[Translated article] Real-world persistence with dolutegravir/lamivudine versus bictegravir/emtricitabine/tenofovir-alafenamide among persons with HIV.

OBJETIVES: The main objective was to compare the persistence between dolutegravir/lamivudine (DTG/3TC) and bictegravir/emtricitabine/tenofovir-alafenamide (BIC/FTC/TAF) and to analyze reasons for discontinuation. METHODS: We conducted a retrospective, non-interventional, descriptive, and longitudinal study. All human immunodeficiency virus (HIV) patients over 18 years treated with DTG/3TC or BIC/FTC/TAF in our center were included. Persistence after first year was compared using the χ2 test. Kaplan-Meier survival analysis was performed. RESULTS: Three hundred fifty-eight patients were included. 99.5% versus 90.99% of patients were persistent after the first year for DTG/3TC and BIC/FTC/TAF respectively (p=.001). Persistence with DGT/3TC was 1237 days (IC95% 1216-1258) and persistence with BIC/FTC/TAF was 986 days [(IC95% 950-1021); p<.001]. The difference was remained after adjusting for covariates with the cox regression model [HR=8.2 (IC95% 1.03-64.9), p=.047]. The main reasons for discontinuation for BIC/FTC/TAF were toxicity/tolerability. CONCLUSION: In our study, patients have a high persistence. Patients on DTG/3TC treatment are more persistent compared to BIC/FTC/TAF, although BIC/FTC/TAF have worse baseline characteristics. The main reason for discontinuation of BIC/FTC/TAF is tolerability/toxicity.

Safety and Efficacy of the Combination Lurbinectedin plus Doxorubicin from a Phase 1b Trial in Patients with Advanced/Metastatic Soft-Tissue Sarcoma.

PURPOSE: While cytotoxic chemotherapy is the standard first-line treatment for patients with metastatic soft-tissue sarcoma (STS), clinical outcomes remain suboptimal. Our prior study showed lurbinectedin plus doxorubicin is well tolerated with promising clinical activity in STS. We designed this phase 1b trial to optimize dosing as the basis for a randomized trial in leiomyosarcoma and to further explore the safety profile and efficacy signal. PATIENTS AND METHODS: Patients had advanced/metastatic STS and no prior anthracycline/lurbinectedin/trabectedin. Escalation followed a 3 + 3 design with 3-week cycles: lurbinectedin (3.2 mg/m2 day 1) and two doxorubicin levels (DL1, 25 mg/m2 day 1; DL2, 25 mg/m2 days 1 and 8). The primary objectives were to identify the maximum tolerated dose and recommended dose for subsequent randomized trials. RESULTS: Ten patients were enrolled in a 6-month period. The most common treatment-emergent adverse events were grade (G) 2 fatigue and nausea, and G2 cytopenias with no febrile neutropenia events. There were two dose-limiting toxicities (DLTs) at DL2 [day 8 (G2 alanine aminotransferase [ALT]/aspartate aminotransferase increase, G3 neutropenia)], and one DLT in DL1 (G3 ALT increase). These were reversible and all patients continued the study. DL1 was chosen for further study. At the time of data cutoff, the estimated median progression-free survival is 16.5 months [95% confidence interval (CI), 6.0-ND]. The objective response rate was 60% (6/10 confirmed partial responses). CONCLUSIONS: In this phase 1b study, the recommended dose is lurbinectedin 3.2 mg/m2 in combination with doxorubicin 25 mg/m2 every 3 weeks. The study combination was well tolerated and demonstrated intriguing clinical activity.

Feasibility, safety, efficacy and potential scaling-up of sofosbuvir-based HCV treatment in Central and West Africa: (TAC ANRS 12311 trial).

Access to Hepatis C treatment in Sub-Saharan Africa is a clinical, public health and ethical concern. The multi-country open-label trial TAC ANRS 12311 allowed assessing the feasibility, safety, efficacy of a specific care model of HCV treatment and retreatment in patients with hepatitis C in Sub Saharan Africa. Between November 2015 and March 2017, with follow-up until mid 2019, treatment-naïve patients with HCV without decompensated cirrhosis or liver cancer were recruited to receive 12 week-treatment with either sofosbuvir + ribavirin (HCV genotype 2) or sofosbuvir + ledipasvir (genotype 1 or 4) and retreatment with sofosbuvir + velpatasvir + voxilaprevir in case of virological failure. The primary outcome was sustained virological response at 12 weeks after end of treatment (SVR12). Secondary outcomes included treatment adherence, safety and SVR12 in patients who were retreated due to non-response to first-line treatment. The model of care relied on both viral load assessment and educational sessions to increase patient awareness, adherence and health literacy. The study recruited 120 participants, 36 HIV-co-infected, and 14 cirrhotic. Only one patient discontinued treatment because of return to home country. Neither death nor severe adverse event occurred. SVR12 was reached in 107 patients (89%): (90%) in genotype 1 or 2, and 88% in GT-4. All retreated patients (n = 13) reached SVR12. HCV treatment is highly acceptable, safe and effective under this model of care. Implementation research is now needed to scale up point-of-care HCV testing and SVR assessment, along with community involvement in patient education, to achieve HCV elimination in Sub-Saharan Africa.

