablets of, adjusted to a dose of 0.3-0.4 mg/kg, orally on an empty stomach once daily for three days. The primary efficacy endpoint was the time at which clinical symptoms first showed an improving trend by 168 h after investigational product administration. RESULTS: A total of 1030 eligible participants were assigned to receive the investigational product; 502 participants received ivermectin and 527 participants received a placebo. The primary efficacy endpoint was approximately 96 h (approximately four days) for both ivermectin and placebo groups, which did not show statistically significant difference (stratified log-rank test, p = 0.61). The incidence of adverse events and adverse drug reactions did not show statistically significant differences between the ivermectin and placebo groups (chi-square test, p = 0.97, p = 0.59). CONCLUSIONS: The results show that ivermectin (0.3-0.4 mg/kg), as a treatment for patients with mild COVID-19, is ineffective; however, its safety has been confirmed for participants, including minor participants of 12 years or older (IVERMILCO Study ClinicalTrials.gov number, NCT05056883.).

Prevalence and risk factors of cardiovascular disease among people living with HIV in the Asia-Pacific region: a systematic review.

BACKGROUND: Cardiovascular diseases (CVD) due to atherosclerosis have become one of the major causes of death among people living with HIV (PLHIV) since effective antiretroviral therapy (ART) has been available throughout the world. However, the epidemiologic evidence of this problem from the Asia-Pacific region remains unclear. We conducted a systematic review of the situation and risk factors for CVD among PLHIV in countries with the greatest impact of CVD attributable to HIV in the Asia-Pacific region. METHODS: A systematic search in PubMed/MEDLINE, EMBASE, and the Cochrane Database of Systematic Reviews databases for articles published before 2019 was conducted. Publications reported situations and risk factors both traditional and HIV-specific for CVD among PLHIV in the region were included. Two reviewers working on duplicate and quality assessments, independently extracted data, and thematically analyzed the data. RESULTS: Among PLHIV, the prevalence of subclinical CVD ranged from 10 to 28% and the incidence rate of clinical CVD ranged from 0.37 to 1.17 /100 person-years. Clinical CVD was frequently observed in the early era of the highly active antiretroviral therapy. A higher prevalence of subclinical CVD such as abnormal cIMT and carotid plaques was frequently observed in the PLHIV rather than in the nonHIV population and a high proportion of early onset of CVD was found among young PLHIV adults. The traditional risk factors for CVD such as hypertension, diabetes and smoking behavior were prevalent in both PLHIV and nonHIV populations ranging from 5 to 45%. HIV-specific risk factor, and lower CD4 presented almost twice the significantly increased risks for CVD while the synergistic interaction among traditional risk factors, i.e., diabetes mellitus, dyslipidemia and family history steeply increased the risk for CVD among PLHIV by almost 20 times. CONCLUSION: The limited existing data suggested the risk of early CVD among PLHIV. We identified the crucial gaps in HIV/CVD work from the Asia-Pacific region and recommended longer prospective studies with larger sample sizes or meta-analyses to better capture CVD risk and interactions of crucial risk factors of this vulnerable population in this region. REGISTRATION NUMBER: INPLASY202290108 ( https://inplasy.com/inplasy-2022-9-0108/ ).

Thailand's national strategic plan on antimicrobial resistance: progress and challenges.

Antimicrobial resistance is a serious threat that affects all countries. The Global Action Plan on antimicrobial resistance and the United Nations Political Declaration on antimicrobial resistance set standards for countries to resolve antimicrobial resistance challenges under the One Health approach. We assess progress and challenges in implementing Thailand's national strategic plan on antimicrobial resistance 2017-2022, discuss interim outcomes and share lessons learnt. Major progress includes: establishing a national governance mechanism that leads high-impact policy on antimicrobial resistance and consolidates actions and multisectoral collaboration; creating a monitoring system and platform to track implementation of the strategic plan; and converting strategies of the strategic plan into actions such as controlling the distribution and use of antimicrobials in humans and animals. Interim results indicate that antimicrobial consumption in animals has nearly halved (exceeding the national goal of a 30% reduction) whereas other goals have not yet reached their targets. We have learnt that elevating antimicrobial resistance to high-level visibility and establishing a national governance mechanism is an important first step, and a monitoring and evaluation system should be developed in parallel with implementation. Securing funds is crucial. Policy coherence is needed to avoid duplication of actions. Highly ambitious goals, although yet to be achieved, can advance actions beyond expectations. Political commitment and collaboration across different sectors will continue to play important roles but might not be sustained without a well-designed governance structure to support long-term actions to address antimicrobial resistance.

