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The Lancet. HIV Jul 2024Randomised comparative data on efficacy and safety of second-line antiretroviral therapy (ART) after failure of non-nucleoside reverse transcriptase inhibitors (NNRTIs)... (Randomized Controlled Trial)
Randomized Controlled Trial Comparative Study
Dolutegravir plus boosted darunavir versus recommended standard-of-care antiretroviral regimens in people with HIV-1 for whom recommended first-line non-nucleoside reverse transcriptase inhibitor therapy has failed (DEFT): an open-label, randomised, phase 3b/4 trial.
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
DEFT 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.
Topics: Humans; Darunavir; HIV Infections; Female; Adult; Male; Oxazines; Pyridones; HIV-1; Heterocyclic Compounds, 3-Ring; Viral Load; Middle Aged; Piperazines; Reverse Transcriptase Inhibitors; Ritonavir; Standard of Care; Anti-HIV Agents; Drug Therapy, Combination; Emtricitabine; Treatment Outcome; Antiretroviral Therapy, Highly Active; Tenofovir; CD4 Lymphocyte Count; Treatment Failure; Lamivudine
PubMed: 38788744
DOI: 10.1016/S2352-3018(24)00089-4 -
Journal of Acquired Immune Deficiency... Jun 2024
Effects of Combination of Ethanol With Ritonavir, Lopinavir or Darunavir on Expression and Localization of the ER-Associated Set Protein and Infection of HIV-1 Pseudovirus in Primary Human Cells.
Topics: Humans; Ritonavir; Darunavir; HIV-1; Lopinavir; Ethanol; Anti-HIV Agents; Cells, Cultured; HIV Infections; HIV Protease Inhibitors
PubMed: 38771756
DOI: 10.1097/QAI.0000000000003411 -
International Journal of Antimicrobial... May 2024Despite its effectiveness, combination antiretroviral treatment (cART) has a limited effect on HIV DNA reservoir, which establishes early during primary HIV infection...
Despite its effectiveness, combination antiretroviral treatment (cART) has a limited effect on HIV DNA reservoir, which establishes early during primary HIV infection (PHI) and is maintained by latency, homeostatic T-cells proliferation, and residual replication. This limited effect can be associated with low drug exposure in lymphoid tissues and/or suboptimal adherence to antiretroviral drugs (ARVs). The aim of this study was to assess ARV concentrations in plasma, peripheral blood mononuclear cells (PBMCs) and lymph nodes (LNs), and their association to HIV RNA and HIV DNA decay during PHI. Participants were randomised to receive standard doses of darunavir/cobicistat (Arm I), dolutegravir (Arm II) or both (Arm III), with a backbone of tenofovir alafenamide and emtricitabine. Total HIV DNA was measured using digital-droplet PCR in PBMCs at baseline, 12 and 48 weeks. Drug concentrations in plasma and PBMCs were determined at 2, 12 and 48 weeks (LNs at 12 weeks) by UHPLC-MS/MS. Seventy-two participants were enrolled, mostly male (n=68), with a median age of 34 years and variable Fiebig stages (V-VI 57.7%, I-II 23.9%, and III-IV 18.3%). Twenty-six patients were assigned to Arm I, 27 to Arm II and 19 to Arm III. After 48 weeks, most patients had undetectable viremia, with minor differences in HIV RNA decay between arms. Patients with Fiebig I-II showed faster HIV RNA and HIV DNA decay. Intracellular tissue penetration was high for nucleoside analogues and low-moderate for darunavir and dolutegravir. Only tenofovir diphosphate concentrations in PBMCs showed correlation with HIV DNA decay. Overall, these results indicate that the timing of treatment initiation and intracellular tenofovir penetration are primary and secondary factors, respectively, affecting HIV reservoir.
PubMed: 38768738
DOI: 10.1016/j.ijantimicag.2024.107200 -
Southern African Journal of HIV Medicine 2024In South African antiretroviral guidelines, selected patients failing second-line protease inhibitor (PI)-based therapy qualify for genotypic resistance testing - those...