Pharmacokinetics and Safety of Lurbinectedin Administrated with Itraconazole in Cancer Patients: A Drug-Drug Interaction Study.

This open-label, two-part, phase Ib drug-drug interaction study investigated whether the pharmacokinetic (PK) and safety profiles of lurbinectedin (LRB), a marine-derived drug, are affected by co-administration of itraconazole (ITZ), a strong CYP3A4 inhibitor, in adult patients with advanced solid tumors. In Part A, three patients were sequentially assigned to Sequence 1 (LRB 0.8 mg/m2, 1-h intravenous [IV] + ITZ 200 mg/day oral in Cycle 1 [C1] and LRB alone 3.2 mg/m2, 1 h, IV in Cycle 2 [C2]). In Part B, 11 patients were randomized (1:1) to receive either Sequence 1 (LRB at 0.9 mg/m2 + ITZ in C1 and LRB alone in C2) or Sequence 2 (LRB alone in C1 and LRB + ITZ in C2). Eleven patients were evaluable for PK analysis: three in Part A and eight in Part B (four per sequence). The systemic total exposure of LRB increased with ITZ co-administration: 15% for Cmax, area under the curve (AUC) 2.4-fold for AUC0-t and 2.7-fold for AUC0-∞. Co-administration with ITZ produced statistically significant modifications in the unbound plasma LRB PK parameters. The LRB safety profile was consistent with the toxicities described in previous studies. Co-administration with multiple doses of ITZ significantly altered LRB systemic exposure. Hence, to avoid LRB overexposure when co-administered with strong CYP3A4 inhibitors, an LRB dose reduction proportional to CL reduction should be applied.

Long-term outcomes of bictegravir/emtricitabine/tenofovir alafenamide as first-line therapy and as switch strategy in virologically suppressed persons with HIV: data from the ICONA cohort.

OBJECTIVES: To assess the effectiveness of bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) among people poorly represented in clinical trials and potentially at higher risk of suboptimal response to ART. METHODS: Observational cohort study on persons with HIV (PWH) enrolled in ICONA who started BIC/FTC/TAF as initial therapy or as switching regimen while virologically suppressed. Primary endpoint was time to treatment failure (TF): new AIDS/death or virological failure (VF) or discontinuation for toxicity/failure. Secondary endpoints were time to treatment discontinuation for toxicity (TDT) and to VF. Groups of interest were those aged >50 years, female sex, and advanced HIV disease at first ART start. Probability of the events overall and according to groups and adjusted HR for every endpoint were calculated by Kaplan-Meier curves and Cox regression models. RESULTS: Nine hundred and thirty-three ART-naive and 1655 ART-experienced PWH initiated BIC/FTC/TAF. Over a median follow-up of 69.8 weeks, 89 (9.6%) PWH at their first regimen experienced TF. PWH aged >50 years had 1.83-fold (95% CI: 1.19-2.83) higher risk of TF; PWH with advanced HIV disease had 2.21-fold (95% CI: 1.53-3.82) higher risk; there were no differences in TF according to sex.Over a median follow-up of 146.3 weeks, 109 (6.6%) out of 1655 switching PWH experienced TF; no differences were found in the risk of TF, TDT and VF according to groups of interest. CONCLUSIONS: Overall, BIC/FTC/TAF is well tolerated and virologically effective in the real-world scenario for ART-naive and -experienced PWH. Older ART-naive PWH and those with advanced HIV disease may respond less well as the burden of diseases might compromise treatment efficacy.

Sofosbuvir-velpatasvir in children 3-17 years old with hepatitis C virus infection.

BACKGROUND: The safety and efficacy of sofosbuvir-velpatasvir in children aged 3-17 years with chronic hepatitis C virus (HCV) infection of any genotype were evaluated. METHODS: In this Phase 2, multicenter, open-label study, patients received once daily for 12 weeks either sofosbuvir-velpatasvir 400/100 mg tablet (12-17 years), 200/50 mg low dose tablet or oral granules (3-11 years and ≥17 kg), or 150/37.5 mg oral granules (3-5 years and <17 kg). The efficacy endpoint was sustained virologic response 12 weeks after therapy (SVR12). Dose appropriateness was confirmed by intensive pharmacokinetics in each age group. FINDINGS: Among 216 patients treated, 76% had HCV genotype 1% and 12% had genotype 3. Rates of SVR12 were 83% (34/41) among 3-5-year-olds, 93% (68/73) among 6-11-year-olds, and 95% (97/102) among 12-17-year-olds. Only two patients experienced virologic failure. The most common adverse events were headache, fatigue, and nausea in 12-17-year-olds; vomiting, cough, and headache in 6-11-year-olds; and vomiting in 3-5-year-olds. Three patients discontinued treatment because of adverse events. Four patients had serious adverse events; all except auditory hallucination (n = 1) were considered unrelated to study drug. Exposures of sofosbuvir, its metabolite GS-331007, and velpatasvir were comparable to those in adults in prior Phase 2/3 studies. Population pharmacokinetic simulations supported weight-based dosing for children in this age range. INTERPRETATION: The pangenotypic regimen of sofosbuvir-velpatasvir is highly effective and safe in treating children 3-17 years with chronic HCV infection.

