1. INTRODUCTION AIM AND OBJECTIVES RESULTS MATERIALS METHODS
Tracing and Modelling Hepatitis C virus Epidemic in Libyan Health Care Settings A H. El-Bouzedi 1., J. Ameen, M 2., M.Griffith3., M.A. Daw4. Department of Mathematics Statistics Division Faculty of Advanced Technology University of Glamorgan1,2,3 and Department of Medical Microbiology Faculty of Medicine Tripoli University-Libya 4.
INTRODUCTION
AIM AND OBJECTIVES
RESULTS
The epidemic of hepatitis C virus (HCV), discovered in The World Health Organization has declared hepatitis C is major public health issue worldwide, with approximately 3% of the world’s population infected with hepatitis C virus (HCV). There are more than 170 million chronic carriers at risk of developing liver cirrhosis and hepatocellular carcinoma (HCC) .
A national epidemiological study were conducted in Libya estimated that 1.19% of Libyan general population was HCV seropositive in , and so approximately 70,000 persons were infected with hepatitis, which has population of 6,
To obtain projection of the long term squeal of HCV infections in Libya, including cirrhosis, liver failure and hepatocellular carcinoma (HCC), and HCV related mortality, this required know of the disease stage for this currently infected population and /or time of infection, as well as the progression of HCV disease stages. These parameters are unknown and need to be estimate.
To overcome these difficulties, mathematical modelling has been employed in France and elsewhere by Deuffic et al, (1999, 2006). This model was adopted in this research to reconstruct the past infection curve and to project HCV related mortality in Libya until Hence, Delphi technique was involved in the process of estimating only the parameters of the natural history.
The overall aim of this thesis is to investigate the epidemiology and the natural history of the hepatitis C virus in Libya, then to model the past incidence of HCV and project the furtherance of deaths that associated with HCV. This is achieved through the following objectives .
The objectives of the research are outlined below:
1. Highlights on the Geographical location of Libya, Historical setting, Health, Environmental and Geo-medical research that has taken place on the subject since the recognition of the infectious diseases start in Libya.
2. Explore the various different aspects of the disease, its natural history and epidemiology. Consider the benefits of modelling the natural history of hepatitis C and for another infectious disease such as HIV/AIDS.
3. Discus the sources of the data collection and organized to, use within more robust model of hepatitis C virus. Apply the robust model to Libya data and investigate differences in the model output and compared to France and Egypt.
4. Summarise and analyse the data collected to determine the age distributions at the time of HCV infections and investigate the associated factors that influencing hepatitis C infection to find out the common risk factors of HCV transmission in Libya. Also, estimating the proportion of the consequences of the blood scarring reduction of HCV transfusion associated infections after 1998.
5. Explore the geographical distribution of HCV-genotypes in Libya and model, the four genotypes of HCV to determine the significant factors that influencing the infection of HCV-genotypes. Compare the prevalence of different HCV genotypes from different parts of Libya with that found in the rest of the world especially the neighbouring countries.
6. Demonstrate the use of the model proposed by Deuffic et al., (1999, 2006). The model investigates the number of hepatocellular carcinoma deaths and uses the back calculation method to identify unknown model parameters, the most important of which are the age and sex specific transition rates from chronic hepatitis to cirrhosis.
7. In the absence of relevant information about the parameters values of HCV disease, progressions, Delphi technique were employed involving medical specialists in liver diseases to estimate the parameters of HCV disease progression, which will be used in the modelling process.
8. Make recommendations as to how the modelling of HCV can proceed, identifying data that need to be collected. Consider how the results of the modelling can be used within the public health sector
The age of all 3227 subjects at time of infections ranged between 1 and 79 years with an average of ± years for both sexes and divided into two groups of sex and organized in 10-year of age class as shown in Figure 1.1.