BACKGROUND
In South African antiretroviral guidelines, selected patients failing second-line protease inhibitor (PI)-based therapy qualify for genotypic resistance testing - those with PI resistance receive darunavir-based third-line regimens; those without PI resistance continue current regimen with adherence support. The Western Cape province, from September 2020, implemented a strategy of tenofovir-lamivudine-dolutegravir (TLD) for patients, provided there was no tenofovir resistance, irrespective of PI resistance.
OBJECTIVES
To evaluate virologic outcomes with TLD among adults failing second-line PI regimens with no tenofovir resistance.
METHOD
An observational cohort study comparing outcomes in patients switched to TLD with those continuing the same PI or switched to darunavir-based regimens. Follow-up was until virologic suppression (HIV-1 RNA < 400 copies/mL), or at the point of censoring.
RESULTS
One hundred and thirty-three patients switched to TLD, 101 to darunavir-based regimens, and 121 continued with the same PI. By 12 months, among patients with PI resistance, 42/47 (89%) in the TLD group had HIV-1 RNA < 400 copies/mL compared to 91/99 (92%) in the darunavir group (hazard ratio, 1.11; 95% confidence interval, 0.77-1.60). In patients without PI resistance, 66/86 (77%) in the TLD group had HIV-1 RNA < 400 copies/mL compared to 42/120 (35%) in those continuing with the same PI (hazard ratio, 4.03; 95% confidence interval, 2.71-5.98). Two patients receiving TLD developed virologic failure with high-level dolutegravir resistance.
CONCLUSION
Amongst patients failing second-line PI with no PI resistance, switching to TLD was associated with higher virologic suppression, likely due to improved adherence. Virologic outcomes were similar in patients with PI resistance switched to darunavir-based regimens or TLD.
PubMed: 38725705
DOI: 10.4102/sajhivmed.v25i1.1567 -
Antiviral Therapy Apr 2024Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) fixed-dose combination (FDC) was developed as a once-daily, complete antiretroviral (ARV) regimen... (Randomized Controlled Trial)
Randomized Controlled Trial
Assessment of swallowability and acceptability of scored darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) fixed-dose combination (FDC) tablets in HIV-1-infected children aged ≥6 to <12 years, using matching placebo tablets: A randomized study.
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.
Topics: Humans; Male; HIV Infections; Female; Cobicistat; Child; Emtricitabine; Tablets; HIV-1; Anti-HIV Agents; Tenofovir; Darunavir; Drug Combinations; Alanine; Cross-Over Studies; Deglutition; Adenine
PubMed: 38725258
DOI: 10.1177/13596535241248282 -
Therapeutic Drug Monitoring Jun 2024Carbamazepine (CBZ) is an antiseizure medication known to induce the expression of cytochrome P4503A metabolic enzymes. Here, we describe a man living with HIV who...
BACKGROUND
Carbamazepine (CBZ) is an antiseizure medication known to induce the expression of cytochrome P4503A metabolic enzymes. Here, we describe a man living with HIV who underwent several changes in the daily dose of CBZ, which resulted in different induction effects on darunavir trough concentrations.
METHODS
A 59-year-old man with HIV, successfully undergoing maintenance antiretroviral treatment with darunavir/cobicistat once daily (combined with raltegravir), was prescribed CBZ for recurrent trigeminal neuralgia. Over subsequent months, the patient underwent various changes in the doses (from 200 to 800 mg/d) and trough concentrations (from 3.6 to 18.0 mg/L) of CBZ, guided by clinical response to trigeminal neuralgia.
RESULTS
A highly significant inverse association was observed between darunavir trough concentration and both CBZ dose or trough concentration (coefficient of determination >0.75, P < 0.0001). Ultimately, the darunavir dose was increased to 600 mg twice daily with ritonavir and dolutegravir to ensure optimal antiretroviral coverage, anticipating potential further uptitration of CBZ doses.
