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The course of HIV-2 infection is longer compared to HIV-1 infection, but without effective antiretroviral therapy (ART), a substantial proportion of infected patients will progress to AIDS and die. Antiretroviral drugs in clinical use were designed for HIV-1 and, unfortunately, some do not work as well, or do not work at all, for HIV-2. This is the case for non-nucleoside reverse transcriptase inhibitors (NNRTIs), the fusion inhibitor enfuvirtide (T-20), most protease inhibitors (PIs), the attachment inhibitor fostemsavir and most broadly neutralizing antibodies. Integrase inhibitors work well against HIV-2 and are included in first-line therapeutic regimens for HIV-2-infected patients. However, rapid emergence of drug resistance and cross-resistance within each drug class dramatically reduces second-line treatment options. New drugs are needed to treat infection with drug-resistant isolates. Here, we review the therapeutic armamentarium available to treat HIV-2-infected patients, as well as promising drugs in development. We also review HIV-2 drug resistance mutations and resistance pathways that develop in HIV-2-infected patients under treatment.<\/jats:p>","DOI":"10.3390\/ijms24065905","type":"journal-article","created":{"date-parts":[[2023,3,21]],"date-time":"2023-03-21T03:15:03Z","timestamp":1679368503000},"page":"5905","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Antiretroviral Treatment of HIV-2 Infection: Available Drugs, Resistance Pathways, and Promising New Compounds"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4187-0670","authenticated-orcid":false,"given":"In\u00eas","family":"Moranguinho","sequence":"first","affiliation":[{"name":"Instituto de Investiga\u00e7\u00e3o do Medicamento (iMed.ULisboa), Faculdade de Farm\u00e1cia, Universidade de Lisboa, 1649-019 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0176-5585","authenticated-orcid":false,"given":"Nuno","family":"Taveira","sequence":"additional","affiliation":[{"name":"Instituto de Investiga\u00e7\u00e3o do Medicamento (iMed.ULisboa), Faculdade de Farm\u00e1cia, Universidade de Lisboa, 1649-019 Lisboa, Portugal"},{"name":"Centro de Investiga\u00e7\u00e3o Interdisciplinar Egas Moniz (CiiEM), Instituto Superior de Ci\u00eancias da Sa\u00fade Egas Moniz, 2829-511 Caparica, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2022-8921","authenticated-orcid":false,"given":"In\u00eas","family":"B\u00e1rtolo","sequence":"additional","affiliation":[{"name":"Instituto de Investiga\u00e7\u00e3o do Medicamento (iMed.ULisboa), Faculdade de Farm\u00e1cia, Universidade de Lisboa, 1649-019 Lisboa, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,21]]},"reference":[{"key":"ref_1","unstructured":"Faria, N.R., Esbj\u00f6rnsson, J., and Lemey, P. 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