CROI 2020 Abstract eBook

Abstract eBook

Poster Abstracts

Results: CVS cytokines clustered separately at baseline, with 17/28 higher in ART- than ART+ women, including IL1b, IL1a, IL6, MIP1a, MIP1b, RANTES, IP10, and Eotaxin. In ART- only, genital tract VL (gVL) correlated positively with IL1b (R=0.72; 95%CI 0.55-0.84) and IL8 concentrations (R=0.66; 95%CI 0.47-0.80). None of the cytokines predicted gVL in ART+. Compared to baseline CVS, cIUCD insertion in ART- women resulted in significantly elevated concentrations of IL-6, MCP-1, MIP-1a, MIP-1b, RANTES, GCSF, IL-15 at 3-month follow-up, of which MCP1, MIP1a, and GCSF remained high at 6m. A more significant increase in CVS cytokines was observed after cIUCD insertion in ART+WLHIV, with 19/29 cytokines elevated at 3-months, of which 15 remained high at 6m. In contrast, among ART- women, LNG-IUS resulted in suppression of IL12p70, IP10, VEGF, GM-CSF at 3-months (IL12p70 and VEGF remaining low at 6 months). In ART+ women, LNG-IUS had a more moderate effect than cIUCD, with 6/28 cytokines elevated at 3 months, of which half resolved by 6 months. Despite differences in cytokine changes in cIUCD compared to LNG-IUS users, overall profiles did not differ significantly by IUCD type by PCA. PLSDA suggested that MCP1 best differentiated IUCD groups, irrespective of ART status. Conclusion: These data suggest that cIUCD insertion was associated with increased genital cytokine concentrations in HIV+ women irrespective of ART status. LNG-IUS was initially less inflammatory, particularly in ART- women. Although certain genital cytokines were positively associated with gVL in ART-, changes in inflammatory profiles associated with either IUCD did not increase gVLs in ART+. 1065 MOLECULAR PERTURBATIONS INDUCED BY DMPA, COPPER IUD, AND LNG IMPLANT IN ECHO TRIAL Prachi M. Gupta 1 , Sydney A. Nelson 1 , Gregory K. Tharp 1 , Maricianah A.Onono 2 , Gonasangrie Nair 3 , Thesla Palanee-Phillips 4 , Hossaena Ayele 5 , Laura Noël- Romas 5 , Kelly Arnold 6 , Jared Baeten 7 , Jo-Ann Passmore 8 , Adam Burgener 5 , Heather Jaspan 8 , Renee Heffron 7 , Steven E. Bosinger 1 1 Yerkes National Primate Research Center, Atlanta, GA, USA, 2 Kenya Medical Research Institute, Nairobi, Kenya, 3 Desmond Tutu HIV Foundation, Cape Town, South Africa, 4 Wits Reproductive Health and HIV Institute, Johannesburg, South Africa, 5 University of Manitoba, Winnipeg, MB, Canada, 6 University of Michigan, Ann Arbor, MI, USA, 7 University of Washington, Seattle, WA, USA, 8 University of Cape Town, Cape Town, South Africa Background: Previous studies have suggested alterations in mucosal immunity in women using hormonal contraceptives, specifically intramuscular depot medroxyprogesterone acetate (DMPA-IM). The results of the ECHO trial found that women randomized to DMPA-IM, copper intrauterine device (IUD), and the levonorgestrel (LNG) implant experienced similar HIV incidence rates. Transcriptomics and proteomics of genital samples, collected fromwomen in the ECHO trial, were used to characterize molecular perturbations induced in the vaginal compartment by initiation of contraception. Methods: Endocervical cytobrush and vaginal soft cups were collected from a total of 202 women at enrollment and after one month of initiating DMPA, LNG or IUD for RNA-Seq and proteomic analysis. RNA exome capture beads were used to generate enriched libraries for Illumina based RNA-Seq. Paired analyses were carried out for each study-arm using DESeq2, with participant ID and visits as input factors. Gene set enrichment analysis (GSEA) was conducted for each study-arm to identify gene-sets or pathways specifically enriched in one or more study-arm. Results: The number of differentially expressed genes detected between month 1 and enrollment visits were 505, 314, and 83 among women randomized to DMPA-IM, LNG and IUD, respectively. Women using DMPA-IM or LNG showed a higher perturbation in vaginal gene-expression relative to IUD users. GSEA demonstrated that prevalent antiviral signaling pathways (IFNA, IFNG, KEGG RIG-I like and T-cell signaling), had similar enrichment across the three study-arms. Gene-sets comprising genes related to inflammatory responses, NFkB target genes and serpins were differentially induced in the three study-arms. Mass spectrometry based proteomic analysis of mucosal fluid identified 1021 human proteins in the (150) participants profiled, identifying proteins involved in inflammation, antimicrobial activity, epithelial function, and humoral immunity. Conclusion: These data demonstrate enhanced perturbation of inflammatory pathways among women using DMPA-IM and LNG that provide mechanistic insights into the biological impact of these contraceptives. While the magnitude and/or durability of these changes do not ultimately impact HIV susceptibility, they may have implications for other sexually transmitted infections.

