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Systematic review and meta-analysis of hepatitis C virus infection in the Democratic Republic of Congo
p u b l i c h e a l t h x x x ( 2 0 1 6 ) 1 e9
Available online at www.sciencedirect.com
Public Health journal homepage: www.elsevier.com/puhe
Review Paper
Systematic review and meta-analysis of hepatitis C virus infection in the Democratic Republic of Congo B.A. Muzembo, T. Akita, T. Matsuoka, J. Tanaka* Department of Epidemiology, Infectious Disease Control and Prevention, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
article info
abstract
Article history:
Objectives: Hepatitis C virus (HCV) infection is endemic in the Democratic Republic of the
Received 21 January 2016
Congo (DRC), where the prevalence of HCV antibodies (anti-HCV) is reported to range from
Received in revised form
0.2% to 13.7%. However, the reported prevalence rates have been inconsistent. Therefore, a
25 April 2016
meta-analysis of observational studies was conducted to provide updates on the preva-
Accepted 16 June 2016
lence of HCV infection in the DRC.
Available online xxx
Study design: Systematic review and meta-analysis. Methods: Medline, EMBASE and Google Scholar were searched for publications reporting on
Keywords:
HCV infection in the DRC up to autumn 2015. In addition, a manual search was undertaken
Democratic Republic of the Congo
to detect relevant papers. Studies performed in groups at low risk of HCV (blood donors and
Hepatitis C virus
pregnant women) were used for the meta-analysis. The random effects model was used to
Epidemiology
estimate the pooled prevalence of anti-HCV.
Prevalence
Results: Sixteen studies with 13,799 participants (aged 6 monthse71 years) met the inclu-
Review
sion criteria. The studies were performed in blood donors, pregnant women, military
Meta-analysis
personnel, individuals with human immunodeficiency virus, children, commercial sex workers, Congolese patients living in Canada, patients with sickle cell disease and hospitalized patients. The reviewed studies revealed the presence of anti-HCV in almost all studied age groups and did not differ between sexes. The pooled prevalence of anti-HCV was 2.9% [95% confidence interval 1.5e4.3%]. Subgroup analyses revealed that the prevalence rates of anti-HCV in blood donors and pregnant women were 2.7% (95% confidence interval: 1.1e4.4%) and 3.3% (1.4e5.1%), respectively. Conclusions: HCV infection remains an issue of public concern in the DRC, demonstrating a need for adequate hepatitis control programmes. Efforts must be made to virtually eliminate transfusion-transmitted HCV throughout the country. © 2016 Published by Elsevier Ltd on behalf of The Royal Society for Public Health.
* Corresponding author. Department of Epidemiology, Infectious Disease Control and Prevention, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan. Tel.: þ81 82 257 5160; fax: þ81 82 257 5164. E-mail address: [email protected] (J. Tanaka). http://dx.doi.org/10.1016/j.puhe.2016.06.017 0033-3506/© 2016 Published by Elsevier Ltd on behalf of The Royal Society for Public Health. Please cite this article in press as: Muzembo BA, et al., Systematic review and meta-analysis of hepatitis C virus infection in the Democratic Republic of Congo, Public Health (2016), http://dx.doi.org/10.1016/j.puhe.2016.06.017
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Introduction Hepatitis C virus (HCV) infection is one of the most challenging health problems to face humanity for decades, especially in developing countries where the disease remains highly endemic. HCV is considered to be endemic in the Democratic Republic of the Congo (DRC). It is estimated that HCV affects approximately 647,000 Congolese1 and 130e150 million people throughout the world.2 HCV infection is usually self-limited in the initial stages, but failure of the immune system to clear the virus leads to chronicity. Chronic hepatitis C is often clinically insidious but develops progressively and persistently over years or decades. Chronic infection with HCV is a serious public health concern as it is linked to hepatic cirrhosis and hepatocellular carcinoma3,4 and can ultimately cause premature death.5 Despite being one of the most common bloodborne infections endemic in the DRC, little attention has been paid to HCV-related health issues. Hepatitis virus screening is not yet implemented routinely, and the lack of effective care and treatment programmes make matters worse.6,7 Furthermore, the DRC is not currently listed in the HCV synthesis project.8 Some medical institutions in the DRC fail to perform HCV screening on donated blood.9 Therefore, patients undergoing blood transfusions are at high risk of HCV infection. As an example, a 2013 study in transfused children reported that the prevalence of anti-HCV was 13.5%.10 Different studies have reported inconsistent prevalence rates of HCV in the DRC. The prevalence of HCV antibodies (anti-HCV) has been estimated to vary from 0.2%11e13.7%.12 Published reviews have not focused specifically on the DRC.1,13,14 In addition, these reviews reported heterogeneous results. In 2015, a meta-analysis of two observational studies reported that the prevalence of anti-HCV was 2.1%,1 whereas this had previously been estimated to be 4.3%14 and 5.5%.13 In light of the above discrepancies in the literature, a metaanalysis of available data would be scientifically relevant. To help inform policy identifies the appropriate intervention in a given country, it is advised that the number of people with undiagnosed HCV infection in the general population should be estimated.15,16 In order to conduct similar studies in the DRC, it is crucial to estimate the magnitude of the problem. Therefore, this study was designed to summarize epidemiological studies on HCV infection in the DRC. The potential relevance of this study in epidemiology is that it provides valuable insights in planning future studies in order to help promote prevention and enhance community advocacy in the country.
Methods
epidemiology guidelines were followed.18 Medline, EMBASE and Google Scholar were searched to identify articles on HCV infection in the DRC. The search was based on literature published up to September 2015 using the following keywords: ‘hepatitis C, prevalence, Democratic Republic of Congo’, and ‘hepatitis C, incidence, Democratic Republic of Congo’. Previous reviews on the prevalence of HCV infection in the DRC were also scrutinized for comparison purposes. All studies published in English and French were included. The titles and abstracts of the retrieved studies were screened, followed by exclusion of reviews, studies not related to the DRC, and studies solely related to other types of viral hepatitis such as hepatitis B virus. Extracted information included year of publication, year of data collection, study setting and design, sample size and demographics of participants, methods used to detect anti-HCV and reported prevalence of anti-HCV (HCV infection). Genotype distribution was also recorded for applicable conditions.
Assessment of study quality The quality of reporting was assessed based on the information disclosed to the reader.19 A checklist was conceived including information related to the objective of the study, sample size (>100), year of blood/data collection, description of the study setting, inclusion of a control group, adjustment for confounding factors, and discussion on limitations. Serological and HCV confirmatory tests were also examined. A score of ‘1’ was given for each reported item. Studies were classified as high quality (score 8e10), moderate quality (score 5e7) or poor quality (score 4).20,21
Statistical analysis The prevalence of individuals with anti-HCV was considered as the effect size. Both fixed and random effects (DerSimonianeLaird) were applied to assess the suitable model type for the data using Excel (Microsoft Corp., Redmond, WA, USA). Initially, the variance and weighted means of studies were calculated using the fixed model. Next, the random effects model was fitted for pooled prevalence. The random effects model was used to report the pooled prevalence of anti-HCV and 95% confidence intervals (CI). The degree of heterogeneity across the analysed studies was quantified using Cochran's Q and I2 statistics. I2 50% was considered to indicate substantial heterogeneity.22 Metaanalysis was only performed in eight studies because combining data from low- and high-risk populations was deemed to be inappropriate. Using Excel (Microsoft Corp.), the variance of the studies and their weights in the fixed model were determined using the following formula:
Study design
vi ¼ pi 1 pi ni ; and wi ¼ 1=vi
A systematic review and meta-analysis was undertaken.
