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Keywords:

  • hepatitis C;
  • non responders;
  • retreatment;
  • hepatitis C

Abstract

  1. Top of page
  2. Abstract
  3. Definitions of non-response ()
  4. Causes of non-response ()
  5. Viral factors
  6. Type and dose of interferon α/dose of ribavirin
  7. Host factors
  8. Approaches to achieving a sustained virological response in prior non-responders to treatment for chronic hepatitis C
  9. New therapies for the treatment of hepatitis C
  10. Therapeutic vaccines and other potential immune modulators
  11. Preventive strategies in non-responders
  12. Conflicts of interest
  13. References

All but about 10% of patients with chronic hepatitis C (CHC) (predominantly those infected with genotype 1) can respond to some degree to ‘combination’ therapy with interferon (IFN) and ribavirin. The slower the virological response to treatment, the less likely sustained viral clearance will take place. Many factors influence response to antiviral therapy; most cannot be reversed (e.g. sex, age, cirrhosis, genotype and viral load). A sustained viral clearance is considerably facilitated by compliance with full-dose therapy for the prescribed time. The potential cause(s) for non-response need(s) to be ascertained before attempting retreatment. The 10% of patients who are true ‘null’ responders may respond to the new specifically targeted antiviral therapies but whether the response can be sustained off-therapy is unclear. Adjunctive therapies may facilitate response to retreatment if intolerance to treatment leading to diminished or absent doses was problematic in the past. Retreatment with a long-acting IFN and an adequate ribavirin dose (15 mg/kg), but given for 72 weeks in prior relapsers following 48 weeks of treatment, will enhance sustained virological response (SVR) rates. No benefit is gained from changing one pegylated IFNα (PEG IFNα) to another unless the treatment duration is extended. Only α-interferons are effective. For those individuals who still fail to achieve SVR, recruitment to trials of new treatments should be encouraged particularly for those with advanced liver disease. Lifestyle modification may be appropriate in attempt to reduce the chance of complications of liver disease, namely hepatocellular carcinoma, by smoking cessation, eliminating obesity and increasing coffee consumption.

Antiviral therapy for chronic hepatitis C (CHC) has been available for nearly 20 years (i.e. since the days of non-A, non-B hepatitis) (1). The initial component of treatment, namely interferon (IFN), remains but its ‘combination’ with oral ribavirin provides enhanced efficacy (2, 3). Increasing the molecular size via pegylation of IFN, and thus delaying its metabolism, causes IFN to remain detectable in serum for up to 7 days. This allows injections to be given weekly (aiding compliance) and further improves the sustained virological response (SVR) rates in CHC (4, 5). The potential added value of the new specifically targeted antiviral therapies (STAT-C) is only now being evaluated; currently, all are required to be given in combination with the current standard of care, namely pegylated IFNα (PEG IFNα) plus ribavirin, to maintain viral suppression.

In order to optimize regimens for retreating those who have failed prior treatment, it is preferable to know both the treatment dosing record and the initial virological responses during their failed therapy. Unfortunately, these data are often not available. Thus, patients described as non-responders are a very heterogeneous population; some may have been responders had they received sufficient therapy.

Definitions of non-response (Table 1)

  1. Top of page
  2. Abstract
  3. Definitions of non-response ()
  4. Causes of non-response ()
  5. Viral factors
  6. Type and dose of interferon α/dose of ribavirin
  7. Host factors
  8. Approaches to achieving a sustained virological response in prior non-responders to treatment for chronic hepatitis C
  9. New therapies for the treatment of hepatitis C
  10. Therapeutic vaccines and other potential immune modulators
  11. Preventive strategies in non-responders
  12. Conflicts of interest
  13. References
Table 1.   Definitions: non-response
  1. HCV, hepatitis C virus; LLD, lower limit of detection.

