- Email: [email protected]
Treatment of naive patients with chronic hepatitis C
Journal of Hepatology 1999:31: (Suppl. 1): 168-173 Printed in Denmark All rights reserved Mtmksgaard
Copyright 8 European Association for the Study of the Liver 1999
. Copenhagen
Journal of Hepatology ISSN 0169-5185 ISBN 87-16-16386-9
Treatmentof naive patients with chronic hepatitis C Ola Weiland Department of Immunology, Microbiology, Pathology, and Infectious Diseases, Division of Infectious Diseases, Karolinska Institute at Huddinge Hospital, Huddinge, Sweden
‘Reatment of chronic hepatitis C virus (I-ICV) infection in naive patients with interferon alpha alone or in combination with ribavhin is reviewed. Two placebo-controlled random&xl studies including 150 patients have shown that ribavirin as single therapy at standard dosage (15 mg/kg bodyweight in two divided doses daily) only reduces ALT levels transiently during therapy, whereas HCV RNA levels are not substantially reduced. Interferon alpha (IFN) alone at standard dosage (3 MU t.i.w.) given for 12 months results in sustained virological response (SR) rates of some 15-25 % depending on the genotype and baseline HCV RNA levels. Ribavirin in combination with alpha interferon, in standard doses for 6-12 months significantly improves the sustained biochemical and virological response rates 2-3 times compared with IFN alone for 12 months. In the future, combination therapy will become standard therapy for most naive patients, at least those with unfavourable viral parameters such as a high
baseline viral load (>2-3 million gE/ml serum) and genotype la+lh In patients with favourable baseline viral characteristics (genotypes 2 and 3, irrespective of viral load) 6 months of combination therapy is likely to be sufficient, whereas those with unfavourable viral baseline characteristics will need longer combination treatment. Both genotype and baseline viral load need to be assessed to optimise the choice of therapy. Many questions must still be answered, such as the optimal dose of ribavirin and IFN in combination regimens, and the optimal treatment length. Furthermore, should induction treatment be used in combination regimens? What regimen should be used for patients with more advanced disease such as those with cirrhosis and decompensation?
0
(2, 3). The mechanism of ribavirin’s effect is poorly understood. Possible mechanisms include depletion of the intracellular triphosphate pools through direct inhibition of inosine monophosphate dehydrogenase, inhibition of the 5’-cap structure of viral mRNA and inhibition of the viral dependent RNA polymerases. It has, however, been suggested that ribavirin does not act as an antiviral drug, but rather as an immune modulator preserving Thl and reducing Th2 cytokine production (4). Recently, three placebo-controlled studies, one small initial study and two large multinational multicentre studies, have evaluated combination therapy versus IFN monotherapy in naive patients (2, 5, 6). The results in these studies are reviewed in this paper.
of naive PatientS with chronic hepatitis C virus (HCV) infection achieve viral eradication from standard interferon alpha (IFN) therapy (1). Due to the risk of serious adverse reactions, patients with autoimmune disorders, thyroid dysfunction, decompensated cirrhosis, thrombocytopenia, extrahepatic manifestations and posttransplant patients are usually not treated. Combination treatment with IFN and ribavirin significantly increases the sustained virological response (SR) rates in patients with relapse after an earlier IFN course and has become standard treatment for this category of patients NLY A SMALL fIXCtiOn
Correspondence: Prof. Ola Weiland, Department of Immunology, Microbiology, Pathology, and Infectious Diseases, Division of Infectious Diseases, Karolinska Institute at Huddinge Hospital, S-141 86 Huddinge, Sweden. Tel: 46 8 585 800 00. Fax: 46 8 585 819 16. e-mail: [email protected]
168
Key words: Alpha interferon; Anti-viral therapy; Chronic hepatitis; Hepatitis C; Hepatitis C virus RNA, Ribavirin.
Material
and Methods
Placebo-controlled randomised studies or metanalyses known to the author or identified through a Medline search where alpha interferon
Treatment of naive patients with HCV infection
alone or in combination with ribavirin was used for treatment of chronic HCV infection were reviewed. Definition of response to treatment
End-of-therapy (ETR) and sustained responses (SR) were defined as biochemical (normal ALT levels) or virological (a negative HCV RNA test result by PCR) at the end of treatment and at follow-up ~6 months post treatment. Treatment schemes
If not stated otherwise, the alpha interferon dose given was 3 MU t.i.w. and the ribavirin dose 1200 mg for patients heavier than 75 kg and 1000 mg for patients below this weight.
