Elaboración del mapa de riesgos

In the last 10 years, considerable progress has been achieved in the management of chronic hepatitis C, both in terms of viral endpoints and histologic endpoints. Several main treatment regimens have been assessed in large trials, the first being approved in 1990 (standard interferon regimen monotherapy with three injections three times a week (tiw)) and the last in 2002 (combination of ribavirin and PEG interferon). The specifics of these treatments are: (i) standard interferon alpha (alpha 2a or 2b, 3 million units (MU) tiw) for 24 weeks and then 48 weeks (Thevenot et al., 2001); (ii) a combination of standard interferon (3 MU tiw) and ribavirin (1 000–1 200 mg/day) for 24 weeks or 48 weeks (Poynard et al.,

1998a, 2000c; McHutchison et al., 1998); (iii) PEG interferon for 48 weeks (alpha 2a 180 µg, or alpha 2b at three doses: 0.5, 1.0 or 1.5 µg/kg) (Heathcote et al., 2000; Zeuzem et al., 2000; Lindsay et al., 2001); and (iv) 48 weeks of

combination PEG interferon and ribavirin (different doses of PEG and ribavirin) (Manns et al., 2001; Fried et al., 2002; Hadziyannis et al., 2002). Combination therapy has always been more effective than interferon monotherapy, even PEG interferon monotherapy.

Two PEG interferons are currently licensed. The first is a 12 kD PEG interferon alpha 2b that is dosed according to bodyweight (1.5 µg/kg, once a week) and combined with ribavirin adjusted also by weight (11 mg/kg) (Manns et al., 2001), which is a dose ranging from 800 to 1 400 mg/day. The second is a 40 kD PEG interferon alpha 2a which is used at a fixed dose of 180 µg/week and is

combined with ribavirin at a dose of 1 000 or 1 200 mg/day (Fried et al., 2002; Hadziyannis et al., 2002). There has been no direct comparison of efficacy, but results from the published trials suggest that the two compounds have similar response rates and similar adverse events.

A summary of treatment progress is shown in Figure 2. Results are presented according to HCV genotype, the main factor associated with viral response. The histological impacts of these 10 different regimens on fibrosis stage and

necroinflammatory grade have been demonstrated (Poynard et al., 2002c). All regimens significantly reduced fibrosis progression rates in comparison with rates

before treatment. The reversal of cirrhosis was observed in 75 of 153 patients (49 %) with baseline cirrhosis (Poynard et al., 2002a).

The choice of 24 or 48 weeks for combination therapy has been clarified for the former combination therapy of interferon and ribavirin but is as yet unknown for the current one including PEG interferon and ribavirin. In one study using PEG interferon alpha 2a in combination with ribavirin for 24 or 48 weeks, patients with HCV genotype 1 significantly improved their sustained virological response with longer treatment, independent of pretreatment viral load. No such difference was seen for patients with HCV genotype 2 or 3, independent of pretreatment HCV-RNA levels. Furthermore, patients with HCV genotype 1 responded better to higher dosages (1 000–1 200 mg/daily) of ribavirin (Hadziyannis et al., 2002). Based on previous results, it would not be prudent to recommend a strategy based only on virological characteristics. Besides viral load or viral kinetics, several independent response factors have been identified. Taking into account only the viral factors is an oversimplification that could lead to errors in different populations (Poynard et al., 2000c). Therefore, both the other independent factors of response

Figure 2: Progress in the treatment of chronic hepatitis C. Percentage of patients with undetectable HCV RNA at the end of follow-up, according to genotype (G1-4-5-6, G2-3)

Percentage of patients

Control IFN 24 w IFN 48 w IFN-R PEG-R

G1-4-5-6 G2-3 0 20 40 60 80 100 1 1 5 20 15 40 35 80 48 88

and the tolerance to treatment should be taken into account when deciding the length of therapy. Because of the antifibrotic effect of interferon, it is possible that a longer duration of treatment could benefit patients with extensive fibrosis or rapid fibrosis progression (Shiffman et al., 1999; Sobesky et al., 1999; Poynard et al., 2002d). Because of the economic burden of cirrhosis complications, treatments are cost-effective (Siebert et al., 2003).

