Sex and Hepatitis C Transmission
The study article follows this Editorial.
Norah A. Terrault, M.D., M.P.H. 1
1Division of Gastroenterology, University of California at San Francisco, San Francisco, California
While there is sufficient evidence to support the conclusion that sexual transmission of hepatitis C virus (HCV) occurs, quantifying the magnitude of an individual's risk of HCV acquisition by sexual contact has been more challenging. The available data suggest the efficiency of transmission by the sexual route is low. Nonetheless, since sex is a common behavior and the reservoir of HCV-infected individuals is substantial, sexual contact likely contributes to the total burden of HCV infection in the United States. However, for individuals in long-term monogamous relationships, <3% of sexual partners are found to be HCV-infected and, in prospective studies, the incidence is reported to be <0.1% per year. The current study confirms these prior prevalence and incidence estimates. This low frequency of HCV in the steady sexual partners of HCV-infected individuals is what underlies the recommendation that these couples need not change their sexual practices.
Sex as a mode of HCV transmission remains a subject of debate. The issue is not whether the virus can be transmitted by sexual contact but rather what the magnitude of the risk is and what factors influence the risk of transmission. Since sexual transmission cannot be observed directly or experimentally manipulated, establishing sex as the mode of transmission requires the demonstration of new infection in a susceptible partner following sexual contact, the confirmation of the same viral stains in the sexual partner, and the exclusion of nonsexual modes of HCV acquisition. Several detailed case reports meet these minimal requirements and provide convincing evidence that HCV can be transmitted by sexual contact (1-3). However, these case reports do not define the magnitude of risk. To evaluate this, the rate of HCV infection in different risk groups including those engaged in high-risk sexual behaviors, those with newly acquired HCV infection, and those in long-term partnerships have been evaluated. The apparently disparate estimates of risk from these different populations have fueled the ongoing controversy regarding the role of sex in HCV transmission.
In 20% of persons with newly acquired acute hepatitis C, sex with multiple partners or sex with an anti-HCV-infected person in the preceding 6 months is the only identifiable risk factor for infection (4). Indeed, in the United States, sex is the second most common risk factor for HCV acquisition among those with acute hepatitis C. At apparent odds with this figure, is the relatively low prevalence of HCV infection reported in groups at high risk for sexually transmitted diseases, such as sex workers, attendees at sexually transmitted disease clinics, and men having sex with men. In these "high-risk sex" groups, the prevalence of anti-HCV ranges from 4% to 6% (5), a rate somewhat higher than the general population but much lower than other sexually transmitted viruses such as hepatitis B virus and human immunodeficiency virus. Among those engaged in higher-risk sexual activities, lack of condom use, total number of lifetime sexual partners, anal intercourse, intercourse with mucosal trauma, and HIV infection are linked with presence of anti-HCV. These associations are consistent with HCV being a sexually transmitted virus. However, the frequent coexistence of injection drug use in persons who engage in high-risk sexual activities complicates the picture and, in these settings, defining the independent contribution of sex to HCV acquisition can be difficult. For example, the rates of HCV infection among persons who engage in higher-risk sexual activities but deny injection drug use are not dissimilar to those of the general population (5).
Heterosexual couples in long-term monogamous relationships represent the most common form of sexual partnership. While the available data indicate that the risk of HCV transmission in persons in steady monogamous sexual relationships is lower than those with multiple partners or those at risk for sexually transmitted diseases, the question of "how low is the risk" remains. Earlier studies reported HCV prevalence rates as high as 24% in steady sexual partners of those with chronic HCV infection, but these studies suffered from several methodological flaws that led to an overestimation of the rate of HCV transmission by sex (5). In particular, the lack of detailed virological analysis of HCV antibody concordant couples was a major limitation of earlier studies. More recent studies of monogamous couples that utilized sequence analyses of the virus in the partners to determine whether antibody concordant couples are infected with a similar viral species report prevalence rates of HCV of 2% or less in the partners (6-9). Thus, studies lacking virological analyses of antibody concordant couples have substantially overestimated the frequency of HCV transmission by sex.
Prospective cohort studies also suggest the risk of HCV acquisition in monogamous couples is low. Prior studies reported incidence rates of 2.3-6 per 1,000 person-years (10, 11). In the study Veysel et al. in this issue of The American Journal of Gastroenterology, none of the 216 HCV-negative spouses seroconverted over the 3-yr mean follow-up period. This low incidence of new infections among monogamous couples supports the current clinical practice of not recommending that such couples change their sexual practices (4, 12).