‘Null’<2 log[DOWNWARDS ARROW]HCV RNA at 12 weeks
‘Slow’>2 log[DOWNWARDS ARROW]HCV RNA at 12 weeks (detectable)
‘Breakthrough’RNA detectable on therapy but RNA positive at end of treatment
‘Relapser’RNA undetectable at end of treatment – detectable on cessation of treatment (need to know LLD HCV RNA)

The precise classification of the type of prior non-response to antiviral therapy determines retreatment strategy and outcome. Approximately 10% (predominantly genotype 1) of patients are ‘null’ responders, in that they have a minimal (<2 log) decline in hepatitis C virus (HCV) RNA by 12 weeks into antiviral therapy, whereas slow responders are defined as those who have a >2 log decline in HCV RNA at 12 weeks but the virus remains detectable [i.e. only achieve a partial early virological response (pEVR)]. Those who have undetectable HCV RNA at 12 weeks into therapy are described as having a complete EVR (cEVR). As the testing for HCV RNA has increased in sensitivity so have these definitions. Rarely, patients who achieve undetectable RNA on therapy revert to being RNA positive while remaining on therapy – such breakthroughs are most often caused by either intermittent or continuous reduction or cessation of a component of antiviral therapy. Relapsers are those who maintain viral clearance while on treatment, but HCV RNA becomes detectable once again when therapy is stopped.

Causes of non-response (Table 2)

  1. Top of page
  2. Abstract
  3. Definitions of non-response ()
  4. Causes of non-response ()
  5. Viral factors
  6. Type and dose of interferon α/dose of ribavirin
  7. Host factors
  8. Approaches to achieving a sustained virological response in prior non-responders to treatment for chronic hepatitis C
  9. New therapies for the treatment of hepatitis C
  10. Therapeutic vaccines and other potential immune modulators
  11. Preventive strategies in non-responders
  12. Conflicts of interest
  13. References
Table 2.   Risk factors for non-response to treatment for monoinfection: hepatitis C
Viral factorsHost factors
  1. IR, insulin resistance.

Genotype 1Cirrhosis
High viral load (>400 000 IU/L)Obesity (IR)
Genetics

The chance of achieving an SVR in mono-infected individuals varies considerably depending on three major factors. Unfortunately, these factors, which are not related to therapy, are often irreversible:

  • 1
    viral – genotype and viral load;
  • 2
    treatment-related – type, dose, duration and adherence to therapy; and
  • 3
    host – presence of cirrhosis, obesity, hepatic steatosis, insulin resistance and genetic factors that include: ethnicity, older age and hepatic gene expression ‘omics’ and genetic polymorphisms of genes involved in the immune response to infection with viruses.

Viral factors

  1. Top of page
  2. Abstract
  3. Definitions of non-response ()
  4. Causes of non-response ()
  5. Viral factors
  6. Type and dose of interferon α/dose of ribavirin
  7. Host factors
  8. Approaches to achieving a sustained virological response in prior non-responders to treatment for chronic hepatitis C
  9. New therapies for the treatment of hepatitis C
  10. Therapeutic vaccines and other potential immune modulators
  11. Preventive strategies in non-responders
  12. Conflicts of interest
  13. References

Genotype 1 infections are the most IFN resistant, particularly when the virus is present in a high titre. The cut-off for determining a high titre, whether >400 000 or >600 000 or >800 000 IU/L, is debatable but clinical observation suggests that an HCV RNA titre of <400 000 IU/L at baseline is most likely to be associated with subsequent SVR (6).

In the past, examination of viral kinetics during antiviral therapy suggested that at least 32 weeks of maintained undetectability of HCV RNA was required for genotype 1 infections to achieve an SVR (7), but now with more sensitive and more frequent testing it has been observed that if undetectable HCV RNA is achieved shortly after the introduction of antiviral therapy [i.e. a rapid virological response (RVR) is achieved at 4 weeks], then 24 and not 48 weeks of therapy even for genotype 1 may be sufficient to achieve SVR (8, 9). With genotype 1, those with a cEVR have double the likelihood of achieving SVR than those with a pEVR (not so for the other genotypes), who have no chance of SVR with a pEVR (10). For other more IFN-sensitive genotypes (e.g. genotypes 2 and 3), 24 weeks (maybe even less) is no worse than 48 weeks of therapy in terms of rates of SVR (11).