Pharmacokinetics and safety of coformulated bictegravir, emtricitabine, and tenofovir alafenamide in children aged 2 years and older with virologically suppressed HIV: a phase 2/3, open-label, single-arm study.

BACKGROUND: Coformulated bictegravir, emtricitabine, and tenofovir alafenamide is a single-tablet regimen and was efficacious and well tolerated in children and adolescents with HIV (aged 6 years to <18 years) in a 48-week phase 2/3 trial. In this study, we report data from children aged at least 2 years and weighing 14 kg to less than 25 kg. METHODS: We conducted this open-label, multicentre, multicohort, single-arm study in South Africa, Thailand, Uganda, and the USA. Participants were virologically suppressed children with HIV, aged at least 2 years, weighing 14 kg to less than 25 kg. Participants received bictegravir (30 mg), emtricitabine (120 mg), and tenofovir alafenamide (15 mg) once daily, switching to bictegravir (50 mg), emtricitabine (200 mg), and tenofovir alafenamide (25 mg) upon attaining a bodyweight of at least 25 kg. The study included pharmacokinetic evaluation at week 2 to confirm the dose of coformulated bictegravir, emtricitabine, and tenofovir alafenamide for this weight band by comparing with previous adult data. Primary outcomes were bictegravir area under the curve over the dosing interval (AUCtau) and concentration at the end of the dosing interval (Ctau) at week 2, and incidence of treatment-emergent adverse events and laboratory abnormalities until the end of week 24 in all participants who received at least one dose of bictegravir, emtricitabine, and tenofovir alafenamide. This study is registered with ClinicalTrials.gov, NCT02881320. FINDINGS: Overall, 22 participants were screened (from Nov 14, 2018, to Jan 11, 2020), completed treatment with bictegravir, emtricitabine, and tenofovir alafenamide (until week 48), and entered an extension phase. The geometric least squares mean (GLSM) ratio for AUCtau for bictegravir was 7·6% higher than adults (GLSM ratio 107·6%, 90% CI 96·7-119·7); Ctau was 34·6% lower than adults (65·4%, 49·1-87·2). Both parameters were within the target exposure range previously found in adults, children, or both". Grade 3-4 laboratory abnormalities occurred in four (18%) participants by the end week 24 and six (27%) by the end of week 48. Drug-related adverse events occurred in three participants (14%) by the end of week 24 and week 48; none were severe. No Grade 3-4 adverse events, serious adverse events, or adverse events leading to discontinuation occurred by the end of week 24 and week 48. INTERPRETATION: Data support the use of single-tablet coformulated bictegravir (30 mg), emtricitabine (120 mg), and tenofovir alafenamide (15 mg) for treatment of HIV in children aged at least 2 years and weighing 14 kg to less than 25 kg. FUNDING: Gilead Sciences.

Lurbinectedin in small cell lung cancer: real-world experience of a multicentre national early access programme.

BACKGROUND AND AIMS: Lurbinectedin is a novel oncogenic transcription inhibitor active in several cancers, including small cell lung cancer (SCLC). We aimed to describe the first Australian experience of the clinical efficacy and tolerability of lurbinectedin for the treatment of SCLC after progression on platinum-containing therapy. METHODS: Multicentre real-world study of individuals with SCLC initiating lurbinectedin monotherapy (3.2 mg/m2 three-weekly) on an early access programme between May 2020 and December 2021. Key outcomes were clinical utilisation, efficacy and tolerability. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method. Outcome data were collected within the AUstralian Registry and biObank of thoRacic cAncers (AURORA). RESULTS: Data were analysed for 46 individuals across seven sites. Lurbinectedin was given as second- (83%, 38/46) or subsequent- (17%, 8/46) line therapy, mostly with prior chemoimmunotherapy (87%, 40/46). We report dose modifications (17%, 8/46), interruptions/delays (24%, 11/46), high-grade toxicities (28%, 13/46) and hospitalisations (54%, 25/46) during active treatment. The overall response rate was 33% and the disease control rate was 50%. Six-month OS was 44% (95% confidence interval (CI): 29.0-57.1). Twelve-month OS was 15% (95% CI: 6.5-26.8). From lurbinectedin first dose, the median PFS was 2.5 months (95% CI: 1.8-2.9) and OS was 4.5 months (95% CI: 3.5-7.2). From SCLC diagnosis, the median OS was 12.9 months (95% CI: 11.0-17.2). Individuals with a longer chemotherapy-free interval prior to lurbinectedin had longer PFS and OS. CONCLUSION: This real-world national experience of lurbinectedin post-platinum chemotherapy and immunotherapy for individuals with SCLC was similar to that reported in clinical trials.

