Population pharmacokinetics of ravidasvir in adults with chronic hepatitis C virus infection and impact of antiretroviral treatment.

Ravidasvir (RDV) is a novel NS5A inhibitor that exhibits potent pan-genotypic inhibition of hepatitis C virus (HCV) replication. Sofosbuvir (SOF) plus RDV was demonstrated to be efficacious and safe in adults with active HCV infection, including those living with HIV (LWHIV), in the STORM-C-1 trial. We assessed the population pharmacokinetics (PK) of RDV in a sub-study nested within STORM-C-1 conducted in Thailand and Malaysia. SOF (400 mg) plus RDV (200 mg) was administered orally once daily for 12 weeks to adults with chronic HCV infection, but without cirrhosis and for 24 weeks to those with compensated cirrhosis. Intensive and sparse PK samples were collected at 4, 8, and 12 weeks after treatment initiation. Population PK parameters of RDV and the impact of covariates were evaluated using nonlinear mixed-effects modeling. Five hundred ninety-four participants were included, 235 (40%) had compensated cirrhosis, and 189 (32%) were LWHIV. RDV plasma concentrations were best described by a two-compartment model with first-order elimination. Oral clearance (CL/F) and volume of distribution (Vd/F) parameters were allometrically scaled on fat-free mass. Concomitant antiretroviral treatment (ART) increased RDV CL/F by 30%-60%, with efavirenz-based ART having the largest impact. Females had 16% lower RDV CL/F than males, and higher albumin levels reduced RDV central volume of distribution. While several covariates impact RDV CL/F and Vd/F, the effect on RDV exposures was not clinically relevant based on the efficacy data reported in this diverse Asian adult population. There were no meaningful drug-drug interactions in adults LWHIV on ART.

Molnupiravir versus favipiravir in at-risk outpatients with COVID-19: A randomized controlled trial in Thailand.

OBJECTIVES: Evaluate and compare the efficacy and safety of molnupiravir and favipiravir in outpatients with mild to moderate COVID-19 and at risk of severe COVID-19. METHODS: In an open-label, parallel-group, multicenter trial in Thailand, participants with moderate COVID-19 and at least one factor associated with severe COVID-19 were randomly assigned 1:1 to receive oral molnupiravir or oral favipiravir (standard of care). Phone calls for remote symptom assessment were made on Days 6, 15, and 29. Participants with worsening symptoms were instructed to return to the hospital. The primary endpoint was pulmonary involvement by Day 29, as evidenced by ≥2 of the following: dyspnea, oxygen saturation <92% or imaging. RESULTS: Nine hundred seventy-seven participants (487 molnupiravir, 490 favipiravir) were enrolled from 8 July 2022 to 19 January 2023. 98% had received ≥1 dose of COVID-19 vaccine and 83% ≥3 doses. By Day 29, pulmonary involvement occurred in 0% (0/483) in molnupiravir arm versus 1% (5/482) in favipiravir arm (-1.0%; Newcombe 95.2% CI: -2.4% to -0.0%; P = 0.021); all-cause death in 0% (0/483) and <1% (1/482); COVID-19 related hospitalization in <1% (1/483) and 1% (3/482); treatment-related adverse event in 1% (5/483) and 1% (4/486); and serious adverse event in 1% (4/483) and 1% (4/486). CONCLUSIONS: Favipiravir and molnupiravir had a similar efficacy and safety profile. Whether either of the two reduced the risk of complications during the omicron era in this population with a low risk of pulmonary involvement and a high vaccine coverage remains unclear. There were no differences in any of the safety endpoints. THAI CLINICAL TRIALS REGISTRY ID: TCTR20230111009.

Paediatric abacavir-lamivudine fixed-dose dispersible tablets and ritonavir-boosted lopinavir granules in neonates exposed to HIV (PETITE study): an open-label, two-stage, single-arm, phase 1/2, pharmacokinetic and safety trial.