Most published studies of HCV and sex lack information on the frequency and types of sexual practices engaged in by the population studied. Based upon what is known about transmission of other sexually transmitted viruses, the risk of HCV transmission by sex would be predicted to be higher in those engaged in anal intercourse, sex with trauma to the genital mucosa, or in the presence of other sexually transmitted diseases. Unfortunately, information on risk of HCV acquisition with specific sexual practices is unavailable. The current study evaluated frequency of sexual contact. All couples denied condom use and "various sexual practices," but additional details on specific sexual practices were not included. The authors found anti-HCV positive couples had a higher sexual contact frequency than couples without evidence of HCV in the spouse in the retrospective cohort, and suggested that frequency of intercourse influenced risk of HCV infection. However, in the prospective cohort, none of the HCV-negative spouses seroconverted during the follow-up even though the frequency of sexual contact was reportedly ~6-fold higher than in the retrospective study. These results likely reflect differences in accuracy of recall of sexual practices and point toward the challenges in evaluating frequency of sexual contact and types of sexual practices in retrospective studies.
Where does this leave physicians in terms of counseling patients with HCV infection about sex? First and foremost, the issue of sex and HCV transmission needs to be discussed with each HCV-infected person and recommendations tailored to the individual's specific sexual situation. For those in monogamous partnerships, the partner should be offered HCV testing (4). The couple should be counseled that the risk of sexual transmission is very low and because of this very low risk, use of condoms is not specifically recommended. However, due to an absence of information on certain types of sexual practices, those engaged in sexual practices that may be more permissive of transmission, such as anal intercourse or sex with trauma to genital mucosa, should be advised to use condoms during these activities. I also recommend the use of condoms if the couple is having sex during a woman's menses. For HCV-infected persons with multiple sexual partners, use of condoms is recommended not only for prevention of HCV transmission but also for all sexually transmitted diseases. Finally, for those HCV-infected persons with new sexual relationships that evolve to longer-term monogamous relationships, specific recommendations regarding if and when condom use can be discontinued are not available. Ultimately, each monogamous couple must decide upon whether a "low risk" of transmission translates into a need of condom use or not. Physicians can facilitate this decision by assisting patients and their partners to interpret the available data regarding sex and HCV, and providing them with the most current guidelines regarding prevention of sexual transmission.
1. Capelli C, Prati D, Bosoni P, et al. Sexual transmission of hepatitis C virus to a repeat blood donor. Transfusion 1997;37: 436-40.
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2. Sanchez-Beiza L, Bravo R, Toribio R, et al. Sexual transmission of two different HCV types causing acute hepatitis C. Vox Sang 1996;71: 244-5.
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3. Quer J, Murillo P, Esteban J, et al. Sexual transmission of hepatitis C virus from a patient with chronic disease to his sex partner after removal of an intrauterine device. Sex Transm Dis 2003;30: 470-1.
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4. CDC. Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease. MMWR 1998;47: 1-38.
5. Terrault N. Sexual activity as a risk factor for hepatitis C. Hepatology 2002;36: S99-105.
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6. Vandelli C, Renzo F, Romano L, et al. Lack of evidence of sexual transmission of hepatitis C among monogamous couples: Results of a 10-year prospective follow-up study. Am J Gastroenterol. 2004;99: 855-9.
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7. Lai K, Young K, Cheng P, et al. Interspousal transmission of hepatitis C virus: Application of comparing the variability of HVR1 nucleotide region. Hepatogastroenterology 2004;51: 791-5.
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8. Boonyarad V, Chutaputti A, Choeichareon S, et al. Interspousal transmission of hepatitis C in Thailand. J Gastroenterol 2003;38: 1053-9.
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9. Terrault NA, Busch M, Murphy E, et al. Sexual transmission of hepatitis C virus in heterosexual monogamous couples-The HCV partners. Hepatology 2003;38(Suppl 1):A183.
10. Piazza M, Sagliocca L, Tosome G, et al. Sexual transmission of hepatitis C virus and efficacy of prophylaxis with intramuscular immune serum globulin. Arch Intern Med 1997;157: 1537-44.