Switch to bictegravir/emtricitabine/tenofovir alafenamide from dolutegravir-based therapy.

OBJECTIVE: To evaluate the efficacy and safety of 96 weeks of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) treatment in participants switching from dolutegravir (DTG)-based therapy. DESIGN: Studies 1489 (NCT02607930) and 1490 (NCT02607956) were phase 3 randomized, double-blind, active-controlled, first-line therapy trials in people with HIV-1. After 144 weeks of DTG-based or B/F/TAF treatment, participants could enter a 96-week open-label extension (OLE) of B/F/TAF. METHODS: A pooled analysis evaluated viral suppression (HIV-1 RNA <50 copies/ml) and changes in CD4 + cell count at OLE Weeks 48 and 96, treatment-emergent resistance, safety, and tolerability after switch from a DTG-based regimen to B/F/TAF. Outcomes by prior treatment were summarized using descriptive statistics and compared by two-sided Wilcoxon rank sum test. RESULTS: At OLE Week 96, participants who switched to B/F/TAF ( N  = 519) maintained high levels of virologic suppression (99.5 and 99.1% in those switching from DTG/abacavir/lamivudine and DTG+F/TAF, respectively) and CD4 + cell count, with no treatment-emergent resistance to B/F/TAF. Twenty-one participants experienced drug-related adverse events after switching, with diarrhea, weight gain, and headache occurring most commonly. There were no cases of proximal renal tubulopathy, drug-related Grade 4 adverse events, or serious adverse events. Two participants discontinued B/F/TAF due to treatment-related adverse events. Participants who switched from DTG/abacavir/lamivudine experienced statistically significant greater weight gain than those who switched from DTG+F/TAF; however, median weight change from the blinded phase baseline to OLE Week 96 was numerically similar across treatment groups. CONCLUSION: This medium-term analysis demonstrates the safety and efficacy of switching to B/F/TAF from a DTG-containing regimen in people with HIV-1.

A pivotal bridging study of lurbinectedin as second-line therapy in Chinese patients with small cell lung cancer.

This single-arm, multi-center clinical trial aimed to evaluate the safety, tolerability, DLT, recommended dose (RD), preliminary efficacy, and pharmacokinetics (PK) characteristics of lurbinectedin, a selective inhibitor of oncogenic transcription, in Chinese patients with advanced solid tumors, including relapsed SCLC. Patients with advanced solid tumors were recruited in the dose-escalation stage and received lurbinectedin in a 3 + 3 design (two cohorts: 2.5 mg/m2 and 3.2 mg/m2, IV, q3wk). The RD was expanded in the following dose-expansion stage, including relapsed SCLC patients after first-line platinum-based chemotherapy. The primary endpoints included safety profile, tolerability, DLT, RD, and preliminary efficacy profile, while the secondary endpoints included PK characteristics. In the dose-escalation stage, ten patients were included, while one patient had DLT in the 3.2 mg/m2 cohort, which was also the RD for the dose-expansion stage. At cutoff (May 31, 2022), 22 SCLC patients were treated in the ongoing dose-expansion stage, and the median follow-up was 8.1 months (range 3.0-11.7). The most common grade ≥ 3 treatment-related adverse events (TRAEs) included neutropenia (77.3%), leukopenia (63.6%), thrombocytopenia (40.9%), anemia (18.2%), and ALT increased (18.2%). The most common severe adverse events (SAEs) included neutropenia (27.3%), leukopenia (22.7%), thrombocytopenia (18.2%), and vomiting (9.1%). No treatment-related deaths occurred. The Independent Review Committee (IRC)-assessed ORR was 45.5% (95% CI 26.9-65.3). Lurbinectedin at the RD (3.2 mg/m2) showed manageable safety and acceptable tolerability in Chinese patients with advanced solid tumors, and demonstrates promising efficacy in Chinese patients with SCLC as second-line therapy.Trial registration: This study was registered with ClinicalTrials.gov NCT04638491, 20/11/2020.

Comparative efficacy and safety of Sofosbuvir/Velpatasvir and Danoprevir for the treatment of chronic hepatitis C: the real-world data in China.

