Table of Contents
Credits
Hosts: Anshel Kenkare, Sara Dong
Guest: Mike Reid
Writing: Anshel Kenkare, Sara Dong
Edited and Produced by Sara Dong with support from the Infectious Diseases Society of America (IDSA)
Our Guests
Anshel Kenkare, MD
Dr. Anshel Kenkare is a 2nd year Internal Medicine resident at the Montefiore Primary Care and Social Internal Medicine program. He is interested in a career in ID focused in Public Health and Environmental Stewardship
Mike Reid, MD
Dr. Mike Reid is an Associate Professor at UCSF. He currently serves as the Chief Science Officer for PEPFAR in the Bureau of Global Health Security and Diplomacy in the US State Department. He also serves as Associate Director of the Center for Global Health Diplomacy, Delivery and Economics at UCSF. He mentioned his substack, which you can check out here: https://reimaginingglobalhealth.substack.com/about
Culture
Anshel did a recent tour of southwest US national parks! He especially loved Arches National Park
Mike shared that he recently took a walk on Camino de Santiago in northern Spain
Consult Notes
We focused on use of lenacapavir for HIV prevention in this episode. Lenacapavir just received FDA approval for this in June.
- What is lenacapavir? Lenacapavir is a first-in-class HIV-1 capsid inhibitor that works by binding to the HIV capsid protein at multiple stages of the viral lifecycle. This novel antiretroviral disrupts the nuclear uptake and release of DNA and inhibits capsid assembly/functions.
- Yeztugo (lenacapavir) is now the first and only FDA-approved HIV prevention option, which is administered subcutaneously every 6 months. This is a major breakthrough and you can read the release from Gilead below:
Approval for Yeztugo (Lenacapavir) was based on the PURPOSE 1 and PURPOSE 2 trial data that showed ≥99.9% of Participants Remained HIV Negative on Twice-Yearly Injectable Yeztugo
- Lenacapavir is effective in reducing HIV transmission in several populations including MSM, transgender and nonbinary people who have sex with men, and cisgender women
- PURPOSE 1: Bekker LG, Das M, Abdool Karim Q, Ahmed K, Batting J, Brumskine W, Gill K, Harkoo I, Jaggernath M, Kigozi G, Kiwanuka N, Kotze P, Lebina L, Louw CE, Malahleha M, Manentsa M, Mansoor LE, Moodley D, Naicker V, Naidoo L, Naidoo M, Nair G, Ndlovu N, Palanee-Phillips T, Panchia R, Pillay S, Potloane D, Selepe P, Singh N, Singh Y, Spooner E, Ward AM, Zwane Z, Ebrahimi R, Zhao Y, Kintu A, Deaton C, Carter CC, Baeten JM, Matovu Kiweewa F; PURPOSE 1 Study Team. Twice-Yearly Lenacapavir or Daily F/TAF for HIV Prevention in Cisgender Women. N Engl J Med. 2024 Oct 3;391(13):1179-1192. doi: 10.1056/NEJMoa2407001. Epub 2024 Jul 24. PMID: 39046157.
- Randomized trial of 5338 adolescent girls and young women in South Africa and Uganda —> subcutaneous lenacapavir every 26 wks —> No patients who received lenacapavir acquired HIV. So an HIV incidence that was statistically indistinguishable from zero, which has not been found before in a prevention trial
- Compared to daily oral TDF-FTC and daily TAF-FTC
- PURPOSE 2: Kelley CF, Acevedo-Quiñones M, Agwu AL, Avihingsanon A, Benson P, Blumenthal J, Brinson C, Brites C, Cahn P, Cantos VD, Clark J, Clement M, Creticos C, Crofoot G, Diaz RS, Doblecki-Lewis S, Gallardo-Cartagena JA, Gaur A, Grinsztejn B, Hassler S, Hinojosa JC, Hodge T, Kaplan R, Lacerda M, LaMarca A, Losso MH, Valdez Madruga J, Mayer KH, Mills A, Mounzer K, Ndlovu N, Novak RM, Perez Rios A, Phanuphak N, Ramgopal M, Ruane PJ, Sánchez J, Santos B, Schine P, Schreibman T, Spencer LY, Van Gerwen OT, Vasconcelos R, Vasquez JG, Zwane Z, Cox S, Deaton C, Ebrahimi R, Wong P, Singh R, Brown LB, Carter CC, Das M, Baeten JM, Ogbuagu O; PURPOSE 2 Study Team. Twice-Yearly Lenacapavir for HIV Prevention in Men and Gender-Diverse Persons. N Engl J Med. 2025 Apr 3;392(13):1261-1276. doi: 10.1056/NEJMoa2411858. Epub 2024 Nov 27. PMID: 39602624.
