UCSF International Research and the Connection to the HIV Community

October 4, 2012

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Agenda

I. Scale of the issues

II. What have we done?

III. What more needs to be done?

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Agenda

Scale of the IssuesSize and scope of international researchPotential for adverse outcomesInefficiencies

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Size and Scope of UCSF International Research

• 199+ faculty with funded research or active CHR-approved project with an international component

• Working in more than 100+ countries (primarily in resource constrained settings)

• $77.67M+ extramural awards received since Feb 2012 include a component conducted aboard

• More than 250 students and trainees

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Size and Scope of UCSF International Research

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Scale of the Issues: Potential for Adverse Outcomes

• Natural and political disasters (Ebola outbreak in Uganda, post-election riots in Kenya)

• Illness and trauma (medical care in resource limited settings, evacuation, notification of UCSF leadership, family, etc.)

• Charges of research misconduct (ethics of research vs. standards here, informed consent challenges)

• Violation of laws there or policies here (hiring foreign staff, banking and other funding transactions)

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Scale of the Issues: Inefficiencies

• Multiple UCSF Departments working in the same site without coordination (travel, staff, etc.)

• Many sites used for similar projects, even in the same country

• Multiple systems used for similar tasks (data collection, etc.)

• Questions of faculty oversight of UCSF trainees. UCSF faculty privileges at other sites vs. UCSF status of local faculty members

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Agenda

What have we done?

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Welcome to My World!

• CFAR: Co-Director

• ARI: Director

• GHS: Research Director

• CTSI-GHP: Director

• CTSI: Board of Directors

• DOM: Associate Chair for Global Health

• VA: Clinician

• NCIRE: Board Chair

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HIV at UCSF

• Research funding: Well over $100M annually from USG

• Research conducted domestically and in numerous RLS» Uganda, Kenya, Tanzania, Zimbabwe, South Africa, India, Brazil

• Care at SFGH, Parnassus, VA

• Education focused at SFGH

• Efforts coordinated by well established organizations

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HIV Coordination at UCSF

• AIDS Research Institute» “Umbrella” meant to connect every aspect of HIV research at all

sites providing communication, development.

• Center for AIDS Research» NIH P-30 center grant with $3M annual budget

» Convenes, coordinates, sustains investigative community with cores, pilot grants, mentorship

• Center for AIDS Prevention Studies» NIH center grant supporting large group of

behavioral/prevention scientists in DOM Division of Prevention Sciences

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Selected Larger HIV Research Groups

• HIV/AIDS Division at SFGH (Havlir)

• Division of Experimental Medicine at SFGH (McCune)

• Gladstone Institute of Virology and Immunology at MB(Greene)

• Blood Systems Research Institute at Blood Bank (Busch)

• SF DPH AIDS Research Group (Buchbinder)

• Institute of Global Health at Beale Street (Rutherford)

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Selected Interlaced Research Groups

• Bixby Center: Maternal and Child Health with large HIV effort in Kisumu Kenya (Craig Cohen)

• Curry Center at SFGH: TB (Hopewell)

• Public Health Group at GHS: Malaria (Feachem)

• Proctor Foundation: Ophthalmology including onchocirciasis

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Silo

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What Have We Done? 1.

• Research policy review for RAB

• Risk management actively engaged in providing services (travel insurance, email alerts, post-exposure prevention management)

• Convened the International Research Advisory Council (IRAC) across all schools and disciplines

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What Have We Done? 2.

The UCSF International Projects Database: Provides access to public information; facilitating collaboration, communication, expertise, and development of new proposals. Current awards of UCSF global researchers through July 2012 Data feeds to Profiles, plans for automation of data capture with new central systems rollout in 2013

Example of search result:

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What Have We Done? 3.

Global Research Consulting: Launched July 2011. One hour of free consultation. Predominantly enquiries regarding international grants administration and policy.

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What have We done? 4.

GlobalResearch Forum: Launched April 2012An online moderated forum for global health research interest groups.

GlobalResearch Forum: Launched April 2012An online moderated forum for global health research interest groups.

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Agenda

What more needs to be done?

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What More Needs to be Done? 1.

• Follow-up on initial RAB policy analysis

» Continue to identify relevant policies governing global health research and educational

activities reviewing policies and policy gaps to facilitate work in medium and lower

income countries including:

» Finalizing policy on post-exposure prophylaxis for UCSF employees (and foreign staff

members working on UCSF projects?)

» Develop policies and procedures for UC foreign affiliate operations

» Define banking/financial policies and guidelines for registered entities

» Define policies re: shipping specimens to US vs. research performed in-country

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What More Needs to be Done? 2.

• Monitor OE pre-ward teams with extensive global research experience to

evaluate efficiency, effectiveness compared to similar grants by other teams

• Provide more effective training of research personnel here and abroad in

support of active research projects

• Improve tracking of grants, multiple PI’s and specific sites (city, hospital, etc.,

not just country)

• Better integrate research and educational activities given similar policy

applications

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What More Needs to be Done? 3.

• Provide a One Stop Shop for UCSF International Activities from pre-award

to project close out – including project management

• Experts here helping to facilitate the work there, including:

» Maintaining accurate and current database of resources here and in-country available

for research support

» Compliance (both ethical and fiscal)

» Data collection, sharing, and analysis

» Capacity building (for research, education, and research administration and

management)

» Support for educational placement and supervision of UCSF students, residents, trainees

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What More Needs to be Done? 4.The Global Resource HUB: Uses new and existing data as a central resource for researchers, program staff working abroad and international visiting scholars. Goal is to provide tool set designed specifically for the elimination of barriers for the global researcher.

