BACKGROUND:

Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) fixed-dose combination (FDC) was developed as a once-daily, complete antiretroviral (ARV) regimen therapy to address the need for simplified protease inhibitor-based ARV regimens. This study assessed the swallowability and acceptability for long-term use of scored placebo tablets matching the D/C/F/TAF FDC tablets in children living with HIV-1.

METHODS:

This study (NCT04006704) was a Phase 1, open-label, randomized, single-dose, 2-period, 2-sequence crossover study in children living with HIV-1, aged ≥6 to <12 years and weighing ≥25 to <40 kg, on a stable ARV regimen for ≥3 months. Participants were asked to swallow whole (size, 21 × 11 × 7 mm) and split matching placebo D/C/F/TAF tablets. Swallowability of the matching placebo D/C/F/TAF tablets (primary endpoint) was assessed by observers. Acceptability of taking matching placebo D/C/F/TAF tablets and current ARVs was evaluated by participants using a 3-point questionnaire. Participants rated the acceptability for long-term daily use of the placebo D/C/F/TAF tablets, and observers assessed how easily caregivers could split a scored tablet by hand, using 3-point questionnaires.

RESULTS:

Among the 24 participants who enrolled and completed the study, 95.8% (23/24) were able to swallow the whole and split matching placebo D/C/F/TAF tablets after 1 or 2 attempts. Most participants (>70%) rated the acceptability of tablets for long-term daily use as acceptable or good to take. Breaking the tablets was considered easy or OK by 79.2% (19/24) of caregivers.

CONCLUSION:

Scored D/C/F/TAF FDC tablets are swallowable - with whole favoured over split - and considered at least acceptable for long-term daily intake in children living with HIV-1 aged ≥6 to <12 years.

TRIAL REGISTRATION:

ClinicalTrials.gov Identifier: NCT04006704.

OBJECTIVES:

To describe the validation of a sensitive high performance liquid chromatography tandem mass spectrometry (LC-MS/MS) method allowing the simultaneous quantification of darunavir (DRV) and etravirine (ETR) in peripheral blood mononuclear cells (PBMCs) and its application in a cohort of HIV-1 infected patients.

METHODS:

Blood samples were obtained from 110 patients. PMBCs were isolated using density gradient centrifugation. Drug extraction from PBMCs was performed with a 60:40 methanol-water (MeOH-H2O) solution containing deuterated IS (DRV-d9 and ETR-d8). The chromatographic separation was performed on a RP18 XBridge™ column.

RESULTS:

The geometric mean (GM) of cell associated concentration ([DRV]CC) and plasmatic concentration ([DRV]plasma) were 360.5ng/mL (CI95%:294.5-441.2) and 1733ng/mL (CI95%:1486-2021), respectively. A geometric mean intracellular (IC)/plasma ratio (GMR) of 0.21 (CI95%:0.18-0.24) was calculated. Adjusted for dose/body surface area and post-intake time, a statistically significant correlation was observed between [DRV]Plasma and the eGFR (p=0.002) and between [DRV]Plasma and the concomitant use of ETR (p=0.038). For the 10 patients receiving ETR in addition to DRV, the GM of [ETR]Plasma (available for 8 out of 10 patients) and [ETR]CC were 492.3ng/mL and 2951ng/mL respectively. The GMR of ETR was 7.6 (CI95%: 3.61-13.83).

CONCLUSIONS:

A handy and sensitive high performance LC-MS/MS method allowing the simultaneous quantification of DRV and ETR in PBMCs has been described and successfully applied in the largest cohort of DRV-treated patients reported to date. ETR accumulates more efficiently in PBMCs compared to DRV. We have also highlighted a possible impact of ETR on DRV plasma concentrations requiring further investigations.

BACKGROUND:

Longer-term outcome data following second-line antiretroviral therapy initiation in resource-limited settings is limited, especially in regions where genotypic resistance is inaccessible. This analysis evaluated extended efficacy and tolerability data from the D2EFT study.