BACKGROUND: Existing solid antiretroviral fixed-dose combination formulations are preferred over liquid formulations in children, but their suitability for neonates is unknown. We evaluated the pharmacokinetics and safety of paediatric abacavir-lamivudine fixed-dose dispersible tablets and ritonavir-boosted lopinavir granules in neonates. METHODS: In this open-label, two-stage, single-arm, phase 1/2, pharmacokinetic and safety trial, generic abacavir- lamivudine (120:60 mg) double-scored dispersible tablets and lopinavir boosted with ritonavir (40:10 mg) granules were studied. Neonates exposed to HIV (≥37 weeks gestational age) of no more than 3 days of age with birthweights of 2000-4000 g were identified through routine care in a tertiary hospital in Cape Town, South Africa. In stage 1, the pharmacokinetics and safety of two single doses were assessed to select the multidose strategy for stage 2. Neonates received a single dose of abacavir-lamivudine (30:15 mg, a quarter of a tablet) and lopinavir boosted with ritonavir (40:10 mg - one sachet) orally between 3 days and 14 days of age, and a second dose of a quarter tablet of abacavir-lamivudine and lopinavir boosted with ritonavir (80:20 mg, two sachets) 10-14 days later in stage 1. The multidose strategy selected in stage 2 was a quarter of the abacavir-lamivudine (30:15 mg) fixed-dose dispersible tablet once per day and two sachets of the lopinavir boosted with ritonavir (80:20 mg) granules twice per day from birth to age 28 days. In both stages two intensive pharmacokinetic visits were done, one at less than 14 days of life (pharmacokinetics 1) and another 10-14 days later (pharmacokinetics 2). Safety visits were done 1-2 weeks after each pharmacokinetic visit. Primary objectives were to assess pharmacokinetics and safety of abacavir, lamivudine, and lopinavir. Pharmacokinetic endpoints were area under the concentration time curve (AUC), maximum concentration, and concentration at end of dosing interval in all participants with at least one evaluable pharmacokinetic visit. Safety endpoints included grade 3 or worse adverse events, and grade 3 or worse treatment-related adverse events, occurring between study drug initiation and end of study. This completed trial is registered with the Pan African Clinical Trials Registry (PACTR202007806554538). FINDINGS: Between Aug 18, 2021, and Aug 18, 2022, 24 neonates were enrolled into the trial and received study drugs. Eight neonates completed stage 1, meeting interim pharmacokinetic and safety criteria. In stage 2, 16 neonates received study drugs. Geometric mean abacavir and lamivudine exposures (AUC0-24) were higher at 6-14 days (51·7 mg × h/L for abacavir and 17·2 mg × h/L for lamivudine) than at 19-24 days of age (25·0 mg × h/L and 11·3 mg × h/L), whereas they were similar for lopinavir over this period (AUC 0-12 58·5 mg × h/L vs 46·4 mg × h/L). Abacavir geometric mean AUC0-24 crossed the upper reference range at pharmacokinetics 1, but rapidly decreased. Lamivudine and lopinavir AUC0-tau were within range. No grade 2 or worse adverse events were related to study drugs. One neonate had a grade 1 prolonged corrected QT interval using the Fridericia method that spontaneously resolved. INTERPRETATION: Abacavir-lamivudine dispersible tablets and ritonavir-boosted lopinavir granules in neonates were safe and provided drug exposures similar to those in young infants. Although further safety data are needed, this regimen presents a new option for HIV prevention and treatment from birth. Accelerating neonatal pharmacokinetic studies of novel antiretroviral therapies is essential for neonates to also benefit from state-of-the-art treatments. FUNDING: Unitaid.

Hepatitis B prevalence and associated factors in adults presenting for infection screening in northern Thailand.

Background and aims: Hepatitis B is a leading cause of morbidity and mortality worldwide. In view of the World Health Organization 2030 targets, effective screening of chronic infection is crucial. We have assessed the prevalence and risk factors of hepatitis B surface antigen in adults presenting for screening. Methods: Free-of-charge and anonymous services for simultaneous hepatitis B, hepatitis C, human immunodeficiency virus and syphilis screening and counseling were provided in four facilities in northern Thailand. Analyses were performed separately in clients born before integration into the 1992 hepatitis B vaccine Thailand's Expanded Program on Immunization and in clients born afterwards. Results: Between October 2015 and August 2020, hepatitis B surface antigen prevalence was 7.2 % (185/2578) in clients born before 1992 (95 % confidence interval [CI] = 6.2%-8.2 %). In the multivariable analysis, characteristics independently associated with a higher risk of infection were being born male (adjusted odds ratio [aOR] = 1.49, 95 % CI = 1.10-2.01) and being part of a hill tribe (aOR = 1.65, 95 % CI = 1.01-2.70). Forty-two percent were unaware of their infection. In clients born in 1992 or afterwards, prevalence was 1.5 % (43/2933) (95 % CI = 1.1%-2.0 %) and characteristics independently associated with a higher risk were being born between 1992 and 1995 (aOR = 1.90, 95 % CI = 1.00-3.61), being born male (aOR = 2.60, 95 % CI = 1.34-5.07), being part of a hill tribe (aOR = 5.09, 95 % CI = 2.52-10.26) and having ever injected drugs (aOR = 4.33, 95 % CI = 1.23-15.24). Conclusions: Risk factor-based screening would miss many chronic hepatitis cases. Screening all adults once in their lifetime may be beneficial until the second generation of immunized infants have reached adult age.

Uptake, acceptability and interpretability of 3-in-1 rapid blood self-testing for HIV, hepatitis B and hepatitis C.

