A Comparison of Seminal Hepatitis C Virus (HCV) RNA Levels During Recent and Chronic HCV Infection in HIV-Infected and HIV-Uninfected Individuals
A Comparison of Seminal Hepatitis C Virus (HCV) RNA Levels During Recent and Chronic HCV Infection in HIV-Infected and HIV-Uninfected Individuals
Daniel Bradshaw 2 3
Francois Lamoury 2
Beth Catlett 0
Tanya L. Applegate 2
John Mcallister 0
Gregory J. Dore 2
Gail V. Matthews 2
Mark Danta 1
0 St Vincent's Hospital , Sydney , Australia
1 St Vincent's Clinical School , UNSW Australia
2 Kirby Institute
3 Chelsea and Westminster Hospital , London , United Kingdom
Background. We aimed to characterize seminal hepatitis C virus (HCV) RNA dynamics in human immunodeficiency virus (HIV)-positive men with acute HCV infection given its potential role in sexual transmission of HCV. Methods. Men with acute HCV infection (duration, ≤12 months) or chronic HCV infection (duration, >12 months) were prospectively recruited. Paired semen and blood samples were assayed for HCV RNA levels. Results were analyzed using χ2, Fisher exact, Mann-Whitney U, and Kruskal-Wallis tests. Results. Eighteen men (27.3%) had acute HCV and HIV coinfection, 22 (33.3%) had chronic HCV infection and HIV coinfection, and 26 (39.4%) had chronic HCV monoinfection. HCV RNA was detected in semen specimens from 29 of 66 men (43.9%). The median HCV RNA level in blood was 4.0 log IU/mL higher than that in semen. HCV RNA levels were correlated in semen and blood (r2 = 0.142). Neither HIV positivity nor acute HCV infection was associated with an increased frequency of seminal HCV RNA detection. Among men with acute HCV and HIV coinfection, the median HCV RNA level in blood specimens from those with seminal HCV RNA was higher than that in blood specimens from those without seminal HCV RNA (P = .001). Seminal HCV RNA was detected in ≥1 sample for 26 of 35 men (74.3%) attending follow up. Conclusions. HCV RNA was detected in semen during both acute and chronic HCV infection. This was unaffected by HIV positivity or the phase of HCV infection. Elevated seminal HCV RNA levels could contribute to sexual transmission of HCV, but other factors, including high-risk behaviors, may be the main drivers for HCV transmission in HIV-infected individuals.
Increasing incidence rates of acute hepatitis C virus
(HCV) infection in human immunodeficiency virus
(HIV)–positive men who have sex with men (MSM)
have been reported in many industrialized nations
]. Transmission occurs predominantly through
the permucosal route, with most individuals denying
injection drug use (IDU). This implies transmission
across an intact or disrupted mucosal barrier, usually
following sexual exposure. Among HIV-uninfected
heterosexuals, sexual transmission of HCV is rare, with one
study estimating a frequency of 1 transmission per
190 000 sexual acts . Sexual transmission of HCV is
considered to be less efficient than for HIV, probably
owing to a lower level of virus in genital secretions
and the absence of suitable target cells in the anogenital
For HIV-infected MSM, the biological mechanism
underlying sexual transmission of HCV remains
unclear, although is likely related to multiple factors.
Behavioral factors include serosorting with respect to
HIV status, involvement in high-risk sexual activities,
and use of permucosally administered recreational
drugs. Biological factors include HIV coinfection and sexually
transmitted infections (STIs), particularly ulcerative
mucocutaneous infections, such as syphilis and lymphogranuloma
]. Permucosal transmission may be related to direct
transfer of virus in blood present during sex [
], exposure to
], or exposure to semen containing virus .
