{"doi":"10.1093/cid/ciab364","title":"Reply to Ramirez and Diaz-Quijano","abstract":"To the Editor—We thank Drs Ramírez and Diaz-Quijano for their comments on our study [1]. We agree with their statements about the importance of reporting the components of composite endpoints. As they have noted, our study reported 10 (2.0%) and 6 (1.2%) deaths among the 500 participants per arm randomized to continued co-trimoxazole or chloroquine prophylaxis, respectively. This imbalance comes despite the analysis of the composite endpoint of time to first World Health Organization (WHO) human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) stage 3 or 4 event or death suggesting a reduction in disease burden among participants receiving co-trimoxazole relative to participants receiving chloroquine (9.6% vs 12.4% of participants with the composite primary endpoint, respectively). The very low mortality rate, and the difficulty in detecting statistically significant differences when events are so rare, highlight the critical need for carefully crafted composite endpoints. A limitation of our study is that the analyses of all-cause mortality and the composite endpoints are not directly comparable. As noted in the Methods section, when participants experienced a WHO HIV/AIDS stage 3 or 4 event, they discontinued their assigned treatment and restarted co-trimoxazole prophylaxis for the remainder of the study. Hence, the analysis of all-cause mortality includes roughly 10% of chloroquine participants who experienced a stage 3 or 4 event after randomization and then crossed over to co-trimoxazole prophylaxis following their clinical event. Because of the ethical imperative to restart standard-of-care therapy, we cannot know the effect of chloroquine prophylaxis on all-cause mortality had these sickest participants remained on chloroquine.","journal":"Clinical Infectious Diseases","year":2021,"id":220647,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9551,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":729297,"name":"Matthew Downs","orcid":null,"position":1,"is_corresponding":false},{"id":260137,"name":"Miriam K. Laufer","orcid":"0000-0001-8300-9593","position":2,"is_corresponding":false},{"id":429806,"name":"Matthew B. Laurens","orcid":"0000-0003-3874-581X","position":0,"is_corresponding":true}],"reference_count":1,"raw_metadata":null,"created_at":"2026-07-18T23:53:46.965811Z","pmid":"33900389","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}