Download Effect of Early Syphilis Infection on Plasma Viral Load and CD4 Cell

ORIGINAL INVESTIGATION
Effect of Early Syphilis Infection
on Plasma Viral Load and CD4 Cell Count
in Human Immunodeficiency Virus–Infected Men
Results From the FHDH-ANRS CO4 Cohort
Witold Jarzebowski, MD, MSc; Eric Caumes, MD; Nicolas Dupin, MD; David Farhi, MD, MPH;
Anne-Sophie Lascaux, MD; Christophe Piketty, MD, PhD; Pierre de Truchis, MD; Marie-Anne Bouldouyre, MD;
Ouda Derradji, MD; Jérome Pacanowski, MD; Dominique Costagliola, PhD; Sophie Grabar, MD, PhD;
for the FHDH-ANRS CO4 Study Team
Background: Concomitant syphilis and human immunodeficiency virus (HIV) infection is increasingly frequent in industrialized countries.
Methods: From a large hospital cohort of HIV-infected
patients followed up in the Paris area between 1998 and
2006, we examined the effect of early syphilis on plasma
HIV-1 RNA levels and CD4 cell counts. We compared
282 HIV-1–infected men diagnosed as having incident
primary or secondary syphilis with 1233 syphilis-free men
matched for age (±5 years), sexual orientation, participating center, length of follow-up (±6 months), and immunologic and virologic status before the date of syphilis diagnosis (index date). Increase in viral load (VL)
(plasma HIV-1 RNA) of at least 0.5 log or a rise to greater
than 500 copies/mL in patients with previously controlled VL during the 6 months after the index date was
analyzed, as were CD4 cell count variations and CD4 slope
after the index date.
Results: During the 6 months after the index date, VL
increase was observed in 77 men with syphilis (27.3%) and
in 205 syphilis-free men (16.6%) (adjusted odds ratio
[aOR], 1.87; 95% CI, 1.40-2.49). Even in men with a VL
of less than 500 copies/mL undergoing antiretroviral
therapy, syphilis was associated with a higher risk of VL
increase (aOR, 1.52; 95% CI, 1.02-2.26). The CD4 cell
count decreased significantly (mean, −28/µL) compared
with the syphilis-free group during the syphilis episode
(P=.001) but returned to previous levels thereafter.
Conclusions: In HIV-infected men, syphilis was associated with a slight and transient decrease in the CD4 cell
count and with an increase in VL, which implies that
syphilis may increase the risk of HIV transmission, even
in patients receiving antiretroviral therapy and with a VL
of less than 500 copies/mL.
Arch Intern Med. 2012;172(16):1237-1243.
Published online July 23, 2012.
doi:10.1001/archinternmed.2012.2706
H
UMAN IMMUNODEFIciency virus (HIV) and
Treponema pallidum, the
causative agent of syphilis, are sexually transmitted. In industrialized countries, the incidence of syphilis fell markedly in the 1990s1
because of simple preventive measures, behavioral changes, and better access to
screening during the early years of the HIV
pandemic. A resurgence of syphilis was
See also page 1252
Author Affiliations are listed at
the end of this article.
Group Information: A list of
the FHDH-ANRS CO4 Study
Team members can be found at
http://www.ccde.fr.
noted in the 2000s in Europe and North
America, mainly in men who have sex with
men (MSM).2,3 In France, where mandatory notification of syphilis was abrogated
in 2000, a syphilis surveillance network
confirmed the resurgence of syphilis in
MSM, particularly in Paris,4 up to 2007.5,6
ARCH INTERN MED/ VOL 172 (NO. 16), SEP 10, 2012
1237
Interactions between syphilis and HIV
infection are not fully documented. 7,8
Syphilis causes genital lesions that are
known to increase the risk of HIV transmission.9,10 Several studies11-16 have examined the effect of syphilis on HIV viral load
(VL) and the CD4 cell count in the era of
combination antiretroviral therapy (cART),
See Invited Commentary
at end of article
but they gave conflicting results. Most of
these studies were small, had limited follow-up, and did not account for the effect of cART.
