Acute Cytotoxicity but No Increased SHIV Infection Risk after Rectal Application of a Highly Osmolar

Personal Lubricant in an Animal ModelEllen 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 PreventionDivision of HIV/AIDS Prevention1

Disclaimer: The findings and conclusions in this presentation are those of the presenter and do not necessarily represent the views of the CDC.

Goal: To determine whether a commercially available lubricant causes rectal cytotoxicity and increases HIV/ SHIV risk in a macaque model.

Study Goal and Design

2

Design:a. Purchased a lubricant with osmolality of 8,064

mOsm/kg, pH of 4.4, poly-quaternium 15+

b. Phase I: cytotoxicity evaluation in n=9 cynomolgus macaques

c. Phase II: SHIV infection risk evaluation in n=21 macaques

Phase I: Cytotoxicity Evaluation

Experimental Details:• Non-traumatic rectal lube; 3 mL internal + 2 mL

external• Specimens: rectal swabs (cytokines, pH, bacteria),

washes (sloughing, blood); biopsies (tissue architecture, infiltration) 3

Goals: • To develop animal model• To determine rectal cytotoxicity, i.e.,

inflammation, bleeding, tissue damage• To establish time course of lube effects

Lube applications biopsySpecimen collections

1 2 3 4 5 6week

7

48hrs15m 30m 4hrs 24hrs2hrs

Result: Inflammation 30 min after lubricant use

Control buffer Lubricant

IL-6

(pg/

mg)

0

20

40

BL15m

30m

2h

4h

24h

48h

BL15m

30m

2h

4h

24h

48h

0

20

40

median“acute” specimens only

***p<0.0001Wilcoxon rank-sum testLube

Specimens

4

Example: Pro-inflammatory cytokine IL-6 in rectal secretions

• Inflammation observed • Peak of inflammation 30 minutes after lube; subsided• Other cytokines upregulated as well• Detailed analysis reported at CROI ‘14

Other Results

LubricantControl buffer

after 6 applicationsweek 3

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• 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

Phase II: SHIV risk after lube use

1 2 3 4 5 6 study week

30 min

Lube

Infection?Virus Shedding?

SHIVSF162P3

6

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)

SHIV Risk Results

Virus dose (TCID*50)

Buffer-treated Lube-treated

25,000 + - -5,000 + + - - +2,500 - + + + - - - +1,250 - - - - - - - + +500 - - - - - - + +250 - - - - - - - + + - - - + +50 - - - - + - -

12.5 - - - - -1.25   - - -

+ 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)

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Continued Lube treatment does not affect infection course

0 +1 +2012345

Rectal SHIV shedding

Weeks relative to peak viremia0 5 10

log 1

0RN

A co

pies

/mL

02468

10

0 5 10

Plasma SHIVSF162P3

Controls Lube-treated

8

• 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

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Summary

• Results from the infection risk study were unexpected because 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

Discussion, Future Directions

11

Co-authors:Sundaram A Vishwanathan Richard J WolitskiWei LuoCharles E RoseDianna M Blau Monica R MorrisTheodros TsegayeTara C HenningSherif R ZakiDavid A GarberLeecresia T JenkinsDorothy L Patton, University of WashingtonR. Michael HendryJanet 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.