INTRODUCTION: Early diagnosis is key to achieving the goal of eliminating transmission of HIV and hepatitis B and C. We assessed the uptake, acceptability and interpretability of self-testing using a 3-in-1 rapid diagnostic test (RDT) in facility-based services. METHODS: Stand-alone testing services were provided free of charge to consenting individuals aged ≥15 years in five facilities in northern Thailand. Clients were invited to choose between self-testing by fingerprick or venepuncture by a healthcare worker (HCW). In each facility, several clients could simultaneously self-test in separate private areas using TriQuik™ (Genlantis, San Diego, CA, USA), a single immunochromatographic cassette detecting HIV-1/2 antibody, hepatitis B surface antigen (HBsAg) and hepatitis C antibody (HCAb). An interactive program on a tablet computer was developed to collect socio-demographic, behavioural and satisfaction data and provide information to guide the self-test process, including video instructions, results interpretation and a picture of the cassette for immediate remote review by the HCW. When the HCW interpreted an HIV self-test as positive, the HCW collected blood by venepuncture for immediate confirmation. RESULTS: Between October 2020 and April 2022, 4119 clients presented for testing for the first time as part of the project. Of them, 3462 (84.0%) opted for self-testing. Among self-testers, 1801 (52.0%) were born female, the median age was 27 years (interquartile range, 22-36), 661 (19.1%) belonged to at least one key population and 2124 (61.4%) had never been tested for HIV; 3329 (99.8% of those who answered) reported being "very satisfied" or "satisfied" with the testing process. The proportions of test results interpreted as positive by self-testers among those interpreted as positive by HCWs were 95% for HIV-1/2 antibody, 95% for HBsAg and 78% for HCAb. CONCLUSIONS: These proportions were higher than those observed in a previous study evaluating another 3-in-1 RDT for HIV, HBsAg and HCAb, possibly due to the use of video instructions instead of paper-based instructions, lower prevalence and co-infection rates, or lower percentages of clients with low education level. Multiplex self-testing simplified and streamlined the service delivery process and was well accepted. HCW assistance proved to be essential in a limited number of cases.

Chronic Kidney Disease in a Large National Human Immunodeficiency Virus Treatment Program.

Tenofovir disoproxil fumarate (TDF) is associated with a risk of chronic kidney disease (CKD), especially in Asian populations. Data from the Thai national health insurance system was used to assess CKD incidence in patients receiving antiretroviral therapy in real-world practice. We analyzed data from patients who initiated one of the following first-line regimens: zidovudine + lamivudine + nevirapine (AZT + 3TC + NVP); zidovudine + lamivudine + efavirenz (AZT + 3TC + EFV); tenofovir + lamivudine + nevirapine (TDF + 3TC + NVP); tenofovir + lamivudine/emtricitabine + efavirenz (TDF + 3TC/FTC + EFV); and tenofovir +lamivudine +lopinavir/ritonavir (TDF + 3TC + LPV/r). CKD was defined as glomerular filtration rate <60 mL/min/1.73 m2 for >3 months, or a confirmed 2010 WHO diagnosis (ICD-10 code N183, N184, or N185). Death competing risk survival regression models were used. Among 27,313 participants, with a median age of 36.8 years and median follow-up of 2.3 years, 245 patients (0.9%) were diagnosed with CKD (incidence 3.2 per 1000 patient-years; 95% CI 2.8−3.6). Compared with patients receiving AZT + 3TC + NVP, the risk of CKD measured by adjusted sub-distribution hazard ratio (aSHR) was 6.5 (95% CI 3.9−11.1) in patients on TDF + 3TC + LPV/r, 3.8 (95% CI 2.3−6.0) in TDF + 3TC + NVP, and 1.6 (95% CI 1.2−2.3) in TDF + 3TC/FTC + EFV. Among patients receiving TDF, compared with those receiving TDF + 3TC/FTC + EFV, the aSHR was 4.0 (95% CI 2.3−6.8) in TDF + 3TC + LPV/r and 2.3 (95% CI 1.4−3.6) in TDF + 3TC + NVP. TDF was associated with an increased risk of CKD, especially when combined with LPV/r or NVP.

Zika Virus Immunoglobulin G Seroprevalence among Young Adults Living with HIV or without HIV in Thailand from 1997 to 2017.