METHODS:

D2EFT is a completed, multicenter, phase IIIB/IV, randomized, open-label trial in 14 low- and middle-income countries. People with HIV who had failed first-line non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens were switched to one of ritonavir-boosted darunavir plus two nucleoside reverse transcriptase inhibitors (DRV/r+2NRTIs), ritonavir-boosted darunavir plus dolutegravir (DTG+DRV/r), or dolutegravir with tenofovir disoproxil fumarate plus either lamivudine or emtricitabine (DTG+TDF/XTC), with or without pre-switch genotyping. Here we report virological suppression at 96 weeks, defined as HIV RNA <50 copies/mL in a modified intention-to-treat population.

RESULTS:

Between November 2017 and January 2022, 1190 participants were screened, 828 were randomized and 826 were included in the analysis. At week-96, the proportions of participants with HIV RNA <50 copies/mL were 191/251 (76.1%) in DRV/r+2NRTIs, 215/251 (85.7%) in DTG+DRV/r and 231/283 (81.6%) in DTG+TDF/XTC. The treatment differences (95% CIs) in proportions achieving virological suppression were 9.6% (2.7, 16.4) in DTG+DRV/r and 9.0% (1.4, 16.6) in DTG+TDF/XTC, compared to DRV/r+2NRTIs. Intermediate or high-level dolutegravir resistance was identified in 3/27 (13%) of virological failures in individuals taking DTG+TDF/XTC, but in no one taking DTG+DRV/r. No darunavir resistance was observed.

CONCLUSIONS:

After 96 weeks of follow-up, DTG+DRV/r and DTG+TDF/XTC demonstrated virological superiority over DRV/r+2NRTIs after first-line NNRTI-failure. However, emerging dolutegravir resistance, which was observed only in individuals taking DTG+TDF/XTC, requires ongoing global surveillance.

The purpose of this study is to demonstrate non-inferiority in efficacy while switching to a once-daily single-tablet regimen containing darunavir (DRV)/ cobicistat (COBI)/ emtricitabine (FTC)/ tenofovir alafenamide (TAF) (D/C/F/TAF tablet) relative to continuing the current regimen consisting of a boosted protease inhibitor (bPI) combined with tenofovir disoproxil fumarate (FTC/TDF) in virologically-suppressed (human immunodeficiency virus type 1 ribonucleic acid \[HIV-1 RNA\] concentrations less than \[\<\] 50 copies per milliliter \[copies/mL\]) HIV-1 infected participants.

INTERVENTION:

Product Name: Darunavir/Cobicistat/Emtricitabine/Tenofovir alafenamide (D/C/F/TAF) FDC tablet (Placebo) Pharmaceutical Form: Film‐coated tablet Pharmaceutical form of the placebo: Film‐coated tablet Route of administration of the placebo: Oral use

CONDITION:

Human Immunodeficiency Virus Type 1 ; MedDRA version: 20.1 Level: LLT Classification code 10068341 Term: HIV‐1 infection System Organ Class: 100000004862 Therapeutic area: Diseases [C] ‐ Virus Diseases [C02]

PRIMARY OUTCOME:

; Secondary Objective: The secondary objectives are: ; • To assess the acceptability of swallowing the scored film coated D/C/F/TAF FDC tablet, taken as a whole tablet and as a split tablet; • To assess the acceptability of the intake of the scored film‐coated D/C/F/TAF FDC tablet, if to be taken daily as a whole tablet and as a; split tablet.; • To assess the ease of splitting the scored film‐coated D/C/F/TAF FDC tablet.; Main Objective: The primary objective is to assess the ability to swallow the scored film‐coated D/C/F/TAF FDC tablet, irrespective of the mode of intake. Primary end point(s): 1. The ability to swallow the tablet, irrespective of the mode of intake. Timepoint(s) of evaluation of this end point: 1. Day 1

SECONDARY OUTCOME:

; Secondary end point(s): 1. A 3‐point questionnaire to assess the acceptability of the intake of the ; whole tablet and as a split tablet by the participant and by the caregiver. ; 2. A 3‐point questionnaire to assess the acceptability of the intake of the ; whole tablet and as a split tablet by the participant, if to be taken daily. ; 3. A 3‐point questionnaire to assess the ease of splitting the tablet by ; the participant's caregiver. ; 4. A questionnaire to assess the swallowing difficulties as reported by ; the observer. ; 5. Assessment of adverse events (AEs).; ; Timepoint(s) of evaluation of this end point: 1 to 6: Within 15 minutes after each observed intake and before next intake ; 7: Throughout the study;

INCLUSION CRITERIA:

