Phylodynamics of the German HIV-1 Subtype A and C epidemic AREVIR 06.05.2017 Kirsten Hanke

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Distribution of HIV-1 subtypes worldwide

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The origin and diversity of the HIV-1 pandemic, Hemelaar Trends in Molecular Medicine Volume 18, Issue 3, p182–192, March 2012

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German subtype A epidemic is attributed to two

independent virus variants

Subtype A circulates endemically in Germany

since 30 years

13 German clusters from which 6 are still active

Early infections by Eastern African variant among

MSM and HET (origin in Kenya, Kongo and

Uganda)

1995-2005 strong spread of the Eastern European

variant (AFSU) among PWID

Recent infections mainly by Eastern European

variant especially among German MSM

Most recent transmission clusters are German

MSM clusters formed after 2013

Review Subtype A

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147 RKI samples: 92 MolSurv, 48 SC, 6 DS Sampling period 1992-2016 Reference panel: 442 closely related subtype C sequences retrieved by BLAST

search of the Los Alamos HIV database Bayesian phylogenetic analysis using BEAST v1.8.3 discrete asymmetric

diffusion models to infer epidemiological linkage among geographic regions and transmission groups

Multitype-tree Birth-Death and Birth-Death skyline (BDSKY) analyses (BEAST v2.4) to estimate changes in effective reproduction numbers (Re)

AIM: Characterization of the German Subtype C epidemic (e.g. course of the

epidemic, origin, affected risk groups) Identification and characterization of endemic German clades. Dating of their

first common ancestor in Germany Identification of active clusters showing ongoing transmission events

Analysis of Subtype C

Risk n % HET 73 50,3

MSM 35 24,1 PWID 10 6,9

PPI 2 1,4 X 27 17,2

sum 147 100,0

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Phylogenetic origin of SubC in Germany: at least 2 subepidemics

Southern African clade

Eastern African clade

Brazil

India

Second Eastern African introduction

1963

1968

1966 1975

1972

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Criteria: Clades with posterior probability = 1 At least 3 German subtype C sequences within this clade the common ancestor is estimated to have introduced infection in

Germany

Identification of clades originating in Germany

Criteria: at least two infections have occurred within this clade during the last 3

years

Active clades showing ongoing transmission in Germany

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German SubC clusters 10 German clusters 4 x HET 4 x MSM; 1 x MSM/HET 1 x Mixed PWID

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Phylogenetic origin of German SubC clusters

Southern African clade

Eastern African clade

Brazil

India

Second Eastern African introduction

German SubC clusters

10 German Sub C cluster als bunte Tabelle # size tMRCA subclade origin Risk active

1 13 2010 South Africa ZW, ZM, MZ PWID (HET/MSM) +

2 7 2004 South Africa ZA MSM +

3 5 2008 South Africa FI, NO, ZA, BW MSM -

4 4 1997 South Africa ZM, ZA, ZW HET -

5 4 2007 South Africa BW, ZA HET -

6 3 2012 (South Africa) DRC, MA MSM +

7 3 2014 Eastern Africa BR MSM/HET +

8 9 2007 Eastern Africa BR MSM +

9 3 2002 Eastern Africa TZ, BI HET -

10 3 2005 Eastern Africa ET, SD HET/PPI +

SubC is increasing again in Germany: Estimation of effective reproduction numbers (Re)

HET

MSM

PWID

active inactive

Re Eastern African clade

Re South African clade

Re: estimates the average number of secondary cases per infectious case in a population made up of both susceptible and non-susceptible hosts.

R e

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Subtype C is traditionally transmitted by heterosexual contacts

HET

MSM

PWID

PPI

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Impact of the various transmission routes on the German epidemic

Eastern African subclade

South African subclade

R e R e

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All PWID infected with subtype C in

one cluster cluster 1, 13 individuals 10 PWID, 1 MSM, 1 HET, 1 unknown 11 male, 2 female (both PWID) 26-42 years old Nationality: 10 DE, 1 GR, 1 LV, 1 KZ Country of infection: Germany First registered infection in Germany:

03/2015 10 individuals sampled between

02-05/2016 tMRCA 2010 or 2015, respectively Area of living: Munich (and Augsburg)

Strong increase of PWID mediated infections in I/2016

Risk

PWID HET MSM

2010 2015

Transmitted SDRM

559; 94%

5; 1% 17, 3%

10, 2% 1 1

34; 6%

SDRM in all samples (n=589)

Sensitive PI NNRTI NRTI PI/NNRTI NNRTI/NRTI

134; 90.5%

3; 2.0%

8; 5.4%

2; 1.4% 1; 0.7%

14; 9.5%

SDRM of RKI samples only (n=147)

