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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
Disclaimer: The findings and conclusions in this presentation are those of
the presenter and do not necessarily represent the views of the CDC.
National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention
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Division of HIV/AIDS Prevention
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:
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
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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
15m
week 1
30m
2
Lube applications
2hrs
3
4hrs
4
24hrs
5
Specimen collections
48hrs
6
biopsy
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)
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7
Result: Inflammation 30 min after lubricant use
Example: Pro-inflammatory cytokine IL-6
in rectal secretions
Specimens
Lube
“acute”
specimens only
•
•
•
•
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IL-6 (pg/mg)
Control buffer
40
Lubricant
40
20
20
0
0
BL 15 30 2 4 24 48
m m h h h h
*
*
*p<0.0001
Wilcoxon ranksum test
median
BL 15 30 2 4 24 48
m m h h h h
Inflammation observed
Peak of inflammation 30 minutes after lube; subsided
Other cytokines upregulated as well
Detailed analysis reported at CROI ‘14
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
Phase II: SHIV risk after lube use
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 (AID50); Hypothesis: AID50 (ctrl) > AID50 (lube)
SHIVSF162P3 Infection?
Virus Shedding?
30 min
Lube
1
6
2
3
4
5
6
study week
SHIV Risk Results
+ one animal exposed, infected
Virus dose
(TCID*50)
25,000
5,000
2,500
1,250
500
250
50
12.5
1.25
- one animal exposed, uninfected
Buffer-treated
Lube-treated
+
++
-+++
-----------++
----+
---
---+
---+
---++
----++
---++
-----
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
Controls
Lube-treated
Plasma SHIVSF162P3
Rectal SHIV shedding
10
5
8
log10RNA
copies/mL
4
6
3
4
2
2
1
0
0
5
10
0
5
10
0
Weeks relative to peak viremia
8
0
+1
+2
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
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Discussion, Future Directions
•
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.
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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.
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