Antiviral Therapy 13:729–732
Case report
Is transmission of HIV-1 in non-viraemic
serodiscordant couples possible?
Martin Stürmer 1*, Hans W Doerr 1, Annemarie Berger 1 and Peter Gute 2
JW Goethe University Hospital, Institute for Medical Virology, Frankfurt, Germany
Infektiologikum, Frankfurt, Germany
1
2
*Corresponding author: E-mail: M.Stuermer@em.uni-frankfurt.de
Several studies have shown that HIV-1 transmission in
serodiscordant couples is significantly reduced when the
plasma viral load (pVL) in the infected partner is low or
undetectable. However, residual infectivity in the seminal compartment despite undetectable pVL has also been
shown. Here we report HIV-1 transmission in a serodiscordant couple despite successful antiretroviral therapy of
the HIV-infected partner. The newly infected partner had
a negative HIV-1 screening ELISA when his HIV-1-­positive
partner was already on antiretroviral treatment with
undetectable pVL, which remained undetectable beyond
the time of seroconversion in the initially negative partner.
Frozen blood samples were analyzed phylogenetically from
the HIV-1-positive patient and the newly infected partner
before treatment and shortly after seroconversion, respectively; they showed a true relationship. On the basis of
these data, the present report suggests that transmission
of HIV-1 can occur despite undetectable pVL. This should
be added to the discussion of prevention strategies, which
should not advise the abandonment of safer-sex practices
without referring to the relatively low but not impossible
risk of HIV-1 transmission in this context.
One major obstacle in the realization of prevention
strategies is the belief that the risk of HIV-1 transmission in discordant couples virtually disappears due
to a low or undetectable plasma viral load (pVL) if
the infected partner is on highly active antiretroviral
therapy (HAART; reviewed in [1]). Previous studies
have demonstrated that a lower pVL is associated with
decreased sexual transmission in discordant heterosexual partnerships [2], possibly due to a simultaneous
decrease of HIV RNA in semen [3]. Quinn and colleagues [2] reported no transmission in discordant heterosexual partnerships in Uganda when the pVL was
<1,500 copies/ml (51 couples, median follow-up of
22.5 months). Moreover, Vernazza and colleagues [3]
showed that the likelihood of having detectable HIV
in semen with undetectable pVL was low: only 2/114
patients were observed with detectable HIV RNA in
semen, and both were included very early in their study.
In addition, a mathematical model calculated the heterosexual transmission probability as 3 per 10,000 episodes of intercourse with 1,000 copies of HIV RNA in
semen per ejaculate [4]. On the basis of these data the
risk of transmission should be rated as very low. However, it has been shown that there might be residual low
level viral load in the seminal compartment [3,5], and
the present report suggests that sexual transmission at
the individual level may occur despite an undetectable
pVL (<50 copies/ml).
The index patient is a 39 year old homosexual man
diagnosed as HIV-1-seropositive on 14 January 1999.
He started HAART on 15 July 2000 using a therapy
regimen well-established in the Frankfurt HIV cohort
comprising zidovudine, lamivudine and efavirenz [6];
on 13 September 2002 efavirenz was replaced by
nevirapine due to toxicity. Shortly after the start of
treatment, pVL (quantified using the Cobas Amplicor
HIV-1 Monitor test kit version 1.5 UltraSensitive assay
[Roche Diagnostics GmbH, Mannheim, Germany] with
a limit of detection of 50 copies/ml) was <50 copies/ml
(7 November 2000). The index patient’s pVL remained
undetectable beyond the time point when his partner seroconverted and the CD4+ T-cell count reached
adequate levels (Figure 1). Both the patient and the
treating physician have independently confirmed that
no other sexually transmissible disease (STD) could be
detected clinically or by any laboratory parameter.
The index patient’s partner is also a 39 year old homosexual man. He was found to be HIV-1-­seronegative in
June 2002; this test was carried out anonymously at the
local public health department and therefore a printed
report is unavailable. However, the time period of the test
has been confirmed by both the patient and the treating
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Figure 1. Changes of plasma viral load and CD4+ T-cell count values over time for the index patient
1x106
1,600
AZT/3TC/EFV
AZT/3TC/NVP
1,400
1x105
1x104
1,000
1x103
800
600
1x102
400
10
200
0
Jul 98
CD4+ T-cell count, cells/mm3
Viral load, log10 copies/ml
1,200
0
Dec 99
Apr 01
Sep 02
Jan 04
May 05
Changes of plasma viral load (solid line) and CD4+ T-cell count (dotted line) values over time for the index patient. The start of the respective therapy regimen is
indicated by arrows. Possible time of transmission (last negative and first positive HIV test of the newly infected partner) is indicated by a grey area. AZT, zidovudine;
EFV, efavirenz; NVP, nevirapine; 3TC, lamivudine.
physician. Additionally, the head of the local public health
department confirmed that there were only two HIV-1positive test results at his department in June and July
2002, one belonging to a female patient and one to a
known HIV-positive patient. The first positive HIV antibody test for the index patient’s partner was reported on
12 July 2004. Shortly after, his pVL was 21,800 copies/ml
and CD4+ T-cell count was 338 cells/mm3. He remained
untreated, with pVL and CD4+ T-cell count ranging from
21,800–231,500 copies/ml, and 263–414 cells/mm3,
respectively (data not shown).
