CROI 2024 Abstract eBook

Abstract eBook

Poster Abstracts

other than L. crispatus , most often L. iners (Figure). A L. crispatus -dominant microbiome was identified in 40.6% (4-wks) and 25.8% (8-wks) of participants in the LACTIN-V arm compared to 0% and 9%, respectively in the placebo arm (4-wks: p= 0.047; 8-wks: p= 0.096). The proportion of activated HIV target cells (CD3+/CD4+/CD38+/HLA-DR+/CCR5+ T cells) within the total T cell population (CD3+) increased from post-MTZ (0-wks) to 4-wks in the placebo arm (0.38 log 10 fold change) which was not observed in the LACTIN-V arm (0.03 median log 10 fold change; p = 0.009). The change in 13 cyto/chemokines between pre-MTZ and 4-wks was not statistically different by arm. Three quarters of participants in both arms "strongly agreed" or "agreed" they would use the product again. Adverse events (AEs) occurred in 77.8% of all participants. All local solicited AEs, most commonly vaginal discharge, were grade 1 with no significant difference by arm. Conclusion: LACTIN-V after MTZ increased L. crispatus colonization. Women treated with LACTIN-V had fewer activated cervical CD4+ HIV target cells than those in the placebo arm. We did not observe statistically significant differences in vaginal cytokines between arms. The product was safe and highly acceptable (clinicaltrials.gov:NCT0502221).

and elicit a long pharmacokinetic (PK) tail. In previous studies, investigational LAI Dolutegravir (DTG) formulations failed to sustain plasma DTG concentrations above the 4× PA-IC 90 beyond two months. To overcome these limitations, we propose to develop an ultra-long-acting (ULA) biodegradable and removable in-situ forming implant (ISFI) with DTG. Here, we performed long-term safety and PK studies evaluating time-to-completion (ongoing), depot removal at various intervals, PK tail, and drug biodistribution in plasma, tissues, and organs post implant removal. Methods: ISFIs were comprised of high concentration DTG (350 mg/mL) in a stable suspension. Female BALB/c mice (n=6) were injected subcutaneously (SC) with 50 µL of DTG ISFI formulation. Plasma samples were collected longitudinally to quantify drug concentration and TNF-α and IL-6 levels over ≥180 days. At day 30, 90, and 180 post administration, implants were removed via a small skin incision to quantify residual DTG and determine implant degradation over time. Plasma samples were collected longitudinally post implant removal to assess the PK tail. Biodistribution of DTG in plasma, organs, and SC tissue was assessed post implant removal. Results: ULA DTG ISFIs sustained plasma DTG concentrations well above the 4× PA-IC 90 for ≥180 days (Fig A) and with low plasma TNF-α and IL-6 concentrations. Significant decrease in plasma DTG was achieved within 1 week post implant removal with 17-, 22-, and 24-fold decrease for implants removed at 30, 90, and 180 days respectively; however, complete elimination of DTG was not yet achieved post depot removal (Fig B). Tissue DTG concentrations revealed high DTG accumulation in the proximal SC tissue as a likely explanation of the long PK tail. ISFIs were easily retrievable at 30, 90, and 180 days post-injection with ~69%, ~45%, and ~41% DTG remaining and ~13%, 49%, and 58% decrease in implant mass at 30, 90, and 180 removal respectively. Conclusion: Here we report a biodegradable, removable, and ULA DTG ISFI and demonstrated safety and plasma PK for ≥180 days and assessed the PK tail. We demonstrated the first ULA injectable of DTG for HIV PrEP that can be removed if needed. This comprehensive study further characterized the PK tail via a full biodistribution, and future directions include safety, PK and efficacy studies in non-human primates. 1138 RCT of Lactobacillus crispatus CTV-05 to Lower HIV Risk in Young South African Women Anke Hemmerling 1 , Caroline Mitchell 2 , Suuba Demby 2 , Musie Gebremichael 2 , Joseph Elsherbini 2 , Jiawu Xu 2 , Nondumiso Xulu 3 , Johnathan Shih 2 , Krista L. Dong 2 , Vaneshree Govender 4 , Vanessa S. Pillay 2 , Thomas P. Parks 5 , Thumbi Ndung'u 3 , Doug S. Kwon 2 , Craig R. Cohen 1 1 University of California San Francisco, San Francisco, CA, USA, 2 Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA, 3 University of KwaZulu-Natal, Durban, South Africa, 4 The Aurum Institute, Johannesburg, South Africa, 5 Osel, Inc, Mountain View, CA, USA Background: Absence of vaginal lactobacilli and corresponding genital inflammation is associated with adverse reproductive health outcomes, including female HIV acquisition. In women in sub-Saharan Africa, a high prevalence of vaginal dysbiosis may offer an opportunity to develop Lactobacillus crispatus biotherapeutics for HIV prevention. Methods: We conducted a randomized, placebo-controlled, trial of cis-women age 18-23 with Nugent score 4-10 on vaginal Gram stain who completed a course of oral metronidazole (MTZ). Women were randomized (2:1) to use vaginal applicators containing 2X10 9 CFU of L. crispatus CTV-05 (LACTIN-V) or placebo for 4 weeks. Vaginal samples were collected prior to MTZ, at enrollment (0-wks), immediately after study product (4-wks), and 4 weeks later (8-wks). The vaginal microbiota was assessed by 16S rRNA gene sequencing, endocervical immune cells by flow cytometry and vaginal fluid inflammatory markers by Luminex. Results: 45 black South African women were randomized to LACTIN-V (N=32) and placebo (N=13). At enrollment, immediately after MTZ, 54.8% (LACTIN V) vs. 66.7% (placebo) presented with Lactobacillus -dominant microbiota