where i, ni and pi denote index, sample size and prevalence of the study respectively. Using their mean and variance:
Search strategy and selection criteria w¼ The preferred reporting items for systematic reviews and metaanalysis17 and meta-analysis of observational studies in
X . wi k; i
Please cite this article in press as: Muzembo BA, et al., Systematic review and meta-analysis of hepatitis C virus infection in the Democratic Republic of Congo, Public Health (2016), http://dx.doi.org/10.1016/j.puhe.2016.06.017
p u b l i c h e a l t h x x x ( 2 0 1 6 ) 1 e9
s2w ¼
. X w2i kw2 ðk 1Þ
Results
i
Search outcomes
statistics U and b t were calculated: U ¼ ðk 1Þ w s2w ðkwÞ b t ¼ maxf0; ðQ ðk 1ÞÞ=Ug Next, weight in the random effects model w*i and pooled b were obtained using: prevalence p w*i ¼ 1 b¼ p
2 b t þ vi
.X X w*i pi w*i i
i
Finally, the heterogeneity of the studies was evaluated using the following two formulae: Q¼
3
X 2 b and I2 ¼ 100*fQ ðk 1Þg=Q wi pi p i
The selection process is displayed in Fig. 1. The search identified 318 potentially relevant publications. After the exclusion of 197 duplicate publications, 121 titles and abstracts were screened. Of these, 15 articles were excluded because they were not pertinent to the study. Further evaluation excluded 90 publications because they were deemed to be irrelevant, leaving 16 unique publications with 13,799 individuals for inclusion in the qualitative synthesis. Twelve publications were written in English and four were written in French. Eight studies (n ¼ 8692) performed in groups at low risk for HCV (blood donors and pregnant women) were included in the quantitative synthesis.11,23e29 Three reviews estimating the prevalence of HCV infection in the DRC at global and regional levels were chosen for comparative purposes1,13,14 (Table 1).
Characteristics of studies
Statistical analyses using Excel (Microsoft Corp.) were confirmed using Comprehensive Meta-Analysis Software version 3 (Biostat Inc., Englewood, NJ, USA). Both textual narrative and synthesis methods were used to present the results.
The included studies are shown in Table 2. They were published from 1991 to 2015. Of the 16 reviewed studies, only one was a cohort study,26 and the others were cross-sectional
Fig. 1 e Publications selection process. Please cite this article in press as: Muzembo BA, et al., Systematic review and meta-analysis of hepatitis C virus infection in the Democratic Republic of Congo, Public Health (2016), http://dx.doi.org/10.1016/j.puhe.2016.06.017
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Table 1 e Reviews on the prevalence of hepatitis C virus (HCV) infection in the Democratic Republic of the Congo (DRC). Authors, year
Number of included studies
Madhava et al., 200213
3
Gower et al., 201424
N/A
Riou et al., 20151
2
Objective
Sample size
Prevalence of anti-HCV % (a: 95% CI or b: PI)
Type of review
To estimate the prevalence of HCV infection in sub-Saharan Africa To estimate the prevalence, viraemia and genotypes of HCV infection in the world To estimate the prevalence of HCV infection in African adults
2572
5.5 (4.3e6.6)a
Systematic review
N/A
4.3 (3.2e13.7)a
Systematic review
2094
2.1 (0.4e12.0)b
Systematic review and meta-analysis
N/A, not available; CI, confidence interval; PI, prediction interval.
studies. The studies were performed in selected groups of pregnant Congolese, including blood donors,11,24e27 23,28,30 military personnel,1,2,31 individuals with women, human immunodeficiency virus (HIV),32 children aged <5 years,33 transfused children,10 and patients with sickle cell disease (SCD).34 Hospitalized patients,35 commercial sex workers (CSWs)23 and Congolese patients living in Canada36 were also examined. Quality assessment revealed that 15 studies were of moderate quality, and one study was classified as high quality23 (Table S1, see online supplementary material). No published representative population-based studies on HCV in the DRC could be located. The studies were conducted in five of the former 11 provinces; most were performed in the capital city Kinshasa,10,12,23,30,31 except for four studies that were conducted in Bukavu,24e26,32 two studies in Kisangani,27,34 two studies in Maniema,28,33 one study in Kamina,11 and one study in an unknown location (rural DRC).35 Two studies assessed the prevalence and genotype diversity of viraemic HCV (RNApositive),12,31 but one of them did not provide the prevalence of anti-HCV,31 along with the study conducted in Congolese patients living in Canada.36 Most importantly, anti-HCV was detected in all studied age groups, ranging from six months to 71 years and did not differ between sexes. The screening assays used most often for detecting anti-HCV were enzyme immunoassays and immunochromatographic rapid tests (Table 2).
Prevalence of anti-HCV infection As shown in Fig. 2, the pooled prevalence of anti-HCV in eight studies was 2.9% (95% CI: 1.5e4.3%). There was significant heterogeneity across the included studies (I2 ¼ 95.6%; Cochran's Q ¼ 158.4; P < 0.001). Sensitivity analysis did not influence the robustness of the pooled estimate. Subgroup analyses revealed that the prevalence rates of anti-HCV in blood donors (age 15e65 years) and pregnant women (age 14e48 years) were 2.7% (95% CI: 1.1e4.4%) and 3.3% (95% CI: 1.4e5.1%), respectively (Figs. 3 and 4). The prevalence of antiHCV in primary studies was highest among military personnel (13.7%),12 followed by transfused children (13.5%)10 and individuals with HIV (10%),32 whereas the lowest prevalence of anti-HCV was in blood donors (0.2%).11
Hospital-based study The earliest published study of the prevalence of anti-HCV in the DRC was hospital based; this study was performed in 1991,35 which was two years after the discovery of HCV. This
study used stored sera that were initially collected to investigate the prevalence of HIV in 173 individuals admitted to hospitals in rural DRC. In this study, 6.4% of sera were positive for anti-HCV using enzyme-linked immunosorbent assay. Unfortunately, these authors did not provide information on the age and sex of the participants, and the geographical area where the study was conducted.