Placebo-controlled interferon and ribavirin combination studies Early pilot studies showed that a high percentage of relapsers, and O-25% of non-responders to previous alpha interferon therapy have a sustained virological response when ribavirin is combined with interferon for 24 weeks as reviewed at the NIH consensus meeting in 1997 (1, 2). The high response rate in former relapsers has recently been confirmed in a large placebo-controlled study (3). A meta-analysis conducted in Europe has shown that both naive and relapse patients with low response rates to alpha interferon, such as patients with genotype 1b and cirrhosis, will also have an increased rate of sustained response virologically, by a factor of 2-3, to combination treatment compared with IFN monotherapy (7). The favourable results of combination treatment in naive patients seen in early pilot studies (8-11) have recently been confirmed in three controlled studies (5, 6, 12). In the first Swedish study, which compared 24 weeks of combination treatment with 24 weeks IFN
monotherapy, the overall virological SR rate increased 2-fold with combination therapy in naive patients (12). In patients with a high baseline viral load, however, the increase in virological SR was lo-fold with the combination. It thus increased from 4% in the IFN group to nearly 40% in the combination group in patients with baseline HCV RNA levels >3 million gE/ml serum. In patients with low baseline viral loads (<3 milion gE/ ml) combination treatment was not shown to be better than IFN alone in this study (Table 1). Patients with virological SR in the Swedish study have had a lasting response now for more than 2 years after the end of treatment (Weiland et al., unpublished). This suggests that an SR after combination therapy is long lasting, similar to that reported after IFN treatment alone of at least 5 years (13, 14). The Swedish study was not large enough to determine the importance of genotypes and host-related factors such as age at onset, gender and histological stage and grade. In the two large placebo-controlled international multicentre studies organised by Schering-Plough and including more than 1700 patients, this was investigated more completely (5, 6). The two studies were nearly identical in methodology, although the international study only included one IFN/placebo group with 48 weeks of treatment, whereas the US multicentre study included IFN/placebo treatment for 24 and 48 weeks. The US study (6) showed that the 24-week IFN/placebo arm rendered fewer virological SR than the 48-week arm (13/231 (6%) vs 29/225 (13%), ~~0.007) and hence this arm will not be discussed further. The very low virological SR in the 24-week IFN monotherapy US study
TABLE 1 End-of-treatment and SR virological response in the Swedish randomised placebo-controlled treated 24 weeks according to baseline viral load
study* in naive patients with chronic HCV infection
End-of-treatment
Baseline viral load
HCV RNA 53 million gE/ml serum HCV RNA >3 million aElm serum
Sustained response
IFN/ribavirin
IFN/placebo
IFN/ribavirin
IFN/placebo
8/21 (38%) 18129(62%)
13/24 (54%) 13/26 (50%)
6/21 (29%) 12129(4 1%Y
8124 (33%) II26 (4%)a
* Reference (12). ap<0.0009, Fisher’s exact test.
TABLE 2 End-of-treatment (ETR) and sustained (SR) virological response (percentages) in two randomised controlled multicentre studies performed in naive patients with chronic HCV infection according to treatment schedule Study
ETR IFN/placebo 48 weeks
ETR IFN/ribavirin 24 weeks
ETR IFN/ribavirin 48 weeks
Poynard et al. (5) n=832 McHutchison et al. (6) n=681 Total n=1513
931278 (33%) 54/225 (24%) 1471503(29%)
1571277(57%) 121/228 (53%) 2781505 (55%)
1451277(52%) 115/228 (50%) 2601505 (5 1%)
SR IFN/placebo 48 weeks 53/278 (19%) 29/225 (13%) 82/503 (16%)
SR IFN/ribavirin 24 weeks
SR IFN/ribavirin 48 weeks
961277 (35%) 70/228 (31%) 1661505(33%)
118/277 (43%) 87/228 (38%) 205/505 (41%)
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0. Weiland
arm compared with that in the Swedish study may partly be explained by the high prevalence of genotype 1 in the US (72%) compared with the Swedish study (44%). Table 2 shows the virological end-of-treatment (ETR) and sustained (SR) response according to treatment arm. Overall, the virological ETR was nearly doubled by combination treatment, reaching 50% in the combination arm irrespective of treatment length. The SR, however, was further improved by extending the combination treatment from 24 to 48 weeks with corresponding SR rates of 33% and 41%, respectively Q.KO.01, Chi-square). Hence, the SR improvement with combination treatment was due to increased ETR and diminished relapse rates compared with IFN monotherapy. Tables 3 and 4 show the virological SR according to baseline HCV RNA level and genotype in the different treatment arms. Overall there was a 3-fold higher response rate in the combination arms than in the IFN arm in patients with high baseline HCV RNA levels and a 10% further increase in response rate when the combination treatment was prolonged from 24 to 48 weeks (p
TABLE 3 Sustained (SR) virological response (percentages) according to baseline viral load in the different treatment arms in two randomised controlled multicentm studies performed in naive patients with chronic HCV infection Study
Poynard et al. (5) HCV RNA >2 million gE/ml HCV RNA <2 million gE/ml
SR IFN/placebo 48 weeks
SR IFN/ribavirin 24 weeks
24/183 (13%)
481169 (28%)
64/l 62 (40%)
29/95 (31%)
48/108 (44%)
54/l 15 (47%)
441166 (27%)
54/152 (36%)
26/62 (42%)
33176(43%)
35/345 (10%)
92/335 (27%)
118/314 (38%)
47058 (30%)
74/170 (44%)
871191 (46%)
McHutchison et al. (6) HCV RNA 1l/162 (7%) >2 million gE/ml HCV RNA 18/63 (29%) <2 million gE/ml Total HCV RNA >2 million gE/ml HCV RNA <2 million gE/ml
170
SR IFN/ribavirin 48 weeks
TABLE 4 Sustained (SR) virological response (percentages) according to genotype in the different treatment arms in two randomised controlled multicentre studies performed in naive patients with chronic HCV infection Study
Poynard et al. (5) Genotype l* Genotype non- 1**
SR IFN/placebo 48 weeks 20/179 (11%) 33199 (33%)
McHutchison et al. (6) Genotype 1 1l/162 (7%) Genotype non-l 18/63 (29%) Total Genotype 1 Genotype non- 1
33/341 (10%) 511162(31%)
SR IFN/ribavirin 24 weeks
SR IFN/ribavirin 48 weeks
32/177 (18%) 64/100 (64%)
56/180 (31%) 62/97 (64%)
26064 (16%) 44164 (69%)
46/166 (28%) 41/61 (66%)
58/341 (17%) 102/346 (29%) 110064 (67%) 103058 (65%)
*Includes a few genotypes 4,5 or 6 cases. **Genotypes 2 and 3 cases.
with IFN alone (p
Combined prediction of virological SR by genotype and viral load The virological SR according to the combined influence of baseline viral load and genotype was briefly given in the US study (6). In patients with genotype non-l the virological SR was the same with 24 and 48 weeks of combination treatment and 2-fold better than IFN monotherapy, irrespective of baseline viral load (6). This indicates that 24 weeks of combination treatment is enough for favourable genotypes like 2 and 3, irrespective of viral load. In patients with genotype 1 and low baseline HCV RNA this also seems to be the case, whereas 48 weeks’ combination therapy is better in patients with genotype 1 and high baseline viral load (6). In the analysis of the US and international multicentre studies, the combined action of baseline viral load and genotype on the virological SR confirmed this (Janice Albrecht, personal communication) (Table
Treatment of naive patients with HCV infection TABLE 5 Sustained (SR) virological response (percentages) according to baseline HCV RNA levels and genotype in the different treatment arms in two random&d controlled multicentre studies. * Performed in naive patients with chronic HCV infection Genotype/viral load
SR IFN/placebo 48 weeks
SR IFNlribavirin 24 weeks
SR IFN/ribavirin 48 weeks
Non-1152 million Non. 1/>2 million 1152 million 02 million
36% 26% 25% 3%
61% 62% 32% 10%
64% 60% 33% 27%
*References (5, 6).
