IJE Advance Access originally published online on January 12, 2005
International Journal of Epidemiology 2005 34(1):160-165; doi:10.1093/ije/dyh370
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IJE vol.34 no.1 © International Epidemiological Association 2005; all rights reserved.
Article |
Estimation of the risk of transmission of hepatitis C between spouses in Egypt based on seroprevalence data
1 Department of Epidemiology and Preventive Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
2 National Hepatology and Tropical Medicine Research Institute, Cairo, Egypt
3 Assiut University Cancer Institute, Assiut, Egypt
4 Center for Field and Applied Research, Qalubyia, Egypt
5 Assiut University Faculty of Medicine, Assiut, Egypt
6 Present address: National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA
* Corresponding author. Department of Epidemiology and Preventive Medicine, University of Maryland, Baltimore, 660 W. Redwood Street, Baltimore, MD 21201-1596, USA. E-mail: lmagder{at}epi.umaryland.edu
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Abstract |
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Background Transmission of hepatitis C virus (HCV) between spouses could be due to sexual contact, sharing needles, or other routes. There is uncertainty regarding the degree to which HCV is transmitted between spouses.
Methods Data from a 1997 cross-sectional serological survey of HCV in two communities in Egypt were used to estimate the risk of transmission between spouses by simultaneously modelling the probabilities of community acquisition and spousal transmission of HCV as functions of known predictors.
Results We estimate that the probability of wife-to-husband transmission was 34% (95% CI: 15–49%) and 10% (95% CI: 0–26%) for anti-HCV-positive wives with and without detectable HCV RNA, respectively. The probability of husband-to-wife transmission was estimated to be 3% (95% CI: 0–13%) and 0% (95% CI: 0–9%) for husbands with and without detectable HCV RNA, respectively, at the time of the survey. There was moderate evidence that the probability of wife-to-husband transmission differed from that of husband-to-wife transmission (P = 0.076), and there was greater risk of transmission from those with detectable RNA at the time of the survey (P = 0.046). We estimate that 6% of those infected acquired HCV from their spouse.
Conclusion Our study results support the possibility that HCV is transmitted between spouses in Egypt. Further research is needed to identify the exact routes of transmission so that preventive measures can be instituted.
Keywords Disease transmission, Egypt, hepatitis C virus, partner studies, sexually transmitted diseases
Accepted 14 September 2004
Previous studies1–4 and systematic reviews5,6 have generally concluded that hepatitis C virus (HCV) infection can be transmitted between spouses, but that the risk of transmission is low. However, there are a number of questions that have not been well addressed. Does the risk of transmission from husband to wife differ from the risk of transmission from wife to husband? Is there a risk of transmission from a spouse who is anti-HCV-positive but who does not have evidence of viraemia? Is the transmission sexual or via other routes?
The ideal study design to address such questions is a prospective study. However, a prospective study would require a very large number of subjects and a prolonged follow-up time. Seroprevalence data are easier to collect and are already available for some communities. Unfortunately, since it is generally impossible to know the directionality and timing of transmission based on seroprevalence data, it is difficult to estimate transmission risk. However, when data are available on seroprevalence and risk factors for infection from a representative sample of individuals in a community, a method proposed by Magder and Brookmeyer7 can provide some insight into the risks and direction of spousal transmissions, as well as into factors that affect transmission.
We conducted a large serological survey in two communities in Egypt. The method of Magder and Brookmeyer was applied to the resulting data to obtain estimates of the risk of transmission of HCV between spouses and of the proportion of infections acquired from spouses.