Each potential participant must satisfy all of the following criteria to be enrolled in the study: 1. Male or female. 2. =6 to <12 years of age. 3. Have a body weight of at least 25 kg and less than 40 kg. 4. Has documented chronic HIV‐1 infection. 5. Must be on a stable ARV regimen for at least 3 months prior to screening. 6. Has documented plasma HIV‐1 ribonucleic acid (RNA) <400 copies/mL within 6 months prior to screening. 7. Parent(s) (preferably both if available or as per local requirements) or their legally acceptable representative must sign an ICF indicating that he or she understands the purpose of, and procedures required for, the study and is willing to allow the child to participate in the study. Assent is also required of children capable of understanding the nature of the study (typically 7 ye

INTERVENTION:

Product Code: GS‐9883/F/TAF Pharmaceutical Form: Film‐coated tablet INN or Proposed

INN:

GS‐9883 Current Sponsor code: GS‐9883 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 50‐ INN or Proposed

INN:

EMTRICITABINE CAS Number: 143491‐57‐0 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 200‐ INN or Proposed

INN:

Tenofovir Alafenamide CAS Number: 379270‐37‐8 Other descriptive name: TENOFOVIR ALAFENAMIDE Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 25‐

CONDITION:

Human Immunodeficiency Virus (HIV‐1) Infection ; MedDRA version: 18.1 Level: LLT Classification code 10068341 Term: HIV‐1 infection System Organ Class: 100000004862 Therapeutic area: Diseases [C] ‐ Virus Diseases [C02]

PRIMARY OUTCOME:

Main Objective: To evaluate the efficacy of switching to a FDC of GS‐9883/F/TAF versus continuing on a regimen consisting of boosted atazanavir or darunavir plus either FTC/TDF or ABC/3TC in HIV‐1 infected adult subjects who are virologically suppressed as determined by the proportion of subjects with virologic failure (HIV‐1 RNA >= 50 copies/mL) at Week 48 Primary end point(s): The proportion of subjects with virologic failure (HIV‐1 RNA >= 50 copies/mL) at Week 48 as defined by the modified US FDA snapshot algorithm Secondary Objective: To evaluate the safety and tolerability of the two treatment groups through Week 48 Timepoint(s) of evaluation of this end point: Week 48

SECONDARY OUTCOME:

Secondary end point(s): ‐ The proportion of subjects with HIV‐1 RNA < 50 copies/mL at Week 48 as defined by the US FDA snapshot algorithm; ; ‐ The change from baseline in CD4+ cell counts at Week 48 Timepoint(s) of evaluation of this end point: Week 48

INCLUSION CRITERIA:

1) The ability to understand and sign a written informed consent form, which must be obtained prior to initiation of study procedures 2) Aged 18 years or older 3) Currently receiving antiretroviral regimen consisting of ritonavir or cobicistat boosted ATV or DRV plus either FTC/TDF or ABC/3TC for 6 months or more preceding the screening visit 4) HIV RNA < 50 copies/mL at the screening visit 5) Normal ECG (or if abnormal, determined by the Investigator to be not clinically significant) 6) Adequate renal function 7) Hepatic transaminases (AST and ALT) <= 5 x upper limit of normal (ULN) 8) Total bilirubin <= 1.5 mg/dL (<= 26 umol/L), or normal direct bilirubin 9) Adequate hematologic function (absolute neutrophil count >= 750/mm3 (>= 0.75 GI/L); platelets >= 50,000/mm3 (>= 50 GI/L); hemoglobin >= 8.5 g/dL (>= 85 g/L)) 10) Serum amylase <= 5 × ULN (subjects with serum amylase > 5 × ULN will remain eligible if serum lipase is <= 5 × ULN)<br