Figure: 1.1 Percentage of infections in males, to females and total
Figure 1.1 shows the infections of HCV are higher in males than females also, male to female percentage was highest in the age group years, were among a total of 1181 (36.6%), 882 were males and 299 females (M: F=2. 9:1.0). The next, frequent age group was in persons aged years, 705 (22%) and within these 514 were males and 191 were females (M: F =2. 7:1.0). The risk factors were identified in only 2046 patients (63%); were 1473 (%70) males and 623 (30%) females. The relative contribution to the risks associated with hepatitis C virus (HCV) infection, collected from the patient’s hospital record, is classification into 10 categories as shown in table 1.1
MATERIALS
Epidemiological data were collected from the patients hospitals record for 3227 subjects confirmed with chronic hepatitis C with known sources of infection as well as the HCV-Genotypes and, several other variables were obtained. Overall, 2204 (68%) were male and 1023 (32%) were female. Also, the HCC mortality data from were collected from the patients deaths files and the death rates of the Libyan general population from were estimated.
Table: 1.1 show the percentage of HCV infections with the risk exposure.
METHODS
Risks exposure (categories)
Male %
Female
Total
Blood transfusion(B.T)
6.32%
4.90%
11.22%
Blood transfusion + operation
3.90%
4.34%
8.24%
Dental procedures
6.66%
2.36%
9.02%
Caesarean
0.00%
0.87%
IDUs
12.30%
0.12%
12.43%
Haemodialysis
1.58%
0.65%
2.23%
Intrafamilial
1.02%
0.99%
2.01%
Surgery
3.07%
1.92%
4.99%
Others
7.16%
2.26%
9.42%
Unknown
26.28%
13.29%
39.57%
68.30%
31.70%
100.00%
The epidemiology of HCV infection was investigated in Libya where several methods are involved and employed, descriptive statistics, used to investigating the associated factors that influencing HCV to find the common risk factors of HCV transmission in Libya. Binary logistic regression analysis were performed for each HCV genotype using a 2 stage modelling, to identify the comment frequent HCV-genotypes and, determines the significant factors that influencing the infection of HCV-genotypes. Odd ratio and relative risk used to estimate the proportion of HCV infected cases that can prevented by eliminating the risk exposures identified to be of importance in this case control study is explored here with the information extracted from the national survey of the national exposure to these factors and the estimated relative risk adjusted for age, gender and for all risk factors. Also, Two rounds Delphi technique was employed to estimate the four unknown parameters of the annual probability transition of HCV disease progression. Applied and modified the model proposed by Deuffic et al (1999 and 2006) to the situation of Libya which based on the backcalculation method (the infection curve) in combination with Markov model, to reconstruct the past history of HCV infection in accordance with what is currently known about the natural history of the disease and with the available Libya epidemiological data, and to project the number of HCV-related HCC deaths in the future
It is clear from the information reported in table 1.1 the intravenous drug use(IDUs) is high (12.43% of all subjects) while it was very rarely reported in females (0.12%). This is probably an underestimate due to the social stigma associated with drug use among females.

2. Age at acquisition (years)
The following Figure 1.2 represents the percentage of males and female subjects infected with HCV in the five different residential locations (regions) as classified in eight regions.
In general, the present study noted that exposure to risk factors had no significant relationship to the HCV-genotype distribution, except for Caesarean section, with a predominance of HCV-genotype 4 representing more than 50 % of the cases compared to the overall average of 31.5%. Intravenous drug users (IDUs) had a significant relation to HCV-genotype distribution with a predominance of genotype 1 (49.2%), compared to an overall average of 37.4%, as well as genotype 3 (32.6%), compared to an overall average of 15.9%.
It appears that the differential prevalence of HCV-genotypes has links to the geographic areas of origin. In Libya the results showed that HCV-genotype1 is more common in the Tripoli region (40.5%) than other areas. HCV-genotype 2 was common in East regions (23.6%). The present study recorded both HCV-genotypes 3 and 4 were more common in the South regions of Libya with percentages of 22.5% and 49.3%, respectively. HCV-genotype 4 was also reported in east and west Libya. HCV-genotypes 5 and 6 were not recorded in any patient included in this study
Modelling the natural history of HCV infectious diseases. It is clear that the end-stage of HCV is hepatocellular carcinoma (HCC). Practically modelling justification the data were classified in proportion into two types of gender and risks and the age of infection distribution draws information gathered from patient’s hospitals record to produce the percentage of males and females infected via transfusion or other routes. The classified data shown in the Table 1.2.