La résistance aux antimicrobiens fait peser une sérieuse menace sur la planète tout entière. Le Plan d'action mondial pour combattre la résistance aux antimicrobiens ainsi que la Déclaration politique des Nations Unies sur la résistance aux agents antimicrobiens ont défini des normes pour les pays, afin qu'ils puissent faire face aux enjeux liés à la résistance aux antimicrobiens selon l'approche «One Health¼. Nous avons évalué les progrès et défis de la mise en œuvre du plan stratégique national de la Thaïlande en la matière pour 2017­2022, mais aussi discuté des résultats provisoires et partagé les enseignements tirés. Parmi les principaux progrès accomplis figurent l'établissement d'un mécanisme de gouvernance national pour mener une politique à impact élevé sur la résistance aux antimicrobiens, renforcer les actions et favoriser la collaboration intersectorielle; la création d'un système de surveillance et d'une plateforme pour suivre la mise en œuvre du plan stratégique; et enfin, la conversion des stratégies du plan en actions telles que le contrôle de la distribution et de l'usage des antimicrobiens chez les humains et les animaux. Les résultats provisoires indiquent que la consommation d'antimicrobiens chez les animaux a diminué de moitié (ce qui est supérieur à l'objectif national d'une réduction de 30%), tandis que les autres objectifs n'ont pas encore été atteints. Nous avons constaté qu'accroître la visibilité de la résistance aux antimicrobiens et instaurer un mécanisme de gouvernance national constituaient des étapes cruciales, et qu'un système de surveillance et d'évaluation devait être développé parallèlement à la mise en œuvre. L'obtention de financements est elle aussi essentielle. Une politique cohérente est nécessaire pour éviter de multiplier les actions similaires. Fixer des objectifs très ambitieux, même s'ils ne sont pas encore atteints, permet en outre de faire progresser les actions au-delà des attentes. Enfin, l'engagement politique et la collaboration entre différents secteurs continueront à jouer un rôle prépondérant, mais ne pourront peut-être pas se poursuivre sans une structure de gouvernance bien conçue, capable de soutenir des actions à long terme visant à remédier à la résistance aux antimicrobiens.

La resistencia a los antimicrobianos es una grave amenaza que afecta a todos los países. El Plan de Acción Mundial sobre la resistencia a los antimicrobianos y la Declaración Política de las Naciones Unidas sobre la resistencia a los antimicrobianos establecen normas para que los países resuelvan los problemas de resistencia a los antimicrobianos en el marco del enfoque «Una única salud¼. Evaluamos los avances y los desafíos en la aplicación del plan estratégico nacional de Tailandia sobre la resistencia a los antimicrobianos 2017-2022, analizamos los resultados provisionales y compartimos las lecciones aprendidas. Entre los principales avances se encuentran: el establecimiento de un mecanismo de gobernanza nacional que lidera la política de alto impacto sobre la resistencia a los antimicrobianos y consolida las acciones y la colaboración multisectorial; la creación de un sistema de seguimiento y una plataforma para seguir la aplicación del plan estratégico; y la conversión de las estrategias del plan estratégico en acciones como el control de la distribución y el uso de antimicrobianos en humanos y animales. Los resultados provisionales indican que el consumo de antimicrobianos en animales se ha reducido casi a la mitad (superando el objetivo nacional de una reducción del 30 %), mientras que otros objetivos aún no han alcanzado sus metas. Hemos aprendido que elevar la resistencia a los antimicrobianos a una visibilidad de alto nivel y establecer un mecanismo de gobernanza nacional es un primer paso importante, y que debe desarrollarse un sistema de seguimiento y evaluación en paralelo a la implementación. Asegurar los fondos es crucial. La coherencia política es necesaria para evitar la duplicación de acciones. Unos objetivos muy ambiciosos, aunque todavía no se hayan alcanzado, pueden hacer avanzar las acciones más allá de las expectativas. El compromiso político y la colaboración entre los distintos sectores seguirán desempeñando un papel importante, pero podrían no mantenerse sin una estructura de gobernanza bien diseñada que apoye las acciones a largo plazo para hacer frente a la resistencia a los antimicrobianos.

A retrospective study of survival and risk factors for mortality among people living with HIV who received antiretroviral treatment in a resource-limited setting.

BACKGROUND: The availability and accessibility of effective antiretroviral therapy (ART) for people living with HIV (PLWH) has substantially improved in the past two decades in resource-limited settings. Therefore, evaluation of survival is needed in the current setting. METHOD: We retrospectively analyzed secondary data of the national AIDS program database from national health security region number 4 among PLWH who were ART-naive between January 2014 and December 2018. All PLWH were followed until December 2019 to evaluate their survival status and possible risk factors related to death. RESULTS: A total of 42,229 PLWH were identified, of which 14,053 were ART-naive and thus enrolled in the study. Sixty-seven percent were male, the mean ± SD age was 35 ± 12 years, and the median (IQR) baseline CD4 count was 162 (44-353) cells/mm3. Regarding medical care benefits, 46% had a universal health coverage scheme, 34% had a national social security scheme, and 2% had a civil servants medical benefit scheme. A total of 2142 (15%) mortalities occurred during the total follow-up period of 28,254 patient-years. The mortality rate was 7.5 (95% CI 7.2-7.9) per 100 person-years. Survival rates at 1, 2, 3, 4 and 5 years after HIV registration were 88.2% (95% CI 87.6-88.7%), 85.3% (95% CI 84.6-85.9%), 82.9% (95% CI 81.9-83.4%), 81.3% (95% CI 80.5-82.0%) and 75.1% (95% CI 73.5-76.8%), respectively. The Cox proportional hazards model showed that all-cause mortality was associated with a history of ART switching (HR = 7.06, 95% CI 4.53-11.00), major opportunistic infections during ART (HR = 1.93, 95% CI 1.35-2.77), baseline CD4 count ≤ 200 vs. > 500 cells/mm3 (HR = 4.00, 95% CI 1.45-11.11), age ≥ 50 vs. < 30 years (HR = 1.77, 95% CI 1.12-2.78), and receiving nevirapine-based regimens(HR = 1.43, 95% CI 1.04-1.97). CONCLUSIONS: This study demonstrated the substantial mortality rate over the consecutive 5 years of the follow-up period among PLWH who received ART in a resource-limited setting. Early case finding and prompt initiation of ART as well as continuous HIV care are a cornerstone to improve survival.