Background: Randomised comparative data on efficacy and safety of second-line antiretroviral therapy (ART) after failure of non-nucleoside reverse transcriptase inhibitors (NNRTIs) across diverse geographical settings are scarce. The aim of this study was to evaluate optimal second-line ART for people with HIV. Methods: D2EFT is a completed international, randomised, open-label, phase 3b/4 trial evaluating three second-line ART strategies in adults (aged ≥18 years) with HIV-1 for whom first-line NNRTI therapy has failed. The study was done at 28 sites across 14 countries in Asia, Africa, and Latin America. It was originally designed to compare recommended standard of care (ritonavir-boosted darunavir [800 mg darunavir plus 100 mg ritonavir once daily] plus two nucleoside reverse transcriptase inhibitors [NRTIs; dosed once or twice daily]) with a novel nucleoside sparing regimen of dolutegravir (50 mg once daily) with ritonavir-boosted darunavir. The study was adapted during the first year to add a third arm of dolutegravir (50 mg once daily) with fixed tenofovir disoproxil fumarate (300 mg once daily) plus either lamivudine (300 mg once daily) or emtricitabine (200 mg once daily). Participants were randomly assigned with a computer-generated, blocked randomisation scheme (block size of two) stratified by site, previous tenofovir disoproxil fumarate use, and HIV viral load. The trial was designed to evaluate non-inferiority of either interventional arm against standard of care for the primary outcome of virological suppression, as determined by HIV RNA load of less than 50 copies per mL at 48 weeks. The prespecified non-inferiority margin was 12%. Comparisons were made with a modified intention-to-treat population, including all participants randomly assigned but excluding administrative withdrawals. This study is registered with ClinicalTrials.gov, NCT03017872. Findings: 1190 individuals were screened; 828 participants were enrolled between Nov 1, 2017, and Dec 31, 2021. Two participants were unable to receive their assigned regimen for administrative reasons; and 826 participants were included in analyses. Median age was 39 years (IQR 33–46), and 450 (54%) participants were female. Baseline median CD4 count was 206 cells per μL (23–354) and median HIV RNA was 15 400 copies per mL (3600–65 986). The proportion of participants with HIV RNA of less than 50 copies per mL at 48 weeks was 194 (75%) of 257 in the ritonavir-boosted darunavir plus two NRTIs group, 222 (84%) of 264 in the ritonavir-boosted darunavir plus dolutegravir group, and 227 (78%) of 291 in the dolutegravir with tenofovir disoproxil fumarate plus either lamivudine or emtricitabine group. Compared with ritonavir-boosted darunavir plus two NRTIs, the difference in virological suppression was 8·6% (95% CI 1·7 to 15·5; p=0·016) for dolutegravir plus ritonavir-boosted darunavir and 6·7% (–1·2 to 14·4; p=0·093) for dolutegravir with tenofovir disoproxil fumarate plus either lamivudine or emtricitabine. Six deaths occurred, none of which were related to treatment. 19 pregnancies (11 livebirths) occurred with no congenital defects. Interpretation: In individuals experiencing failure of an NNRTI-based first-line ART, a switch to either dolutegravir plus ritonavir-boosted darunavir or dolutegravir with tenofovir disoproxil fumarate plus either lamivudine or emtricitabine, without universal access to genotyping, was non-inferior in achieving viral suppression compared with ritonavir-boosted darunavir plus two NRTIs. These global data support the most recent WHO treatment guidelines. Funding: UNITAID; National Institute of Allergy and Infectious Diseases, USA; National Health and Medical Research Council, Australia; ViiV Healthcare; and Janssen.

INTERVENTION:

Trade Name: REYATAZ 300 mg cápsulas duras Pharmaceutical Form: Capsule, hard INN or Proposed

INN:

ATAZANAVIR Other descriptive name: ATAZANAVIR Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 300‐ Trade Name: PREZISTA 400 mg comprimidos recubiertos con película Pharmaceutical Form: Film‐coated tablet INN or Proposed

INN:

DARUNAVIR ETANOLATO Other descriptive name: DARUNAVIR ETANOLATO Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 400‐

CONDITION:

Tratamiento para pacientes infectados por el VIH‐1 sin tratamiento previo ; MedDRA version: 13 Level: LLT Classification code 10020160 Term: Enfermedad por

VIH PRIMARY OUTCOME:

Main Objective: Comparar el efecto sobre los niveles de colesterol total entre las dos ramas de tratamiento a las 24 semanas de seguimiento Primary end point(s): Comparar la diferencia respecto al basal de los niveles de colesterol total entre las dos ramas de tratamiento a las 24 semanas de seguimiento. Secondary Objective: Comparar el efecto entre las dos ramas de tratamiento sobre:; 1. Perfil lipídico; 2. Riesgo cardiovascular; 3. Metabolismo de la glucosa; 4. Biomarcadores inflamatorios y anti‐inflamatorios; 5. Actividad antiviral; 6. Recuento de células CD4; 7. Seguridad y tolerabilidad; 8. Cambios en la composición corporal

