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Sexual Activity as a Risk Factor for Hepatitis C

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  • claudine intexas
    http://www.natap.org Sexual Activity as a Risk Factor for Hepatitis C Norah A. Terrault Gastroenterology Division, Department of Medicine, University of
    Message 1 of 2 , Dec 11, 2003
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      http://www.natap.org

      Sexual Activity as a Risk Factor for Hepatitis C

      Norah A. Terrault Gastroenterology Division, Department of Medicine,
      University of California, San Francisco, CA. Hepatology November 2002


      ��..While there is sufficient evidence to support the conclusion that
      sexual transmission of HCV occurs, quantifying the magnitude of an
      individual's risk of HCV acquisition by sexual contact is more
      difficult�.�

      ABSTRACT. The accumulated evidence indicates that hepatitis C virus
      (HCV) can be transmitted by sexual contact but much less efficiently
      than other sexually transmitted viruses, including hepatitis B virus
      and human immunodeficiency virus (HIV). However, because sex is such
      a common behavior and the reservoir of HCV-infected individuals is
      sizable, sexual transmission of HCV likely contributes to the total
      burden of infection in the United States.

      Risk of HCV transmission by sexual contact differs by the type of
      sexual relationship. Persons in long-term monogamous partnerships are
      at lower risk of HCV acquisition (0% to 0.6% per year) than persons
      with multiple partners or those at risk for sexually transmitted
      diseases (0.4% to 1.8% per year). This difference may reflect
      differences in sexual risk behaviors or differences in rates of
      exposure to nonsexual sources of HCV, such as injection drug use or
      shared razors and toothbrushes. In seroprevalence studies in
      monogamous, heterosexual partners of HCV-infected, HIV-negative
      persons, the frequency of antibody-positive and genotype-concordant
      couples is 2.8% to 11% in Southeast Asia, 0% to 6.3% in Northern
      Europe, and 2.7% in the United States.

      Among individuals at risk for sexually transmitted diseases (STDs),
      the median seroprevalence of antibody to HCV (anti-HCV) is 4% (range,
      1.6% to 25.5%). HIV coinfection appears to increase the rate of HCV
      transmission by sexual contact.

      Current recommendations about sexual practices are different for
      persons with chronic HCV infection who are in steady monogamous
      partnerships versus those with multiple partners or who are in
      short-term sexual relationships.

      What factors increase the risk of HCV transmission by sexual contact?


      HIV coinfection is associated with higher rates of anti-HCV in
      persons engaged in higher-risk sexual practices. Additionally, in
      studies of STD clinic attendees and men having sex with men, other
      STDs (herpes simplex virus, Trichomonas, gonorrhea) and sexual
      practices that may traumatize the mucosa (e.g., anal receptive sex)
      are more frequent in anti-HCV positive than anti-HCV negative
      individuals, suggesting these factors increase the sexual
      transmission of HCV. Whether the risk of HCV transmission differs for
      males versus females is unclear. In one study of heterosexual couples
      in STD clinics, anti-HCV�positive female clinic attendees were 3.7
      times more likely to have an anti-HCV-positive male partner than the
      anti-HCV-positive male clinic attendees. The titer of HCV RNA and HCV
      genotype do not appear to influence the risk of HCV transmission, but
      high-quality studies to assess these virological factors are lacking.
      The stage or clinical status of liver disease of the HCV-infected
      individual is also not predictive of transmission risk. However,
      studies to date have focused only on individuals with chronic
      disease; whether individuals with acute hepatitis represent a
      subgroup at particular risk for HCV transmission is unknown.

      Current recommendations are as follows:

      1. HCV-positive individuals in longer-term monogamous relationships
      need not change their sexual practices. If couples wish to reduce the
      already low risk of HCV transmission by sexual contact, barrier
      precautions may be used. Partners of HCV-positive persons should be
      considered for anti-HCV testing.

      2. For HCV-infected individuals with multiple or short-term sexual
      partners, barrier methods or abstinence are recommended.

      The following are additional �common-sense� recommendations:

      3. Use of barrier precautions if other STDs are present, if having
      sex during menses, or if engaging in sexual practices that might
      traumatize the genital mucosa.

      4. Couples should not share personal items that may be contaminated
      by blood such as razors, toothbrushes, and nail-grooming equipment.

      Future research needs

      Additional prevalence and incidence studies may help to refine the
      current estimates of risk but will not be predicted to substantially
      change the overall findings of a low risk of HCV transmission by
      sexual contact. To be informative, such studies must include detailed
      virological analyses of antibody- and genotype-concordant sexual
      partners and perform complete ascertainment of nonsexual sources of
      HCV. Because the rate of transmission is low, a large sample size
      (greater than 1,000 individuals and/or partners) would be required to
      have sufficient power to determine the specific factors associated
      with HCV transmission. Given the cost, time, and logistics of
      executing large prevalence and incidence studies, and the
      questionable ability of such studies to advance our knowledge about
      key features of sexual transmission of HCV, alternative research
      strategies are necessary.

