Rectal Mucosa Ian McGowan MD DPhil FRCP University of Pittsburgh, PA, USA 21st July, 2018 AIDS2018 Amsterdam.

Slides:



Advertisements
Similar presentations
Recommendations for STD Clinical Preventive Services for Persons Living with HIV/AIDS.
Advertisements

Dr. Carol Odula (Obs./Gyn.) May 7 th 2013 Preparing for pre-exposure prophylaxis (PrEP) to prevent HIV infection.
Rectal microbicides Bridget Haire International Rectal Microbicides Advocates (IRMA)
Preparing for pre-exposure prophylaxis (PrEP) to prevent HIV infection James Wilton Project Coordinator Biomedical Science of HIV Prevention
Journal Club Alcohol, Other Drugs, and Health: Current Evidence July–August 2013.
HIV in Texas: The Ways Forward Ann Robbins Manager of HIV/STD Prevention and Care Department of State Health Services.
A. D. Smith, 1 A. Muhaari 2 E. M. van der Elst 2 D. Kowuor, 2 A.Davies, 2 C Agwanda, 1 M. Price, 3 F. Priddy, 3 H. S. Okuku, 2 S.M. Graham, 4 E. J. Sanders.
Potential role of PEP, PrEP and ART for HIV Prevention among Men who have Sex with Men Frits van Griensven, PhD, MPH Division of HIV/AIDS Prevention US.
Are people living with HIV less likely to pass HIV to others if they are on treatment? Exploring the use of treatment as prevention James Wilton Project.
Use of Antivirals in Prevention Oral and Topical Prophylaxis
Introduction to HIV New Prevention Technologies (NPTs)
Slide 1 of 9 From J Marrazzo, MD, at Los Angeles, CA: April 22, 2013, IAS-USA. IAS–USA Jeanne Marrazzo, MD, MPH Professor of Medicine University of Washington.
XIX International AIDS Conference
DEVELOPING DUAL COMPARTMENT MPTS THAT WORK UP FRONT AND FROM BEHIND José Fernández Romero Population Council September 9, 2015.
National Working Group on Microbicides The Basics of Microbicides Amitrajit Saha PATH January 2007.
Moving the Rectal Microbicide Agenda Forward; Results from a Scientific, Ethical, and Community Consultative Process Ian McGowan MD PhD FRCP University.
What Is Currently in the Pipeline & What is Ideal for an ARV-based Prevention Candidate? Carl W. Dieffenbach, Ph.D. Director, Division of AIDS, NIAID,
The Microbicide Trials Network Group 3 Lindsay O. Bryant Danielle M. Campbell Alan D. Johnson Leroy Smith Jr. Kendra M. Taylor May 31, 2016.
Rectal microbicides, where are we? Kim Mulji Naz Foundation International.
Implications of Anal Intercourse and Rectal use of Products in Vaginal Microbicide Trials Ian McGowan MD PhD FRCP.
Welcome South Africa 4 Rectal Microbicides A Stakeholder Consultation on Rectal Microbicide Research and Advocacy Please sign in.
IAS July 1 The Caprisa 004 result in context Sheena McCormack Clinical Scientist MRC Clinical Trials Unit.
N ORTHWEST A IDS E DUCATION AND T RAINING C ENTER Pre-exposure Prophylaxis for HIV Prevention Efficacy and the importance of adherence Joanne Stekler,
Looking Ahead to MTN-017 Ross D. Cranston MD, FRCP Microbicide Trials Network IRMA.
New Prevention Technologies Workshop Module 2: NPTs in context
Antiretrovirals for HIV Prevention: Progress and Challenges Kenneth H. Mayer, M.D. Brown/Miriam/Fenway.
CHAIN OF INFECTION STI POINT OF VIEW.
HIV and Women Collaborating Across Borders to Advance the Health of Women IAS 2012 Gina M. Brown, M.D. July 22, 2012.
Rodney C. Perkins 1, Grace K. Douglass 2, Victoria C. Ta 2, Aurnell Dright 1, Michael Fomundam 2, Ying Li 3, Michael Plankey 3 Sexually Transmitted Infection.
Expanded PrEP implementation across Australia Expanded implementation of PrEP across Australia 1.
Expanded PrEP implementation in NSW (EPIC-NSW) 1 AIDS 2016 | 22 July 2016.
Seeking HIV-testing Only: Missed Opportunity for HIV Prevention?
International AIDS Conference
Conflict of Interest I have acted as a Consultant on an education workshop organised by Gilead Sciences.
Integrating Diagnostic Services at Point of Care
Information about HIV Prevention Options
Regulatory Considerations for Approval: FDA perspective
Hepatitis C.
PrEP for HIV Prevention
1University of Kentucky, Lexington, Kentucky
What’s All the Fuss About the Microbiome?
Module 4 (c) Stopping PrEP
Rectal Microbicides: Where We’re Heading
On behalf of The MTN-020/ASPIRE Study Team
Ian McGowan MD DPhil FRCP University of Pittsburgh Pittsburgh, PA, USA
On Demand PrEP for Men at High Risk for HIV IPERGAY
Role of Explant Tissue Infection Assays Ian McGowan MD DPhil FRCP University of Pittsburgh, PA, USA 26th July, Paris, France Wednesday October 7th 15.
Gut Microbiota Linked to Sexual Preference and HIV Infection
Module 4 (a) Getting started on PrEP
Non-ARV Based Interventions to Combat HIV/AIDS: New Insights and Initiatives Yves Lévy Inserm, VRI.
Sexually Transmitted Infections in Europe, 2012
UZ-UCSF Annual Research Day 8 April 2016
MULTIPURPOSE PREVENTION TECHNOLOGY (MPT) PRODUCT PIPELINE & THEIR POTENTIAL ACCEPTABILITY AMONG ADOLESCENT GIRLS & YOUNG WOMEN Barbara Friedland, Population.
A study of high risk African American women, 15 to 21 years of age
The HIV Prevention Landscape
David Magnuson, Trevor Hawkins, Robertino Mera
22th International AIDS Conference
One pill a day, can keep HIV away
PrEP introduction for Adolescent Girls and Young Women
MTN-037 Protocol Overview
AIDSACTIONBALTIMORE PREP UP TOWN HALL
Rectal Gels for PrEP Are They an Option?
José Bauermeister PhD, MPH University of Pennsylvania MTN BRWG Member
Rectal Microbicide Protocol Status
HIV.
D. T. Hamilton, MPH PhD, S. M. Goodreau, PhD, S. M. Jenness, PhD, P. S
Impact of Tenofovir Chemoprophylaxis on HIV Prevention Programs Questions and Implications from Local Experience Charles L. Henry, Director County of Los.
Lesson 3: Treatment as Prevention
HIV Resistance in the Context of PrEP
Presentation transcript:

