Illicit Drug Use on Spontaneous Hepatitis C Clearance

The Impact of Illicit Drug Use on Spontaneous Hepatitis C Clearance: Experience from a Large Cohort Population Study

Hossein Poustchi, Saeed Esmaili, Ashraf Mohamadkhani, Aghbibi Nikmahzar, Akram Pourshams, Sadaf G. Sepanlou, Shahin Merat, Reza Malekzadeh*
Digestive Disease Research Center, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Tehran, Iran

Abstract
Background and Aims
Acute hepatitis C infection usually ends in chronic infection, while in a minority of patients it is spontaneously cleared. The current population-based study is performed on a large cohort in Golestan province of Iran to examine the demographic correlates of Spontaneous Hepatitis C Clearance.
Methods
Serum samples used in this study had been stored in biorepository of Golestan Cohort Study. These samples were evaluated for anti hepatitis C Virus by third generation Enzyme-linked immunosorbent assay (ELISA). Subjects who tested positive were then invited and tested by Recombinant Immunoblot Assay (RIBA) and Ribonucleic Acid Polymerase Chain Reaction test (PCR). If tested positive for RIBA, subjects were recalled and the two tests were re-done after 6 months. Those subjects who again tested positive for RIBA but negative for PCR were marked as cases of spontaneous clearance.

Results
49,338 serum samples were evaluated. The prevalence of Chronic Hepatitis C Virus (CHCV) infection based on PCR results was 0.31%. Among those who had acquired hepatitis C, the rate of SC was 38%. In multivariate analysis, illicit drug use both Injecting Use (OR = 3.271, 95% CI: 1.784–6.000, p-value<0.001) and Non-Injecting Use (OR = 1.901, 95% CI: 1.068–3.386, p-value = 0.029) were significant correlates of CHCV infection versus SC.

Conclusions
Illicit drug use whether intravenous or non-intravenous is the only significant correlate of CHCV, for which several underlying mechanisms can be postulated including repeated contacts with hepatitis C antigen.

Citation: Poustchi H, Esmaili S, Mohamadkhani A, Nikmahzar A, Pourshams A, et al. (2011) The Impact of Illicit Drug Use on Spontaneous Hepatitis C Clearance: Experience from a Large Cohort Population Study. PLoS ONE 6(8): e23830. doi:10.1371/journal.pone.0023830
Editor: Paul Proost, University of Leuven, Rega Institute, Belgium
Received: February 25, 2011; Accepted: July 26, 2011; Published: August 24, 2011
Copyright: © 2011 Poustchi et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This study was funded by Tehran University of Medical Sciences. The study was not supported by any other internal or external resources. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
* E-mail: malek@ams.ac.ir

Introduction
Hepatitis C virus (HCV) infection is an important global health problem with estimates of 170 million HCV-infected individuals worldwide [1], [2]. Prevalence of hepatitis C all around the world ranges from 0.02% to18% [3]. In Iran, several studies have been performed on seroprevalence of HCV. Based on a comprehensive systematic review by Alavian et al. [4], the prevalence of HCV infection among the general population in 6 out of 30 provinces of Iran is 0.16%. Also the estimated seroprevalence of HCV in a more recent population-based study by Merat et al. [5] is around 0.5%, which is concordant with previous studies on blood donors (0.08%–1.3%) [6], [7].

In majority of patients exposed to HCV, the disease becomes chronic, but in a proportion of cases ranging from 14% to 45% the virus is spontaneously cleared from the body and the Ribonucleic Acid Polymerase Chain Reaction test (PCR) test becomes negative [8][15].
Several factors have been proposed as correlates of HCV persistence, including viral and demographic factors, and also route of disease transmission. [8][11], [14][19].
Among demographic factors, male gender [19][23], older age [14], [23], and ethnic background [12], [21], [24] are suggested as correlates for HCV persistence. Host genetic variation is also assumed to explain the heterogeneity in HCV persistence across individuals because such differences occur even if individuals are exposed to the same HCV strain [18], [25], [26].
Certain high risk behaviors also increase the risk of HCV persistence, namely illicit drug use (both Injecting and non-Injecting) [21], [27], alcohol consumption [12], [14], and unprotected sexual behaviors that lead to co-infection with Human Immunodeficiency Virus (HIV) and Hepatitis B Virus (HBV) [14], [28][30]. Still, there are major controversies on the role of these risk factors in various studies.

Along with effective prevention of HBV by universal vaccination in developing countries including Iran, HCV is becoming a more important public health concern replacing HBV [31][33]. There are quite a few studies that report the high rate of HCV co-infection with HBV, HIV, and venereal diseases such as syphilis in Iran [34], [35] especially among prisoners [36], which needs immediate attention. Appropriate policy-making in this regard necessitates accurate estimation of HCV burden. Distinguishing patients who spontaneously clear HCV from those who develop progressive liver disease and their risk factors is crucial for decision making.
In the current study, we have determined the rate of HCV spontaneous clearance (SC) and its demographic and host correlates in a large prospective population-based study in Iran.

Results
All subjects whose serum had tested positive for third generation Enzyme-linked immunosorbent assay (ELISA) were recruited for baseline examination and were recalled after 6 months and no subject was missed in the prospective phase of the study. Three hundred and eighty one (381) subjects tested positive for ELISA, among them, 247 subjects were also positive for Recombinant Immunoblot Assay (RIBA), therefore 134 subjects were labeled as false positive. Chronic HCV infection (CHCV) was confirmed in 152 subjects by PCR and the 95 cases with negative PCR was labeled as SC. During repeat serological testing after 6 months all CHCV subjects remained positive and in none of SC cases did the result of the test change. The HCV seroprevalence in Golestan cohort was 0.5% based on the result of RIBA, and 0.31% based on the result of PCR and 38.5% of infected subjects had spontaneously cleared the infection.
There was no significant difference in the mean age between the 4 groups (CHCV, SC, false positives, and HCV negatives). The frequency of males was significantly higher among subjects with CHCV infection (73.7%) and cases of SC (52.6%) than false positives (47.0%) and HCV negatives (40.0%) (p<0.001).

