Susan Little, MD, of UC San Diego AntiViral Research Center, presents "Strategies for HIV Epidemic Control" at AIDS Clinical Rounds

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AIDS CLINICAL ROUNDS

2. Susan Little, M.D.
Professor of Medicine
University of California San Diego
Strategies for HIV Epidemic Control
7/18/141

3. Epidemic spread of infection
 Understanding the spread of infectious diseases in
populations is key to controlling them.
 Epidemic disease spread determined by properties of the
pathogen (contagiousness, the length of the infection
period, severity, etc.) and network structures within the
population.
 An understanding of these issues may provide insights for
preventing the spread of disease.
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4. Epidemic Disease Control
 Infection control options
 Treatment as prevention/Universal test and
treat
 Network-focused interventions
 Improved methods to guarantee privacy
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5. Strategies to prevent/control infectious diseases
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 Reduce contact rate (case finding & isolation, contact tracing &
quarantine, behavior change)
 Reduce infectiousness (treatment, vaccination)
 Reduce susceptibility (vaccination, immune globulin)
 Interrupt transmission (infection control)
 Identify and control reservoir/source (pest/vector control,
environmental disinfection)
 Reduce prevalence of infectious sources (identify and control
infectious sources)
 Reduce duration of infectiousness (treatment, vaccination)
 Increase herd immunity (vaccination)
4

6. Strategies to prevent/control HIV
7/18/14
 Reduce contact rate (case finding & isolation, contact tracing &
quarantine, behavior change)
 Reduce infectiousness (treatment, vaccination)
 Reduce susceptibility (vaccination, immune globulin)
 Interrupt transmission (infection control ≈ treatment)
 Identify and control reservoir/source (pest/vector control,
environmental disinfection)
 Reduce prevalence of infectious sources (identify and control
infectious sources)
 Reduce duration of infectiousness (treatment, vaccination)
 Increase herd immunity (vaccination)
5

7. Summary of HIV prevention options
7/18/14
 Case finding (testing)
 Contact tracing (partner services for recently infected)
 Behavior change (durable?)
 Identify and treat infectious sources
 Identify and treat susceptible recipients
6

8. HIV Intervention Strategies
7/18/14
 Universal test and treat strategies: theoretically plausible
 Acceptability: issues of stigma
 Feasibility: model presumes annual testing
 Resources: estimated costs are greater initially
 ARTAccess: by 2012,ART accessed by 65% of 15 million global “target”
 Acute Infection: 20-50% of transmission may occur in setting of acute HIV
(not captured by routineAb screening).
 Targeted strategies
 How to prioritize target populations?
 Will locally effective interventions translate to success at the population
level?
7

9. Epidemic Disease Control
 Infection control options
 Treatment as prevention/Universal test and
treat
 Network-focused interventions
 Improved methods to guarantee privacy
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10. Treatment as Prevention
A strategy that considers “universal” HIV
testing with immediate antiretroviral therapy
(ART) with the goal of reducing HIV
transmission (HIV incidence) and eventual
“elimination” of disease
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12. Conclusions from modeling exercise
Universal and annual voluntary HIV testing followed by
immediate ART (irrespective of CD4 cell count and combined
with other prevention interventions) could:
 Eliminate HIV transmission in 5-10 years
 Eliminate HIV infection in 40 years
 Initial resources would be higher but over time, given the
reduction in HIV incidence, this approach may provide cost
savings
 Estimated costs are within UNAIDS estimates for universal
access for a population this size
7/18/14Granich, et al. Lancet 200911

13. Treatment as Prevention: HPTN 052
Sheth PM, et al. AIDS. 2009;23:2050-2054. 7/18/14
Cohen M. NEJM 2011
1,763 sero-discordant couples (97% heterosexual)
HIV infected partners: 890 men, 873 women
I-ART
(CD4 350-550)
D-ART
(CD4 <250, >200)
39 Transmissions
28 Linked 11 Unlinked
I-ART:
1 Transmission
D-ART:
27 Transmissions
96% Protection
Associated with
Immediate ART
12

14. Test and Treat (Treatment as Prevention)
Studies (1)
 HPTN 071 (PopART): Richard Hayes/Sara Fidler, n=1.2 million
 3 arm, 2-country (Zambia & S.Africa) cluster-randomized trial:
 Full combination prevention and immediate ART
 Combination prevention with SOC ART (CD4<350)
 SOC
 Endpoint: HIV incidence (at 36 months)
 Botswana combination prevention program (BCPP): Max Essex
 Pair-matched, community-randomization design (30 villages)
 Interventions: enhanced HTC (>90%), MC (>80%), PMTCT, improved
LTC/treatment (>90%/60%),ART for those withVL ≥ 10,000 (regardless of
CD4)
 Endpoint: HIV incidence (within 3 years) 7/18/1413
2013/4 International HIV Treatment as Prevention Workshop