CONCLUSIONS
The impact of CBZ on boosted darunavir exposure seemed to be dose- and concentration-dependent. The management of such drug-drug interactions in daily practice was facilitated through therapeutic drug monitoring. This case underscores the importance of a multidisciplinary approach that incorporates both antiretroviral and nonantiretroviral comedications contributing to the optimal management of polypharmacy in individuals living with HIV.
Topics: Humans; Darunavir; Male; Middle Aged; Carbamazepine; Drug Interactions; HIV Infections; Trigeminal Neuralgia; Ritonavir; Anticonvulsants; Pyridones; Heterocyclic Compounds, 3-Ring; Piperazines; Oxazines; Dose-Response Relationship, Drug; Anti-HIV Agents; Drug Monitoring
PubMed: 38723113
DOI: 10.1097/FTD.0000000000001179 -
Clinical Infectious Diseases : An... May 2024In this randomised, controlled study in 14 low- and middle-income countries, individuals taking dolutegravir with darunavir/ritonavir for 48 weeks had a greater increase...
In this randomised, controlled study in 14 low- and middle-income countries, individuals taking dolutegravir with darunavir/ritonavir for 48 weeks had a greater increase in systolic and diastolic blood pressure than individuals taking two nucleoside reverse transcriptase with darunavir/ritonavir. The difference remained significant after controlling for confounding factors including weight gain.
PubMed: 38721980
DOI: 10.1093/cid/ciae256 -
Water Research Jun 2024Separate collection and treatment of urine optimizes nutrient recovery and enhances micropollutant removal from municipal wastewater. One typical urine treatment train... (Comparative Study)
Comparative Study
Separate collection and treatment of urine optimizes nutrient recovery and enhances micropollutant removal from municipal wastewater. One typical urine treatment train includes nutrient recovery in three biological processes: anaerobic storage, followed by aerobic organics degradation concurrently with nitrification. These are usually followed by activated carbon adsorption to remove micropollutants. However, removing micropollutants prior to nitrification would protect nitrifiers from potential inhibition by pharmaceuticals. In addition, combining simplified biological treatment with activated carbon adsorption could offer a cheap and robust process for removing micropollutants where nutrient recovery is not the first priority, as a partial loss of ammonia occurs without nitrification. In this study, we investigated whether activated carbon adsorption could also take place between the three biological treatment steps. We tested the effectiveness of micropollutant removal with activated carbon after each biological treatment step by conducting experiments with anaerobically stored urine, organics-depleted urine, and nitrified urine. The urine solutions were spiked with 19 pharmaceuticals: amisulpride, atenolol, atenolol acid, candesartan, carbamazepine, citalopram, clarithromycin, darunavir, diclofenac, emtricitabine, fexofenadine, hydrochlorothiazide, irbesartan, lidocaine, metoprolol, N-acetylsulfamethoxazole, sulfamethoxazole, trimethoprim, venlafaxine, and two artificial sweeteners, acesulfame and sucralose. Batch experiments were conducted with powdered activated carbon (PAC) to determine how much activated carbon achieve which degree of micropollutant removal and how organics, pH, and speciation change from ammonium to nitrate influence adsorption. Micropollutant removal was also tested in granular activated carbon (GAC) columns, which is the preferred technology for micropollutant removal from urine. The carbon usage rates (CUR) per person were lower for all urine solutions than for municipal wastewater. The results showed that organics depletion would be needed when micropollutant removal was the sole aim of urine treatment, as the degradation of easily biodegradable organics prevented clogging of GAC columns. However, CUR did hardly improve with organics-depleted urine compared to stored urine. The lowest CUR was achieved with nitrified urine. This resulted from the additional organics removal during nitrification and not the lower pH or the partial conversion of ammonium to nitrate. In addition, we showed that the relative pharmaceutical removal in all solutions was independent of the initial pharmaceutical concentration unless the background organics matrix changed considerably. We conclude that removal of micropollutants in GAC columns from organics-depleted urine can be performed without clogging, but with the drawback of a higher carbon usage compared to removal from nitrified urine.
