As the majority of the epidemiological surveys of the surveyed populations were conducted in the 1990s, the projection of the meta-prevalences on the resident population on January 1, 2014 may overestimate the phenomenon, especially in the case of the elderly population. Although the risk of new infections among the elderly is considered to be minimal, we can presume that the endemic diffusion has been reduced due to the new specific treatments that have been introduced over the years and with regard to the specific mortality for decompensated cirrhosis and liver cancer. Therefore, we have proceeded as follows:
- We have considered the basic population as the resident population on January 1, 1995 by sex, age, and region of residence (we have assumed that the proportion of adult/elderly subjects who were infected as a result of transfusions and dialysis since 1995 is negligible, and therefore, significantly stable with regard to the endemic diffusion among the adult population).
- We projected the model to 10 years (2005) based on the following assumptions:
- Likelihood of transition, per the model (Table 2).
- Likelihood of specific death, 5.3% (Table 2).
- Likelihood of transplant has not been considered.
- Percentage of emergence (our assessment).
Percentage of treated (subjects); only F4 and F4s 100% of the emerged (subjects) (our assessment).
SVR% of 30.7%: simple average of the response rate to the introduction of pegylated interferon (PegIFN) (Adapted from the US Food and Drug Administration, Antiviral Drugs Advisory Committee Meeting, April 27–28, 2011, Silver Spring, MD).
Spontaneous remission rate of 25%.
We calculated the specific outgoing weights (as a result of death, healing by remission, and SVR%) for each age between 28 and 90 years at 2005 (national weights).
The model was projected from 2005 to 2014 based on the same assumptions, with the exception of SVR% assumed equal to 62.5%: average response between pegylated interferon/ribavirin (PegIFN/RBV) and PegIFN/RBV/direct-acting antiviral drugs.
We calculated the specific outgoing weights for each age between 38 and 90 years at 2014 (national weights).
- F0 = 0%
- F1 = 0%
- F2 = 20%
- F3 = 40%
- F4 = 40%
- F4s = 40%
Regarding the estimate of emerged patients, that is, all subjects known to and treated by the National Health Service (NHS), we have assumed the following emergence rates per stage, with respect to the model at 2014 (our assessment):
- F0 = 10%
- F1 = 15%
- F2 = 20%
- F3 = 50%
- F4 = 60%
- F4s = 80%
The implemented model enables a punctual estimate per age of the surveyed parameters (HCV+, HCV RNA+, genotype of total and emerged population); in the analysis of the results, the data have been grouped into 3 age groups (youths: 18–34, adults: 35–69, and elderly: 70+).
The distribution by genotype has been estimated according to a 2-stage procedure based on the 9 population studies that are included in the estimate of the HCV meta-prevalences, which are employed to identify the geographical trends (northern Italy vs central–southern Italy). We applied Italian studies of hospital and outpatient populations to estimate the genotype distribution.[30–33]
Based on the studies that are deemed eligible for the purposes of the survey (refer to Table 3 and the supporting materials for details) to determine the relevant meta-analysis of prevalence and considering that the analyzed studies predominantly date to the period from 1991 to 2000 (some were previous studies were conducted using frozen serum), these estimates can be considered to be valid for the mid-1990s.
In 1995, 3166,393 HCV+ subjects (95% credible interval [CrI]: 2527,484–3887,328)—1428,674 males and 1737,719 females—were estimated in Italy, with a prevalence of 5.57% (95% CrI: 4.45%–6.84%); this prevalence is considerably to be higher in southern Italy and the islands (8.1%) than in central–northern Italy (4.1%). In the same year, 2284,286 million HCV RNA+ subjects (95% CrI: 1829,944–2807,443)—1030,175 million men and 1254,110 million women—were estimated, with a prevalence of 4.02% (95% CrI: 3.22%–4.94%); this prevalence is considerably higher in southern Italy and the islands (5.7%) than in central–northern Italy (3.1%).
Due to the lack of recent populations, a Markovian model has been employed, as described in Section 2. We have estimated the effect of the introduction of infection contrast policies in the 1990s and the gradual appearance of increasingly effective treatments.
The endemic load of HCV in the Italian population considerably decreased in 2014: the number of HCV+ subjects decreased to 1569,215 (95% CrI: 1202,630–2021,261) with a 2.58% prevalence (95% CrI: 1.98%–3.33%). The contraction of RNA+ subjects over the years is significant: it decreased to 828,884 (95% CrI: 615,892–1081,123) with a 1.36% prevalence (95% CrI: 1.01%–1.78%) (refer to Table 4).
Table 4 also enables an analysis of the different impacts of the effectiveness of the treatments before and after 2005.
The total distribution by sex remains approximately constant over time, with a higher female component (54.4% of cases). If we consider the population aged below 35 years, a prevalence in the specific population of 0.9% is observed for both sexes. In contrast from the 1990s to the principal methods of infection of the epidemic, a significant alteration in composition by age of the infected population is evident: 70+ year old HCV+ subjects increased from 28.1% in 1995 to 45% in 2014. The median age in 1995 was 61 years, which increased to 68 years in 2014. Therefore, the distribution of HCV+ subjects by age group highlights a large imbalance toward the older groups: only 6.4% of positive subjects are aged between 18 and 34 years, with a prevalence of 0.9%; 48.3% of positive subjects are aged between 35 and 69 years, with a prevalence of 2.6%; and 45.3% of positive subjects are aged over 70 years, with a specific prevalence of 7.5%.