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Methods |
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Community surveys
In 1997 we conducted surveys in two communities in Egypt: one in the Nile delta in Lower Egypt and one in the Assiut governate south of Cairo in Upper Egypt. Each community had a population of
11 000 inhabitants. Details of the design and execution of the surveys and some results are provided in four previous publications.8–11 The Nile delta community was mapped and a systematic sample of 50% of the households was selected for the survey. In the Upper Egypt community all households were selected for the survey. Sampled households were visited and residents were invited to participate. Those who provided informed consent were interviewed using a structured questionnaire to identify potential exposures that might be related to HCV acquisition. In addition, participants were asked to provide a serum sample for analysis for anti-HCV and markers of viraemia (HCV RNA). In the Nile delta community, 70% of the sampled households agreed to participate and 75% of the individuals in participating households agreed to provide serum samples. In the Upper Egypt community 72% of the sampled individuals agreed to participate and 87% of these agreed to provide serum samples. |
Laboratory methods |
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All samples were tested for anti-HCV IgG by a second-generation enzyme immunoassay (EIA 2.0, Abbott Laboratories, Chicago, IL) according to the manufacturer's instructions. HCV seropositivity was defined by a ratio of optical density to the cut-off value
1.0. Samples with a ratio between 0.8 and 1.0 (grey zone) were retested in duplicate, and those repeatedly greater than 1.0 were considered positive. HCV RNA was assessed in the EIA seropositive samples using a direct reverse transcritase PCR method as previously described.12 Briefly, HCV RNA was amplified using nested PCR directly from the serum using primers specific for 5' UT.13
Statistical methods
For each married couple there are four possible outcomes with respect to anti-HCV: (1) both partners are anti-HCV-positive, (2) only the husband is positive, (3) only the wife is positive, and (4) neither partner is anti-HCV-positive. Magder and Brookmeyer7 showed that when data on risk factors for community acquisition are available, this information can be combined with the serologic outcomes to estimate transmission probabilities. In brief, the method involves simultaneously modelling the probabilities of community acquisition and spousal transmission. Let pch and pcw stand for the probability of acquisition of HCV from the community for the husbands and wives, respectively. Also, let phw and pwh stand for the probability of transmission from husband to wife, and from wife to husband, respectively. Then, based on this notation, assuming that the occurrences of community and household acquisition are independent, we can write the probabilities of each outcome as follows:
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The probability of community acquisition of HCV infection was modelled as a function of age and a variable indicating a history of parenteral exposure. History of parenteral exposure was defined as a history of surgery, transfusion, venous or urinary catheterization, abortion, caesarean section, or parenteral treatment for schistosomiasis. These exposures were chosen based on our previous analyses of risk factors for HCV infection in this community.10,11 The association between parenteral exposure and risk of infection was assumed to be the same for both communities and both sexes. The relationship between age and community acquisition of HCV was modelled using a linear spline with nodes at ages 15, 25, 35, 45, and 55 years. The spline was allowed to differ between the men and women and between one community and the other. Age in this model represents the background risk for community acquisition due to unmeasured risk factors.
The probabilities of transmission were allowed to vary based on whether or not the potentially transmitting spouse was PCR-positive for HCV RNA. These probabilities were also allowed to differ for husband-to-wife transmission and wife-to-husband transmission but were assumed to be the same for both communities. In secondary analyses we fit models that made stronger assumptions (e.g. assuming that husband-to-wife transmission equalled wife-to-husband transmission). These secondary models were compared with the main model using a likelihood ratio test to quantify the evidence in the data with respect to the stronger assumptions.
Maximum likelihood estimates of the parameters in the model were found using routines developed in R, version 0.64.1 (www.r-project.org). Confidence intervals were computed by inverting likelihood ratio tests.
After fitting our models, it was possible to estimate the probabilities that each infected person acquired the infection from the community or from the partner. For example, if both partners were anti-HCV-positive, the probability that the wife acquired the infection from the husband is
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Those married couples in which one of the partners had died before our survey could not be included in our analysis. Since HCV infection is a risk factor for mortality, this could lead to a biased distribution of seropositivity in our sample. To reduce the potential for this bias, we included in this analysis only couples in which the wife was under 50 years of age.
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Results |
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Sample
In the Nile delta community there were 975 men and 744 women in the community survey who reported being married. This included 665 couples. Of these couples, 92 were excluded because the wife was not under 50 years of age, and 13 were excluded because the husband was polygamous. Of the remaining 560 couples, 90 were excluded due to lack of complete information on either the serological results or the risk factors, leaving 470 couples available for the analysis.
In the Upper Egypt community there were 1634 men and 1132 women in the community survey who reported being married. This included 1032 couples. Of these couples, 160 were excluded because the wife was not under 50 years of age, and 10 were excluded because the husband was polygamous. Of the remaining 862 couples, 91 were excluded due to lack of complete information on either the serological results or the risk factors, leaving 771 couples available for the analysis.
The age distributions and exposure histories of individuals used in our analyses are shown in Table 1. The wives tended to be younger than their husbands. The husband was between 0 and 10 years older than the wife in 78% of the couples.