Zika virus (ZIKV) epidemiological data in Thailand are limited. We assessed ZIKV IgG seroprevalence among young adults during 1997-2017 and determined factors associated with ZIKV IgG seropositivity. This retrospective laboratory study included randomly selected subjects aged 18-25 years participating in large clinical studies conducted in Thailand during 1997-2017. Stored plasma samples were analyzed for ZIKV IgG using an ELISA test (Anti-Zika Virus IgG, EUROIMMUN, Lübeck, Germany). Sociodemographic, clinical and laboratory data were used in univariable and multivariable analyses to identify factors associated with ZIKV IgG positivity. Of the 1648 subjects included, 1259 were pregnant women, 844 were living with HIV and 111 were living with HBV. ZIKV IgG seroprevalence was similar among the HIV-infected and -uninfected pregnant women (22.8% vs. 25.8%, p-value = 0.335) and was overall stable among the pregnant women, with a 25.2% prevalence. Factors independently associated with ZIKV IgG positivity included an age of 23-25 years as compared to 18-20 years, an HIV RNA load below 3.88 log10 copies/mL and birth in regions outside northern Thailand. Our study shows that a large proportion of the population in Thailand probably remains susceptible to ZIKV infection, which could be the ground for future outbreaks. Continued surveillance of ZIKV spread in Thailand is needed to inform public health policies.

Proximal tubular dysfunction in pregnant women receiving tenofovir disoproxil fumarate to prevent mother-to-child transmission of hepatitis B virus.

BACKGROUND: Data evaluating the risk of proximal tubular dysfunction in women receiving tenofovir disoproxil fumarate for the prevention of mother-to-child transmission (PMTCT) of HBV are scarce. OBJECTIVES: To assess the risk of proximal tubulopathy in pregnant women receiving tenofovir disoproxil fumarate for PMTCT of HBV. PATIENTS AND METHODS: We used urine samples collected from HBV monoinfected pregnant women who participated in a Phase III, multicentre, randomized, double-blind, placebo-controlled clinical trial assessing a tenofovir disoproxil fumarate short course from 28 weeks gestational age (28-wk-GA) to 2 months post-partum (2-months-PP) for PMTCT of HBV in Thailand. Markers of tubular dysfunction, including retinol binding protein, kidney injury molecule-1, α1-microglobuin and ß2-microglobulin, were assayed at 28- and 32-wk-GA and 2-months-PP visits. Proximal tubulopathy was defined as the presence of ≥2 of the following: tubular proteinuria, euglycaemic glycosuria and increased urinary phosphate. RESULTS: A total of 291 women participated in the study. No kidney-related adverse events were severe, and none led to tenofovir disoproxil fumarate discontinuation. At 2-months-PP, 3 of the 120 (3%) evaluated women in the tenofovir disoproxil fumarate group experienced proximal tubulopathy versus 3 of 125 (2%) in the placebo group (P = 1.00). None of the six women met the criteria for proximal tubulopathy at 12-months-PP but proteinuria persisted in three of them. No growth abnormalities were found at 1 year of age in infants born to mothers with proximal tubulopathy at 2-months-PP. CONCLUSIONS: In these HBV-infected pregnant and breastfeeding women, tenofovir disoproxil fumarate administered from 28-wk-GA to 2-months-PP was not associated with a higher risk of proximal tubulopathy.

Pharmacokinetics and Safety of the Abacavir/Lamivudine/Lopinavir/Ritonavir Fixed-Dose Granule Formulation (4-in-1) in Neonates: PETITE Study.

BACKGROUND: Antiretroviral options for neonates (younger than 28 days) should be expanded. We evaluated the pharmacokinetics, safety, and acceptability of the "4-in-1" fixed-dose pediatric granule formulation of abacavir/lamivudine/lopinavir/ritonavir (30/15/40/10 mg) in neonates. METHODS: The PETITE study is an ongoing phase I/II, open-label, single-arm, 2-stage trial conducted in South Africa. In stage 1, term neonates exposed to HIV on standard antiretroviral prophylaxis (nevirapine ± zidovudine) received single dose(s) of the 4-in-1 formulation, followed by intensive pharmacokinetic sampling and safety assessments. At each PK visit, blood was drawn after an observed dose at 1, 2, 4, 8, and 12 hours postdose. In this study, we have reported the planned interim pharmacokinetic and safety analysis after completion of the single-dose administration. RESULTS: Sixteen neonates, with a median (range) birth weight of 3130 g (2790-3590 g), completed 24 pharmacokinetic visits. The 4-in-1 formulation imposed relatively high doses of abacavir [8.6 mg/kg (6.6-11.4)] and lamivudine [4.3 mg/kg (3.3-5.7)] but lower doses of lopinavir [11.5 mg/kg (8.8-15.2)]. The geometric means (GM, 90% CI) AUC0-12 of abacavir, lamivudine, and lopinavir were 29.87 (26.29-33.93), 12.61 (10.72-14.83), and 3.49 (2.13-5.72) µg.h/mL, respectively. Lopinavir GM AUC0-12 was below the predefined target (20-100 µg.h/mL), and ritonavir concentrations were only detectable in 4 of the 120 (3%) samples. No adverse events were related to study drugs. No neonate had difficulty swallowing the 4-in-1 formulation. CONCLUSIONS: The high doses of abacavir and lamivudine (in mg/kg) and AUCs were safe, and the formulation was well tolerated; however, lopinavir/ritonavir exposures were extremely low, preventing its use in neonates use in neonates. Alternative pediatric solid antiretroviral formulations must be studied in neonates.