The new standard treatment is the combination of PEG interferon with ribavirin, but there is so far just one comparison between 48 and 24 weeks’ treatment duration (Hadziyannis et al., 2002). Therefore, a detailed analysis of the combination of interferon and ribavirin is still useful for the clinician.

Efficacy of the ribavirin and standard interferon

combination regimen: lessons from the past

Efficacy of combination regimens on viral endpoints

When the results of two pivotal trials of a ribavirin and interferon combination were combined (McHutchison et al., 1998; Poynard et al., 1998a), the database included 1 744 treatment-naive patients. At the end of treatment, the percentage of patients with undetectable HCV RNA was significantly higher in the combination groups: 51 % in the IFN-R 48 week, 55 % in the IFN-R 24 week, 29 % in the IFN 48 week, and 29 % in the IFN 24 week group (Figure 3a). At the end of the follow-up, the percentage of patients with sustained undetectable HCV RNA was

Figure 3: Efficacy of combination ribavirin (Riba)-interferon (IFN) (a) at the end of the treatment and (b) at the end of 24 weeks’ (w) follow-up. Adapted with permission (Poynard et al., 1998a, 2000c; McHutchison et al., 1998)

(a) End-of-treatment response (b) 24 weeks’ follow-up

Percentage of patients ( n =1 744) p < 0.001 Treatments

(IFN 3MU +/– Riba 1.0–1.2 g)

IFN-Riba 48 w IFN 48 w IFN-Riba 24 w IFN 24 w Percentage of patients ( n =1 744) p < 0.001 Treatments

(IFN 3MU +/– Riba 1.0–1.2 g) 0 50 0 20 40 60

also higher in the combination groups 41, 33, 16 and 6 % respectively, with significant differences between all these groups (Figure 3b).

These results demonstrated that there was a combination effect without duration effect on the end-of-treatment response and that there was both a combination effect and a duration effect on the sustained response.

Efficacy of combination regimens on transaminases

There was a strong correlation between the impact of treatment on viral load and transaminases (Figure 4). However, transaminases’ activity had a lower specificity for sustained response than viral load. In all, 12 % of patients with normal ALT levels at the end of follow-up were PCR positive.

Efficacy of combination regimens on histologic endpoints

There was a significant improvement in activity grades (Figure 5a) and fibrosis progression rates (Figure 5b) when biopsies performed 24 weeks after the end of treatment were compared to baseline biopsies. Improvement was greater in sustained responders.

Figure 4: (a) ALT and (b) virological response to combination ribavirin–interferon in 536 patients treated for 48 weeks. Adapted with permission (Poynard et al., 1998a, 2000c; McHutchison et al., 1998)

(a) ALT response (b) Virological response

Means of ALT x upper limit normal

Non-responders Relapsers Sustained responders Weeks 0 4 12 24 36 48 60 72 4 3 2 1 0

Means of log viral load

Non-responders Relapsers Sustained responders Weeks 0 4 12 24 36 48 60 72 6 5 4 3 2

Factors associated with treatment response and ‘a la carte’ regimen

Careful analysis of pivotal trials has confirmed the independent prognostic values of five baseline characteristics (Poynard et al., 2000c). HCV genotypes 2 and 3 were associated with better response to the combination than other genotypes. For viral load, the receiver operating characteristics curves showed that there was no threshold that had either a positive or negative predictive value. Therefore, the simplest way to classify viral load into ‘high’ or ‘low’ values was to take the median value, which was 3.5 million copies. For age, the threshold of 40 years seemed to have the best accuracy. Because the multivariate analysis showed that these five factors could only explain 20 % of the variability of the sustained response, we need to identify the other independent factors. These analyses have excluded the possibility that the kinetics of viral load at 4 or 12 weeks allow very early therapeutic decisions to be made.

Is a treatment with interferon alone sufficient among patients with many favourable factors?

It has been demonstrated that there is no place for interferon monotherapy (PEG or non-PEG) for either 24 or 48 weeks, even in patients with the most favourable risk profile. Among patients with genotype 2 or 3 and low viral load, the sustained response rate was much greater with 24 weeks’ combination regimen (71 %) than with 48 weeks of interferon monotherapy (40 %, p < 0.001). Even for PEG

interferon, the results were lower than for the combination (Heathcote et al., 2000; Zeuzem et al., 2000; Lindsay et al., 2001).