Rectal Mucosa Ian McGowan MD DPhil FRCP University of Pittsburgh, PA, USA 21st July, 2018 AIDS2018 Amsterdam

Disclosures Chief Medical Officer at AELIX Therapeutics, Barcelona, Spain Chief Scientific Officer at Orion Biotechnology, Ottawa, Canada Chair of the Scientific Advisory Board at ABIVAX, Paris, France

Overview Rectal susceptibility to HIV/STI Potential interventions Rectal microbicides State of the science Trial findings Ongoing and future studies Funding for microbicide research

Anatomical Considerations Sagittal section Anatomical Considerations

GALT Vulnerability to HIV PBMC GALT T cells GALT CD4+/CCR5+ T cell in blood & gut Anton PA et al AIDS 2000

Rectal Susceptibility to HIV/STI

Rectal STIs Bacterial Viral Protozoal Microbial dysbiosis Chlamydia, gonorrhea, syphilis Viral HSV, HBV, HCV, CMV, HPV, HIV Protozoal Entamoeba, cryptosporidium, giardia Microbial dysbiosis

Increasing Incidence of Rectal STIs Objective: Use of preexposure prophylaxis (PrEP) for HIV raises concerns about sexually transmitted infection (STI) incidence because of decreased condom use among MSM. This study examines whether PrEP is associated with STIs in the 12 months following PrEP prescription relative to the 12 months prior to PrEP and if STI rates are higher among PrEP users relative to individuals receiving postexposure prophylaxis (PEP). Design: Retrospective cohort study including PrEP users with more than 12 months of follow-up before PrEP prescription and individuals receiving PEP from 2010 to 2015 at Clinique l’Actuel (Montre´al, Canada). Methods: Incidence of chlamydia, gonorrhoea, syphilis and hepatitis C virus over 12 months was compared before and after PrEP; and for PrEP versus PEP users using Poisson models to generate incidence rate ratios (IRRs) with 95% confidence intervals (CIs) and adjusted IRRs (aIRRs) controlling for frequency of STI-screening visits. Models comparing PrEP and PEP users were further adjusted for age and education. Results: One hundred and nine PrEP and 86 PEP users were included. Increased rates of STIs were observed in the 12 months after PrEP relative to the 12 months prior (IRR: 1.72, CI: 1.22–2.41; aIRR: 1.39, CI 0.98–1.96). PrEP users were also at higher STI risk relative to PEP users (IRR: 2.18, CI: 1.46–3.24; aIRR: 1.76, CI: 1.14–2.71). Conclusion: Increased rates of STIs among individuals after initiation of PrEP may suggest greater risk behaviours during the first year on PrEP. Further studies are needed to measure long-term trends in STI acquisition following PrEP initiation. Nguyen VK et al AIDS 2018 IRR: Incidence Rate Ratios

