The HIV-1 subtype B epidemic amongst men who have sex with
men (MSM) is resurgent in many countries despite the widespread use of
effective combination antiretroviral therapy (cART). In this combined
mathematical and phylogenetic study of observational data, we aimed to find out
the extent to which the resurgent epidemic is the result of newly introduced
strains or of growth of already circulating strains.
As of November 2011, the ATHENA observational HIV cohort of
all patients in care in the Netherlands since 1996 included HIV-1 subtype B polymerase sequences from 5,852 patients. Patients who
were diagnosed between 1981 and 1995 were included in the cohort if they were
still alive in 1996. The ten most similar sequences to each ATHENA sequence
were selected from the Los Alamos HIV Sequence Database, and a phylogenetic
tree was created of a total of 8,320 sequences. Large transmission clusters
that included ≥10 ATHENA sequences were selected, with a local support value ≥
0.9 and median pairwise patristic distance below the fifth percentile of
distances in the whole tree. Time-varying reproduction numbers of the large
MSM-majority clusters were estimated through mathematical modeling. We
identified 106 large transmission clusters, including 3,061 (52%) ATHENA and
652 Los Alamos sequences. Half of the HIV sequences from MSM registered in the
cohort in the Netherlands (2,128 of 4,288) were included in 91 large
MSM-majority clusters. Strikingly, at least 54 (59%) of these 91 MSM-majority
clusters were already circulating before 1996, when cART was introduced, and
have persisted to the present.
Overall, 1,226 (35%) of the 3,460 diagnoses
among MSM since 1996 were found in these 54 long-standing clusters. The
reproduction numbers of all large MSM-majority clusters were around the
epidemic threshold value of one over the whole study period. A tendency towards
higher numbers was visible in recent years, especially in the more recently
introduced clusters. The mean age of MSM at diagnosis increased by 0.45
years/year within clusters, but new clusters appeared with lower mean age.
Major strengths of this study are the high proportion of HIV-positive MSM with
a sequence in this study and the combined application of phylogenetic and
modeling approaches. Main limitations are the assumption that the sampled
population is representative of the overall HIV-positive population and the
assumption that the diagnosis interval distribution is similar between
clusters.
The resurgent HIV epidemic amongst MSM in the Netherlands is
driven by several large, persistent, self-sustaining, and, in many cases,
growing sub-epidemics shifting towards new generations of MSM. Many of the
sub-epidemics have been present since the early epidemic, to which new
sub-epidemics are being added.
Below: Proportional contribution of new HIV-1 diagnoses amongst all MSM in the ATHENA cohort by decade of birth
Below: Diagnosis and growth of transmission clusters over time.
Cluster types within the phylogenetic tree are defined as
follows. Singletons (in blue) are clusters of size 1, or cases whose sequence
solely clustered with sequences from the Los Alamos HIV Sequence Database.
Small clusters (in green) comprise sequences from 2–9 ATHENA patients. Large
clusters comprise sequences from ten or more patients in the ATHENA cohort.
Amongst those, non-MSM-dominant clusters (in brown) contain a majority of
sequences from non-MSM patients, whilst MSM-majority clusters contain a
majority of sequences from MSM patients. Among large MSM-majority clusters,
pre-1996 clusters (in dark orange) are defined as those in which the first
diagnosed patient in the cluster was diagnosed before 1996, and post-1996
clusters are defined as those in which all patients in the cluster were
diagnosed in or after 1996. Large MSM-majority post-1996 clusters are
stratified as “time of MRCA pre-1996” (in light orange) when the estimated time
of the MRCA is before 1996, and “time of MRCA post-1996” (in purple) when the
estimated time of the MRCA is in or after 1996. (A) Number of MSM registered in
the ATHENA cohort in the Netherlands with a sequence in this study by year of
diagnosis and by cluster type. (B) Number of clusters of each type by year of
first diagnosed case in each cluster.
By:
Daniela Bezemer, Ard van Sighem, Luuk Gras, Rob van den
Hengel, Peter Reiss
HIV Monitoring Foundation,
Amsterdam, the Netherlands
Anne Cori, Oliver Ratmann, Frank de Wolf, Christophe Fraser
Medical Research Council Centre
for Outbreak Analysis and Modelling, Department of Infectious Disease
Epidemiology, School of Public Health, Imperial College London, London, United
Kingdom
Hillegonda S. Hermanides, Ashley J. Duits
Red Cross Blood Bank Foundation,
Willemstad, Curaçao
Bas E. Dutilh
Centre for Molecular and
Biomolecular Informatics, Nijmegen Centre for Molecular Life Sciences, Radboud
University Medical Centre, Nijmegen, the Netherlands
Bas E. Dutilh
Department of Marine Biology,
Institute of Biology, Federal University of Rio de Janeiro, Rio de Janeiro,
Brazil
Bas E. Dutilh
Theoretical Biology and
Bioinformatics, Utrecht University, Utrecht, the Netherlands
Nuno Rodrigues Faria
Department of Zoology,
University of Oxford, Oxford, United Kingdom
Peter Reiss
Department of Global Health,
Academic Medical Center, Amsterdam, the Netherlands
Peter Reiss
Amsterdam Institute for Global
Health and Development, Amsterdam, the Netherlands
