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As there were several outcome measures that could be used to indicate HCV disease severity, a variable was created to summarise disease progression.

A participant was considered to have ‘severe liver disease’ if they had:

•Diedfromliver-relateddiseaseor

•Everhadoneormoreofthefollowingsignsofliverdisease:cirrhosis,primarylivercancer,ascites,

varices, decompensated liver disease, portal hypertension, encephalopathy, hepatomegaly or splenomegaly or

•Everhadafibrosisscoreof3or4onabiopsyscoredfrom0to4orascorebetween4and6ona

biopsy scored from 0 to 6 (note: this is “worst” biopsy result, not necessarily most recent one; some patients may have improved on treatment)

A participant was considered to have ‘moderate liver disease’ if they had none of the above and had either:

•Afibrosisscoreof2onabiopsyscoredfrom0to4orascoreof3onabiopsyscoredfrom0to6or

•Moderateorsevereinflammationonanybiopsy

All other participants were classified as having ‘mild or no liver disease’.

Using these criteria, 27% (n=217) of chronically infected participants, 22% (n=11) of participants with no RNA results and 2% (n=7) of those who never tested RNA positive were classified as having severe liver disease by latest follow-up. A further 20% of chronically infected participants and 1% of those who never became chronically infected were classified as having moderate liver disease. By latest follow-up, 53%

of chronically infected participants and 97% of participants who never became chronically infected were classified as having mild or no liver disease.

Tables 22 and 23 show the effects of some key host and virus characteristics on the odds of having severe liver disease. Only participants who tested RNA positive at some stage (ever chronically infected) were

included in these analyses as 92% of the 235 participants with severe disease had tested RNA positive and this approach allowed the effects of genotype to be assessed.

The determinants of having severe liver disease in the database cohort were high alcohol intake, older age at end of latest follow-up, male gender, longer duration of RNA positivity and HCV genotype 3 (table 22).

Table 23 shows the same model with source of infection substituted for gender. These factors cannot be assessed together using a logistic regression model as gender is too closely linked to source of infection in the database population. This model indicates that participants infected through blood transfusions/

treatment for renal disease and those infected through clotting factors were more likely to have severe liver disease by latest follow-up compared to those infected through anti-D. All associations between these characteristics and severe liver disease were statistically significant and the influence of each of these factors on disease severity was independent of the effects of all of the other factors in the table.

The most important factor in disease progression was alcohol intake. Participants who had high alcohol intake had almost five times higher odds of having severe disease than those without. However, the number of chronically infected database participants with high alcohol intake was low (n=64) and due to its sensitivity, alcohol consumption data may be inaccurately reported. Figure 17 shows the prevalence of severe liver disease by duration of RNA positivity and alcohol intake.

Participants who were RNA positive for more than twenty years had approximately two fold higher odds of having severe liver disease compared to those infected for less than twenty years. The odds of having severe liver disease were almost three times higher for males compared to females. Participants who were aged 50 years or older at latest follow-up were more likely to have severe liver disease than younger participants.

Table 22. Factors associated with severe liver disease in chronically infected participants - logistic regression model (n=710)

Factors associated with having severe liver disease Odds Ratio P-value 95% Confidence interval Alcohol consumption

Non drinker/within recommended limits/moderately high 1 Reference Reference High (>40 units per week or alcohol abuse in chart) 4.96 <0.001 2.72 - 9.06 Age at end of latest follow-up

<50 years 1 Reference Reference

50 to 64 years 2.29 0.002 1.37 - 3.84

65+ years 3.29 <0.001 1.87 - 5.80

Gender

Female 1 Reference Reference

Male 2.85 <0.001 1.83 - 4.44

Genotype

Genotype 1 1 Reference Reference

Genotype 2 0.92 0.849 0.37 - 2.24

Genotype 3 2.00 0.008 1.20 - 3.34

Duration of RNA positivity

<20 years 1 Reference Reference

20+ years 1.88 0.016 1.12 - 3.14

Table 23. Factors associated with severe liver disease in chronically infected participants - logistic regression model (n=708)

Factors associated with having severe liver disease Odds Ratio P-value 95% Confidence interval Alcohol consumption

Non drinker/within recommended limits/moderately high 1 Reference Reference

High (>40 units per week or alcohol abuse in chart) 4.65 <0.001 2.54 - 8.53 Age at end of latest follow-up

<50 years 1 Reference Reference

50 to 64 years 1.92 0.013 1.15 - 3.20

65+ years 2.26 0.005 1.28 - 4.00

Source of infection

Anti-D 1 Reference Reference

Transfusion/renal 3.08 <0.001 1.97 - 4.81

Clotting factors 2.25 0.015 1.17 - 4.34

Genotype

Genotype 1 1 Reference Reference

Genotype 2 0.64 0.330 0.26 - 1.57

Genotype 3 1.70 0.042 1.02 - 2.84

Duration of RNA positivity

<20 years 1 Reference Reference

20+ years 2.17 0.003 1.30 - 3.64

Explanatory note: The odds ratios shown are a measure of the odds of severe liver disease in one group (e.g. males) divided by the odds of severe disease in another group (the reference group e.g. females).

An odds ratio of 1 indicates that severe liver disease is equally likely in both males and females and an odds ratio of more than 1 for males indicates that severe disease is more likely in males. P-values of <0.05 were taken to indicate a statistically significant difference between the distribution of severe disease in the category of the factor being assessed and the reference category of that factor.

18.0

% of chronically infected participants with severe liver disease A

Source of infection

Infected for <20 years, did not have high alcohol intake Infected for 20+ years, did not have high alcohol intake Infected for <20 years, had high alcohol intake Infected for 20+ years, had high alcohol intake

Figure 17. Percentage of chronically infected participants with severe liver disease by source of infection, duration of RNA positivity and alcohol consumption

Note: Numbers in some categories are very low and percentages should be interpreted with caution