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11. Kao J, Chen P, Yang P, et al. Intrafamiliar transmission of hepatitis C virus: The important role of infections between spouses. J Infect Dis 1992;166: 900-3.
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12. Consensus Development Panel. National Institutes of Health Consensus Development Conference Statement: Management of Hepatitis C: 2002-June 10-12, 2002. Hepatology 2003;36: S3-S20.
Sexual Transmission of HCV between Spouses
The American Journal of Gastroenterology
Veysel Tahan, M.D. 1 , Cetin Karaca, M.D. 1 , Beytullah Yildirim, M.D. 1 , Aysun Bozbas, M.D. 1 , Resat Ozaras, M.D. 1 , Kadir Demir, M.D. 1 , Erol Avsar, M.D. 1 , Ali Mert, M.D. 1 , Fatih Besisik, M.D. 1 , Sabahattin Kaymakoglo, M.D. 1 , Hakan Senturk, M.D. 1 , Yilmaz Cakaloglu, M.D. 1 , Cem Kalayci, M.D. 1 , Atilla Okten, M.D. 1 , and Nurdan Tozun, M.D. 1
1Marmara University School of Medicine, Department of Gastroenterology Altunizade; Istanbul University Medical Faculty, Department of Gastroenterohepatology; Istanbul University Cerrahpasa Medical Faculty, Department of Gastroenterohepatology; and Marmara University School of Medicine, Department of Gastroenterohepatology, Istanbul, Turkey
--Our study did not find an increased risk of acquiring HCV for the spouses.
-- the number of total sexual intercourse is important and may be an independent risk factor for sexual transmission
--The role of sexual route in the transmission of the virus is controversial.
--The prevalence of HCV infection is higher among prostitutes, male homosexuals, sex partners of patients infected with both HCV and HIV, and partners of injection drug use, suggesting a route of sexual transmission.
-- The prevalence of anti-HCV among the spouses of chronic hepatitis C patients ranges between 0% and 27%. Our study showed a relatively lower seroprevalence rate of 2% between the spouses of CHC patients, a figure similar to the reported rate of general population seropositivity of 1.8% in our country.
--Several studies on HCV transmission have compared RNA sequence homologies showing <100% homology between spouses. This finding makes the role of sexual intercourse per se for HCV transmission between spouses debatable.
BACKGROUND AND AIMS: The sexual transmission of hepatitis C virus (HCV) is debated. By excluding other risk factors, the role of sexual intercourse in the transmission could be detected more accurately. We screened HCV prevalence and risk factors in the spouses of chronic hepatitis C (CHC) patients and followed the seroconversion rate of anti-HCV negative spouses.
PATIENTS AND METHODS: Six hundred spouses of CHC patients were recruited. The spouses' HCV risk factors were questioned and the spouses were tested for anti-HCV. The 216 spouses who were anti-HCV negative were checked annually for anti-HCV.
RESULTS: Anti-HCV was positive in 12 of 600 (2%) of the spouses. Of the 12 anti-HCV positive spouses, 11 were HCV-RNA positive. Of anti-HCV positive and negative spouse groups, mean age was 52.3 ± 9.8 and 49.8 ± 12.4 yr; duration of marriage was 1521 ± 506.7 and 1532.4 ± 670.2 wk (p> 0.05); and the number of total sexual intercourse was 434 ± 295 and 307 ± 333 (p= 0.055), respectively. In our prospective study, none of the spouses developed anti-HCV seroconversion in mean 35.7 ± 6.3 months and 257.9 ± 72.2 sexual intercourse.
CONCLUSIONS: Anti-HCV was found positive in 2% of the spouses. None of the seronegative spouses developed seroconversion in the 3-yr follow-up period. This is the first study that stresses the importance of the total number of sexual intercourse in sexual transmission (p= 0.055). Our results of special monogamous group with very limited risk factors support the role of number of total sexual intercourse in HCV transmission. However, the seroprevalence rate of the spouses was still within the upper limit of our country population.
Hepatitis C virus (HCV) is transmitted mainly by contact with infected blood. However, in up to 50% of cases the transmission route cannot be identified. The role of sexual route in the transmission of the virus is still controversial. The prevalence of anti-HCV antibody among the sexual partners of chronic hepatitis C (CHC) patients ranges between 0% and 27% (1-8). The duration of marriage has been correlated with the rate of HCV infection (4) and the presence of HCV in semen has been reported (9). Male-to-female transmission seems to be more common than female-to-male transmission (10).
