Quantifying the Aftermath: Recent Outbreaks Among People Who Inject Drugs and the Utility of Phylodynamics

(See the Major Article by Ragonnet-Cronin et al, on pages 1875–82.) Despite increasing access to effective combination antiretroviral therapies, outbreaks of human immunodeficiency virus-1 (HIV-1) transmission continue to arise in vulnerable key populations in the setting of concentrated epidemics. In the context of an ongoing opioid crisis, socioeconomic inequalities, and limited access to care or harm reduction measures, there have been several prominent outbreaks among people who inject drugs (PWID). For example, 135 new HIV diagnoses were recorded from January to April 2015 within a network of PWID in a rural community of about 4200 persons in Indiana, United States [1]. In Canada, a disproportionate number of new HIV-1 diagnoses are accumulating in Aboriginal communities in Saskatchewan, driven by a long history of social and economic disparities, injection drug use, and a critical lack of access to HIV services [2]. Some severe HIV-1 outbreaks have become foci of detailed retrospective case studies with the objective of understanding the main drivers of transmission rates. Recent studies in this area have combined conventional methods, such as contact tracing, with relatively newer approaches based on the analysis of pathogen sequences, such as phylogenetic reconstruction [3] or genetic clustering [4]. A genetic cluster is a group of sequences that are more similar to each other than to the remaining sequences in the sample population. Genetic clustering methods have been used in virology research for several decades to classify subtypes [5], and increasingly more often to identify potential transmission outbreaks, particularly in the field of HIV-1 research [6]. These retrospective studies generally aim to identify cases in clusters defined by location and/or time that are also closely linked epidemiologically, that is, in terms of the number of transmission events separating them. This growing popularity of applying genetic clustering to potential outbreaks has been accompanied by increased scrutiny of the underlying methods [7]. For instance, multiple studies have observed that clusters of genetic similarity may result from oversampling acute and early infections [8, 9] instead of elevated transmission rates. This implies that clusters based on genetic similarity tend to group together individuals diagnosed early after infection and already engaged with HIV prevention and care services [9]. Phylodynamics is a term coined by Grenfell and colleagues [10] to refer to the emerging science of reconstructing how virus phylogenies are shaped by evolution and the underlying immunological and epidemiological processes in the host population. Clustering is a rudimentary form of phylodynamic inference, because clusters are often derived from features of phylogenetic tree shapes (eg, compact and robust subtrees [11]) and interpreted in an epidemiological context. Extracting clusters of infections can also yield smaller and reproducible targets for a more detailed phylodynamic analysis [12]. Because most phylodynamic analyses require computationally demanding methods (eg, numerical solution of differential equations, Monte Carlo sampling), targeting a defined cluster can significantly reduce the processing time required to estimate parameters that have a fundamental and time-dependent role in understanding the unfolding disease dynamics, such as the basic reproduction number (R0) [13–16]. However, downsizing for computational tractability is not necessarily straightforward, as poorly identified clusters (eg, due to nonepidemiological effects such as over-sampling) can falsely masquerade as growing epidemics [17]. In this issue of The Journal of Infectious Diseases, Ragonnet-Cronin and colleagues present a detailed analysis of the epidemic dynamics in a genetic cluster of related HIV-1 infections among PWID in Scotland. In the context of a resurgence of HIV diagnoses among PWID in 2015, the authors analyzed 228 HIV-1 pol sequences that were collected for routine baseline resistance testing, together with large numbers of related sequences from protected (UK HIV Drug Resistance Database, UKRDB) and public (Los Alamos National Laboratory, LANL) databases, for a total of 2572 sequences. Pairwise distance clustering identified a single large cluster of 104 HIV-1 subtype C sequences from PWIDs in Scotland. More than two-thirds of cases in the cluster were diagnosed after 2014. A lack of contemporaneous data may have contributed to the absence of background sequences in this cluster, because neither the UKRDB nor the LANL database contained samples more recent than 2014 when they were accessed for this study. All sequences in the cluster carried a combination of minor drug resistance mutations (E138A and V179E), which are more common among subtype C infections [18] and seldom observed in the United Kingdom. Next, the authors employed a Bayesian sampling method to fit a “birth-death skyline” model [19] to this cluster to reconstruct the effective reproductive number (Re), the expected number of secondary infections per case over the course of an epidemic; Re values greater than 1 suggest a growing epidemic. The model was adjusted to accommodate a shift in sampling rates over time. Overall, the mean Re was estimated at 1.5 cases with periods of elevated Re mapped to 2008–2010 and 2014–2016. It was unclear whether similar estimates of Re might have been obtained from subtrees relating nonclustered HIV-1 