Hepatitis C Infection and Related Factors in Hemodialysis Patients in China: Systematic Review and Meta-Analysis

Abstract

Background and Aims. To provide a comprehensive and reliable tabulation of available data on the epidemiological characteristics and risk factors for hepatitis C virus (HCV) infection in maintenance hemodialysis (HD) patients in China, and to help inform prevention programs and guide future research. Methods. A systematic review was constructed based on the computerized literature database by two reviewers independently. Ninety-five percent confidence intervals (CI) of infection rates were calculated using the approximate normal distribution model. Odds ratios and 95% CI were calculated by fixed or random effects models. Results. Forty-three studies met our inclusion criteria. The pooled prevalence of HCV infection among HD patients in China was 41.1% (95% CI 39.5–42.6%). No significant difference was found in HCV infection rates between male and female HD patients (OR = 0.75, 95% CI 0.52–1.07, p = 0.11). HD patients with blood transfusion were 5.65 times more likely to be infected with HCV than HD patients without blood transfusion. A longer duration of HD was associated with increased HCV prevalence. Co-infection with hepatitis B virus did not increase the probability of HCV infection among HD patients (OR = 1.19, 95% CI 0.34–3.20, p = 0.73). Conclusions. Viral hepatitis is still one of the main complications in HD patients, with hepatitis C being the most common one. The key to reducing the incidence of viral hepatitis in HD patients is to control contagion and reduce the frequency of blood transfusion and cross-infection.

Keywords:

• hepatitis C virus
• hemodialysis
• meta-analysis
• enzyme immunoassay (EIA)
• Chinese

INTRODUCTION

Hemodialysis, widely used in the clinic, is an effective means for the treatment of end-stage renal disease and prolongs lives of patients with uremia. However, due to the long-term blood transfusion therapy, the lower resistances of the body, as well as cross-iatrogenic infection, HD patients were highly vulnerable to viral hepatitis infection. In recent years, studies found that the hepatitis C virus infection rate is the greatest in HD patients, as high as 34.3–42.6%.[1,2]

As a type of parenteral virus, HCV can induce acute or chronic or severe hepatitis. Compared with the hepatitis B virus, the hepatitis C virus more easily becomes chronic, more quickly causes the development of liver cirrhosis, and has a closer relationship with hepatocellular carcinoma.[3,4] HD patients are at high risk for HCV infection. HCV infection in HD patients not only affects quality of life, but also increases mortality rate and complications and decreases the long-term survival rate of renal transplantation.[5,6]

Hemodialysis is the predominant way for HCV transmission in China. However, a number of inconsistencies existed between the national reports and national descriptions. This paper aims to collate and integrate the available data on the epidemiological characteristics and risk factors for HCV infection in HD patients in China, and provide a reliable basis to formulate the prevention and control plans and a clear direction for research.

METHODS

Search Strategy and Study Selection

We searched EMBASE and PubMed to identify suitable studies from January 1995 to December 2007. References in articles identified were also searched manually. The search terms were hepatitis C virus or HCV and hemodialysis and China. A CNKI (China National Knowledge Infrastructure) search from January 1995 to December 2007 was also undertaken for Chinese articles related to HCV and hemodialysis. Other relevant articles and reports by WHO and the Chinese Ministry of Health were utilized.

A study was included in the meta-analysis when it fulfilled the following criteria:

• study designs: cohort, case-control study, or cross-sectional;

• specifying a sample origin; and

• using EIA for testing sero-markers of HBV and HCV.

The exclusion criteria were as follows:

• not specifying sample origins;

• overlapping time intervals of sample collection from the same origin;

• being a subset of a published article by the same authors; and

• presenting confusing data or probable errors.

• Two reviewers independently judged study eligibility while screening the citations; disagreement was resolved by consensus.

Data Extraction

Two reviewers independently evaluated each identified study and abstracted relevant characteristics, including author; publication year; province of sample origin; sample size; number of subjects infected with HCV, HBV, or co-infected with both; gender; and duration of hemodialysis.

Statistical Analysis

The 95% CI of the HCV infection rates among HD patients for each of the included studies was calculated using the approximate normal distribution model. The odds ratio (OR) with 95% CI was used to estimate the strength of association for each study. Before performing meta-analyses, homogeneity of effect sizes was assessed by the Q statistic, and between-study heterogeneity was considered to be significant for p < 0.10. Data considered to be sufficiently homogeneous were pooled. Because publication bias is of concern for meta-analysis, we tested for the potential presence of this bias using funnel plots and the Egger's test. Data manipulation and statistical analyses were undertaken using STATA 7.0 (STATA Corporation, College Station, Texas, USA, 2001) and Review Manager (RevMan) 4.2 (The Cochrane Collaboration, Oxford, United Kingdom, 2003).