Sensitive PI NNRTI NRTI PI/NNRTI

No accumulation of SDRM in German subC clusters

NNRTI SDRM NRTI SDRM PI SDRM

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German subtype C epidemic is attributed to two

independent virus variants

10 German clusters from which 6 are still active

Early infections (until early 1990s) mainly by HET

transmission (both clades)

1993-2007 drop in subtype C infections

Since 2007 strong increase of infections in both

subclades especially for MSM (but also HET)

Until 2005 no transmission among PWID observed

strong increase in one transmission cluster within

South African subclade in I/2016

Among active clusters are 4 MSM clusters, 1 PWID

cluster and 1 HET cluster (infections occurred in

Ethiopia)

MSM clusters in Eastern African subclade are

phylogeographically linked with epidemic in Brazil

Spread of Subtype C to Germany

Brazil

South Africa

DRC

Ethiopia

India

Germany

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Subtype A Subtype C

Phylogenetic origin of German epidemic

Eastern Africa & Central/Western Africa + FSU

Eastern Africa (in part via Brazil) & Southern Africa

tMRCA (95% HPD) 1953.6 (1951.2-1965) 1963.6 (1956-1967.6)

# of German clusters 13 10

# of active clusters 6 6

Risk groups cluster (HET/MSM/PWID)

6 HET, 5 MSM, 2 mixed PWID 4 HET, 4 MSM, 1 mixed HET/MSM, 1 PWID

Risk groups current epidemic (clusters)

1 HET, 3 MSM, 2 PWID

1 HET, 4 MSM, 1 PWID

TDR in clusters PI TDR in 2 MSM clusters No cluster associated TDRs

Sequences analyzed 183 (in total 743) 147 (in total 589)

Comparison with SubA epidemic

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Similar analyses with other nonB subtypes (G, F, CRF01AE and CRF02AG)

Huge subtype B analysis 1983-2017: >5000 sequences

Outlook

Diagnostic labs: InzSurv/MolSurv HIV-1 Seroconverter

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Andrea Hauser Claudia Kücherer Karolin Meixenberger Norbert Bannert

Acknowledgments

Barbara Gunsenheimer-Bartmeyer Viviane Bremer Alexandra Hofmann Daniel Schmidt

RKI – Unit HIV and other Retroviruses

RKI - Unit HIV/AIDS, STI and Blood-borne Infections

Bioinformatics Denise Kühnert, Zürich Nuno R. Faria, Oxford Oliver Pybus, Oxford Max von Kleist, Berlin Kaveh Youssef, Berlin

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ancestral subtype C strain of HIV-1 migrated from Kinshasa to the southern provinces of the Democratic Republic of the Congo (DRC) migration occurred via major rail networks connecting Kinshasa with southern DRC

ancestral subtype C strain of HIV-1 was introduced into the southern Katanga region of the DRC in the late 1930s (95% HPD 1919 – 1957) then spread independently to east and southern African respectively

tMRCA of the southern African HIV-1 subtype C epidemic at around 1960 (95% HPD 1956 – 1964), with similar estimates for individual countries within the region

large number of infections were introduced into South Africa via foreign migrants from other southern African nations during the 1970s and 80s

strong periods of epidemic growth during the 1970s and 1980s for the southern African epidemic. The origin of the subtype C epidemic in the region can be placed around 1960 (95% HPD 1956 –

 1964) with strong periods of epidemic growth during the 1970s and 80s for the southern African region and during the 1980s and 90s for South Africa. The periods of strong epidemic growth coincide with periods of socio-political changes in the region during the latter part of the 20th century. The results from the phylogenetic reconstruction support that migration played an important role in facilitating the introduction and spread of the virus throughout the region and in South Africa in particular. Furthermore, the usage of older sequences provided more accurate estimates of the origin and rate of growth of the epidemic than previous subtype C studies, which used mostly contemporary sequences, further reducing uncertainty in our estimates. (Wilkinson 2015 http://www.nature.com/articles/srep16897)

a substantial proportion of subtype C infections in east Africa resulted from dissemination of a single HIV local variant, probably originated in Burundi during the 1960s. Burundi was the most important hub of dissemination of that subtype C clade in east Africa, fueling the origin of new local epidemics in Ethiopia, Kenya, Tanzania and Uganda. Subtype C lineages of southern African origin have also been introduced in east Africa, but seem to have had a much more restricted spread (Delatorre & Bello, 2012 https://www.ncbi.nlm.nih.gov/pubmed/22848653)

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