Rectal Microenvironment Burgener A et al. Curr Opinion Immunol 2015

Rectal Microenvironment Burgener A et al. Curr Opinion Immunol 2015

Microbial Dysbiosis Noguera-Julian M et al. Ebiomedicine 2016 The bacterial genus composition of the human fecal microbiome is mainly linked to HIV transmission group. a) The bacterial genus composition of the fecal microbiota in the Barcelona test dataset (BCN0) was largely determined by HIV transmission group, with MSM being enriched in the Prevotella cluster and non-MSM in the Bacteroides cluster. Genera with mean abundance of at least 2% across all samples are represented in colors; those with < 2% abundance are grouped into the category “Others”. Each column represents one individual. A similar plot for the Stockholm cohort is shown in Supplementary Fig. 12. b) Non-metric multidimensional scaling (NMDS) ordination plots of Bray–Curtis distances showing that microbiomes in the BCN0, BCN1 and STK datasets mainly cluster by HIV transmission group (MSM vs. non-MSM) rather than by HIV serostatus. Ellipses include 95% of samples. Similar plots using other distances are shown in Supplementary Figs. 8 to 10. c) Partitioning around medoids (PAM) analysis of the BCN0 dataset showing this population structure in this dataset is better explained by 2 rather than more clusters, with reasonable Silhouette support. This information was used to define the Bacteroides and Prevotella clusters in our study. d) Abundance box plots showing that MSM were enriched in Prevotella and non-MSM (HTS or PWID) were enriched in Bacteroides. Comparisons between MSM and the non-MSM categories were always highly significant (p < 0.001) after adjusting for multiple comparisons using the Benjamini–Hochberg method. Plots of all genera showing significant differences between MSM and non-MSM categories are shown in the Supplementary Figs. 13 to 15. Noguera-Julian M et al. Ebiomedicine 2016

Prevotella Dominance in MSM Hts: Heterosexual MSM: men who have sex with men PWID: IV drug use Noguera-Julian M et al. Ebiomedicine 2016

Microbial Dysbiosis Noguera-Julian M et al. Ebiomedicine 2016 Pescatore N et al. AIDS Res Hu Retro 2018 The bacterial genus composition of the human fecal microbiome is mainly linked to HIV transmission group. a) The bacterial genus composition of the fecal microbiota in the Barcelona test dataset (BCN0) was largely determined by HIV transmission group, with MSM being enriched in the Prevotella cluster and non-MSM in the Bacteroides cluster. Genera with mean abundance of at least 2% across all samples are represented in colors; those with < 2% abundance are grouped into the category “Others”. Each column represents one individual. A similar plot for the Stockholm cohort is shown in Supplementary Fig. 12. b) Non-metric multidimensional scaling (NMDS) ordination plots of Bray–Curtis distances showing that microbiomes in the BCN0, BCN1 and STK datasets mainly cluster by HIV transmission group (MSM vs. non-MSM) rather than by HIV serostatus. Ellipses include 95% of samples. Similar plots using other distances are shown in Supplementary Figs. 8 to 10. c) Partitioning around medoids (PAM) analysis of the BCN0 dataset showing this population structure in this dataset is better explained by 2 rather than more clusters, with reasonable Silhouette support. This information was used to define the Bacteroides and Prevotella clusters in our study. d) Abundance box plots showing that MSM were enriched in Prevotella and non-MSM (HTS or PWID) were enriched in Bacteroides. Comparisons between MSM and the non-MSM categories were always highly significant (p < 0.001) after adjusting for multiple comparisons using the Benjamini–Hochberg method. Plots of all genera showing significant differences between MSM and non-MSM categories are shown in the Supplementary Figs. 13 to 15.