Effect of Oral Oseltamivir on Virological Outcomes in Low-risk Adults With Influenza: A Randomized Clinical Trial.

BACKGROUND: Duration of viral shedding is a determinant of infectivity and transmissibility, but few data exist about oseltamivir's ability to alter viral shedding. METHODS: From January 2012 through October 2017, a randomized, double-blinded multicenter clinical trial was conducted in adults aged 18-64 years at 42 sites in Thailand, the United States, and Argentina. Participants with influenza A or B and without risk factors for complications of influenza were screened for the study. Eligible participants were randomized to receive oseltamivir 75 mg or placebo twice daily for 5 days. The primary endpoint was the percentage of participants with virus detectable by polymerase chain reaction in nasopharyngeal swab at day 3. RESULTS: Of 716 adults screened for the study, 558 were randomized, and 501 were confirmed to have influenza. Forty-six participants in the pilot study were excluded, and 449 of the 455 participants in the population for the primary analysis had day 3 viral shedding results. Ninety-nine (45.0%) of 220 participants in the oseltamivir arm had virus detected at day 3 compared with 131 (57.2%) of 229 participants in the placebo arm (absolute difference of -12.2% [-21.4%, -3.0%], P =; .010). The median time to alleviation of symptoms was 79.0 hours for the oseltamivir arm and 84.0 hours for the placebo arm (P =; .34) in those with confirmed influenza infection. CONCLUSIONS: Oseltamivir decreased viral shedding in this low-risk population. However, in the population enrolled in this study, it did not significantly decrease the time to resolution of clinical symptoms. CLINICAL TRIALS REGISTRATION: NCT01314911.

Zero Transmission of Middle East Respiratory Syndrome: Lessons Learned From Thailand.

New emerging pathogens can quickly become a global health threat in this era. A number of Middle East respiratory syndrome (MERS) outbreaks have been linked to healthcare facilities. The healthcare-associated transmission of Middle East respiratory syndrome coronavirus (MERS-CoV) has been attributed to overcrowding, delayed diagnosis, and the breakdown of infection control systems. Strict infection control precautions and a well-prepared hospital system may have contributed to no nosocomial transmission occurring during the treatment of MERS-CoV infections imported to Thailand. The recent outbreaks of MERS and previous emerging infections provide valuable lessons to be learned. Continuous vigilance and strengthening of infection control systems will shape the capacity to prevent and control MERS-CoV or new emerging disease transmission.

Real-Life Clinical Practice of Using the Xpert MTB/RIF Assay in Thailand.

BACKGROUND: Delayed diagnosis of tuberculosis (TB) and drug-resistant TB are major challenges of TB control in Thailand. This study assessed the practicality of the Xpert MTB/RIF assay in a real-life setting with high prevalence of human immunodeficiency virus (HIV) infection and pulmonary tuberculosis (PTB). METHODS: This prospective study was conducted at 3 large tertiary care hospitals. Patients who had suspected PTB were enrolled into the study. Expectorated sputum samples were sent for staining, mycobacterial culture, and Xpert MTB/RIF. RESULTS: Four hundred ninety-four patients were enrolled. From 355 cases with final diagnosis of PTB, 263 (71.8%) had definite diagnosis and 92 cases had probable diagnosis. Among TB culture-positive cases, Xpert MTB/RIF had 100% and 81% sensitivity in sputum smear-positive and smear-negative groups, respectively. The specificity was 95.7%. The sensitivity and positive predictive value of Xpert MTB/RIF in culture-negative but clinically diagnosed PTB was 37.8% and 83.8%, respectively. Centrifugation was required in 59% cases with scanty sputum. Five cases were false-positive by Xpert MTB/RIF in patients with nontuberculous mycobacteria, old PTB scar, and immune reconstitution syndrome. Discordant rifampicin susceptibility results of Xpert MTB/RIF and mycobacteria growth indicator tube (MGIT) were confirmed by using rpoB gene sequencing, which raised the sensitivity of Xpert MTB/RIF in detecting rifampicin resistance to 93.8%. CONCLUSIONS: Xpert MTB/RIF is an effective tool in diagnosing PTB but will be more cost-effective for sputum-negative patients and in settings with high prevalence of rifampicin resistance. Early diagnosis of TB results in early treatment and implementation of strategies to limit spreading of TB. Sputum centrifugation may increase the yield of Xpert MTB/RIF.

HEALTHCARE-ASSOCIATED INFECTIONS AT SELECTED HOSPITALS IN THAILAND.