      The key research questions relate to identifying the specific factors
      that promote or prevent sexual transmission of HCV. Issues of
      critical importance include whether the level of HCV RNA predicts
      risk of transmission, if other STDs such as herpes simplex virus 2 or
      Trichomonas increase the risk of HCV acquisition, whether specific
      sexual practices (e.g., anal versus vaginal sex) affect the risk of
      HCV, whether transmission is more likely to occur during acute rather
      than chronic hepatitis C, and whether females are at higher risk of
      HCV acquisition through sex than males. The insights gained by
      addressing these specific questions will allow more detailed future
      recommendations for HCV-infected persons and their sexual partners
      and ultimately lead to interventions that may reduce the risk of
      transmission of HCV through sexual contact.

      BACKGROUND

      Percutaneous exposures, such as blood transfusion and injection drug
      use, are well-established risk factors for hepatitis C virus (HCV)
      infection. The risk of HCV transmission by sexual contact, however,
      is less well defined. The accumulated epidemiologic evidence
      indicates that HCV can be transmitted by sexual contact but much less
      efficiently than other sexually-transmitted viruses, including
      hepatitis B virus and human immunodeficiency virus (HIV).

      There are several case reports of acute hepatitis C occurring in
      persons whose only risk factor appeared to be a HCV-infected sexual
      partner. The strength of these reports lay in their ability to
      document seroconversion in an individual at risk in temporal
      relationship to sexual activity with an HCV-infected partner. The
      mode of transmission was ascertained by carefully questioning the
      infected individual to exclude nonsexual sources of HCV. A high
      degree of sequence homology between the viral strains in the sexual
      partners provided virological confirmation that a transmission event
      had occurred.

      While there is sufficient evidence to support the conclusion that
      sexual transmission of HCV occurs, quantifying the magnitude of an
      individual's risk of HCV acquisition by sexual contact is more
      difficult. Epidemiologic studies have had several methodological
      shortcomings that tend to overestimate the proportion of HCV
      infections attributed to sexual contact. Early studies used
      first-generation antibody to HCV (anti-HCV) assays which have a
      higher false positive rate than second- and third-generation assays.
      Studies varied in the completeness of risk ascertainment in partners,
      and many failed to carefully exclude HCV acquisition from nonsexual
      sources:

      When evaluating a partner for possible acquisition of HCV through
      sexual contact, it is essential to exclude other sources of HCV. The
      female partner may have her own risk factor for HCV infection, such
      as a prior history of injection drug use or blood transfusion (A).
      Alternatively, she may have been infected by her partner, but the
      mode of transmission may have been nonsexual, such as sharing of
      needles, razors, or other contaminated personal items.

      Nondisclosure of injection drug use is particularly important because
      assessing the independent contribution of sexual activity in HCV
      transmission is difficult in the presence of injection drug use.
      Finally, only a limited number of studies performed virological
      analyses to confirm that anti-HCV concordant sexual partners were
      infected with the same virus.

      Sexual transmission has been evaluated in different populations of
      HCV-infected individuals. Two main risk groups are discernable: (1)
      those who are more sexually promiscuous and likely to have multiple
      sexual partners, including female sex workers, men having sex with
      men, those in HIV surveillance studies, and attendees of
      sexually-transmitted diseases (STDs) clinics; and (2) those in steady
      monogamous sexual relationships. Rates of anti-HCV positivity vary by
      risk group, with higher rates of HCV reported in persons at risk for
      STDs and lower rates in heterosexual partners in long-term
      relationships. This difference in rate of HCV infection may reflect
      differences in sexual risk behaviors (frequency or type of sexual
      activities). Alternatively, differences between risk groups may
      reflect differing rates of exposure to nonsexual sources of HCV, such
      as injection drug use, as well as other potential risk factors such
      as intranasal cocaine use and tattooing, or sharing of razors and
      toothbrushes. The findings regarding sexual transmission defined by
      one risk group may not be generalizable to others.

      Detection of HCV RNA in Bodily Fluids

      Sexual transmission of virus occurs when infected body secretions or
      infected blood are exchanged across mucosal surfaces. The presence of
      virus in body secretions is necessary but may not be sufficient for
      transmission to occur. Other factors that may influence transmission
      include the titer of virus in body secretions, the integrity of the
      mucosal surfaces, and the presence of other genital infections (viral
      or bacterial).

      Studies to detect HCV RNA in semen (seminal fluid and cells), vaginal
      secretions, cervical smears, and saliva have yielded mixed results.
      Failure to detect HCV RNA in body secretions may be caused by
      technical factors, including specimen collection and storage, and the
      ability to exclude cellular components and to overcome the presence
      of polymerase chain reaction inhibitors. Even in studies using
      optimal methods to isolate HCV RNA, the minority of samples were
      positive for HCV RNA and all positive samples were of low titer
      (equal to 102 copies/mL). A low titer of virus in genital secretions
      may be one reason that HCV is transmitted less efficiently than
      hepatitis B virus or HIV. Additionally, there may be an absence of
      suitable target cells in the genital tract to allow infection to
      occur or infection may require the presence of abnormal mucosa.
      Finally, while the presence of HCV RNA in semen and vaginal or
      cervical secretions supports the contention that HCV is sexually
      transmissible, a cell culture system or animal model is needed to
      prove that the HCV RNA detected in genital secretions represents
      infectious virus.

