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  • claudine intexas
    NATAP - www.natap.org Should Mild HCV Infection Be Treated? Treatment of histologically mild hepatitis C virus infection with interferon and ribavirin: a
    Message 1 of 1 , Jan 26, 2005
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      NATAP - www.natap.org

      Should Mild HCV Infection Be Treated?

      Treatment of histologically mild hepatitis C virus infection with interferon and ribavirin: a multicentre randomized controlled trial���

      Journal of Viral Hepatitis
      January 2005

      --- The sustained viral response rate in this study of patients with histologically mild chronic hepatitis C is similar to those obtained in the two landmark studies of interferon and ribavirin combination therapy, in which no distinction based on histology, was made.

      --- this study demonstrates that the treatment outcome in patients with histologically mild liver disease is likely to be as good as those with progressive fibrosis and is in agreement with two recent smaller studies that found equivalent response rates in patients with normal aminotransferase levels

      --- We therefore conclude that any rationale to treat patients with histologically mild hepatitis C must be based on factors other than enhanced response rates.

      ---Treatment improved quality of life for patients achieving SVR & for some patients who did not achieve SVR

      --- before treatment is started, the potential gains to patients in terms of a virological cure and quality of life need to be balanced by a discussion of possible deteriorations in quality of life, both during and after therapy and the risk of adverse effects.

      --- There was considerable variation in the effect of treatment on quality of life at 24 weeks post-therapy. Sixty-one per cent of the successfully treated patients reported an improvement in physical health (PCS). However, of equal importance, 39% reported deterioration. The control group reported deteriorations in all subscales. This suggests that, over the course of 18 months follow-up, there were true deteriorations in well-being in the control patients, or the absence of treatment in itself was detrimental to quality of life. A proportion of the study group had normal or near-normal baseline quality of life scores. This group might be considered to have 'asymptomatic' disease. There was a significant correlation between baseline scores and response to treatment in all treated patients, with improvements in those with low baseline scores, who managed to tolerate therapy, and negligible improvements or deteriorations in the 'asymptomatic' group. Thus, the baseline quality of life
      status, along with viral titre and genotype, may be an additional factor in patient selection for therapy.

      --- The results from this study support the American consensus that patients who are symptomatic and infected with genotypes other than type 1 should be treated, probably without the need for a biopsy, as this is the group who stand to benefit most in terms of virological cure and quality of life improvement. A liver biopsy is still indicated for patients infected with genotype 1, as the potential benefits of virological eradication in patients with histologically mild disease, some of whom may never progress, may be outweighed by the side-effects. The low cure rates may not justify the cost of treatment. If the biopsy demonstrates mild disease and the patient is asymptomatic, then treatment may adversely affect quality of life for only a small chance of cure. The policy of 'watchful waiting' should continue to be applied to this group, especially in older patients who may never progress. Our data demonstrate significant improvements in quality of life in patients who were
      symptomatic prior to therapy. Therefore, the decision to treat symptomatic patients with mild disease and genotype 1 infection should be made on a patient-to-patient basis, taking into account any symptomatology that may be attributed to infection, and which might therefore be ameliorated by successful therapy. The patient should be made aware that the chance of viral eradication is reduced but, if successful, he or she may benefit in terms of symptoms and quality of life.

      --- Those who failed to achieve at least a 2-log drop in viral load by 12 weeks of therapy with interferon and ribavirin had a 0% chance of an eventual SVR. If the early virological response (either absolute or rate of fall in viral load) can be used to estimate the likelihood of an SVR, this could reduce the duration of administration of ineffective therapy, thereby increasing cost-effectiveness and reducing unnecessary side-effects.

      --- A policy of treating patients infected with genotypes 2 and 3 without histological staging is therefore likely to be of benefit to patients at all stages of fibrosis, although a formal health economic evaluation is necessary. The case for treating patients with genotype 1 infection and mild liver disease appears less compelling from a virological perspsective and would need to be made on the basis of quality of life gains and health economics.

      Authors: M. Wright 1 , D. Forton 1 , J. Main 1 , R. Goldin 1 , E. Torok 2 , R. Tedder 2 , P. Grant 3 , M. Thursz 1 , N. Naoumov 3 , C. Millson 4 , P. R. Mills 5 , M. Bassendine 6 and H. C. Thomas 1 on behalf of the UK Mild HCV Trial investigators

      Hepatology Section, St Mary's Hospital, Imperial College London; 2Radcliffe Infirmary, Oxford; 3University College London; 4St James University Hospital, Leeds; 5Gartnavel Hospital, Glasgow; 6University of Newcastle

      Summary. Current guidelines advocate no treatment for patients with histologically mild hepatitis C virus (HCV) infection. This was a UK multicentre randomized controlled trial comparing alpha -interferon (3 MU thrice weekly) + ribavirin (1000-1200 mg/day) for 48 weeks with no treatment in treatment na��ve, adult patients with histologically mild chronic HCV infection.