BACKGROUND: Sofosbuvir/Velpatasvir (Epclusa, ECS) is the first pan-genotype direct-acting antiviral agent (DAA) for hepatitis C virus (HCV) infection, and Danoprevir (DNV) is the first DAA developed by a Chinese local enterprise, which is suitable for combined use with other drugs to treat genotype 1b chronic hepatitis C. However, previous reports have never compared the real-world data of ECS and DNV. PATIENTS AND METHODS: 178 chronic hepatitis C patients were retrospectively recruited, and 94cases were accepted with Sofosbuvir/Velpatasvir ± Ribavirin (ECS group), and others (n = 84 treated with DNV combination therapy (DNV group). The HCV genotype, virological response, adverse effects and some laboratory biochemical indexes were contrasted between above two groups in the real world study. RESULTS: DNV group had significantly lower level of alpha-fetoprotein (AFP), lower rates of decompensated cirrhosis ( P < 0.05). ECS group possessed more 6a (31.91% vs.13.10%) while DNV group was provided with more 1b (48.81% vs. 22.34%) patients. Significantly poor liver function was detected in ECS group at 4-week treatment (ALT and AST) and 12-week follow-up (AST) (all P < 0.05). The SVR12 undetectable rates of both groups were 100%, and no serious event was observed during the treatment and follow-up in both groups. CONCLUSION: In this retrospective real-world study, the efficacy of DNV combined therapy is similar to Sofosbuvir/Velpatasvir ± Ribavirin for chronic HCV infection, and the safety is comparable. DNV based therapy is a promising regimen for chronic hepatitis C.

Optimal dose for the efficacy of asenapine in patients with schizophrenia: Real-world data.

AIMS: A meta-analysis of short-term studies revealed no significant differences between the doses of asenapine, 10 and 20 mg/day, in the acute treatment of schizophrenia. However, it should be noted that many patients from clinical practice were excluded, and the dose-response to asenapine in a real-world setting is still unclear. Additionally, the dose-response in the maintenance phase is not clear. This study aimed to evaluate the differences in the efficacy of different asenapine doses in patients with maintenance phase of schizophrenia in a real-world setting. METHODS: This study conducted post-marketing surveillance of asenapine in clinical settings in Japan. It followed patients diagnosed with schizophrenia who received asenapine for the first time for a maximum of 52 weeks. These patients were divided into two categories based on their average daily asenapine dosage: ≤10 mg/day and >10 mg/day. Asenapine efficacy was assessed by adjusting for patient demographics using multivariate logistic regression analysis, employing the Clinical Global Impression-Global Improvement (CGI-I) scale, which has seven categories. RESULTS: A total of 2774 patients were included in the analysis. Of these, 1689 and 1085 patients were treated with asenapine ≤10 mg/day and >10 mg/day, respectively. The CGI-I improvement rate was significantly higher in the asenapine >10 group (p = 0.012) after adjusting for patient background factors. CONCLUSION: These results suggest that asenapine doses >10 mg/day may be more effective than 10 mg/day in the treatment of schizophrenia; however, further studies are needed to confirm these findings.

Weight gain and metabolic disturbances in people living with HIV who start antiretroviral therapy with, or switch to, bictegravir/emtricitabine/tenofovir alafenamide after 48 weeks of treatment: A real-world prospective study.

BACKGROUND: People living with HIV (PLWH) starting or switching to an integrase strand transfer inhibitor-based regimen are more likely to experience weight gain than other classes of antiretroviral regimens. The aim of this study was to evaluate the weight gain and metabolic disturbances in PLWH who start antiretroviral therapy (ART) with bictegravir/emtricitabine/tenofovir alafenamide and in individuals who switch from another ART to BIC/FTC/TAF after 48 weeks. METHODS: A prospective longitudinal study was conducted in an HIV clinic in Mexico. Weight and metabolic parameters were measured at baseline, 24 and 48 weeks. A paired t test and Wilcoxon signed-rank test were applied to evaluate weight and metabolic changes. RESULTS: 160 participants completed measurements, median age was 29 (IQR 26-32) and 30 (IQR 27-34) years old for the treatment-naïve and switch group respectively. In the treatment-naïve group, mean weight change was 3.8 kg (±5.8) (p < .001) and BMI increased 1.3 kg/m2 (±2) (p < .001) at 48 weeks. Incidence of BMI >25 kg/m2 was 28% (95%CI; 18%-40%) and BMI >30 kg/m2 was 7% (95%CI; 2%-16%) at 48 weeks in treatment-naïve individuals. In the switch group, mean weight gain and BMI change at 48 weeks was 2.8 kg (±5.9) and 0.9 kg/m2 (±2.0) respectively (p < .001). Incidence of BMI >25 kg/m2 was 17% (95%CI; 8%-32%) and BMI >30 kg/m2 12.8% (95%CI; 5%-26%) at 48 weeks respectively. CONCLUSIONS: Weight gain should be considered when men PLWH are treated with BIC/FTC/TAF regimen. They should be informed about this possible adverse event and strategies of intervention.