15.  SEARCHTrial: Diane Havlir/Moses Kamya, Uganda and Kenya
 Clustered, community-randomized trial (32 pair-matched communities of
10,000 each)
 Intervention:ART access w/optimized LTC and streamlined care vs. SOC
 Outcome: cumulative 3 and 5-year HIV incidence
 MaxART:Velephi Okello (Swaziland – In country study)
 Regional access to immediateART and various PMTCT options
 Médecines Sans Frontières (MSF) Implementation: RogerTeck
 Promote community scale ofART and PMTCT
 CombinationTrials in SouthAfrica & Uganda: Ruanne Barnabas
 Promote testing, LTC, male circumcision
7/18/1414
Test and Treat (Treatment as Prevention)
Studies (2)
2013/4 International HIV Treatment as Prevention Workshop

16. TasP is biologically plausible, but…
 Massive mobilization of resources necessary
 No specific recommendations for sex workers, drug users, or
MSM
 Retrospective analyses of HIV transmission and ART are mixed.
 HIV incidence has not decreased in Canada, US, EU despite
improved access to testing and treatment
 Marked increases in risk activity in SF are outpacing any decrease
in infectivity due to increasedART use
 ~4300 discordant HET couples in China (2006) – no difference in
seroconversion rates associated w/ART use
7/18/1415
Lu, et al. JAIDS 2010; Nguyen, et al. AIDS 2011

17. Universal Test and Treat: The Present
 HIV testing is the foundation for all ART interventions.
 Early treatment substantially reduces the risk of secondary HIV
transmission.
 The prevention benefit of treatment requires linkage to and retention
in care, and adherence to ART (Gardner EM, et al. CID, 2011).
7/18/14
80
%
89
%
66
%
77
%
77
%
16

18. Epidemic Disease Control
 Infection control options
 Treatment as prevention/Universal test and
treat
 Network-focused interventions
 Improved methods to guarantee privacy
7/18/1417

19. 18
The Challenge….
7/18/14
“Because of the common route of transmission through sexual
networks, interventions against STIs need to be targeted to whole
populations.”
-World Health Organization,2012
“What network theory teaches us is that connections, even within the
most complex systems, are not random (that is, they are not
unpredictable). Instead, networks behave in ways that we can
theorize, model, and predict.”
The PLoS Medicine Editors
It's the Network,Stupid:Why Everything in Medicine Is Connected
PLoS Med 2008

20. Talking about networks…
 Nodes (n): individuals in the network
 Degree (d): connections between nodes
 The degree or degree centrality of a node is the number of
connections (edges) the node has to other nodes in the network 7/18/1419

21. Network Topology
Scale Free
 Real world networks: www, gang
networks, power grid, on-line gaming,
HIV, etc.
 Large majority of nodes have low
degree, but small number (hubs)
have high degree.
Random
 Cannot be used to model real
world networks
 Nodes are connected (or not) with
independent probability: binomial
distribution (for large n)
7/18/1420
Degree distribution: the probability (P) that a randomly chosen node has k
connections: Pdeg(k)

22. Scale-free Networks: preferential attachment
 Connectivity is maintained by a few highly connected “hubs”
 Scale-free networks are vulnerable to coordinated attacks - when the
nodes with the highest number of edges are targeted, the network
breaks down faster than in the case of random node removal.
7/18/1421
Scale-free network (i.e. HIV)
Hubs

23. 7/18/14
HIV is transmitted along a complex contact network
Concept Contact Network Transmission network
Node Individual HIV+ individual
Edge A contact that could lead to HIV transmission, e.g.
sexual, shared needle
Transmission event
Degree = edges
connected to a node
Number of contacts associated with a node Number of transmissions associated with a node
Transmission network is a
subset of the contact network
22
Contact network

24. It pays to target highly connected nodes
Targeting a low degree
node has a local effect
Targeting a high degree
node has a global effect
7/18/1423

25. Example 1: Drug Trafficking Network
Simulation
 Simulations of illicit networks (drug trafficking networks) to determine
areas of vulnerability and resilience.
 Four intervention strategies:
1) Target most connected nodes (high degree centrality)
2) Target nodes which play most important roles
3) Target by a combination of degree centrality and role
4) Random selection
 Quantify the extent of network disruption – the number of nodes in the
largest remaining connected component
7/18/1424 Bright et al, UNSW, Australia (2013)

26. Size of the largest connected component
7/18/1425

27. 7/18/1426
Example 2: Simulations of HIV network
Random vs. Preferential ART
• RandomART (red): 4.1%
fewer infected nodes than
without any intervention
• PreferentialART (black):
31.3% fewer infected nodes
after 3 years than random
ART.
• Highly connected nodes become
infected early and thus receive
ART earlier.
• These nodes are 96% less likely
to transmit to partners
NumberofInfected
Day
ART Non-targeted
ART Targeted
Trewick C, et al. Computational Social Science Society of the Americas, 2013

28. HIV Network Intervention Strategies
7/18/14
 Studies of the UK national HIV database suggest that
random (i.e. uniformly applied) interventions will not be
sufficient to halt the epidemic.
 Interventions must be targeted to high-degree nodes to be
effective.
 San Diego: Dr. Smith working on an NIH funded study
to map HIV transmission dynamics in real time and direct
community specific prevention resources.
Leigh Brown, et al. JID 2011; Brenner et al. AIDS 2013
27

