Clinical Antiviral Efficacy of Remdesivir in Coronavirus Disease 2019: An Open-Label, Randomized Controlled Adaptive Platform Trial (PLATCOV).

BACKGROUND: Uncertainty over the therapeutic benefit of parenteral remdesivir in coronavirus disease 2019 (COVID-19) has resulted in varying treatment guidelines. METHODS: In a multicenter open-label, controlled, adaptive, pharmacometric platform trial, low-risk adult patients with early symptomatic COVID-19 were randomized to 1 of 8 treatment arms including intravenous remdesivir (200 mg followed by 100 mg daily for 5 days) or no study drug. The primary outcome was the rate of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) clearance (estimated under a linear model fit to the daily log10 viral densities, days 0-7) in standardized duplicate oropharyngeal swab eluates, in a modified intention-to-treat population. This ongoing adaptive trial is registered at ClinicalTrials.gov (NCT05041907). RESULTS: The 2 study arms enrolled 131 patients (remdesivir n = 67, no study drug n = 64) and estimated viral clearance rates from a median of 18 swab samples per patient (a total of 2356 quantitative polymerase chain reactions). Under the linear model, compared with the contemporaneous control arm (no study drug), remdesivir accelerated mean estimated viral clearance by 42% (95% credible interval, 18%-73%). CONCLUSIONS: Parenteral remdesivir accelerates viral clearance in early symptomatic COVID-19. Pharmacometric assessment of therapeutics using the method described can determine in vivo clinical antiviral efficacy rapidly and efficiently.

Husband's willingness-to-pay for HIV and syphilis screening at antenatal care clinic under the Thai universal coverage scheme.

BACKGROUND: Screening for sexually transmitted infection (STI) especially HIV as early detection and treatment have been financially supported under the Thai Universal Coverage (UC) scheme since 2009 (THB140 for HIV). However, the implementation has not been evidence-based, strategic risk-based, nor economically evaluated whereas husbands who accompanied the pregnant women are likely to have a lower risk than those who did not come along. This study is aimed to determine the husband's willingness-to-pay (WTP) for his HIV and syphilis screening tests and potential factors affecting STI screenings at the antenatal care (ANC) clinic of a tertiary hospital in Thailand. METHODS: A pilot open-ended interview was conducted among 50 participants to estimate the mean and standard deviation of WTP prices for HIV and syphilis screening tests. A questionnaire was developed to obtain demographics, STI knowledge and screening history, as well as two contingent valuation methods (bidding and payment scale), using the mean WTP prices identified from the pilot study as a starting WTP with »SD step-up/down. The survey of 200 randomly selected husbands of pregnant women was conducted at King Chulalongkorn Memorial Hospital from April to June 2018. Descriptive statistics and logistic regression were used for data analysis. RESULTS: During the study period, 597 pregnant women received their first ANC. Of 368 accompanying husbands, 200 were enrolled in the study. Their median age was 31 (IQR 27-36) years old and 67% had a first child. Eighty-eight percent of the participants were willing to test for the STIs. Based on the bidding method, WTP prices for HIV and syphilis screening tests were US$14.5 (IQR 12.4-14.5) and US$9.7 (IQR 10-12), respectively. The payment scale method suggested approximately three-quarters of the WTP prices from the bidding method. CONCLUSIONS: The husbands who accompanied their pregnant wives to the ANC clinic showed positive behaviors according to the propitious selection theory. They tend to cooperate well with STI testing and are willing to pay at least two times the price of the STI screening tests. The financial support to promote STI screenings should be reconsidered to cover other groups with higher sexual behavior risks and less WTP.

Comparison of piperacillin plasma concentrations in a prospective randomised trial of extended infusion versus intermittent bolus of piperacillin/tazobactam in paediatric patients.

OBJECTIVES: To be effective, piperacillin/tazobactam (PTZ) unbound plasma levels need to be above the minimum inhibitory concentration (MIC) at least 50% of the time between dosing intervals (50% fT>MIC). This study aimed to compare the plasma piperacillin concentrations at the mid-dosing intervals (Cmid, 50% fT) and the proportion of patients achieving 50% fT>MIC between extended infusion (EI) and intermittent bolus (IB) methods in children. METHODS: A prospective, randomised trial of EI versus IB of PTZ was conducted in children aged 1 month to 18 years. The PTZ dose was 100 mg/kg intravenously every 8 h. Patients were randomly assigned to receive EI (4-h infusion) or IB (30-min infusion). The primary outcome that was measured was plasma piperacillin Cmid. RESULTS: Ninety patients with a median age (IQR) of 48 months (16-127) were enrolled. The most common indication for PTZ use was pneumonia (32.2%). Geometric mean (95% CI) plasma piperacillin Cmid of EI versus IB was 51.9 mg/L (40.6-66.6) versus 6.0 mg/L (4.2-8.6) (P < 0.01). The EI group had a trend of higher proportion of patients who achieved 50% fT>4xMIC (72.7% versus 30.0%; P = 0.06). CONCLUSIONS: PTZ administration with EI resulted in a higher Cmid compared with IB. In settings with increased piperacillin MICs, this approach should be implemented, particularly during the empirical treatment period.

Dose recommendations for intravenous colistin in pediatric patients from a prospective, multicenter, population pharmacokinetic study.