Given the resurgence of sexually transmitted infections in MSM, it is important
to examine the effect of syphilis on HIV
infection for patient management and for
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Author Affil
Publique-Hô
Groupe Hos
Broca HôtelBiostatistiqu
Paris, Franc
and Grabar)
Paris (Drs Ja
Costagliola,
Université P
Paris 6, Pari
Costagliola)
Publique-Hô
Hôpital Pitié
de Maladie I
tropicales, P
and Costagli
Paris Descar
Dupin, Farh
Assistance P
de Paris, Hô
Service de d
vénérologie
National de
(Drs Dupin
Assistance P
de Paris, Hô
Service d’im
Créteil, Fran
Assistance P
de Paris, Hô
Georges Pom
d’immunolo
(Dr Piketty)
Publique-Hô
Hôpital Raym
Service de m
spécialisée, G
de Truchis);
Intercommunal R
Service de m
de maladies
Aulnay-sous
Bouldouyre)
Publique-Hô
Hôpital Paul
des maladies
tropicales, L
France (Dr D
Assistance P
de Paris, Hô
Service des m
infectieuses
(Dr Pacanow
Group Infor
the FHDH-A
Team memb
http://www.c
METHODS
count in the year before the index period: ⬍200, 200-349, 350499, or ⱖ500/µL), and virologic status (mean plasma VL in the
year before the index period: ⬍500, 500-4999, 5000-29 999,
and ⱖ30 000 copies/mL). Each patient was followed for 2 years
before and 2 years after the index period and was required to
have at least 2 available CD4 cell counts before the index period, 1 during, and 2 after.
PATIENTS AND DATA SOURCES
STATISTICAL ANALYSIS
From the FHDH cohort, we selected all HIV-1–infected men
followed in the Paris region (Ile-de-France) between January
1, 1998, and December 31, 2006. This region was chosen because a French syphilis outbreak that began in 2001 was concentrated in the Paris area4 and because we needed access to
the patients’ medical records to validate the diagnoses of syphilis.
Briefly, the FHDH is a nationwide hospital-based clinical cohort created in 1989.17 In the Paris region, 24 hospitals contribute data on HIV-infected patients. The only FHDH inclusion criteria are HIV-1 or HIV-2 infection and written informed
consent. Sociodemographic, clinical, therapeutic, and laboratory data are collected at least every 6 months. The FHDH has
been approved by the French computer watchdog body (Commission Nationale de l’Informatique et des Libertés).
Sociodemographic, immunologic, and virologic characteristics before the index period were compared by using univariate conditional logistic regression analysis. To assess the impact of syphilis on HIV plasma VL, baseline VL was defined as
the last value obtained before the index period. A VL increase
was defined as either an increase in the plasma HIV RNA level
of more than 0.5 log in patients with a baseline VL of at least
500 copies/mL or a value of at least 500 copies/mL in patients
with a baseline VL of less th an 500 copies/mL. We considered
only the first virologic increase in the 6 months after the index
date in patients with available VL in this time frame. Logistic
regression with random intercepts to account for matching was
used to estimate odds ratios (ORs) and 95% CIs associated with
VL increase in patients with syphilis vs syphilis-free patients,
overall and in various subgroups.20
Linear mixed models were used to compare patients with
syphilis and syphilis-free patients who experienced a VL increase in terms of the first available VL in patients with a baseline VL of less than 500 copies/mL or the change in VL from
baseline in patients with a baseline VL of at least 500 copies/
mL. Time from VL increase to a VL of less than 500 copies/mL
or below the baseline VL was estimated using the Turnbull estimation for interval-censored data.21 Differences between groups
were assessed using a generalization of the log-rank test without stratification as the matching was no longer maintained in
this subgroup. The impact of syphilis on CD4 cell counts and
slopes during and after the index period was studied by analyzing longitudinal CD4 values in a multivariate linear mixed
model. As the effect of cART on the CD4 cell count depends
on age,22 we adjusted this analysis for age, cART status, and
the interaction between age and cART status (eAppendix).
Finally, based on the results of the previous models, we evaluated the relative effects of VL increase and syphilis on the change
in CD4 cell counts during the index period using linear mixed
models assessing the effects of syphilis group, VL increase, and
the interaction between syphilis and VL increase. All the tests
were 2-sided, and P⬍.05 was considered statistically significant. Commercially available (SAS; SAS Institute, Inc) and free
(R) software programs were used for all the analyses.
public health reasons. We, therefore, studied the independent effect of syphilis on HIV VL and CD4 cell counts
in HIV-infected men followed in the French Hospital Database on HIV (FHDH).