The different rates of sexual transmission may be the result of sexual behaviors such as frequency and type of sexual activities. Previous studies reported that anti-HCV positivity in partners increased with the duration of marriage or partnership, suggesting the risk of sexual transmission correlates with frequency of contact (4). To assess the risk of heterosexual HCV transmission, we examined 600 patients with chronic HCV-associated liver disease and their spouses retrospectively with respect to their estimated total sexual intercourse in the follow-up of index cases, and activity with duration of marriage, duration of CHC follow-up period, and other risk factors that could affect the couple for HCV transmission by sexual and nonsexual routes. We also followed the 216 anti-HCV negative partners of CHC patients prospectively.
The prevalence of HCV infection is higher among prostitutes, male homosexuals, and partners of intravenous drug abusers. There seems to be a positive correlation between the HCV infection and the number of sexual partners, sexual activities involving a trauma or anal intercourse, history of other sexually transmitted diseases, and those coinfected with HIV.
HCV is known to be transmitted primarily by exposure to infected blood. However, in up to 50% of cases, no recognizable transmission route could be detected. Furthermore, the implementation of HCV screening in blood banks has virtually eliminated the risk of HCV infection by transfusion in most countries. The role of sexual route in the transmission of the virus is controversial. The prevalence of HCV infection is higher among prostitutes (11), male homosexuals (12-14), and sex partners of patients infected with both HCV and HIV (15), suggesting a route of sexual transmission. Sexual exposures for a period of 6 months prior to the onset of illness were reported by 15% of persons who recently acquired hepatitis C, and two-thirds of them had a sexual contact with an anti-HCV positive partner (16).
The worldwide prevalence of HCV infection is almost 3%, equivalent to 170 million infected persons. The prevalence rates are lowest in the United Kingdom and Scandinavian countries (0.01-0.1%), slightly higher in America, Western Europe, (0.2, 0.5%) and intermediate in Eastern Europe, the Mediterranean, the Middle East, and the Indian subcontinent (1-5%) (17). The prevalence of anti-HCV among the spouses of chronic hepatitis C patients ranges between 0% and 27% (1-8). Our study showed a relatively lower seroprevalence rate of 2% between the spouses of CHC patients, a figure similar to the reported rate of general population seropositivity of 1.8% in our country (18). Several studies on HCV transmission have compared RNA sequence homologies showing <100% homology between spouses. This finding makes the role of sexual intercourse per se for HCV transmission between spouses debatable.
The duration of marriage has also been correlated with the rate of HCV infection (4). Guadagnino et al. (19) showed that the spouses who had been married to the index cases for longer than 20 yr had a 7.5-fold risk of HCV seropositivity compared to those married for less than 20 yr. They concluded that sexual contact plays an independent role in the spread of HCV infection in the family setting. Caporaso et al. (20) reported an incidence of anti-HCV seropositivity of 15.6% in their studies evaluating the transmission of HCV between spouses in HCV positive subjects; however, after adjusting for various confounders, the authors concluded that sexual transmission does not seem to play a role in the intrafamilial spread of HCV infection. In contrast, a study from Japan found spouses with anti-HCV positive partners to be twice as likely to have anti-HCV positivity than spouses with anti-HCV negative partners; however, 50% of the couples harbored different HCV genotypes (7).
Studies in monogamous couples demonstrate a lower risk of sexual transmission in this group (21). In our previous study, we reported anti-HCV positivity between all monogamous spouses as 0.78% (8). Since those studies involved mostly monogamous couples and showed a low risk of sexual transmission, our colleagues did not recommend the use of condoms for monogamous sexual relationships. Although 14 partners (2.3%) were in multipartnerships, none of them were anti-HCV positive; there was no condom usage in any of the couples. Anal intercourse, sexual activity involving a trauma, and the presence of other sexually transmitted diseases such as coinfection with HIV are thought to increase the rate of transmission of HCV infection but these conditions were not present in our groups. Although no transmission parameter has been found to be statistically significant, total number of sexual intercourses was close to significance level in the group of anti-HCV positive spouses (p= 0.055) and the sexual transmission may be related to a slightly higher prevalence of anti-HCV positivity than that of our general population. Another evidence in favor of low probability of HCV transmission via sexual route is the low viral load detected in semen (9, 22). Results from Asian countries indicate that interspousal transmission becomes more critical with longer duration of a partnership (4, 6, 7); however, similar data from Western countries are rare (19, 20, 23). In our study, duration of marriage was not correlated with the rate of transmission; although the age of the spouse tends to correlate with anti-HCV positivity, it did not reach statistical significance.