Although several studies have examined seminal HCV RNA
levels, the dynamics of HCV in semen remain poorly
characterized. Early studies failed to identify seminal HCV RNA in men
with chronic HCV infection [
], although most published
since 2000 reported detection rates of 10%–40% [
14, 17, 18
Seminal levels of HCV RNA in HIV-infected men may be
elevated , although the data are conflicting [
]. A possible
relationship between HCV RNA levels in blood and semen has also been
14, 17, 20
]. Of those studies examining RNA levels
longitudinally, most describe an intermittent process [
14, 21, 22
Only 1 study reported seminal HCV RNA levels in acute HCV
], with similarly low levels of detection in acute and
chronic infection. However, it could be postulated that acute
infection differs from chronic infection, owing to fluctuating viral
dynamics in blood among individuals with acute infection [
No study has examined the possible relationship between
STIs and seminal HCV RNA level, although epidemiological
data imply an association between STIs and incident HCV
infection in HIV-positive MSM engaging in high-risk sex but
denying IDU [
1, 2, 9–11, 25
]. Furthermore, data from
HIVmonoinfected men suggest an association between seminal
HIV RNA level and concomitant STIs [
We aimed to characterize the dynamics of seminal HCV
RNA levels in acute men with acute HCV and HIV coinfection
through comparison of these data with those for individuals
with chronic HCV, with or without HIV coinfection. We also
sought to describe the possible relationship between STIs and
seminal HCV RNA levels.
This study was conducted according to the Declaration of
Helsinki and approved by the research ethics committee of St
Vincent’s Hospital (Sydney, Australia).
This was a longitudinal cohort study of HCV RNA–positive
men not currently receiving therapy for HCV who were
recruited prospectively between November 2009 and October 2013
from the hepatitis clinic at St Vincent’s Hospital.
Seventy men participated and were assigned to one of 3 groups:
acute or recent HCV infection plus HIV-1 infection (AHCV/
HIV+), chronic HCV infection plus HIV-1 infection (CHCV/
HIV+), and chronic HCV infection plus no HIV infection
(CHCV/HIV−). A fourth group (acute HCV infection plus
no HIV infection) comprised only 4 individuals and was
therefore excluded from subsequent analysis. Subjects with chronic
HCV infection were those who tested positive for HCV RNA
for >12 months. Subjects with acute or recent HCV infection
were those who tested positive for anti-HCV antibody or
HCV RNA ≤6 months before enrollment and had either (1)
acute clinical infection (defined as symptomatic seroconversion
or an alanine aminotransferase level of >10 times the upper
limit of normal, excluding other causes of acute hepatitis, within
12 months before enrollment) or (2) asymptomatic HCV
infection with seroconversion (defined as a negative result of a test
for anti-HCV antibody during the 12 months before the initial
positive result of a test for anti-HCV antibody).
The date of HCV acquisition was estimated according to
previously described formulae (Supplementary Table 1) [
“Duration of infection” was defined as the time from the estimated
date of HCV infection to the date of the baseline visit [
Individuals were excluded if HCV RNA was undetectable at
enrollment. All participants provided written, informed consent
for the collection of samples and subsequent analysis.
Participants provided demographic details and sexual and drug-use
histories through completion of a questionnaire. Clinical and
laboratory data were collected from hospital records. The
most likely mode of HCV transmission was determined by
the clinician at initial screening. When both sexual and
IDUassociated exposures occurred within 6 months of the estimated
date of acquisition, the IDU route was assigned.
Paired blood and semen samples were collected in
ethylenediaminetetraacetic acid–coated containers from each individual.
Repeat samples were available from 35 men between 12 and
24 weeks following their first visit. The reasons that 31 men
did not provide repeat samples were as follows: subsequent
initiation of anti-HCV therapy (15 cases), failure to reattend the
clinic (14 cases), and illness (2 cases). Semen samples were
taken to the laboratory, where liquefaction was allowed to
occur, and were centrifuged at 800 ×g for 10 minutes. The
seminal plasma supernatant was harvested and recentrifuged at
1350 ×g for 15 minutes, and the resultant supernatant was
stored at −80°C until required.
After removal of the seminal plasma, the cell pellet,
consisting of spermatozoa and inflammatory cells, was resuspended in
up to 13 mL of phosphate-buffered saline and centrifuged at
700 ×g for 10 minutes. The supernatant was discarded, and
the pellet was resuspended in an additional 1 mL of
phosphate-buffered saline. This was divided into 1-mL aliquots and
microcentrifuged at 12 000 ×g for 5 minutes. The supernatant
was discarded by tipping, and the pellet was stored at −80°C.