VERIFICATION OF SYPHILIS DIAGNOSES
Cases of syphilis were extracted from the FHDH, which uses
International Classification of Diseases, Tenth Revision, codes. For
code A53.9 (syphilis unspecified as early or late) and for 10%
of other cases randomly selected with a code corresponding to
primary or secondary syphilis (codes A51.0 to A51.4), trained
research assistants examined the medical records to determine whether the patient had primary or secondary syphilis.
As 91% of cases with codes A51.0 to A51.4 were confirmed,
no further checking was organized for those cases. Of the cases
coded A53.9, 42% were ascertained as primary/secondary syphilis and were included. Early neurosyphilis (n=6) and ocular
syphilis (n=5) were not included in this analysis because their
treatment differs from that of other forms of early syphilis.
DEFINITION OF SYPHILIS STATUS
AND PERIOD
The index date was the date of syphilis diagnosis. For each patient, syphilis status was divided into 3 periods (eFigure; http:
//www.archinternmed.com). The index period was the period
of active syphilis, from the beginning of the incubation period
(estimated to be 45 days before diagnosis of primary syphilis
and 90 days before diagnosis of secondary syphilis18) until cure
(estimated to be 2 months after diagnosis). As in other studies,11,12,14 the length of the index period had to be wide enough
to include routine HIV variables but narrow enough to capture those affected by syphilis.
STUDY POPULATIONS
We studied 2 matched groups of HIV-1–infected men: patients with syphilis and syphilis-free patients (reference group).
The syphilis group consisted of men diagnosed as having incident primary or secondary syphilis after enrollment in the
FHDH. The reference patients were selected from the FHDH
by using an incidence density sampling approach.19 Each patient with syphilis was matched with up to 5 syphilis-free patients followed in the same FHDH participating center at the
index date (±6 months) according to age (±5 years), sexual orientation (MSM vs others), immunologic status (mean CD4 cell
RESULTS
CHARACTERISTICS OF THE PATIENTS
A total of 628 men followed in the Paris region and diagnosed as having primary or secondary syphilis between January 1, 1998, and December 31, 2006, were
identified in the FHDH (Figure 1). Of these, 230 men
had already been diagnosed as having syphilis at inclusion in the FHDH, 95 had too few available CD4 cells,
and the primary/secondary nature of syphilis could not
be validated in 21 cases because the medical records could
not be retrieved. Therefore, 282 men with an incident
diagnosis of primary (n=64) or secondary (n=218) syphilis fulfilled the inclusion criteria. The matched refer-
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ence group consisted of 1233 HIV-1–infected men without syphilis.
The main characteristics of the population are given
in Table 1. Most patients were MSM (89%), and their
median age was 38 years. Before the index date, 85% of
the patients were undergoing cART. The median CD4 cell
count was 481/µL, and the VL was less than 500 copies/mL in 58% of patients. The syphilis and syphilis-free
groups were well matched, except for age, and all the models were, therefore, adjusted for age as a continuous variable. Patients with secondary syphilis had slightly more
advanced HIV disease than did those with primary syphilis: 19% and 8% of patients, respectively, had already had
an AIDS-defining event when diagnosed as having syphilis (P=.03).
FHDH cohort
28 956 HIV-1–infected men
Observed between 1998 and
2006 in the Paris region
No prior history of syphilis
133 Men with latent or
tertiary syphilis
28 195 Men without syphilis
230 Cases of prevalent syphilis
diagnosed at inclusion in
the FHDH
95 Patients with insufficient
CD4 cell counts available
21 Patients with unavailable
medical records
IMPACT OF SYPHILIS
ON PLASMA HIV RNA LEVELS
Eighteen patients in the reference group and 3 in the
syphilis group had no available VL values in the 6 months
after the index date and were not included in this analysis. A VL increase occurred during the first 6 months after the index date in 77 patients (27.3%) in the syphilis
group and in 205 patients (16.6%) in the syphilis-free
group. Regardless of the group, three-quarters of the VL
increases occurred less than 2 months after the index date
(P = .84).