5). Table 5 clearly shows that combination treatment is better in all combinations of genotype and viral load, and that 24 weeks of combination treatment is enough for genotypes 2 and 3 irrespective of viral load and also for genotype 1 if the viral load is below 2 million copies per ml.
Others have found that the final virological SR can already be predicted by week 4 (17) when a positive HCV RNA test is predictive of a non-response in 99% and 97% for IFN monotherapy for 6 and 12 months, respectively (17). The same authors claimed that a positive HCV RNA after 12 weeks of treatment was also predictive of a non-response in 100% of patients given combination therapy for 6 months (17). In the US multicentre study, the authors state that 12 out of 125 combination-treated patients positive for HCV RNA at 12 weeks achieved virological SR when treated for 48 weeks (18). Based on this finding, it was recommended that treatment not be stopped before 24 weeks if HCV RNA was positive. On the other hand, none of the patients achieved virological SR if HCV RNA was positive after 12 weeks of treatment in relapse patients given combination treatment for 6 months (3). Based on these different findings, no firm recommendations as to when treatment should stop, can be given. The optimal time is likely to be different depending on genotype and baseline viral load,
Histological outcome Pretreatment and post-treatment liver-biopsy specimens were available in 6873% of patients in two large multicentre studies (5, 6), and in 90% of the patients in the Swedish study (12). Overall histological improvement occurred in all treated patients and was generally more pronounced in the combination treatment. The effect was most marked in patients with a sustained response, paralleling the virological outcome. Treatment had no significant effect on fibrosis. Progression of fibrosis, however, was halted with treatment as reviewed by Poynard in another session of the consensus meeting. Overall, patients with more advanced liver histology, in particular cirrhosis, responded less well. The number of cirrhotic patients, however, was too small (5’/0) to allow firm conclusions in the multicentre studies. Schalm et al. (15), however, have shown that patients with cirrhosis also respond better to combination therapy than to IFN monotherapy, and that combination therapy reaches results in cirrhotic patients equivalent to IFN monotherapy results in noncirrhotic patients with 24 weeks of combination therapy courses.
Adverse effects The number of adverse effects increased with combination treatment and withdrawals reached 19% with 48 weeks of combination treatment versus 14% with IFN alone for 48 weeks. Dose reductions were common, and were due to anaemia in 7-9% of combinationtreated patients, and due to other adverse events slightly more often in these patients. This is important, especially since patients with more advanced liver disease, most in need of treatment, were not included in these studies and can be anticipated to have more adverse effects. Thus, the percentage of patients with cirrhosis only reached 5% in the international and US studies (5, 6) and decompensated patients were excluded. Combination treatment also caused significantly more dyspnea, pharyngitis, pruritis, nausea, insomnia and anorexia compared to IFN alone. In the last 24 weeks of treatment in the 48-week combination group, adverse psychological effects (depression, irritability, insomnia, anxiety) were often the cause for withdrawals.
Discussion Can virological SR be predicted during treatment? The NIH consensus meeting in 1997 stated that treatment should be stopped if no response had been achieved 12 weeks into treatment. However, if HCV RNA is still positive 12 weeks into treatment, 5% of any virological SR will be missed, according to the Swedish experience with IFN monotherapy (16).
Combination treatment was clearly more beneficial than IFN alone in naive patients, and increased the response rate 2-3-fold; in some categories with unfavourable virological demographics such as high baseline viral load and genotypes la and lb, the response rate was increased even more. Although combination treatment was generally well tolerated, ribavirin induced a dose dependent and reversible haemolysis, re171
0. Weiland
quiring dose tapering in slightly less than 10% of treated patients. This dose tapering, however, did not change the favourable treatment outcome. In the future, combination treatment will become standard therapy for most, if not all, naive patients since it is clearly associated with an increased virological SR which parallels histological improvement. This, in turn, probably stops and possibly reverses the deterioration and slowly evolving fibrosis seen in the liver, as has been shown in patients with virological SR after IFN monotherapy (13, 14). Recently, this has also been documented in a few patients 2 years after stopping combination treatment (19). In this small series, diminished fibrosis was also noted (19). Since adverse effects will increase with combination treatment, close monitoring must be performed. There is a question whether all naive patients with chronic HCV infection should receive combination treatment or if a small subset with mild disease, low viral load and favourable genotypes can still be treated with interferon alone as a first choice of treatment. Since 6 months of combination treatment is superior to 12 months of IFN monotherapy, the shorter course is more likely to be chosen by patients. Based on the two large controlled studies, it seems reasonable to suggest that all patients with genotypes 2 and 3 receive combination therapy for 24 weeks, which also seems to be enough for genotype 1 patients with low baseline viral loads. This approach would also reduce adverse events, in particular the adverse psychological effects that were common causes of treatment withdrawal in the latter 24 weeks of the 48 weeks of combination treatment. Patients with a high baseline viral load and genotype 1 benefit most from the prolonged combination treatment of 48 weeks, and this therapy should probably be reserved for these patients. For this latter group, a positive qualitative HCV RNA test after 12 weeks of therapy should probably not be an indication to stop treatment, since one in 10 such patients will eventually clear the virus if treated for 48 weeks. For all other categories, this must be further evaluated from the database generated by the large studies, which can provide predictive data for the fmal virological SR in patients with a positive HCV RNA test at weeks 4, 12 and 24 of treatment, according to genotype, viral load and treatment length. Many patients had to taper their ribavirin dose due to treatment-induced anaemia, yet the response in these patients was more favourable than with IFN monotherapy. This seems to indicate that the optimal ribavirin dose has not yet been defined, and indicates that lower doses can be used with the same efficacy and fewer adverse effects (5, 6). 172
In the future, it is likely that the optimal ribavirin dose will be lower than that used in the controlled studies (5, 6, 12). This will decrease the adverse events and in particular dose dependent anaemia and reduce costs of treatment. The optimal dose of IFN in combination treatment must also be further studied. According to viral kinetic studies during IFN treatment, higher doses than those presently used seem to be needed in patients infected with genotype 1 (20). Kinetic studies also indicate that induction IFN treatment can result in better response rates than doses three times a week (20), in particular for genotype 1 patients. Many questions remain to be answered: Can patients with more advanced disease tolerate combination therapy and prolonged combination therapy? Is the risk of drug resistance reduced with combination treatment? What treatment should be given to transplant patients and children? A major issue is the management of the many patients who do not respond to combination treatment. Hopefully, new and better nucleoside analogues, helicase and protease inhibitors, and optimised ribavirin and IFN schedules will be developed and become available for these patients in the near future.
