Can HCV Be Cured: more on longterm outcomes in Sustained Virologic Responders

10-Year Follow-up After Interferon- Therapy for Chronic Hepatitis C: all 5 patients with sustained viral response remained HCV-RNA negative by liver biopsy

Long-term histologic improvement and loss of detectable intrahepatic HCV RNA in patients with chronic hepatitis C and sustained response to interferon-alpha therapy

Durability of Sustained Virologic Response: 3 year follow-up

Durability Of Viral Response To Interferon Ribavirin Combination In Patients With Chronic Hepatitis C: of 311 SVRs, during 3 years follow-up 7 patients had late relapse
     T. Poynard, J. McHutchison, G. Davis, R. Esteban, J. Albrecht, M. Ling, IHIT. group, Paris, France

The combination of interferon (IFN) and ribavirin (I/R;Rebetron,Schering-Plough) is the standard treatment with higher early sustained response than IFN alone, but there remains little long term follow-up to insure that responses persist.

Aim: To assess the durability of the 6-month post-treatment ("sustained") virologic response to I/R.

Methods: 2089 patients were enrolled in 4 randomized trials of 24 to 48 weeks of IFN+-R for either naive or IFN relapsers. 455 patients treated by I/R were sustained responders (SR: HCV-RNA negative at the end of treatment and 6 months later). 311 of these SR agreed to participate in long-term follow-up (107 naive treated 24 wks I/R, 147 naive 48 wks I/R and 57 relapsers treated 24 wks I/R. Late relapse rates for SR were reported beginning 6 months after the treatment was stopped Serum HCV RNA was measured by quantitative PCR (NGI, sensitivity <100 copies per ml).

Results: During 3 years follow-up, 7 patients had a late relapse: 3 patients among naive treated 24wks (none after 2 years), 1 among the naive treated 48wks (none after 2 years),2 among relapsers. The corresponding percentages at 3 years (Kaplan Meier) of patients without late relapse among early SR were 97+/-1.7%, 99+/-1%, and 93%+/-5.1% respectively. No factor was associated with these late relapses (logrank, Cox).

Conclusion: Few patients with chronic hepatitis C who remain HCV-RNA negative for 6 months following completion of treatment with combination interferon-ribavirin will subsequently relapse. So far among naive patients, no patient had a late relapse after two years of sustained response.

from Can J Gastroenterol 2000 Jul-Aug;14 Suppl B:77B-80B
Long term follow-up of patients with chronic hepatitis C treated with interferon alpha
     Collier JD, Adams PA, Feinman V, Ghent C, Witt-Sullivan H, Minuk G, Krajden M, Heathcote J.
Department of Medicine, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada.

Interferon alpha (IFN alpha) treatment for chronic hepatitis C induces a sustained biochemical and virological response at six months after completing 24 weeks of therapy in approximately 10% of patients. The long term durability of this 'sustained' response is still controversial. The aim of this multicentre study was to assess the long term virological response in patients considered to have achieved a sustained biochemical response six months after completing IFN treatment. The majority (36 of 41) of the sustained responders identified had been treated for six months with IFN therapy. Twenty-nine of the 41 patients (70%) had undetectable hepatitis C virus (HCV) RNA after a mean follow-up of 38 months after cessation of treatment (range six to 92 months). All but one of those 29 individuals had normal serum alanine aminotransferase (ALT) levels. Of the 16 patients (out of 41) who had been tested for HCV RNA six months after treatment, HCV RNA remained undetectable in 14 (88%) at final follow-up. Serum ALT values in the 11 of 12 patients whose HCV RNA was positive at final follow-up were lower than pretreatment values, and in six cases were within the normal range. The long term sustained virological response in those considered a 'sustained responder' six months after receiving only six months of IFN is high. Measurement of ALT is an unreliable marker of sustained response to therapy.

from J Hepatol 1999;31 Suppl 1:244-9
Long-term efficacy of treatment of chronic hepatitis C with alpha interferon or alpha interferon and ribavirin.
     Barnes E, Webster G, Jacobs R, Dusheiko G.
Department of Medicine, Royal Free and University College School of Medicine, London, United Kingdom.