This study aimed to determine the prevalence of healthcare-associated infections (HAIs), all-cause mortality, document the bacterial pathogens isolated in HAIs, and determine the risk factors associated with HAIs and all-cause mortality at selected hospitals in Thailand. A survey with a total time frame of 10 days was conducted at selected 50 hospitals across Thailand during January 2014: 19 primary government hospitals, 15 secondary government hospitals, 13 tertiary government hospitals, 2 private hospitals and 1 government university hospital. Of 15,475 cases reviewed, 688 patients had 791 HAIs (1.1 HAI per infected patient). The rate of HAI was 4.4% (95%CI: 4.1-4.8): 7.3% (95%CI: 4.6-9.3) at the university hospital surveyed, 5.0% (95%CI: 4.6-5.4) at the tertiary hospitals surveyed, 3.9% (95%CI: 3.4-4.6) at the secondary hospitals surveyed, 2.0% (95%CI: 1.3-2.7) at the primary hospitals surveyed, and 1.6% (95%CI: 0.5-2.8) at the private hospitals surveyed. The ward with the frequent number of HAI was the intensive care unit (17%). The two most commonly affected age ranges were those aged >60 years and <1 year. Of the 791 HAIs found in this survey, the 3 most frequently reported types of HAI were: respiratory tract infections (n=377, 48%), urinary tract infections (n=176, 22%) and surgical site infections (n=55, 7%). Of the 688 patients with a HAI, 24% died within three months of this survey. The most frequently reported bacterial pathogen was Acinetobacter species (17%). On multivariate analysis, HAIs were significantly associated with patient age <1 year, a university hospital, having major surgery, urinary catheterization, being on a respiratory ventilator, having a tracheostomy, and having central venous catheterization (p <0.05). Death was associated with patient age <1 year, a university hospital, being on a surgical or medical ward, being on a ventilator, and having a central venous catheter (p <0.05). HAIs are major public health problems in the studied hospitals and result in substantial mortality.

Effect of nutritional counseling on low-density lipoprotein cholesterol among Thai HIV-infected adults receiving antiretroviral therapy.

HIV-infected patients receiving antiretroviral therapy have increased risk of metabolic syndrome, including dyslipidemia. In this study, we determined whether individual nutritional counseling reduced dyslipidemia, particularly low-density lipoprotein (LDL) cholesterol, among HIV-infected patients with dyslipidemia not currently taking lipid-lowering medication. We conducted a randomized 24-week trial among HIV-infected patients with dyslipidemia who were on antiretroviral therapy and were eligible to initiate therapeutic lifestyle changes according to the Thai National Cholesterol Education Program. Participants were randomly assigned to an intervention group that received individual counseling with a nutritionist for seven sessions (baseline, weeks 2, 4, 8, 12, 18, and 24) and a control group that received standard verbal diet information at baseline and nutritional counseling only at week 24. A 24-h recall technique was used to assess dietary intake for both groups at baseline and week 24. Lipid profile (total cholesterol, LDL, high-density lipoprotein (HDL), and triglyceride) was measured at baseline and after 12 and 24 weeks of therapy. An intention-to-treat and linear mixed model were used. Seventy-two patients were randomly assigned, and 62 (86%) participants completed their lipid profile test. After 12 weeks of follow-up, there were significant reductions in the intervention group for total cholesterol (-14.4 ± 4.6 mg/dL, P = .002), LDL cholesterol (-13.7 ± 4.1 mg/dL, P = .001), and triglyceride (-30.4 ± 13.8 mg/dL, P = .03). A significant reduction in LDL cholesterol was also observed in the control group (-7.7 ± 3.8 mg/dL, P = .04), but there were no significant differences in change of mean lipid levels between the groups at 12 weeks of follow-up. After 24 weeks, participants assigned to the intervention group demonstrated significantly greater decreases in serum total cholesterol (-19.0 ± 4.6 vs. 0.2 ± 4.3 mg/dL, P = .003) and LDL cholesterol (-21.5 ± 4.1 vs. -6.8 ± 3.8 mg/dL, P = .009). There were no significant changes in HDL cholesterol or triglyceride levels in either group.

Integrated therapy for HIV and tuberculosis.

Tuberculosis (TB) has been the most common opportunistic infection and cause of mortality among HIV-infected patients, especially in resource-limited countries. Clinical manifestations of TB vary and depend on the degree of immunodeficiency. Sputum microscopy and culture with drug-susceptibility testing are recommended as a standard method for diagnosing active TB. TB-related mortality in HIV-infected patients is high especially during the first few months of treatment. Integrated therapy of both HIV and TB is feasible and efficient to control the diseases and yield better survival. Randomized clinical trials have shown that early initiation of antiretroviral therapy (ART) improves survival of HIV-infected patients with TB. A delay in initiating ART is common among patients referred from TB to HIV separate clinics and this delay may be associated with increased mortality risk. Integration of care for both HIV and TB using a single facility and a single healthcare provider to deliver care for both diseases is a successful model. For TB treatment, HIV-infected patients should receive at least the same regimens and duration of TB treatment as HIV-uninfected patients. Currently, a 2-month initial intensive phase of isoniazid, rifampin, pyrazinamide, and ethambutol, followed by 4 months of continuation phase of isoniazid and rifampin is considered as the standard treatment of drug-susceptible TB. ART should be initiated in all HIV-infected patients with TB, irrespective of CD4 cell count. The optimal timing to initiate ART is within the first 8 weeks of starting antituberculous treatment and within the first 2 weeks for patients who have CD4 cell counts <50 cells/mm(3). Non-nucleoside reverse transcriptase inhibitor (NNRTI)-based ART remains a first-line regimen for HIV-infected patients with TB in resource-limited settings. Although a standard dose of both efavirenz and nevirapine can be used, efavirenz is preferred because of more favorable treatment outcomes. In the settings where raltegravir is accessible, doubling the dose to 800 mg twice daily is recommended. Adverse reactions to either antituberculous or antiretroviral drugs, as well as immune reconstitution inflammatory syndrome, are common in patients receiving integrated therapy. Early recognition and appropriate management of these consequences can reinforce the successful integrated therapy in HIV-infected patients with TB.