The relationship started in August 2000, both partners
deny having any other sexual relationships from that time
on. According to independent questioning, the couple
practiced safer-sex at the beginning, but had unprotected
anal sexual intercourse on several occasions starting in
May 2003.
To rule out the possibility that the initially HIV-1­negative partner acquired his infection through a third
person, a phylogenetic analysis was carried out as
reported elsewhere [7]. The analysis is based on protease and reverse transcriptase sequences that have
been shown to be sufficient for the reconstruction
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of transmission events [8]. A sample from the index
patient was available from before he started HAART
in 1999 (‘index’ in Figure 2) and a sample from the
newly infected partner was obtained shortly after the
first positive HIV-1 test (‘partner’ in Figure 2). Samples
from local control groups collected during the same
time frame were also analyzed, some of which were
known to be related as described elsewhere [7].
Figure 2 shows the relationship between the sequences
obtained from the index patient and his partner; they are
clearly closely related although the time points of sample collection were approximately 5 years apart. Both
sequences formed a single cluster with a bootstrap value
of 99; the distance between both sequences was 0.001
on a length of 1,176 bases and the mean average distance of all sequences was 0.033 (data not shown). Local
control group samples known to be related clustered as
expected, but none of them formed a cluster with the
sequences from the index patient and his partner.
To our knowledge, this is the first report showing
HIV-1 transmission in a serodiscordant couple despite
an undetectable pVL (<50 copies/ml) in the infected
partner. Although many people discuss the likelihood
© 2008 International Medical Press
22/7/08 13:25:38
Non-viraemic HIV-1 transmission
Figure 2. Phylogenetic tree of the protease/reverse transcriptase region
Cont 15
Cont-24
B-AF286365
Cont 20
B-AF075719
B-M17449
B-K02013
B-K03455
B-U12055
Cont 3
Cont 25
B-M38429
B-U63632
B-M38431
B-U43141
Cont 29
Cont 30
Cont 13
Cont 28
Cont 9
Cont 26
Cont 1
Cont 10
Cont 14
Cont 2
Cont 12
Cont 17
Cont 5
Cont 6
Cont 16
Cont 8
Index
Partner
Cont 7
B-U69593
Cont 18
Cont 23
B-K02007
B-M26727
Cont 22
B-U21135
Cont 11
B-M17451
Cont 4
Cont 27
Cont 19
Cont-21
N-AJ006022
0.01
Phylogenetic tree of the protease/reverse transcriptase region of GenBank isolates indicated by their subtype and accession number, local control group patient isolates
indicated by ‘cont’ and consecutive numbering, and the isolates of the index patient (indicated by ‘index’) and his partner (indicated by ‘partner’). Trees were generated
by a bootstrap test with 10,000 replications on the basis of the Neighbor-Joining method with Kimura 2‑parameter substitution module, and rooted against a subtype
N isolate. Bootstrap values are shown on the nodes.
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of transmission events in this context, no such case has
been reported in the literature yet. Recently, a new discussion about prevention strategies in serodiscordant
couples has been started; some experts even argue for
no longer recommending safer-sex practices with the
hitherto lack of published case reports supporting the
epidemiological data. However, the current case suggests that transmission can occur in non-viraemic serodiscordant couples. The cluster formed in the phylogenetic analysis was unique and both the bootstrap value
and the sequence similarity reached levels significantly
associated with a true relationship of the two sequences,
ruling out the possibility of transmission from a third
person. The HIV-1-positive partner had a persistently
undetectable pVL encompassing the time of the last
negative (June 2002) and the first positive HIV-1 test
(12 July 2004) of his initially HIV-1-negative partner,
and the time between first undetectable pVL (7 November 2000) and the last negative HIV-1 screening test was
19 months. There are also some limitations regarding
this case report. Although it has been shown that not
all drugs reach sufficient concentrations in semen, the
drugs used during the time period of possible transmission are known to penetrate the genital compartment
quite well (reviewed in [9,10]). Already published data
showed residual low level viral load in the seminal compartment, but mainly in the early phase of a suppressive
HAART regimen [3,5]. Short periods of non-adherence
or occurrence of other STDs might result in residual
viral replication, so that transmission is more likely.
This cannot be ruled out completely by the regular
viral load determinations with undetectable pVL shown
in Figure 1 (2002: 5 June, 4 September, 1 October, 16
October and 20 November; 2003: 26 February, 28 May,
20 August and 20 November; 2004: 26 February and
12 July), but both the index patient and the treating
physician independently confirmed good adherence and
the absence of any STDs. Although this case is of a retrospective nature dated back approximately 5 years, a
continuously good adherence is based on the patient’s
statement, and the seronegative HIV test in 2002 was
done anonymously without an available written report,
all data were independently and personally confirmed
by the authors. Taken together, we feel confident that
the present case report suggests that transmission can
occur despite undetectable pVL. Therefore, we cannot
support any recommendations that abandon the use of
safer-sex practices in this context without mentioning
the possibility of HIV-1 transmission.
Disclosure statement
The authors declare no conflicts of interest.
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Accepted for publication 15 April 2008
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