      How prevalent is the risk factor of sexual activity in acute
      hepatitis C?

      The Centers for Disease Control and Prevention collects detailed risk
      factor data on cases of acute hepatitis C identified through the
      Acute Hepatitis Sentinel County Surveillance program. Between 1995
      and 2000, 18% of individuals with acute community-acquired HCV
      infection reported sexual contact with an anti-HCV�positive person in
      the preceding 6-month period (two thirds of cases) or multiple sexual
      partners (one third of cases) as their only risk factor for HCV
      acquisition. Currently, sexual activity ranks as the second most
      common risk factor for HCV reported by individuals with acute
      hepatitis. This suggests that sexual transmission may contribute
      significantly to the total burden of HCV infection in the U.S.
      population.

      What is the prevalence of HCV in persons at risk for STDs?

      In U.S. seroprevalence studies conducted among those at risk for
      STDs, 1.6% to 25.5% of individuals were anti-HCV positive (Table 1).

      Table 1. Seroprevalence of anti-HCV among individuals at risk for
      STDs

      First you�ll see listed below the risk group, followed by the %
      HCV-infected (range & average, followed by the factors associated
      with being antibody HCV+.

      Female sex workers
      1%-19% (6%); Number of partners, other STDs, non-use of condoms, sex
      with trauma

      MSM
      2.9%-13% (4%); With IDU included: risk for IDU > sexual factors; if
      IDU excluded: anti-HIV positivity, number of partners

      STD clinic attendees
      1.6%-26% (4%); With IDU included: risk for IDU > sexual factors

      1.6%-7% (if no IDU history); If IDU excluded: number of recent and
      lifetime sexual partners, high-risk sexual contacts, anti-HIV
      positivity

      Abbreviations: STDs, sexually transmitted disease(s); MSM, men who
      have sex with men; IDU, injection drug use; HIV, human
      immunodeficiency virus.

      Median rates of anti-HCV positivity were 6% among female sex workers,
      4% among men having sex with men, and 4% among attendees of STD
      clinics and individuals participating in HIV surveillance studies
      (Table 1). The HCV seroprevalence rates were lower than other viral
      infections such as hepatitis B virus and HIV.7 In those studies
      including persons with a history of injection drug use, anti-HCV
      positivity was more strongly associated with drug use than with
      factors related to sexual practices. In those studies limited to
      individuals without a history of injection drug use, factors
      predictive of anti-HCV positivity included the number of recent and
      lifetime partners, high risk sexual practices (variably defined),
      other STDs, and anti-HIV positivity. These factors are consistent
      with a sexual route of transmission.

      In persons engaged in higher-risk sexual behaviors, those with HIV
      infection were more likely to be anti-HCV positive (odds ratio, 2.5
      to 4.4) than those who were HIV negative, even after controlling for
      other sexual factors that might enhance risk of transmission such as
      number of partners, non-use of condoms, and other STDs. The precise
      mechanism by which HIV increases the risk of sexual transmission of
      HCV is unknown.

      What is the prevalence of HCV infection in monogamous heterosexual
      partners?

      Seroprevalence studies in monogamous, heterosexual partners of
      HCV-infected, HIV-negative persons have reported prevalence rates
      ranging from 0% to 24% in studies from Southeast Asia and Southern
      Europe but lower rates in studies from the United States and Northern
      Europe. North America: 2-4.8%; South America: 11.8%; Africa:
      5.6%-20.7%; Europe 0-5%; Asia: 8.8%-27%.

      The factors most consistently associated with HCV positivity among
      heterosexual partners were the presence of percutaneous risk factors
      for HCV (injection drug use, blood transfusion, sharing glass
      syringes). Early studies found the rate of HCV positivity in partners
      increased with the longer duration of marriage, suggesting risk of
      sexual transmission correlated with frequency of contact. However,
      subsequent studies adjusting for age did not find a consistent
      relationship between the duration of the sexual relationship and HCV
      positivity in partners.

      The majority of published studies did not evaluate
      antibody-concordant couples with additional virological testing to
      confirm that partners were infected with the same virus. In the more
      informative studies, genotyping was used to evaluate
      antibody-concordant couples. In all cases, use of genotyping led to a
      reduction in the estimated rate of transmission by sexual contact.

      Genotyping, however, is suboptimal for determining whether partners
      are infected with the same virus because HCV genotypes that are
      prevalent in the population may be present in both partners but
      represent HCV infection from different sources. The importance of
      nucleotide sequencing was highlighted in a detailed study of 24
      anti-HCV concordant heterosexual couples from France. The
      investigators found 12 of the 24 couples (50%) had concordant
      genotypes, 7 had discordant genotypes, and 5 were untypable. Seven of
      the 12 genotype-concordant couples were further analyzed by sequence
      analysis of the hypervariable region of E2 (envelope region of the
      HCV genome) and only 3 couples had highly homologous viral strains
      that were consistent with a transmission event. Interestingly, in
      each of the 3 concordant couples, an alternative, nonsexual mode of
      HCV transmission was present. Thus, overestimation of the rate of
      sexual transmission of HCV occurs if antibody testing alone is used
      to assess sexual pairs. Based on only those seroprevalence studies
      using genotyping or sequence analysis to evaluate antibody concordant
      couples, the estimated prevalence of HCV among heterosexual couples
      in monogamous relationships is 2.8% to 11% in Southeast Asia, 0% to
      6.3% in Northern Europe, and 2.7% in the United States.