Comparing the efficacy and safety of a first-line regimen with emtricitabine/tenofovir alafenamide fumarate plus either bictegravir or dolutegravir: Results from clinical practice.

BACKGROUND: First-line integrase strand transfer inhibitor-based regimens have become commonly used in clinical practice over the last decade. This study aimed to analyse and compare the efficacy and safety of bictegravir (BIC) and dolutegravir (DTG) when prescribed in association with emtricitabine/tenofovir alafenamide (FTC/TAF) as part of a first-line regimen for the treatment of human immunodeficiency-1 (HIV-1) infection. METHODS: Treatment-naïve people living with HIV (PLWHIV) starting a first-line regimen with either BIC/FTC/TAF (BIC group) or FTC/TAF+DTG (DTG group) were analysed. Snapshot analyses were performed after 24 and 48 weeks to evaluate virological efficacy. In addition, differences in the rate of treatment discontinuation (TD) between the two groups were evaluated using the Kaplan-Meier method and the log rank test. RESULTS: Data from 327 PLWHIV were analysed: 140 in the DTG group and 187 in the BIC group. At 48 weeks, 90.0% of individuals in the DTG group and 86.7% of those in the BIC group achieved HIV-RNA <50 copies/mL. In total, 88 and 38 cases of TD were observed in the DTG group and BIC group, respectively. The estimated probability of maintaining the study regimen at week 48 was 59.5% in the DTG group and 84.2% in the BIC group. Analysing changes in immunological parameters after 48 weeks, median improvements of +169 cell/mm3 (P<0.001) and +233 cell/mm3 (P<0.001) were observed in the DTG group and the BIC group, respectively. CONCLUSIONS: Both BIC and DTG, in combination with FTC/TAF, show promising efficacy and safety as first-line strategies in clinical practice, with favourable immunological recovery even in the short term.

Twelve-month effectiveness and safety of bictegravir/emtricitabine/tenofovir alafenamide in people with HIV: Real-world insights from BICSTaR cohorts.

BACKGROUND: Real-world evidence is an essential component of evidence-based medicine. The aim of the BICSTaR (BICtegravir Single Tablet Regimen) study is to assess effectiveness and safety of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) in antiretroviral treatment-naïve (TN) and treatment-experienced (TE) people with HIV. METHODS: BICSTaR is a prospective, observational cohort study. Participants (≥18 years) are being followed for 24 months. A pooled analysis is presented at 12 months, with the primary endpoint of effectiveness (HIV-1 RNA <50 copies/mL) and secondary endpoints of safety and tolerability (as per protocol). An exploration of patient-reported outcome measures using standardized questionnaires is included. RESULTS: Between June 2018 and May 2021, 1552 people with HIV were enrolled across 12 countries. The analysed population comprised 1509 individuals (279 TN, 1230 TE); most were white (76%), male (84%) and had one or more comorbid conditions (68%). Median age was 47 years. After 12 months of B/F/TAF treatment, HIV-1 RNA was <50 copies/mL in 94% (221/236) of TN participants and 97% (977/1008) of TE participants. Median CD4 cell count increased by 214 cells/µL (p < 0.001) in TN participants and 13 cells/µL (p = 0.014) in TE participants; median CD4/CD8 ratios increased by 0.30 and 0.03, respectively (both p < 0.001). Persistence was high at 12 months (TN, 97%; TE, 95%). No resistance to B/F/TAF emerged. Study drug-related adverse events occurred in 13% of participants through 12 months, leading to B/F/TAF discontinuation in 6%. CONCLUSIONS: The findings of this study provide robust real-world evidence to support the broad use of B/F/TAF in both TN and TE people with HIV.

Bictegravir/Emtricitabine/Tenofovir Alafenamide Treatment: Efficacy and Tolerability in Clinical Practice.

Objective: Analysis of bictegravir/emtricitabine/tenofovir alafenamide (BFTAF) efficacy and safety in virologically suppressed people living with HIV (PLWH) in clinical practice. Patients and methods: The retrospective cohort study, which included adult treatment-experienced and virologically suppressed PLWH, switched to BFTAF from June 2019 to June 2021. Efficacy and safety were evaluated as virological failure (VF=2 consecutive HIV-RNA>50 copies/mL or a single HIV-RNA>400 copies/mL) and treatment failure (TF=VF or discontinuation for any reason) until data freezing (August 2022). Results: Of the 1040 PLWH included, 67.8% switched from elvitegravir/cobicistat/FTAF. VF occurred in 4.2% (n=44), with incidence rate of 1.63 per 1000 person-months of follow-up (PMFU) and probability at 24-30 months of 3.8%-4.0%, respectively. Out of the 44 VF, in 75% virological re-suppression was achieved while maintaining BFTAF. Discontinuation occurred in 15% after a median time of 13.5 months of follow-up, with an incidence rate of 5.67 per 1000 PMFU, and a probability at 24-30 months of 11.9%-15.3%, respectively. Main discontinuation reasons were simplification (51.3%) and toxicity (21.8%, involving CNS in half of cases). TF occurred in 18.6% with an incidence rate of 7.01 per 1000 PMFU after a median time of 13.6 observation months; probability at 24-30 months was 14.8%-18.4%, respectively. Conclusion: BFTAF has proven effective and well tolerated in clinical practice.