Studies in patients with SCD and children Three studies were identified for this group. They outlined that blood transfusion remains one of the main channels for iatrogenic spread of HCV in the DRC.10,33,34 In 2013, Katabuka et al.10 highlighted that some medical institutions in the DRC face many challenges in screening donated blood for major infectious agents including HCV. History of blood transfusion was investigated in a retrospective cross-sectional study of 127 patients with SCD (mean age 15 [standard deviation 11] years).34 The authors found that the prevalence of HCV infection was 7.9% in patients with SCD with a history of blood transfusion not screened for HCV, whereas anti-HCV could not be found in those who had not been transfused. A study that analysed data from 781 children (age 6e59 months) found that history of blood transfusion was a risk factor for HCV. Infection with HCV was more common in children with a history of blood transfusion (7%) compared with those without a history of blood transfusion (2.5%).33 The same study found a higher prevalence of anti-HCV (11%) in children whose mother had a blood transfusion during pregnancy compared with those whose mother had not had a blood transfusion during pregnancy (2.2%).33
Studies including blood donors All reviewed studies in blood donors were published within the last five years.11,24e27,32 The reported prevalence of antiHCV in Congolese blood donors is non-negligible, ranging from 0.2%11 to 4.1%.27 All of these studies found that HCV infection is common among Congolese blood donors and raise questions regarding the safety of blood transfusion in the DRC. Furthermore, these studies found that the use of paid blood donors is common in the DRC, along with family and voluntary blood donors. Transfusions with unscreened blood are sometimes performed in emergency situations using the recipients' relatives as donors.37 Among five studies that were performed in blood donors, only one reported an incidence rate of 17.1 (9.2e28.9) per 1000 person-years in a 2-year followup study carried out in 2986 volunteer blood donors from Bukavu between 2010 and 2012, with seroconversion detected
Please cite this article in press as: Muzembo BA, et al., Systematic review and meta-analysis of hepatitis C virus infection in the Democratic Republic of Congo, Public Health (2016), http://dx.doi.org/10.1016/j.puhe.2016.06.017
Setting
Study design
Sample size
Iles et al., 201312 Katabuka et al., 201310
Kinshasa Kinshasa
CS CS
299 371
Kabinda et al., 201032
Bukavu
CS
209
Batina Agasa et al., 201034
Kisangani
Retrospective CS
Laurent et al., 200123 Tibbs et al., 199135 Laurent et al., 200123 Batina Agasa et al., 201227
Kinshasa Rural DRC Kinshasa Kisangani
Kabinda et al., 201528
Population; agea (range)
Sex
Year of data/blood collection
HCV serological tests
Reported prevalence of anti-HCV (%)
M M; F
2007 2008
ELISA HCV rapid test
13.7 13.5
M; F
2008
ELISA
10
127
Military personnel; 38.7 (21e71) Transfused children 59.5 (18 months13 years)b HIV-positive patients; 36.7 ± 11.7 (N/A) Patient with SCD; 15.5 ± 11.1
M; F
2008
CS CS CS CS
1144 173 1092 1247
CSWs; 25.8 (14e55) Hospital community; N/A Pregnant women; 25.6 (14e45) Blood donors; 31.1 ± 13.1 (17e64)
F N/A F M; F
Maniema
CS
581
Pregnant women; 25 (15e48)
F
1988 1986 1990 2005 and 2006 2013
Kabinda et al., 201424 Kabinda et al., 201425 Kabinda et al., 201533
Bukavu Bukavu Maniema
CS CS CS
595 1079 781
Blood donors; N/A (18e65) Voluntary blood donors; 26 (18e60) Children; 34 (6e59 months)b
M; F M; F M; F
2014 2010 2013
Kabinda et al., 201426 Liu et al., 200030 Nzaji and Ilunga, 201311
Bukavu Kinshasa Kamina
Cohort study CS CS
2986 97 1015
Voluntary blood donors; 23 (N/A) Pregnant women; N/A Blood donors; 28 ± 6 (15e56)
M; F F M; F
2010 1996 2008
Murphy et al., 201536 Iles et al., 201431
Canada Kinshasa
N/A CS
4 1999
N/A Military personnel; 44 (22e27)
N/A M
2001e2006 2007
Immunochromatographic test and ELISA EIA ELISA EIA Immunochromatographic test Immunochromatographic test HCV rapid test HCV rapid test Immunochromatographic test HCV rapid test and ELISA ELISA Immunochromatographic test ELISA/PCR N/A
rapid
7.9
rapid
6.6 6.4 4.3 4.1
rapid
4.1
rapid
3.9 3.8 2.8
rapid
2.1 1 0.2 N/A N/A
CS, cross-sectional; HCV, hepatitis C virus; SCD, sickle cell disease; CSWs, commercial sex workers; HIV, human immunodeficiency virus; EIA, enzyme immunoassay; ELISA, enzyme-linked immunosorbent assay; PCR, polymerase chain reaction; N/A, not available. a Age (mean/median) in years. b Age in months.
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Table 2 e General characteristics of the studies included in this review. Authors, year
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Prevalence (%)
Prevalence (%)
Fig. 2 e Forest plot of studies on the prevalence of hepatitis C virus in the Democratic Republic of the Congo. Pooled prevalence of hepatitis C virus antibodies was estimated using the random effects model (I2 ¼ 95.6%; Cochran's Q ¼ 158.4; P < 0.001).
Prevalence (%)
Fig. 3 e Forest plot of studies on the prevalence of hepatitis C virus in blood donors in the Democratic Republic of the Congo. The random effects model was used to estimate the pooled prevalence of hepatitis C virus antibodies (I2 ¼ 96.6%; Cochran's Q ¼ 116.9; P < 0.001).
Fig. 4 e Forest plot of studies on the prevalence of hepatitis C virus in pregnant women in the Democratic Republic of the Congo. The random effects model was used to estimate the pooled prevalence of hepatitis C virus antibodies (I2 ¼ 75.9%; Cochran's Q ¼ 8.292; P < 0.001).
conducted in 1144 CSWs and 1092 pregnant women using blood primarily collected to screen for HIV and sexually transmitted infections (STIs).23 The prevalence of anti-HCV was not significantly different between CSWs (6.6%) and pregnant women (4.3%). The prevalence of HCV in CSWs with a history of blood transfusion was 13.1%, compared with 5.5% in those without a history of blood transfusion. In unadjusted analyses, the prevalence of HCV infection was higher (9.9%) in CSWs who had more than five years of prostitution tenure compared with those who had less (5.4%). The authors highlighted the possible transmission of HCV by unsafe injection practices when treating STIs in CSWs.23 In studies in pregnant women,23,28 risk factors associated with HCV could not be detected among the studied parameters including age, marital status and HIV status. Of the three studies in pregnant women,23,28,30 only one study assessed the history of blood transfusion, without detecting a higher risk of HCV infection in those with a history of blood transfusion.28 However, the study found that 6.5% of the participants had scarification or tattoos, representing risk factors for HCV transmission.
Studies on genotype distribution in 12 donors.26 The authors estimated that the residual risk of HCV transmission from the window was 3.1 per 1000 donations, indicating that blood transfusion may have the potential to disseminate HCV in the DRC. In another study conducted among volunteer blood donors in Bukavu, Kabinda et al.25 reported a higher prevalence of HCV in rural participants (9.2%) compared with those living in urban areas (3.3%). The authors highlighted important issues about unequal access to treatment for blood donors diagnosed with an HCVrelated liver disease; less-privileged individuals with HCVrelated liver disease have limited access to medical treatment.
Studies in CSWs and pregnant women A pioneering study investigating the relationship between sexual behaviour and the prevalence of HCV infection was
Few attempts have been made to address the genetic diversity of HCV in the DRC. In total, HCV genotypes in Congolese were reported by three recently published studies in 2013e2015.12,31,36 Two studies12,31 by the same authors identified genotype 4, whereas another study36 reported genotype 7. Genotype 4 is likely to predominate in the DRC as well as genotype 7. In the study of HCV infection among soldiers in Kinshasa, Iles et al.12 identified genotype 4 in 11 RNA-positive samples (3.7%; 11/299). The authors reported that genotype 4 split into subtypes 4k and 4c was only found in military personnel born before 1956, whereas subtype 4r was detected in those born after 1956. Genotype 4 was also reported with genetic diversity of HCV, including subtypes 4c, 4h, 4k, 4r and 4drc in 60 RNA-positive samples (3%; 60/1999) from military personnel.31 However, the study by Iles et al.31 was unable to detect genotype 7 despite using the same procedures as those previously used to identify genotype 7 in Congolese.36
Please cite this article in press as: Muzembo BA, et al., Systematic review and meta-analysis of hepatitis C virus infection in the Democratic Republic of Congo, Public Health (2016), http://dx.doi.org/10.1016/j.puhe.2016.06.017
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Studies on age and HCV Except for five studies12,23,25,27,31 which reported that HCV infection might be related to age in the DRC, HCV infection could not be explained by age in the other included studies. The studies by Iles et al.12,31 found that both anti-HCV and viral RNA-positive rates were positively correlated with age. Older men (aged 57 years) were more likely to be diagnosed positive for HCV-RNA compared with younger men (age <57 years).12,31 In three other studies, individuals in their 30s were more likely to be diagnosed positive for anti-HCV,23,25,27 whereas HCV infection was found in all studied age groups.