The HCV genotypes were the same between infected couples; they all were genotype 1b, as it is the most prevalent genotype in Turkey (24).
Whether the risk of HCV transmission differs between sexes is unclear (1). Male-to-female transmission may be more common than female-to-male transmission (10). However, in our study, the ratios of female-to-male versus male-to-female couples were 2.5 versus 1.4, respectively, and this was not statistically significant. On the other hand, "index" case may not be the first one to be infected and then transmit the virus to his/her spouse. Even the development of the infection in the spouse does not necessarily mean a sexual transmission. This is the main pitfall of such cohort studies; the spouses may be infected from other sources like the rest of the population. Molecular studies that are not the aim of the current study may detect whether the virus in the spouses is the same or not. To the best of our knowledge, our retrospective study constitutes one of the largest series on CHC patients and their spouses (600 index CHC patients and 600 spouses).
In a recently published study, Vandelli et al. examined 895 monogamous heterosexual partners of CHC patients and followed 776 couples for a 10-yr period prospectively. The average weekly rate of sexual intercourse was 1.8 and three spouses became anti-HCV and HCV-RNA positive after 7, 8, and 9 yr, respectively. In one couple, the genotype of the spouse was discordant from that of her husband, and in another two cases, genotypes were concordant; however molecular analysis of the HCV isolates was not linked. Their data indicate the risk as extremely low or even null. They also screened 967 sexual partners of CHC patients and 33 (3.4%) were anti-HCV positive but they were not questioned and were excluded from their study; so the detailed data are lacking for the differences between anti-HCV positive and negative partners in their study (25).
In our prospective study, the average weekly rate of sexual intercourse was 1.9, which accounted for a higher rate than the previous study. In about 3-yr follow-up, none of the partners acquired HCV infection and our data also supported the belief that the risk of HCV infection by the sexual transmission is very low or even null. In our retrospective study, the average weekly rate of sexual intercourse was 1.73 and anti-HCV positive and negative partners were questioned and examined thoroughly for the number of their previous sexual intercourses and HCV transmission parameters. Although a partner's anti-HCV seroprevalence rate of 2% was within the upper normal limit of our population, the number of sexual intercourse was close to statistical significance (p= 0.055).
Our study did not find an increased risk of acquiring HCV for the spouses. This finding was even more significant with the consideration of the high percentage of long-lasting sexual partnerships; the duration of marriage being 1,521 ± 506.7 versus 1532.4 ± 670.2 wk in anti-HCV positive and negative spouse groups, respectively, all with unprotected sexual intercourse and without any additional risk factors for HCV transmission. Evaluation of the questionnaires and statistical analysis revealed very low risk for HCV transmission in the everyday life of couples.
In conclusion, the number of total sexual intercourse is important and may be an independent risk factor for sexual transmission. Neither other sexual nor nonsexual behaviors had an influence on the risk of interspousal transmission in our spouse groups.
Moreover, our prospective study with 216 CHC patients and their spouses revealed no sexual transmission in about 3 yr of follow-up. We therefore suggest that the risk of HCV transmission between monogamous sex partners may be related to the number of sexual intercourse, when evaluated retrospectively. The absence of any evidence of transmission in the spouses of HCV patients in the 3-yr follow-up period suggests that this relation is not very strong.
All spouses reported sexual activity with the study patient. Anti-HCV positivity was found in 12 of 600 (2%) of spouses (F/M: 4/8). This rate was 8 of 320 (2.5%) and 4 of 280 (1.4%) in male and female spouses, respectively. All anti-HCV positive spouses but one were HCV-RNA positive and the genotypes were all 1b. Three of the anti-HCV positive spouses were diagnosed with cirrhosis. The average weekly rate of sexual intercourse was 1.73 in the retrospective study. Of anti-HCV positive and negative spouses, the duration of marriage was 1521 ± 506.7 and 1532.4 ± 670.2 wk (p> 0.05); the number of total sexual intercourse was 434 ± 295 and 307 ± 333 (p= 0.055); and the follow-up period of the corresponding CHC patient was 209.6 ± 137.5 and 147 ± 165.5 wk (p= 0.035), respectively.
