搜索结果：The New England journal of medicine

Once-daily, single-tablet regimens have transformed care for persons living with human immunodeficiency virus type 1 (HIV-1); however, challenges to adherence continue to limit effective treatment. Long-acting oral-drug combinations could offer new options with less frequent dose administration. We conducted a phase 3, double-blind, randomized, active-controlled, noninferiority trial in 12 countries to evaluate the efficacy and safety of a switch to once-weekly oral islatravir-lenacapavir (ISL/LEN) from once-daily oral bictegravir-emtricitabine-tenofovir alafenamide (B/F/TAF) in adults in whom HIV-1 had been virologically suppressed for at least 6 months while they were receiving B/F/TAF. Participants were assigned in a 1:1 ratio to receive once-weekly ISL/LEN (2 mg/300 mg) or to continue once-daily B/F/TAF for 96 weeks; all received matched placebo for the alternative regimen. The primary end point was the percentage of participants with an HIV-1 RNA level of 50 copies per milliliter or higher at week 48, as determined by the Food and Drug Administration-defined snapshot algorithm. Noninferiority was determined at a margin of 4 percentage points. A total of 607 participants underwent randomization; 304 were assigned to the ISL/LEN group and 303 to the B/F/TAF group. A total of 21% of the participants were women, 31% were Black, 26% were Hispanic or Latine, and 15% were 65 years of age or older. At week 48, an HIV-1 RNA level of 50 copies per milliliter or higher was reported in no participants in the ISL/LEN group and 1 (0.3%) in the B/F/TAF group (difference, -0.3 percentage points; 95.002% confidence interval [CI], -1.4 to 0.8); an HIV-1 RNA level of less than 50 copies per milliliter was reported in 284 (93.4%) and 280 (92.4%), respectively (difference, 1.0 percentage point, 95% CI, -3.2 to 5.2). The mean change in the CD4+ T-cell count at week 48 was -10 cells per microliter with ISL/LEN and -18 cells per microliter with B/F/TAF (least-squares mean difference, 12 cells per microliter; 95% CI, -16 to 39). The trial regimen was discontinued owing to adverse events in 6 participants (2.0%) in the ISL/LEN group and 5 (1.7%) in the B/F/TAF group; serious adverse events occurred in 16 (5.3%) and 14 (4.6%), respectively. Among persons with virologically suppressed HIV-1, once-weekly oral ISL/LEN was noninferior to once-daily B/F/TAF in maintaining HIV viral load suppression. (Funded by Gilead Sciences and Merck Sharp and Dohme; ISLEND-1 ClinicalTrials.gov number, NCT06630286.).

The development of effective treatment strategies for human immunodeficiency virus (HIV) infection is a major achievement. Antiretroviral drugs inhibit key steps in the viral replication cycle and consist of six mechanistic classes: HIV entry inhibitors, reverse-transcriptase inhibitors (both nucleosides and nonnucleosides), capsid inhibitors, integrase inhibitors, and protease inhibitors. Antiretroviral therapy (ART) suppresses viral replication, thereby enhancing immune function, decreasing morbidity and mortality, and preventing viral transmission. Consequently, ART is recommended for all persons with HIV infection. On the basis of randomized clinical trials, the Food and Drug Administration has approved 36 antiretroviral drugs for the treatment of HIV infection since 1987; of these, 28 are currently available in the United States, and combination ART regimens are used. Initial preferred ART regimens are potent, convenient, and unlikely to cause side effects and consist of an HIV integrase inhibitor with a high barrier to resistance combined with one or two nucleoside reverse-transcriptase inhibitors. In the majority of patients using current ART regimens, viral replication is durably suppressed below detectable levels. Patients receiving ART are monitored for virologic response over time, and if virologic failure occurs, the next regimen is selected on the basis of treatment history and the results of drug-resistance testing; often, antiretroviral drugs from new classes are administered. Today, the life expectancy of someone with HIV infection who consistently takes ART approaches that of the general population.

