CROI 2025 was held in San Francisco, March 9-12, and highlighted promising therapeutic modalities for HIV treatment and prevention, as well as management of other infectious diseases in people with HIV. This article summarizes some key highlights and takeaways from the conference.
The opening session featured numerous speakers highlighting advances in basic science including gene therapy, interaction of public health and policy with drug use, and the importance of community advocacy and research engagement. Rebecca Denison was the named lecturer for this year’s Martin Delaney presentation highlighting the past 40-plus years of HIV, discussing the changes and advances that have been made, and the lack of progress in certain areas.1 Ms. Denison’s presentation was moving and engaging, prompting everyone to do their part in advocating for individuals living with and at risk for HIV. These presentations are available for those who were unable to attend the conference, and I would highly recommend checking them out, especially Ms. Denison’s.
Pre-Exposure Prophylaxis (PrEP) Updates
One of the highlights regarding HIV prevention was a study looking at lenacapavir (LEN; Gilead) once yearly for pre-exposure prophylaxis (PrEP). (LEN under the brand name Sunlenca is indicated for the treatment of multidrug-resistant HIV-1, but is not yet indicated for PrEP.2) Jogiraju et al reported pharmacokinetic data for 2 formulations of once-yearly administration of LEN at the meeting, which were subsequently published in Lancet on March 11.3,4 This open-label study evaluated 2 dose formulations of LEN 5,000 mg administered intramuscularly to healthy participants with serum levels collected at predetermined intervals for up to 56 weeks. A total of 40 people were evaluated, with 20 in each dose formulation. Maximum concentrations were reached at 84.1 days for formulation 1 and 69.9 days for formulation 2. The median LEN concentrations at 52 weeks remained higher than the median concentrations of the twice-monthly formulation at week 26. These results demonstrate that the concentrations of the once-yearly LEN formulation exceeded those of the twice-yearly formulation, which has shown efficacy in previous phase 3 trials.
The most common adverse events (AEs) observed were injection site pain, which was mild (grade 1 or 2) and resolved quickly.3,4 These results demonstrated the potential of a once-yearly, long-acting injectable agent for PrEP, which will need to be investigated further for clinical use.
In addition to the once-yearly LEN data discussed above, the pharmacokinetics, safety and efficacy data of LEN in adolescents enrolled in the PURPOSE 1 study were presented. Adolescents 16 and 17 years of age in phase 3 trials typically were excluded until the PURPOSE program. This program evaluated twice-yearly LEN use for PrEP and included adolescents and young adults ages 16 to 25. Gill et al presented results from people 16 to 17 years of age, of which a total of 56 were randomized to LEN every 6 months. LEN concentrations, measured at predetermined times, demonstrated similar trough concentrations in the adolescent and adult participants. AEs were similar in both groups, with the most common being injection site reactions. Other more common reactions included low-grade nodules, pain, and swelling, as well as headache, genitourinary chlamydia, and urinary tract infection. From an efficacy standpoint, no reports of incident HIV infections occurred for either the adolescent or adult groups. These results demonstrate the efficacy and safety of twice-yearly LEN in adolescents 16 to 17 years of age much earlier than typically seen due to the historical exclusion of this group from phase 3 trials.5
On-Demand PrEP
