Download Primary HIV Infection, Phylogenetics, and Antiretroviral Prevention

E D I T O R I A L C O M M E N TA R Y
Primary HIV Infection, Phylogenetics, and Antiretroviral
Prevention
Deenan Pillay1 and Martin Fisher2
1
Centre for Infections, Health Protection Agency, and Department of Infection, University College London, and 2Department of HIV/Genitourinary Medicine, Brighton
and Sussex University Hospitals, Brighton, United Kingdom
(See the article by Brenner et al., on pages 951–9.)
Over the past 10 years, the world has witnessed one of the most significant chronic disease interventions ever seen—that
of highly active antiretroviral therapy
(HAART) for HIV infection. Morbidity
and mortality have plummeted in those
areas of the world with unrestricted access
to these drugs [1], and HIV/AIDS has
been transformed from an almost certain
death sentence to, for those receiving
treatment, a long-term, manageable disease, with a potentially normal life expectancy. By contrast, this success has not
been matched by reductions in HIV transmissions over the same period. Indeed,
current surveillance data suggest that
transmissions are increasing in resourcerich communities—particularly among
men who have sex with men (MSM) [2],
in addition to the large epidemics ongoing
within the resource-poor world. Such increases represent a public health failure.
The inevitable outcome of widespread
HAART use in the midst of increasing
HIV transmission—namely, transmission
Received 22 November 2006; accepted 22 November 2006;
electronically published 16 February 2007.
Potential conflicts of interest: none reported.
Reprints or correspondence: Prof. Deenan Pillay, University
College London, Centre of Virology, Windeyer Bldg., 46 Cleveland St., London W1T 4JF, UK ([email protected]).
The Journal of Infectious Diseases 2007; 195:924–6
2007 by the Infectious Diseases Society of America. All
rights reserved.
0022-1899/2007/19507-0003$15.00
DOI: 10.1086/512090
of drug-resistant viruses—has now become a worldwide reality [3–5].
The suboptimal impact of safe sex messages over the past 20 years suggests that
more innovative and effective preventive
strategies are required. More research is
necessary to uncover the dynamics and
drivers of transmission within different
communities and risk groups, to inform
an evidence base for such interventions.
Phylogenetic approaches have long been
used for illustrating the evolutionary relationships among HIV strains, leading to
fundamental insights into cross-species
transmissions, spread of specific viral
lineages, and recombination [6]. These
methodologies have also been used to
study specific transmission events. However, until recently, the paucity of large
sequence data sets and the expense in generating such data have limited studies to
the investigation of individual transmission events and/or outbreaks [7, 8]. With
the increasingly widespread implementation of HIV resistance testing, involving
the generation of large volumes of sequences from the pol gene (∼10% of the
complete genome), these limitations have
been overcome. Epidemiological and cohort approaches to HIV transmission dynamics can now be complemented by
phylogenetic data. We estimate that there
may be many hundreds of thousands of
HIV-1 sequences potentially available for
924 • JID 2007:195 (1 April) • EDITORIAL COMMENTARY
analysis from resistance-testing laboratories worldwide. The original hesitation
with using pol sequences for evolutionary studies—they are relatively conserved
compared with gag and env genes and may
also be subject to bias (apparent convergent evolution) due to drug-resistance
mutations—has been generally overcome
[9, 10], and a number of recent studies
have taken advantage of the ever-growing
sequence repositories. Although the identification of specific transmission events
with high statistical confidence through
phylogenetics will always be subject to significant caveats (e.g., cannot exclude a
common, unknown source of 2 similar
infections, cannot identify direction of
transmission, and ignores the potential of
superinfection), as well as ethical concerns
(consent for use to identify potential
sources of infection), the potential to provide insights into transmission dynamics
within communities is now being realized.
Indeed, as guidelines on undertaking resistance testing at first diagnosis [11, 12]
become implemented, we will move toward a complete set of viral sequences for
all diagnosed individuals within defined
geographical areas. This will represent a
resource of huge potential for the detailed
study of HIV transmission dynamics and
will be a model for the study of other
human pathogens. Laboratories holding
data as a product of resistance testing must
be encouraged to share sequences to facilitate such studies.
In this issue of the Journal, Brenner et
al. [13] have used phylogenetic analyses
on such a local sequence data set to explore the likely source of new infections
in the mainly MSM Quebec cohort. They
use well-established methods of HIV-1 pol
gene analysis, incorporating very high
bootstrap values and low genetic distance
criteria, to demonstrate the high transmission rate from those with primary HIV
infection (PHI) and show that nearly 50%
of acute infections within their cohort as
a whole are linked to other primary infections. As discussed above, phylogenetic
analyses on their own cannot provide definitive evidence for transmission events;
however, the consistency between this and
other studies using such phylogenetic
techniques in individuals with PHI [14,
15] suggests that their conclusion—that
primary infection is a critical period for
onward transmission of HIV—is valid.