A significant part of the modelling which has been undertaken in this area has been centred on the Back-calculation technique.
Figure 1.2: Percentage of infected subjects with HCV in different regions.
RESULTS
The results in Figure 1.2 shows that hepatitis C virus is reported in Tripoli more than any other region were 1675 (51%) patients confirmed with HCV, among them 1274 (39.5%) males and 401 (12.4%) were females. Followed by 343 (10.6%) infected subjects from the East, 212 (6.6%) patients males and 131 (4.1) were females. Next 309 (9.6%) patients from the West between them 162 (5%) males and 147 (4.6) infected females. Then patients recorded HCV from the South were 150 (4.6) were surrounded by 90 (2.8%) males and 60 (1.9%) females.
The major factors that proved to be significant for HCV infection among males were Intravenous drug use (IDUs) (18.0% vs 0.2%, OR = 83.5 (95% CI ) followed by Blood transfusion (15.4% vs 8.7% OR=1.9 (95%CI ) , haemodialysis (2.3% vs 0.1% OR= 24.9 (95% CI 9-69) and Multiple sex (1.9% vs 0.7% OR=2.3 (95% CI ). Surgery was not a risk factor for HCV infection among males and even exposure among the cases to surgery was statistically lower than among controls (14.6% vs 18.6%)
Among females, the major factors that proved to be significant for HCV infection were Blood transfusion (32.2% vs 6.7% OR=6. 6 (95%CI ) followed by haemodialysis (2.1% vs 0.3% OR= 7.2 (95% CI ) and Intravenous drug use (IDUs) (0.40% vs 0.1%, OR = 8.9 (95% CI ). Similar to males, surgery was not a risk factor for HCV infection among females (P: value 0.122). Although, the proportions that were of cases reduced of HCV transmission after 1998 due to the screening of blood transfusion introduction were found to be 12%.
In addition, this study has not found dental procedures or tattooing to be associated with transmission of HCV; however body piercing was a statistically significant risk factor for HCV. On the basis of the findings of this study, a consistently higher prevalence of HCV infection in older age groups (35 years and over) was noted. Since the introduction of blood and blood product screening the spread of HCV is mainly facilitated by needle sharing. The most common form of this is through intravenous drug users (IDUs), which now makes up over 80% of all new Hepatitis C cases.
Out of the 3227 subjects confirmed with HVC, 1501 patients (46%) were investigated for the HCV-genotypes results available in their hospital records. The most common HCV-genotype in Libyan patients was genotype 1 with 37.4%, followed by genotype 4 (31.6%), then genotype 3 (15.9%) and lastly genotype 2 (15.1%) of all subjects.
As for gender distribution of HCV-genotypes in this study, it was clear that genotype1 was higher in males (38.4%) than females (35.7%). Genotype 3 was also higher in males than females (20.8% versus 6.9%); whereas Genotype 2 was found to be lower in males than females (13.6% versus 17.7%).
Distribution of HCV-genotype by age confirmed a high predominance of genotype1 in children and young patients (88% at age 0-9 and 78 % age group years). HCV- genotype 2 was noticeably distributed as twice to three times as overall average proportional distribution among patients above fifty years of age. HCV-genotype 3 was significantly higher in patients aged years; while HCV-genotype 4 was evenly distributed in almost all age groups, except in those below 20 years age group where it was lower than average.
Table:1.2 Source of infection as been found in the hospital patient’s record.
