NEJM original articles

Background. Twice-yearly subcutaneous lenacapavir has been shown to be efficacious for prevention of human immunodeficiency virus (HIV) infection in cisgender women. The efficacy of lenacapavir for preexposure prophylaxis (PrEP) in cisgender men, transgender women, transgender men, and gender-nonbinary persons is unclear.

Methods. In this phase 3, double-blind, randomized, active-controlled trial, we randomly assigned participants in a 2:1 ratio to receive subcutaneous lenacapavir every 26 weeks or daily oral emtricitabine-tenofovir disoproxil fumarate (F/TDF). The primary efficacy analysis compared the incidence of HIV infection in the lenacapavir group with the background HIV incidence in the screened population. The secondary efficacy analysis compared the incidence of HIV infection in the lenacapavir group with that in the F/TDF group.

Results. Among 3265 participants who were included in the modified intention-to-treat analysis, HIV infections occurred in 2 participants in the lenacapavir group (0.10 per 100 person-years; 95% confidence interval [CI], 0.01 to 0.37) and in 9 participants in the F/TDF group (0.93 per 100 person-years; 95% CI, 0.43 to 1.77). The background HIV incidence in the screened population (4634 participants) was 2.37 per 100 person-years (95% CI, 1.65 to 3.42). The incidence of HIV infection in the lenacapavir group was significantly lower than both the background incidence (incidence rate ratio, 0.04; 95% CI, 0.01 to 0.18; P<0.001) and the incidence in the F/TDF group (incidence rate ratio, 0.11; 95% CI, 0.02 to 0.51; P = 0.002). No safety concerns were identified. A total of 26 of 2183 participants (1.2%) in the lenacapavir group and 3 of 1088 (0.3%) in the F/TDF group discontinued the trial regimen because of injection-site reactions.

Conclusions. The HIV incidence with twice-yearly lenacapavir was significantly lower than the background incidence and the incidence with F/TDF. (Funded by Gilead Sciences; PURPOSE 2 ClinicalTrials.gov number, NCT04925752.).

Background. Oral anticoagulation is recommended after ablation for atrial fibrillation among patients at high risk for stroke. Left atrial appendage closure is a mechanical alternative to anticoagulation, but data regarding its use after atrial fibrillation ablation are lacking.

Methods. We conducted an international randomized trial involving 1600 patients with atrial fibrillation who had an elevated score (≥2 in men and ≥3 in women) on the CHA₂DS₂-VASc scale (range, 0 to 9, with higher scores indicating a greater risk of stroke) and who underwent catheter ablation. Patients were randomly assigned in a 1:1 ratio to undergo left atrial appendage closure or receive oral anticoagulation. The primary safety end point, tested for superiority, was non-procedure-related major bleeding or clinically relevant nonmajor bleeding. The primary efficacy end point, tested for noninferiority, was a composite of death from any cause, stroke, or systemic embolism at 36 months. The secondary end point, tested for noninferiority, was major bleeding, including procedure-related bleeding, through 36 months.

Results. A total of 803 patients were assigned to undergo left atrial appendage closure, and 797 to receive anticoagulant therapy. The mean (±SD) age of the patients was 69.6±7.7 years, 34.1% of the patients were women, and the mean CHA₂DS₂-VASc score was 3.5±1.3. At 36 months, a primary safety end-point event had occurred in 65 patients (8.5%) in the left atrial appendage closure group (device group) and in 137 patients (18.1%) in the anticoagulation group (P<0.001 for superiority); a primary efficacy end-point event had occurred in 41 patients (5.3%) and 44 patients (5.8%), respectively (P<0.001 for noninferiority); and a secondary end-point event had occurred in 3.9% and 5.0% (P<0.001 for noninferiority). Complications related to the appendage closure device or procedure occurred in 23 patients.

Conclusions. Among patients who underwent catheter-based atrial fibrillation ablation, left atrial appendage closure was associated with a lower risk of non-procedure-related major or clinically relevant nonmajor bleeding than oral anticoagulation and was noninferior to oral anticoagulation with respect to a composite of death from any cause, stroke, or systemic embolism at 36 months. (Funded by Boston Scientific; OPTION ClinicalTrials.gov number, NCT03795298.).

Background. The effects and risks of the use of intravenous thrombolysis between 4.5 and 24 hours after the onset of a posterior circulation ischemic stroke are not well studied.

Methods. In a trial conducted in China, we randomly assigned patients with posterior circulation stroke, without extensive early hypodensity on computed tomography and with no planned thrombectomy, to receive alteplase (0.9 mg per kilogram of body weight; maximum dose, 90 mg) or standard medical treatment 4.5 to 24 hours after the onset of symptoms. The primary outcome was functional independence (defined as a score of 0 to 2 on the modified Rankin scale; scores range from 0 to 6, with higher scores indicating greater disability) at 90 days. The key safety outcomes were symptomatic intracranial hemorrhage and death.

Results. A total of 234 patients were enrolled; 117 were assigned to the alteplase group and 117 to the standard-treatment group. The median score on the National Institutes of Health Stroke Scale was 3 (interquartile range, 2 to 6) (scores range from 0 to 42, with higher scores indicating greater neurologic deficit). A higher percentage of patients in the alteplase group than in the standard-treatment group had functional independence at 90 days (89.6% vs. 72.6%; adjusted risk ratio, 1.16; 95% confidence interval [CI], 1.03 to 1.30; P = 0.01). The incidence of symptomatic intracranial hemorrhage within 36 hours was 1.7% in the alteplase group and 0.9% in the standard-treatment group. At 90 days, 5.2% of the patients in the alteplase group and 8.5% of those in the standard-treatment group had died.

Conclusions. Among Chinese patients with mainly mild posterior circulation stroke who did not receive thrombectomy, alteplase administered 4.5 to 24 hours after stroke onset resulted in a higher frequency of functional independence at 90 days than standard medical care. (Funded by the National Natural Science Foundation of China; EXPECTS ClinicalTrials.gov number, NCT05429476.).

Background. Next-generation sequencing has enabled precision therapeutic approaches that have improved the lives of children with rare diseases. Congenital diarrhea and enteropathies (CODEs) are associated with high morbidity and mortality. Although treatment of these disorders is largely supportive, emerging targeted therapies based on genetic diagnoses include specific diets, pharmacologic treatments, and surgical interventions.

Methods. We analyzed the exomes or genomes of infants with suspected monogenic congenital diarrheal disorders. Using cell and zebrafish models, we tested the effects of variants in newly implicated genes.

Results. In our case series of 129 infant probands with suspected monogenic congenital diarrheal disorders, we identified causal variants, including a new founder NEUROG3 variant, in 62 infants (48%). Using cell and zebrafish models, we also uncovered and functionally characterized three novel genes associated with CODEs: GRWD1, MYO1A, and MON1A.

Conclusions. We have characterized the broad genetic architecture of CODE disorders in a large case series of patients and identified three novel genes associated with CODEs. (Funded by the National Institutes of Health and others.).