The correlates of HCV acquisition in univariate and multivariate logistic regression were sought. The ultimate correlates in multivariate analysis were: history of blood transfusion, history of imprisonment, family history of hepatitis, cigarette smoking, Non-Injecting Drug Use (Non-IDU), and Injecting Drug Use (IDU) (table 1).


Discussion
To the best of our knowledge, the current study is the first that has been conducted in such a large scale on HCV spontaneous clearance in Iran. In this study we were able to demonstrate that 38.5% of HCV infected subject might clear HCV infection spontaneously which is in agreement with many previous studies [8][10], [12][14], [37]. Also we found that both IDU and non-IDU are the main correlates of CHVC that significantly decrease the chance of SC among those patients who have acquired HCV infection.
Over 50% of the total estimated 170 million HCV cases in the world occur among illicit drug users and over 75% of incident infections occur in this population [3]. It is known that, illicit drug use is the major correlate of HCV persistence [21], [23], [37]. Several hypotheses have been suggested to explain the underlying mechanisms of this finding which mainly include: inefficient immunological response [38] which is due to HIV in co-infected subjects [12], [14], [39] other co-infection or co-morbidities [40], [41], and finally repeated -infection [27].

As for IDU, frequent monitoring of HCV infection status among those who clear a primary infection demonstrated that re-infection of HCV following control of a primary infection is common [42], with detection of one or more subsequent infections in almost 50% of cleared subjects [43]. In a study by Aitken and colleagues, re-infection was documented in 46% of previously cleared IDUs [44]. This data suggests that prior clearance of HCV infection may not provide immunity against re-infection. However it is of interest to know that the rate of self limited infection in subjects who previously cleared the virus is higher than subjects who do not clear the virus after initial infection [43], [45]. Furthermore, maximum viral load and also duration of viremia in re-infected cases are lower compared to the primary infection [43].
Our results are in discordance with findings of Lewis-Ximenez et al. [46], who found no relationship between illicit drug use or age and rates of SC. The only correlate of CHCV infection reported by them was low HCV antibody values [46]. The insignificant results in this study may have been due to the small sample size. Similarly, Santantonio et al. [47] found no demographic factors as correlates of HCV persistence. The possible explanation is that IDUs in Italy may be less likely to reuse syringes for drug injection.
Our results on the role of Non-IDU in HCV persistence are in accord with previous studies [21], [27], [48], but there are no agreed upon mechanism for this finding. Some studies imply that nasal inhalation or oral exposure may be plausible routes of transmission probably through shared intranasal canola contaminated with blood [48].

In our study, the seroprevalence of HCV based on RIBA is 0.5%, which is similar to that reported by Merat et al. [5]; however, the seroprevalence of HCV in our results based on PCR is 0.31% which is again similar to that reported by Alavian et al. [4]. The risk factors that correlate with HCV acquisition in our study (table 1) are also similar to many previous reports.
In the current study, the rate of SC is significantly higher among females versus males. Also in the univariate logistic regression, male gender is a significant predictor of HCV persistence, and this is supported by previous data [21], [22], [49]. Some previous studies have reported that the rate of SC is higher among females. The apparently higher rate of HCV SC in females is postulated to be due to effect of sex hormone [50] or attributed to genetic and immunological differences between males and females. In our study, gender was not found to be a significant correlate of HCV persistence in multivariate logistic regression analysis. The main reason for this finding may be the fact that IDU is more common among males. This finding implies that the inherent attributes of female gender have probably no direct effect on the natural history of CHCV which is discordant with previous studies [20], [22], [25], [49], [51]. With a similar justification, the seemingly protective role of body piercing in HCV persistence is due to the fact that in our study, women added up to 95.4% of subjects who had pierced while the percentage declined to 1.3% among those who had not, which shows that body piercing is associated with gender and thus is a confounder.

Since the Golestan Cohort Study (GCS) is an aged cohort and the median age of our subjects was 54 years, re-infection might have happened several times and seroconversion might have happened at unknown time; therefore, our cohort may represent a selection of subjects who have recovered from multiple bouts of HCV infections. Studies in older HCV infected subjects documented that prior clearance of HCV decreases the rate of persistent re-infection compared to initial infection [29], [45]; therefore, the duration of re-infection in subjects who have cleared multiple infections may be progressively shorter with each re-infection and this may have been the case in our study too but longer follow up is required to document this claim.
Lastly we compared the rate of SC in Turkmens versus non-Turkmens and in Turkmens versus immigrants from the southern province of Sistan and Balouchestan, who are the second major ethnic group residing in Golestan. Contrary to other studies, we did not find significant difference in the rate of SC between different ethnic groups residing in the province of Golestan. [12], [21], [24].

The main strengths of our study are the prospective population-based design and the large sample size which have been tested. The main limitation is the absence of young subjects in study population. Other limitation includes absence of HCV genotype data.
In conclusion this study revealed a 38.5% spontaneous clearance rate among HCV infected subjects in Golestan. We were able to demonstrate that illicit drug use, either Injecting or non-Injecting, are the main correlates of HCV persistence in Golestan province. Harm reduction interventions including distribution of sterile syringes among IDUs, can be an effective strategy to prevent HCV infection and re-infection in this population, which may play an important role in reducing the burden of HCV infection in Iran. Further studies which include younger age populations are necessary in future.

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Abstract
Introduction
Results
Discussion
Materials and Methods
Acknowledgments
Author Contributions
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