Drumond et al presented pharmacokinetic modeling data on the optimal dose/duration of tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) for on-demand PrEP to achieve optimal drug concentrations in the female genital tract. The researchers used 1,000 profiles for various dosing simulations including 2-1-1, 2-2-1, 2-2-2, 2-1-1-1, 2-2-1-1-, and 2-2-2-2. All the evaluated regimens demonstrated concentrations with above 80% EC90 at day 5. The use of a 4-dose regimen, either 2-2-2-2 or 2-1-1-1, demonstrated achievement of more than 80% EC90 at day 7 (95% and 84%, respectively). Noting that this study evaluated pharmacokinetic modeling without testing in patients, the 2-1-1-1 regimen may be a preferable option when considering balancing efficacy with safety and tolerability. The study results show that from a pharmaco- kinetic standpoint, on-demand PrEP should achieve adequate concentrations for HIV protection in cisgender females up to 7 days with the use of a 4-dose, on-demand regimen that may be considered for future clinical trials.6
Treatment Updates
Related Content
On the treatment side, there were several key updates presented at CROI, including data on doravirine/islatravir (DOR/ISL), new data for long-acting cabotegravir-rilpivirine (LA-CAB+RPV), and broadly neutralizing antibodies (bNAbs).7-11
Doravirine/islatravir
A single-tablet regimen of DOR, a non-nucleoside reverse transcriptase inhibitor (NNRTI) and ISL, a nucleoside reverse transcriptase translocation inhibitor (NRTTI) under investigation, was evaluated in an ongoing phase 3 study of its use in people who were switched from bictegravir-emtricitabine-tenofovir alafenamide (BIC/FTC/TAF; Biktarvy, Gilead) for efficacy and safety. Note that the lower dose of ISL was used because previous studies observed decreased CD4+ counts when higher doses were used. Individuals who had documented viral suppression with HIV-1 RNA of 50 copies/mL or lower for at least 3 months currently on BIC/TAF/FTC were randomly switched to DOR/ISL or continued on BIC/TAF/FTC in a 2:1 ratio. Patients were excluded if they had a history of treatment failure or known resistance to DOR. A total of 513 participants were enrolled, with 342 switching to DOR/ISL and the remainder continuing on BIC/TAF/FTC. The study results demonstrated noninferiority of DOR/ISL, with 1.5% of participants on DOR/ISL having an HIV RNA of 50 copies/mL or higher and 0.6% in the BIC/TAF/FTC arm, thus meeting the predetermined noninferiority margin. Adverse effects were similar in both groups, with similar discontinuation rates in both treatment arms. A total of 86 participants who were randomized to the DOR/ISL arm had confirmed hepatitis B virus (HBV) core antibody positivity at study entry. These individuals were monitored closely at each study visit with HBV DNA and HBV surface antigen (HBsAg) testing, with 2 participants demonstrating low-level viremia with HBV DNA less than 50 copies/mL without detectable HBsAg. There were 2 new cases of acute HBV identified in the DOR/ISL arm with no new cases found in the BIC/TAF/FTC arm. Compared with prior observations with the higher ISL dose, DOR/ISL was not associated with decreases in lymphocyte counts.7
A similar trial was conducted evaluating the efficacy and safety of switching from standard antiretroviral therapy (sART), including 2- and 3-drug regimens, to DOR/ISL. The methodology of this study was similar to the previous one, including individuals who were virally suppressed with HIV-1 RNA (=50 copies/mL) for at least 3 months on ART. There were 551 people enrolled, with 366 randomized to switch to DOR/ISL while the others continued sART. HIV-1 RNA was 50 copies/mL or higher in 1.4% of participants randomly chosen to receive DOR/ISL and 4.9% on sART, which met the predetermined noninferiority criteria. A total of 95.6% and 91.9% of individuals had HIV-1 RNA less than 50 copies/mL in the DOR/ISL and sART arms, respectively. When examining individuals on DOR/ISL who were not virally suppressed, 2 of those were found to have significant resistance-associated mutations. The rates of adverse effects were similar in both treatment arms, with no participants discontinuing DOR/ISL due to decreased lymphocyte counts.8
These studies show the safety and efficacy of DOR/ISL in maintaining viral suppression and offer an INSTI-free treatment regimen.