The major objective of treatment of chronic hepatitis C virus (HCV) infection is to prevent progression to cirrhosis, and thereby prevent complications of end-stage liver disease. The established treatment of chronic HCV is with alpha interferon. Recent results with ribavirin and alpha interferon together suggest that combination antiviral therapy will become the benchmark treatment. For both naive and relapsed patients, however, it has become important to assess the long-term outcome of treatment, in order to gauge whether treatment has indeed modified the natural history of chronic hepatitis C virus infection. It seems likely that most sustained responders (85-90%) treated with combination ribavirin and alpha interferon will continue to have a long-term biochemical and virological response, as has been demonstrated with alpha interferon alone, but further long-term follow-up of patients treated with combination therapy is required.

from Ann Intern Med 1997 Nov 15;127(10):875-81
Long-term histologic improvement and loss of detectable intrahepatic HCV RNA in patients with chronic hepatitis C and sustained response to interferon-alpha therapy.
      Marcellin P, Boyer N, Gervais A, Martinot M, Pouteau M, Castelnau C, Kilani A, Areias J, Auperin A, Benhamou JP, Degott C, Erlinger S.
Hopital Beaujon, Clichy, France.

Background: Less than 20% of patients with chronic hepatitis C have a sustained response to interferon-alpha therapy. The long-term benefit of interferon-alpha with regard to hepatic viral clearance and histologic improvement remains unknown. OBJECTIVE: To determine the long-term biochemical, virologic, and histologic outcomes in patients with chronic hepatitis C who have a sustained response to interferon-alpha therapy.

Design: Prospective cohort study. SETTING: University hospital. PATIENTS: 80 patients who had chronic hepatitis C, had a sustained biochemical and virologic response to interferon-alpha therapy, and were followed for at least 12-months. MEASUREMENTS: Serum hepatitis C virus (HCV) RNA detected by polymerase chain reaction (PCR); HCV genotyping determined by line probe assay; liver histologic studies; liver HCV RNA detected by PCR on frozen liver tissue samples (in 27 patients); and repeated measurements of serum alanine aminotransferase (ALT) levels. Liver biopsy was done before treatment in all 80 patients, and at least one biopsy was done in 69 patients 1 to 6 years after treatment.

Results: The 80 patients had follow-up 1 to 7.6 years (mean +/- SD, 4.0 +/- 2.0 years) after interferon-alpha treatment. The follow-up period was 1, 2, 3, 4, 5, 6, and more than 6 years in 11, 13, 14, 18, 10, 12, and 2 patients, respectively, after the end of therapy. During the entire follow-up period, 93% (95% CI, 84% to 97%) of patients had persistently normal serum ALT levels. Serum HCV RNA remained undetectable in 96% (CI, 89% to 99%) of patients. A comparison of liver histologic findings before and 1 to 6.2 years after interferon-alpha treatment showed a clear improvement in 94% (CI, 83% to 99%) of patients. In 62% of patients, the last biopsy done showed normal or nearly normal histologic findings. Liver HCV RNA was detectable before treatment in all 13 patients tested and was undetectable 1 to 5 years after treatment in all 27 patients tested.

Conclusions: In patients with chronic hepatitis C who have persistently normal serum ALT levels and no detectable serum HCV RNA 6 months after interferon-alpha therapy, a long-term sustained biochemical and virologic response is generally seen. This response is associated with an absence of detectable intrahepatic HCV RNA and marked histologic improvement.
 PMID: 9382365 [PubMed - indexed for MEDLINE]

from Journal of Viral Hepatitis 6 (3), 237-242
Histological and virological long-term outcome in patients treated with interferon-a2b and ribavirin for chronic hepatitis C
     R. Schvarcz1, H. Glaumann1, 2, O. Reichard3 and O. Weiland1

Long-term virological and histological outcome following interferon-a2b (IFN-a2b) and ribavirin treatment for 24 weeks was studied in 20 patients with chronic hepatitis C who were without a lasting response to IFN as monotherapy. Following combination therapy, sustained virological response (SR) was achieved in 12 patients (i.e. hepatitis C virus (HCV) RNA negative in serum 6months post-treatment). Eleven of these patients remained HCV RNA negative in serum 2 years post-treatment. A virological long-term response (LTR) was more frequent in patients with a previous end-of-treatment response to IFN monotherapy than in non-responders. Liver histology at follow-up, ?24months post-treatment, showed substantial improvement in patients with a virological LTR to the combination treatment. In all nine patients biopsied at the 2-year follow-up, liver inflammation had disappeared totally (grade=0), and the stage (fibrosis) had improved. In contrast, no significant changes in grade or stage were noted in patients with a virological non-LTR to combination treatment. A significant improvement in inflammation was noted, in patients with a virological LTR, from 3.6 to 0.2 (P<0.01) and in fibrosis from 2.0 to 1.4 (P<0.05) whereas the corresponding scores for patients with a virological non-LTR did not change significantly, from 3.1 to 1.5 for inflammation and for fibrosis from 1.3 to 1.3. We conclude that patients with chronic hepatitis C who achieve a virological sustained response 6months post-treatment with IFN-a2b and ribavirin will remain virological responders for a follow-up period of least 24months, concomitant with a disappearance of inflammatory activity and a marked improvement of fibrosis in the liver.

from J Hepatol 1999 May;30(5):783-7
Long-term follow-up of chronic hepatitis C patients with sustained virological response to alpha-interferon.
     Reichard O, Glaumann H, Fryden A, Norkrans G, Wejstal R, Weiland O.
Department of Infectious Diseases at Danderyd, University Hospital, Karolinska Institutet, Stockholm, Sweden.