Discussion The overall prevalence of anti-HCV in the reviewed studies was estimated to be 2.9% (95% CI: 1.5e4.3%). This prevalence confirms that HCV infection remains a significant public health problem in the DRC. The results suggest the need for a strong commitment from Congolese policy makers, including adequate hepatitis control programmes. It is possible that the prevalence reported in this study could have been underestimated as studies included in the meta-analysis were performed in low-risk groups (blood donors and pregnant women). Most studies included in the meta-analysis were of moderate quality and used convenient sampling methods. Therefore, it is difficult to extrapolate the estimate to the general population. Nevertheless, the estimate from this study might provide a picture of the prevalence of anti-HCV in the DRC. Although five studies reported a possible correlation between HCV infection and age, when reviewed systematically, the evidence indicates that HCV infection affects individual of all ages in the DRC. These results suggest a possible ongoing risk of HCV transmission in the DRC. The above explanation stems from transmission patterns of HCV, where infection transmitted through unsafe injections and non-sterile equipment is likely to be found in all the age groups.38 The use of non-sterile equipment and injection therapy are frequent in the DRC. Furthermore, traditional practices performed with non-sterile equipment and injections from unqualified medical providers are common in the country. Circumcision in males, ear piercing in females, home birth, scarification and tattooing are likely to be performed with unsterile equipment in Congolese rural settings and poor communities, thus contributing to HCV transmission. This may be a normal occurrence in the DRC because it is still a fragile and country after a lengthy period of civil unrest and armed struggle, where the health care system is facing challenges.39e41 This is consistent with a previous study which demonstrated that HCV infection benefits from social upheaval to spread within a country.3 The highest prevalence of HCV infection was reported in a study in Kinshasa among military personnel (13.7%).12 This may also be the consequence of various factors including the war in the DRC, where bloodborne viruses were likely to take advantage of unsafe medical practices and limited access to appropriate medical care, especially in the battlefield.
7
In the DRC, blood transfusions remain among the primary routes of HCV transmission.27 Notably, transfusion of unsafe blood was underscored by the reviewed studies to contribute to the transmission of bloodborne pathogens, including HCV infection.10,23,33,34 Screened blood for transfusion-transmitted infections with rapid tests and unscreened transfusion blood might sustain this chain of transmission. Donated blood is not screened routinely for transfusion-transmitted infections, including HCV.10,42,43 The use of unscreened blood may have contributed to the iatrogenic transmission of HCV throughout the country. The estimated prevalence (2.9%) of anti-HCV found in this study is similar to that reported by Riou et al., in 2015 (2.1%).1 However, the present study included eight studies with 8692 subjects in the meta-analysis, whereas the study by Riou et al. was limited to two studies with 2094 subjects. Compared with the estimated prevalence of anti-HCV in Cameroon (11.6%)14 and that reported for Egypt (14.7%),14,44 the estimated prevalence of anti-HCV is lower in the DRC. Worldwide, Egypt has the highest prevalence of anti-HCV due to, in part, historical unsafe parenteral antischistosomiasis therapy, where syringes were re-used without sterilization in the 20th century.44 Studies that reported genotype 4 in the DRC are in line with those conducted in the neighbouring countries, showing a predominance of HCV genotype 4.45,46 The presence of HCV genotype 4 across countries in central Africa is attributable, in part, to past exposure to unsafe medical interventions including mass intravenous therapy against yaws, syphilis, malaria, leishmaniasis, transfusion and circumcision initiated by the colonial authorities.1,43,47,48 This study has inevitable limitations. First, the pooled prevalence of HCV infection may be questionable because of the non-inclusion of unpublished data and the absence of population-based studies. It is worth noting that unpublished data have the potential to interfere with pooled prevalence regarding overestimation or underestimation. The paucity of published data, however, would not substantially alter the magnitude of the problem of HCV-related liver disease in the DRC because of the slow improvement in health care settings in the DRC.40,41 Second, heterogeneity across studies included in the pooled analysis was high, this being a common issue when performing a meta-analysis of studies addressing prevalence in selected populations.22 However, the above concern was tempered by the sample size of 8692 subjects included in the random effects model.
Conclusion This review provides compelling evidence that HCV infection remains an issue of public concern in the DRC. Furthermore, results from the reviewed studies highlight the need for adequate hepatitis control programmes and efforts to reduce HCV infection in blood donors. Controlling HCV infection in the current Congolese economic context is complex. Nevertheless, compiling references of publications related to HCV infection in the DRC gives an overview of the magnitude of the problem in the country that may be relevant when planning future studies.
Please cite this article in press as: Muzembo BA, et al., Systematic review and meta-analysis of hepatitis C virus infection in the Democratic Republic of Congo, Public Health (2016), http://dx.doi.org/10.1016/j.puhe.2016.06.017
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Author statements Acknowledgements The authors gratefully acknowledge Dr. Keiko Katayama and Miss Mansongi Biyela Carine for their support and advice during the preparation of this article.
Ethical approval None sought.
Funding None declared.
Competing interests None declared.
references
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12. Iles JC, Abby Harrison GL, Lyons S, Djoko CF, Tamoufe U, Lebreton M, et al. Hepatitis C virus infections in the Democratic Republic of Congo exhibit a cohort effect. Infect Genet Evol 2013;19:386e94. 13. Madhava V, Burgess C, Drucker E. Epidemiology of chronic hepatitis C virus infection in sub-Saharan Africa. Lancet Infect Dis 2002;2:293e302. 14. Gower E, Estes C, Blach S, Razavi-Shearer K, Razavi H. Global epidemiology and genotype distribution of the hepatitis C virus infection. J Hepatol 2014;61:S45e57. 15. Tanaka J, Koyama T, Mizui M, Uchida S, Katayama K, Matsuo J, et al. Total numbers of undiagnosed carriers of hepatitis C and B viruses in Japan estimated by age- and area-specific prevalence on the national scale. Intervirology 2011;54:185e95. 16. Tanaka J, Kumagai J, Katayama K, Komiya Y, Mizui M, Yamanaka R, et al. Sex- and age-specific carriers of hepatitis B and C viruses in Japan estimated by the prevalence in the 3,485,648 first-time blood donors during 1995e2000. Intervirology 2004;47:32e40. 17. Moher D, Liberati A, Tetzlaff J, Altman DG, Group P. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ 2009;339:b2535. 18. Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis of Observational Studies in Epidemiology (MOOSE) group. JAMA 2000;283:2008e12. 19. Huwiler-Muntener K, Juni P, Junker C, Egger M. Quality of reporting of randomized trials as a measure of methodologic quality. JAMA 2002;287:2801e4. 20. Westermann C, Peters C, Lisiak B, Lamberti M, Nienhaus A. The prevalence of hepatitis C among healthcare workers: a systematic review and meta-analysis. Occup Environ Med 2015;72:880e8. 21. Sanderson S, Tatt ID, Higgins JP. Tools for assessing quality and susceptibility to bias in observational studies in epidemiology: a systematic review and annotated bibliography. Int J Epidemiol 2007;36:666e76. 22. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med 2002;21:1539e58. 23. Laurent C, Henzel D, Mulanga-Kabeya C, Maertens G, Larouze B, Delaporte E. Seroepidemiological survey of hepatitis C virus among commercial sex workers and pregnant women in Kinshasa, Democratic Republic of Congo. Int J Epidemiol 2001;30:872e7. 24. Kabinda JM, Michele DW, Donnen P, Miyanga SA, Van den Ende J. Factors for viral infection in blood donors of South Kivu in the Democratic Republic of Congo. Pan Afr Med J 2014;19:385. 25. Kabinda JM, Miyanga SA, Misingi P, Ramazani SY. Hepatitis B and C among volunteer non-remunerated blood donors in Eastern Democratic Republic of Congo. Trans Clin Biol 2014;21:111e5. 26. Kabinda JM, Bulabula AN, Donnen P, Fiasse R, Ende JV, Sondag-Thull D, et al. Residual risk of transmission of HIV and hepatitis B and C by blood transfusion in Bukavu in the Democratic Republic of Congo. Open J Epidemiol 2014;4:157e63. 27. Batina Agasa S, Dupont E, Kayembe T, Bolukaoto B, Kambale K, Tshomba O, et al. Hepatitis C infection markers among blood donors in Kisangani, Democratic Republic of Congo. Rev Med Gd Lacs 2012;1:212e20. 28. Kabinda JM, Akilimali TS, Miyanga SA, Donnen P, Michele DW. Hepatitis B, hepatitis C and HIV in pregnant women in the community in the Democratic Republic of Congo. World J AIDS 2015;5:124e30. 29. Liu Y, Wu F. Global burden of aflatoxin-induced hepatocellular carcinoma: a risk assessment. Environ Health Perspect 2010;118:818e24.