Participants were tested for Chlamydia trachomatis and
Neisseria gonorrhoeae with nucleic acid amplification testing
(NAAT) of first-void urine samples and, for MSM, pharyngeal
and rectal samples. Rectal specimens positive for chlamydial
infection by NAAT underwent serotyping for lymphogranuloma
venereum. Anogenital ulcers were swabbed for detection of
herpes simplex virus type 1 (HSV-1) and HSV-2 DNA. All men
had Treponema pallidum serologic tests performed.
Detection of HCV
HCV RNA was extracted and quantified in blood specimens by
the Abbott m2000 RealTime automated system, according to
the manufacturer’s instructions.
Validation was performed for quantification of HCV RNA
levels in semen by spiking seminal plasma from HCV-uninfected
volunteers with blood from a genotype 3a HCV RNA–positive
donor with a known HCV RNA level (Roche Ampliprep/
Taqman HCV Monitor assay) to produce a reducing HCV
RNA concentration of 6, 5, and 4 log IU/mL. Experiments
were performed in triplicate. RNA extraction and quantification
was performed by the m2000 system. Three further validations
were undertaken with blood specimens from donors infected
with HCV genotype 1a or 3a, to produce a reducing HCV
RNA concentration from 4.5 to 1.0 log IU/mL in HCV RNA–
negative seminal plasma. The lower limit of detection was 1.8
log IU/mL. HCV RNA levels were then quantified in
participating men in aliquots of 200 µL of seminal plasma or an estimated
100 µL of seminal cell pellet suspended in lysis buffer.
Results were analyzed using the χ2 and Fisher exact tests for
categorical variables as appropriate. Mann–Whitney U and
Kruskal–Wallis tests were used for continuous variables. The
r2 coefficient of determination was used to test the strength of
correlation between 2 continuous variables. The Wilcoxon rank
test was used to assess for differences between paired
continuous variables. Statistically significant findings were defined as
those with a P value of <.05.
Baseline characteristics of participants are displayed in Table 1.
For the AHCV/HIV+ group, the median duration of HCV
infection was 12.5 weeks (interquartile range [IQR], 5.6–24.2
weeks); 2 (11.1%) had an infection duration of ≤4 weeks, 1
(5.6%) was negative for anti-HCV immunoglobulin G, 6
(33.3%) had jaundice, and 2 (11.1%) later cleared HCV
spontaneously. Men in the AHCV/HIV+ group were younger (median
age, 45.3 years; IQR, 36.5–49.0 years) than those in the CHCV/
HIV+ group (median age, 49.7 years; IQR, 43.9–54.3 years) and
those in the CHCV/HIV− group (median age, 52.1 years; IQR,
46.8–56.0 years). The AHCV/HIV+ group was more likely to
have a clinician-assigned sexual risk for HCV (10/18 [55.6%]),
compared with the CHCV/HIV+ group (3/22 [13.6%]) and the
CHCV/HIV− group (3/26 [11.5%]). Five of 18 men (27.8%) in
the AHCV/HIV+ group who considered themselves to have
acquired HCV sexually were assigned an IDU risk by the clinician.
Most HIV-infected individuals were MSM (39/40 [97.5%]) and
had achieved a suppressed blood HIV RNA level by means of
antiretroviral therapy (32/40 [80.0%]). The median blood HCV
RNA level in the AHCV/HIV+ group (5.8 log IU/mL; IQR,
4.4–6.2 log IU/mL) was lower than that in the CHCV/HIV+
group (6.4 log IU/mL; IQR, 5.5–6.7 log IU/mL) and the
CHCV/HIV− group (6.1 log IU/mL; IQR, 5.6–6.4 log IU/mL).
The median ALT level in the AHCV/HIV+ group (121.53 U/L;
IQR, 60.0–374.3 U/L) was greater than that in the CHCV/
HIV+ group (75.5 U/L; IQR, 42.5–139.8 IU/L) and the CHCV/
HIV− group (86.5 U/L; IQR, 47.8–171.0 U/L). Half of AHCV/
HIV+ men receiving an STI screen (8/16) had an STI detected,
which was considerably more than the percentage in the
CHCV/HIV+ group (2/20 [10.0%]) and the CHCV/HIV−
group (1/20 [5.0%]). Detailed sexual and drug-use behaviors
for the preceding 6 months were available for 16 AHCV/HIV+
men (88.9%). These demonstrate multiple competing risks.