      The U.S.-specific published data are sparse, with 1 small study (N =
      42) conducted in heterosexual partners of patients attending a liver
      clinic and 2 studies conducted in hemophiliacs (variable proportion
      HIV coinfected). Seroprevalence rates varied from 2.0% to 4.8%.
      Preliminary data from the HCV Partners Study, a cross-sectional study
      of heterosexual monogamous couples, provides the best available
      estimate of risk among U.S. couples. In this study, which excludes
      couples in which injection drug use is present in both partners, the
      prevalence of anti-HCV among 401 partners was 4.2%, with genotype
      concordance present in 2.7% of couples (Terrault N, unpublished
      data).

      What is the incidence of HCV infection in �at risk� individuals?

      A prospective cohort study of discordant couples followed closely for
      newly acquired infection is the ideal method to characterize the risk
      of transmitting HCV through sexual contact. However, even this method
      may not be perfect because the exclusion of couples in which the
      partner is already infected may leave a more selected and less
      representative population of sexual partnerships for follow-up.

      In retrospective cohorts of female partners of hemophiliacs, the
      incidence of HCV infection, defined by presence of anti-HCV, was 1 to
      1.87 per 1,000 person-years; among male partners of women infected by
      contaminated anti-D immunoglobulin, it was 0.28 per 1,000
      person-years; and among liver clinic patients and their sexual
      partners it was 1 to 3.86 per 1,000 person-years.

      In a prospective cohort study of 499 Italian heterosexual monogamous
      couples followed for a mean of 12.4 months, the incidence of new
      infection in sexual partners was 12 per 1,000 person-years. Sequence
      analysis of the anti-HCV positive couples showed a high degree of
      sequence homology in only 50% of couples, suggesting a true incidence
      of 6 per 1,000 person-years.29 In another prospective cohort of 112
      Taiwanese couples followed for an average of 46 months, the incidence
      was 2.3 per 1,000 person-years. The variability in risk of HCV
      infection reported in studies of long-term partners may reflect
      differences in the frequency or types of sexual activity in the
      different populations, but more likely represents differences in the
      rates of nonsexual HCV transmission.

      The incidence of new HCV infections among individuals who are at risk
      for sexually transmitted diseases is higher than in monogamous
      heterosexual couples. In prospective studies conducted in sex workers
      and attendees of STD clinics who were not injection drug users, the
      incidence of HCV was 0.4 to 1.8 per 100 person-years with follow-up
      periods of 1 to 3.7 years. In retrospective cohorts of hemophiliacs
      with high rates of HIV and HCV coinfection (more than 50%), the
      incidence of HCV infection was 0 to 0.19 per 100 person-years in
      sexual partners (primarily females) with a median follow-up of 12 to
      15 years. In these coinfected cohorts, HIV was transmitted more
      frequently than HCV, and partners were more likely to be infected
      with HIV and HCV than HCV alone.

      Summary

      The available data indicate HCV can be sexually transmitted, but the
      efficiency of transmission by the sexual route is low. Nonetheless,
      because sex is a common behavior and the reservoir of HCV-infected
      individuals is substantial (approximately 2.7 million), sexual
      contact likely contributes to the total burden of HCV infection in
      the United States. The contribution of sexual transmission is
      supported by findings from the Acute Hepatitis Surveillance Study, in
      which 18% of newly infected individuals reported sexual contact with
      an HCV-infected person or multiple sexual partners as their only risk
      factor for HCV acquisition.

      For the individual with chronic HCV infection, the estimated risk of
      sexual transmission of virus is 0% to 0.6% per year for those in
      monogamous relationships, and 1% per year for those with multiple
      sexual partners. Because risk varies by type of sexual relationship,
      the recommendations for preventing transmission of HCV differ for
      those in monogamous relationships versus those with multiple or
      short-term sexual partners. The latter group is not only at risk for
      HCV acquisition, but also for other types of sexually transmitted
      diseases, including HIV.


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    • w.m.landstra
      HI.Good article.Barrier precautions,does that means condooms?Why not say so.Sounds like language used by the Pope,he does.nt want to use the word
      Message 2 of 2 , Dec 12, 2003
      • 0 Attachment
        HI.Good article.Barrier precautions,does that means condooms?Why not say
        so.Sounds like language used by the Pope,he does.nt want to use the word
        condom.Traumatize the genital mucosa,meaning don.t be to raft on your
        parner?.Is it not?.I think the above mangened and monogamous relations are
        the bottomline of prevention.The latter the most difficult.Willem.
        ----- Original Message -----
        From: "claudine intexas" <claudineintexas@...>
        To: "gi" <giworld-hepatitis@yahoogroups.com>; "Web Warriors"
        <HepCWebWarriors@yahoogroups.com>
        Sent: Friday, December 12, 2003 5:31 AM
        Subject: [GIWorld-Hepatitis] Sexual Activity as a Risk Factor for Hepatitis
        C