Therefore, the peak of the epidemic with the greater number of serious consequences has been overcome. By 2014, the cases of cirrhosis and its complications were less than approximately 56% compared with the case studies in 1995. The dynamics of the phenomenon generated the assumption that the peak of the epidemic was attained prior to 2005 and prior to the estimate obtained by Deuffic-Burban, which estimated that the peak of the epidemic in Italy would occur in 2008.
The evident predominance of adult and elderly subjects, with an old or very old infection, inevitably entails a significant number of HCV RNA+ subjects in the advanced stages of the illness. According to our estimates, approximately 400,000 subjects have cirrhosis, decompensated cirrhosis, and hepatocarcinoma, with an average age of 69.5 years and a median age of 70 years.
The distribution by age and Metavir score F4 and F4s (F4s also includes the subjects who are affected by hepatocarcinoma) is shown in Fig. 4.
A total of 52.9% (95% CrI: 48.6%–56.7%) of the subjects belong to genotype 1a1b; 27.7% (95% CrI: 23.9%–31.5%) of the subjects belong to genotype 2a2b; 11.8% (95% CrI: 9.0%–14.9%) of the subjects belong to genotype 3, and 7.7% (95% CrI: 1.4%–14.0%) of the subjects belong to genotype 4 (refer to Table 5).
In the case of formulated emersion, the NHS should be aware and engaged in the treatment of 385,553 (95% CrI: 275,351–520,819) subjects, which accounts for 47% of the HCV RNA+ subjects. The assumed cases of emersion are strictly related to the gravity of the illness and inevitably entail an even greater percentage of elderly subjects. Among the emerged subjects, the 70+-year-olds account for 47.32% (95% CrI: 38.56%–54.71%) compared with only 2.78% (95% CrI: 1.60%–4.53%) of subjects aged below 34 years.
In methodological terms, the estimated prevalence in Italy poses a number of challenges, which primarily derive from changes in the etiology of the infection over time.
Therefore, the model that we have adopted employs the meta-prevalences that are estimated based on epidemiological studies of Italian populations that are applied by cohorts with the risk of uniform infection. We incorporated the estimates using a Markovian model and a correction based on the supermortality caused by the large percentage of subjects that became infected a long time ago.
Regarding HCV infection, Italy is undoubtedly a peculiar case among Western countries. The Italian endemic load is unquestionably higher than the endemic load in other countries. However, the struggle against the transmission of the epidemic with the greatest impact and the introduction of increasingly effective specific treatments has curbed the spread of HCV since the 1990s. The model confirms a significant reduction in prevalence over the last 20 years, which is estimated at 2.6%, and the predominance of the percentage of elderly subjects in advanced stages of the disease: cirrhosis, decompensated cirrhosis, and hepatocarcinoma, of which 70+-year-olds account for 55% of the total number of these subjects.
The main peculiarity of the infection in Italy, therefore, is the vast difference in the epidemiological structure of the cases, with a predominance in Italy, of cases in the preserological period compared with recent cases, which are primarily related to drug abuse.
Our studies have confirmed that the prevalence of HCV among youth and adults in Italy is comparable to the prevalence of other developed countries: for west European countries, Gower et al has estimated a prevalence of 0.9% (95% confidence interval: 0.7%–1.5%). Therefore, the difference can be interpreted as the result of the high prevalence of elderly and very elderly subjects. However, the model highlights that the most serious effects of the disease (cirrhosis, decompensated cirrhosis, and hepatocarcinoma) have peaked, and a further gradual and significant reduction over the coming years is projected due to new treatments that ensure very high percentages of SVR.
The change of the infection's etiology over time has also determined the considerable diversity in prevalence across the country, with a higher prevalence in southern Italy by 1.8% compared with central–northern Italy (3.8% vs 2.0%). With regard to conditions of seropositivity, the higher prevalence decreases to 0.8% for subjects with a viral load (1.9% vs 1.1%).
Although they generate the hope of eradicating this disease, at least locally, the introduction of new and highly effective antiretroviral treatments on the market poses a problem of sustainability due to the high cost of these treatments.
These financial constraints are probably directing Italian health authorities toward priority treatment of more serious cases—cases that have already emerged or will emerge in the forthcoming years as a result of occasional specimens or the evolution of the disease.
This type of strategy inevitably entails the treatment of elderly or very elderly subjects, which does not bode well for the rapid eradication of the disease.
The assumptions that are adopted with respect to emergence have produced an estimated percentage of 47% of HCV RNA+ subjects, who are unknown to the health services.
Therefore, we hope that proactive strategies and policies may be assessed to enable the emergence of unknown cases, especially among the younger members of the population at risk.
The proposed model elaborates estimates of the endemic load of HCV in Italy by adopting a meta-analysis of the studies of Italian populations and explicitly considering the changes in the etiology of the disease in the different cohorts (by year of birth) of the population and the impact of effective treatments since the 1990s.
A significant limitation of the proposed model is its lack of consideration of the endemic load of HCV in the immigrant population, which is undoubtedly increasing and originates in countries in which the disease is endemic.
Another limitation is the adoption of emergence estimates based on clinical experience, of which the impact has been assessed by a Probability Sensitivity Analysis.
The proposed model aims to support policymakers in the determination of rational action plans by providing estimates of the emerged and nonemerged infected population by age, gender, gravity, and genotype, as well as by geographical area. In the future, the model may contribute to simulations of the costs and outcomes of the different action strategies that are adopted by the health authorities.
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HCV genotype prevalence; HCV Metavir score prevalence; HCV prevalence; HCV RNA+ prevalence; hepatitis C epidemiology; Italy; meta-prevalence
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