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Prevalence of anti-HCV
Tables 2 and 3 show the prevalence of anti-HCV in each community in subgroups defined by sex, marital status, spouse's serological status, and whether there was exposure to a parenteral risk factor. The results are classified into broad age groups in order to control (to some extent) for the confounding effect of age, but the stratification was limited by the necessity of having denominators of sufficient size in each subgroup. The seroprevalence was much higher in the Nile delta community than in the Upper Egypt community. As expected, prevalence increased with age. Also, those reporting exposure to a parenteral risk factor generally had higher rates of anti-HCV. Partners of seropositive spouses, and especially HCV RNA-positive spouses, had higher rates of anti-HCV.
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Regression models
Table 4 shows the results from our analysis based on simultaneously modelling the risks of community acquisition and spousal transmission of HCV. The model allowed the probabilities of husband-to-wife transmission to differ from the probabilities of wife-to-husband transmission, and it allowed the transmission probabilities to vary according to the transmitting spouse's HCV-RNA status. The data are most consistent with low husband-to-wife transmission, moderate wife-to-husband transmission, and increased transmission from HCV-RNA-positive spouses. The wide confidence intervals reflect the difficulty of teasing out these different relationships using seroprevalence data. In this model, parenteral exposures were estimated to increase the odds of having anti-HCV by a factor of 1.8 (95% CI: 1.5–2.2).
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We fitted additional models using various other assumptions. Comparing our model with the results of a model that did not allow transmission to vary by HCV RNA status using a likelihood ratio test, we concluded that there is moderate evidence that transmission did vary according to the spouse's HCV RNA status (P = 0.046). Comparing our model with one that assumed husband-to-wife transmission was equal to wife-to-husband transmission, we again found moderate evidence that these probabilities differed (P = 0.076). Based on this model, we estimated that the probability of transmission from a spouse with the antibody was 4% (95% CI: 1–16% ) and that the probability of transmission from an HCV RNA-positive spouse was 12% (95% CI: 7–20%). We also fitted a model that assumed the probability of a spouse's ever having transmitted HCV to his\her partner increased with age, but there was not strong evidence that this was the case (P = 0.71). Based on other models, there was also no significant difference between the villages with respect to the effect of parenteral exposure (P = 0.17) and the spousal transmission probabilities (P = 0.64).
Proportion of cases due to spousal transmission
Given estimates from the model it is possible to calculate the probability that each person with anti-HCV acquired the infection from his/her spouse. Adding up these probabilities and dividing by the total number of infections results in an estimate of the proportion of cases acquired from a spouse. Using this approach, we estimate that of the 436 husbands with anti-HCV, 34 (8%) acquired the infection from their wives. And of the 258 wives with anti-HCV, 6 (2%) acquired the infection from their husbands. If we base our estimates on a model that assumes husband-to-wife transmission equals wife-to-husband transmission, we estimate that 11 (3%) of the husbands with anti-HCV acquired their infection from their wives, and 27 (10%) of the wives with anti-HCV acquired their infection from their husbands.
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Discussion |
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Based on our models,
40 (6%) of 694 married individuals with anti-HCV in the two communities acquired HCV infection from their spouses. Thus, the large majority of infections are acquired in the community and not from spousal transmission. Our data provide moderate evidence (P = 0.076) that there is a greater probability of wife-to-husband transmission than husband-to-wife transmission of HCV in Egypt. The data also provide support for the plausible hypothesis that the probability of transmission is greater if the spouse is positive for HCV RNA (P = 0.046). It has been pointed out that estimating spousal transmission based on concordance in married couples can lead to an overestimate due to the possibility that both spouses acquire the infection from community exposures.14 Rao et al.15 suggest that familial clustering of HCV is largely due to parenteral treatments for schistosomiasis experienced in common by a family. By explicitly including community exposures in our models (including parenteral treatment for schistosomiasis), we account for this possibility in our method of estimation. Also, if the observed concordance between husbands and wives were due entirely to confounding of similar community exposures, one would not expect to see greater concordance between husbands and wives associated with the HCV RNA positivity of one of the partners, as we observed. This observation is consistent with previous observations3,16,17 and suggests that person-to-person transmission is taking place.