        > http://www.natap.org
        >
        > Sexual Activity as a Risk Factor for Hepatitis C
        >
        > Norah A. Terrault Gastroenterology Division, Department of Medicine,
        > University of California, San Francisco, CA. Hepatology November 2002
        >
        >
        > "...While there is sufficient evidence to support the conclusion that
        > sexual transmission of HCV occurs, quantifying the magnitude of an
        > individual's risk of HCV acquisition by sexual contact is more
        > difficult.."
        >
        > ABSTRACT. The accumulated evidence indicates that hepatitis C virus
        > (HCV) can be transmitted by sexual contact but much less efficiently
        > than other sexually transmitted viruses, including hepatitis B virus
        > and human immunodeficiency virus (HIV). However, because sex is such
        > a common behavior and the reservoir of HCV-infected individuals is
        > sizable, sexual transmission of HCV likely contributes to the total
        > burden of infection in the United States.
        >
        > Risk of HCV transmission by sexual contact differs by the type of
        > sexual relationship. Persons in long-term monogamous partnerships are
        > at lower risk of HCV acquisition (0% to 0.6% per year) than persons
        > with multiple partners or those at risk for sexually transmitted
        > diseases (0.4% to 1.8% per year). This difference may reflect
        > differences in sexual risk behaviors or differences in rates of
        > exposure to nonsexual sources of HCV, such as injection drug use or
        > shared razors and toothbrushes. In seroprevalence studies in
        > monogamous, heterosexual partners of HCV-infected, HIV-negative
        > persons, the frequency of antibody-positive and genotype-concordant
        > couples is 2.8% to 11% in Southeast Asia, 0% to 6.3% in Northern
        > Europe, and 2.7% in the United States.
        >
        > Among individuals at risk for sexually transmitted diseases (STDs),
        > the median seroprevalence of antibody to HCV (anti-HCV) is 4% (range,
        > 1.6% to 25.5%). HIV coinfection appears to increase the rate of HCV
        > transmission by sexual contact.
        >
        > Current recommendations about sexual practices are different for
        > persons with chronic HCV infection who are in steady monogamous
        > partnerships versus those with multiple partners or who are in
        > short-term sexual relationships.
        >
        > What factors increase the risk of HCV transmission by sexual contact?
        >
        >
        > HIV coinfection is associated with higher rates of anti-HCV in
        > persons engaged in higher-risk sexual practices. Additionally, in
        > studies of STD clinic attendees and men having sex with men, other
        > STDs (herpes simplex virus, Trichomonas, gonorrhea) and sexual
        > practices that may traumatize the mucosa (e.g., anal receptive sex)
        > are more frequent in anti-HCV positive than anti-HCV negative
        > individuals, suggesting these factors increase the sexual
        > transmission of HCV. Whether the risk of HCV transmission differs for
        > males versus females is unclear. In one study of heterosexual couples
        > in STD clinics, anti-HCV-positive female clinic attendees were 3.7
        > times more likely to have an anti-HCV-positive male partner than the
        > anti-HCV-positive male clinic attendees. The titer of HCV RNA and HCV
        > genotype do not appear to influence the risk of HCV transmission, but
        > high-quality studies to assess these virological factors are lacking.
        > The stage or clinical status of liver disease of the HCV-infected
        > individual is also not predictive of transmission risk. However,
        > studies to date have focused only on individuals with chronic
        > disease; whether individuals with acute hepatitis represent a
        > subgroup at particular risk for HCV transmission is unknown.
        >
        > Current recommendations are as follows:
        >
        > 1. HCV-positive individuals in longer-term monogamous relationships
        > need not change their sexual practices. If couples wish to reduce the
        > already low risk of HCV transmission by sexual contact, barrier
        > precautions may be used. Partners of HCV-positive persons should be
        > considered for anti-HCV testing.
        >
        > 2. For HCV-infected individuals with multiple or short-term sexual
        > partners, barrier methods or abstinence are recommended.
        >
        > The following are additional "common-sense" recommendations:
        >
        > 3. Use of barrier precautions if other STDs are present, if having
        > sex during menses, or if engaging in sexual practices that might
        > traumatize the genital mucosa.
        >
        > 4. Couples should not share personal items that may be contaminated
        > by blood such as razors, toothbrushes, and nail-grooming equipment.
        >
        > Future research needs
        >
        > Additional prevalence and incidence studies may help to refine the
        > current estimates of risk but will not be predicted to substantially
        > change the overall findings of a low risk of HCV transmission by
        > sexual contact. To be informative, such studies must include detailed
        > virological analyses of antibody- and genotype-concordant sexual
        > partners and perform complete ascertainment of nonsexual sources of
        > HCV. Because the rate of transmission is low, a large sample size
        > (greater than 1,000 individuals and/or partners) would be required to
        > have sufficient power to determine the specific factors associated
        > with HCV transmission. Given the cost, time, and logistics of
        > executing large prevalence and incidence studies, and the
        > questionable ability of such studies to advance our knowledge about
        > key features of sexual transmission of HCV, alternative research
        > strategies are necessary.
        >
        > The key research questions relate to identifying the specific factors
        > that promote or prevent sexual transmission of HCV. Issues of