Syphilis was significantly associated with VL increase, overall (adjusted OR [aOR], 1.87; 95% CI, 1.402.49) and in the different subgroups (Figure 2). The
risk of VL increase was 1.56 (95% CI, 1.06-2.30) in patients with a VL of less than 500 copies/mL and 1.52 (95%
CI, 1.02-2.26) in cART-treated patients with a VL of less
than 500 copies/mL. The risk of VL increase associated
with syphilis was higher in patients who were not taking cART at the index date than in patients receiving cART
(P = .04): the aORs were 3.61 (95% CI, 1.85-7.06) and
1.65 (95% CI, 1.19-2.28), respectively. The risk of VL
increase did not differ significantly between patients with
primary and secondary syphilis (P = .34).
Table 2 describes the VL increase. Among patients
who experienced VL increase, the median VL at the time
of the increase was 54 000 copies/mL in the syphilis group
and 11 318 copies/mL in the syphilis-free group (P = .01).
The median duration of VL increase was not significantly different between the syphilis and syphilis-free
groups, but in patients with a baseline VL of less than
500 copies/mL, it was shorter in the syphilis group (1.6
and 4.8 months, respectively; P = .01).
IMPACT OF SYPHILIS ON THE CD4 CELL COUNT
628 Men with first diagnosis of
primary or secondary syphilis
between 1998 and 2006
1233 Men in the syphilis-free group
(reference group)
Up to 5 patients followed at
index date individually matched
for age (±5 years), MSM,
clinical center, immunologic
and virologic status before
syphilis infection with ≥2 CD4
measurements before,
1 during, and 2 after the
index period
282 Men in the syphilis group
Incident syphilis between 1998
and 2006
Validated using medical records.
Patients with ≥2 CD4 measurements before, 1 during, and
2 after the episode
64 Primary syphilis
218 Secondary syphilis
Figure 1. Flowchart of study participation. FHDH indicates French Hospital
Database on HIV; HIV, human immunodeficiency virus; and MSM, men who
have sex with men.
sode, but the difference was no longer significant (−3/
µL, P = .78). No significant difference was noted between
the groups regarding the slope of the CD4 cell count after the episode (P = .56). The effect of syphilis was similar regardless of the CD4 cell count before syphilis diagnosis (⬍350/µL or ⱖ350/µL), the primary or secondary
nature of syphilis, the baseline VL (⬍500 or ⱖ500 copies/
mL), and the study period (before or after 2004) (data
not shown).
As syphilis was associated with a decline in CD4 cells
and an increase in VL, we tested the interaction between syphilis and VL increase with respect to the CD4
cell count (eTable 2). Compared with patients who did
not experience VL increase, the decrease in the CD4 cell
count at the index date was larger in patients who experienced VL increase in the first 6 months after the episode (7/µL vs −35/µL, P ⬍ .001). In patients who experienced VL increase, the decrease in the CD4 cell count
at the index date was larger in patients with syphilis (−70/
µL) than in syphilis-free patients (−22/µL) (P = .02). No
significant interaction was found between syphilis and
VL increase (P = .34).
Results of the multivariate mixed model are shown in
Figure 3, and the full results are given in eTable 1. Pa-
COMMENT
tient age and the duration of cART were significantly associated with changes in the CD4 cell count or slope. No
period effect was found in the syphilis-free group. Compared with the syphilis-free group, the CD4 cell count
decreased significantly (mean [SD]: −28/µL [8/µL]) during the syphilis episode (P = .001) and returned to previous levels (mean [SD]: 25/µL [10/µL]) after the epi-
The results of this study of a large cohort of HIV-1–
infected men in France indicate that early syphilis is associated with a nearly 2-fold increase in the risk of VL
elevation in the months after diagnosis, even in patients
receiving effective cART, and also with a moderate and
transient decrease in the CD4 cell count.