sequences from the same site—such an analysis would not have to be limited to subtype C sequences from the clinic and could establish the cluster as representing an outbreak rather than a sampling artifact. This is timely work that compellingly represents the utility of current phylodynamic methods in HIV-1 research. While retrospective studies are useful for understanding the historical context of an outbreak, they are often deployed after large numbers of cases have already been diagnosed. Thus, the authors raise an important question of whether a more timely application of clustering and/or phylodynamic analysis might better support HIV-1 prevention efforts by alerting public health personnel at an earlier stage of the outbreak. This particular outbreak was flagged early because of a rare drug-resistance profile. By the time the reported analysis was completed, however, an estimated two-thirds of the outbreak had been sampled through a research-driven initiative, rather than active surveillance. How early could the cluster have been detected by phylodynamic methods or by case counting [20] had the resistance profile not been so notable? We believe there was a missed opportunity to address this question by comparing estimates of Re or case counts against the background for time-censored databases. How many cases could have been averted through timely intervention, triggered into action by assessing changing cluster dynamics? We highlight these points to call for a profound shift in use and further development of phylodynamic methods. Specifically, they need to be able to provide timely and actionable information for public health, to differentiate emerging or active subepidemics from those that are “latent” instead of being applied retrospectively. Phylodynamic methods offer the opportunity for a more automated approach to identifying developing outbreaks in the population at large, by comparing the changing cluster profile in a database over time. Previously, near-real-time monitoring was demonstrated as feasible in British Columbia, Canada, finding a single cluster that expanded by 11 cases in 3 months, and subsequently initiating follow up strategies where identifying information was securely handled within the preexisting clinical and public health frameworks [21]. New technologies, both in sequencing and computational tools, bring this goal within reach, as evidenced during the recent Zika outbreaks [22, 23]. However, real-time sampling requires us to re-evaluate our assumptions and standardized practices in phylodynamics. Genetic clusters do not capture the full extent of an outbreak, because these constructs cannot account for unsampled infected individuals. Reaching these undiagnosed individuals is imperative to support public health efforts. Moreover, because the objective is to detect outbreaks while the proportion of sampled infections is low, birth-death models such as employed in this study no longer hold high sampling fractions as an advantage over coalescent models. We also need more-flexible models to account for changes in sampling strategy over time, both in terms of the proportion sampled, and where from. Karcher and colleagues recently showed that preferential sampling can bias phylodynamic estimates [24], whereas Hall and colleagues have illustrated issues with sampling of structured populations for the coalescent skyline family of models [25]. Technical improvements are not the only challenge for contemporaneous outbreak studies; there are also ethical considerations that these novel methods bring to the fore, especially regarding the identifiability of sequence information. This, of course, is true of all studies handling HIV data, but the importance of how changing technologies can clash with current definitions of patient privacy and informed consent bears reiterating. In the context of evaluating subepidemics, phylodynamic studies are primarily interested in what is happening at the population, rather than the individual, level. Carrying out phylodynamic analyses within the ethical framework of public health does not necessarily require informed consent, but the stoichiometry of that framework requires a significant public health benefit to outweigh the individual-level risk. As a research field, we need to demonstrate this benefit, working together with a range of knowledge users and stakeholders—public health officials, physicians, ethicists, persons living with or at risk of acquiring HIV, and community advisory board representatives—to optimize the advantages that novel phylodynamics approaches can bring to public health, while not jeopardizing our ethical and legal responsibilities to people living with HIV [26, 27]. Until we can develop more timely applications of phylodynamics, our contribution to the ethical equation would remain as being prospectors sifting the aftermath of an epidemic for the largest human toll. Disclaimer. The views expressed are those of the authors and should not be construed to represent the positions of the US Army or the Department of Defense. Financial support. This work was supported by the Canadian Institutes of Health Research (grant numbers PJT-153391, BOP-149562, FRN-130609); by the Government of Canada through Genome Canada and the Ontario Genomics Institute (grant number OGI-131); and by a cooperative agreement (W81XWH-11-2-0174) between the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., and the US Department of Defense. Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

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