- Randomized trial of PrEP in 3200 men and gender-diverse patients in mostly the US but included many international research sites —> twice yearly lenacapavir reduced incidence of new HIV infection by 96%
- Lenacapavir was also more effective than daily oral TDF-FTC in preventing new HIV infections
- All 9 patients diagnosed with new HIV infection had low or no adherence to TDF-FTC before diagnosis
- Similar adverse events between groups
- Mike shared the key take-aways:
- Near perfect prevention with lenacapavir (100% efficacy in PURPOSE 1, 96% efficacy in PURPOSE 2 with statistical superiority over daily oral PrEP)
- Highlights that oral PrEP is only as good as when people take it (an din PURPOSE 1, many people just didn’t take or didn’t take continuously during the research period) —> so speaks to potential value of lenacapavir in setting of adherence challenges
- Mild injection site reactions but overall patients did well
Anshel and Mike discussed the potential rollout of lenacapavir as well as impacts of defunding PEPFAR. Here are some references they mentioned:
- Defunding PEPFAR and rates of HIV in sub Saharan Africa as a consequence
- PEPFAR Program Impact Tracker: https://pepfar.impactcounter.com/
- Across LMICs, an anticipated average of international aid reductions plus discontinued PEPFAR support could cause additional 4.43-10.75 million new HIV infections and 0.77-2.93 million HIV-related deaths. Brink DT, Martin-Hughes R, Bowring AL, Wulan N, Burke K, Tidhar T, Dalal S, Scott N. Impact of an international HIV funding crisis on HIV infections and mortality in low-income and middle-income countries: a modelling study. Lancet HIV. 2025 May;12(5):e346-e354. doi: 10.1016/S2352-3018(25)00074-8. Epub 2025 Mar 26. Erratum in: Lancet HIV. 2025 Dec;12(12):e817. doi: 10.1016/S2352-3018(25)00095-5. PMID: 40157378.
- 90-day freeze would result in 60,000 excess HIV deaths: Hontelez JAC, Goymann H, Berhane Y, Bhattacharjee P, Bor J, Chabata ST, Cowan F, Kimani J, Knox J, Lora WS, Lungu C, Manne-Goehler J, Mauti J, Moshabela M, Mpembeni RM, Wa Mwanza M, Ndung’u T, Omondi E, Phiri S, Siedner M, Tanser FC, de Vlas SJ, Bärnighausen TW. The impact of the PEPFAR funding freeze on HIV deaths and infections: a mathematical modelling study of seven countries in sub-Saharan Africa. EClinicalMedicine. 2025 Apr 25;83:103233. doi: 10.1016/j.eclinm.2025.103233. PMID: 40626258; PMCID: PMC12230335.
- UNAIDS estimated 6.3 million excess deaths will result in next 4 years: https://news.un.org/en/story/2025/02/1159901
- Even after pause was lifted, PrEP services were no longer being funded: https://www.prepwatch.org/wp-content/uploads/2025/05/Impact-of-Stop-Work-Order-300525.pdf
Infographics
Goal
Listeners will be able to understand the use of lenacapavir for HIV prevention
Learning Objectives
After listening to this episode, listeners will be able to:
- Describe the mechanism of action for lenacapavir
- Discuss the supporting trial data for use of lenacapavir for HIV prevention (specifically characteristics of PURPOSE 1 and PURPOSE 2 trials)
- Consider challenges to potential rollout of lenacapavir
Disclosures
Our guests (Anshel Kenkare, Mike Reid) as well as Febrile podcast and hosts report no relevant financial disclosures
Citation
Kenkare, A., Reid, M., Dong, S. “#123: Lenacapavir for HIV Prevention”. Febrile: A Cultured Podcast. https://player.captivate.fm/episode/f0cc22ed-56f4-4b3b-bce0-767f8eb9f6b8/