References 1. Statement F! Management of hepatitis C: NIH consensus development conference panel statement. Hepatology 1997: 26 (suppl 1): 2s-10s. 2. Reichard 0, Schvarcz R, Weiland 0. Therapy of hepatitis C: alpha interferon and ribavirin. Hepatology 1997: 26 (suppl 1): 108S-11 IS. 3. Davis G, Esteban, Muir R, Rustgi V et al. Interferon alpha-2b alone or in combination with ribavirin for the treatment of relapse of chronic hepatitis C. N Engl J Med 1998: 339: 1493-1499. 4. Hultgren C, Milich D, Weiland 0, Sallberg M. The antiviral compound ribavirin modulates the T helper (Th)l/ThZ subset balance in hepatitis B and C virus-specitic immune responses. J Gen Virol 1998: 79: 2381-2391. 5. Poynard T, Marcellin P, Lee S et al. Random&d trial of interferon alpha-2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alpha-2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. Lancet 1998: 352: 1426 1432. 6. McHutchison J, Gordon S, Schiff E et al. Interferon alpha-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. N Engl J Med 1998: 339: 148>1492. 7. Schahn S, Hansen B, Chemello L et al. Ribavirin enhances the efficacy but not the adverse effects of interferon in chronic hepatitis C: a meta-analysis of individual patient data from European centers. J Hepatol 1997: 26: 961-966. 8. Chemello L, Cavaletto L, Bernardinello E, Guido M, Pontisso P, Alberti A. The effect of interferon alpha and ribavirin combination therapy in naive patients with chronic hepatitis C. J Hepato1 1995: 23 (suppl 2): 8-12. 9. Braconier J, Paulsen 0, Engman K, Widell A. Combined alphainterferon and ribavirin treatment for chronic hepatitis C virus infection. Stand J Infect Dis 1995: 27: 325329. 10. Kakumu S, Yoshioko K, Wakita T, Ishikawa T, Takayanagi M, Higashi Y. A pilot study of ribavirin and interferon beta for the treatment of chronic hepatitis C. Gastroenterology 1993: 105: 507-512.
Treatment of naive patients with HCV infection 11. Lai M-Y, Kao J-H, Yang P-M et al. Long-term efficacy of ribavirin plus interferon alpha in the treatment of chronic hepatitis C. Gastroenterology 1996: 111: 1307-1312. 12. Reichard 0, Norkrans G, Fryden A, Braconier J, Sonnerborg A, Weiland 0. Randomised, double-blind, placebo-controlled trial of interferon alpha-2b with and without ribavirin for chronic hepatitis C. Lancet 1998: 351: 83-87. 13. Marcellin P, Boyer N, Gervais A et al. Long-term histologic improvement and loss of detectable intrahepatic HCV RNA in patients with chronic hepatitis C and sustained response to interferon-alpha therapy. Ann Intern Med 1997: 127: 8755881. 14. Reichard 0, Glaumann H, Frydtn A, Norkrans G, Wejstal R, Weiland 0. Long-term follow-up of chronic hepatitis C patients with sustained virological response to alpha-interferon. J Hepatol 1999: 30: 783-787. 15. Schahn S, Weiland 0, Hansen B et al. and the EUROHEP Study Group for Viral Hepatitis. Interferon/ribavirin treatment for chronic hepatitis C with and without cirrhosis: a meta-analysis of individual patient data. Gastroenterology, in press.
16. Weiland 0, Braconier J, Fryden A et al. Influence of pretreatment factors on outcome of interferon alpha treatment in patients with chronic hepatitis C infection. Stand J Infect Dis 1999: 31: 115118. 17. Brouwer J, Hansen B, Niesters H, Schahn S. Early prediction of response in interferon monotherapy and in interferon-ribavirin combination therapy for chronic hepatitis C: HCV RNA at 4 weeks versus ALT J Hepatol 1999: 30: 192-198. 18. Poynard T. Interferon alpha for chronic hepatitis C infection Correspondence - Author’s reply. Lancet 1999: 353: 499-500. 19. Schvarcz R, Glaumann H, Reichard 0, Weiland 0. Histological and virological long-term outcome in patients treated with interferon alpha-2b and ribavirin for chronic hepatitis C. J Viral Hepatitis 1999: 6: 237-242. 20. Neumann A, Lam N, Dahari H et al. Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-alpha therapy. Science 1998: 282: 103-107.