or MIP-1b, suggesting that chemotaxis was not the major mechanism for the DMPA-IM driven accumulation of target cells in the genital tract. Conclusion: For the first time in a randomised clinical trial, we demonstrate that DMPA-IM, but not the copper IUD nor LNG-implant, induced an increase in the abundance of potentially infectable Th17 HIV target cells expressing CD38, CCR5 and a4b7 in the female genital tract. Despite their possible susceptibility to HIV infection, Th17 cells play an important role in epithelial barrier repair. It is therefore interesting to speculate whether increased Th17 cell frequency and activation status associated with DMPA-IM reflect epithelial barrier damage. 1063 INCREASED GENITAL INFLAMMATION IN WOMEN RANDOMIZED TO COPPER IUD IN THE ECHO TRIAL Tanko F. Ramla 1 , Rubina Bunjun 1 , Shameem Jaumdally 1 , Smritee Dabee 1 , Anna- Ursula Happel 1 , Hoyam Gamieldien 1 , Rushil Harryparsad 1 , Marisiana A. Onono 2 , Gonasangrie Nair 3 , Thesla Palanee-Phillips 4 , Caitlin W. Scoville 5 , Jared Baeten 5 , Renee Heffron 5 , Heather Jaspan 1 , Jo-Ann Passmore 1 1 University of Cape Town, Cape Town, South Africa, 2 Kenya Medical Research Institute, Kisumu, Kenya, 3 Desmond Tutu HIV Foundation, Cape Town, South Africa, 4 Wits Reproductive Health and HIV Institute, Johannesburg, South Africa, 5 University of Washington, Seattle, WA, USA Background: The inflammatory milieu of the lower female genital tract contributes substantially to HIV acquisition risk. In the randomized ECHO trial, we investigated whether the intramuscular injectable depo- medroxyprogesterone acetate (DMPA-IM) influenced genital inflammation, relative to the levonorgestrel implant (LNG-Implant) and non-hormonal copper intrauterine device (Copper-IUD). Methods: Cervicovaginal secretions (CVS) were collected via menstrual cups at three sites (Cape Town and Johannesburg [South Africa], and Kisumu [Kenya]) fromwomen who participated in the ECHO trial comparing HIV incidence rates among women randomized (1:1:1) to different types of contraceptives. For this sub-analysis, concentrations of 27 cytokines were measured by Luminex in matched CVS from 190 women (DMPA-IM: n=67; LNG-Implant: n=63; Copper- IUD: n=60) with samples collected at baseline (pre-contraceptive initiation), 1 and 6 months post-contraceptive initiation. Results: After adjusting for multiple comparisons, genital cytokine concentrations were significantly elevated at 6 months post-contraceptive initiation in women randomized to Copper-IUD compared to matched baseline. These included IL-1b (p=0.0002), IL-6 (p=0.0003), TNF-a (p=0.0002), MIP-1a (p=0.0002), MIP-1b (p=0.0003), IP-10 (p=0.005) and IL-8 (p=0.001). In contrast, there were no significant changes in cytokine levels in DMPA-IM and LNG-Implant users at 6 months post-contraceptive initiation. No changes in CVS cytokines were observed at 1 month post-contraceptive initiation in any arm. Conclusion: Overall, these results show that use of the Copper-IUD non- hormonal contraceptive option in ECHO, appeared to be more inflammatory than the hormonal contraceptives DMPA-IM or LNG-Implant. Despite the ECHO trial showing no significant difference in HIV incidence between the three contraceptive arms, our finding of late rather than early genital inflammation in women using the Copper-IUD requires further investigation. 1064 ELEVATED GENITAL CYTOKINES IN HIV-INFECTED WOMEN USING COPPER AND LEVONORGESTREL IUDs Jo-Ann Passmore 1 , Musalula Sinkala 1 , Nai-Chung Hu 1 , Shameem Jaumdally 1 , Hoyam Gamieldien 1 , Smritee Dabee 1 , Heidi Jones 2 , Donald R. Hoover 3 , Nontokozo Langwenya 1 , Landon Myer 1 , Catherine S. Todd 4 1 University of Cape Town, Cape Town, South Africa, 2 City University of New York, New York, NY, USA, 3 Rutgers University, Piscataway, NJ, USA, 4 FHI 360, Durham, NC, USA Background: Intrauterine contraceptive devices (IUCD) may increase genital inflammatory cytokine concentrations in HIV+ women despite antiretroviral therapy (ART). We compared the effect of copper (cIUCD) versus levonorgestrel intrauterine system (LNG-IUS) on genital cytokines in both ART using (ART+) and non-ART using (ART-) women. Methods: In a secondary analysis of an RCT, menstrual cup cervicovaginal secretions (CVS) were collected in ART- and ART+ women randomized 1:1 to cIUCD or LNG-IUS. 28 cytokines were measured in 104 age-matched participants with CVS collected at enrolment and then 3m and 6m post-IUCD insertion (ART- n=48; ART+ n=56). We compared cytokine clustering by IUCD and ART use by Principle Component Analysis (PCA) and Partial Least Squares Discriminant Analysis (PLSDA).

Poster Abstracts

CROI 2020 400