Seven men (43.8%) had a lifetime history of IDU
(methamphetamine use in 6 cases), of whom 5 (71.4%) reported injecting
methamphetamine on a less-than-weekly basis. The median
number of sex partners in the preceding six months was 20
(IQR, 8–42 partners); 12 men (75.0%) reported participation in
group sex (Supplementary Table 2).
HCV RNA in Semen
Twenty-nine men (43.9%) had HCV RNA detected in seminal
plasma at baseline. Men with detectable seminal HCV RNA had
a higher median blood level of HCV RNA (6.2 log IU/mL; IQR,
5.8–6.7 log IU/mL) than those with undetectable seminal HCV
RNA (5.8 log IU/mL; IQR, 4.8–6.3 log IU/mL; P = .002, by the
Mann–Whitney U test). The frequency of HCV RNA detection
in semen was similar between HIV-infected men (15/40
[37.5%]) and HIV-uninfected men (14/26 [53.8%]; P = .191)
and between men with acute HCV infection (7/18 [38.9%])
and those with chronic HCV infection (22/48 [45.8%];
P = .613). Urethral STI was not associated with detection of
HCV RNA in semen (P = 1.000). Table 2 outlines factors
associated with detection of HCV RNA in seminal plasma.
HCV RNA levels were weakly correlated in seminal plasma
and blood (r2 = 0.142; P = .002; Figure 1). The blood HCV RNA
level had a threshold, 5 log IU/mL, below which seminal HCV
RNA was not detected. The seminal HCV RNA level ranged from
<1.8 log IU/mL to 3.7 log IU/mL; 5 individuals, all of whom were
infected with HIV, had an HCV RNA level of >3 log IU/mL,
compared with 0 HIV-uninfected men (5/40 vs 0/26; P = .148).
The median HCV RNA level was 4.0 log IU/mL greater in blood
than seminal plasma (6.1 log IU/mL [IQR, 5.4–6.5 log IU/mL] vs
2.1 log IU/mL [IQR, 1.8–2.6 log IU/mL]). The median seminal
Data are no. (%) of participants or median value (interquartile range). See Methods for descriptions of the study groups.
Abbreviations: ALT, alanine aminotransferase; cART, combination antiretroviral therapy; MSM, men who have sex with men; NA, not applicable; STI, sexually
a As determined by the clinician.
b Due to Chlamydia trachomatis.
HCV RNA level was similar across the 3 groups, with values of 2.2
log IU/mL (IQR, 1.9–3.3 log IU/mL) in the AHCV/HIV+ group,
2.3 log IU/mL (IQR, 1.8–3.4 log IU/mL) in the CHCV/HIV+
group, and 2.0 log IU/mL (IQR, 1.8–2.4 log IU/mL]) in the
CHCV/HIV− group (P = .431, by the Kruskal–Wallis test).
Among men in AHCV/HIV+ group, the median blood HCV
RNA level in those with detectable HCV RNA in semen was
significantly higher than that in those with undetectable HCV
RNA in semen (6.2 log IU/mL [IQR, 6.0–6.6 log IU/mL] vs
4.6 log IU/mL [IQR, 3.2–5.7 log IU/mL]; P = .001), but the
difference was not significant in the CHCV/HIV+ group (6.6 log
IU/mL [IQR, 5.6–6.7] vs 6.2 log IU/mL [IQR, 5.5–6.6 log
IU/mL]; P = .451) or the CHCV/HIV− group (6.2 log IU/mL
[IQR, 5.7–6.7 log IU/mL] vs 6.0 log IU/mL [IQR, 5.3–6.2 log
IU/mL]; P = .105; Figure 2). A correlation between blood and
seminal HCV RNA levels in the AHCV/HIV+ group was
observed (r2 = 0.426; P = .003).
To determine whether the cellular fraction of semen could
also contain HCV that was possibly not detected in the plasma
component, the cell pellet was analyzed. Of 11 individuals for
whom both seminal plasma and cell pellets were assayed,
4 (36.4%) had detectable HCV RNA in cell pellets, and
6 (54.5%) had detectable HCV RNA in seminal plasma. For
2 men with detectable HCV RNA in seminal plasma, HCV
RNA was not detected in the cell pellet. For 4 men, HCV
RNA was detectable in both seminal plasma and cell pellets,
although at a reduced magnitude in cell pellets (median
reduction, 0.6 log IU/mL). For 5 men, HCV RNA was not detected
in seminal pellets or plasma. Therefore, reduced detection of
HCV RNA in cell pellets versus seminal plasma was observed.
