50% of new HIV infections flow from primary infection, likely limits effectiveness of prevention technologies

A recent study out of Quebec appears to indicate that up to half of all new HIV infections flow from individuals with primary infection.

Primary infection is defined as the first few weeks and months after infection when viral loads are highest in the infected individual. Antiretroviral medications typically reduce viral load to an undetectable level. “Treatment experienced” individuals, those who are on medications and doing well, do not efficiently transmit the virus through sexual activity. (HIV is not an efficiently transmissible disease, anyway. In anal intercourse, which is generally considered more risky than vaginal intercourse, the transmission event occurs in 6 out of every 10,000 acts for insertive partners, i.e. men, and 82 out of every 10,000 acts for receptive partners, i.e. women or men. Source: Ask InSite, UCSF.)

The researchers conclude:

… that despite recent advances in prevention
technologies, such as circumcision or treating sexually transmitted
infections “these strategies may be of limited effectiveness if
individuals at or near to [primary HIV infection] represent a major
source of onward transmission, because many such interventions depend
on an initial positive diagnosis.”
 

Clearly, testing at or near the time of primary infection represents the best intervention in preventing transmission. Obviously, it is difficult to do. Hence, “normalizing” HIV testing in the health care system would likely answer the question of how to reach individuals early in their infection. A spotty health care system such as Africa has – and unfortunately among the poor in the United States – would seem to be one of the greatest obstacles to normalizing prevention efforts, especially testing.

Circumcision has been offered as an answer to “getting ahead of the curve” in transmission of this disease. However, it seems clear that getting ahead of the curve is far more dependent on knowing in whom and where infection is occurring rather than throwing a wide net over everyone, such as mass circumcision would seem to do. For the millions who are not at a high risk for HIV, circumcision offers nothing except known risks and physical, sexual, and financial costs.

Note: The article is not primarily about how this finding impacts on the debate over the implementation of male circumcision.

Aidsmap story after the jump.

Primary HIV infection responsible for half of all HIV transmission in Quebec

Primary HIV infection accounts for half of all onward transmission,
according to rigorous phylogenetic analysis data from Quebec, Canada
published in the April 1st edition of the Journal of Infectious Diseases.
An accompanying editorial suggests that whilst identifying and treating
early HIV infections are challenging, they are important prevention
strategies that have the potential to serve both individual and public
health.

A number of recent studies have suggested that early HIV infection
may disproportionately contribute to onward transmission. Notably, a
2005 study of monogamous heterosexual couples in Rakai, Uganda – where
one partner was HIV-positive and one HIV-negative at the start of the
study – found that the rate of sexual HIV transmission within the first
two and a half months was almost twelve-times greater than that
observed in chronic HIV infection.

Using phylogenetic analysis to study primary transmission clusters

Although there are limits as to what phylogenetic analysis can ‘prove’ in terms of HIV transmission between two individuals, it can be used somewhat more reliably to estimate transmission events within a larger population.

Investigators in Quebec are particularly well placed to undertake
phlyogenetic analysis to ascertain whether HIV transmission is likely
due to early or chronic HIV infection, due to two factors:

  • In 1997, they established a primary HIV infection cohort, which
    provides longitudinal data on viral evolution, drug resistance,
    transmission risk factors, and disease progression.
  • They have a large database of HIV gene sequences available
    (with samples from about 20% of all diagnosed individuals in Quebec),
    due to the routine genotypic testing, since 2001, of recently infected
    and newly diagnosed individuals, as well as treatment-experienced
    individuals for whom antiretroviral therapy (ART) has failed.

Consequently, they analysed HIV gene sequences (from the pol
region) in 215 participants in their primary HIV infection cohort, as
well as an additional 502 recently infected (i.e. within six months of
seroconversion) individuals from their genotypic testing database. A
total of 593 unique subtype B infections were identified; a further 65
non-subtype B infections (10% of all recent infections) were excluded
from subsequent analysis.

The investigators utilised extremely rigorous phylogenetic analysis
methods, with very high bootstrap values (98% or greater), and found
that half (293/593) of all primary HIV infections were grouped in 75
different transmission clusters. Half of the clusters involved between
two and four individuals; the rest were larger clusters (a median of
nine individuals, ranging between five and 17 individuals). The average
time from the first to last infection within each cluster was 15
months, although this ranged from one month to 37 months, depending on
the number of individuals in the cluster.