Age at acquisition (years)
Males
Females
Transfusion
(n=286)
Other Source
(n=1918)
Total
(n=2204)
(n=274)
(n=749)
(n=1023)
0-9
3.1
2.0
2.1
0.4
2.4
1.9
10-19
8.0
2.8
3.4
3.6
4.3
4.1
20-29
17.8
24.1
23.3
13.1
20.7
18.7
30-39
36.0
40.6
40.0
30.7
28.7
29.2
40-49
14.3
15.7
15.6
26.3
50-59
9.4
7.0
7.4
16.4
13.8
14.5
60-69
7.3
5.2
5.4
8.5
8.2
70-79
3.8
2.6
2.7
2.2
2.9
100.0%
The Back Calculation technique reconstructed the natural history of HCV infection in Libya up to Also the model allows tracing the incidence of HCV epidemic in Libya back to 1960`s. The annual incidences of the HCV past infection curve were predicted up to 2005 and the best estimate, shows in Figure 1.3
Figure 1.3.: Infection curve obtained assuming a logistic function.

3. The incidence in Figure 1
The incidence in Figure 1.3 showed a consistent increasing rate of HCV infections to a peak of 1597 new seroconversions in 1997 followed by 12% a decline in 1998 coincident with the decline in transfusion, when blood and blood product screening was introduced in Libya. HCV incidence was estimated to be 1700 (between 1400 and 2000) in The year 1976 was considered as a mid-epidemic year for the period between 1973 and 1979 with CI 95%, and a slop at 2.56 (CI 95%: 0.92 – 4.43).
The stages of the disease from infected through cirrhosis and on to HCC can be reasonably well characterized, which means that the population can be compartmentalized with probabilities of moving from state to state. These four figures of the disease progression were obtained by the consensus of medical experts in two rounds of Delphi technique. The figures were 90% Proportion of new infections that progress to chronicity 1 year after infection, 3% Transition probability (per year) from cirrhosis to death from liver failure, 2% Transition probability (per year) from cirrhosis to HCC and 45% transition probability (per year) from HCC to death from HCC.
As a consequence the model projected the number of HCC through the years 2035, in the absence of effective treatment (see Figure 1.4), foresees that the incidence of HCC deaths related to HCV would increase annually until It is valued for the incidence of HCC deaths related HCV is 175 men and 66 women in 2035, compared with the incidence observed in 2005 of 120 men and 28 women. On the other hand, the model predicts the number of HCV-related HCC deaths per year would continue to rise till 2035, by approximately 160% in men and 200% in women, in the absence of effective treatment. In contrast, males (of all ages) have higher risk 2-7 times than women. Moreover, Death of patient due to HCC which could be attributed to HCV in Libya was found 34%. The median time from infection with HCV to the onset of cirrhosis and HCC, then to death due to HCC, information was estimated and found to be that infected male patient at age 30 with HCV found to be followed by cirrhosis within 30 years and another six years to be HCC, and another four years to death due to HCC, with a total of 40 years from infection with HCV till death.
The results indicated that the most common HCV-genotypes distributed in Libya was, genotype 1. This was followed by genotype 4 and Genotype 3 was the third most common frequent genotype. While, genotype 2 found to be the less common prevalent in the Libyan and confirmed that the absence of genotype 5 and genotype 6 in Libyan patients.. Genotype1 was the highest percentage in males than females. Whilst, genotype 2 was lower in percentage in males than females. Genotype 3 shows a higher percentage in males than females.
The HCV-genotype distribution by age certainly confirmed a high predominance of genotype 1 in the age groups below 20 years. The distribution of genotype 2 was noticeable, twice, or three times the overall average proportion among those above fifty years of age. Genotype 3 was significantly higher among those aged years. Genotype 4 was evenly distributed in all age groups, except in the below 20 years age group where it was lower than average.
The study illustrates that exposure to risk factors had no significant relationship to the HCV-genotype distribution, except for Caesarean section, with a predominance of genotype 4. Also, intravenous drug users (IDUs) had a significant relation to genotype distribution with predominance of genotype 1 as well as genotype 3.