RESULTS

We identified 320 studies about the infection of hepatitis C virus among HD patients from computerized literature databases and reference lists of systematic reviews. After an independent review by two reviewers, a total of 277 studies were excluded due to one of the following reasons:

• using the polymerase chain reaction (PCR) method for detecting HCV;

• not about HD patients;

• containing obvious errors;

• using a survey design that did not meet the selection criteria;

• having the same authors publish several reports on the same patients; and

• not being of high quality.

Overall, 43 articles (41 Chinese and 2 English) were included in the meta-analysis (see Table 1). These 43 studies were published from January 1995 to December 2007 included a total of 3831 patients, with the number of study subjects ranging from 17 to 286.

Table 1 The pooled prevalence of HCV infection among HD patients in China

Prevalence of HCV Infection among HD Patients in China

Region

As seen in Table 1, data were obtained from 19 of the 34 administrative units. The pooled prevalence of HCV infection among HD patients in China was 41.1% (95% CI 39.5–42.6%). Dramatic geographical differences in pooled HCV infection rates among HD patients have been observed. The highest rates were found in Jilin (69.4%, 95% CI 60.3–78.5%), followed by Xinjiang (67.0%, 95% CI 57.8–76.2%), then Taiwan (61.5%, 95% CI 55.5%-67.4%) and Shanghai (53.9%, 95% CI 47.3–60.5%). Lower rates were found in Beijing (19.8%, 95% CI 14.2–25.4%) and Jiangxi (14.3%, 95% CI 3.7–24.9%).

Sex

Six studies that specified sex included 316 males and 253 females. The results showed no significant difference in HCV infection rates between males and females (OR = 0.75, 95% CI 0.52–1.07, p = 0.11), and there was no significant statistical heterogeneity (chi-square = 5.76, p = 0.33) (see Table 2). The Egger's test suggested there was no significant publication bias.

Table 2 Difference of HCV infection rates between male HD patients and female HD patients in China

Risk Factors for HCV Infection among HD Patients in China

Blood Transfusion

The eligible studies included 997 HD patients with blood transfusion and 529 HD patients without blood transfusion. Meta-analysis showed that HD patients with blood transfusion were 5.65 times more likely to be infected with HCV than HD patients without blood transfusion. (OR = 5.65, 95% CI 3.69–8.66, p < 0.00001) (see Table 3). The Egger's test suggested there was no significant publication bias.

Table 3 Difference of HCV infection rates between male HD patients and female HD patients in China

Reuse of Dialyzers

Many studies have observed that there is a relation between HCV infection and the reuse of dialyzers.[49–51] One-time use of dialyzers caused significantly lower HCV infection rates than reuse, and a significant reduction of HCV infection rate has been seen after improving this process.[52,53]

Duration of Hemodialysis

Eight studies included 593 long-term (>1 year) HD patients and 265 short-term (<1 year) HD patients. There was no significant statistical heterogeneity (chi-square = 10.87, p = 0.21) between the two groups. Our meta-analysis with the fixed-effect model demonstrated there was a significant difference of HCV infection rates between the two groups (OR = 7.92, 95% CI 5.42–11.59, p < 0.00001) (see Table 4). There was no significant publication bias by the Egger's test.

Table 4 Difference of HCV infection rates between male HD patients and female HD patients in China

Five studies included 158 anti-HCV positive HD patients and 249 anti-HCV negative HD patients. Our meta-analysis with the random-effects model demonstrated a significant difference of duration of hemodialysis between the two groups (WMD = 15.41, 95%CI 6.64–24.19, p = 0.0001) (see Table 5). There was no significant publication bias by the Egger's test.

Table 5 Difference of HCV infection rates between male HD patients and female HD patients in China

Co-Infection with Hepatitis B Virus (HBV) among HD Patients in China

Our meta-analysis with the random-effects model showed that there was no significant difference of HCV infection rate between hepatitis B surface antigen (HBsAg )(+) HD patients and HBsAg (−) HD patients (OR = 1.19, 95% CI 0.34–3.20, p = 0.73) (see Table 6). The six relevant studies included 150 HBsAg (+) HD patients and 562 HBsAg (−) HD patients.