Neoadjuvant cisplatin-based chemotherapy is a standard therapy for muscle-invasive bladder cancer. The efficacy and safety of neoadjuvant and adjuvant (perioperative) enfortumab vedotin-pembrolizumab as compared with neoadjuvant cisplatin-based chemotherapy in persons with this cancer are unclear. We conducted a phase 3, open-label, randomized trial involving adults with muscle-invasive bladder cancer eligible for cisplatin-based chemotherapy and radical cystectomy with pelvic lymph-node dissection (cystectomy). Participants were assigned to receive neoadjuvant enfortumab vedotin-pembrolizumab (4 cycles; enfortumab vedotin [1.25 mg per kilogram of body weight on days 1 and 8] and pembrolizumab [200 mg on day 1] every 3 weeks), cystectomy, and 5 cycles of enfortumab vedotin and 13 cycles of pembrolizumab as adjuvant therapy or to receive neoadjuvant cisplatin-gemcitabine (4 cycles; cisplatin [70 mg per square meter of body-surface area on day 1] plus gemcitabine [1000 mg per square meter on days 1 and 8] every 3 weeks) and cystectomy. The primary end point was event-free survival; key secondary end points were overall survival and pathological complete response. Safety was assessed. A total of 405 participants were assigned to receive enfortumab vedotin-pembrolizumab and 403 to receive cisplatin-gemcitabine. The median time from randomization to the data-cutoff date was 33.6 months (range, 22.5 to 53.6). A total of 86.7% of the participants in the enfortumab vedotin-pembrolizumab group and 89.6% of those in the cisplatin-gemcitabine group underwent cystectomy. At 2 years, estimated event-free survival was 79.4% with enfortumab vedotin-pembrolizumab and 66.2% with cisplatin-gemcitabine (hazard ratio for an event or death, 0.53; 95% confidence interval [CI], 0.41 to 0.70; P<0.001); estimated overall survival was 86.9% and 81.3%, respectively (hazard ratio for death, 0.65; 95% CI, 0.48 to 0.89; two-sided P&#x2009;=&#x2009;0.006). A pathological complete response occurred in 55.8% and 32.5% of the participants (P<0.001). The incidence of grade 3 or higher adverse events of any cause was 75.7% with enfortumab vedotin-pembrolizumab and 67.2% with cisplatin-gemcitabine. Among participants with muscle-invasive bladder cancer eligible for cisplatin-based chemotherapy, perioperative enfortumab vedotin-pembrolizumab led to significantly better event-free and overall survival outcomes and a significantly higher incidence of pathological complete response than neoadjuvant cisplatin-gemcitabine, but with more adverse events of grade 3 or higher. (Funded by Merck Sharp and Dohme and others; KEYNOTE-B15/EV-304 ClinicalTrials.gov number, NCT04700124.).

Public health emergencies require rapid generation, synthesis, and translation of clinical evidence into practice guidelines; yet, systematic synthesis of the challenges and lessons from these processes remains limited. The purpose of this study was to examine how evidence on anticoagulation in COVID-19 was generated and translated into clinical guidance, using randomized controlled trials (RCTs) as a case study, and to contextualize these processes with an individual participant data meta-analysis (IPDMA). Systematic searches identified RCTs comparing therapeutic- vs nontherapeutic-dose anticoagulation in noncritically ill patients hospitalized for COVID-19. Trial characteristics, evidence accumulation, and associated guideline recommendations were summarized over time. An IPDMA was performed to estimate summary treatment effects using mixed-effects logistic regression. Evidence evolved from an early coordinated platform RCT (preprint May 2021) to subsequent RCTs published between June 2021 and July 2023. In exploratory counterfactual sequential IPDMA, the pooled treatment effect on organ support or death became statistically significant in May 2021, approximately 13 months after first patient enrollment (adjusted OR: 0.73; 95% CI: 0.58-0.91; 6 RCTs, n = 3,944). Guideline recommendations shifted from uniform endorsement of prophylactic-dose anticoagulation in 2020 to recommendations supporting therapeutic-dose anticoagulation in 2022, with variation in certainty across guidelines. Individual participant data were obtained after completion of data transfer in April 2024 and included 7 RCTs comprising 6,362 patients. Therapeutic-dose anticoagulation reduced the odds of organ support or death (12.9% vs 16.2%; adjusted OR: 0.81; 95% CI: 0.67-0.97). Major bleeding was rare (0.8% vs 0.5%). The COVID-19 anticoagulation experience highlights how delays in coordination, data sharing, and synthesis can slow the translation of evidence into practice. Therapeutic-dose anticoagulation was associated with reduced odds of organ support or death and, in this context, serves as a case study of how evidence emerges and is acted upon under conditions of uncertainty. Strengthening coordinated research networks, platform trial infrastructures, prioritized funding, and near-real-time cross-trial synthesis may improve the timeliness, reliability, and responsiveness of evidence systems during future health emergencies.

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