      The aim was to compare benefits, safety and efficacy of combination therapy with alpha -interferon 2b and ribavirin for 48 weeks with no treatment (current standard management) in this patient group.

      In the treatment group 32 of 98 (33%) patients achieved a sustained virological response (SVR). Patients infected with genotype 1 had a lower SVR than those infected with genotype non-1 (18%vs 49%P = 0.02). No patients who failed to achieve a 2-log drop in viral load at 12 weeks achieved SVR.

      Improvements in quality of life 24 weeks postcessation of therapy compared with baseline using the SF-36 questionnaire measures were observed in the treated group. For patients with mild HCV infection with viral genotype non-1, the results are sufficiently good to suggest that therapeutic decisions should no longer be biopsy-driven. For patients infected with genotype 1, a liver biopsy is still indicated as the low chance of SVR is outweighed by an unacceptable burden of side-effects. Patients who fail to respond by 12 weeks of therapy should have their treatment curtailed early.

      [both SVR & non-SVRs had improvements in quality of life] Health-related quality of life outcomes. Comparisons between baseline and post-week 24 scores were made for patients in three groups: sustained virological responders (SVRs), treatment failures (non-SVRs) including nonresponders and relapsed patients, and the control group. The individual differences between the baseline and post-week 24 scores for the eight scales of the SF-36 and the two summary scales were compared across the three groups. Data were available for 24 of 32 (75%) of the SVRs, 44 of 68 (65%) of the non-SVRs and 58 of 98 (56%) of the control group. Data were unavailable for those patients who had failed to attend their postweek 24 visits, and for those who had not filled in the questionnaires correctly.

      At 24 weeks after the end of treatment, there was a mean improvement in seven of eight of the SF-36 scales in the SVRs, in five of eight in the non-SVRs and in zero of eight in the control group, where substantial reductions were seen. Similarly the mean change in the physical and mental component summary scores (PCS and MCS) showed improvements in the SVRs and non-SVRs groups with deterioration in the controls. The changes in the PCS were more marked than in the MCS, with 16 of 24 (67%) of the SVRs, 27 of 44 (61%) of the non-SVRs and 24 of 58 (41%) of the controls reporting an improvement (P < 0.05 for SVRs and non-SVRs compared with controls). There were no statistical differences in the MCS.

      There was substantial variation in the magnitude and direction of change in the SF-36 scores from baseline to 24 weeks post-treatment. Despite this variation, the mean change in PCS was significantly greater in the SVRs compared with the controls (P = 0.04). There were no statistical differences between non-SVRs and SVRs or controls, although there was a trend to greatest improvement in the SVRs. This is likely to be due to the relatively small sample size. There were significant improvements in three of eight of the SF-36 subscales (bodily pain, general health and vitality P = 0.01) in the SVRs compared with the controls. These are reflected in the PCS. There was an overall deterioration in only one subscale (role function emotion) in the SVRs, which was significantly different to the improvement seen in the non-SVRs (P < 0.05).

      There were significant inverse correlations between baseline PCS and the change in PCS in both the SVRs (R = -0.46, P = 0.02) and non-SVRs (R = -0.45, P = 0.002) but not the controls. This suggests that individuals with low well-being scores prior to treatment saw a sustained improvement 24 weeks after therapy, regardless of virological outcome. In contrast, patients with preserved baseline well-being scores experienced no long-term improvement.

      Predictive value of early virological response
      Quantitative virology was performed on patients who had attended five of six of their initial early visits (days 0, 3, 7, 10 and 14, and week 12) and for whom there was a follow up sample at 24 weeks postcompletion of therapy. Seventeen control patients and 51 active treatment patients fulfilled these criteria. A week 12 quantitative sample was available for 75 of the treated patients. In the control patients, there was very little variation in the viral load from baseline. In the treated patients the degree of fall in viral load was examined for its relationship to final outcome at the different time points using ROC curves. Viral load drop gave the best area under the curve at day 10 followed by week 12. A 2-log drop at 10 days gave a positive predictive value (PPV) of 81% for eventual viral clearance, while patients who failed to achieve a 2-log drop had only an 18% chance of SVR. If measured at 12 weeks, no patient who failed to achieve a 2-log drop went on to SVR, with a 57% PPV
      if there was a 2-log drop.

