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Re: DOES GENDER, AGE, OR SCHISTOSOMIASIS COINFECTION INFLUENCE CHRONICITY OF HEPATITIS C?

Dear Editor,

A paper by Bahr I, et al. in Gut reported hepatitis C virus (HCV) clearance in 4,720 residents of an Egyptian village having an HCV antibody (anti-HCV) prevalence of 19.3%.1 They reported 61.5% of those having anti-HCV also had HCV-RNA. Compared to males, females were more likely to have cleared the virus: 55.4% of anti-HCV positive females had HCV-RNA compared with 66.3% of males (P = 0.001). However, they noted no age-related differences in clearance and results of analysis of coinfections with schistosomiasis were not reported.

Our data collection and handling was very similar to theirs and the virology was performed in the same laboratory.2-5 Variables investigated were gender; age stratified by decades; and history of, and infection with, schistosomiasis. The statistical significance of observed differences in HCV persistence rates was assessed using the Pearson Chi Square test. To estimate associations with persistence, while controlling for other variables, we used Mantel-Haenszel estimate of relative risks. S. mansoni and S. haematobium ova were microscopically detected in stool using a modified Kato technique and in urine using nucleopore filters.

In two communities,2,3 14.9% of 10,030 subjects had anti-HCV and 61.0% of these also had HCV-RNA . Anti-HCV positive males were more likely than females to have HCV-RNA: age adjusted relative risk (RR) was 1.2 (P=0.10; Table). Anti-HCV positive inhabitants under age 20 were less likely (p=0.04) to be HCV-RNA positive than older persons (55.3% vs 62.2%). A history of schistosomiaisis was not a risk for RT-PCR positivity. However, 70.9% of the 117 anti-HCV positive subjects with active schistosomal infections had HCV-RNA in comparison (p=0.03) with 59.4% of the 1,031 who did not have Schistosoma ova detected in their urine or stools. This increased risk was only present in the Nile delta village where S. mansoni is transmitted;2 72.8% of 103 with S. mansoni ova in their stools were RT-PCR positive compared (RR=1.7; P=0.02) with 58.8% of 640 not having schistosomiasis (Table). When adjusted for gender and age S. mansoni infection remained a risk for HCV-RNA persistence.

Analysis of data from pregnant women from three other villages showed 15.5% of 1,798 had anti-HCV and 158 (56.6%) of these 279 also had HCV- RNA.4 The RT-PCR positive rate in women less than 20 (47.8%) was less (P=0.37) than in those 20 or older (57.4%) and those with active S. mansoni infections (72.2%) were more likely (P=0.13) to have HCV-RNA than those not having schistosomiasis (52.3%). Age-adjusted RR for the association between S. mansoni infection and RT-PCR positivity was 2.3 (95% CI; 0.8-7.1; P=0.13), but none of these differences were statistically significant.

Even if clearance is one percent per year, it would reduce prevalence of HCV-RNA in older adults and might hide evidence that the young are more likely to clear infections.6,7 Another potential bias could occur when older subjects with persistent infections are dropped from the sampled population because of death or are not available due to complications of HCV infection. Cross-sectional prevalence studies, unlike incidence studies, cannot pinpoint risk of persistence, but several potential biases would be towards reducing ability to show HCV infections in women and children are more likely to clear than those in men and adults, and it would dilute the effect co-infections with S. mansoni would have on HCV persistence. We elected not to combine data from our cross-sectional survey and pregnant women studies because of differences in selection criteria. Although HCV clearance differences among our subgroups were often large, statistical significance at the 5% level, despite the relatively large numbers of subjects, was not always reached.

Infection with S. mansoni, but not S. haematobium, was associated with persistence of HCV infections. Previous studies by Kamal and her colleagues of acute HCV infections in patients with, and without, concomitant schistosomiasis mansoni reported those with schistosomiaisis were less likely to clear HCV-RNA.8 Biological plausibility supports this relationship between schistosomiasis mansoni and persistence of HCV. S. mansoni, but not S. haematobium, causes many granulomas in the liver which could locally inhibit generation of HCV-specific CD4+/Th1 T-cell responses,8 leading to greater persistence and severity of HCV infections in patients with coinfections. Our community-based data showing persistence following HCV infection may be less frequent than reported from hospital-based patients, also supports reports that children and women are more likely to clear their infections than adults and men.1, 9- 11

References

1. Bakr I, Rakacewicz C, El-Hosseiny M, Ismail S, El-Daly M, El-Kafrawy S, et al. Higher clearance of HCV infection in females compared to males. Gut 2006; Jan 24 [Epub ahead of print].

2. Abdel-Aziz F, Habib M, Mohamed MK, et al. Hepatitis C virus (HCV) infection in a community in the Nile Delta: Population description and HCV prevalence. Hepatology 2000;32:111-5.

3. Nafeh MA, Medhat A, Shehata M, et al. Hepatitis C in a community in Upper Egypt: 1. Cross-sectional survey. Am J Trop Med Hyg 2000;63:236-41.

4. Stoszek SK, Narooz S, Saleh D, Mikhail N, Kassem E, Hawash Y, et al. Prevalence of and risk factors for hepatitis C in rural Egyptian women. Trans R Soc Trop Med Hyg 2006;100:102-7.

5. Abdel-Hamid M, Edelman DC, Highsmith WE, Constantine NT. Optimization, assessment, and proposed use of a direct nested reverse transcription-polymerase chain reaction protocol for the detection of hepatitis C virus. J Hum Virol 1997;1:58-65.

6. Alter HJ, Seeff LB. Recovery, persistence, and sequelae in hepatitis C virus infection: a perspective on long-term outcome. Semin Liver Dis 2000;20:17-35.

7. Thomas DL, Astemborski J, Rai RM, Anania FA, Schaeffer M, Galai N, et al. The natural history of hepatitis C virus infection: host, viral, and environmental factors. JAMA 2000;284:450-6.

8. Kamal SM, Rasenack JW, Bianchi L, Al-Tawil A, El-Sayed Khalifa K, Peter T, et al. Acute hepatitis C without and with schistosomiasis: correlation with hepatitis C-specific CD4(+) T-cell and cytokine response. Gastroenterology 2001;121:646-56.

9. Yamakawa Y, Sata M, Suzuki H, Noguchi S, Tanikawa K. Higher elimination rate of hepatitis C virus among women. J Viral Hepat 1996;3:317-21.

10. Kenny-Walsh E for the Irish Hepatology Research Group. Clinical outcomes after hepatitis C infection from contaminated anti-D immune globulin. N Engl J Med 1999;340:1228-33.

11. Vogt M, Lang T, Frosner G, Klinger C, Sendl AF, Zeller A, et al. Prevalence and clinical outcome of hepatitis C infection in children who underwent cardiac surgery before the implementation of blood-donor screening. N Engl J Med 1999;341:866-70.