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Table 1. Characteristics of the Patients by Study Group
Patients Without Syphilis
(Reference Group)
(n = 1233)
Variable
Age, median (IQR), y
Age class, No. (%)
18-34 y
35-44 y
ⱖ45 y
Men who have sex with men, No. (%)
AIDS before the index period, No. (%)
cART before the index period, No. (%)
CD4 cell count in the year before the index period, mean (range), /µL
Last CD4 cell count before the index period, No. (%)
⬍200/µL
200-349/µL
350-499/µL
ⱖ500/µL
Mean pHIV RNA in the year before the index period, median (IQR), copies/mL
Last pHIV RNA class before the index period, No. (%)
⬍500 copies/mL
500-4999 copies/mL
5000-29 999 copies/mL
ⱖ30 000 copies/mL
pHIV RNA before the index period according to cART, No. (%)
⬍500 copies/mL
ⱖ500 copies/mL without cART
ⱖ500 copies/mL with cART
No. of VL measurements per patient before the index period, mean (SD)
Patients With Syphilis
(n = 282)
P Value a
39 (35-43)
37 (34-43)
⬍.001
285 (23.1)
712 (57.8)
236 (19.1)
1098 (89.1)
227 (18.4)
1054 (85.5)
480 (351-632)
80 (28.4)
150 (53.2)
52 (18.4)
250 (88.7)
46 (16.3)
231 (81.9)
476 (348-620)
.22
99 (8.0)
222 (18.0)
343 (27.8)
569 (46.2)
5241 (499-28 622)
21 (7.5)
49 (17.4)
76 (27.0)
136 (48.2)
6821 (499-31 146)
⬎.99
.54
.22
.16
.36
.38
726 (58.9)
147 (11.9)
170 (13.8)
190 (15.4)
160 (56.7)
29 (10.3)
50 (17.7)
43 (15.3)
.43
726 (58.9)
174 (14.1)
333 (27.0)
5.7 (2.6)
160 (56.7)
51 (18.1)
71 (25.2)
5.5 (2.8)
.39
.21
Abbreviations: cART, combination antiretroviral therapy; IQR, interquartile range; pHIV, plasma human immunodeficiency virus; VL, viral load.
a Obtained by univariate conditional logistic regression.
Syphilis vs syphilis free
aOR
(95% CI)
CD4 <350/µL
2.63 (1.53-4.52)
CD4 ≥350/µL
1.73 (1.23-2.41)
pVL ≥500 copies/mL
2.38 (1.58-3.60)
pVL <500 copies/mL
1.56 (1.06-2.30)
No cART
3.61 (1.85-7.06)
cART
1.65 (1.19-2.28)
cARt and pVL
<500 copies/mL
1.52 (1.02-2.26)
Before 2004
2.02 (1.42-2.88)
After 2004
1.58 (0.93-2.67)
Secondary syphilis
2.00 (1.45-2.77)
Primary syphilis
1.41 (0.74-2.68)
1.87
All
0.5
1.0
2.0
5.0
(1.40-2.49)
10.0
aOR and 95% CI
Figure 2. Impact of syphilis on plasma viral load (pVL) increase in various
subgroups. Results are from logistic regression with random effects and are
adjusted for age. A VL increase was defined as either an increase in the
plasma human immunodeficiency virus RNA level of more than 0.5 log in
patients with a baseline VL of at least 500 copies/mL or a value of at least
500 copies/mL in patients with a baseline VL of less than 500 copies/mL.
aOR indicates adjusted odds ratio; and cART, combination antiretroviral
therapy.
These results confirm the increased risk of VL elevation in patients with syphilis (aOR, 1.9) observed in some
studies11,12,16 but not in others.13,14 However, previous studies included fewer patients (38-118 patients) and had less
robust designs, sometimes with no control group. The
strength of this cohort study is that it enabled us to study
time-specific changes related to syphilis infection by comparing matched patients with and without syphilis. This
design helps circumvent the usual bias of observational
studies regarding causal inferences. The specific relationship between syphilis and VL increase is suggested by the
following results. First, VL increase was more frequent in
patients with syphilis than in syphilis-free controls. Second, in patients with a baseline VL of less than 500 copies/
mL, the duration of VL increase was shorter in patients
with syphilis, suggesting that it was directly related to the
syphilis episode, which was rapidly cured with the use of
antibiotic agents that rapidly clear T pallidum. Third, the
independent association between CD4 cell count decline
and VL increase suggests that syphilis, similar to other infections, may activate viral replication, which, in turn, may
affect CD4 cell production or turnover.