        > critical importance include whether the level of HCV RNA predicts
        > risk of transmission, if other STDs such as herpes simplex virus 2 or
        > Trichomonas increase the risk of HCV acquisition, whether specific
        > sexual practices (e.g., anal versus vaginal sex) affect the risk of
        > HCV, whether transmission is more likely to occur during acute rather
        > than chronic hepatitis C, and whether females are at higher risk of
        > HCV acquisition through sex than males. The insights gained by
        > addressing these specific questions will allow more detailed future
        > recommendations for HCV-infected persons and their sexual partners
        > and ultimately lead to interventions that may reduce the risk of
        > transmission of HCV through sexual contact.
        >
        > BACKGROUND
        >
        > Percutaneous exposures, such as blood transfusion and injection drug
        > use, are well-established risk factors for hepatitis C virus (HCV)
        > infection. The risk of HCV transmission by sexual contact, however,
        > is less well defined. The accumulated epidemiologic evidence
        > indicates that HCV can be transmitted by sexual contact but much less
        > efficiently than other sexually-transmitted viruses, including
        > hepatitis B virus and human immunodeficiency virus (HIV).
        >
        > There are several case reports of acute hepatitis C occurring in
        > persons whose only risk factor appeared to be a HCV-infected sexual
        > partner. The strength of these reports lay in their ability to
        > document seroconversion in an individual at risk in temporal
        > relationship to sexual activity with an HCV-infected partner. The
        > mode of transmission was ascertained by carefully questioning the
        > infected individual to exclude nonsexual sources of HCV. A high
        > degree of sequence homology between the viral strains in the sexual
        > partners provided virological confirmation that a transmission event
        > had occurred.
        >
        > While there is sufficient evidence to support the conclusion that
        > sexual transmission of HCV occurs, quantifying the magnitude of an
        > individual's risk of HCV acquisition by sexual contact is more
        > difficult. Epidemiologic studies have had several methodological
        > shortcomings that tend to overestimate the proportion of HCV
        > infections attributed to sexual contact. Early studies used
        > first-generation antibody to HCV (anti-HCV) assays which have a
        > higher false positive rate than second- and third-generation assays.
        > Studies varied in the completeness of risk ascertainment in partners,
        > and many failed to carefully exclude HCV acquisition from nonsexual
        > sources:
        >
        > When evaluating a partner for possible acquisition of HCV through
        > sexual contact, it is essential to exclude other sources of HCV. The
        > female partner may have her own risk factor for HCV infection, such
        > as a prior history of injection drug use or blood transfusion (A).
        > Alternatively, she may have been infected by her partner, but the
        > mode of transmission may have been nonsexual, such as sharing of
        > needles, razors, or other contaminated personal items.
        >
        > Nondisclosure of injection drug use is particularly important because
        > assessing the independent contribution of sexual activity in HCV
        > transmission is difficult in the presence of injection drug use.
        > Finally, only a limited number of studies performed virological
        > analyses to confirm that anti-HCV concordant sexual partners were
        > infected with the same virus.
        >
        > Sexual transmission has been evaluated in different populations of
        > HCV-infected individuals. Two main risk groups are discernable: (1)
        > those who are more sexually promiscuous and likely to have multiple
        > sexual partners, including female sex workers, men having sex with
        > men, those in HIV surveillance studies, and attendees of
        > sexually-transmitted diseases (STDs) clinics; and (2) those in steady
        > monogamous sexual relationships. Rates of anti-HCV positivity vary by
        > risk group, with higher rates of HCV reported in persons at risk for
        > STDs and lower rates in heterosexual partners in long-term
        > relationships. This difference in rate of HCV infection may reflect
        > differences in sexual risk behaviors (frequency or type of sexual
        > activities). Alternatively, differences between risk groups may
        > reflect differing rates of exposure to nonsexual sources of HCV, such
        > as injection drug use, as well as other potential risk factors such
        > as intranasal cocaine use and tattooing, or sharing of razors and
        > toothbrushes. The findings regarding sexual transmission defined by
        > one risk group may not be generalizable to others.
        >
        > Detection of HCV RNA in Bodily Fluids
        >
        > Sexual transmission of virus occurs when infected body secretions or
        > infected blood are exchanged across mucosal surfaces. The presence of
        > virus in body secretions is necessary but may not be sufficient for
        > transmission to occur. Other factors that may influence transmission
        > include the titer of virus in body secretions, the integrity of the
        > mucosal surfaces, and the presence of other genital infections (viral
        > or bacterial).
        >
        > Studies to detect HCV RNA in semen (seminal fluid and cells), vaginal
        > secretions, cervical smears, and saliva have yielded mixed results.
        > Failure to detect HCV RNA in body secretions may be caused by
        > technical factors, including specimen collection and storage, and the
        > ability to exclude cellular components and to overcome the presence
        > of polymerase chain reaction inhibitors. Even in studies using
        > optimal methods to isolate HCV RNA, the minority of samples were
        > positive for HCV RNA and all positive samples were of low titer