Lack of Association between Adverse Pregnancy Outcomes and Zika Antibodies among Pregnant Women in Thailand between 1997 and 2015.

Data about Zika virus infection and adverse pregnancy outcomes in Southeast Asia are scarce. We conducted an unmatched case-control study of Zika virus (ZIKV) serology in pregnant women enrolled in human immunodeficiency virus (HIV) or hepatitis B virus (HBV) perinatal prevention trials between 1997 and 2015 in Thailand. Case and control groups included women with and without adverse pregnancy outcomes. Plasma samples collected during the last trimester of pregnancy were tested for ZIKV IgG/IgM and Dengue IgG/IgM (Euroimmun, AG, Germany). Case newborn plasma samples were tested for ZIKV IgM and ZIKV RNA (Viasure, Spain). The case group included women with stillbirth (n = 22) or whose infants had microcephaly (n = 4), a head circumference below the first percentile (n = 14), neurological disorders (n = 36), or had died within 10 days after birth (n = 11). No women in the case group were positive for ZIKV IgM, and none of their live-born neonates were positive for ZIKV IgM or ZIKV RNA. The overall ZIKV IgG prevalence was 29%, 24% in the case and 34% in the control groups (Fisher's exact test; p = 0.13), while the dengue IgG seroprevalence was 90%. Neither neonatal ZIKV infections nor ZIKV-related adverse pregnancy outcomes were observed in these women with HIV and/or HBV during the 18-year study period.

Efficacy and safety of ravidasvir plus sofosbuvir in patients with chronic hepatitis C infection without cirrhosis or with compensated cirrhosis (STORM-C-1): interim analysis of a two-stage, open-label, multicentre, single arm, phase 2/3 trial.

BACKGROUND: In low-income and middle-income countries, affordable direct-acting antivirals are urgently needed to treat hepatitis C virus (HCV) infection. The combination of ravidasvir, a pangenotypic non-structural protein 5A (NS5A) inhibitor, and sofosbuvir has shown efficacy and safety in patients with chronic HCV genotype 4 infection. STORM-C-1 trial aimed to assess the efficacy and safety of ravidasvir plus sofosbuvir in a diverse population of adults chronically infected with HCV. METHODS: STORM-C-1 is a two-stage, open-label, phase 2/3 single-arm clinical trial in six public academic and non-academic centres in Malaysia and four public academic and non-academic centres in Thailand. Patients with HCV with compensated cirrhosis (Metavir F4 and Child-Turcotte-Pugh class A) or without cirrhosis (Metavir F0-3) aged 18-69 years were eligible to participate, regardless of HCV genotype, HIV infection status, previous interferon-based HCV treatment, or source of HCV infection. Once daily ravidasvir (200 mg) and sofosbuvir (400 mg) were prescribed for 12 weeks for patients without cirrhosis and for 24 weeks for those with cirrhosis. The primary endpoint was sustained virological response at 12 weeks after treatment (SVR12; defined as HCV RNA <12 IU/mL in Thailand and HCV RNA <15 IU/mL in Malaysia at 12 weeks after the end of treatment). This trial is registered with ClinicalTrials.gov, number NCT02961426, and the National Medical Research Register of Malaysia, NMRR-16-747-29183. FINDINGS: Between Sept 14, 2016, and June 5, 2017, 301 patients were enrolled in stage one of STORM-C-1. 98 (33%) patients had genotype 1a infection, 27 (9%) had genotype 1b infection, two (1%) had genotype 2 infection, 158 (52%) had genotype 3 infection, and 16 (5%) had genotype 6 infection. 81 (27%) patients had compensated cirrhosis, 90 (30%) had HIV co-infection, and 99 (33%) had received previous interferon-based treatment. The most common treatment-emergent adverse events were pyrexia (35 [12%]), cough (26 [9%]), upper respiratory tract infection (23 [8%]), and headache (20 [7%]). There were no deaths or treatment discontinuations due to serious adverse events related to study drugs. Of the 300 patients included in the full analysis set, 291 (97%; 95% CI 94-99) had SVR12. Of note, SVR12 was reported in 78 (96%) of 81 patients with cirrhosis and 153 (97%) of 158 patients with genotype 3 infection, including 51 (96%) of 53 patients with cirrhosis. There was no difference in SVR12 rates by HIV co-infection or previous interferon treatment. INTERPRETATION: In this first stage, ravidasvir plus sofosbuvir was effective and well tolerated in this diverse adult population of patients with chronic HCV infection. Ravidasvir plus sofosbuvir has the potential to provide an additional affordable, simple, and efficacious public health tool for large-scale implementation to eliminate HCV as a cause of morbidity and mortality. FUNDING: National Science and Technology Development Agency, Thailand; Department of Disease Control, Ministry of Public Health, Thailand; Ministry of Health, Malaysia; UK Aid; Médecins Sans Frontières (MSF); MSF Transformational Investment Capacity; FIND; Pharmaniaga; Starr International Foundation; Foundation for Art, Research, Partnership and Education; and the Swiss Agency for Development and Cooperation.