Although the risk of VL increase associated with syphilis was higher in patients without cART (aOR, 3.61) than
in patients receiving cART (aOR, 1.65), note that syphilis had an effect on VL even in cART-treated patients with
a VL of less than 500 copies/mL before diagnosis (aOR,
1.52). These results have important implications for HIV
transmission, particularly regarding the recent concept
of “treatment as prevention,” which may inappropriately lead patients to relax their sexual precautions when
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Table 2. pHIV RNA Level at VL Increase in the First 6 Months After the Index Date and the Duration of VL Increase According
to Baseline pHIV RNA Level a
Baseline pHIV RNA Level
⬍500 Copies/mL
Patients With VL Increase
Variable
pHIV RNA at VL
increase, median
(IQR), copies/mL
Change in pHIV RNA
from baseline at VL
increase, median
(IQR), log10
copies/mL
Duration with an
increased VL, median
(IQR), mo b
Syphilis Free
(n = 205)
Syphilis
(n = 77)
11 318
54 000
(1990-56 004) (3600-179 000)
6.4
(1.4-17.9)
4.9
(1.0-15.8)
P
Value
.01
.13
Syphilis Free
(n = 109)
ⱖ500 Copies/mL
Syphilis
(n = 35)
P
Value
2070
3600
(1150-20 600) (1392-10 500)
4.8
(1.1-NA)
1.6
(1.6-7.3)
.76
Syphilis Free
(n = 96)
Syphilis
(n = 42)
27 275
141 406
(9955-128 152) (67 150-293 419)
.01
P
Value
.001
4.37
(3.91-5.01)
5.08
(4.70-5.42)
.001
7.7
(2.3-17.9)
4.9
(1.0-NA)
.91
Abbreviations: IQR, interquartile range; NA, not applicable; pHIV, plasma human immunodeficiency virus; VL, viral load.
a A VL increase is defined as an increase of 0.5 log or a pHIV RNA level greater than 500 copies/mL in the 6 months after the index date.
b Duration with an increased VL is the time elapsed from VL increase to a VL of fewer than 500 copies/mL or to a VL below the baseline VL
estimated using the
Peto-Turnbull estimation of survival function. P values were obtained using a generalization of the log-rank test.
they are treated and have a controlled VL. Indeed, these
data indicate that syphilis increases HIV VL and may,
therefore, increase the risk of transmission, even when
VL was previously controlled by cART. Semen HIV RNA
levels correlate with plasma HIV RNA levels, and even a
small increase in plasma HIV RNA levels increases the
risk of HIV transmission.23 According to the results of a
model-based study,24 a plasma HIV RNA level of 3600
copies/mL, as observed herein during the syphilis episode in patients with controlled VL, is associated with a
rate of HIV transmission to sexual partners of approximately 15 per 100 person-years.
The present study population consisted mainly of MSM
infected by syphilis, which is often used as a proxy for
at-risk sexual behavior. This population is not covered
by the Swiss guideline regarding HIV transmission during effective ART,25 which concerns couples in stable relationships and who have no other sexually transmitted
infections. The present results indicate that populations
with high-risk sexual behavior, in whom syphilis reinfection is relatively common,26,27 must be warned of the
risk of HIV transmission and be advised to use condoms. Physicians should also bear in mind the possibility of syphilis when a patient receiving cART has an unexplained increase in VL or a decrease in the CD4 cell
count. Because syphilis is often clinically misdiagnosed,
its early diagnosis and, thereby, early treatment rely on
physicians and patients8 who should be aware of its effect on HIV variables.
We found that the impact of syphilis on VL was transient, as half of the episodes resolved within 5 months, suggesting a modest individual impact regarding its public
health effect. In patients with a VL of less than 500 copies/
mL, the VL increase duration was shorter in patients with
syphilis than in syphilis-free patients. This might be due
to early effective treatment of syphilis,28 whereas in syphilisfree patients, the cause of the VL increase may be less easy
to eradicate. We observed a clear temporal relationship between syphilis infection and VL elevation, followed by rapid
Difference in CD4 cell counts between patients
with syphilis and syphilis-free patients
3 (9) cells/µL
(P = .73)
0
–28 (8) cells/µL
(P = .001)
Before
+25 (10) cells/µL
(P = .008)
Index
period
(syphilis
infection)
After
Time
Figure 3. Adjusted differences in CD4 cell counts between patients with
syphilis and syphilis-free patients. Results are selected from the multivariate
linear mixed model and are given as mean (SD) (see also eTable 1).