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Copyright 8 European Association for the Study of the Liver 1999
. Copenhagen
Journal of Hepatology ISSN 0169-5185 ISBN 87-16-16386-9
Treatmentof naive patients with chronic hepatitis C Ola Weiland Department of Immunology, Microbiology, Pathology, and Infectious Diseases, Division of Infectious Diseases, Karolinska Institute at Huddinge Hospital, Huddinge, Sweden
‘Reatment of chronic hepatitis C virus (I-ICV) infection in naive patients with interferon alpha alone or in combination with ribavhin is reviewed. Two placebo-controlled random&xl studies including 150 patients have shown that ribavirin as single therapy at standard dosage (15 mg/kg bodyweight in two divided doses daily) only reduces ALT levels transiently during therapy, whereas HCV RNA levels are not substantially reduced. Interferon alpha (IFN) alone at standard dosage (3 MU t.i.w.) given for 12 months results in sustained virological response (SR) rates of some 15-25 % depending on the genotype and baseline HCV RNA levels. Ribavirin in combination with alpha interferon, in standard doses for 6-12 months significantly improves the sustained biochemical and virological response rates 2-3 times compared with IFN alone for 12 months. In the future, combination therapy will become standard therapy for most naive patients, at least those with unfavourable viral parameters such as a high
baseline viral load (>2-3 million gE/ml serum) and genotype la+lh In patients with favourable baseline viral characteristics (genotypes 2 and 3, irrespective of viral load) 6 months of combination therapy is likely to be sufficient, whereas those with unfavourable viral baseline characteristics will need longer combination treatment. Both genotype and baseline viral load need to be assessed to optimise the choice of therapy. Many questions must still be answered, such as the optimal dose of ribavirin and IFN in combination regimens, and the optimal treatment length. Furthermore, should induction treatment be used in combination regimens? What regimen should be used for patients with more advanced disease such as those with cirrhosis and decompensation?
0
(2, 3). The mechanism of ribavirin’s effect is poorly understood. Possible mechanisms include depletion of the intracellular triphosphate pools through direct inhibition of inosine monophosphate dehydrogenase, inhibition of the 5’-cap structure of viral mRNA and inhibition of the viral dependent RNA polymerases. It has, however, been suggested that ribavirin does not act as an antiviral drug, but rather as an immune modulator preserving Thl and reducing Th2 cytokine production (4). Recently, three placebo-controlled studies, one small initial study and two large multinational multicentre studies, have evaluated combination therapy versus IFN monotherapy in naive patients (2, 5, 6). The results in these studies are reviewed in this paper.
of naive PatientS with chronic hepatitis C virus (HCV) infection achieve viral eradication from standard interferon alpha (IFN) therapy (1). Due to the risk of serious adverse reactions, patients with autoimmune disorders, thyroid dysfunction, decompensated cirrhosis, thrombocytopenia, extrahepatic manifestations and posttransplant patients are usually not treated. Combination treatment with IFN and ribavirin significantly increases the sustained virological response (SR) rates in patients with relapse after an earlier IFN course and has become standard treatment for this category of patients NLY A SMALL fIXCtiOn
Correspondence: Prof. Ola Weiland, Department of Immunology, Microbiology, Pathology, and Infectious Diseases, Division of Infectious Diseases, Karolinska Institute at Huddinge Hospital, S-141 86 Huddinge, Sweden. Tel: 46 8 585 800 00. Fax: 46 8 585 819 16. e-mail: [email protected]
168
Key words: Alpha interferon; Anti-viral therapy; Chronic hepatitis; Hepatitis C; Hepatitis C virus RNA, Ribavirin.
Material
and Methods
Placebo-controlled randomised studies or metanalyses known to the author or identified through a Medline search where alpha interferon
Treatment of naive patients with HCV infection
alone or in combination with ribavirin was used for treatment of chronic HCV infection were reviewed. Definition of response to treatment
End-of-therapy (ETR) and sustained responses (SR) were defined as biochemical (normal ALT levels) or virological (a negative HCV RNA test result by PCR) at the end of treatment and at follow-up ~6 months post treatment. Treatment schemes
If not stated otherwise, the alpha interferon dose given was 3 MU t.i.w. and the ribavirin dose 1200 mg for patients heavier than 75 kg and 1000 mg for patients below this weight.
Placebo-controlled interferon and ribavirin combination studies Early pilot studies showed that a high percentage of relapsers, and O-25% of non-responders to previous alpha interferon therapy have a sustained virological response when ribavirin is combined with interferon for 24 weeks as reviewed at the NIH consensus meeting in 1997 (1, 2). The high response rate in former relapsers has recently been confirmed in a large placebo-controlled study (3). A meta-analysis conducted in Europe has shown that both naive and relapse patients with low response rates to alpha interferon, such as patients with genotype 1b and cirrhosis, will also have an increased rate of sustained response virologically, by a factor of 2-3, to combination treatment compared with IFN monotherapy (7). The favourable results of combination treatment in naive patients seen in early pilot studies (8-11) have recently been confirmed in three controlled studies (5, 6, 12). In the first Swedish study, which compared 24 weeks of combination treatment with 24 weeks IFN
monotherapy, the overall virological SR rate increased 2-fold with combination therapy in naive patients (12). In patients with a high baseline viral load, however, the increase in virological SR was lo-fold with the combination. It thus increased from 4% in the IFN group to nearly 40% in the combination group in patients with baseline HCV RNA levels >3 million gE/ml serum. In patients with low baseline viral loads (<3 milion gE/ ml) combination treatment was not shown to be better than IFN alone in this study (Table 1). Patients with virological SR in the Swedish study have had a lasting response now for more than 2 years after the end of treatment (Weiland et al., unpublished). This suggests that an SR after combination therapy is long lasting, similar to that reported after IFN treatment alone of at least 5 years (13, 14). The Swedish study was not large enough to determine the importance of genotypes and host-related factors such as age at onset, gender and histological stage and grade. In the two large placebo-controlled international multicentre studies organised by Schering-Plough and including more than 1700 patients, this was investigated more completely (5, 6). The two studies were nearly identical in methodology, although the international study only included one IFN/placebo group with 48 weeks of treatment, whereas the US multicentre study included IFN/placebo treatment for 24 and 48 weeks. The US study (6) showed that the 24-week IFN/placebo arm rendered fewer virological SR than the 48-week arm (13/231 (6%) vs 29/225 (13%), ~~0.007) and hence this arm will not be discussed further. The very low virological SR in the 24-week IFN monotherapy US study
TABLE 1 End-of-treatment and SR virological response in the Swedish randomised placebo-controlled treated 24 weeks according to baseline viral load
study* in naive patients with chronic HCV infection
End-of-treatment
Baseline viral load
HCV RNA 53 million gE/ml serum HCV RNA >3 million aElm serum
Sustained response
IFN/ribavirin
IFN/placebo
IFN/ribavirin
IFN/placebo
8/21 (38%) 18129(62%)
13/24 (54%) 13/26 (50%)
6/21 (29%) 12129(4 1%Y
8124 (33%) II26 (4%)a
* Reference (12). ap<0.0009, Fisher’s exact test.