Impact of Zika virus on the human type I interferon osteoimmune response.

BACKGROUND: The developing field of osteoimmunology supports importance of an interferon (IFN) response pathway in osteoblasts. Clarifying osteoblast-IFN interactions is important because IFN is used as salvage anti-tumor therapy but systemic toxicity is high with variable clinical results. In addition, osteoblast response to systemic bursts and disruptions of IFN pathways induced by viral infection may influence bone remodeling. ZIKA virus (ZIKV) infection impacts bone development in humans and IFN response in vitro. Consistently, initial evidence of permissivity to ZIKV has been reported in human osteoblasts. HYPOTHESIS: Osteoblast-like Saos-2 cells are permissive to ZIKV and responsive to IFN. METHODS: Multiple approaches were used to assess whether Saos-2 cells are permissive to ZIKV infection and exhibit IFN-mediated ZIKV suppression. Proteomic methods were used to evaluate impact of ZIKV and IFN on Saos-2 cells. RESULTS: Evidence is presented confirming Saos-2 cells are permissive to ZIKV and support IFN-mediated suppression of ZIKV. ZIKV and IFN differentially impact the Saos-2 proteome, exemplified by HELZ2 protein which is upregulated by IFN but non responsive to ZIKV. Both ZIKV and IFN suppress proteins associated with microcephaly/pseudo-TORCH syndrome (BI1, KI20A and UBP18), and ZIKV induces potential entry factor PLVAP. CONCLUSIONS: Transient ZIKV infection influences osteoimmune state, and IFN and ZIKV activate distinct proteomes in Saos-2 cells, which could inform therapeutic, engineered, disruptions.

Appointment reminders to increase uptake of HIV retesting by at-risk individuals: a randomized controlled study in Thailand.

INTRODUCTION: Frequent HIV testing of at-risk individuals is crucial to detect and treat infections early and prevent transmissions. We assessed the effect of reminders on HIV retesting uptake. METHODS: The study was conducted within a programme involving four facilities providing free-of-charge HIV, syphilis and hepatitis B and C testing and counselling in northern Thailand. Individuals found HIV negative and identified at risk by counsellors were invited to participate in a three-arm, open-label, randomized, controlled trial comparing: (a) "No Appointment & No Reminder" (control arm); (b) "No Appointment but Reminder": short message service (SMS) sent 24 weeks after the enrolment visit to remind booking an appointment, and sent again one week later if no appointment was booked; and (c) "Appointment & Reminder": appointment scheduled during the enrolment visit and SMS sent one week before appointment to ask for confirmation; if no response: single call made within one business day. The primary endpoint was a HIV retest within seven months after the enrolment visit. The cost of each reminder strategy was calculated as the sum of the following costs in United States dollars (USD): time spent by participants, counsellors and hotline staff; phone calls made; and SMS sent. The target sample size was 217 participants per arm (651 overall). RESULTS: Between April and November 2017, 651 participants were randomized. The proportion presenting for HIV retesting within seven months was 11.2% (24/215) in the control arm, versus 19.3% (42/218) in "No Appointment but Reminder" (p = 0.023) and 36.7% (80/218) in "Appointment & Reminder" (p < 0.001). Differences in proportions compared to the control arm were respectively +8.1% (95% CI: +1.4% to +14.8%) and +25.5% (+17.9% to +33.2%). The incremental cost-effectiveness ratios of "No Appointment but Reminder" and "Appointment & Reminder" compared to the control arm were respectively USD 0.05 and USD 0.14 per participant for each 5% increase in HIV retesting uptake within seven months. CONCLUSIONS: Scheduling an appointment and sending a reminder one week before was a simple, easy-to-implement and affordable intervention that significantly increased HIV retesting uptake in these at-risk individuals. The personal phone call to clients probably contributed, and also improved service efficiency.

Impact of Counseling Methods on HIV Retesting Uptake in At-Risk Individuals: A Randomized Controlled Study.