      Virological response. As expected, no patients in the control group demonstrated loss of HCV RNA either at the end of the control period or at the end of follow-up. End of treatment follow-up data were available for 97 of 98 patients in the treated group and 87 of 98 patients in the control group. The length of time on therapy was variable and not all patients were able to complete the full treatment protocol. At the end of the trial, 13 patients in the treatment group failed to attend for their postweek 24 visit. In the control group 28 patients failed to attend their final visit. All were recorded as being PCR positive in line with the intention-to-treat principle. Forty-three of 98 (44%) patients in the treatment group (interferon and ribavirin) demonstrated an end-of-treatment response (EOTR) and 32 of 98 (33%) achieved an SVR. Analysis by viral genotype demonstrated a 30% EOTR and a 18% SVR for patients infected with genotype 1 and a 60% EOTR and 49% SVR for those infected with
      genotype non-1 (P = 0.02).

      Independent factors associated with a SVR. There were no significant differences in EOTR or SVR according to sex, age (less than or greater than 40), baseline ALT (raised or normal) or baseline viral load (above or below 4 x 105 IU/mL).

      Logistic regression analysis of all treated patients showed that of age, gender, ALT, viral genotype and baseline viral load, only viral genotype was an independent predictor for SVR (P = 0.002). This remained true when the analysis was restricted to those patients who completed 24 weeks or more of therapy. There was no association between viral genotype and baseline viral load.

      Safety. As expected, because of the nature of the treatment there was an excess of events in the treatment group. There was a significant number of adverse events reported in the control arm of the study, despite there being no placebo component.

      There were four hospitalizations amongst trial patients, all in the treatment arm. These are recorded in Table 4. Patient 1 had completed 36 weeks of therapy but a diagnosis of gastric carcinoma was made and he died before the end of follow-up. The remaining three discontinued treatment in accordance with the protocol. Two patients were admitted following episodes of self-poisoning. One had a history of previous suicide attempts but failed to disclose this at either the screening or baseline visits and the other was known to have a history of mild-moderate depression but had been assessed as suitable for treatment by a senior psychiatrist. Adverse events resulted in 56 recorded dose adjustments. Ten were withdrawn completely (four of these because of hospitalizations as detailed above and six because of inability to tolerate side-effects on the part of the patient), 16 required reduction of interferon alone, four required reduction of both drugs and 26 required reduction of ribavirin
      alone. In all 30 patients where reduction in the dose of ribavirin was required, the reason was the development of anaemia (haemoglobin below 10 mg/dL).

      INTRODUCTION. United Kingdom and European guidelines advocate that patients with hepatitis C virus (HCV) infection, who have only mild histological changes on liver biopsy should not be routinely treated with antiviral agents, but should be managed by observation, with periodic liver biopsies to assess for progression. Guidelines suggesting a watch and wait policy for mild disease were produced at a time when alpha -interferon monotherapy was the only treatment available for HCV, with low sustained viral response rates and high costs.

      It is impossible to predict from a single biopsy that shows mild disease, whether it represents a state of long-term minimal liver disease or early disease, which will ultimately progress. Individuals with histologically mild disease may have the potential to progress to cirrhosis sufficiently rapidly for treament at the stage of mild disease to be cost-effective. It is increasingly clear that HCV infection has an impact on patients beyond liver damage. Clinicians who care for HCV-infected patients will have observed the disparity between the degree of hepatic histological abnormality and the patients' symptoms. Disabling symptoms such as fatigue, malaise, bodily pain, joint symptoms, cognitive symptoms and depression are common and severely reduce quality of life in afflicted individuals. These do not correlate with severity of disease. Therefore, in addition to improving liver disease, therapy for mild HCV infection may also improve the extrahepatic symptoms and quality of life.

      Large multicentre studies have confirmed the benefit of combination therapy with alpha -interferon and ribavirin in treatment na��ve and relapsed chronic HCV patients with raised alanine transaminases, and was until recently the gold standard treatment in the UK for progressive liver disease.The aims of this study were to examine the safety and efficacy of combination therapy in patients with histologically mild liver disease. A combination of alpha -interferon (3 MU thrice weekly) and ribavirin (1000-1200 mg/day) was compared with no treatment (current standard management) in patients with histologically mild HCV infection.

      Patient selection. Treatment na��ve, adult patients with mild chronic hepatitic C (Ishak necroinflammatory score <=3, fibrosis score <=2 on liver biopsy within 1 year prior to the screening visit) were identified. Serum was positive for HCV by qualitative polymerase chain reaction (PCR) assay. Patients with both normal and raised alanine aminotransferase values were included. Written informed consent was obtained.

      Patients with liver disease of other aetiology, HIV coinfection, ongoing psychiatric morbidity, intravenous drug use, excessive alcohol intake (>28 units for men and >21 units for women), cardiovascular disease, uncontrolled diabetes mellitus, haemophilia, organ transplants and autoimmune disease were excluded, as were those unable to practise contraception.

      The study was approved by local ethics committees of the host institutions and by the multiple regional ethics committee.

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