Background/Aims: This study aimed to determine the long-term outcome of hepatitis C virus (HCV)-infected patients who respond to interferon treatment with clearance of serum HCV RNA.

Methods: We performed a long-term biochemical, virological, and histological follow-up of all sustained virological responders, defined as those who became HCV RNA negative at follow-up 6 months after the end of treatment, from 3 controlled interferon trials performed in Sweden between 1988 and 1994.

Results: At biochemical and virological long-term follow-up performed in 26 sustained virological responders 3.5-8.8 years (mean +/- SD, 5.4+/-1.6 years) after the end of IFN therapy, 22 patients (85%) had normal serum ALT levels, and 24 patients (92%) were HCV RNA negative in serum. Liver biopsies performed in 23 patients 2.1-8.7 years (mean +/- SD, 5.0+/-1.8 years) after end of treatment showed no or minimal inflammation, whereas mild and probably irreversible fibrosis was seen in a few patients.

Conclusion: In this well-defined material of sustained responders to IFN therapy, the long-term prognosis was excellent. Nearly all had a durable response, not only biochemically and virologically, but more importantly also histologically with normalisation or near normalisation of previous histological lesions.

from Rev Esp Enferm Dig 2001 Jun;93(6):353-63
Long-term response to interferon plus ribavirin in patients with chronic hepatitis C refractory to interferon.
     M, Lujan M, Valeros D, Tuset C, Marcaida G, Garcia V, Cors R, Carbonell P.
Hepatology Section, Service of Digestive Diseases, Hospital General Universitario, Valencia, Spain.

Objective: A sustained response (SR) to interferon (IFN) is only observed in 15-20% of patients with chronic hepatitis C (CHC). The aim of this study was to determine the long-term effectiveness and safety of the treatment with IFN plus ribavirin (RIB) over two years in CHC patients without SR to IFN. DESIGN: A prospective and open longitudinal follow-up study was conducted over 3 years.

Patients & Methods: A total of 77 CHC patients were included: 63 non-responders (NR) and 14 relapsers (R) to IFN. Patients were treated with IFN (3 MU s.c. three times a week) and RIB (1,000-1,200 mg p.o. daily) for 12 months. Treatment tolerance and viral response (HCV-RNA in serum < 1,000 copies/ml) were assessed after 1, 3, 6 and 12 months of treatment. SR and relapsing rates were subsequently evaluated 6, 12 and 24 months after the end of the treatment, together with those variables capable of predicting SR.

Results: At the end of the treatment, 19/77 patients responded (24.7%), 9/63 (14.3%) were non-responders and 10/14 (71.4%) relapsers, and these same patients exhibited SR after 6 months. The SR rate two years after treatment was 22.1% [8/63 (12.7%) NR and 9/14 (64.3%) R]. The relapse rate after 6 months and two years was respectively 0 and 10.5% (2/77). Independent variables capable of predicting SR were negative viremia conversion within the first month of treatment, maintenance of such negative viremia after 6 months, and R status to IFN. Side effects were recorded in 90.9% of cases (70/77), the most frequent being pseudoinfluenza syndrome. Treatment had to be discontinued in 33.8% of patients (26/77).

Conclusions: Combined IFN-RIB therapy for 12 months in CHC patients without SR to IFN obtains a long-term SR of 22.1%, this rate being higher in relapsers to prior IFN therapy (64.3% in R versus 12.7% in NR).

from J Hepatol 2001 May;34(5):748-55
Long-term beneficial effects in sustained responders to interferon-alfa therapy for chronic hepatitis C
     Bruno S, Battezzati PM, Bellati G, Manzin A, Maggioni M, Crosignani A, Borzio M, Solforosi L, Morabito A, Ideo G, Podda M.
Department ofMedicine, Surgery and Dentistry, School of Medicine Ospedale San Paolo, University of Milan, Italy.

Background/Aims: Assessment of chronic hepatitis C outcome in sustained responders to interferon requires prolonged observation and close monitoring. We prospectively studied the impact of sustained response on histology and clinically relevant outcomes.

Methods: The 47 sustained responders (ten with cirrhosis) from two interferon trials involving 235 chronic hepatitis C patients (81 with cirrhosis) were included. Hepatitis C virus (HCV) RNA was assessed every 6 months, liver histological changes from baseline, 6-12 and 48-72 months after treatment discontinuation.