These sequences were then compared with 135 treatment-naive, and
660 treatment-experienced individuals with chronic HIV infection, and
they rarely clustered with the samples from the individuals with
primary HIV infection (1% of treatment-naive and 2.7% of
treatment-experienced).

Half of all transmission was due to primary/early infection

After analysing all the data, the investigators concluded that whilst
primary/early HIV infection represented just 10% of the total sequenced
samples in the genotypic resistance database, they accounted for 49% of
all onward transmission events. In contrast, they found that
treatment-naive and treatment-experienced chronically infected
individuals accounted for 15% and 12% of onward transmission,
respectively.

The investigators do not account for the remaining quarter of
infections, but note that they “doubtless missed some” primary HIV
infection in Quebec during the study period. They add that since many
people with early HIV infection are undiagnosed “the role of acute
infection may be underestimated.”

They do, however, rule out a substantial onward transmission role
for successfully treated, chronically infected individuals in Quebec
(who are not included in their resistance database, or in this
analysis) because of the much lower average viral load (2.58 log10 copies/ml in this population.

Indeed, average plasma viral loads for each of the groups in this
analysis were much higher: the highest viral loads (associated with a
higher risk of transmission) were seen in recently-infected and
treatment-naive chronically infected individuals (4.6 and 4.7 log10 copies/ml). This compares with 4.1 log10 copies/ml in treatment-experienced individuals.

Behaviour and resistance data

After analysing behavioural data from the 215 individuals in the
primary HIV infection cohort no significant differences were seen
within or between heterosexual or homosexual sex or injecting drug use
in terms of small, large or no transmission clusters.

There was also no difference seen between in terms of numbers of sexual
partners and small, large or no transmission clusters. The
investigators note that “clustering could not be attributed to
differences in behavioural risk factors” and that “this suggests that
different infections may vary in transmissability, and further study is
necessary.”

About 15% of individuals with primary/early HIV infection had
resistance to at least one drug class, although NNRTI resistance was
much more likely to be seen than NRTI or PI resistance. “It is
noteworthy,” the investigators write, “that approximately half of
transmitted resistance can be attributed to clustered infections but
that transmission of viruses containing mutations associated with
resistance to nucleoside or protease inhibitors was diminished in
clustered infections, possibly because of reduced viral fitness.”

Diagnose and treat HIV infection earlier for individual and public health

In an accompanying editorial two British doctors, Deenan Pillay and
Martin Fisher, argue that “as clinical management of HIV infection
improves and HAART suppression of viraemia is maintained for longer
periods of time, the source of further transmission will shift more
toward untreated (including undiagnosed) individuals.”

They note that there are many barriers to diagnosing HIV infection during its early stages, and that diagnoses are often missed in GP and hospital settings.
But they welcome recent moves to normalise HIV testing in the United
States, and stress that in order to diagnose early infection
appropriate tests such as combined antibody-antigen tests or pooled HIV-RNA testing should be utilised.
“However,” they write, “we argue that the current focus on increasing
HIV diagnoses through more widespread testing requires a parallel
strategy for minimising ongoing transmission.”

They also argue that despite recent advances in prevention
technologies, such as circumcision or treating sexually transmitted
infections “these strategies may be of limited effectiveness if
individuals at or near to [primary HIV infection] represent a major
source of onward transmission, because many such interventions depend
on an initial positive diagnosis.”

Even though HAART is “expensive, and relatively toxic”, they argue
that “recent improvements in drug formulations (thus enhancing
adherence) and reductions in HAART toxicities” make it feasible to
treat HIV-positive individuals much earlier than current guidelines
suggest.

Consequently, although they concede that this is currently a
“contentious” concept, they believe that “changing the paradigm of
treatment rationale” and “extending treatment to those with higher CD4
cell counts” for the “benefit of individual and community” is a
strategy worth studying.

“It is now time to evaluate application of the most potent intervention
to treat this disease – namely, antiretroviral therapy – to its
prevention,” they conclude. “Furthermore, strategies to improve
recognition of recent infection, in addition to identifying undiagnosed
chronic infection, are crucial for effective implementation of
prevention strategies.”

References

Brenner BG et al. High rates of forward transmission events after acute/early HIV-1 infection. J Infect Dis 195: 951-59, 2007.

Pillay D and Fisher M. Primary HIV infection, phylogenetics, and antiretroviral prevention. J Infect Dis 195: 924-26, 2007.

http://www.nam.co.uk/en/news/13DEE80D-3BAA-41C5-96FD-DBA07276F6B7.asp?type=preview

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