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Ellen Kersh, PhD Microbiologist, Preclinical Evaluation Team,

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  1. Acute Cytotoxicity but No Increased SHIV Infection Risk after Rectal Application of a Highly Osmolar Personal Lubricant in an Animal Model Ellen Kersh, PhD Microbiologist, Preclinical Evaluation Team, Laboratory Branch, DHAP, NCHHSTP, CDC IRMA Webinar, June 4, 2014 National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention Division of HIV/AIDS Prevention Disclaimer: The findings and conclusions in this presentation are those of the presenter and do not necessarily represent the views of the CDC. 1

  2. Study Goal and Design • Goal: • To determine whether a commercially available lubricant causes rectal cytotoxicity and increases HIV/ SHIV risk in a macaque model. • Design: • Purchased a lubricant with osmolality of 8,064 mOsm/kg, pH of 4.4, poly-quaternium 15+ • Phase I: cytotoxicity evaluation in n=9 cynomolgus macaques • Phase II: SHIV infection risk evaluation in n=21 macaques 2

  3. Phase I: Cytotoxicity Evaluation • Goals: • To develop animal model • To determine rectal cytotoxicity, i.e., inflammation, bleeding, tissue damage • To establish time course of lube effects biopsy Lube applications Specimen collections 15m 30m 2hrs 4hrs 24hrs 48hrs week 1 2 3 4 5 6 7 • Experimental Details: • Non-traumatic rectal lube; 3 mL internal + 2 mLexternal • Specimens: rectal swabs (cytokines, pH, bacteria), washes (sloughing, blood); biopsies (tissue architecture, infiltration) 3

  4. Result: Inflammation 30 min after lubricant use Example: Pro-inflammatory cytokine IL-6 in rectal secretions Control buffer Lubricant * * 40 40 Specimens *p<0.0001 Wilcoxon rank- sum test Lube IL-6 (pg/mg) 20 20 “acute” specimens only median 0 0 BL 15 m 30 m 2 h 4 h 24 h 48 h BL 15 m 30 m 2 h 4 h 24 h 48 h • Inflammation observed • Peak of inflammation 30 minutes after lube; subsided • Other cytokines upregulated as well • Detailed analysis reported at CROI ‘14 4

  5. Other Results • Tissue sloughing: Rectal washes had epithelial tissue pieces, associated with blood • No change in pH • No striking changes in bacterial microflora • Biopsies showed limited inflammatory cell infiltrates at 30 minutes post lube • Biopsies also showed healing within 7 days Control buffer Lubricant after 6 applications week 3 5

  6. Phase II: SHIV risk after lube use SHIVSF162P3 Infection? Virus Shedding? • Goals: • To determine SHIV risk of rectal lube use at a time point with demonstrated inflammation (30 min) • Design: • Compared SHIV infection risk in n=21 macaques, in lube and control buffer groups • Determined virus dose with 50% of animals infected (AID-50); Hypothesis: AID50 (ctrl) > AID50 (lube) 30 min Lube study week 1 2 3 4 5 6 6

  7. SHIV Risk Results + one animal exposed, infected - one animal exposed, uninfected AID50 (control) =1,721 TCID50(95% CI 414, 7165) AID50 (lube)=196,336 TCID50 (95% CI 1.0, 4.5x1010) Not different (p = 0.4467; logistic regression models) 7

  8. Continued Lube treatment does not affect infection course Controls Lube-treated Plasma SHIVSF162P3 Rectal SHIV shedding 10 5 8 4 log10RNA copies/mL 6 3 4 2 2 1 0 0 0 +1 +2 0 5 10 0 5 10 Weeks relative to peak viremia 8

  9. Summary • One hyperosmolar, low pH lubricant induced short-lived rectal cytotoxicity in an animal model • This was not associated with increased SHIV infection risk • Study limitations: • Only one product • Only non-traumatic lube application • Animal models for increased risk testing have limits in sensitivity 9

  10. Discussion, Future Directions • Results from the infection risk study were unexpectedbecause of cytotoxicity • More data could clarify the real-world effects of lubricant use • The employed non-human primate model may not have been sufficiently suitable for detecting enhanced infection risk. • We plan to evaluate additional lubricants in additional cytotoxicity and risk models. 10

  11. Co-authors: Sundaram A Vishwanathan Richard J Wolitski Wei Luo Charles E Rose Dianna M Blau Monica R Morris Theodros Tsegaye Tara C Henning Sherif R Zaki David A Garber Leecresia T Jenkins Dorothy L Patton, University of Washington R. Michael Hendry Janet M McNicholl Disclaimer: The findings and conclusions in this presentation are those of the presenter and do not necessarily represent the views of the CDC. 11