Detailed Transmission Network Analysis of a Large Opiate-Driven Outbreak of HIV Infection in the United States

Abstract

In January 2015, an outbreak of undiagnosed human immunodeficiency virus (HIV) infections among persons who inject drugs (PWID) was recognized in rural Indiana. By September 2016, 205 persons in this community of approximately 4400 had received a diagnosis of HIV infection. We report results of new approaches to analyzing epidemiologic and laboratory data to understand transmission during this outbreak. HIV genetic distances were calculated using the polymerase region. Networks were generated using data about reported high-risk contacts, viral genetic similarity, and their most parsimonious combinations. Sample collection dates and recency assay results were used to infer dates of infection. Epidemiologic and laboratory data each generated large and dense networks. Integration of these data revealed subgroups with epidemiologic and genetic commonalities, one of which appeared to contain the earliest infections. Predicted infection dates suggest that transmission began in 2011, underwent explosive growth in mid-2014, and slowed after the declaration of a public health emergency. Results from this phylodynamic analysis suggest that the majority of infections had likely already occurred when the investigation began and that early transmission may have been associated with sexual activity and injection drug use. Early and sustained efforts are needed to detect infections and prevent or interrupt rapid transmission within networks of uninfected PWID.

Keywords: HIV outbreak; PWID; phylodynamic; transactional sex; transmission network.

Figure 1.

Contact tracing network, human immunodeficiency virus (HIV) outbreak, Scott County, Indiana, 2015. Each blue (uninfected) circle represents a person at high risk of HIV infection. Red circles represent HIV-positive individuals. Each circle is sized according to the number of high-risk contacts reported by the corresponding individual or partner, with scale shown in the figure. IDU, injection drug use contact; sex, sexual contact; sex+IDU, sexual and injection drug use contact.

Figure 2.

Distribution of risk exposure type by the total number of unique reports of high-risk contact per individual, by contact type (injection drug use contact [IDU], sexual contact only [sex], and both sexual and injection drug use contact [sex+IDU]; A) and the total number of unique reports of high-risk contact per individual by contact type and viral genetic subgroup (A–F and O; B). Note scaling differences on x-axes for each contact type.

Figure 3.

Quantification of human immunodeficiency virus (HIV) infection risk levels, by decision tree analysis based on behavioral risk factors, including number of injection drug–using and sex partners. The decision tree is colored and scaled with respect to the prevalence of HIV-positive persons within each node. Each split in the decision tree is statistically significant (P < .05). IDU, injection drug use contacts; sex, sexual contacts; sex+IDU, sexual and injection drug use contacts.

Figure 4.

Human immunodeficiency virus (HIV) polymerase (pol) sequence analyses. Genetic subgroups in the phylogeny (branches) and network (nodes) are colored as shown in the key. A, Phylogeny of 183 HIV pol sequences, colored by genetic subgroup, from the Indiana outbreak and local Indiana reference pol sequences (gray). Phylogenetic analyses were conducted using FastTree maximum likelihood analysis. Circles are sized according to the corresponding individual’s number of reported high-risk contacts. Confidence values for branching patterns were assessed by using the Shimodaira-Hasegawa (sh) test and are given as probabilities at nodes (*, sh > 0.80; ◊, sh > 0.90). B, Genetic distance (d) network, using a d threshold of ≤0.1%. Ref, reference.

Figure 5.

Genetic distance and inferred human immunodeficiency virus (HIV) transmission networks. Circles represent a polymerase (pol) sequence isolated from an HIV-infected person. Lines represent close genetic links between HIV sequences. Genetic subgroups in the network (nodes) are colored as shown in the key. A, HIV pol genetic distance (d) network, using a d cutoff of ≤1.5%. B, Nonisomorphic minimum spanning trees (MSTs) of the HIV pol genetic distance network. C, Inferred transmission network based on the synthesis of the pol genetic distance network in panel A and the MSTs in panel B. Lines represent inferred transmission events, with the thickness proportional to 1.0 – d. Bridge, sequence from person in network linking genetic subgroups; CSW, commercial sex worker contact and/or transactional sexual contact; earliest observed diagnosis, person in network identified during outbreak investigation who had the earliest HIV infection diagnosis; IDU, injection drug use; unreported, contact information not reported.

Figure 6.

Cumulative human immunodeficiency virus (HIV) diagnoses (red) and simulated incidence (light blue), by date. Mean cumulative seroconversion dates over time are in dark blue. Dot-dashed vertical gray lines indicate important dates during the outbreak response and their corresponding locations on the curve (horizontal black arrows). By use of avidity indices determined by serological HIV recency testing (Supplementary Materials), outbreaks were simulated to infer the time course of the outbreak. The panel on right shows an expanded view of results on the timeline during the first half of 2015.