Topics: Adsorption; Water Pollutants, Chemical; Nitrification; Charcoal; Anaerobiosis; Waste Disposal, Fluid; Wastewater; Urine; Pharmaceutical Preparations; Water Purification
PubMed: 38692253
DOI: 10.1016/j.watres.2024.121615 -
Journal of Pharmacy Practice Apr 2024Despite the effectiveness of the TRIO regimen in maintaining viral suppression, as seen in the ANRS 139 TRIO trial, one drawback is the high pill burden. However, with...
Despite the effectiveness of the TRIO regimen in maintaining viral suppression, as seen in the ANRS 139 TRIO trial, one drawback is the high pill burden. However, with the development of newer antiretrovirals, this regimen can be simplified. The combination of both co-formulated darunavir/cobicistat and dolutegravir/rilpivirine keeps the integrity of the TRIO regimen while decreasing daily pill count from 12 to 2 tablets daily. The purpose of this case series is to demonstrate the efficacy of this regimen as there is a current lack of data. This case series included patients with no resistance to dolutegravir, rilpivirine, or darunavir, who were switched to the modified TRIO regimen between June 1st 2018 to June 1st 2022. The primary outcome was the proportion of patients with plasma HIV-RNA levels <50 copies/mL by 24 weeks. At week 24, all patients (n = 9) had a HIV-RNA <50 copies/mL. At week 48, one patient did not have a VL available. However, out of the remaining 8 patients, all maintained an HIV-RNA of <50 copies/mL at week 48. HIV-RNA levels remained suppressed when patients were switched to the modified TRIO regimen. In addition, the pill burden was reduced which can add to overall patient satisfaction.
PubMed: 38682780
DOI: 10.1177/08971900241247618 -
Pharmaceutics Apr 2024Although antiretroviral therapy (ART) can suppress peripheral HIV, patients still suffer from neuroHIV due to insufficient levels of ART drugs in the brain. Hence, this...
Although antiretroviral therapy (ART) can suppress peripheral HIV, patients still suffer from neuroHIV due to insufficient levels of ART drugs in the brain. Hence, this study focuses on developing a poly lactic-co-glycolic acid (PLGA) nanoparticle-based ART drug delivery system for darunavir (DRV) using an intranasal route that can overcome the limitation of drug metabolic stability and blood-brain barrier (BBB) permeability. The physicochemical properties of PLGA-DRV were characterized. The results indicated that PLGA-DRV formulation inhibits HIV replication in U1 macrophages directly and in the presence of the BBB without inducing cytotoxicity. However, the PLGA-DRV did not inhibit HIV replication more than DRV alone. Notably, the total antioxidant capacity remained unchanged upon treatment with both DRV or PLGA-DRV in U1 cells. Compared to DRV alone, PLGA-DRV further decreased reactive oxygen species, suggesting a decrease in oxidative stress by the formulation. Oxidative stress is generally increased by HIV infection, leading to increased inflammation. Although the PLGA-DRV formulation did not further reduce the inflammatory response, the formulation did not provoke an inflammatory response in HIV-infected U1 macrophages. As expected, in vitro experiments showed higher DRV permeability by PLGA-DRV than DRV alone to U1 macrophages. Importantly, in vivo experiments, especially using intranasal administration of PLGA-DRV in wild-type mice, demonstrated a significant increase in the brain-to-plasma ratio of DRV compared to the free DRV. Overall, findings from this study attest to the potential of the PLGA-DRV nanoformulation in reducing HIV pathogenesis in macrophages and enhancing drug delivery to the brain, offering a promising avenue for treating HIV-related neurological disorders.
PubMed: 38675216
DOI: 10.3390/pharmaceutics16040555