The differential prevalence of HCV genotypes appears to be linked to the geographic areas of origin. HCV genotypes have been distributed around Libya and determined in the present study the results show genotype 1 is common in the Tripoli regions. Moreover, Genotype 2 was common in the East and genotype 3 was common in the South. The source of these types of HCV-genotype may be due to the presence of foreigners living illegally in all parts of Libya, as well as the uncontrolled borders from the four directions, and also from Libyan people who travel to other countries. Finally, the study confirmed that the prevalence of genotype 4 appears to be the most common type frequent in the South of Libya. This is very expected because; the South of Libya is bordered with other African countries. Social relationships are widely present between the south of Libya and its neighbouring countries. The results showed that genotype 4 was the most prevalent genotype in the eastern region of Libya.
The Delphi method is an iterative process to collect and distill the anonymous judgments of experts using a series of data collection and analysis techniques interspersed with feedback. I share my experience in using Delphi technique and that my personal experience with the technique will both stimulate ideas and provide a starting point for the research on natural history of HCV disease progression, to gather consensus of opinion from a selected panel around the transition probability (per year) from hepatitis C infection to chronic hepatitis, from cirrhosis to death from liver failure, from cirrhosis to HCC and from HCC to death from HCC for prototyping decisions. For this research Self-administering questionnaire after piloted by six professors specialized in Gastroenterology was distributed to 15 expert panels to give an opinion on HCV disease progression. Each of them was willing to respond and the questionnaire contained four questions related to the four parameters of the HCV disease stages. We were able to collect 100% response in a group of fifteen medical experts involve in Delphi study. Two rounds of Delphi method were conducted asked each of experts to describe the transition probability per year for the four parameters. The consensuses were 100% obtained in the second round with a 100% response rate.
The natural history model can be used as a short term predictor for hepatitis C (HCV) related hepatocellular carcinoma (HCC) deaths in Libya. Various aspects of the model have been investigated and been shown to be of great use as an initial indication of the spread of hepatitis C.
Modelling has enabled us to trace the HCV epidemic in Libya back to 1960’. The model predicts that HCC mortality increase by the year 2035 in the absence effective treatment. The importance of age and sex factor in the progression of chronic hepatitis was quantitatively assessed. For example, the values that were generated by the objective function model were of a smooth shape with small confidence interval suggesting that realistic age and sex specific transition parameters had been estimated. It also showed that there were additional pieces of information that could be elicited from the model such as the time to onset of the various stages of the disease. Theses time have corroborated other estimates of progression and therefore provide patterns validating the parameter values defining the model. Because the risk of cirrhosis increases dramatically with age, treatment should be proposed as soon as possible, even for young patients, when fibrosis begins. Finally, we recommend the Libyan health authority to improve the health services and the patient filing system, to do so they should learn from the other countries such as the United Kingdom.
Figure: 1.4 Best fit between observed and estimated deaths of HCC attributable to HCV and prediction until 2035 for patients infected before This graph shows the infection for all ages.
Conclusion
Modelling the natural history of HCV in Libya and was not as easy as modeling other infectious diseases. At this time, it could be taken as similar to that of HIV
This study considered as the first trial In Libya to determine age and sex distribution of 3227 subjects confirmed with HVC.
The factors that attested to be significant influencing the HCV infection among males was the intravenous drug use, followed by Blood transfusion, haemodialysis and multiple sex. Infection through to surgery statistically was lower and not a risk factor for HCV infection among males. While, the factors that proved to be significant for HCV infection among females was Blood transfusion, followed by haemodialysis and Intravenous drug use (IDUs). Similar to males, surgery was not a risk factor for HCV infection among females and no cases were reported to have multiple sex among the female cases, and it could be of the culture and the attitude of the Libyan people as the evaluated as stigma.
The study based on the finding that the HCV infection in Libya is consistently, higher prevalence in older age groups, The Centres for Disease Control and Prevention (CDC) should put into practice a targeted risk-based HCV screening program using the screening guidelines for persons who are 35 years of age or older for early detection and management. Also, this study supported that, the risk of HCV infection is low in Libya, but the future health care burden of prior HCV infections could be substantial in the general community.
Department of Mathematics Statistics Division University of Glamorgan - ; Department of Microbiology Tripoli University -