Guidelines for antiretroviral therapy in HIV-1 infected adults and adolescents 2014, Thailand.

New evidence has emerged regarding when to commence antiretroviral therapy (ART), optimal treatment regimens, management of HIV co-infection with opportunistic infections, and management of ART failure. The 2014 guidelines were developed by the collaborations of the Department of Disease Control, Ministry of Public Health (MOPH) and the Thai AIDS Society (TAS). One of the major changes in the guidelines included recommending to initiating ART irrespective of CD4 cell count. However, it is with an emphasis that commencing HAART at CD4 cell count above 500 cell/mm(3) is for public health, in term of preventing HIV transmission and personal benefit. In tuberculosis co-infected patients with CD4 cell counts ≤50 cells/mm(3) or with CD4 cell counts >50 cells/mm(3) who have severe clinical disease, ART should be initiated within 2 weeks of starting tuberculosis treatment. The preferred initial ART regimen in treatment naïve patients is efavirenz combined with tenofovir and emtricitabine or lamivudine. Plasma HIV viral load assessment should be done twice a year until achieving undetectable results; and will then be monitored once a year. CD4 cell count should be monitored every 6 months until CD4 cell count ≥350 cells/mm(3) and with plasma HIV viral load <50 copies/mL; then it should be monitored once a year afterward. HIV drug resistance genotypic test is indicated when plasma HIV viral load >1,000 copies/mL while on ART. Ritonavir-boosted lopinavir or atazanavir in combination with optimized two nucleoside-analogue reverse transcriptase inhibitors is recommended after initial ART regimen failure. Long-term ART-related safety monitoring has also been included in the guidelines.

COMPARISON OF THAI GOVERNMENT MANUFACTURED TENOFOVIR (TENOFOVIR GPO300) WITH PRIVATELY MANUFACTURED TENOFOVIR (VIREAD) USED ALONG WITH LAMIVUDINE AND EFAVIRENZ TO TREAT THAI HIV PATIENTS.

The Thai Government Pharmaceutical Organization (GPO) has produced a nucleotide reverse transcriptase inhibitor, tenofovir disoproxil fumarate (Tenofovir GPO300). No clinical trial to date has compared plasma tenofovir concentrations, renal function, and treatment responses in HIV-infected patients who received Teno- fovir GPO300 versus Viread (original tenofovir) as part of an antiretroviral regimen. We studied 129 antiretroviral treatment (ART)-naive HIV-1 infected patients who received an antiretroviral regimen of lamivudine, efavirenz and Tenofovir GPO300 (n = 65) or Viread (n = 64). We examined plasma tenofovir concentrations (12 hours after dosing), serum creatinine, estimated glomerular filtration rate (eGFR) using the Modification in Diet in Renal Disease (MDRD) study formula, fractional excretion of phosphate (FEphos), CD4 and plasma HIV-1 RNA levels at 12 weeks, and CD4 and plasma HIV-1 RNA levels at 24 weeks after initiating the drugs. At baseline, the mean ± SD subject body weight was 54 ± 10 kilograms and the mean ± SD subject age was 37 ± 8 years. At baseline, the median (IQR) CD4 count was 44 (18-120) cells/ mm3 and the median (IQR) HIV-1 RNA level was 5.8 log copies/ml. At baseline, the mean ± SD eGFR was 134.8 ± 43.6 ml/min/1.73 m2. The baseline values for the two groups were not significantly different from each other (p > 0.05). At 12 weeks, the mean ± SD plasma tenofovir concentration was 106.9 ± 41.5 ng/ml among the patients who received Tenofovir GPO300 and 100.7 ± 49.4 ng/ml among those who received Viread (p = 0.437). At week 12, there were no differences between those who rceived Tenofovir GPO300 and Vilead in mean serum creatinine (0.78 vs 0.81 mg/dl, p = 0.283), mean eGFR (117.9 vs 109.1 ml/min/1.73 m2, p = 0.089), decline in eGFR from baseline (-21.8 vs -20.6 ml/min/1.73 m2, p = 0.860) or mean FEphos (11.4 vs 11.2, p = 0.923). The median CD4 cell counts and number of patients with undetectable plasma HIV-1 RNA at week 24 were not significantly different (p > 0.05) between those who took Tenofovir GPO300 and Viread. In summary, plasma tenofovir concentrations, changes in renal function, urinary phosphate excretion and treatment responses were comparable between HIV-infected patients who received Tenofovir GPO300 and Viread-containing non-nucleoside reverse transcriptase regimens.

CYP2B6 18492T->C polymorphism compromises efavirenz concentration in coinfected HIV and tuberculosis patients carrying CYP2B6 haplotype *1/*1.