Longitudinal Detection of HCV RNA in Semen
Thirty-five men (53.0%) reattended the clinic at a median
duration of 18.0 weeks (IQR, 14.6–25.6 weeks) after enrollment.
Median blood HCV RNA levels at baseline (6.0 log IU/mL;
IQR, 5.4–6.6 log IU/mL) were similar to those at follow-up
(6.0 log IU/mL; IQR, 5.6–6.5 log IU/mL; P = .576, by the
Wilcoxon test). Two men (5.7%), both of whom were in the AHCV/
HIV+ group, had an STI (rectal chlamydial infection and rectal
gonorrhea, respectively). Nine men for whom HCV RNA was
HCV RNA in Seminal Plasma
undetectable in seminal plasma at baseline had HCV RNA
detected during follow-up; of these, 7 were from the CHCV/
HIV+ group and 1 each was from the CHCV/HIV− and
AHCV/HIV+ groups. Considering both baseline and follow-up
samples, 38 of 66 participants (57.6%) had seminal HCV RNA
detected at some point.
Baseline levels of HCV RNA in blood were associated with
longitudinal detection of seminal HCV RNA. Among men
with 2, 1, and 0 seminal plasma samples positive for HCV
RNA, the level of HCV RNA in blood was 6.4 log IU/mL
(IQR, 5.9–6.7 log IU/mL), 6.0 log IU/mL (IQR, 5.5–6.5 log
IU/mL), and 5.2 log IU/mL (IQR, 3.9–6.0 log IU/mL),
respectively (P = .009, by the Kruskal–Wallis test; Figure 3).
For the AHCV/HIV+ group, a relationship was observed
between the baseline HCV RNA level in blood and longitudinal
detection of seminal HCV RNA. For men with 2, 1, and 0
semen samples positive for HCV RNA, the level of HCV RNA
in blood was 6.0 log IU/mL (IQR, 5.9–6.2 log IU/mL), 6.2 log
IU/mL (IQR, 4.8–6.6 log IU/mL), and 4.6 log IU/mL (IQR, 2.9–
5.2 log IU/mL), respectively (P = .019). For men with chronic
HCV infection, there was no significant difference in baseline
HCV RNA level in blood according to the number of seminal
specimens in which HCV RNA was detected.
Overall, 43.9% of men had seminal HCV RNA detected, with
the frequency increasing to 56.7% during longitudinal
sampling. A relationship was identified between HCV RNA levels
in blood and semen in HIV-infected men with recently acquired
HCV (P = .001). HCV RNA levels in this group were correlated,
although levels in semen were 4.0 log IU/mL lower than those
in blood (r2 = 0.426). Furthermore, longitudinal detection of
HCV in semen was associated with HCV RNA levels in blood
in the AHCV/HIV+ group (P = .019). These relationships were
not identified in men with chronic HCV infection, irrespective
of HIV status, or in a previous study of individuals with acute
HCV infection and HIV coinfection [
As previously reported, a threshold of 5 log IU/mL was
identified, below which detection of seminal HCV RNA did not
]. The only factor associated with HCV RNA
detection in semen was the HCV RNA level in blood, which suggests
that a largely passive process determines seminal dynamics.