Transmission between spouses is often assumed to be sexual. However, other routes of transmission between married couples are possible. Some studies have found high rates of infection among non-spouse household contacts of individuals with HCV.5 The plausibility of non-sexual, non-parenteral household transmission is supported by the fact that HCV RNA has often been found in the saliva of patients with and without serum HCV RNA.18–20 Pooling studies in a systematic review, Ackerman et al. reported that HCV RNA was found in the saliva of 79 out of 168 patients (47%) with circulating HCV RNA, and in 7 out of 54 patients (7%) with anti-HCV but no circulating RNA.21 Parenteral transmission between spouses is also a possibility (e.g. the sharing of a needle for injections, which often happens in formal and informal health care settings in these communities).
A previous study4 reported data suggesting that male-to-female HCV transmission in the United States occurs with greater probability than female-to-male transmission. In the United States the most common route of current transmission is intravenous drug use.4 Our analysis suggests that the opposite is occurring in Egypt, where the risk factors for HCV infection are very different.
The fact that spousal transmission risk did not increase with age was surprising. It would seem likely that older couples have been infected for a longer time and have had more opportunities to transmit the disease. There are a number of possible explanations. First, although the data provide no evidence of an increase in risk with age, our results cannot rule this out owing to the width of the confidence intervals. Second, it is possible that there are host factors or behaviours that affect the probability of infecting or becoming infected with HCV that do not change during the course of a marriage. Third, it is possible that maximum infectiousness is a short-term phenomenon occurring either early in infection or sporadically. Several studies purported to show that the probability of spousal transmission increased with the duration of the marriage,22,23 but these studies failed to control for age, and age is a likely confounder.
The fact that the partners of those who are anti-HCV-positive but HCV-RNA-negative have a higher rate of anti-HCV than those with partners who are negative for anti-HCV (Table 2) should not be taken as evidence that transmission can occur from those who are not viraemic. First, the directionality of the transmission is unknown, and second, transmission could have occurred earlier, when the transmitting spouse was viraemic. Our determination of the absence of viraemia was based on a single negative PCR test, which cannot rule out chronic viraemia24 or viraemia at an earlier period after infection.
It is believed that community acquisition in Egypt occurs as a result of the re-use of needles for injections in traditional or formal health care settings.10,11 However, it was difficult to obtain good information about re-use of needles, and a history of injections is ubiquitous and thus could not be used to identify those at higher risk for community acquisition. Generally experienced risk factors such as this are included in our models as part of the background risk for community acquisition, represented by the variable age.
The power of our analytical approach depends on the presence of a strong risk factor for community acquisition of disease that can provide information regarding which of the two partners is more likely to be the source of the disease.7 In this study, reporting of a parenteral risk factor was only moderately predictive of anti-HCV. Another risk factor in the model, age, was likely to be collinear between the husbands and wives, reducing its effectiveness in helping to probabilistically identify the source. The method might be more powerful in populations where there is a strong community risk factor such as intravenous drug abuse.
The probabilities of transmission estimated in this article are rather crude epidemiological parameters, indicating only the probability of transmission at any time between spouses. This necessarily averages over the duration of infectious exposure in the couples, the nature of contact between the couples, and the variability of infectiousness over time. More specific parameters could be estimated only if we knew the duration of infection, the duration of the marriage, the number of contacts, and other relevant information.
Greater power for assessing risk of transmission between spouses is available from studies of incident cases. We are in the process of following the subjects from the two communities to identify incident cases to obtain additional insight into the risk and risk factors related to transmission of HCV between spouses.
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Acknowledgments |
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This research was supported by the Hepatitis C Prevention Project, US AID grant number 263-G-00-96-00043-00, and the Wellcome Trust–Burroughs Wellcome Fund grant numbers 059113/Z/99/A (Egypt) and 059113/Z/99/Z (USA). We thank the many members of the Hepatitis C Prevention Project team who collected the data used in this article: the field teams from the Center for Field and Applied Research and Assiut University Department of Tropical Medicine who collected the data and blood samples; the technologists in the Viral Hepatitis Reference Laboratory who performed the laboratory tests; the members of the Data Management Team at the National Hepatology and Tropical Medicine Research Institute who managed the data; and Mar Jan Ostrowski and the administrative staff who supported all these efforts.
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References |
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