TABLE 2 End-of-treatment (ETR) and sustained (SR) virological response (percentages) in two randomised controlled multicentre studies performed in naive patients with chronic HCV infection according to treatment schedule Study
ETR IFN/placebo 48 weeks
ETR IFN/ribavirin 24 weeks
ETR IFN/ribavirin 48 weeks
Poynard et al. (5) n=832 McHutchison et al. (6) n=681 Total n=1513
931278 (33%) 54/225 (24%) 1471503(29%)
1571277(57%) 121/228 (53%) 2781505 (55%)
1451277(52%) 115/228 (50%) 2601505 (5 1%)
SR IFN/placebo 48 weeks 53/278 (19%) 29/225 (13%) 82/503 (16%)
SR IFN/ribavirin 24 weeks
SR IFN/ribavirin 48 weeks
961277 (35%) 70/228 (31%) 1661505(33%)
118/277 (43%) 87/228 (38%) 205/505 (41%)
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arm compared with that in the Swedish study may partly be explained by the high prevalence of genotype 1 in the US (72%) compared with the Swedish study (44%). Table 2 shows the virological end-of-treatment (ETR) and sustained (SR) response according to treatment arm. Overall, the virological ETR was nearly doubled by combination treatment, reaching 50% in the combination arm irrespective of treatment length. The SR, however, was further improved by extending the combination treatment from 24 to 48 weeks with corresponding SR rates of 33% and 41%, respectively Q.KO.01, Chi-square). Hence, the SR improvement with combination treatment was due to increased ETR and diminished relapse rates compared with IFN monotherapy. Tables 3 and 4 show the virological SR according to baseline HCV RNA level and genotype in the different treatment arms. Overall there was a 3-fold higher response rate in the combination arms than in the IFN arm in patients with high baseline HCV RNA levels and a 10% further increase in response rate when the combination treatment was prolonged from 24 to 48 weeks (p
TABLE 3 Sustained (SR) virological response (percentages) according to baseline viral load in the different treatment arms in two randomised controlled multicentm studies performed in naive patients with chronic HCV infection Study
Poynard et al. (5) HCV RNA >2 million gE/ml HCV RNA <2 million gE/ml
SR IFN/placebo 48 weeks
SR IFN/ribavirin 24 weeks
24/183 (13%)
481169 (28%)
64/l 62 (40%)
29/95 (31%)
48/108 (44%)
54/l 15 (47%)
441166 (27%)
54/152 (36%)
26/62 (42%)
33176(43%)
35/345 (10%)
92/335 (27%)
118/314 (38%)
47058 (30%)
74/170 (44%)
871191 (46%)
McHutchison et al. (6) HCV RNA 1l/162 (7%) >2 million gE/ml HCV RNA 18/63 (29%) <2 million gE/ml Total HCV RNA >2 million gE/ml HCV RNA <2 million gE/ml
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SR IFN/ribavirin 48 weeks
TABLE 4 Sustained (SR) virological response (percentages) according to genotype in the different treatment arms in two randomised controlled multicentre studies performed in naive patients with chronic HCV infection Study
Poynard et al. (5) Genotype l* Genotype non- 1**
SR IFN/placebo 48 weeks 20/179 (11%) 33199 (33%)
McHutchison et al. (6) Genotype 1 1l/162 (7%) Genotype non-l 18/63 (29%) Total Genotype 1 Genotype non- 1
33/341 (10%) 511162(31%)
SR IFN/ribavirin 24 weeks
SR IFN/ribavirin 48 weeks
32/177 (18%) 64/100 (64%)
56/180 (31%) 62/97 (64%)
26064 (16%) 44164 (69%)
46/166 (28%) 41/61 (66%)
58/341 (17%) 102/346 (29%) 110064 (67%) 103058 (65%)
*Includes a few genotypes 4,5 or 6 cases. **Genotypes 2 and 3 cases.
with IFN alone (p
Combined prediction of virological SR by genotype and viral load The virological SR according to the combined influence of baseline viral load and genotype was briefly given in the US study (6). In patients with genotype non-l the virological SR was the same with 24 and 48 weeks of combination treatment and 2-fold better than IFN monotherapy, irrespective of baseline viral load (6). This indicates that 24 weeks of combination treatment is enough for favourable genotypes like 2 and 3, irrespective of viral load. In patients with genotype 1 and low baseline HCV RNA this also seems to be the case, whereas 48 weeks’ combination therapy is better in patients with genotype 1 and high baseline viral load (6). In the analysis of the US and international multicentre studies, the combined action of baseline viral load and genotype on the virological SR confirmed this (Janice Albrecht, personal communication) (Table
Treatment of naive patients with HCV infection TABLE 5 Sustained (SR) virological response (percentages) according to baseline HCV RNA levels and genotype in the different treatment arms in two random&d controlled multicentre studies. * Performed in naive patients with chronic HCV infection Genotype/viral load
SR IFN/placebo 48 weeks
SR IFNlribavirin 24 weeks
SR IFN/ribavirin 48 weeks
Non-1152 million Non. 1/>2 million 1152 million 02 million
36% 26% 25% 3%
61% 62% 32% 10%
64% 60% 33% 27%
*References (5, 6).