Seminal HCV RNA levels were generally low (median, 2.1
log IU/mL), although a small but important proportion of
men (5/66 [7.6%]) had levels of >3 log IU/mL. Seminal virus
may well be infectious, because only 10–20 viral particles are
required to establish a productive infection [
the infectiousness of seminal HCV remains to be confirmed,
such as by using luciferase reporter assays [
This study did not identify HIV coinfection as associated with
an increased level of seminal HCV RNA. Although 5
HIVinfected men, compared with 0 HIV-uninfected individuals,
had seminal HCV RNA levels of >3 log IU/mL, perhaps implying
heightened infectiousness, this difference was not statistically
significant (P = .148), and too few HIV-negative individuals with
acute HCV infection were identified to examine semen dynamics
in this group. Previous reports of the possible role of HIV in
determining seminal HCV dynamics are conflicting [
14, 19, 32
Neither CD4 T-cell count nor blood HIV RNA level was
associated with HCV RNA detection in this and previous studies,
suggesting that any possible interaction is not mediated by
immunosuppression. Furthermore, there appears to be no association
between the seminal HIV RNA level and the seminal HCV
RNA level [
]. Any interaction is likely to be indirect, perhaps
mediated by HIV-associated immunoactivation. Alternatively,
HIV infection may increase susceptibility to HCV infection,
such as through impairment of rectal immune responses, which
are permanently depleted following primary HIV infection [
The proportion of individuals with detectable seminal HCV
RNA rose to 57.6% after inclusion of individuals with
undetectable seminal HCV RNA at baseline but detectable HCV RNA at
follow-up. This represents a higher level of HCV RNA
detection, compared with previous reports [
14, 17, 18, 20–22, 32
For men with 2 clinic visits, 14 of 35 (40.0%) had HCV RNA
detected intermittently. Previous studies have also highlighted
an intermittent process, which may represent a truly episodic
phenomenon or reflect low levels of seminal HCV RNA
(median, 2.1 log IU/mL) close to the threshold of detection [
Single-time-point assays are therefore likely to underestimate
seminal HCV RNA levels. The high level of seminal detection
identified here probably also reflects the high sensitivity of the
m2000 assay. Future work with the m2000 involving intensive
sampling during the very early acute stage of HCV infection
could improve characterization of seminal HCV RNA dynamics.
As previously reported, HCV RNA was detected in the
seminal pellet at lower levels than for seminal plasma,
suggesting that HCV in the male reproductive tract is predominantly
14, 18, 19
]. Briat et al performed limiting-dilution
cloning and phylogenetic analysis for 2 individuals with chronic
HCV infection and reported clustering of quasispecies in blood
and semen [
]. Conventional Sanger sequencing for the HCV
core E2 region, followed by phylogenetic analysis, for an
individual in the current study also identified clustering between
blood-derived and semen-derived sequences (data are available
on request). This further supports the notion that HCV is
unlikely to replicate in semen. The finding of some individuals
with elevated HCV RNA levels in blood but undetectable
HCV RNA in semen could be explained by the presence of
seminal viremia below the lower limit of detection of the
assay (<1.8 log IU/mL), intermittent detection, or preferential
transfer of some quasispecies into semen [
Urethral STI was not associated with seminal detection of
HCV RNA, a finding for which there are several possible
explanations. First, although many STIs were observed in the AHCV/
HIV+ group, only 1 STI was urethral, so a relationship may have
been missed. Second, the epidemiological association of STIs
with HCV transmission may represent a marker for high-risk
activities. Third, STIs may increase mucosal susceptibility to
HCV infection, rather than HCV shedding. Given strong
relationships between seminal herpesvirus DNA and seminal
HIV-1 RNA, a possible interaction between herpesviruses (eg,
HSV-2) and seminal HCV remains to be explored [
Several other characteristics of this cohort are noteworthy.
