Preventing mother-to-child transmission of hepatitis B virus is an opportunity to prevent lifelong infection and associated complications. This randomized, placebo-controlled trial in Thailand ...assessed tenofovir to prevent HBV infection in infants.
In an open-label, randomized, noninferiority trial, dolutegravir-based antiretroviral therapy was compared with standard care in children and adolescents starting first- or second-line therapy for ...HIV type 1 infection. Dolutegravir-based ART was superior to standard-care ART.
There are gaps in knowledge and experience of antiretroviral pre-exposure prophylaxis (PrEP) delivery in adolescents.
This pilot study enrolled Thai adolescents 14-20 year-old without HIV who ...reported risk behaviour. All participants were offered daily tenofovir/emtricitabine (TDF-FTC) and followed for 24 weeks. HIV testing, renal function, bone density scan, and sexually transmitted infection (STI) testing including syphilis serology and urine molecular testing for gonorrhoea and C. trachomatis were performed at baseline and weeks 12 and 24. Adherence was evaluated through intracellular tenofovir diphosphate (TFV-DP) levels in dried blood spots.
Of the 61 enrolled adolescents, median age 18.1 (IQR: 14.8-20.9) years, 46 (75.4%) were males and 36 (59%) were MSM. Retention to week 24 was 80.3%. One third (36%) had TFV-DP levels consistent with taking ≥6 pills/week at week 12 and 29% at week 24. The factors associated with taking ≥6 pills/week were being MSM (adjusted odds ratio aOR: 53.2, 95% CI: 1.6-1811; p = 0.027), presence of STI at baseline (aOR: 9.4, 95% CI: 1.5-58.5; p = 0.016), and self-report of decreased condom use while taking PrEP (aOR: 8.7, 95% CI: 1.4-56.6; p = 0.023). 31% had an STI at baseline and this declined to 18% at week 24. No renal or bone toxicity was observed and there were no HIV seroconversions.
Daily oral PrEP with FTC-TDF in high-risk Thai adolescents is feasible, accepted, well-tolerated, and had no increased risk compensation; however, low adherence was a major challenge. Adolescent-specific PrEP strategies including long-acting modalities are needed for successful HIV prevention.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In sub-Saharan Africa (SSA), adolescent girls and young women (AGYW) ages 15 to 24 years represent <10% of the population yet account for 1 in 5 new HIV infections. Although oral pre-exposure ...prophylaxis (PrEP) with tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) can be highly effective, low persistence in PrEP programs and poor adherence have limited its ability to reduce HIV incidence among women. A total of 336 AGYW participating in the PEPFAR-funded DREAMS PrEP program in western Kenya were enrolled into a study of PrEP use conducted between 6/2019 to 1/2020. AGYW, who used daily oral TDF/FTC, completed interviews and provided dried blood spots (DBS) for measurement of tenofovir-diphosphate (TFV-DP) concentrations at enrollment and 3 months later, and 176/302 (58.3%, 95% confidence interval 95% CI 52.3 to 63.8) met our definition of PrEP persistence: having expressed intention to use PrEP and attended both the second interview and an interim refill visit. Among AGYW with DBS taken at the second interview, only 9/197 (4.6%, 95% CI 1.6 to 7.5) had protective TFV-DP levels (greater than or equal to700 fmol/punch) and 163/197 (82.7%, 95% CI 77.5 to 88) had levels consistent with no recent PrEP use (<10 fmol/punch). Perception of being at moderate-to-high risk for HIV if not taking PrEP was associated with persistence (adjusted odds ratio, 10.17 95% CI 5.14 to 20.13, p < 0.001) in a model accounting for county of residence and variables that had p-value 90% indicated they were using PrEP to prevent HIV, although almost all had non-protective TFV-DP levels. Limitations included short study duration and inclusion of only DREAMS participants. Many AGYW persisted in the PrEP program without taking PrEP frequently enough to receive benefit. Notably, AGYW who persisted had a higher self-perceived risk of HIV infection. These AGYW may be optimal candidates for long-acting PrEP.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Individual drug concentration data can be a valuable tool for the clinical management of antiretroviral therapy (ART) for the treatment of HIV infection. High performance liquid chromatography (HPLC) ...based assays are currently the gold standard for drug measurement but its high cost and requirement of technical expertise limits its widespread use. Simpler user-friendly and inexpensive detection assays are needed. A novel immunochromatographic (IC) strip test to detect HIV-1 protease inhibitors (PIs) was fabricated by combining the proteolysis activity of HIV-protease (PR) and an immunochromatographic reaction. The PIs-IC strip cut-off to detect lopinavir (LPV) concentrations was set at 1,000 ng mL−1. We evaluated this novel PIs-IC strip for the semi-quantification of HIV PIs in plasma samples collected from healthy subjects and HIV-infected patients receiving antiretroviral treatment with and without LPV. LPV plasma drug levels were quantified by HPLC and evaluated (blinded to the HPLC results) using the PIs-IC strip. Results of plasma samples tested using the PIs-IC strip were available within 5 min. Using the PIs-IC strip test the accuracy, specificity and sensitivity were 97.8%, 97.1%, and 100%, respectively, compare to the gold-standard assay, to detect LPV in human plasma samples. This novel PIs-IC strip test could be used as a simple tool for the rapid monitoring of PIs levels in HIV-infected patients, although further clinical evaluation is needed.
