Phylodynamically Estimated HIV Diversification Rates Reveal Prevention

of HIV-1 by Antiretroviral Therapy

Jeffrey B. Joy, Richard H. Liang, Rosemary M. McCloskey, Thuy Nguyen, Chanson J. Brumme, Guillaume Colley, Robert S. Hogg, Julio S.G. Montaner, P. Richard Harrigan, and Art F.Y.

Poon

Conflict of Interest

• I have no conflict of interest to declare.

What is Phylodynamics?

• How epidemiological, and immunological processes act to shape viral phylogenies

• Complementary approach to epidemiological data

• Utilizing only viral sequence data

• When combined with clinical and demographic attribute data can yield insights into epidemic dynamics

What is a virus phylogeny?

A virus phylogeny is a family tree of virus sequences

What is a virus phylogeny?

A virus phylogeny is a family tree of virus sequences

TimePast Present

TimePast Present

Phylogenetic Epidemiological InferencesHIV.Seq.1

HIV.Seq.2

HIV.Seq.3HIV.Seq.4

HIV.Seq.5

HIV.Seq.7

HIV.Seq.8

HIV.Seq.9

HIV.Seq.10

HIV.Seq.11HIV.Seq.

12HIV.Seq.

13HIV.Seq.14

HIV.Seq.6

TemporalDistribution of Nodes

(branching points)

151023

Distribution Branch Lengths

Treatment Prevents HIV Transmission

• Antiretroviral treatment reduces individual plasma viral loads to undetectable levels

• Reduces HIV related morbidity and mortality

• Reduces the risk of HIV transmission

IAS 2015

• We’ve heard strong evidence that treatment, especially early treatment, is highly beneficial

• UN 90-90-90 workshop

• Results of HPTN 052 trial

Quantifying Treatment Success at Preventing Transmission

Remains a Significant Challenge

Quantifying Treatment Success at Preventing Transmission

Remains a Significant Challenge

• Can we use methods of analyzing viral sequence data to make inferences about the effectiveness of treatment at reducing HIV transmission rates?

Diversification Rate

Slow DiversificationRate

Rapid DiversificationRate

Tim

e

• Diversification rate is the rate of splitting of branches in a phylogenetic tree relative to time

• In a virus phylogeny diversification rate approximates transmission rate

Treatment and Diversification Rate• Can uniquely assign an integrated diversification rate of a lineage to a tip in the tree

• We test the hypothesis that treated HIV lineages will display slower diversification (transmission) rates relative to untreated HIV lineages Slow Diversification

RateRapid Diversification

Rate

Tim

e

British Columbia HIV Sequences from the BC CfE

Database• 27,296 sequences (RT and Protease)

• 7,747 unique patients

• Annotated with patient and sequence attributes e.g.

• Sampling time

• Date of commencement of antiretroviral therapy

• Gender and age

Dataset Curation• Censored cases of transmitted drug

resistance - defined as presence of resistance in pre therapy sample

• Treatment experienced - defined as sequences collected after initiation of antiretroviral therapy

• Treatment inexperienced - defined as sequences collected before initiation of antiretroviral therapy

Distribution of Risk Factors

Phylogenetic Trees• Generated a distribution of 1000

phylogenetic trees using approximate Maximum Likelihood (FastTree2)

Price, M.N., et al. 2010. FastTree 2 approximately maximum-likelihood trees for large alignments. PloS One 5.3: e9490.

Diversification Rates of BC HIV Epidemic• Calculated lineage specific diversification

rates for each HIV lineage in each of 1000 trees

• Calculated the mean for each lineage

• Mapped associated rates onto phylogenetic trees

• Compared treated lineages to untreated lineages

BC HIV Diversification Rate

Treated Infections Transmit HIV Significantly Less

Untreated

TreatedN=562

N=1626

N=1028

N=831 N=116

N=332

N=2049

N=3546

Phylogenetics Shows Reduced Transmission in Treated Lineages• Measure derived directly from

secondary analysis of sequence data provides independent confirmation that treatment significantly reduces HIV transmission

• Lineage rather than group level

• Replicated across risk exposure categories

Acknowledgements• BC Centre for Excellence Molecular

Lab