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30. Liu HF, Muyembe-Tamfum JJ, Dahan K, Desmyter J, Goubau P. High prevalence of GB virus C/hepatitis G virus in Kinshasa, Democratic Republic of Congo: a phylogenetic analysis. J Med Virol 2000;60:159e65. 31. Iles JC, Raghwani J, Harrison GL, Pepin J, Djoko CF, Tamoufe U, et al. Phylogeography and epidemic history of hepatitis C virus genotype 4 in Africa. Virology 2014;464e465:233e43. 32. Kabinda JM, Katchunga BP. Les hepatites virales B et C chez les porteurs du virus de l’immunodeficience humaine a Bukavu (Sud-Kivu), Republique democratique du Congo. J Afr Hepatol Gastroenterol 2010;4:203e35. 33. Kabinda JM, Akilimali TS, Miyanga SA, Donnen P, Michele DW. Hepatitis B, hepatitis C and HIV among children 6 to 59 months in the community in the Democratic Republic of Congo. Open J Pediatr 2015;5:171e8. 34. Batina Agasa S, Dupont E, Kayembe T, Molima P, Malengela R, Kabemba S, et al. Multiple transfusions for sickle cell disease in the Democratic Republic of Congo: the importance of the hepatitis C virus. Trans Clin Biol 2010;17:254e9. 35. Tibbs CJ, Palmer SJ, Coker R, Clark SK, Parsons GM, Hojvat S, et al. Prevalence of hepatitis C in tropical communities: the importance of confirmatory assays. J Med Virol 1991;34:143e7. 36. Murphy DG, Sablon E, Chamberland J, Fournier E, Dandavino R, Tremblay CL. Hepatitis C virus genotype 7, a new genotype originating from central Africa. J Clin Microbiol 2015;53:967e72. 37. Batina A, Kabemba S, Malengela R. Infectious markers among blood donors in Democratic Republic of Congo (DRC). Rev Med Brux 2007;28:145e9. 38. Wasley A, Alter MJ. Epidemiology of hepatitis C: geographic differences and temporal trends. Semin Liver Dis 2000;20:1e16. 39. Witter S. Health financing in fragile and post-conflict states: what do we know and what are the gaps? Soc Sci Med 2012;75:2370e7. 40. Muzembo BA, Mbutshu LH, Ngatu NR, Malonga KF, Eitoku M, Hirota R, et al. Workplace violence towards Congolese health care workers: a survey of 436 healthcare facilities in Katanga province, Democratic Republic of Congo. J Occup Health 2015;57:69e80.
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41. Ngatu NR, Phillips EK, Wembonyama OS, Hirota R, Kaunge NJ, Mbutshu LH, et al. Practice of universal precautions and risk of occupational blood-borne viral infection among Congolese health care workers. Am J Infect Control 2012;40. 68e70e1. 42. Mbendi Nlombi C, Longo-Mbenza B, Mbendi Nsukini S, Muyembe Tamfum JJ, Situakibanza Nanituma H, Vangu Ngoma D. Prevalence of HIV and HBs antigen in blood donors. Residual risk of contamination in blood recipients in East Kinshasa, Democratic Republic of the Congo. Med Trop 2001;61:139e42. 43. Schneider WH, Drucker E. Blood transfusions in the early years of AIDS in sub-Saharan Africa. Am J Public Health 2006;96:984e94. 44. Cuadros DF, Branscum AJ, Miller FD, Abu-Raddad LJ. Spatial epidemiology of hepatitis C virus infection in Egypt: analyses and implications. Hepatology 2014;60:1150e9. 45. Xu LZ, Larzul D, Delaporte E, Brechot C, Kremsdorf D. Hepatitis C virus genotype 4 is highly prevalent in central Africa (Gabon). J Gen Virol 1994;75:2393e8. 46. Njouom R, Pasquier C, Ayouba A, Gessain A, Froment A, Mfoupouendoun J, et al. High rate of hepatitis C virus infection and predominance of genotype 4 among elderly inhabitants of a remote village of the rain forest of South Cameroon. J Med Virol 2003;71:219e25. 47. Pepin J, Lavoie M, Pybus OG, Pouillot R, Foupouapouognigni Y, Rousset D, et al. Risk factors for hepatitis C virus transmission in colonial Cameroon. Clin Infect Dis 2010;51:768e76. 48. Pepin J, Labbe AC. Noble goals, unforeseen consequences: control of tropical diseases in colonial Central Africa and the iatrogenic transmission of blood-borne viruses. Trop Med Int Health 2008;13:744e53.
Appendix A. Supplementary data Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.puhe.2016.06.017.
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Review Paper
Systematic review and meta-analysis of hepatitis C virus infection in the Democratic Republic of Congo B.A. Muzembo, T. Akita, T. Matsuoka, J. Tanaka* Department of Epidemiology, Infectious Disease Control and Prevention, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
article info
abstract
Article history:
Objectives: Hepatitis C virus (HCV) infection is endemic in the Democratic Republic of the
Received 21 January 2016
Congo (DRC), where the prevalence of HCV antibodies (anti-HCV) is reported to range from
Received in revised form
0.2% to 13.7%. However, the reported prevalence rates have been inconsistent. Therefore, a
25 April 2016
meta-analysis of observational studies was conducted to provide updates on the preva-
Accepted 16 June 2016
lence of HCV infection in the DRC.
Available online xxx
Study design: Systematic review and meta-analysis. Methods: Medline, EMBASE and Google Scholar were searched for publications reporting on
Keywords:
HCV infection in the DRC up to autumn 2015. In addition, a manual search was undertaken
Democratic Republic of the Congo
to detect relevant papers. Studies performed in groups at low risk of HCV (blood donors and
Hepatitis C virus
pregnant women) were used for the meta-analysis. The random effects model was used to
Epidemiology
estimate the pooled prevalence of anti-HCV.
Prevalence
Results: Sixteen studies with 13,799 participants (aged 6 monthse71 years) met the inclu-
Review
sion criteria. The studies were performed in blood donors, pregnant women, military
Meta-analysis
personnel, individuals with human immunodeficiency virus, children, commercial sex workers, Congolese patients living in Canada, patients with sickle cell disease and hospitalized patients. The reviewed studies revealed the presence of anti-HCV in almost all studied age groups and did not differ between sexes. The pooled prevalence of anti-HCV was 2.9% [95% confidence interval 1.5e4.3%]. Subgroup analyses revealed that the prevalence rates of anti-HCV in blood donors and pregnant women were 2.7% (95% confidence interval: 1.1e4.4%) and 3.3% (1.4e5.1%), respectively. Conclusions: HCV infection remains an issue of public concern in the DRC, demonstrating a need for adequate hepatitis control programmes. Efforts must be made to virtually eliminate transfusion-transmitted HCV throughout the country. © 2016 Published by Elsevier Ltd on behalf of The Royal Society for Public Health.