Systematic face-to-face pre-HIV test counseling is costly and may discourage clients to present for regular testing. In a randomized, controlled, non-inferiority trial conducted in four facilities providing free-of-charge anonymous HIV testing in Thailand, participants received either: standard counseling according to national guidelines (reference); computer-assisted counseling: interactive counseling on a tablet computer followed by an invitation to ask questions to the counselor; or on-demand counseling: invitation to ask questions to the counselor. Primary endpoint was a HIV retest within 7 months after enrolment visit. Following the planned interim analysis, on-demand counseling was discontinued for futility. In the final analysis in 1036 HIV-uninfected at-risk participants, computer-assisted counseling was non-inferior to standard counseling and had similar acceptability and improvements in HIV knowledge and sexual risk behaviors; however, it significantly reduced the time spent by counselors on counseling. Implementation of pre-HIV test computer-assisted counseling may ease the burden on staff involved in HIV testing.

Recommended First-Line Antiretroviral Therapy Regimens and Risk of Diabetes Mellitus in HIV-Infected Adults in Resource-Limited Settings.

OBJECTIVE: The use of some antiretroviral drugs has been associated with a higher risk of diabetes mellitus (DM) in HIV-infected patients, but the risk associated with antiretroviral drug combinations remains unclear. We investigated the association between first-line antiretroviral therapy (ART) regimens, recommended by the World Health Organization (WHO) in 2016, and the risk of DM in adults. METHOD: We selected all HIV-infected adults within the Thai National AIDS Program who started a first-line ART regimen consisting the following between October 2006 and September 2013: zidovudine+lamivudine+nevirapine; tenofovir disoproxil fumarate (TDF)+lamivudine+nevirapine; zidovudine+lamivudine+efavirenz; TDF+lamivudine/emtricitabine+efavirenz; zidovudine+lamivudine+ritonavir-boosted lopinavir (LPV/r); or TDF+lamivudine+LPV/r. Diagnosis of DM was defined as having at least 2 of the following characteristics: fasting plasma glucose ≥126 mg/dl, 2010 WHO ICD-10 codes E11-E14, or prescription of antidiabetic drugs. To identify ART regimens associated with DM, we used competing risks regression models that considered mortality without DM as a competing event and adjusted for sex, age, pancreas disease, and stratified by groups defined by a score summarizing the propensity to receive a specific first-line ART regimen. RESULTS: Data from 35 710 adults (49.1% male; median age, 35.0 years; median follow-up, 2.0 years) were included. In the multivariable analysis with zidovudine+lamivudine+nevirapine as the reference group, a higher risk of DM was observed with TDF+lamivudine/emtricitabine+efavirenz (adjusted sub-distribution hazard ratio [aSHR], 1.6; 95% confidence interval [CI], 1.3-1.9), zidovudine+lamivudine+efavirenz (aSHR, 2.0; 95% CI, 1.7-2.3), and TDF+lamivudine+LPV/r (aSHR, 2.7; 95% CI, 1.9-3.9). CONCLUSIONS: Several of the WHO recommended ART regimens, particularly tenofovir + lamivudine +LPV/r and regimens containing efavirenz, may be associated with an increased risk of DM.

Incidence and risk factors of loss to follow-up among HIV-infected children in an antiretroviral treatment program.

INTRODUCTION: The success of antiretroviral treatment (ART) programs can be compromised by high rates of patient loss to follow-up (LTFU). We assessed the incidence and risk factors of LTFU in a large cohort of HIV-infected children receiving ART in Thailand. METHODS: All children participating in a multicenter cohort (NCT00433030) between 1999 and 2014 were included. The date of LTFU was 9 months after the last contact date. ART interruption was defined as ART discontinuation for more than 7 days followed by resumption of treatment. Baseline and time-dependent risk factors associated with LTFU were identified using Fine and Gray competing risk regression models with death or referral to another hospital as competing events. RESULTS: Of 873 children who were followed during a median of 8.6 years (interquartile range 4.5-10.6), 196 were LTFU, 73 died, and 195 referred. The cumulative incidence of LTFU was 2.9% at 1 year, 7.3% at 5 years and 22.2% at 10 years. Children aged 13 years and more had a 3-fold higher risk (95% confidence interval 2.06-4.78) of LTFU than those younger. Children who had interrupted ART within the previous year had a 2.5-fold higher risk (1.12-5.91) than those who had not. The risk of LTFU was lower in children stunted (height-for-age Z-scores <-2 SD) (0.42-0.96) or underweight (weight-for-age Z-scores <-2 SD) (0.24-0.97). CONCLUSION: Adolescence, ART interruption and absence of growth deficit were associated with LTFU. These may be warnings that should draw clinicians' attention and possibly trigger specific interventions. Children with no significant growth retardation may also be at risk of LTFU.