The future Global Resource HUBGHRS web portal: Working issues

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What more needs to be done? 5.

• Review and provide feedback on UCOP draft policy on International Activities

UCSF has initiated registration of UC foreign affiliate offices in two PEPFAR countries and is now

registered in Tanzania as “Global Programs.” Legal registration in country allows researchers to:

– Open a local bank account

– Lease space

– Hire local staff

– Apply for work visas for UCSF staff working locally

Please review the enclosed:

– Context sheet

– UCOP Draft policy on International Activities

– Summary of comments to the UCOP policy

Four Prevention Opportunities

YEARS

Treatment Of HIVReduced Infectivity

INFECTED

YEARS

UNEXPOSED

Behavioral,Structural

Circumcision

CondomsARV

Therapy

Cohen et al, JCI, 2008Cohen IAS 2008

HOURS

VaccinesART PrEP

Microbicides

EXPOSED (precoital/coital)

72h

VaccinesART PEP

EXPOSED (postcoital)

Prevention Phase 4

Treatment of the Infected Person to Reduce Transmission?

Observational data & HPTN 052

Treatment to Decrease Transmission?

• Many models in other infectious diseases: TB, HSV

• Early evidence in HIV» AZT in pregnant women decreased MCT by 75%

» AZT PEP immediately accepted even without definite evidence

• Surprisingly vigorous debate» Combination ARV therapy decreased viremia below detection

and in genital fluids to a level that lead to many arguments whether it could be detected or not

» Intense reaction to Swiss recommendation re: no condoms needed if suppressed

29Quinn et al N Engl J Med 2000

Transmission Risk Strongly Related to Viral Load

30Quinn et al N Engl J Med 2000

Transmission Risk Strongly Related to Viral Load

“Research is urgently needed to develop and evaluate cost-effective methods such as effective and inexpensive antiretroviral therapy…” “could reduce infectivity of and susceptibility to HIV-1 and prevent further sexual transmission of the virus”

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© 2000 Lippincott Williams & Wilkins, Inc. Published by Lippincott Williams & Wilkins, Inc.

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Antiretroviral Therapy Reduces HIV Titer in Semen

Potent antiretroviral treatment of HIV-infection results in suppression of the seminal shedding of HIV.Vernazza, Pietro; Troiani, Luigi; Flepp, Markus; Cone, Richard; Schock, Jody; Roth, Felix; Boggian, Katia; Cohen, Myron; Fiscus, Susan; Eron, Joseph

AIDS. 14(2):117-121, January 28, 2000.

Fig. 1. Detection rate of HIV in semen. Detection rates of cell-free and cell-associated HIV in drug naive historical controls (white) and treated individuals (black) in seminal plasma (HIV-RNA) and seminal cells (HIV-DNA). Seminal cells were only analysed in a subgroup of men from one centre.

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HPTN 052: Impact of earlier ART on HIV transmission and disease progression

1763 HIV discordant couples (HIV+ partner CD4 350-550)

HAART at 250

1° endpoint: HIV infection in HIV-negative partnerCo- 1° endpoint: HIV disease progression in HIV+ partner

Follow couples for 5 yrs

Immediate HAART

All receiving HIV prevention services

13 sites in 9 countries: Botswana, Brazil, India,

Kenya, Malawi, South Africa, Thailand, United States,

Zimbabwe

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HPTN 052: Impact of earlier ART on HIV transmission and disease progression

1763 HIV discordant couples

(HIV+ partner CD4 350-550)

877 delayed HAART (CD4

250)

*96% reduction in HIV transmission to HIV-

negative partner, median follow-up 2 years

1 transmission* & 3 cases of

extrapulmonary TB

886 immediate HAART

All receiving HIV prevention services

27 transmissions*& 17 cases of

extrapulmonary TB

Update at AIDS 2012 extends benefit in AIDS delay and cost effectiveness

Continued Debate about Starting ARV

Now Affected by Prevention Application

When to Start ARV TherapyMovement to Earlier Initiation

Current ARV more potent, convenient, safeLess transmitted resistanceNew drugs control resistant HIVRecognition of end organ damage of untreated infection

Longer duration of ARV therapy adds cost, toxicityRisk of additional generation of resistance

Favors early

therapy

Favors later

therapy

When to Start ART: IAS–USA Recommendations 2012

• Patient readiness should be considered when deciding to initiate ART

• ART is recommended and should be offered regardless of CD4 cell count

• The strength of the recommendation and quality of the evidence increases as CD4 count decreases and in the presence of certain conditions

Thompson et al JAMA 2012

CD4 count at HAART Initiation, 2003–5Probably Improving but Far to Go

Egger M, et al. 14th CROI, Los Angeles 2007, #62

Questions in Treatment as Prevention

• Would starting ARV therapy at time of diagnosis reduce HIV incidence at the community level?

» Can we find those infected but not engaged?

» What is the cost/benefit/risk balance of additional time on ARV?

• Is PREP cost-effective? Will it be paid by government, insurance?

• Does PREP displace vaginal ARV microbicides as prevention modality?

• Will biologic prevention alter commitment to behavioral prevention strategies? Cause of syphilis resurgence in MSM?

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Thanks!