This assertion is biologically plausible
because PHI represents a period of extremely high viral load levels. Indeed, prospective longitudinal studies among heterosexual HIV-1 serodiscordant couples in
the developing world have clearly demonstrated that viral load and early stage of
infection are predictors of transmission
[16, 17], alongside the presence of sexually
transmitted infections [18] and circumcision status [19]. Large prospective studies continue to investigate the impact of
empirically or syndromically treating sexually transmitted infections or suppressing
herpes simplex infection, as well as the use
of male circumcision, on reductions in
transmission.
However, these strategies may be of limited effectiveness if individuals at or near
to PHI represent a major source of onward
transmission, because many such interventions depend on an initial positive diagnosis. It is well recognized that the
symptoms associated with PHI are nonspecific, and this entity frequently remains
undiagnosed by health care providers. Indeed, it is estimated that only a small pro-
portion of infected individuals are diagnosed in early infection [20]. By contrast,
active ascertainment and high levels of
testing can improve the diagnosis of recent
infection, to the extent that up to 50% of
recent infections can be identified [21].
Normalization of HIV testing within
health care settings, such as the policy recently announced by the Centers for Disease Control and Prevention, is clearly a
major advance [22]. However, it must be
recognized that selection of testing strategies must also be appropriate for optimizing the detection of early infection,
such as combined antibody-antigen tests
[23] or pooled HIV-RNA testing [24].
What are the advantages of early HIV
diagnosis with regard to prevention of
transmission? First, it is recognized that an
HIV diagnosis per se results in subsequent
risk reduction [25]. However, more contentious is the potential role of antiretroviral therapy in reducing transmission.
Although reductions in plasma viremia are
mirrored by reductions in the transmissible virus in the genital tract [26], there
has been little discussion of the prevention
role of HAART outside of mother-to-child
transmission and, more recently, preexposure prophylaxis scenarios [27]. Current guidelines for initiating HAART are
based on the risk-benefit for the infected
individual, and treatment is rarely recommended with a CD4 cell count 1350
cells /mL [11]. As clinical management of
HIV infection improves and HAART suppression of viremia is maintained for
longer periods of time, the source of further transmissions will shift more toward
untreated (including undiagnosed) individuals. We should therefore consider the
role of extending treatment to those with
higher CD4 cell counts, for benefit of individual and community. Such an extension can now be contemplated in light of
recent improvements in drug formulations (thus enhancing adherence) and reductions in HAART toxicities [28]. Indeed, one study of HAART use at high
CD4 cell counts to prevent transmission
in discordant couples is underway [29]. A
possible implication of such a policy could
be the risk of emergence of drug resistance
and subsequent transmission. Against this
must be cited the low risk of resistance
emerging for those starting on current
HAART triple therapies [30]. Indeed, as
treatment efficacy continues to improve,
an increasing proportion of transmitted
resistance is likely to originate from untreated individuals [31], who are themselves infected with resistant strains and
in whom high levels of viremia persist
without reversion of virus to wild type
[32]. This, therefore, identifies a further
reason for extending treatment.
Changing the paradigm of treatment rationale is even more pertinent for primary
infection. Trials of short-term HAART in
the setting of PHI are currently under way
[33]. Such trials are largely constructed
around the potential immunological and
virological benefits for the treated individual. In view of the recognition of primary infection as a major driver of transmission, we argue that the reduction of
transmission risk, by reducing viral load,
should also be considered as a measurable
benefit of early interventions.
HAART is no replacement for enhanced
behavioral approaches to reduce transmission. It is expensive, and relatively
toxic, and many regions of the world still
have not implemented therapy to many
of their infected populations. However, we
argue that the current focus on increasing
HIV diagnoses through more widespread
testing requires a parallel strategy for minimizing ongoing transmission. Through
cohort and molecular epidemiological
studies, the importance of early infection
in maintaining these transmissions will be
better understood. It is now time to evaluate application of the most potent intervention to treat this disease—namely, antiretroviral therapy—to its prevention.
Furthermore, strategies to improve recognition of recent infection, in addition
to identifying undiagnosed chronic infection, are crucial for effective implementation of prevention strategies.
EDITORIAL COMMENTARY • JID 2007:195 (1 April) • 925
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