* Corresponding author. Department of Epidemiology, Infectious Disease Control and Prevention, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan. Tel.: þ81 82 257 5160; fax: þ81 82 257 5164. E-mail address: [email protected] (J. Tanaka). http://dx.doi.org/10.1016/j.puhe.2016.06.017 0033-3506/© 2016 Published by Elsevier Ltd on behalf of The Royal Society for Public Health. Please cite this article in press as: Muzembo BA, et al., Systematic review and meta-analysis of hepatitis C virus infection in the Democratic Republic of Congo, Public Health (2016), http://dx.doi.org/10.1016/j.puhe.2016.06.017
2
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Introduction Hepatitis C virus (HCV) infection is one of the most challenging health problems to face humanity for decades, especially in developing countries where the disease remains highly endemic. HCV is considered to be endemic in the Democratic Republic of the Congo (DRC). It is estimated that HCV affects approximately 647,000 Congolese1 and 130e150 million people throughout the world.2 HCV infection is usually self-limited in the initial stages, but failure of the immune system to clear the virus leads to chronicity. Chronic hepatitis C is often clinically insidious but develops progressively and persistently over years or decades. Chronic infection with HCV is a serious public health concern as it is linked to hepatic cirrhosis and hepatocellular carcinoma3,4 and can ultimately cause premature death.5 Despite being one of the most common bloodborne infections endemic in the DRC, little attention has been paid to HCV-related health issues. Hepatitis virus screening is not yet implemented routinely, and the lack of effective care and treatment programmes make matters worse.6,7 Furthermore, the DRC is not currently listed in the HCV synthesis project.8 Some medical institutions in the DRC fail to perform HCV screening on donated blood.9 Therefore, patients undergoing blood transfusions are at high risk of HCV infection. As an example, a 2013 study in transfused children reported that the prevalence of anti-HCV was 13.5%.10 Different studies have reported inconsistent prevalence rates of HCV in the DRC. The prevalence of HCV antibodies (anti-HCV) has been estimated to vary from 0.2%11e13.7%.12 Published reviews have not focused specifically on the DRC.1,13,14 In addition, these reviews reported heterogeneous results. In 2015, a meta-analysis of two observational studies reported that the prevalence of anti-HCV was 2.1%,1 whereas this had previously been estimated to be 4.3%14 and 5.5%.13 In light of the above discrepancies in the literature, a metaanalysis of available data would be scientifically relevant. To help inform policy identifies the appropriate intervention in a given country, it is advised that the number of people with undiagnosed HCV infection in the general population should be estimated.15,16 In order to conduct similar studies in the DRC, it is crucial to estimate the magnitude of the problem. Therefore, this study was designed to summarize epidemiological studies on HCV infection in the DRC. The potential relevance of this study in epidemiology is that it provides valuable insights in planning future studies in order to help promote prevention and enhance community advocacy in the country.
Methods
epidemiology guidelines were followed.18 Medline, EMBASE and Google Scholar were searched to identify articles on HCV infection in the DRC. The search was based on literature published up to September 2015 using the following keywords: ‘hepatitis C, prevalence, Democratic Republic of Congo’, and ‘hepatitis C, incidence, Democratic Republic of Congo’. Previous reviews on the prevalence of HCV infection in the DRC were also scrutinized for comparison purposes. All studies published in English and French were included. The titles and abstracts of the retrieved studies were screened, followed by exclusion of reviews, studies not related to the DRC, and studies solely related to other types of viral hepatitis such as hepatitis B virus. Extracted information included year of publication, year of data collection, study setting and design, sample size and demographics of participants, methods used to detect anti-HCV and reported prevalence of anti-HCV (HCV infection). Genotype distribution was also recorded for applicable conditions.
Assessment of study quality The quality of reporting was assessed based on the information disclosed to the reader.19 A checklist was conceived including information related to the objective of the study, sample size (>100), year of blood/data collection, description of the study setting, inclusion of a control group, adjustment for confounding factors, and discussion on limitations. Serological and HCV confirmatory tests were also examined. A score of ‘1’ was given for each reported item. Studies were classified as high quality (score 8e10), moderate quality (score 5e7) or poor quality (score 4).20,21
Statistical analysis The prevalence of individuals with anti-HCV was considered as the effect size. Both fixed and random effects (DerSimonianeLaird) were applied to assess the suitable model type for the data using Excel (Microsoft Corp., Redmond, WA, USA). Initially, the variance and weighted means of studies were calculated using the fixed model. Next, the random effects model was fitted for pooled prevalence. The random effects model was used to report the pooled prevalence of anti-HCV and 95% confidence intervals (CI). The degree of heterogeneity across the analysed studies was quantified using Cochran's Q and I2 statistics. I2 50% was considered to indicate substantial heterogeneity.22 Metaanalysis was only performed in eight studies because combining data from low- and high-risk populations was deemed to be inappropriate. Using Excel (Microsoft Corp.), the variance of the studies and their weights in the fixed model were determined using the following formula:
Study design
vi ¼ pi 1 pi ni ; and wi ¼ 1=vi
A systematic review and meta-analysis was undertaken.
where i, ni and pi denote index, sample size and prevalence of the study respectively. Using their mean and variance:
Search strategy and selection criteria w¼ The preferred reporting items for systematic reviews and metaanalysis17 and meta-analysis of observational studies in
X . wi k; i
Please cite this article in press as: Muzembo BA, et al., Systematic review and meta-analysis of hepatitis C virus infection in the Democratic Republic of Congo, Public Health (2016), http://dx.doi.org/10.1016/j.puhe.2016.06.017
p u b l i c h e a l t h x x x ( 2 0 1 6 ) 1 e9
s2w ¼
. X w2i kw2 ðk 1Þ
Results
i
Search outcomes
statistics U and b t were calculated: U ¼ ðk 1Þ w s2w ðkwÞ b t ¼ maxf0; ðQ ðk 1ÞÞ=Ug Next, weight in the random effects model w*i and pooled b were obtained using: prevalence p w*i ¼ 1 b¼ p
2 b t þ vi
.X X w*i pi w*i i
i
Finally, the heterogeneity of the studies was evaluated using the following two formulae: Q¼
3
X 2 b and I2 ¼ 100*fQ ðk 1Þg=Q wi pi p i
The selection process is displayed in Fig. 1. The search identified 318 potentially relevant publications. After the exclusion of 197 duplicate publications, 121 titles and abstracts were screened. Of these, 15 articles were excluded because they were not pertinent to the study. Further evaluation excluded 90 publications because they were deemed to be irrelevant, leaving 16 unique publications with 13,799 individuals for inclusion in the qualitative synthesis. Twelve publications were written in English and four were written in French. Eight studies (n ¼ 8692) performed in groups at low risk for HCV (blood donors and pregnant women) were included in the quantitative synthesis.11,23e29 Three reviews estimating the prevalence of HCV infection in the DRC at global and regional levels were chosen for comparative purposes1,13,14 (Table 1).
Characteristics of studies
Statistical analyses using Excel (Microsoft Corp.) were confirmed using Comprehensive Meta-Analysis Software version 3 (Biostat Inc., Englewood, NJ, USA). Both textual narrative and synthesis methods were used to present the results.
The included studies are shown in Table 2. They were published from 1991 to 2015. Of the 16 reviewed studies, only one was a cohort study,26 and the others were cross-sectional
Fig. 1 e Publications selection process. Please cite this article in press as: Muzembo BA, et al., Systematic review and meta-analysis of hepatitis C virus infection in the Democratic Republic of Congo, Public Health (2016), http://dx.doi.org/10.1016/j.puhe.2016.06.017
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Table 1 e Reviews on the prevalence of hepatitis C virus (HCV) infection in the Democratic Republic of the Congo (DRC). Authors, year
Number of included studies
Madhava et al., 200213
3
Gower et al., 201424
N/A
Riou et al., 20151
2
Objective
Sample size
Prevalence of anti-HCV % (a: 95% CI or b: PI)
Type of review
To estimate the prevalence of HCV infection in sub-Saharan Africa To estimate the prevalence, viraemia and genotypes of HCV infection in the world To estimate the prevalence of HCV infection in African adults
2572
5.5 (4.3e6.6)a
Systematic review
N/A
4.3 (3.2e13.7)a
Systematic review
2094
2.1 (0.4e12.0)b
Systematic review and meta-analysis
N/A, not available; CI, confidence interval; PI, prediction interval.
studies. The studies were performed in selected groups of pregnant Congolese, including blood donors,11,24e27 23,28,30 military personnel,1,2,31 individuals with women, human immunodeficiency virus (HIV),32 children aged <5 years,33 transfused children,10 and patients with sickle cell disease (SCD).34 Hospitalized patients,35 commercial sex workers (CSWs)23 and Congolese patients living in Canada36 were also examined. Quality assessment revealed that 15 studies were of moderate quality, and one study was classified as high quality23 (Table S1, see online supplementary material). No published representative population-based studies on HCV in the DRC could be located. The studies were conducted in five of the former 11 provinces; most were performed in the capital city Kinshasa,10,12,23,30,31 except for four studies that were conducted in Bukavu,24e26,32 two studies in Kisangani,27,34 two studies in Maniema,28,33 one study in Kamina,11 and one study in an unknown location (rural DRC).35 Two studies assessed the prevalence and genotype diversity of viraemic HCV (RNApositive),12,31 but one of them did not provide the prevalence of anti-HCV,31 along with the study conducted in Congolese patients living in Canada.36 Most importantly, anti-HCV was detected in all studied age groups, ranging from six months to 71 years and did not differ between sexes. The screening assays used most often for detecting anti-HCV were enzyme immunoassays and immunochromatographic rapid tests (Table 2).