LA-CAB+RPV: The CARES Trial
The results of the CARES trial evaluating the use of long acting cabotegravir plus rilpivirine (LA-CAB+RPV; Cabenuva, ViiV Healthcare) in Africa, which were previously reported up to 48 weeks, were updated with data through week 96 at this year’s CROI. The CARES trial enrolled individuals taking TDF plus lamivudine-emtricitabine (3TC/FTC) plus efavirenz, nevirapine, and dolutegravir (EFV/NVP/DTG) with HIV-1 RNA less than 50 copies/mL at 8 different African sites. Patients who had prior virologic failure, were pregnant or were coinfected with HBV were excluded. Participants were randomly assigned to receive LA-CAB+RPV every 8 weeks or continue current oral ART (oART). The trial used a public health approach and did not require frequent viral load testing or resistance testing at baseline. A total of 512 participants were enrolled, with 255 in the LA-CAB+RPV arm and 257 in the oART arm included in the 96-week analysis. When looking at the primary end point of HIV-1 RNA less than 50 copies/mL at week 96, 96.9% and 97.3% of individuals in the LA-CAB+RPV and oART achieved the outcome demonstrating noninferiority. The study results demonstrated that LA-CAB+RPV was noninferior to current oART, and offers a safe and effective long-term treatment option for individuals suppressed on oART.9
Broadly Neutralizing Antibodies
The EMBRACE study evaluated VH3810109 (N6LS) (ViiV Healthcare), a targeted CD4 binding site antibody that has shown efficacy, safety, and tolerability in the previous phase 1 SPAN trial as well as the phase 2a BANNER trial. This was a randomized, open-label trial at 45 sites across the United States, including Puerto Rico, which enrolled adults with HIV suppressed (HIV-1 RNA <50 copies/mL) on current standard-of-care ART. Participants were randomized in a 2:2:1 fashion to receive N6LS 60 mg/kg IV plus LA-CAB, N6LS 3,000 mg subcutaneously plus rHuPH20 subcutaneously plus LA-CAB, or continue with baseline ART. HIV-1 RNA of 50 copies/mL or higher at month 6 was the primary end point.
A total of 125 participants were enrolled, with 4% (2/50), 6% (3/49), and no individuals meeting the primary end point in the IV, subcutaneous, and baseline ART arms, respectively. Three people experienced confirmed virologic failure, in which no integrase inhibitor resistance was identified; however, 1 person was found to have resistance to N6LS. Participants randomized to the subcutaneous arm had a higher incidence of grade 3 injection site reactions (14%) compared with none in the IV arm. Results of the EMBRACE trial demonstrated that N6LS maintained viral suppression when administered intravenously or subcutaneously in combination with LA-CAB (and rHuPH20 in the subcutaneous arm), with a higher rate of injection site reactions in the subcutaneous arm.10
RIO Trial
The RIO study evaluated the effect of 2LS-bNAbs (ViiV Healthcare) on the time to viral rebound in people who were virally suppressed after starting ART with early HIV. This was a randomized, double-blind, placebo-controlled trial that enrolled individuals who initiated ART with early HIV to receive either 2 IV infusions of 3BNC117-LS and 10-1074-LS at least 20 weeks apart or placebo. ART was discontinued in all patients regardless of which arm the participants were assigned. The primary end point was time to viral rebound, defined as 6 consecutive HIV-1 RNA levels of more than 1,000 copies/mL or 2 HIV-1 RNA levels of more than 100,000 copies/mL, after discontinuation of ART. The study consisted of 68 participants, who were distributed evenly across the intervention and placebo arms.
A total of 25 individuals, 22 in the study drug arm and 3 in the placebo arm, demonstrated no evidence of viral rebound at week 20. Those on the study drug were 91% less likely to experience a rebound compared with placebo at week 20. A total of 13 and 7 individuals were randomized to the study drug arm who did not experience viral rebound at week 48 and 72, respectively. In addition to the primary end point of time to viral rebound, the authors investigated the safety of 3BNC117-LS and 10-1074-LS. They identified 9 serious AEs, including 1 death; however, none of these events were attributed to the study drug. The results of the RIO trial show the safety and sustained viral suppression with the use of bNAbs in individuals off ART compared with placebo.11
COVID-19 Virus Inhibitor
SCORPIO-PEP Trial
Fukushi et al presented results from the SCORPIO-PEP trial, which evaluated ensitrelvir (Shionogi), an oral SARS-CoV-2 3CL protease inhibitor, as post-exposure prophylaxis for household contacts of patients with confirmed COVID-19. The SCORPIO-PEP trial was a multicenter, double-blind, placebo-controlled trial that randomized the household contacts of individuals who tested positive for COVID-19 to receive ensitrelvir or placebo within 72 hours of the index patient’s symptom onset. More than 2,000 household contacts were enrolled, with 1,030 receiving ensitrelvir and 1,011 given placebo.