VL normalization compatible with effective treatment of
syphilis; however, the impact of syphilis treatment on the
subsequent decline in VL was not addressed herein as it
is not systematically recorded in the FHDH.
Regarding the impact of syphilis on the CD4 cell count,
a moderate decrease (approximately −30/µL) was observed during the syphilis episode, followed by a return
to baseline counts. The decrease was similar regardless
of the syphilis, the CD4 cell count, or the VL. Similar results have been obtained in other studies.13,14 Two major mechanisms could contribute to this CD4 cell count
decline: upregulation of HIV replication29 and the immunologic response to syphilis.30,31 These latter 2 studies showed lower CD4 cell counts and higher CD8 cell
counts in patients with syphilis than in patients without
syphilis. Fan et al30 attributed the decline in CD4 cell
counts to Fas-mediated apoptosis. Other researchers32
have observed significant increases in circulating memory
and memory/effector T cells, consistent with an exuberant cellular response to Treponema antigens during the
systemic phase of syphilis.
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Change in slope:
–0.34 cells/µL/mo (P = .56)
The decrease in the CD4 cell count observed at syphilis diagnosis was independently associated with the increase in plasma HIV RNA levels and with syphilis infection. Higher HIV VL may be a consequence of immune
activation and subsequent amplification of HIV replication in the blood.11,12 Cell activation may enhance the surface expression of HIV receptors and coreceptors (CD4,
CCR5, and CXCR4), facilitating HIV entry. In addition,
transcription of viral genes may be upregulated by cytokines expressed in response to coinfection.
Patients with syphilis exhibited a transient decline in
their CD4 cell count. In patients with CD4 cell counts
close to 200/µL, the decline associated with syphilis could
precipitate the occurrence of an AIDS event. In contexts
of limited follow-up and access to ART, in countries where
syphilis diagnosis and treatment can be problematic, the
impact of syphilis on the course of HIV disease is likely
to be more severe than that observed in this study.
This study was limited to patients with primary and
secondary syphilis and excluded those with early ocular
and neurosyphilis. However, it is likely that the effects
observed herein would be even more marked in patients with more severe forms of early syphilis.33,34 We
did not check for concomitant sexually transmitted infections that might also have explained the VL increase.35 Another limitation is that some syphilis-free patients might have contracted syphilis without being
diagnosed or recorded in the database. However, such a
classification error would tend to bias the results toward a reduced effect of syphilis on HIV variables.
In conclusion, these findings indicate that early syphilis in HIV-infected patients is associated with an increase in plasma HIV RNA levels, even in patients with
a plasma VL of fewer than 500 copies/mL while receiving cART. This increase may raise the risk of HIV transmission. Syphilis was also associated with a transient decrease in the CD4 cell count. These results call for
continuing efforts to promote safer sex.
Accepted for Publication: May 5, 2012.
Published Online: July 23, 2012. doi:10.1001
/archinternmed.2012.2706
Author Affiliations: Assistance Publique-Hôpitaux de
Paris, Groupe Hospitalier Cochin Broca Hôtel-Dieu, Unité
de Biostatistique et Epidémiologie, Paris, France (Drs Jarzebowski and Grabar); INSERM U943, Paris (Drs Jarzebowski, Costagliola, and Grabar); Université Pierre et Marie Curie Paris 6, Paris (Drs Caumes and Costagliola);
Assistance Publique-Hôpitaux de Paris, Hôpital PitiéSalpétrière, Service de Maladie Infectieuses et tropicales, Paris (Drs Caumes and Costagliola); Université Paris
Descartes, Paris (Drs Dupin, Farhi, and Grabar); Assistance Publique-Hôpitaux de Paris, Hôpital Tarnier, Service de dermatologie et vénérologie and Centre National de la Syphilis, Paris (Drs Dupin and Farhi);
Assistance Publique-Hôpitaux de Paris, Hôpital Henri
Mondor, Service d’immunologie clinique, Créteil, France
(Drs Lascaux); Assistance Publique-Hôpitaux de Paris,
Hôpital Européen Georges Pompidou, Service
d’immunologie clinique, Paris (Dr Piketty); Assistance
Publique-Hôpitaux de Paris, Hôpital Raymond Poincaré, Service de médecine aigue spécialisée, Garches,
France (Dr de Truchis); Centre Hospitalier Intercommunal Robert Ballanger, Service de médecine interne
et de maladies infectieuses, Aulnay-sous-Bois, France (Dr
Bouldouyre); Assistance Publique-Hôpitaux de Paris,
Hôpital Paul Brousse, Service des maladies infectieuses
et tropicales, Le Kremlin-Bicêtre, France (Dr Derradji);
and Assistance Publique-Hôpitaux de Paris, Hôpital
St-Antoine, Service des maladies infectieuses et tropicales, Paris (Dr Pacanowski).