Results: The mean follow-up was 102 +/- 19 months. HCV RNA became undetectable in 36/47 responders. Four responders, who had remained viremic, later relapsed. The histology progressively improved in non-viremic and viremic patients, with a more marked improvement in the former (P = 0.0089), normalizing in 53 vs. 0% (P = 0.0220). No patient progressed to cirrhosis. One non-viremic cirrhotic patient developed a hepatocellular carcinoma. Non-responders from the two original trials had worse histological outcomes and those with cirrhosis had a higher rate of clinically relevant events compared with cirrhotics showing a sustained biochemical response (4.5 vs. 1.2 cases/100 person-years; CI for the difference, 0.3-6.3).

Conclusions: Most sustained, virological responders without cirrhosis normalize liver histology in the long-term and are cured of the disease. Sustained responders remaining viremic still show histological improvement, albeit to a lesser extent.
PMID: 11434622 [PubMed - in process]

from Hepatogastroenterology 1999 Jul-Aug;46(28):2447-50
Ten year follow-up of patients with chronic hepatitis C treated with interferon.
     Ajello A, Freni MA, Spadaro A, Alessi N, Impellizzeri F, Consolo P, Resta ML, Ferrau O.
Clinica Medica 1, Universita di Messina, Italy.

Background/Aims: The impact of the treatment with interferon (IFN) on the natural history of chronic hepatitis C is not defined. The aim of this study was to evaluate the long term effect of the treatment in patients with chronic hepatitis C.

Methodology: In 31 patients with chronic hepatitis C (9 with cirrhosis) consecutively treated with recombinant alpha 2a interferon (r alpha 2a IFN), the evolution of the disease at 10 years from the therapy was evaluated by means of upper endoscopy, liver ultrasonography (US), liver function tests and hepatitis C virus (HCV) viremia.

Results: Among 10/31 patients previously classified as responders, only 1 has signs of evolution to cirrhosis; HCV-RNA is still present in 2. Among 21 non-responder patients, 5 developed hepatocarcinoma (HCC) and 4 died during the follow-up; HCV-RNA is present in all the patients still alive. The 6 patients already cirrhotic when treated have clinical signs of progression to Child class B and C. The biochemical, ultrasonographical and endoscopical evaluation shows onset of cirrhosis in 7 of the others.

Conclusions: Patients with chronic hepatitis C who respond to treatment with interferon have good outcome and rare evolution to cirrhosis. The treatment does not seem to influence the natural history of the disease in non-responders.

from Ital J Gastroenterol Hepatol 1999 Aug-Sep;31(6):454-8
Comment in: Ital J Gastroenterol Hepatol. 1999 Aug-Sep;31(6):459-61
Clinical outcome of chronic hepatitis C in patients treated with interferon: comparison between responders and non-responders
     Morisco F, Marmo R, Iasevoli P, Sessa G, Tuccillo C, Del Vecchio Blanco C, Caporaso N.
Department of Food Science, University of Naples Federico II, Italy.

Aim: To evaluate the prognosis of chronic hepatitis C in relation to interferon therapy response and the persistence of therapeutic benefits.

Patients/Methods: We studied the clinical outcome of 191 patients with chronic infection (152 chronic hepatitis C and 39 cirrhosis) treated with recombinant alpha-interferon (3-6 MU on alternate days for 1 year) during a mean period of 47 months (range 22.5-73.8). Control tests were done at 6-month intervals. HCV RNA was determined pre- and post-treatment in all participants, but continued yearly in long-term responders. The appearance of cirrhosis was estimated using a non-invasive method that utilizes a model based on clinical, instrumental and biochemical variables. Ascites, encephalopathy, haemorrhage, hepatocellular carcinoma, and death were considered liver-disease-related events.

Results: A total of 39 patients were long-term responders, 36 relapsers, and 116 non-responders; 92% of long-term responders cleared HCV RNA and remained negative throughout the study period. The 3 HCV-RNA-positive long-term responders continued being so. No biochemical relapse was observed in long-term responders regardless of virological status. New cirrhosis was observed in 3/30 relapsers, in 9/85 non-responders, and in no long-term responders. Overall, 9 episodes of severe events occurred in 20% of cirrhotics and in 0.6% of chronic hepatitis, all non-responders.

Conclusions: Long-term response interrupts the progression to cirrhosis and reduces the incidence of severe complications. Multivariate analysis revealed that "baseline diagnosis of cirrhosis" was the only independent factor predictive of an unfavourable outcome of chronic
PMID: 10575561 [PubMed - indexed for MEDLINE]


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