Prevalence of anti-HCV infection As shown in Fig. 2, the pooled prevalence of anti-HCV in eight studies was 2.9% (95% CI: 1.5e4.3%). There was significant heterogeneity across the included studies (I2 ¼ 95.6%; Cochran's Q ¼ 158.4; P < 0.001). Sensitivity analysis did not influence the robustness of the pooled estimate. Subgroup analyses revealed that the prevalence rates of anti-HCV in blood donors (age 15e65 years) and pregnant women (age 14e48 years) were 2.7% (95% CI: 1.1e4.4%) and 3.3% (95% CI: 1.4e5.1%), respectively (Figs. 3 and 4). The prevalence of antiHCV in primary studies was highest among military personnel (13.7%),12 followed by transfused children (13.5%)10 and individuals with HIV (10%),32 whereas the lowest prevalence of anti-HCV was in blood donors (0.2%).11
Hospital-based study The earliest published study of the prevalence of anti-HCV in the DRC was hospital based; this study was performed in 1991,35 which was two years after the discovery of HCV. This
study used stored sera that were initially collected to investigate the prevalence of HIV in 173 individuals admitted to hospitals in rural DRC. In this study, 6.4% of sera were positive for anti-HCV using enzyme-linked immunosorbent assay. Unfortunately, these authors did not provide information on the age and sex of the participants, and the geographical area where the study was conducted.
Studies in patients with SCD and children Three studies were identified for this group. They outlined that blood transfusion remains one of the main channels for iatrogenic spread of HCV in the DRC.10,33,34 In 2013, Katabuka et al.10 highlighted that some medical institutions in the DRC face many challenges in screening donated blood for major infectious agents including HCV. History of blood transfusion was investigated in a retrospective cross-sectional study of 127 patients with SCD (mean age 15 [standard deviation 11] years).34 The authors found that the prevalence of HCV infection was 7.9% in patients with SCD with a history of blood transfusion not screened for HCV, whereas anti-HCV could not be found in those who had not been transfused. A study that analysed data from 781 children (age 6e59 months) found that history of blood transfusion was a risk factor for HCV. Infection with HCV was more common in children with a history of blood transfusion (7%) compared with those without a history of blood transfusion (2.5%).33 The same study found a higher prevalence of anti-HCV (11%) in children whose mother had a blood transfusion during pregnancy compared with those whose mother had not had a blood transfusion during pregnancy (2.2%).33
Studies including blood donors All reviewed studies in blood donors were published within the last five years.11,24e27,32 The reported prevalence of antiHCV in Congolese blood donors is non-negligible, ranging from 0.2%11 to 4.1%.27 All of these studies found that HCV infection is common among Congolese blood donors and raise questions regarding the safety of blood transfusion in the DRC. Furthermore, these studies found that the use of paid blood donors is common in the DRC, along with family and voluntary blood donors. Transfusions with unscreened blood are sometimes performed in emergency situations using the recipients' relatives as donors.37 Among five studies that were performed in blood donors, only one reported an incidence rate of 17.1 (9.2e28.9) per 1000 person-years in a 2-year followup study carried out in 2986 volunteer blood donors from Bukavu between 2010 and 2012, with seroconversion detected
Please cite this article in press as: Muzembo BA, et al., Systematic review and meta-analysis of hepatitis C virus infection in the Democratic Republic of Congo, Public Health (2016), http://dx.doi.org/10.1016/j.puhe.2016.06.017
Setting
Study design
Sample size
Iles et al., 201312 Katabuka et al., 201310
Kinshasa Kinshasa
CS CS
299 371
Kabinda et al., 201032
Bukavu
CS
209
Batina Agasa et al., 201034
Kisangani
Retrospective CS
Laurent et al., 200123 Tibbs et al., 199135 Laurent et al., 200123 Batina Agasa et al., 201227
Kinshasa Rural DRC Kinshasa Kisangani
Kabinda et al., 201528
Population; agea (range)
Sex
Year of data/blood collection
HCV serological tests
Reported prevalence of anti-HCV (%)
M M; F
2007 2008
ELISA HCV rapid test
13.7 13.5
M; F
2008
ELISA
10
127
Military personnel; 38.7 (21e71) Transfused children 59.5 (18 months13 years)b HIV-positive patients; 36.7 ± 11.7 (N/A) Patient with SCD; 15.5 ± 11.1
M; F
2008
CS CS CS CS
1144 173 1092 1247
CSWs; 25.8 (14e55) Hospital community; N/A Pregnant women; 25.6 (14e45) Blood donors; 31.1 ± 13.1 (17e64)
F N/A F M; F
Maniema
CS
581
Pregnant women; 25 (15e48)
F
1988 1986 1990 2005 and 2006 2013
Kabinda et al., 201424 Kabinda et al., 201425 Kabinda et al., 201533
Bukavu Bukavu Maniema
CS CS CS
595 1079 781
Blood donors; N/A (18e65) Voluntary blood donors; 26 (18e60) Children; 34 (6e59 months)b
M; F M; F M; F
2014 2010 2013
Kabinda et al., 201426 Liu et al., 200030 Nzaji and Ilunga, 201311
Bukavu Kinshasa Kamina
Cohort study CS CS
2986 97 1015
Voluntary blood donors; 23 (N/A) Pregnant women; N/A Blood donors; 28 ± 6 (15e56)
M; F F M; F
2010 1996 2008
Murphy et al., 201536 Iles et al., 201431
Canada Kinshasa
N/A CS
4 1999
N/A Military personnel; 44 (22e27)
N/A M
2001e2006 2007
Immunochromatographic test and ELISA EIA ELISA EIA Immunochromatographic test Immunochromatographic test HCV rapid test HCV rapid test Immunochromatographic test HCV rapid test and ELISA ELISA Immunochromatographic test ELISA/PCR N/A
rapid
7.9
rapid
6.6 6.4 4.3 4.1
rapid
4.1
rapid
3.9 3.8 2.8
rapid
2.1 1 0.2 N/A N/A
CS, cross-sectional; HCV, hepatitis C virus; SCD, sickle cell disease; CSWs, commercial sex workers; HIV, human immunodeficiency virus; EIA, enzyme immunoassay; ELISA, enzyme-linked immunosorbent assay; PCR, polymerase chain reaction; N/A, not available. a Age (mean/median) in years. b Age in months.
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5
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Table 2 e General characteristics of the studies included in this review. Authors, year
6
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Prevalence (%)
Prevalence (%)
Fig. 2 e Forest plot of studies on the prevalence of hepatitis C virus in the Democratic Republic of the Congo. Pooled prevalence of hepatitis C virus antibodies was estimated using the random effects model (I2 ¼ 95.6%; Cochran's Q ¼ 158.4; P < 0.001).
Prevalence (%)
Fig. 3 e Forest plot of studies on the prevalence of hepatitis C virus in blood donors in the Democratic Republic of the Congo. The random effects model was used to estimate the pooled prevalence of hepatitis C virus antibodies (I2 ¼ 96.6%; Cochran's Q ¼ 116.9; P < 0.001).