5). Table 5 clearly shows that combination treatment is better in all combinations of genotype and viral load, and that 24 weeks of combination treatment is enough for genotypes 2 and 3 irrespective of viral load and also for genotype 1 if the viral load is below 2 million copies per ml.
Others have found that the final virological SR can already be predicted by week 4 (17) when a positive HCV RNA test is predictive of a non-response in 99% and 97% for IFN monotherapy for 6 and 12 months, respectively (17). The same authors claimed that a positive HCV RNA after 12 weeks of treatment was also predictive of a non-response in 100% of patients given combination therapy for 6 months (17). In the US multicentre study, the authors state that 12 out of 125 combination-treated patients positive for HCV RNA at 12 weeks achieved virological SR when treated for 48 weeks (18). Based on this finding, it was recommended that treatment not be stopped before 24 weeks if HCV RNA was positive. On the other hand, none of the patients achieved virological SR if HCV RNA was positive after 12 weeks of treatment in relapse patients given combination treatment for 6 months (3). Based on these different findings, no firm recommendations as to when treatment should stop, can be given. The optimal time is likely to be different depending on genotype and baseline viral load,
Histological outcome Pretreatment and post-treatment liver-biopsy specimens were available in 6873% of patients in two large multicentre studies (5, 6), and in 90% of the patients in the Swedish study (12). Overall histological improvement occurred in all treated patients and was generally more pronounced in the combination treatment. The effect was most marked in patients with a sustained response, paralleling the virological outcome. Treatment had no significant effect on fibrosis. Progression of fibrosis, however, was halted with treatment as reviewed by Poynard in another session of the consensus meeting. Overall, patients with more advanced liver histology, in particular cirrhosis, responded less well. The number of cirrhotic patients, however, was too small (5’/0) to allow firm conclusions in the multicentre studies. Schalm et al. (15), however, have shown that patients with cirrhosis also respond better to combination therapy than to IFN monotherapy, and that combination therapy reaches results in cirrhotic patients equivalent to IFN monotherapy results in noncirrhotic patients with 24 weeks of combination therapy courses.
Adverse effects The number of adverse effects increased with combination treatment and withdrawals reached 19% with 48 weeks of combination treatment versus 14% with IFN alone for 48 weeks. Dose reductions were common, and were due to anaemia in 7-9% of combinationtreated patients, and due to other adverse events slightly more often in these patients. This is important, especially since patients with more advanced liver disease, most in need of treatment, were not included in these studies and can be anticipated to have more adverse effects. Thus, the percentage of patients with cirrhosis only reached 5% in the international and US studies (5, 6) and decompensated patients were excluded. Combination treatment also caused significantly more dyspnea, pharyngitis, pruritis, nausea, insomnia and anorexia compared to IFN alone. In the last 24 weeks of treatment in the 48-week combination group, adverse psychological effects (depression, irritability, insomnia, anxiety) were often the cause for withdrawals.
Discussion Can virological SR be predicted during treatment? The NIH consensus meeting in 1997 stated that treatment should be stopped if no response had been achieved 12 weeks into treatment. However, if HCV RNA is still positive 12 weeks into treatment, 5% of any virological SR will be missed, according to the Swedish experience with IFN monotherapy (16).
Combination treatment was clearly more beneficial than IFN alone in naive patients, and increased the response rate 2-3-fold; in some categories with unfavourable virological demographics such as high baseline viral load and genotypes la and lb, the response rate was increased even more. Although combination treatment was generally well tolerated, ribavirin induced a dose dependent and reversible haemolysis, re171
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quiring dose tapering in slightly less than 10% of treated patients. This dose tapering, however, did not change the favourable treatment outcome. In the future, combination treatment will become standard therapy for most, if not all, naive patients since it is clearly associated with an increased virological SR which parallels histological improvement. This, in turn, probably stops and possibly reverses the deterioration and slowly evolving fibrosis seen in the liver, as has been shown in patients with virological SR after IFN monotherapy (13, 14). Recently, this has also been documented in a few patients 2 years after stopping combination treatment (19). In this small series, diminished fibrosis was also noted (19). Since adverse effects will increase with combination treatment, close monitoring must be performed. There is a question whether all naive patients with chronic HCV infection should receive combination treatment or if a small subset with mild disease, low viral load and favourable genotypes can still be treated with interferon alone as a first choice of treatment. Since 6 months of combination treatment is superior to 12 months of IFN monotherapy, the shorter course is more likely to be chosen by patients. Based on the two large controlled studies, it seems reasonable to suggest that all patients with genotypes 2 and 3 receive combination therapy for 24 weeks, which also seems to be enough for genotype 1 patients with low baseline viral loads. This approach would also reduce adverse events, in particular the adverse psychological effects that were common causes of treatment withdrawal in the latter 24 weeks of the 48 weeks of combination treatment. Patients with a high baseline viral load and genotype 1 benefit most from the prolonged combination treatment of 48 weeks, and this therapy should probably be reserved for these patients. For this latter group, a positive qualitative HCV RNA test after 12 weeks of therapy should probably not be an indication to stop treatment, since one in 10 such patients will eventually clear the virus if treated for 48 weeks. For all other categories, this must be further evaluated from the database generated by the large studies, which can provide predictive data for the fmal virological SR in patients with a positive HCV RNA test at weeks 4, 12 and 24 of treatment, according to genotype, viral load and treatment length. Many patients had to taper their ribavirin dose due to treatment-induced anaemia, yet the response in these patients was more favourable than with IFN monotherapy. This seems to indicate that the optimal ribavirin dose has not yet been defined, and indicates that lower doses can be used with the same efficacy and fewer adverse effects (5, 6). 172
In the future, it is likely that the optimal ribavirin dose will be lower than that used in the controlled studies (5, 6, 12). This will decrease the adverse events and in particular dose dependent anaemia and reduce costs of treatment. The optimal dose of IFN in combination treatment must also be further studied. According to viral kinetic studies during IFN treatment, higher doses than those presently used seem to be needed in patients infected with genotype 1 (20). Kinetic studies also indicate that induction IFN treatment can result in better response rates than doses three times a week (20), in particular for genotype 1 patients. Many questions remain to be answered: Can patients with more advanced disease tolerate combination therapy and prolonged combination therapy? Is the risk of drug resistance reduced with combination treatment? What treatment should be given to transplant patients and children? A major issue is the management of the many patients who do not respond to combination treatment. Hopefully, new and better nucleoside analogues, helicase and protease inhibitors, and optimised ribavirin and IFN schedules will be developed and become available for these patients in the near future.