First, most in the AHCV/HIV+ group (10/18 [55.6%]) were
infected with HCV through the sexual route, implying that
permucosal exposure remains the major transmission route in
this group and underlining the potential importance of seminal
virus. However, a significant minority (8/18 [44.4%]) had an
IDU exposure, as in a previous Australian study [
IDUassociated exposure to HCV in HIV-positive MSM in other
developed countries is probably less common [
3, 4, 36
Interestingly, 5 individuals (27.8%) in the AHCV/HIV+ group
considered themselves to have acquired HCV sexually but were
assigned an IDU route by the clinician, raising the possibility
that estimates of sexual transmission may be conservative in
Australia. Men in the CHCV/HIV+ group were more likely to
have acquired HCV through IDU than those in the AHCV/
HIV+ group, although the difficulty of establishing the mode
of transmission many years after HCV acquisition may make a
comparison problematic. However, sexual transmission could
represent an increasingly important mode of transmission
among HIV-positive MSM in recent years [
]. Second, a majority
of those in the AHCV/HIV+ group reported participating in
group sex, which is known to be associated with HCV
]. Third, as noted previously, methamphetamine was the
preferred injected drug for those reporting IDU [
The study has limitations, particularly with regard to
uncertainty about true date of infection and the small number of
individuals in the very early stages of HCV infection. Only 1
individual with early acute HCV infection was identified
(duration, <4 weeks), and only 1 man had a very high level of HCV
RNA in blood (>7 log IU/mL). It is not, therefore, possible to
ascertain whether, during very early acute HCV infection,
extremely high HCV RNA levels in blood may translate into
higher HCV levels in semen, thus representing a period of
In our study, presentation of recently acquired HCV infection
was variable, as reflected in the wide IQRs for the baseline HCV
RNA level in blood (median, 5.8 log IU/mL; IQR, 4.4–6.2 log
IU/mL) and ALT level (median, 121.5 U/L; IQR, 60.0–374.3
U/L), compared with values for men with chronic HCV
infection. HCV RNA levels in blood in the AHCV/HIV+ group were
lower than in the CHCV/HIV+ group, probably because of low
numbers of subjects with early acute infection, which is known
to be associated with elevated HCV RNA levels. Additionally,
the group contained several individuals with very low HCV
RNA levels, consistent with the period of fluctuating viremia
frequently observed during the first few months of HCV
infection. This is likely to have reduced the overall median HCV
RNA level. Nevertheless, the proportion with spontaneous
clearance of HCV (2/18 [11.1%]) was at the lower bound of
the range reported for other HIV-positive cohorts (0%–40%)
]. The lack of individuals included with very early infection
reflects the difficulties with diagnosis of acute HCV infection, in
which many individuals are asymptomatic and identified
through (often relatively moderate) increases in the ALT level.
Uncertainty around the true date of infection is common,
especially for the majority of patients who do not present with
jaundice, as was typical in our study. Nevertheless, despite the
broader eligibility criteria than in many studies, most patients
enrolled had had infection for ≤6 months (ie, acute infection),
as calculated through standard methods.
This study has important implications for public health
interventions, particularly in view of the urgent need for effective
interventions to reduce HCV transmission in HIV-positive
MSM. Current sources of information for MSM reflect the
uncertainty surrounding the role of seminal virus for HCV
transmission. This study highlights that seminal HCV RNA can be
detected in individuals with both recently acquired and chronic
HCV infection. It is plausible that high HCV RNA levels in
semen could translate into an increased risk of sexual
transmission. It is important to note, however, that because neither HIV
infection nor recent HCV infection was significantly associated
with seminal HCV RNA detection, sexual transmission of HCV
may not be driven primarily by seminal virus. More likely,
transmission occurs through a combination of factors, with
seminal HCV RNA playing a role in the context of high-risk
behaviors. Nonetheless, given that HCV infections in many
individuals with recently acquired HCV are undiagnosed, safer-sex
messages should be reinforced, particularly with regard to
condom use. Equally, HIV-infected MSM with HCV
coinfection, especially those with high levels of HCV RNA in blood,
should be counseled regarding their possible heightened sexual
infectiousness. These messages should complement existing
strategies for reducing transmission risks associated with
permucosal blood exposure from traumatic sexual practices and
parenteral exposure from IDU.
Supplementary materials are available at The Journal of Infectious Diseases
online (http://jid.oxfordjournals.org/). Supplementary materials consist of
data provided by the author that are published to benefit the reader. The
posted materials are not copyedited. The contents of all supplementary
data are the sole responsibility of the authors. Questions or messages
regarding errors should be addressed to the author.
Acknowledgments. We thank Rebecca Hickey and the staff and patients
of the Immunology and Infectious Diseases B Ambulatory Care Unit, St
Vincent’s Hospital; the staff of the Viral Hepatitis Clinical Research
Programme, Kirby Institute, UNSW Australia (Sydney, Australia); and the
HIV Immunovirology Laboratory, St Vincent’s Hospital.
Financial support. This work was supported by the Australian National
Health and Medical Research Council (grant 568859).
Potential conflicts of interest. All authors: No reported conflicts.
All authors have submitted the ICMJE Form for Disclosure of Potential
Conflicts of Interest. Conflicts that the editors consider relevant to the
content of the manuscript have been disclosed.
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