Fig. 4 e Forest plot of studies on the prevalence of hepatitis C virus in pregnant women in the Democratic Republic of the Congo. The random effects model was used to estimate the pooled prevalence of hepatitis C virus antibodies (I2 ¼ 75.9%; Cochran's Q ¼ 8.292; P < 0.001).
conducted in 1144 CSWs and 1092 pregnant women using blood primarily collected to screen for HIV and sexually transmitted infections (STIs).23 The prevalence of anti-HCV was not significantly different between CSWs (6.6%) and pregnant women (4.3%). The prevalence of HCV in CSWs with a history of blood transfusion was 13.1%, compared with 5.5% in those without a history of blood transfusion. In unadjusted analyses, the prevalence of HCV infection was higher (9.9%) in CSWs who had more than five years of prostitution tenure compared with those who had less (5.4%). The authors highlighted the possible transmission of HCV by unsafe injection practices when treating STIs in CSWs.23 In studies in pregnant women,23,28 risk factors associated with HCV could not be detected among the studied parameters including age, marital status and HIV status. Of the three studies in pregnant women,23,28,30 only one study assessed the history of blood transfusion, without detecting a higher risk of HCV infection in those with a history of blood transfusion.28 However, the study found that 6.5% of the participants had scarification or tattoos, representing risk factors for HCV transmission.
Studies on genotype distribution in 12 donors.26 The authors estimated that the residual risk of HCV transmission from the window was 3.1 per 1000 donations, indicating that blood transfusion may have the potential to disseminate HCV in the DRC. In another study conducted among volunteer blood donors in Bukavu, Kabinda et al.25 reported a higher prevalence of HCV in rural participants (9.2%) compared with those living in urban areas (3.3%). The authors highlighted important issues about unequal access to treatment for blood donors diagnosed with an HCVrelated liver disease; less-privileged individuals with HCVrelated liver disease have limited access to medical treatment.
Studies in CSWs and pregnant women A pioneering study investigating the relationship between sexual behaviour and the prevalence of HCV infection was
Few attempts have been made to address the genetic diversity of HCV in the DRC. In total, HCV genotypes in Congolese were reported by three recently published studies in 2013e2015.12,31,36 Two studies12,31 by the same authors identified genotype 4, whereas another study36 reported genotype 7. Genotype 4 is likely to predominate in the DRC as well as genotype 7. In the study of HCV infection among soldiers in Kinshasa, Iles et al.12 identified genotype 4 in 11 RNA-positive samples (3.7%; 11/299). The authors reported that genotype 4 split into subtypes 4k and 4c was only found in military personnel born before 1956, whereas subtype 4r was detected in those born after 1956. Genotype 4 was also reported with genetic diversity of HCV, including subtypes 4c, 4h, 4k, 4r and 4drc in 60 RNA-positive samples (3%; 60/1999) from military personnel.31 However, the study by Iles et al.31 was unable to detect genotype 7 despite using the same procedures as those previously used to identify genotype 7 in Congolese.36
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Studies on age and HCV Except for five studies12,23,25,27,31 which reported that HCV infection might be related to age in the DRC, HCV infection could not be explained by age in the other included studies. The studies by Iles et al.12,31 found that both anti-HCV and viral RNA-positive rates were positively correlated with age. Older men (aged 57 years) were more likely to be diagnosed positive for HCV-RNA compared with younger men (age <57 years).12,31 In three other studies, individuals in their 30s were more likely to be diagnosed positive for anti-HCV,23,25,27 whereas HCV infection was found in all studied age groups.
Discussion The overall prevalence of anti-HCV in the reviewed studies was estimated to be 2.9% (95% CI: 1.5e4.3%). This prevalence confirms that HCV infection remains a significant public health problem in the DRC. The results suggest the need for a strong commitment from Congolese policy makers, including adequate hepatitis control programmes. It is possible that the prevalence reported in this study could have been underestimated as studies included in the meta-analysis were performed in low-risk groups (blood donors and pregnant women). Most studies included in the meta-analysis were of moderate quality and used convenient sampling methods. Therefore, it is difficult to extrapolate the estimate to the general population. Nevertheless, the estimate from this study might provide a picture of the prevalence of anti-HCV in the DRC. Although five studies reported a possible correlation between HCV infection and age, when reviewed systematically, the evidence indicates that HCV infection affects individual of all ages in the DRC. These results suggest a possible ongoing risk of HCV transmission in the DRC. The above explanation stems from transmission patterns of HCV, where infection transmitted through unsafe injections and non-sterile equipment is likely to be found in all the age groups.38 The use of non-sterile equipment and injection therapy are frequent in the DRC. Furthermore, traditional practices performed with non-sterile equipment and injections from unqualified medical providers are common in the country. Circumcision in males, ear piercing in females, home birth, scarification and tattooing are likely to be performed with unsterile equipment in Congolese rural settings and poor communities, thus contributing to HCV transmission. This may be a normal occurrence in the DRC because it is still a fragile and country after a lengthy period of civil unrest and armed struggle, where the health care system is facing challenges.39e41 This is consistent with a previous study which demonstrated that HCV infection benefits from social upheaval to spread within a country.3 The highest prevalence of HCV infection was reported in a study in Kinshasa among military personnel (13.7%).12 This may also be the consequence of various factors including the war in the DRC, where bloodborne viruses were likely to take advantage of unsafe medical practices and limited access to appropriate medical care, especially in the battlefield.
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In the DRC, blood transfusions remain among the primary routes of HCV transmission.27 Notably, transfusion of unsafe blood was underscored by the reviewed studies to contribute to the transmission of bloodborne pathogens, including HCV infection.10,23,33,34 Screened blood for transfusion-transmitted infections with rapid tests and unscreened transfusion blood might sustain this chain of transmission. Donated blood is not screened routinely for transfusion-transmitted infections, including HCV.10,42,43 The use of unscreened blood may have contributed to the iatrogenic transmission of HCV throughout the country. The estimated prevalence (2.9%) of anti-HCV found in this study is similar to that reported by Riou et al., in 2015 (2.1%).1 However, the present study included eight studies with 8692 subjects in the meta-analysis, whereas the study by Riou et al. was limited to two studies with 2094 subjects. Compared with the estimated prevalence of anti-HCV in Cameroon (11.6%)14 and that reported for Egypt (14.7%),14,44 the estimated prevalence of anti-HCV is lower in the DRC. Worldwide, Egypt has the highest prevalence of anti-HCV due to, in part, historical unsafe parenteral antischistosomiasis therapy, where syringes were re-used without sterilization in the 20th century.44 Studies that reported genotype 4 in the DRC are in line with those conducted in the neighbouring countries, showing a predominance of HCV genotype 4.45,46 The presence of HCV genotype 4 across countries in central Africa is attributable, in part, to past exposure to unsafe medical interventions including mass intravenous therapy against yaws, syphilis, malaria, leishmaniasis, transfusion and circumcision initiated by the colonial authorities.1,43,47,48 This study has inevitable limitations. First, the pooled prevalence of HCV infection may be questionable because of the non-inclusion of unpublished data and the absence of population-based studies. It is worth noting that unpublished data have the potential to interfere with pooled prevalence regarding overestimation or underestimation. The paucity of published data, however, would not substantially alter the magnitude of the problem of HCV-related liver disease in the DRC because of the slow improvement in health care settings in the DRC.40,41 Second, heterogeneity across studies included in the pooled analysis was high, this being a common issue when performing a meta-analysis of studies addressing prevalence in selected populations.22 However, the above concern was tempered by the sample size of 8692 subjects included in the random effects model.
Conclusion This review provides compelling evidence that HCV infection remains an issue of public concern in the DRC. Furthermore, results from the reviewed studies highlight the need for adequate hepatitis control programmes and efforts to reduce HCV infection in blood donors. Controlling HCV infection in the current Congolese economic context is complex. Nevertheless, compiling references of publications related to HCV infection in the DRC gives an overview of the magnitude of the problem in the country that may be relevant when planning future studies.
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Author statements Acknowledgements The authors gratefully acknowledge Dr. Keiko Katayama and Miss Mansongi Biyela Carine for their support and advice during the preparation of this article.
Ethical approval None sought.
Funding None declared.
Competing interests None declared.
references
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Appendix A. Supplementary data Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.puhe.2016.06.017.
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