Figure 5: Improvement of histology after combination ribavirin–interferon. Adapted with permission (Poynard et al., 2000d)

(a) Activity grade (b) Fibrosis progression rate

Improvement in Metavir score (%) P < 0.0001 n = 541 100 75 50 25 0 Combination Monotherapy 82 74 37 31 14 Responders Non- responders Control Fibrosis progression rate P < 0.0001 n = 1 361 0.2 0.1 0.0 – 0.1 – 0.2 Combination Monotherapy Responders Non- responders Control 0.062 0.034 0.111 – 0.156 – 0.157

Duration of the combination regimen: 12, 24 or 48 weeks?

The first question is whether treatment can be stopped at 12 weeks in some subgroups of patients because of a high probability of non-response (Consensus statement, 1999). There is now much evidence in patients treated with PEG interferon and ribavirin to stop treatment at 12 weeks in non-responders without extensive fibrosis (Pawlotsky, 2002).

From data concerning non-PEG interferon with ribavirin, this approach could not be recommended because in the 48-week regimen, among the patients who had a positive PCR at 12 weeks, we observed a sustained response in 10 % of patients. Even the 24-week regimen induces a sustained response in 4 % of these patients (Poynard et al., 2000c). Furthermore, the antifibrotic effect of 24 to 48 weeks’ treatment in non-responders is a benefit for patients with extensive fibrosis (Shiffman et al., 1999; Poynard et al., 2000d, 2002b). The choice of 24 or 48 weeks for combination therapy using non-PEG interferon has been clarified (Table 2). In patients who are PCR negative at 24 weeks (59 % of the patients in these studies), the goal is to reduce the relapse rate. There was an overall highly significant improvement with 48 weeks of treatment (74 % sustained responders) versus 24 weeks (59 % sustained responders). Since patients with many favourable response factors benefit less from 48 weeks of treatment, consideration can be given to stopping at 24 weeks for these patients. A simple strategy could be to consider only the HCV genotype, and stop treatment at week 24 in genotype 2 and 3 responders, since the sustained response was 82 % in patients treated for 24 weeks versus 84 % in patients treated for 48 weeks. However, from our results, it seems hazardous to recommend a strategy based only on virological

characteristics. There were, in fact, five independent response factors, and to take into account only one factor among these five is an oversimplification that could lead to errors in different populations or subgroups (Poynard et al., 2000c). For example, we have identified that patients with genotype 2 or 3 who are PCR negative at 24 weeks and who have extensive fibrosis will have a better sustained response with 48 weeks of treatment: 80 %, compared with 65 % in patients whose treatment is stopped at 24 weeks. For a population of older men with extensive fibrosis, the choice of 48 weeks’ duration in responders should not be based only on genotype and viral load. The decision should be based on both the number of independent factors and the tolerance to the combination.

Table 2:

interferon (IFN) and ribavirin combination according to baseline characteristics (%)

Baseline characteristic IFN–ribavirin IFN–ribavirin

48 weeks 24 weeks Genotype 65 67 2 or 3 30 18 1, 4, 5 or 6 Mean HCV RNA ≤ 3.5 x 106_{copies/ml 44 40} > 3.5 x 106 _{copies/ml 38 26} Age ≤ 40 years 48 40 > 40 years 34 26 Fibrosis stage No or portal fibrosis 43 36

Septal fibrosis or more 36 23

Gender

Female 46 39

Male 38 30

Combination of virological factors

Genotypes 2, 3 ≤ 3.5 x 106 _{65 71}

Genotypes 2, 3 > 3.5 x 106 _{65 62}

Genotypes 1, 4, 5, 6 ≤ 3.5 x 106 _{33 26}

Genotypes 1, 4, 5, 6 > 3.5 x 106 _{27 10}

Combination of non-virological factors

Women ≤ 40 years, no or portal fibrosis 57 56

Men > 40 years, septal fibrosis or more 34 25

Extreme favourable population

Women ≤ 40 years, no or portal fibrosis, 79 69

genotypes 2, 3 ≤ 3.5 x 106_copies

Extreme unfavourable population

Men > 40 years, septal fibrosis or more, 9 8

Efficacy of PEG interferon