Correspondence: Sophie Grabar, MD, PhD, Unité de Biostatistique et Epidémiologie, Groupe Hospitalier Cochin Broca Hôtel-Dieu, Hôtel-Dieu, 1 place du Parvis
Notre-Dame, 75181 Paris CEDEX 4, France (sophie
[email protected]).
Author Contributions: Drs Jarzebowski, Caumes, Costagliola, and Grabar had full access to all the data of the
study and take responsibility for the integrity of the data
and the accuracy of the data analysis. Study concept and
design: Costagliola and Grabar. Acquisition of data: Jarzebowski, Dupin, Farhi, Lascaux, Piketty, de Truchis,
Bouldouyre, Derradji, and Pacanowski. Analysis and interpretation of data: Jarzebowski, Caumes, Dupin, Costagliola, and Grabar. Drafting of the manuscript: Jarzebowski, Caumes, Costagliola, and Grabar. Critical revision
of the manuscript for important intellectual content: Jarzebowski, Dupin, Farhi, Lascaux, Piketty, de Truchis, Bouldouyre, Derradji, Pacanowski, Costagliola, and Grabar.
Statistical analysis: Jarzebowski, Costagliola, and Grabar. Administrative, technical, and material support: Costagliola. Study supervision: Caumes, Costagliola, and Grabar.
Financial Disclosure: None reported.
Funding/Support: The FHDH-ANRS CO4 is supported
by Agence Nationale de Recherches sur le SIDA et les
Hépatites, Institut National de la Santé et de la Recherche Médicale, and the French Ministry of Health.
Role of the Sponsors: The study sponsors had no role
in the study design, data collection, data analysis, data
interpretation, or writing of the article.
Previous Presentation: This original work was presented in part as a poster at the 10th International Congress on HIV and Drug Therapy in HIV Infection; November 7-11, 2010; Glasgow, Scotland.
Online-Only Material: The eAppendix, eTables, and eFigure are available at http://www.archinternmed.com.
Additional Contributions: We thank all the FHDH participants and research assistants, in particular Lydie
Beniguel, PhD, Sandra Firmin, MSc, Mohamed Medjkane,
MD, Selma Trabelsi, MSc, and Sara William-Faltaos,
PharmD, PhD.
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INVITED COMMENTARY
Prevention, Detection, and Treatment
of Coinfections
A Priority in Human Immunodeficiency Virus–Infected Persons
to Reduce Viral Load and Consequent Disease Progression and Transmission
I
n the July 23, 2012, online and September 10, 2012,
print versions of Archives, an impressive French
clinical surveillance system has been used to assess the impact of syphilis infection on the viral load (VL)
and CD4⫹ cell counts of human immunodeficiency virus (HIV)–infected men.1 In France, the national health
system facilitates high continuity in primary care, reduces fiscal barriers to care, and enables clinical data to
be harvested readily for outcomes research. Because this
system facilitates the management of sexually transmitted infections (STIs) in the context of HIV primary care,
it is markedly easier to examine the impact of coinfec-
tion than in systems in which patients are evaluated for
STIs in settings outside of their primary care practice.
This study—ANRS CO4—reports data from a wellknown hospital cohort of HIV-infected patients, the
French Hospital Database on HIV (FHDH). There are 70
hospitals participating in the FHDH, but only the 24 hospitals in the Paris region contributed here. Of the almost 29 000 men followed in the 24 Paris-region HIV clinics, 628 had a first syphilis diagnosis between 1998 and
2006. The investigators conducted a nested casecontrol study from the cohort of HIV-infected men followed up for all or some of the years 1998 through 2006.
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