1. Microbicides A Scientific Update
Ian McGowan MD PhD FRCP
Center for Prevention Research
David Geffen School of Medicine at UCLA

2. Overview Mucosal transmission of HIV infection
The microbicide pipeline
RT-Inhibitor microbicides
Combination microbicides
Formulation science
Rectal microbicides
Microbicides and PREP
Microbicide development and the community

3. Mucosal Transmission of HIV Infection

4. Mucosal Targets for HIV Infection
Shattock and Moore, Nat Rev Microbiol, 2003

5. Not Just the Mucosa…. HIV Increased virus replication and spread
Afferent
lymphatics
Increased
virus
replication
and spread
Draining
lymphoid tissue

6. The Microbicide Pipeline

7. Microbicide Mechanisms of Action
Killing or inactivating pathogens
Creating physical barriers
Strengthening body’s natural defenses
Preventing viral entry into cells
Inhibiting viral replication

8. Viral Targets for Microbicides
Shattock and Moore, Nat Rev Microbiol, 2003

9. Preclinical Microbicide Candidates
Uncertain
Defense
Enhancers
Entry / Fusion
Inhibitors
Ciclopiroxolamine
Praneem polyherbal
MucoCept HIV
Lime Juice
Acidform™ gel
Cellulose sulfate
Cellulose acetate
Carraguard
VivaGel
Dextrin-2 sulfate
Cyanovirin-N
C85FL
K5-N, OS(H)
SAMMA
Invisible condom
Novaflux
Porphyrins
PSC Rantes
BMS-806
BMS
CMPD167
C52L
Tobacco-derived antibodies / fusion proteins
Anti-ICAM-1 Ab mAb B12, 2G12
mAb 2F5, 4E10
CD4 IgG2
T20
T-1249
SCH-C, D
UK-427,857
TAK 779
AMD3100
SFD-1
Bicyclams
Aptamers
Membrane
Disruption
Replication
Alkyl sulfates
Savvy (C31G)
Beta cyclodextrin
Tenofovir
TMC-120
UC-781
MIV-150
MC1220
C-731, 988

10. Microbicides in Clinical Trials
Phase
Membrane
Disruption
Defense
Enhancers
Entry Fusion
Inhibitors
Replication 1
AcidformTM
Lime Juice
Lactobacillus
VivaGelTM
Cellulose acetate
PC-815
UC-781
TMC-120
1/2
Invisible
CondomTM 2
(Praneem)
Tenofovir
2/2B
C31G
BufferGelTM
PRO-2000
(0.5% & 2%) 3
Carraguard®
Cellulose Sulfate

11. RT-Inhibitor Microbicides

12. RT-Inhibitor Microbicides
Phase
Sponsor
Tenofovir 2
Gilead Sciences
UC-781 1
Biosyn, Inc.
TMC-120
IPM/Tibotec
MIV-150
(PC-815)
(1)
Population Council

13. The Issues Resistance Pharmacokinetics RT Combinations
Seroconversion on study
Exposure in chronically infected subjects
Community implications
Pharmacokinetics
Plasma
Tissue
RT Combinations
Possible synergy

14. HPTN-050 Group Category Tenofovir Dose N A1
Sexually abstinent HIV-negative
0.3% QD 12 A2
1.0% A3
BID A4 B C
Sexually abstinent HIV-positive D
Sexually active HIV-positive
Mayer et al. AIDS 2006

15. HPTN-050 PK Mayer et al. AIDS 2006
HIV was detected in the plasma of 13/24 HIV+ women at Day 0 and 12/24 at Day 14, but in CVL of only 2 women at Day 0 and none at Day 14.
No new resistance mutations evolved in plasma or CVL after 14 days of TFV gel use. No pt. had high level TFV mutations e.g K65R
3 women had plasma mutations associated with low level TFV resistance at Days 0 and 14 (M41L, L210M, +/- T215 I/Y), but 2 also had M184V, which would increase TFV susceptibility.
Mayer et al. AIDS 2006

16. Resistance Issues
What is the relationship between systemic absorption and the development of resistance?
Will the risk be altered by the presence or absence or oral combination therapy?
Could resistance occur during seroconversion?
How should we assess resistance?
What are the therapeutic implications?

17. The Geneva “Consensus” September 2004
RT-Microbicide studies should move ahead in HIV-1 seronegative populations.
Studies in HIV-1 seropositive subjects are also important but should be considered with caution.