OBJECTIVES: The aim of this study was to describe the population pharmacokinetics of intravenous colistin use in children and to propose optimal dosage regimens. METHODS: A prospective, multicenter, population pharmacokinetic (PPK) study was conducted. Phoenix 64 version 8.3 was used for the PPK analysis. Simulations were performed to estimate the probability of target attainment for patients achieving target plasma colistin average steady-state concentrations (Css,avg). RESULTS: A total of 334 plasma colistin concentrations were obtained from 79 pediatric patients with a median age (interquartile range) of 2.6 years (0.8-6.8 years); 73 (92.4%) were admitted to intensive care units. Colistin pharmacokinetics were adequately described by a one-compartment model with first-order elimination along with serum creatinine (SCr) as a significant covariate in colistin clearance. The simulation demonstrated that the recommended dose of 5 mg of colistin base activity (CBA)/kg/day resulted in 18.2-63.0% probability of achieving a target Css,avg of 2 mg/l. With a lower targeted Css,avg of 1 mg/l, colistin dosing with 7.5 mg and 5 mg of CBA/kg/day were adequate for children with SCr levels of 0.1-0.3 mg/dl and >0.3 mg/dl, respectively. CONCLUSIONS: SCr is a significant covariate in colistin clearance in children. Colistin dosing should be selected according to the patient's SCr level and the desired target Css,avg.

A randomized open-label trial of 2-dose or 3-dose pre-exposure rabies prophylaxis among Thai children.

BACKGROUND: World Health Organization changed the recommendation for pre-exposure rabies prophylaxis from 3-dose to 2-dose regimen in 2018. Given limited data of 2-dose regimens in pediatric population, this study aimed to compare the immunogenicity between 2-dose and 3-dose pre-exposure rabies immunization. METHODS: This study was conducted among healthy children aged 2-12 years. They were randomized to 2-dose vaccination (2D) on days 0 and 28 or 3-dose vaccination (3D) on days 0, 7, and 28. Purified Vero cell rabies vaccine (PVRV-Verorab™) was administered intramuscularly. Rabies virus neutralizing antibody (RVNA) titers were measured at 3 time points: 14-day after complete vaccination, 1-year pre-booster vaccination, and 7-day post-booster dose to mimic scenario of rabies exposure. RVNA titers ≥0.5 IU/ml were considered adequate antibody. T cell specific response to rabies vaccine antigen was measured using the interferon-gamma enzyme linked immunospot assay. RESULTS: From September to October 2017, 107 participants (51% males), 78 in 2D group and 29 in 3D group were enrolled. Median age was 5.8 years (IQR 4.4-7.3). All participants had RVNA titers ≥0.5 IU/ml after primary vaccination [GMT 2D: 18.6 (95%CI 15.9-21.8) and 3D: 16.3 (95%CI 13.2-20.1 IU/ml), p = 0.35]. At 1-year prior to receiving the booster, only 80% of the children in 2D group maintained RVNA titers ≥0.5 IU/ml compared to 100% of the children in 3D group (p = 0.01). However, all participants in both groups had RVNA ≥0.5 IU/ml at 7-day post booster vaccination [GMT 2D: 20.9 (95%CI 17.4-25.3) and 3D: 22.2 (95%CI 15.8-31.4) IU/ml (P = 0.75)]. The median number of IFN-γ secreting cells at 7-day post-booster dose was 98 and 128 SFCs per 106 PBMCs in the 2D and 3D groups, respectively (P = 0.30). CONCLUSIONS: Two-dose primary rabies immunization provided adequate antibody at post primary vaccination and post booster. The results support 2-dose regimen of pre-exposure rabies immunization in the pediatric population.

Intensification of antiretroviral treatment with raltegravir for pregnant women living with HIV at high risk of vertical transmission.

Objectives: The rate of vertical HIV transmission for women at high risk of HIV transmission stands at approximately 7.6%. In the present study we describe infant infection rates in women who had received raltegravir (RAL) intensification during pregnancy to a standard three-drug antiretroviral (ART) regimen in Thailand. Methods: This prospective cohort study enrolled HIV-1-positive pregnant women at high risk of vertical transmission, as defined by (1) ART initiation at a gestational age (GA) ≥32 weeks or (2) HIV-1 RNA >1000 copies/mL at GA of 32-38 weeks while on ART. Women received a standard three-drug ART regimen with RAL intensification (400 mg twice daily) until delivery and continued on a three-drug ART regimen after delivery. Plasma HIV-1 RNA testing was performed before intensification and at delivery. Infant HIV-1 status was determined using DNA PCR at birth, and at 1, 2 and 4 months of life. Results: Between February 2016 and November 2017, 154 pregnant women on ART were enrolled into the study with a median CD4 cell count and plasma HIV-1 RNA level of 382 cells/mm3 and 4.0 log10 copies/mL, respectively. The three-drug combination consisted of either a lopinavir/ritonavir- (53%) or efavirenz-based (43%) regimen. Median GA at time of RAL initiation was 34 weeks (interquartile range [IQR] 33-36) and median duration was 21 days (IQR 8-34). The proportion of women who had a plasma HIV-1 RNA <50 and <1000 copies/mL at delivery was 45% and 76%, respectively. There were six infants with HIV infection, three in utero and three peripartum. Overall vertical transmission rate was 3.9% (95% confidence interval [CI] 1.4-8.2). Conclusion: The majority of high-risk pregnant women living with HIV-1 who had received RAL intensification achieved viral suppression at delivery with a relatively low rate of vertical transmission. This intensification strategy represents an option for prevention in HIV-positive women at high risk of vertical transmission.