Data regarding the effect of the CYP2B6 18492T→C polymorphism on plasma efavirenz concentrations and 96-week virologic responses in patients coinfected with HIV and tuberculosis (TB) are still unavailable. A total of 139 antiretroviral-naive HIV-infected adults with active TB were prospectively enrolled to receive efavirenz 600 mg-tenofovir 300 mg-lamivudine 300 mg. Eight single nucleotide polymorphisms (SNPs) within CYP2B6 were genotyped. Seven SNPs, including 64C→T, 499C→G, 516G→T, 785A→G, 1375A→G, 1459C→T, and 21563C→T, were included for CYP2B6 haplotype determination. The CYP2B6 18492T→C polymorphism was studied in 48 patients who carried haplotype *1/*1. At 12 and 24 weeks after antiretroviral therapy, plasma efavirenz concentrations at 12 h after dosing were measured. Plasma HIV RNA was monitored every 12 weeks for 96 weeks. Of 48 patients {body weight [mean±standard deviation (SD)], 56±10 kg}, 77% received a rifampin-containing anti-TB regimen. No drug resistance-associated mutation was detected at baseline. The frequencies of the wild type (18492TT) and the heterozygous (18492TC) and homozygous (18492CC) mutants of the CYP2B6 18492T→C polymorphism were 39%, 42%, and 19%, respectively. At 12 weeks, mean (±SD) efavirenz concentrations of patients who carried the 18492TT, 18492TC, and 18492CC mutants were 2.8±1.6, 1.7±0.9, and 1.4±0.5 mg/liter, respectively (P=0.005). At 24 weeks, the efavirenz concentrations of the corresponding groups were 2.4±0.8, 1.7±0.8, and 1.2±0.4 mg/liter, respectively (P=0.003). A low efavirenz concentration was independently associated with 18492T→C (ß=-0.937, P=0.004) and high body weight (ß=-0.032, P=0.046). At 96 weeks, 19%, 17%, and 28% of patients carrying the 18492TT, 18492TC, and 18492CC mutants, respectively, had plasma HIV RNA levels of >40 copies/ml and developed efavirenz-associated mutations (P=0.254). In summary, the CYP2B6 18492T→C polymorphism compromises efavirenz concentrations in patients who carry CYP2B6 haplotype *1/*1 and are coinfected with HIV and tuberculosis.

ABCC2*1C and plasma tenofovir concentration are correlated to decreased glomerular filtration rate in patients receiving a tenofovir-containing antiretroviral regimen.

OBJECTIVES: To study the correlations of genetic variants of tenofovir tubular transporters, plasma tenofovir concentrations and clinical factors with decreased glomerular filtration rate in HIV-infected patients who received tenofovir. METHODS: A total of 117 HIV-1-infected patients were administered antiretroviral therapy with tenofovir/lamivudine/efavirenz. Two single nucleotide polymorphisms (SNPs), ABCC2*1C c.-24C>T and ABCB1*6 c.3435C>T, were genotyped. At week 24, plasma tenofovir concentration at 12 h after drug intake was measured. Serum creatinine and estimated glomerular filtration rate (eGFR) calculated by the Modification of Diet in Renal Disease study formula were measured every 24 weeks until 96 weeks. RESULTS: Overall, mean ±â€ŠSD age was 37 ±â€Š9 years. Mean ±â€ŠSD baseline eGFR was 130.3 ±â€Š35.0 mL/min/1.73 m(2). The frequencies of wild-type/heterozygous/homozygous mutants of ABCC2*1C were 57%/39%/4% and those of ABCB1*6 were 28%/51%/21%. Mean ±â€ŠSD plasma tenofovir concentration at 24 weeks was 105 ±â€Š46 ng/mL. At week 48, m-ean ±â€ŠSD eGFR of ABCC2*1C CC versus CT/TT was 96 versus 108 mL/min (P = 0.005) and m-ean ±â€ŠSD eGFR of ABCB1*6 CC versus CT/TT was 106 versus 99 mL/min (P = 0.157). Mean ±â€ŠSD tenofovir concentration in ABCC2*1C genotype CC versus CT/TT was 113 ±â€Š47 versus 93 ±â€Š44 ng/mL, respectively (P = 0.018). By multivariate analysis I, decreased eGFR at week 48 was correlated to ABCC2*1C genotype CC (P = 0.001), low eGFR at baseline (P = 0.006) and older age (P = 0.048). By multivariate analysis II, decreased eGFR at week 48 was correlated to high plasma tenofovir concentration (P = 0.001) and low eGFR at baseline (P = 0.019). CONCLUSIONS: HIV-infected patients who carry ABCC2*1C genotype CC at position -24 or have high plasma tenofovir concentration are at risk of decreased glomerular filtration rate.

Risk factors for hospitalization among children with influenza B infection.