INCLUSION CRITERIA:

1. Pacientes de ambos sexos* de edad igual o superior a 18 años 2. Diagnóstico de infección por VIH‐1 (según criterios diagnósticos estándar) 3. No tratados previamente con ningún fármaco antrretroviral 4. Carga viral plasmática 1000 copias/ml 5. Pacientes clínicamente estables en opinión del investigador en el momento de la inclusión 6. Capaces de cumplir el calendario de visitas del estudio y otros requisitos del protocolo 7. Que, adecuadamente informados, otorguen su consentimiento por escrito para participar en el estudio y someterse a las pruebas y exploraciones que ello comporta *Las mujeres en edad fértil deben comprometerse a la abstinencia sexual o a la utilización de métodos anticonceptivos de barrera durante el estudio. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18‐64 years) yes F.1.2.1 Number of subjects for this age range F.1.3 Elderly (>=65 years) yes<

Background: Simplified regimens with reduced pill burden and fewer side-effects are desirable for people living with HIV. We investigated the efficacy and safety of switching to a single-tablet regimen of darunavir, cobicistat, emtricitabine, and tenofovir alafenamide versus continuing a regimen of boosted protease inhibitor, emtricitabine, and tenofovir disoproxil fumarate. Methods: EMERALD was a phase-3, randomised, active-controlled, open-label, international, multicentre trial, done at 106 sites across nine countries in North America and Europe. HIV-1-infected adults were eligible to participate if they were treatment-experienced and virologically suppressed (viral load <50 copies per mL for ≥2 months; one viral load of 50–200 copies per mL was allowed within 12 months before screening), and patients with a history of virological failure on non-darunavir regimens were allowed. Randomisation was by computer-generated interactive web-response system and stratified by boosted protease inhibitor use at baseline. Patients were randomly assigned (2:1) to switch to the open-label study regimen or continue the control regimen. The study regimen consisted of a fixed-dose tablet containing darunavir 800 mg, cobicistat 150 mg, emtricitabine 200 mg, and tenofovir alafenamide 10 mg, which was taken once per day for 48 weeks. The primary outcome was the proportion of participants with virological rebound (confirmed viral load ≥50 copies per mL or premature discontinuations, with last viral load ≥50 copies per mL) cumulative through week 48; we tested non-inferiority (4% margin) of the study regimen versus the control regimen in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT02269917. Findings: The study began on April 1, 2015, and the cutoff date for the week 48 primary analysis was Feb 24, 2017. Of 1141 patients (763 in the study group and 378 in the control group), 664 (58%) had previously received five or more antiretrovirals, including screening antiretrovirals, and 169 (15%) had previous virological failure on a non-darunavir regimen. The study regimen was non-inferior to the control for virological rebound cumulative through week 48 (19 [2·5%] of 763 patients in the study group vs eight (2·1%) of 378 patients in the control group; difference 0·4%, 95% CI −1·5 to 2·2; p<0·0001). No resistance to any study drug was observed. Numbers of discontinuations related to adverse events (11 [1%] of 763 patients in the study group vs four [1%] of 378 patients in the control group) and grade 3–4 adverse events (52 [7%] patients vs 31 [8%] patients) were similar between the two groups. There was a small non-clinically relevant but statistically significant (0·2 [SD 1·1] vs 0·1 [1·1], p=0.010) difference between the two groups in change from baseline in total cholesterol to HDL-cholesterol ratio. Only one serious adverse event (pancreatitis in the study group) was deemed as possibly related to the study regimen. Interpretation: Our findings show the safety and efficacy of single-tablet darunavir, cobicistat, emtricitabine, and tenofovir alafenamide as a potential switch option for the treatment of HIV-1 infection in adults with viral suppression. Funding: Janssen. © 2018 Elsevier Ltd

The purpose of this study is to determine the pharmacokinetic profile of TMC125 400mg with tenofovir DF/emtricitabine FDC (fixed dose combination) 300/200mg all dosed once daily with and without darunavir/ritonavir 800/100 mg once daily in HIV-1 infected, antiretroviral (ARV) naÃ-ve patients (patients who have never received ARV treatment).