The mean duration of marriage did not correlate with anti-HCV positivity. The couples were divided into three groups according to their age: <40 yr (n = 116); 40-59 yr (n = 355); >60 yr (n = 140). The percentage of rates of anti-HCV positivity showed an increasing trend with age; 0.9, 2, and 3.7%, respectively (Table 2). This increase probably reflects the cohort effect rather than the effect of sexual transmission, since in the subjects older than 60 yr, the number of sexual intercourse is clearly lower than that of the remaining. No spouse reported liver disease prior to the marriage. All couples reported unprotected sexual intercourse, without condom. They denied various sexual practices or intravenous drug abuse. Four women reported having several needle-stick injuries, 17 partners (2.8%) had received blood transfusions, 14 partners (2.3%) have been in multipartnerships, however, none of them were anti-HCV positive. Seven couples reported the use of nondisposable syringes in their past, however, only one of them was anti-HCV positive. Thirty spouses shared personal items such as razor, toothbrush, nail clipper, and two of them were in the anti-HCV positive group. Forty-five spouses (7.5%) had a history of previous surgical procedures, two of them were anti-HCV positive (one appendectomy and one dental procedure).
In our prospective study, none of the 216 spouses developed anti-HCV seroconversion in a mean follow-up period of 35.7 ± 6.3 months and a total number of 257.9 ± 72.2 sexual intercourses. The average weekly rate of sexual intercourse was 1.9 in the prospective study.
There was no statistical difference in mean age, and in sexual and nonsexual risk factors for acquiring HCV infection between study patients with anti-HCV-positive and anti-HCV negative spouses.
A total of 600 patients with chronic HCV infection (320 male (53%) and 280 female (47%), mean age 49.9 yr, ranging between 18 yr and 79 yr) were followed by three university hospitals from January 1999 to November 2002 and were enrolled in this study. Chronic HCV-associated liver disease was defined as elevated liver enzymes for at least 6 months and a positive anti-HCV antibody test with a second-generation ELISA. One hundred and seventeen patients (19.5%) had cirrhosis and 483 (80.5%) had chronic hepatitis. The diagnosis was confirmed by liver biopsy in 546 patients (91%). In 306 (51%) cases, the route of transmission of HCV infection was unknown; parenteral exposure was considered as the source of infection in the remainder. No index case was coinfected with HIV.
Informed consents were obtained from all patients both in the prospective and the retrospective studies. The couples completed a questionnaire representing sexual risk factors such as duration of marriage, number of estimated total sexual intercourse and various sexual practices, condom usage, multipartnership and nonsexual risk factors such as the presence of liver disease prior to marriage, history of blood transfusion or needle stick injury, surgery, intravenous drug abuse, share of personal instruments infected with blood.
Our special group of chronic hepatitis C patients consisted of naive, untreated patients who had normal ALT levels or who rejected interferon therapy.
In our retrospective study, 600 CHC patients' spouses with a mean age of 49.8 yr (range: 18-76 yr) were included. The spouses were divided into two groups according to anti-HCV status and their data were compared.
In our prospective study, we excluded both the patients who were given any interferon as the treatment of chronic hepatitis C, and the 216 anti-HCV negative partners of CHC patients (F/M: 101/115; mean age: 51.1 ± 14.5 yr) who could be checked annually for anti-HCV seroconversion. The same questionnaire was applied.
In both studies, serum samples from the spouses were collected and tested for anti-HCV with a second-generation ELISA (Abbott Laboratories, Abbott Park, IL). Every spouse and his/her corresponding patient was tested for HCV-RNA by reverse-transcription polymerase chain reaction (PCR) with primers deduced from the 5'-noncoding region (Amplicor HCV Monitor Test, version 2.0 Roche Diagnostic Systems, Brancburg, NJ, USA). HCV genotypes were determined by a PCR typing assay (Inno-Lipa HCV 2, Innogenetics, Gent, Belgium).
Frequencies between groups were compared using the chi 2 test and Fisher's
exact test. A p value of <0.05 was considered significant.