Data regarding risk factors for hospitalization among children with influenza B infection are limited. We conducted a retrospective study of 184 children with influenza B infection during October 2011 - September 2012 seen at Bamrasnaradura Infectious Diseases Institute, Thailand; clinical and laboratory data were compared between hospitalized and outpatient children. The numbers of hospitalized and outpatient children were 65 (35%) and 119 (65%), respectively. Most children (> 80%) were aged > or = 5 years. The median time from onset of symptoms to starting oseltamivir treatment was significantly longer among hospitalized than outpatient children (3 days vs 2 days, p < 0.05). The significantly more hospitalized children received antibiotics than outpatient children (43% vs 7%, p < 0.05). Complications were more common among hospitalized children than outpatient children (37% vs 2%, p < 0.05). Pneumonia and rhinosinusitis were significantly more common among hospitalized children than outpatient children (p < 0.05). Direct contact history, history of receiving an influenza vaccine, history of a previous influenza infection, body temperature, respiratory symptoms, gastrointestinal symptoms, headache and laboratory findings were not significantly different between the two groups (p > 0.05). In conclusion, delay initiation of antiviral therapy and medical complications (pneumonia and rhinosinusitis) were more common among hospitalized children with influenza B than outpatient children with influenza B in the studied population.

Clinically significant drug interactions among HIV-infected patients receiving antiretroviral therapy.

We conducted a cross sectional study of the outpatient medical records of 1000 HIV-infected patients receiving antiretroviral therapy (ART) in 2011 to determine the incidence of clinically significant drug interactions (CSDI). The severities of the CSDI were graded following the Micromedex" 2.0 database and the Department of Health and Human Services (DHHS) 2012 HIV treatment guidelines. Three hundred thirty-five patients (34%) had 554 episodes of CSDI. Of which 337 episodes (61%), 163 episodes (29%) and 54 episodes (10%) had grades 2, 3 and 4 severity CSDI, respectively. The CSDI were caused by protease inhibitor (PI)-based drug regimens in 79%, by efavirenz-based regimens in 34% and by nevirapine-based regimens in 10% (p<0.001). The three most common grade 4 CSDI were: a PI with simvastatin (n=24), simvastatin with gemfibrozil (n=24) and didanosine with allopurinol (n=2). The three most common grade 3 CSDI were: a PI with a statin drug except simvastatin (n=56), fenofibrate with a statin drug (n=28) and amlodipine with simvastatin (n=14). On multivariate analysis, risk factors associated with CSDI were: receiving a PI-based regimen (OR 14.44; 95% CI: 9.10-22.88), having dyslipidemia (OR 3.94; 95% CI: 1.89-8.21), having >5 items prescribed at a time (OR 1.80; 95% CI: 1.23-2.63), seeing a doctor >4 times a year (OR 1.72; 95% CI: 1.20-2.46), having hypertension (OR 0.60; 95% CI: 0.37-0.98), having a duration of receiving ART of >5 years (OR 0.46; 95% CI: 0.28-0.77) and having a CD4 count of >200 cells/mm3 (OR 0.46; 95%CI: 0.26-0.84). CSDI were common among HIV-infected patients receiving ARV in our outpatient clinic. Patients having a low CD, count, having dyslipidemia, receiving PI-based ART, having a frequent number of visits per year and having a large number of items prescribed at each visit had a greater chance of a CSDI.

Nucleoside reverse transcriptase inhibitor resistance mutations associated with first-line stavudine-containing antiretroviral therapy: programmatic implications for countries phasing out stavudine.

BACKGROUND: The World Health Organization Antiretroviral Treatment Guidelines recommend phasing-out stavudine because of its risk of long-term toxicity. There are two mutational pathways of stavudine resistance with different implications for zidovudine and tenofovir cross-resistance, the primary candidates for replacing stavudine. However, because resistance testing is rarely available in resource-limited settings, it is critical to identify the cross-resistance patterns associated with first-line stavudine failure. METHODS: We analyzed HIV-1 resistance mutations following first-line stavudine failure from 35 publications comprising 1,825 individuals. We also assessed the influence of concomitant nevirapine vs. efavirenz, therapy duration, and HIV-1 subtype on the proportions of mutations associated with zidovudine vs. tenofovir cross-resistance. RESULTS: Mutations with preferential zidovudine activity, K65R or K70E, occurred in 5.3% of individuals. Mutations with preferential tenofovir activity, ≥ two thymidine analog mutations (TAMs) or Q151M, occurred in 22% of individuals. Nevirapine increased the risk of TAMs, K65R, and Q151M. Longer therapy increased the risk of TAMs and Q151M but not K65R. Subtype C and CRF01_AE increased the risk of K65R, but only CRF01_AE increased the risk of K65R without Q151M. CONCLUSIONS: Regardless of concomitant nevirapine vs. efavirenz, therapy duration, or subtype, tenofovir was more likely than zidovudine to retain antiviral activity following first-line d4T therapy.

Prevalence and Risk Factors of Healthcare-Associated Infections among Hospitalized Pediatric Patients: Point Prevalence Survey in Thailand 2021.

