Using phylogenetic analysis and contact tracing to identify HIV transmitters possible, but legally problematic

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Identifying diagnosed and undiagnosed individuals within sexual networks through a combination of contact tracing and phylogenetic analysis may result in improved public health outcomes as long as there are no legal repercussions in doing so, according to a Californian study performed amongst acutely infected gay men published in the January 14th issue of the journal, AIDS.

A second phylogenetic analysis study, using pan-European data and published in February’s Journal of Infectious Diseases, suggests that it may be chronic infection, rather than primary infection, that drives HIV transmission within such sexual networks.

Phylogenetic analysis compares viral gene sequences with a control group in order to determine the likelihood that two or more samples are related. Although phylogenetic analysis is not considered a reliable way to prove that one individual has infected another, it can provide suggestive information about clusters of infection involving two or more individuals that may be useful for public health interventions.

Glossary

phylogenetic analysis

The comparison of the genetic sequence of the virus in different individuals in order to determine the likelihood that two or more samples are related. This involves creating a hypothetical diagram (known as a phylogenetic tree) that estimates how closely related the samples of HIV taken from different individuals are. Phylogenetic analysis is not a reliable way to prove that one individual has infected another, but may identify transmission clusters, which can be useful for public health interventions.

acute infection

The very first few weeks of infection, until the body has created antibodies against the infection. During acute HIV infection, HIV is highly infectious because the virus is multiplying at a very rapid rate. The symptoms of acute HIV infection can include fever, rash, chills, headache, fatigue, nausea, diarrhoea, sore throat, night sweats, appetite loss, mouth ulcers, swollen lymph nodes, muscle and joint aches – all of them symptoms of an acute inflammation (immune reaction).

primary infection

In HIV, usually defined as the first six months of infection.

control group

A group of participants in a trial who receive standard treatment, or no treatment at all, rather than the experimental treatment which is being tested. Also known as a control arm.

transmission cluster

By comparing the genetic sequence of the virus in different individuals, scientists can identify viruses that are closely related. A transmission cluster is a group of people who have similar strains of the virus, which suggests (but does not prove) HIV transmission between those individuals.

Although there are limitations to both phylogenetic analysis and contact tracing, (outlined in detail in this report from CROI last year) combining both methods may be useful in identifying individuals who are transmitting HIV, according to investigators from the University of California San Diego.

To examine the feasibility of such an approach, they obtained contact tracing information voluntarily supplied by 36 mostly white, gay participants in the First Choice Program (FCP) cohort, which had enrolled 369 individuals with acute or early HIV infection (average 76 days) between July 1996 and May 2007. Using the rest of FCP cohort and an additional 268 newly diagnosed primarily white, gay individuals enrolled in the San Diego County Resistance Testing Program (SDC-RTP) as a control group, they used phylogenetic analysis to examine whether the partners named during contact tracing were part of larger HIV transmission clusters in San Diego.

Twelve (33%) of the individuals named via contact tracing were found to have HIV that differed genetically by more than 5%, strongly suggesting that they could not have infected the individuals that named them. The remaining 24 had HIV that differed genetically by less than 1%, suggesting to the researchers a phylogenetic linkage. However, only two of the 36 named individuals did not know that they were HIV-positive – one was found to have primary infection, the other was chronically infected.

When the investigators performed phylogenetic analysis on the combined cohort (comprising all of individuals in the FCP, the SDC-RFP and the 36 named contacts) they found a total of 37 clusters involving 160 individuals (25% of the combined cohort); the largest cluster involved twelve individuals.

Five of the named contacts that could not have infected the individuals that named them were found to cluster with someone else in the cohort. In fact, the 29 individuals named as contacts were found to be 21 times more likely to appear within clusters than members of the SCD-RFP cohort.

“Taken together,” write the investigators, “this information outlines how molecular surveillance and contact tracing can be used to define transmission clusters within a population and identify individuals who have a high likelihood to belong to these clusters. Future studies will need to be performed to determine how these individuals can then be targeted for prevention measures.”

The investigators note, however, that “[t]here is significant concern that [these] public health procedures could place source partners of HIV transmission at legal jeopardy, because in nearly every jurisdiction in the United States, it is illegal to transmit or expose someone to HIV.” In fact, the investigators obtained a “certificate of confidentiality to help protect the identity of the study participants and ensure that investigators will not be forced to divulge confidential research information without their written permission, even in the face of a court order.”

Consequently, they conclude that their methods can only be considered to be useful and safe once “unintended HIV transmission during consensual exposure” is decriminalised and when there is “legal recognition that phylogenetic [analysis] does not prove beyond a reasonable doubt that transmission between partners occurred.”

A second phylogenetic analysis study, using pan-European data obtained from the CASCADE cohort of recently infected individuals, questions some of the methodology of a 2007 study from Canada which suggested that primary infection was driving the HIV epidemic in Quebec.

The main concern of this paper is that the 2007 study combined individuals with both ‘primary’ and ‘early’ HIV infection and consequently overestimated the role of primary, or acute, HIV infection which, the authors of this paper defined as being no longer than the first six months following infection. “Viral load is known to peak less than a month after infection but remains elevated for ~ 10 weeks,” they write. They point out that the average estimated length within transmission clusters in the 2007 was 15 months, which suggests that most infections originated from chronically (albeit relatively recently) infected individuals.

The investigators compared phylogenetic analysis on 165 HIV sequences obtained from CASCADE participants (primarily gay men) with documented acute infection with the rest of the CASCADE cohort (8828 individuals) and found that 18 (11%) were clustered (nine clusters comprising two individuals). Of these, only two clusters were likely to have been as a result of onward primary infection (29 and 104 days after infection) with the remaining clusters averaging 675 days between infections.

“This analysis is not an attempt to measure the force of infection from the acutely HIV infected but a demonstration of the need for rigor in the design and interpretation of such analyses," they write.

“Previous analyses that use liberal definitions of acute HIV infection and do not take into account the transient nature of infection stage may inaccurately calculate the force of infection from this group,” they conclude.

References

Smith DM et al. A public health model for the molecular surveillance of HIV transmission in San Diego, California. AIDS 23, 225-232, 2009.

Brown AE et al. Phylogenetic reconstruction of transmission events from individuals with acute HIV infection: toward more-rigorous epidemiological definitions. JID 199, 427-431, 2009.