Poster Abstracts

1139 A Dual Prevention Pill for HIV and Pregnancy Prevention: A Pilot Study Among Young Women in Zimbabwe Barbara A Friedland 1 , Brady Zieman 1 , Sanyukta Mathur 1 , Irene V. Bruce 1 , Adlight Dandadzi 2 , Petina Musara 2 , Caroline Murombedzi 2 , Lisa B. Haddad 1 , Nyaradzo Mgodi 2 1 Population Council, New York, NY, USA, 2 University of Zimbabwe, Harare, Zimbabwe Background: Effective use of oral pre-exposure prophylaxis (PrEP) has been sub-optimal among young women in sub-Saharan Africa at greatest risk of HIV. We hypothesized that a single dual prevention pill (DPP) combining PrEP and an oral contraceptive (OC) would be preferred, acceptable and increase PrEP adherence compared to PrEP alone. Methods: We enrolled 30 HIV-uninfected, non-pregnant, 16-24-year-old cisgender females currently using OCs in a crossover study in Harare, Zimbabwe, who were randomized (1:1) to the order of using an over-encapsulated DPP and 2 separate pills (PrEP, OC) for 3 28-day cycles each. We assessed if the proportion preferring the DPP vs 2 separate pills was >0.5 (exact binomial test) and the effect of regimen on 4 acceptability domains: use attributes, product attributes, side-effects, impact on sex (Wilcoxon signed-rank tests). We compared adherence by regimen and sequence (generalized estimating equations) via self-report and via tenofovir diphosphate (TFV-DP) levels in dried blood spots indicative of ≥4 doses per week (≥500 fmol/punch at Month 1, 700 fmol/punch at Months 2-6). Population Council Institutional Review Board and 6 ethics committees/regulatory bodies in Zimbabwe approved the protocol. Results: 26/30 women (mean age, 19.4 years) completed the study (Nov 2022-Sep 2023); 4 terminated early. Most were married (47%)/divorced (27%), 97% had completed secondary school, 93% had ≥ 1 child, 84% were somewhat/ very worried about getting HIV in the next 3 months, and 93% thought it was somewhat/very important to avoid pregnancy. At study exit, preference for the DPP was 64% vs 36% for 2 separate pills (p=0.16). Most rated both regimens as acceptable, with no differences between regimens in any domain (all p>0.05). Self-reported adherence was high (>96%), yet 17-18% were adherent to the 2 pills and DPP, respectively, based on TFV-DP levels, with mean TFV-DP levels only 384 fmol/punch (2 pills) and 392 fmol/punch (DPP). There was no difference in adherence by regimen or treatment period (all p>0.05). Adherence

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