Partners in Prevention

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Partners in Prevention

• Jim Hughes
• in collaboration with, and many slides stolen
  from
• Connie Celum
• Mary Campbell
• Jai Lingappa
• Gerry Myers
• Jim Mullins

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HIV and Herpes

• HIV HSV-2 ? increased HIV viral loads

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HIV and Herpes

• HIV HSV-2 ? increased risk of transmitting the
  virus

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HIV and Herpes

• Acyclovir (and related drugs) are very effective
  in suppressing the HSV-2 virus
• Acyclovir has no direct effect on HIV but
• Acyclovir ? ? HSV-2 replication ? ? HIV viral
  load ? ? HIV transmission
• Can we reduce the risk of HIV transmission in
  HSV-2 HIV-positive individuals by treating
  their HSV-2 infection with acyclovir?

?
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Partners in PreventionHSV-2 Suppression to
Prevent HIV Transmission
1 endpoint HIV infection in HIV-negative partner
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Partners in Prevention

• HIV-infected partner (also HSV-2 infected)
  index
• HIV-uninfected partner partner
• Intervention Daily acyclovir (400 mg, bid) given
  to the index
• Primary outcome HIV infection measured on the
  partner compare infection rates between the two
  arms
• Two analyses of interest
• All transmissions (easy)
• Only transmissions from the index (hard)

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Is the index the source of the partners HIV-1
infection?

• HIV viral sequence is extremely variable due to
  rapid mutation rate
• Procedures for determining linkage first
  developed by Gerry Myers, Jim Mullins, Glen
  Satten and colleagues for the Florida Dentist
  Case in the early 1990s

• Phylogenetic Trees
• Genetic Distance
• Amino Acid Signature Pattern

Ou, et al 1992. Science 2561165 Learn and
Mullins. 2003. HIV Sequence Compendium 200322.
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PhylogeneticsBasic Concepts

• Trees are comprised of tips, branches and nodes
• Tips represent the actual gene sequences used to
  create the tree
• A branch is a representation of the genetic
  distance separating tip sequences.
• A node represents the hypothetical ancestor of
  the sequences on the branches stemming from it
• Monophyletic group Clade
• terms used interchangeably
• implies descent from a single common ancestor

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Simple Phylogenetic Tree
monophyletic sequence pair
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Genetic Distance
Number of mismatched
positions Distance ______________________
Number of positions in alignment

• the number of nucleotide changes needed to make
  one sequence the same as another in an alignment
• can be calculated from pairwise comparisons or
  estimated by tracing distances between sequences
  on a phylogram

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PhylogeneticLinkage Analysis
13.4
3.3
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Is the index the source of the partners HIV-1
infection?

• Monophyletic pair
• Gives yes/no answer, but no degree of uncertainty
• Should intervening sequence automatically rule
  out linkage?
• Should lack of an intervening sequence
  automatically confirm linkage?
• Genetic Distance
• Linked partners should have sequences that are
  close unlinked partners should have sequences
  that are not close
• Is there a magic distance which separates
  linked and unlinked? Not quite but

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Smoothed probabilities for distances between
sequence pairs known to be linked or unlinked


linked unlinked
0.0
0.1
0.2
0.3
0.4
Distance
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Bayesian Classification of partner linkage
D distance P(D linked) probability of
distance D assuming linkage (based on
intra-individual sequence pairs and partners
known to be linked) P(D not linked)
probability of distance D assuming no linkage
(based on sequence pairs from apparently unlinked
individuals) P(linked) assumed probability of
linkage before looking at D. P(linked D)
posterior probability of linkage base decision
on this.
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• Issues/Challenges
• At present, the algorithm is based on distances
  only. In principle, additional quantitative data
  could be incorporated into the information D.
• What should the prior P(linked) be?

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• Issues/Challenges
• At present, the algorithm is based on distances
  only. In principle, additional quantitative data
  could be incorporated into the information D.
• What should the prior P(linked) be?
• We set the prior equal to the proportion of
  linked partnerships over all PIP seroconverters
• Most decisions not very sensitive to choice of
  prior

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• Issues/Challenges
• Classification may be based on individual
  sequence pairs (multiple per partnership) or
  consensus sequence pairs (generally one per
  partnership)

• Single consensus sequence may not represent all
  variants
• Combining information from multiple sequence
  pairs poses methodologic challenges
• The transmitting partner may have multiple
  variants but only one may match the variant found
  in the newly infected partner. Should this be
  considered linked? What if the situation is
  reversed?

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Pair 58
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• Contrasts between Bayesian and phylogenetic
  approaches
• Bayesian classifier based on distances only and
  does not explicitly consider context (i.e.
  monophyletic or not)
• In this application, monophyletic approach tends
  to more conservative (more likely to call the
  sequences unlinked) more appropriate for
  courtroom?
• Use of explicit prior assumption in Bayesian
  formulation allows control of conservativeness
• Bayesian classifier can incorporate additional
  information on partnership (e.g. gender, reported
  number of sex partners) in through prior

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Questions

• What scientific question is the PIP trial trying
  to answer?
• Why is it difficult to to determine if one person
  has transmitted the HIV virus to another (even if
  you have virus samples from both individuals)?
• What genetic measurement does the Bayesian
  classifier use to determine the probability of
  transmission?