Pharmacokinetic evaluation of sofosbuvir/velpatasvir for the treatment of Chronic Hepatitis C in pediatrics aged 3 and older.

INTRODUCTION: The World Health Organization proposed targets to eliminate hepatitis C virus (HCV) by 2030, aiming to treat ≥80% of people with HCV, decreasing new chronic infections by 90% and liver-related mortality by 65%. While children/adolescents represent a minority of cases, the true burden is underestimated. Advances in drug development have resulted in simplified treatments that are well-tolerated, effective, and pangenotypic in activity. Sofosbuvir/velpatasvir, a combined nucleotide analog NS5B polymerase inhibitor and NS5A inhibitor, respectively, is approved for HCV treatment for individuals ≥3 years, supported by safety data using lower-dose, novel formulations. AREAS COVERED: This review discusses chemistry, pharmacokinetics/pharmacodynamics, dosing, efficacy, and safety of sofosbuvir/velpatasvir highlighting pediatric data. Literature review included publications/conference abstracts from PubMed, Google, and Google Scholar. Information from key clinical trials/regulatory approvals is reviewed. EXPERT OPINION: Sofosbuvir/velpatasvir is a safe and effective therapy for the treatment of pangenotypic chronic HCV infection with limited cases of virologic relapse and adverse events among pediatric populations aged 3 years and older. However, the tolerability among children less than 6 years could be improved by alternative formulations, if not, shorter treatment durations. An aspirational role of direct-acting antivirals (DAAs) that should be explored is for the prevention of infection in exposed and at-risk pediatric populations.

Tolerability of bictegravir/tenofovir alafenamide/emtricitabine versus dolutegravir/lamivudine as maintenance therapy in a real-life setting.

BACKGROUND: While both the burden of therapy and the individual drugs in bictegravir/tenofovir alafenamide/emtricitabine (BIC/TAF/FTC) and dolutegravir/lamivudine differ, it is unclear whether their real-life tolerability may be also different. METHODS: Single-centre, clinical cohort analysis of all virologically suppressed persons with HIV (PWH) who were first prescribed bictegravir as BIC/TAF/FTC or dolutegravir as dolutegravir/lamivudine and had taken ≥1 dose of study medication. Major outcomes were discontinuations either for any reason or due to toxicity. Incidence was calculated as number of episodes per 100 person-years adjusted through propensity score analysis. RESULTS: Relative to persons treated with BIC/TAF/FTC (n = 1231), persons treated with dolutegravir/lamivudine (n = 821) were older and had more AIDS-defining conditions although better HIV control. After a median follow-up of 52 weeks, adjusted incidence rates for discontinuation were 6.68 (95% CI 5.18-8.19) and 8.44 (95% CI 6.29-10.60) episodes per 100 person-years for BIC/TAF/FTC and dolutegravir/lamivudine, respectively; adjusted incidence rate ratio for dolutegravir/lamivudine was 1.26 (95% CI 0.89-1.78) relative to BIC/TAF/FTC (P = 0.1847). Adjusted incidence rates for discontinuation due to toxicity were 3.88 (95% CI 2.70-5.06) and 4.62 (95% CI 3.05-6.19) episodes per 100 person-years for BIC/TAF/FTC and dolutegravir/lamivudine, respectively; adjusted incidence rate ratio for dolutegravir/lamivudine was 1.19 (95% CI 0.75-1.90) relative to BIC/TAF/FTC (P = 0. 4620). Adverse events leading to discontinuation were neuropsychiatric (n = 42; 2%), followed by gastrointestinal (n = 23; 1%), dermatological (n = 15; 1%) and weight increase (n = 15; 1%), without differences between regimens. CONCLUSIONS: Switching to BIC/TAF/FTC or dolutegravir/lamivudine showed no difference in the risks of overall or toxicity-related discontinuations or in the profile of adverse events leading to discontinuation.

Efficacy, safety, and tolerability of switching to long-acting cabotegravir plus rilpivirine versus continuing fixed-dose bictegravir, emtricitabine, and tenofovir alafenamide in virologically suppressed adults with HIV, 12-month results (SOLAR): a randomised, open-label, phase 3b, non-inferiority trial.