Prevotella and Mucosal Inflammation Potential causes Sexual behavior Multiple partners Condomless RAI Parasexual behavior Douching Lubricant use Recurrent STI Treatment of STIs Consequences? Sui Y et al. Mucosal Immunology 2018 It is unknown whether the gut microbiome affects HIV transmission. In our recent SHIV vaccine study, we found that the naïve rhesus macaques from two different sources had significantly different rates of infection against repeated low-dose intrarectal challenge with SHIVSF162P4 virus. Exploring causes, we found that the more susceptible group of seven macaques had significantly more activated CD4+CCR5+Ki67+ T cells in the rectal mucosa than the more resistant group of 11 macaques from a different source. The prevalence of pre-challenge activated rectal CD4 T cells in the naive macaques correlated inversely with the number of challenges required to infect. Because the two naive groups came from different sources, we hypothesized that their microbiomes may differ and might explain the activation difference. Indeed, after sequencing 16s rRNA, we found differences between the two naive groups that correlated with immune activation status. Distinct gut microbiota induced different levels of immune activation ex vivo. Significantly lower ratios of Bacteroides to Prevotella, and significantly lower levels of Firmicutes were found in the susceptible cohort, which were also inversely correlated with high levels of immune activation in the rectal mucosa. Thus, host microbiome interactions might influence HIV/SIV mucosal transmission through effects on mucosal immune activation.

A Perfect Storm for HIV Infection? Anorectal dysbiosis Increasing incidence of STIs Epithelial damage Vulnerable GALT T cells Impact on PrEP efficacy?

Potential Interventions

Interventions to Reduce STIs Behavioral Partner reduction and condom use Enhanced STI screening and treatment Antibiotic pre-exposure prophylaxis Microbicides

Rectal Microbicides

Rectal Microbicide Formulations

Would They Work? “HIV” (99mTc-SC) in Ejaculate “Microbicide”(111In-DTPA) CHARM-02 Study (Hiruy H et al. AIDS Res Hum Retroviruses 2015)

Where is the Science? Good non-clinical animal model data to support the safety and effectiveness of topical PrEP agents including candidate rectal microbicides Multiple products have advanced through Phase 1 evaluation generating supportive safety, acceptability, and PK/PD data A tenofovir gel has been evaluated in a Phase 2 international multicenter study (MTN-017) As of yet no Phase 2B/3 effectiveness studies

MTN-026 Phase 1 rectal safety, acceptability, and PK/PD evaluation of dapivirine gel N = 27 Clinical sites Pittsburgh, Birmingham, and Bangkok

MTN-033 Phase 1 evaluation of dapivirine gel to determine whether digital / phallic insertion equivalent to applicator insertion of microbicide HIV-uninfected men who have sex with men (MSM) and transgender females who have sex with men, 18 years or older (N=16)

MTN-037 Collaboration with the Population Council Phase 1 dose escalation of MIV-150/Carageenan/Zinc gel Potential activity against HIV. HPV, and HSV-2 Safety, acceptability, and PK/PD Group 1: 4 mL of gel Group 2: 16 mL of gel Group 3: 32 mL of gel Status: Ongoing

DREAM and PREVENT Programs DREAM Program PREVENT Program Natural product Griffithsin isolated from Griffithsia, red alga originally collected off Chatham Island New Zealand Griffithsin is a lectin, one of the most potent HIV-1 entry inhibitors Targets the dense clusters of sugars (glycans) present on the surface of HIV Efficiently manufactured in Nicotiana benthamiana plants Tenofovir prodrug enemas PI: Craig Hendrix, JHU Griffithsin rectal gel PI: Kenneth Palmer, University of Louisville

OB-002H (5P12 RANTES) Phase 1

Single Vaginal Dose Exposure Visit (N = 6 female participants) Screening Visit Enrollment Visit Single Vaginal Dose Exposure Visit (N = 6 female participants) Five Daily Vaginal Dose Exposure Visit (N = 18 female participants) OB-002H: HEC placebo gel (2:1) Follow-up visit Single Rectal Dose Exposure Visit (N = 6 male or female participants) Five Daily Rectal Dose Exposure Visit (N = 18 male or female participants)

Broad Spectrum STI Microbicides Tenofovir (HIV, HBV, HSV) Population Council (HIV, HSV, HPV) Bacterial STIs Antimicrobial peptides Octglycerol1 LL-372 1Wang et al. Drug Dev Ind Pharm. 2012 2Srakaew N et al. Human Reproduction 2014

So Is It Possible? In the absence of federal or philanthropic funding moving a candidate rectal microbicide through to licensure will be very challenging. Big Pharma have the resources and the capacity to make this happen Less certain if they have the interest to do so as this would canabalize the oral PrEP franchise and/or emerging approaches such as IM cabotegravir

Summary The rectal mucosa continues to be a major portal of entry for HIV infection PrEP is a huge advance for HIV prevention but may lead to increases in condomless sex and associated anorectal STIs Further work need to define the role of the microbiome in vulnerability to HIV infection Rectal microbicide development continues but funding will become a critical issues in the next 1-2 years

Thank You