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•Semi-quantitative IC strip is suitable for detecting the therapeutic PIs level in plasma of HIV-infected patients receiving ART.•The IC strip is capable of monitoring any HIV PIs.•The IC strip can be applied for screening the lead compounds for discovering of novel PIs.
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.
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.
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.
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.
•Tenofovir disoproxil fumarate (TDF) is a key drug for HIV prevention and treatment.•Maintaining adherence to TDF is critical for efficacy but can be challenging.•A urine point-of-care (POC) test to ...detect tenofovir could help clinical management.•The development of a urine POC test requires fully characterizing urinary tenofovir excretion.•Among adults with three different adherence patterns, differences in plasma and cumulative urinary TFV excretion were minor following TDF cessation, suggesting measurement is more indicative of last drug ingestion, rather than prior dose patterns.
The aim was to fully characterize the plasma and urine washout pharmacokinetics of tenofovir (TFV) in adults following 6 weeks of controlled levels of tenofovir disoproxil fumarate (TDF) adherence, in order to inform the utility of clinic-based adherence testing.
This was a three-arm, randomized, open-label study in adult volunteers. Participants were randomized to receive TDF 300 mg/emtricitabine (FTC) 200 mg as (1) 7 doses/week (perfect adherence), (2) 4 doses/week (moderate adherence), or (3) 2 doses/week (low adherence). Plasma and urine samples were collected regularly during the 6-week dosing phase and for 4 weeks following drug cessation.
Twenty-eight adults were included in this analysis. Median (range) age was 33 (20–49) years. No differences in TFV pharmacokinetic parameters during the washout were observed across the study arms. Small differences in TFV plasma concentrations occurred across arms between 4 and 10 h post-dose. The cumulative amount of TFV excreted in urine was not different at 24 h post-dose, but at 148 h it was 24.8 mg, 21.0 mg, and 17.2 mg for the perfect, moderate, and low adherence arms, respectively (p = 0.043).
Among adults with different TDF adherence patterns, relative differences in plasma concentrations and cumulative urine extraction of TFV were minor following cessation. TFV measurement in plasma or urine is more indicative of last drug ingestion, rather than prior dose patterns.
To access the long term relationship between efavirenz plasma concentrations and evolution of HIV RNA loads and CD4 cell counts in children.
Retrospective analysis of data from HIV-infected children ...on first line efavirenz-containing regimen. A population pharmacokinetic-pharmacodynamic (PK-PD) model was developed to describe the evolution of HIV RNA load and CD4 cell count (efficacy outcomes) in relation to efavirenz plasma concentration. Individual CYP2B6 516 G>T genotype data were not available for this analysis. A score (ISEFV) quantifying the effect of efavirenz concentrations on the long-term HIV replication was calculated from efavirenz concentrations and PD parameters and, a value of ISEFV below which HIV replication is likely not suppressed was determined. Cox proportional hazards regression models were used to assess the association of the risk of viral replication with ISEFV, and with efavirenz mid-dose concentration(C12).
At treatment initiation, median (interquartile range, IQR) age was 8 years (5 to 10), body weight 17 kg (14 to 23), HIV RNA load 5.1 log10 copies/mL (4.6 to 5.4), and CD4 cell count 71 cells/mm3. A model of PK-PD viral dynamics assuming that efavirenz decreases the rate of infected host cells adequately described the relationship of interest. After adjusting for age, baseline HIV RNA load and CD4 cell counts an ISEFV <85% was significantly associated with a higher risk of viral replication (p-value <0.001) while no significant association was observed with C12 <1.0 mg/L.
The ISEFV score was a good predictor of viral replication in children on efavirenz-based treatment.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
OBJECTIVE:HIV prevention and treatment studies demonstrate that pharmacologic adherence metrics are more accurate than self-report. Currently available metrics use ...liquid-chromatography/tandem-mass-spectrometry (LC-MS/MS), which is expensive and laboratory-based. We developed a specific and sensitive antibody against tenofovir, the backbone of treatment and prevention, but conversion to a lateral flow assay (LFA) – analogous to a urine pregnancy test – is required for point-of-care testing. We describe the development of the first LFA to measure antiretroviral adherence in real-time.
METHODS:Previous work in a directly observed therapy study of providing tenofovir disoproxil fumarate (TDF) to HIV-noninfected volunteers at various simulated adherence patterns defined the appropriate cut-off for the LFA (1500 ng tenofovir/ml urine). We developed the LFA using a sample pad for urine; a conjugate pad coated with TFV-specific antibodies conjugated to colloidal gold nanoparticles; a nitrocellulose membrane striped with tenofovir-antigen (test line) and a control line; with an absorbent pad to draw urine across the reaction membrane.
RESULTS:We tested 300 urine samples collected from the directly observed therapy study by this LFA and the gold-standard method of LC-MS/MS. The LFA demonstrated 97% specificity (95% CI 93–99%) and 99% sensitivity (94–100%) compared with LC-MS/MS. The LFA accurately classified 98% of patients who took a dose within 24 h as adherent.
CONCLUSION:We describe the development and validation of the first point-of-care assay to measure short-term adherence to HIV prevention and treatment in routine settings. The assay is low-cost, easy-to-perform and measures the breakdown product (tenofovir) of both TDF and tenofovir alafenamide (TAF). This assay has the potential to improve HIV and PrEP outcomes worldwide by triggering differentiated service delivery with further study merited.
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