Table 6 Difference of HCV infection rates between male HD patients and female HD patients in China

DISCUSSION

The declining immune function in uremic patients undergoing hemodialysis, especially the cellular immunity,[54] together with a defect of neutrophil function and complement activity weaken the host's ability to resist pathogenic micro-organisms and pathogenic viruses in HD patients. This group is susceptible to various types of hepatitis viruses. In clinical observations, infection with hepatitis B and C and co-infection with both viruses accounts for the vast majority in chronic renal failure patients undergoing hemodialysis.

Foreign reports have observed that the HBV infection rate was 6–7.8% and HCV 20–30% in HD patients.[55,56] Some studies[22,57] have shown that hemodialysis does not increase the prevalence of hepatitis B but significantly increases hepatitis C infection rates in China. Our statistics also found that the hepatitis C infection rate was higher than the rate of hepatitis B infection in HD patients. This could be explained by the increasing detection of signs of hepatitis B in blood donors and wide usage of the hepatitis B vaccine in recent years. Hepatitis B has been better controlled, and hepatitis C has become increasingly prominent.

Hepatitis C is a global epidemic, and infection rate is 3% according to the World Health Organization statistics. It is estimated that about 1.7 million people are infected with HCV, and 35,000 new cases occur each year. National serum epidemiological survey data show that the anti-HCV positivity rate is 3.2% in the general population in China. There is a significant difference in the anti-HCV positivity rate geographically. If you divide the country North and South of the Yangtze River, the North (3.6%) was higher than that of the South (2.9%). There was no significant difference between males and females. There were differences about the prevalence of hepatitis C virus reported in various countries and regions. HCV infection rate was 12.0–25.0% in European HD patients with an average of 17%,[58] the United States 7.6%,[59] and Taiwan 61%.[39]

Dramatic geographic differences in pooled HCV infection rates among HD patients have been observed. Such geographical differences are consistent with the difference of distribution of hepatitis C infection in the normal population. The low rate of HCV infection in Beijing may be related to earlier screening of HCV blood donors.

Huraib[60] reported that the anti-HCV positivity rate was male-dominated, while Chen[39] and Khattab[61] reported the rate to be female-dominated. Our results in this meta-analysis showed that there was no significant difference between male and female.

Uremic patients are often accompanied by severe anemia and malnutrition, requiring blood transfusion to improve the situation of the body. Due to only checking HCV antibody when screening blood donors, some of the donors infected with HCV are false-negative because of a low level and slow antibody response, the existence of the window period, the mutation of the virus, or the reagent antigens not entirely matching the antibodies, leading to blood-transfusion-transmitted HCV infection. A multivariate analysis of risk factors by Domenico showed that blood transfusion was significantly associated with the acquisition of this infection, followed by the length of time on dialysis.[62] Limeng Chen's study[63] showed that the risk of hepatitis C infection increased 1.8% for every one unit of blood transfusion.

The application of EPO to correct anemia in patients with renal anemia, which will reduce blood transfusion volume, is considered to be an effective means to reduce the possibility of HCV infection in HD patients.[63] Wang's study[45] found that the anti-HCV positivity rate was significantly higher in patients with blood transfusion than with hematocrit red blood cell transfusion, advising the use of hematocrit red blood cell transfusion to avoid HCV infection. There may be two reasons for this: the removal of plasma from hematocrit red blood cells reduces the opportunity of the spread of HCV; and the use of hematocrit red blood cells started from 1993, and at that time, the preliminary and review test of anti-HCV antibody would have been carried out. Today, transfusion-transmitted HCV has been effectively controlled.

It is worth noting that HD patients without a history of blood transfusion have a high incidence of hepatitis C infection, suggesting that other channels besides blood transfusion must be considered. Hinrichsen[64] believed that the length of dialysis is the major risk factor for HCV infection, and suggested that the risk of long times is greater than the risk of blood transfusion. The author investigated 43 dialysis centers with 2796 cases of patients in Germany, and the results showed that HCV antibody and HCV-RNA positivity rate were 5.0% and 2.2%, respectively, in all the patients with blood transfusion, but HCV antibody and the HCV-RNA positivity rate were 11.0–71.4% and 8.6–42.0%, respectively, in the patients that were without blood transfusion but had more than a 10-year and 20-year dialysis history. This shows that dialysis can be seen as an independent risk factor to the blood transfusion, and also proves the existence of the dialysis-related iatrogenic transmission route.