        > (equal to 102 copies/mL). A low titer of virus in genital secretions
        > may be one reason that HCV is transmitted less efficiently than
        > hepatitis B virus or HIV. Additionally, there may be an absence of
        > suitable target cells in the genital tract to allow infection to
        > occur or infection may require the presence of abnormal mucosa.
        > Finally, while the presence of HCV RNA in semen and vaginal or
        > cervical secretions supports the contention that HCV is sexually
        > transmissible, a cell culture system or animal model is needed to
        > prove that the HCV RNA detected in genital secretions represents
        > infectious virus.
        >
        > How prevalent is the risk factor of sexual activity in acute
        > hepatitis C?
        >
        > The Centers for Disease Control and Prevention collects detailed risk
        > factor data on cases of acute hepatitis C identified through the
        > Acute Hepatitis Sentinel County Surveillance program. Between 1995
        > and 2000, 18% of individuals with acute community-acquired HCV
        > infection reported sexual contact with an anti-HCV-positive person in
        > the preceding 6-month period (two thirds of cases) or multiple sexual
        > partners (one third of cases) as their only risk factor for HCV
        > acquisition. Currently, sexual activity ranks as the second most
        > common risk factor for HCV reported by individuals with acute
        > hepatitis. This suggests that sexual transmission may contribute
        > significantly to the total burden of HCV infection in the U.S.
        > population.
        >
        > What is the prevalence of HCV in persons at risk for STDs?
        >
        > In U.S. seroprevalence studies conducted among those at risk for
        > STDs, 1.6% to 25.5% of individuals were anti-HCV positive (Table 1).
        >
        > Table 1. Seroprevalence of anti-HCV among individuals at risk for
        > STDs
        >
        > First you'll see listed below the risk group, followed by the %
        > HCV-infected (range & average, followed by the factors associated
        > with being antibody HCV+.
        >
        > Female sex workers
        > 1%-19% (6%); Number of partners, other STDs, non-use of condoms, sex
        > with trauma
        >
        > MSM
        > 2.9%-13% (4%); With IDU included: risk for IDU > sexual factors; if
        > IDU excluded: anti-HIV positivity, number of partners
        >
        > STD clinic attendees
        > 1.6%-26% (4%); With IDU included: risk for IDU > sexual factors
        >
        > 1.6%-7% (if no IDU history); If IDU excluded: number of recent and
        > lifetime sexual partners, high-risk sexual contacts, anti-HIV
        > positivity
        >
        > Abbreviations: STDs, sexually transmitted disease(s); MSM, men who
        > have sex with men; IDU, injection drug use; HIV, human
        > immunodeficiency virus.
        >
        > Median rates of anti-HCV positivity were 6% among female sex workers,
        > 4% among men having sex with men, and 4% among attendees of STD
        > clinics and individuals participating in HIV surveillance studies
        > (Table 1). The HCV seroprevalence rates were lower than other viral
        > infections such as hepatitis B virus and HIV.7 In those studies
        > including persons with a history of injection drug use, anti-HCV
        > positivity was more strongly associated with drug use than with
        > factors related to sexual practices. In those studies limited to
        > individuals without a history of injection drug use, factors
        > predictive of anti-HCV positivity included the number of recent and
        > lifetime partners, high risk sexual practices (variably defined),
        > other STDs, and anti-HIV positivity. These factors are consistent
        > with a sexual route of transmission.
        >
        > In persons engaged in higher-risk sexual behaviors, those with HIV
        > infection were more likely to be anti-HCV positive (odds ratio, 2.5
        > to 4.4) than those who were HIV negative, even after controlling for
        > other sexual factors that might enhance risk of transmission such as
        > number of partners, non-use of condoms, and other STDs. The precise
        > mechanism by which HIV increases the risk of sexual transmission of
        > HCV is unknown.
        >
        > What is the prevalence of HCV infection in monogamous heterosexual
        > partners?
        >
        > Seroprevalence studies in monogamous, heterosexual partners of
        > HCV-infected, HIV-negative persons have reported prevalence rates
        > ranging from 0% to 24% in studies from Southeast Asia and Southern
        > Europe but lower rates in studies from the United States and Northern
        > Europe. North America: 2-4.8%; South America: 11.8%; Africa:
        > 5.6%-20.7%; Europe 0-5%; Asia: 8.8%-27%.
        >
        > The factors most consistently associated with HCV positivity among
        > heterosexual partners were the presence of percutaneous risk factors
        > for HCV (injection drug use, blood transfusion, sharing glass
        > syringes). Early studies found the rate of HCV positivity in partners
        > increased with the longer duration of marriage, suggesting risk of
        > sexual transmission correlated with frequency of contact. However,
        > subsequent studies adjusting for age did not find a consistent
        > relationship between the duration of the sexual relationship and HCV
        > positivity in partners.
        >
        > The majority of published studies did not evaluate
        > antibody-concordant couples with additional virological testing to
        > confirm that partners were infected with the same virus. In the more
        > informative studies, genotyping was used to evaluate
        > antibody-concordant couples. In all cases, use of genotyping led to a
        > reduction in the estimated rate of transmission by sexual contact.
        >
        > Genotyping, however, is suboptimal for determining whether partners
        > are infected with the same virus because HCV genotypes that are
        > prevalent in the population may be present in both partners but