BACKGROUND: Cabotegravir plus rilpivirine is the only approved complete long-acting regimen for the maintenance of HIV-1 virological suppression dosed every 2 months. The SOLAR study aimed to compare long-acting cabotegravir plus rilpivirine every 2 months with continued once-daily bictegravir, emtricitabine, and tenofovir alafenamide for the maintenance of HIV-1 virological suppression in adults living with HIV. METHODS: SOLAR is a randomised, open-label, multicentre, phase 3b, non-inferiority study. The study was done in 118 centres across 14 countries. Participants with HIV-1 RNA less than 50 copies per mL were randomly assigned (2:1), stratified by sex at birth and BMI, to either long-acting cabotegravir (600 mg) plus rilpivirine (900 mg) dosed intramuscularly every 2 months or to continue daily oral bictegravir (50 mg), emtricitabine (200 mg), and tenofovir alafenamide (25 mg). Participants randomly assigned to long-acting therapy had a choice to receive cabotegravir (30 mg) plus rilpivirine (25 mg) once daily as an optional oral lead-in for approximately 1 month. The primary efficacy endpoint was the proportion of participants with virological non-response (HIV-1 RNA ≥50 copies per mL; the US Food and Drug Administration snapshot algorithm, 4% non-inferiority margin; modified intention-to-treat exposed population) at month 11 (long-acting start with injections group) and month 12 (long-acting with oral lead-in group and bictegravir, emtricitabine, and tenofovir alafenamide group). The study is registered with ClinicalTrials.gov, NCT04542070, and is ongoing. FINDINGS: 837 participants were screened between Nov 9, 2020, and May 31, 2021, and 687 were randomly assigned to switch treatment or continue existing treatment. Of 670 participants (modified intention-to-treat exposed population), 447 (67%) switched to long-acting therapy (274 [61%] of 447 start with injections; 173 [39%] of 447 with oral lead-in) and 223 (33%) continued bictegravir, emtricitabine, and tenofovir alafenamide. Baseline characteristics were similar; median age was 37 years (range 18-74), 118 (18%) of 670 were female sex at birth, 207 (31%) of 670 were non-White, and median BMI was 25·9 kg/m2 (IQR 23·3-29·5). At month 11-12, long-acting cabotegravir plus rilpivirine showed non-inferior efficacy versus bictegravir, emtricitabine, and tenofovir alafenamide (HIV-1 RNA ≥50 copies per mL, five [1%] of 447 vs one [<1%] of 223), with an adjusted treatment difference of 0·7 (95% CI -0·7 to 2·0). Excluding injection site reactions, adverse events and serious adverse events were similar between groups. No treatment-related deaths occurred. More long-acting group participants had adverse events leading to withdrawal (25 [6%] of 454 vs two [1%] of 227). Injection site reactions were reported by 316 (70%) of 454 long-acting participants; most (98%) were grade 1 or 2. INTERPRETATION: These data support the use of long-acting cabotegravir plus rilpivirine dosed every 2 months as a complete antiretroviral regimen that has similar efficacy to a commonly used integrase strand transfer inhibitor-based first-line regimen, while addressing unmet psychosocial issues associated with daily oral treatment. FUNDING: ViiV Healthcare.

Switching to Dolutegravir/lamivudine or Bictegravir/Emtricitabine/Tenofovir alafenamide. A comparative real-world study.

BACKGROUND: This real-world study compared the safety and effectiveness of Dolutegravir/lamivudine (D/L) and Bictegravir/Emtricitabine/Tenefovir alafenamide (B/F/T) switch therapy regimens for people living with HIV (PLWH). METHODS: The retrospective study conducted from April 2019 to November 2022, included PLWH with < 50 copies/mL of HIV-RNA prior to recruitment who initiated either D/L or B/F/T switching therapy. The primary objective was to evaluate treatment discontinuation rates; safety and virologic outcomes were also evaluated. RESULTS: 690 PLWH were included, 358 in the D/L and 332 in the B/F/T, and a median follow-up of 728 and 1013 days, respectively. The discontinuation proportions were 8.7% (31 participants, incidence rate of 4.44 per 100 PYFU in the D/L group and 15.3% (51 participants, incidence rate of 6.25 per 100 PYFU) in the B/F/T group. The adjusted hazard ratio for B/F/T discontinuation compared to D/L was 1.20 (95% CI: 0.71;2.0; p = 0.494). Virologic failure (VL > 200 copies/mL in two consecutive measurements) occurred in 1.1% and 0.9% of patients in the D/L and B/F/T groups, respectively. Notably, one patient in D/L group with severe non-adherence and virologic failure developed resistance mutations. CONCLUSIONS: Switching to either B/T/F or D/L treatment for PLWH was effective and well tolerated in this real-world study. Treatment discontinuation rates did not significantly differ between the two regimens.