It is a common phenomenon that the greater frequency of dialysis, the higher the anti-HCV positivity rate. There may be other causes of transmission, such as re-use of the dialyzers and pipelines, frequent cardiopulmonary bypass and repeated needle puncture during the treatment, sharing of dialysis machines and incomplete disinfection, and contamination in the operational process of the dialysis environment. Studies found that hepatitis C virus particles can break into ultrafiltrate samples across the dialysis membrane and cause cross-infection through reverse osmosis.[65] At present, normally adopted disinfection methods for re-used dialyzers include formalin and peracetic acid, which can effectively kill hepatitis C and B viruses. However, there are higher incidences of HCV infection in the dialysis centers that reuse dialyzers than the non-reuse centers, implying that there may be infection channels associated with the process of reuse.

Gladziwa had performed anti-HCV detection in 333 cases of peritoneal dialysis patients from 10 dialysis centers in Germany. The total anti-HCV positivity rate was 5.4% in these dialysis centers and even as high as 30% in some individual dialysis centers. The HCV-RNA was also detected in peritoneal dialysis solutions of anti-HCV-positive patients.[66] Our data show that HD patients have a higher prevalence of hepatitis C virus infection than peritoneal dialysis (PD) patients (OR = 9.95, 95% CI 4.58–21.63, p < 0.00001). There are three possible reasons for this:

1. PD patients have better residual renal function, higher erythropoietin production, and less blood cell damage. The chances of infection through blood transfusions are reduced by reduced blood transfusion volume.

2. PD patients do not have to establish vascular access and cardiopulmonary bypass, so the opportunities of exposure to blood and the chances of spread of HCV through blood decline.

3. Family therapy with a more closed environment is used for the vast majority of PD patients, which may decrease the opportunity of cross-infection between patients.

HCV serology testing mainly relies on ELISA and RIA methods to detect anti-HCV IgG currently. It is an indirect indicator of the immune status after HCV infection and not a sign of viremia. At the same time, researches have shown that renal failure patients with HCV infection were deficient of anti-HCV antibody; therefore, traditional serological methods to detect HCV infection in HD patients may be unsatisfactory. HCV-RNA is the most direct evidence for the diagnosis of HCV infection. This reflects replication and infectivity of the virus and could be seen as a sign of viremia. Positive results can be found by using the PCR technique, as HCV-RNA replication appears a few days after HCV infection.[67] As the sensitivity of the PCR technique in detection of serum hepatitis C virus infection reaches 45 IU/mL based on 95% sensitivity,[68] the HCV-RNA positivity rate is higher or earlier than testing antibody by EIA methods and helpful for early diagnosis. As an expensive, time-consuming operation, the PCR method has not yet been widely used for testing HCV infection in the clinic, so we removed the articles that included in the PCR method.

However, there were also articles that reported that the level of HCV-RNA decreased after repeated dialysis in some patients, even the point where no HCV-RNA could be detected.[69] This could be explained in two ways: on the one hand, dialysis membranes have the ability to adsorb HCV virus particles; on the other hand, HCV-infected patients with long-term hemodialysis had accepted drug treatment. As a result, some scholars[61,70] recommended the joint detection of anti-HCV IgG and HCV-RNA, which can significantly improve the detection rate of HCV infection in HD patients.

CONCLUSION

Despite the early recognition of the high infection rate and enhancement of disinfection and isolation measures, dialysis machines cannot be used separately between anti-HCV-positive and-negative patients, even if HCV-infected patients with increased ALT have not been treated in isolation because of the conditions at that time. In recent years, with the improvement of medical equipment and environment, anti-HCV-positive and -negative patients can be placed in different rooms for treatment. Rehabilitation supplies can be properly disinfected and specifically dealt with, cross-infection in the process of hemodialysis can be more effectively prevented, and all of these will help to reduce HCV infection. But the government is also needed to strengthen the management of blood donors and conduct routine anti-HCV detection with a variety of indicators. Dialysis units would also like to do their regular work to reduce the prevalence of HCV in HD patients, by continuously improving the quality of HD technology and the level of dialysis, fostering direct reasonable nutrition, increasing the resistance of the body, ensuring that all patients be periodically reviewed and vaccinated, reducing blood loss and the frequency and amount of blood transfusion in the process of hemodialysis, and using EPO to correct anemia as much as possible.

LIMITATIONS

These studies were observational and HD patients were not randomly chosen, so selection bias and confounding bias seems inevitable. Information about cases and controls was not always complete nor the reliability of interviews, so the study quality could not be ensured. Additionally, it is difficult for non-Chinese reviewers, editors, and readers to recheck the original materials because much of our data were extracted from articles written in Chinese.

DECLARATION OF INTEREST

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.