References 1. Statement F! Management of hepatitis C: NIH consensus development conference panel statement. Hepatology 1997: 26 (suppl 1): 2s-10s. 2. Reichard 0, Schvarcz R, Weiland 0. Therapy of hepatitis C: alpha interferon and ribavirin. Hepatology 1997: 26 (suppl 1): 108S-11 IS. 3. Davis G, Esteban, Muir R, Rustgi V et al. Interferon alpha-2b alone or in combination with ribavirin for the treatment of relapse of chronic hepatitis C. N Engl J Med 1998: 339: 1493-1499. 4. Hultgren C, Milich D, Weiland 0, Sallberg M. The antiviral compound ribavirin modulates the T helper (Th)l/ThZ subset balance in hepatitis B and C virus-specitic immune responses. J Gen Virol 1998: 79: 2381-2391. 5. Poynard T, Marcellin P, Lee S et al. Random&d trial of interferon alpha-2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alpha-2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. Lancet 1998: 352: 1426 1432. 6. McHutchison J, Gordon S, Schiff E et al. Interferon alpha-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. N Engl J Med 1998: 339: 148>1492. 7. Schahn S, Hansen B, Chemello L et al. Ribavirin enhances the efficacy but not the adverse effects of interferon in chronic hepatitis C: a meta-analysis of individual patient data from European centers. J Hepatol 1997: 26: 961-966. 8. Chemello L, Cavaletto L, Bernardinello E, Guido M, Pontisso P, Alberti A. The effect of interferon alpha and ribavirin combination therapy in naive patients with chronic hepatitis C. J Hepato1 1995: 23 (suppl 2): 8-12. 9. Braconier J, Paulsen 0, Engman K, Widell A. Combined alphainterferon and ribavirin treatment for chronic hepatitis C virus infection. Stand J Infect Dis 1995: 27: 325329. 10. Kakumu S, Yoshioko K, Wakita T, Ishikawa T, Takayanagi M, Higashi Y. A pilot study of ribavirin and interferon beta for the treatment of chronic hepatitis C. Gastroenterology 1993: 105: 507-512.
Treatment of naive patients with HCV infection 11. Lai M-Y, Kao J-H, Yang P-M et al. Long-term efficacy of ribavirin plus interferon alpha in the treatment of chronic hepatitis C. Gastroenterology 1996: 111: 1307-1312. 12. Reichard 0, Norkrans G, Fryden A, Braconier J, Sonnerborg A, Weiland 0. Randomised, double-blind, placebo-controlled trial of interferon alpha-2b with and without ribavirin for chronic hepatitis C. Lancet 1998: 351: 83-87. 13. Marcellin P, Boyer N, Gervais A et al. Long-term histologic improvement and loss of detectable intrahepatic HCV RNA in patients with chronic hepatitis C and sustained response to interferon-alpha therapy. Ann Intern Med 1997: 127: 8755881. 14. Reichard 0, Glaumann H, Frydtn A, Norkrans G, Wejstal R, Weiland 0. Long-term follow-up of chronic hepatitis C patients with sustained virological response to alpha-interferon. J Hepatol 1999: 30: 783-787. 15. Schahn S, Weiland 0, Hansen B et al. and the EUROHEP Study Group for Viral Hepatitis. Interferon/ribavirin treatment for chronic hepatitis C with and without cirrhosis: a meta-analysis of individual patient data. Gastroenterology, in press.
16. Weiland 0, Braconier J, Fryden A et al. Influence of pretreatment factors on outcome of interferon alpha treatment in patients with chronic hepatitis C infection. Stand J Infect Dis 1999: 31: 115118. 17. Brouwer J, Hansen B, Niesters H, Schahn S. Early prediction of response in interferon monotherapy and in interferon-ribavirin combination therapy for chronic hepatitis C: HCV RNA at 4 weeks versus ALT J Hepatol 1999: 30: 192-198. 18. Poynard T. Interferon alpha for chronic hepatitis C infection Correspondence - Author’s reply. Lancet 1999: 353: 499-500. 19. Schvarcz R, Glaumann H, Reichard 0, Weiland 0. Histological and virological long-term outcome in patients treated with interferon alpha-2b and ribavirin for chronic hepatitis C. J Viral Hepatitis 1999: 6: 237-242. 20. Neumann A, Lam N, Dahari H et al. Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-alpha therapy. Science 1998: 282: 103-107.
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