BACKGROUND: Healthcare-associated infections (HAIs) pose a grave threat to patient safety, morbidity, and mortality, contributing to antimicrobial resistance. Thus, we estimated the point prevalence, risk factors, types, and pathogens of HAIs in hospitalized pediatric patients. METHODS: A point prevalence survey (PPS) of HAIs in hospitalized pediatric patients < 18 years old was conducted from March to May 2021. Outcomes, risk factors, and types of HAIs associated with HAIs in 41 hospitals across Thailand were collected. RESULTS: The prevalence of HAIs was 3.9% (95% CI 2.9-5.0%) (56/1443). By ages < 1 month, 1 month-2 years, 2-12 years, and 12-18 years, the prevalence of HAIs was 4.2%, 3.3%, 4.1%, and 3.0%, respectively (p = 0.80). Significant independent risk factors were extended hospital length of stay (LOS) and central venous catheter (CVC) use. Compared to an LOS of <4 days, LOSs of 4-7 days, 8-14 days, and >14 days had adjusted odds ratios (aORs) of 2.65 (95% CI 1.05, 6.68), 5.19 (95% CI 2.00, 13.4), and 9.03 (95% CI 3.97, 20.5), respectively. The use of a CVC had an aOR of 2.45 (95% CI 1.06-5.66). Lower respiratory tract infection (LRTI) was the most common HAI type (46.4%: 26/56). The highest prevalence of HAIs was predominantly observed in LRTI diagnoses, with the highest among these in the <1 month age category at 2.3% (17/738). CONCLUSION: The prevalence of HAIs in hospitalized pediatric patients was 3.9%. Extended LOS and use of CVC were HAI risk factors. A strategy for reducing LOS and reviewing insertion indications or the early planned removal of a CVC was implemented. The surveillance of HAIs stands as a cornerstone and fundamental component of IPC, offering invaluable insights that enhance hospital IPC interventions aimed at preventing HAIs.

Prospective multicentre accuracy evaluation of the FUJIFILM SILVAMP TB LAM test for the diagnosis of tuberculosis in people living with HIV demonstrates lot-to-lot variability.

There is an urgent need for rapid, non-sputum point-of-care diagnostics to detect tuberculosis. This prospective trial in seven high tuberculosis burden countries evaluated the diagnostic accuracy of the point-of-care urine-based lipoarabinomannan assay FUJIFILM SILVAMP TB LAM (FujiLAM) among inpatients and outpatients living with HIV. Diagnostic performance of FujiLAM was assessed against a mycobacterial reference standard (sputum culture, blood culture, and Xpert Ultra from urine and sputum at enrollment, and additional sputum culture ≤7 days from enrollment), an extended mycobacterial reference standard (eMRS), and a composite reference standard including clinical evaluation. Of 1637 participants considered for the analysis, 296 (18%) were tuberculosis positive by eMRS. Median age was 40 years, median CD4 cell count was 369 cells/ul, and 52% were female. Overall FujiLAM sensitivity was 54·4% (95% CI: 48·7-60·0), overall specificity was 85·2% (83·2-87·0) against eMRS. Sensitivity and specificity estimates varied between sites, ranging from 26·5% (95% CI: 17·4%-38·0%) to 73·2% (60·4%-83·0%), and 75·0 (65·0%-82·9%) to 96·5 (92·1%-98·5%), respectively. Post-hoc exploratory analysis identified significant variability in the performance of the six FujiLAM lots used in this study. Lot variability limited interpretation of FujiLAM test performance. Although results with the current version of FujiLAM are too variable for clinical decision-making, the lipoarabinomannan biomarker still holds promise for tuberculosis diagnostics. The trial is registered at clinicaltrials.gov (NCT04089423).

Impact of pharmacogenetic markers of CYP2B6, clinical factors, and drug-drug interaction on efavirenz concentrations in HIV/tuberculosis-coinfected patients.

Comprehensive information on the effects of cytochrome P450 2B6 (CYP2B6) polymorphisms, clinical factors, and drug-drug interactions on efavirenz concentrations in HIV/tuberculosis-coinfected (HIV/TB) patients is unavailable. A total of 139 HIV/TB adults, 101 of whom received a rifampin-containing anti-TB regimen, were prospectively enrolled to receive efavirenz (600 mg)/tenofovir/lamivudine. Nine single nucleotide polymorphisms (SNPs) within CYP2B6 were genotyped. Plasma efavirenz concentrations were measured at 12 weeks. The median (interquartile range [IQR]) efavirenz concentration was 2.3 (1.4 to 3.9) mg/liter. The SNPs (frequencies of heterozygous and homozygous mutants) were 64C>T (10% and 1%), 499C>G (0% and 0%), 516G>T (47% and 8%), 785A>G (54% and 10%), 1375A>G (0% and 0%), 1459C>T (3% and 0%), 3003C>T (44% and 27%), 18492T>C (39% and 6%), and 21563C>T (57% and 5%). The four most frequent CYP2B6 haplotypes identified were *1/*6 (41%), *1/*1 (35%), *1/*2 (7%), and *6/*6 (7%). The heterozygous/homozygous mutation associated with low efavirenz concentrations was 18492T>C (P < 0.001), and those associated with high efavirenz concentrations were 516G>T, 785A>G, and 21563C>T (all P < 0.05). Haplotype *1/*1 was associated with low efavirenz concentrations, and *6/*6, *1/*6, and *5/6 were associated with high efavirenz concentrations. As shown by multivariate analysis, low efavirenz concentrations were significantly associated with the *1/*1 haplotype (beta = -1.084, P = 0.027) and high body weight (beta = -0.076, P = 0.002). In conclusion, pharmacogenetic markers of CYP2B6 have the greatest impact with respect to inducing low plasma efavirenz concentrations in HIV/TB Thai patients.