        > represent HCV infection from different sources. The importance of
        > nucleotide sequencing was highlighted in a detailed study of 24
        > anti-HCV concordant heterosexual couples from France. The
        > investigators found 12 of the 24 couples (50%) had concordant
        > genotypes, 7 had discordant genotypes, and 5 were untypable. Seven of
        > the 12 genotype-concordant couples were further analyzed by sequence
        > analysis of the hypervariable region of E2 (envelope region of the
        > HCV genome) and only 3 couples had highly homologous viral strains
        > that were consistent with a transmission event. Interestingly, in
        > each of the 3 concordant couples, an alternative, nonsexual mode of
        > HCV transmission was present. Thus, overestimation of the rate of
        > sexual transmission of HCV occurs if antibody testing alone is used
        > to assess sexual pairs. Based on only those seroprevalence studies
        > using genotyping or sequence analysis to evaluate antibody concordant
        > couples, the estimated prevalence of HCV among heterosexual couples
        > in monogamous relationships is 2.8% to 11% in Southeast Asia, 0% to
        > 6.3% in Northern Europe, and 2.7% in the United States.
        >
        > The U.S.-specific published data are sparse, with 1 small study (N =
        > 42) conducted in heterosexual partners of patients attending a liver
        > clinic and 2 studies conducted in hemophiliacs (variable proportion
        > HIV coinfected). Seroprevalence rates varied from 2.0% to 4.8%.
        > Preliminary data from the HCV Partners Study, a cross-sectional study
        > of heterosexual monogamous couples, provides the best available
        > estimate of risk among U.S. couples. In this study, which excludes
        > couples in which injection drug use is present in both partners, the
        > prevalence of anti-HCV among 401 partners was 4.2%, with genotype
        > concordance present in 2.7% of couples (Terrault N, unpublished
        > data).
        >
        > What is the incidence of HCV infection in "at risk" individuals?
        >
        > A prospective cohort study of discordant couples followed closely for
        > newly acquired infection is the ideal method to characterize the risk
        > of transmitting HCV through sexual contact. However, even this method
        > may not be perfect because the exclusion of couples in which the
        > partner is already infected may leave a more selected and less
        > representative population of sexual partnerships for follow-up.
        >
        > In retrospective cohorts of female partners of hemophiliacs, the
        > incidence of HCV infection, defined by presence of anti-HCV, was 1 to
        > 1.87 per 1,000 person-years; among male partners of women infected by
        > contaminated anti-D immunoglobulin, it was 0.28 per 1,000
        > person-years; and among liver clinic patients and their sexual
        > partners it was 1 to 3.86 per 1,000 person-years.
        >
        > In a prospective cohort study of 499 Italian heterosexual monogamous
        > couples followed for a mean of 12.4 months, the incidence of new
        > infection in sexual partners was 12 per 1,000 person-years. Sequence
        > analysis of the anti-HCV positive couples showed a high degree of
        > sequence homology in only 50% of couples, suggesting a true incidence
        > of 6 per 1,000 person-years.29 In another prospective cohort of 112
        > Taiwanese couples followed for an average of 46 months, the incidence
        > was 2.3 per 1,000 person-years. The variability in risk of HCV
        > infection reported in studies of long-term partners may reflect
        > differences in the frequency or types of sexual activity in the
        > different populations, but more likely represents differences in the
        > rates of nonsexual HCV transmission.
        >
        > The incidence of new HCV infections among individuals who are at risk
        > for sexually transmitted diseases is higher than in monogamous
        > heterosexual couples. In prospective studies conducted in sex workers
        > and attendees of STD clinics who were not injection drug users, the
        > incidence of HCV was 0.4 to 1.8 per 100 person-years with follow-up
        > periods of 1 to 3.7 years. In retrospective cohorts of hemophiliacs
        > with high rates of HIV and HCV coinfection (more than 50%), the
        > incidence of HCV infection was 0 to 0.19 per 100 person-years in
        > sexual partners (primarily females) with a median follow-up of 12 to
        > 15 years. In these coinfected cohorts, HIV was transmitted more
        > frequently than HCV, and partners were more likely to be infected
        > with HIV and HCV than HCV alone.
        >
        > Summary
        >
        > The available data indicate HCV can be sexually transmitted, but the
        > efficiency of transmission by the sexual route is low. Nonetheless,
        > because sex is a common behavior and the reservoir of HCV-infected
        > individuals is substantial (approximately 2.7 million), sexual
        > contact likely contributes to the total burden of HCV infection in
        > the United States. The contribution of sexual transmission is
        > supported by findings from the Acute Hepatitis Surveillance Study, in
        > which 18% of newly infected individuals reported sexual contact with
        > an HCV-infected person or multiple sexual partners as their only risk
        > factor for HCV acquisition.
        >
        > For the individual with chronic HCV infection, the estimated risk of
        > sexual transmission of virus is 0% to 0.6% per year for those in
        > monogamous relationships, and 1% per year for those with multiple
        > sexual partners. Because risk varies by type of sexual relationship,
        > the recommendations for preventing transmission of HCV differ for
        > those in monogamous relationships versus those with multiple or
        > short-term sexual partners. The latter group is not only at risk for
        > HCV acquisition, but also for other types of sexually transmitted
        > diseases, including HIV.
        >
        >
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