Feasibility of using dried blood spots for HIV viral load testing among HIV-infected individuals in Thailand using QIAGEN QIAsymphony-artus HIV-1 platform.

In settings where plasma preparation and sample centralization are not feasible or inconvenient, dried blood spots (DBS) could be used as an alternative specimen to plasma to assess antiretroviral treatment response among HIV-infected individuals. This study was aimed to (1) validate the recent QIAsymphony-artus assay for DBS HIV viral load (VL) and (2) assess the feasibility of measuring HIV VL on DBS using this assay in Thailand. Ethylenediaminetetraacetic acid-blood samples from 99 HIV-infected individuals were used to prepare paired DBS and plasma. Also, DBS samples were shipped to three distant hospitals in the northern region. After short-term storage, DBS were returned by regular post to the AMS laboratory and were re-tested for HIV VL using the same platform. HIV VL results were compared using Pearson's correlation and Bland-Altman analysis. DBS HIV VL fairly correlated to plasma HIV VL (R = 0.62) with a mean difference of 0.02 log10 IU/mL (SD = 1.06). A high correlation (R = 0.79) was observed between HIV VL in DBS before and after shipping (mean difference = 0.14 log10 IU/mL, SD = 0.74), indicating good stability of HIV RNA in DBS. DBS can be used as an alternative specimen for HIV VL monitoring in Thailand. However, measurement of HIV VL with the QIAGEN QIAsymphony-artus assay should be improved, especially the DBS pre-extraction process.

Perinatal hepatitis B virus transmission in Lao PDR: A prospective cohort study.

BACKGROUND: Mother-to-child transmission of hepatitis B virus (HBV) is the main cause of new infections worldwide. We aimed at assessing the percentage of infants successfully immunized in two major hospitals in Vientiane, Lao PDR where HB immune globulin (HBIg) is not available. METHODS: We studied a prospective cohort of chronically HBV infected pregnant women and their infants until 6 months post-partum from January 2015 to March 2017. All infants received HB vaccine at birth and 6, 10 and 14 weeks thereafter, and HBV status was assessed at 6 months of age. HBV surface gene sequencing was performed in infected mother-infant pairs. RESULTS: Of 153 mothers with HB surface antigen (HBsAg), 60 (39%) had detectable serum HBe antigen (HBeAg). HBeAg positive pregnant women were younger than those negative (median age 26 versus 28 years; p = 0.02) and had a significantly higher HBV viral load at delivery (median 8.0 versus 4.0 log10 IU/mL, p <0.001). Among the 120 infants assessed at 6 months of age, 5 (4%) were positive for HBsAg and had detectable HBV viral load by polymerase chain reaction. All were born to mothers with HBeAg and viral load >8.5 log10 IU/mL. However, only four (3.3%, 95% CI 0.5% to 7.0%) had a virus strain closely related to their mother's strain. HBV surface gene mutations were detected in 4 of the 5 infected infants. Anti-HBs antibody levels were below 10 IU/L in 10 (9%) uninfected infants at 6 months of age. CONCLUSIONS: Mother-to-child transmission occurred less frequently than expected without the use of HBIg. Adding HBIg and/or maternal antiviral prophylaxis may have prevented some of these infections. The observation of unsatisfactory levels of anti-HBs antibodies in 9% of the uninfected infants at 6 months highlights the need for improvement of the universal immunization procedures.

Maternal and Infant Bone Mineral Density 1 Year After Delivery in a Randomized, Controlled Trial of Maternal Tenofovir Disoproxil Fumarate to Prevent Mother-to-child Transmission of Hepatitis B Virus.

In a randomized, double-blind, placebo-controlled trial of tenofovir disoproxil fumarate (TDF) use from 28 weeks gestational age to 2 months postpartum to prevent mother-to-child transmission of hepatitis B virus, there was no significant effect of maternal TDF use on maternal or infant bone mineral density 1 year after delivery/birth. Clinical Trials Registration. NCT01745822.

Tenofovir Exposure during Pregnancy and Postpartum in Women Receiving Tenofovir Disoproxil Fumarate for the Prevention of Mother-to-Child Transmission of Hepatitis B Virus.

We assessed tenofovir exposure during pregnancy and postpartum in hepatitis B virus (HBV)-infected HIV-uninfected women receiving tenofovir disoproxil fumarate (TDF) to prevent mother-to-child transmission of HBV. Data from 154 women who received TDF within a randomized controlled trial were included. Individual plasma tenofovir exposures (area under the concentration-time curve from 0 to 24 h [AUC0-24]) were estimated using a population pharmacokinetic approach. The estimated geometric mean tenofovir AUC0-24 was 20% (95% confidence interval [95% CI], 19 to 21%) lower during pregnancy than during postpartum; this modest reduction in the absence of HBV transmission suggests that no dose adjustment is needed.