29. Degree Distribution of SDPIC Network
A small proportion of individuals
have many connections (high
degree)
7/18/1428

30. SDPIC Network Map
7/18/14
29

31. 30
Example 3: Retrospective Analysis of Self-Selected ART
ART naive
ART >30
days of EDI
ART ≤30
days of EDI
No data
7/18/14

32. Retrospective study of ART
 Network statistic* shows that early (≤30 days since EDI)
treatment results in a significantly lower network
connectivity than does delayed treatment (p<0.05),
even with small samples (N=21 early, N=137 delayed).
 While encouraging, must still prove that such
interventions when delivered in a targeted fashion can
disrupt the entire network.
7/18/14*Wertheim, et al. PLoS One 201131

33. The Future…
 Goal is a prospective, real-time, network informed (i.e., targeted
interventions) trial to evaluate impact of network HIV incidence
Objectives:
 Infer the local HIV transmission network - estimate features of the
underlying infected population and efficacy of potential
interventions.
 Assess the potential of molecular epidemiology and network
statistics to measure the efficacy of ART as a network-based
prevention intervention.
 To develop and deploy privacy preserving methods for analysis and
release of network data. 7/18/1432

34. Hypothesis
We can control the San Diego HIV epidemic (i.e.,
reduce R0<1) by identifying high degree nodes or
“hubs” within the transmission network and
selectively interrupting transmission from these
clusters.
7/18/1433

35. Study Design
 HIV EarlyTest Program – identify persons with HIV
 Provide partner services for acutely and recently infected persons
 Rapid linkage to care
 UCSD AVRC – referral to primary care
 Baseline HIV genotype and routine clinical laboratories
 Universal access to immediateART –
elvitegravir/cobicistat/tenofovir/emtricitabine (Stribild) for 1-5
years
 Compare network connectivity (transmission) in persons who
initiate ART within ≤30 days EDI vs >30 days.
7/18/1434

36. Epidemic Disease Control
 Infection control options
 Treatment as prevention/Universal test and
treat
 Network-focused interventions
 Improved methods to guarantee privacy
7/18/1435

37. 7/18/1436
HIV Transmission & The Law: USA
 In 1990, Congress passed the RyanWhite CAREAct – mandated that
states criminalize the intentional transmission of HIV
 In 2000, Congress reauthorized theAct, but removed the
criminalization requirement – many states kept their laws
 32 States currently have laws that criminalize the transmission of HIV
 25 States criminalize one or more behaviors that pose a low or negligible
risk for transmission
 These laws perpetuate and condone stigma and discrimination against
persons with HIV

38. California (7/2010)
“Any person who exposes another to HIV by engaging in unprotected
sexual activity (anal or vaginal intercourse without a condom) when
the infected person knows at the time of the unprotected sex that he
or she is infected with HIV, has not disclosed his or her HIV-positive
status, and acts with the specific intent to infect the other person with
HIV, is guilty of a felony.”
7/18/1437
http://www.hivandhepatitis.com/hiv-policy-advocacy/3803-hiv-medicine-association-calls-for-repeal-of-hiv-
criminalization-laws
• The divisions between intentional, reckless, and accidental
transmission can be blurred
• The majority of criminal convictions involving sexual transmission
involve an HIV positive person not informing their negative partner
about their status

39. Rhoades vs. Iowa (2008)
 Nick Rhoades (HIV+,VL undetectable) had sexual
encounter with another man – used a condom.
 HIV transmission did not occur
 Other man found out Rhoades was HIV infected, contacted police
 Rhoades received maximum sentence – 25 years in prison and
lifetime registration as a sex offender.
 Months later, sentence suspended – replaced with supervised
probation for 5 years
 Iowa Supreme Court (6/13/14) - sentence reversed
7/18/1438

40. HIV Transmission & The Law: Africa
 USAID has financed the
“Action forWestAfrica
Region HIV-AIDS
program” since 2004
 Instrumental in
developing a model for
HIV-specific criminal law
 27 African countries now
have active laws.
7/18/1439 http://www.change.org/petitions/demand-usaid-to-stop-funding-hiv-criminalization-laws-in-africa

41. Limitations of Phylogenetic Analysis
• Current techniques are NOT reliable enough to estimate the
direction of transmission with certainty.
• Similar strains may be found in many more than two individuals,
especially if they are part of the same transmission network.
7/18/14
A B C
E
D
F
G
H
?
?
40

42. Privacy Challenges
To develop and deploy privacy preserving methods for analyzing
network dynamics in order to share predictions about future
network growth with quantitative estimates of privacy risk.
7/18/1441

43. Phylogentics & Criminal Statutes
Plans
 Assess consumer and provider knowledge and expectations
associated with phylogenetic analyses
 Assess perceptions of acceptable risk and benefit for public health
and personal privacy
 Public health use of these data requires decriminalization
of unintended HIV transmission during consensual
exposure.
7/18/1442

44. 7/18/1443
Acknowledgements
OWEN CLINIC