18. Combination Microbicides

19. Combination Microbicides
Rhesus macaque challenge model
BMS
Binds to gp120
CMPD167
Binds to CCR5
C52L
Inhibits gp41 mediated fusion
Veazey et al. Nature 2005

20. CMPD167 [5.0 mM] $$$$$$$$ Veazey et al. Nature 2005 Group Infection
No Infection
CMPD167 [5.0 mM] + BMS [5.5 mM] +
C52L [1.5 mM]
+ + +
BMS [2.0 mM] + C52L [1.5 mM]
CMPD167 [5.0 mM] + BMS [2.0 mM]
CMPD167 [1.0 mM] + C52L [1.5 mM] +
CMPD167 [5.0 mM] + C52L [1.5 mM]
+ +
CMPD167 [5.0 mM] + Mannan [50 mg ml-1]
BMS [5.5 mM] Challenge delay [2-6 h]
BMS [5.5 mM]
CMPD167 [5.0 mM] Challenge delay [2-12 h]
CMPD167 [5.0 mM]
CMPD167 [1.0 mM]
Mannan [50 mg ml-1]
Controls
CMPD167
[5.0 mM]
$$$$$$$$
Veazey et al. Nature 2005

21. Formulation Science

22. Formulation Innovation
First generation of formulations were not optimized for vaginal or rectal use
2nd generation products being developed on the basis of:
Stability
Rheological properties
Absorption
Local environment (rectum vs. vagina)
Acceptability
Broader range of delivery systems
Gels, foams, films, suppositories, and rings

23. Imaging Where the Product Goes
Charles Lacey MD, & Craig Hendrix MD

24. TMC120 Vaginal Rings
                                                         
Malcolm et al., Journal of Antimicrobial Chemotherapy, 2005

25. Rectal Microbicides

26. Why Develop Rectal Microbicides?
Anal intercourse (AI) is the primary risk factor for HIV transmission among MSM.
The prevalence of AI among the heterosexual population is underappreciated and represents a significant risk for HIV transmission.
Much AI is unprotected.
The rectal mucosa is highly vulnerable to HIV infection.
Based on the N-9 experience, vaginal products may not be suitable for rectal administration.

27. Prevalence of AI International Studies
South Africa: Lane T, Pettifor A, Pascoe S, Fiamma A, Rees H. Heterosexual anal intercourse increases risk of HIV infection among young South African men. AIDS Jan 2;20(1):123-5.
Ramjee G GE. Prevalence of HIV Among Truck Drivers Visiting Sex Workers in KwaZulu-Natal, South Africa. Sex Transm Dis 2002; 29:44-9 Anal sex was practiced by 42% of the men and only 23% of these men reported condom use during anal sex
China: Liu H, Xie J, Yu W, Song W, Gao Z, Ma Z, Detels R. J Acquir Immune Defic Syndr Hum Retrovirol Sep 1;19(1):80-8.
Peru: Caceres C, Oss V, Marin B, Hudes E, al e. Young People and the structure of sexual risks in Lima. AIDS 1997;11((suppl 1)):S67-77.

28. Prevalence of Anal Receptive Sex
Population N
Prevalence of AI
Reference
MSM in EXPLORE study
4295
48 – 54%
Koblin et al. 2003
High risk women
1268
32%
Gross M et al. 2000
College students
210
20%
Civic D 2000
US Survey
15 – 44 years
NSFG
12,571
35-40%
Mosher WD et al. 2005
Californian residents
3545
6-8%
Erickson PI et al. 1995

29. US HIV Infection by Transmission Category* (2004)
(%)
MSM contact
18,203 47
IDU
5,962 15
MSM + IDU
1,372 4
High Risk Heterosexual contact
12,683 33
Other / not identified
335 1
Total
38,553
This slide shows the distribution of transmission categories for HIV/AIDS cases diagnosed in 2004 in 35 areas with confidential name-based HIV infection surveillance.
Approximately 47% of the 38,553 HIV/AIDS cases diagnosed in 2004 among adults and adolescents were attributed to male-to-male sexual contact. An additional 4% of were attributed to male-to-male sexual contact and injection drug use.
Injection drug use accounted for 15% of HIV/AIDS diagnoses, and high risk heterosexual contact accounted for another 33%.
The following 35 areas have had laws or regulations requiring confidential name-based HIV infection surveillance since at least 2000: Alabama, Alaska, Arizona, Arkansas, Colorado, Florida, Idaho, Indiana, Iowa, Kansas, Louisiana, Michigan, Minnesota, Mississippi, Missouri, Nebraska, Nevada, New Jersey, New Mexico, New York, North Carolina, North Dakota, Ohio, Oklahoma, South Carolina, South Dakota, Tennessee, Texas, Utah, Virginia, West Virginia, Wisconsin, Wyoming, Guam and the US Virgin Islands.
The data have been adjusted for reporting delays and cases without risk factor information were proportionally redistributed.
* CDC data from 35 areas with HIV surveillance

