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Current PrEP testing guidelines and testing algorithms in PrEP studies are varied, using single or combinations of rapid antibody\u2010based diagnostic testing, qualitative or quantitative nucleic acid testing, and\/or sample collection for retrospective analyses with sensitive research assays for HIV\u20101 nucleic acid detection. The objective of this commentary is to summarize current and alternative HIV testing approaches for PrEP implementation to guide best practices for individual programmes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>Diagnosing HIV\u20101 in PrEP users is challenging because (1) rarity of breakthrough HIV\u20101 in individuals on PrEP that increases the risk of a false\u2010positive test; (2) modification of acute HIV infection by PrEP; and (3) PrEP delivery in community settings with inadequate testing infrastructure. Current best practices indicate the use of rapid diagnostic tests or self\u2010testing as recommended by national testing algorithms and the World Health Organization (WHO). The use of nucleic acid testing such as plasma HIV\u20101 RNA polymerase chain reaction may allow earlier detection of HIV\u20101 but feasibility and risk of false positive are downsides. Sensitive tests to detect single\u2010copy HIV\u20101 RNA in plasma and integrated proviral DNA in blood mononuclear cells may be important methods to resolve ambiguous HIV\u20101 diagnosis in research settings. Delayed diagnoses could lead to drug resistance emergence under long\u2010acting PrEP selection, whereas single unconfirmed false\u2010positive tests could create diagnostic challenges in users of long\u2010acting PrEP. The cost, feasibility and positive predictive value of HIV tests are important considerations for PrEP programmes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Optimal strategies to detect HIV\u20101 acquisition among users of different PrEP modalities are evolving. While new guidance from the WHO recommends HIV\u20101 testing by serological assays or self\u2010testing with PrEP use, feasible plans for clinical management of rare cases of breakthrough on PrEP and ambiguous diagnoses are still needed. The data from PrEP studies and scale\u2010up will help us assess the value of different tests and testing approaches for their inclusion in HIV detection algorithms across PrEP modalities.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jia2.26491","type":"journal-article","created":{"date-parts":[[2025,7,2]],"date-time":"2025-07-02T07:27:58Z","timestamp":1751441278000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["HIV\u20101 testing in the context of expanding PrEP modalities"],"prefix":"10.1002","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4016-0629","authenticated-orcid":false,"given":"Urvi M.","family":"Parikh","sequence":"first","affiliation":[{"name":"Division of Infectious Diseases Department of Medicine University of Pittsburgh  Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jana L.","family":"Jacobs","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases Department of Medicine University of Pittsburgh  Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Njambi","family":"Njuguna","sequence":"additional","affiliation":[{"name":"FHI 360 Kenya  Nairobi Kenya"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristine","family":"Torjesen","sequence":"additional","affiliation":[{"name":"FHI 360  Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John W.","family":"Mellors","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases Department of Medicine University of Pittsburgh  Pittsburgh Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,7,2]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2024.16984"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2407001"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2411858"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics15122676"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.3389\/frph.2023.1337479"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/jia2.25747"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.3389\/frph.2023.1217835"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2023.1130101"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2023.10.006"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijpharm.2023.123572"},{"issue":"3","key":"e_1_2_10_12_1","article-title":"Barriers to pre\u2010exposure prophylaxis (PrEP) use for HIV: an integrative review","volume":"76","author":"Antonini M","year":"2023","journal-title":"Rev Bras Enferm"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciac752"},{"key":"e_1_2_10_14_1","unstructured":"Centers for Disease Control and Prevention.Clinical guidance for PrEP. 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