The primary end point—the proportion of household contacts who became COVID-positive (defined as a positive COVID-19 polymerase chain reaction test and experiencing at least 1 symptom) by day 10—occurred in 2.9% of those receiving ensitrelvir versus 9.0% in the placebo arm. AE rates were similar in both treatment arms. The study results show that ensitrelvir was effective in preventing the acquisition of SARS-CoV-2 in household contacts when started within 72 hours of symptom onset in the index patient.12
Discussion
CROI 2025 offered promising data from once-yearly PrEP options to new treatment options for people who are unable to tolerate an INSTI-based regimen to continued research investigating HIV cure. This meeting highlighted the incredible progress we have made over the past 40-plus years, current research, and the need for advocacy to ensure that we continue the progress we have made. The information and abstracts presented at CROI 2025 are available publicly via the CROI website, where the information discussed above and much more can be found.13
References
- Denison R. Martin Delaney Presentation: 40+ years of HIV: what’s changed, what hasn’t, what shouldn’t, what must. Presented at: CROI 2025; March 9, 2025; San Francisco, CA. bit.ly/4e0gZgs-IDSE
- Sunlenca. Package insert. Revised November 2024. Accessed May 6, 2025. gilead.com/-/media/files/pdfs/medicines/hiv/sunlenca/sunlenca_pi.pdf
- Jogiraju V, Pawar P, Yager J, et al. Pharmacokinetics and safety of once-yearly LEN [CROI Abstract 154]. In: Top Antivir Med. 2025;33(1).
- Jogiraju V, Pawar P, Yager J, et al. Pharmacokinetics and safety of once-yearly LEN: a phase 1, open-label study. Lancet. 2025;405(10485):1147-1154.
- Gill K, Ndlovu N, Brumskine W, et al. LEN pharmacokinetics, safety and efficacy in adolescents and adults in PURPOSE 1 [CROI ABSTRACT 120]. In: Top Antivir Med. 2025;33(1).
- Drumond JB, Sykes C, Schauer A, et al. Optimizing on-demand tenofovir sisoproxil fumarate/emtricitabine dosing in women for HIV prevention [CROI Abstract 157]. In: Top Antivir Med. 2025;33(1).
- Fox M, Mills AM, Ramgopal M, et al. Switch to DOR/ISL (100/0.25mg) qd from BIC/FTC/TAF: a blinded phase III study in adults with HIV-1 [CROI Abstract 204A]. In: Top Antivir Med. 2025;33(1).
- Fox M, Mngqibisa R, Velez JD, et al. Switch to DOR/ISL (100/0.25mg) qd from oral ART: an open-label phase III study in adults with HIV-1 [CROI Abstract 204B]. In: Top Antivir Med. 2025;33(1).
- Kityo C, Mambule IK, Sokhela SM, et al. Randomized trial of long-acting cabotegravir and rilpivirine in Africa (CARES): week 96 results [CROI Abstract 202]. In: Top Antivir Med. 2025;33(1).
- Leone P, Taiwo B, Gartland M, et al. VH3810109 (N6LS) efficacy and safety in adults who are virologically suppressed: the EMBRACE study [CROI Abstract 202]. In: Top Antivir Med. 2025;33(1).
- Fidler S, Lee MJ, Collins S, et al. RIO: a randomised placebo-controlled study of 2 LS-bNABs in people treated with early HIV [CROI Abstract 107]. In: Top Antivir Med. 2025;33(1).
- Fukushi A, Shinkai M, Clark TW, et al. Ensitrelvir to prevent COVID-19 in households: SCORPIO-PEP phase III placebo-controlled trial results [CROI Abstract 200]. In: Top Antivir Med. 2025;33(1).
- CROI 2025 Abstract Ebook. CROI 2025. Accessed June 6, 2025. croiconference.org/croi-2025-resources/
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Recap of CROI 2025: Key Takeaways for PrEP, HIV Treatment And Other Infectious Diseases