30. UK HIV Infection by Transmission Category
Heterosexual subcategories
Sex between men
This slide shows the total number of diagnoses of HIV in individuals infected through sex between men and women, broken down by sub-category of probable country of infection as well as exposure. Numbers of cases are shown on the vertical axis and the year of diagnosis on the horizontal axis.
The vast majority of those infected through sex between men and women, have been infected in Africa with large increases in recent years. Other increases include those infected in the Caribbean and Europe.
Individuals infected through sex between men and women in the UK, the majority will have had a partner infected abroad mainly Africa, but there are some with partners also infected in the UK – about 20 per year and rising. These individuals will have had heterosexual contact with “high risk” partners in other words; partner(s) who were men who have sex with men and injecting drug users.
Reporting delay will mean that numbers particularly for recent years, will continue to rise. Furthermore, reports indicating heterosexual exposure but with insufficient information to sub-categorize and cases reporting heterosexual exposure in the UK with no evidence of “high risk” partners, are followed up by a research nurse in order to clarify exposure details.
Data on the breakdown of the heterosexual transmission by sub-category of probable country of infection and exposure is updated every three months and published on the HPA website in a set of quarterly surveillance tables – the data behind this slide can be found in Tables?

31. Rectosigmoid Anatomy

32. Modeling Rectal Microbicide Efficacy
0.5
1.5 1 2
Efficacy
0.2
0.4
0.6
0.8 R
No microbicide use
10% microbicide use
30% microbicide use
50% microbicide use R R
Adapted from Breban et al. (In Press)

33. Rectal Safety Assessment
Vaginal Microbicide
(Cellulose sulfate)
Animal
Toxicology
Phase 1
Rectal Safety
Rectal Microbicide
(Product X)
Combination Microbicide
(Tenofovir)
Preclinical Evaluation
Cell lines
Explant studies
Animal models
Animal toxicology
Human studies
Phase 1
Phase 2
Phase 2B/3

34. Rectal Safety of Vaginal Microbicides
Candidate
Murine
Primate
Explant
Human
N-9
+++
Buffergel
Neg ?
C31G
Carraguard
Cellulose sulfate
PRO 2000
SPL7013
Octylglycerol
PMPA
TMC120
UC781

35. Where to Protect and What to Measure?
Hendrix et al., 2004

36. HPTN-056 Study Groups Group 1 Group 2 Group 3 Group 4
HIV-1 negative / anal receptive (N = 4)
Group 2
HIV-1 negative / not anal receptive (N = 4)
Group 3
HIV-1 positive / anal receptive + plasma viral load
> 10,000 (N = 4)
Group 4
HIV-1 positive / anal receptive + plasma viral load < 50 (N = 4)

37. HPTN 056 Study Design Week - 2 + 2 + 4 Screening Baseline Week 2
+ 2
+ 4
Screening
Baseline
Week 2
Week 4
Consent
Physical
Anoscopy
Rectal GC/CH
HIV Ab
CD4 / Viral load
Sigmoidoscopy
Intestinal biopsy at 10cm and 30cm
Cell isolation and flow cytometry
Tissue cytokines
Rectal immunoglobulins
Tissue / rectal secretion viral load

38. Microbicides and PREP

39. PREP – The Key Issues Availability of efficacy data for PREP
Long term safety in seronegative subjects
Tissue PK profile at site of infection
Potential for differential resistance patterns
Animal studies of PREP inconclusive
TDF – negative
TDF / FTC - positive
Consumer preference
Cost

40. Microbicide Development and the Community

41. Regulatory Challenges
Kaplan et al. Science. 2004

42. Community Resistance
Mills et al., BMC Int Health Hum Rights 2005

43. Grant et al. Science. 2005

44. Phase 3 Study of Savvy in Ghana
"The reason we decided to stop the trial was that the group of women who volunteered to participate had such a low incidence of HIV that there was no way for this study to show whether use of Savvy, compared with a placebo gel, would prevent HIV or not,"
Leigh Peterson FHI

45. A New Network?

46. MTN Clinical Trials Portfolio

47. Thank You!
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