Type and dose of interferon α/dose of ribavirin

  1. Top of page
  2. Abstract
  3. Definitions of non-response ()
  4. Causes of non-response ()
  5. Viral factors
  6. Type and dose of interferon α/dose of ribavirin
  7. Host factors
  8. Approaches to achieving a sustained virological response in prior non-responders to treatment for chronic hepatitis C
  9. New therapies for the treatment of hepatitis C
  10. Therapeutic vaccines and other potential immune modulators
  11. Preventive strategies in non-responders
  12. Conflicts of interest
  13. References

Failure to respond to prior therapy very much depends on the type of therapy given (standard or PEG IFN with or without ribavirin), the treatment duration (12) and the dose of ribavirin (13, 14). Whereas induction dosing of IFN does not enhance antiviral responsiveness (15, 16), higher dosing throughout treatment does (14, 17). Two types of PEG IFNα are currently licensed (2a and 2b) that differ in size (12 kDa/40 kDa). These differences are the reasons for their different kinetics, which may influence the type of virological response seen. Hence, when the efficacies of these two drugs were compared (18), the EVR rate was higher with PEG IFNα-2b and the end-of-treatment (EOT) rate was higher with PEG IFNα-2a – predictable from their pharmacokinetics. The higher relapse rates following PEG IFNα-2a do not lead to an overall difference in SVR rates between these two drugs (as the EOT rate is higher with PEG IFNα-2a) – but this may not be so if a longer duration (72 weeks rather than 48 weeks) is prescribed as has been recommended in those who achieve only a pRVR or a pEVR (19, 20).

Patients infected with either genotype 2 or 3 have high rates of SVR whether treated for 48 or 24 weeks, and given a flat dose (800 mg daily) of ribavirin (i.e. 15 mg/kg of ribavirin daily is not required) (11). A recent study conducted in young, slender and mainly genotype 3-infected patients suggests that with 24 weeks of therapy, the rate of SVR was similar with ribavirin at a dose of 400 or 800 mg/day (21). However, if treatment is given for <24 weeks higher doses of ribavirin may be needed to achieve similar SVR rates (22, 23).

Adherence to full-dose antiviral therapy without treatment interruptions, particularly with ribavirin, which must be taken daily for the entire duration, along with PEG IFN is required to achieve the best outcome (24). Non-adherence is likely the most common cause for failure to achieve SVR – thus, when considering retreatment in prior non-responders, the degree of compliance with previous therapy needs to be carefully reviewed. If significant dose reductions were necessary, adjunctive therapy may be appropriate if retreatment is given.

Host factors

  1. Top of page
  2. Abstract
  3. Definitions of non-response ()
  4. Causes of non-response ()
  5. Viral factors
  6. Type and dose of interferon α/dose of ribavirin
  7. Host factors
  8. Approaches to achieving a sustained virological response in prior non-responders to treatment for chronic hepatitis C
  9. New therapies for the treatment of hepatitis C
  10. Therapeutic vaccines and other potential immune modulators
  11. Preventive strategies in non-responders
  12. Conflicts of interest
  13. References

The presence of cirrhosis enhances the likelihood of non-response (6, 25). Obesity, defined as a body mass index (BMI)>30, as well as hepatic steatosis impair the likelihood of viral clearance following antiviral therapy (26, 27). Hepatic insulin resistance common in subjects with hepatitis C increases with an increase in BMI, and insulin resistance may impair antiviral responsiveness when severe (28). However, if an SVR is achieved, insulin resistance is lost even in the absence of weight loss.

Ethnicity independent of dose and body weight when it concerns African Americans reduces the likelihood of treatment responsiveness (29), and is higher in Asians (30). Genomic studies in obese non-responders indicated enhanced expression of SOCS-3, correlated with hepatic insulin resistance (31). Blood levels of proteins, which play a role in viral clearance, have been linked to non-response (e.g. IP-10) (32). It is uncertain whether the lower rate of antiviral responsiveness seen in older age patients can all be attributed to poor tolerance to therapy, a change in gene expression or because the elderly tend to have more hepatic fibrosis, which has a deleterious effect on response to antiviral therapy (33).

Now several authors have reported specific gene signatures in pretreatment liver tissue that predict subsequent response to PEG IFN and ribavirin therapy (32–36). Examination of on-treatment gene expression in liver tissue indicates that subsequent non-responders show very little change in gene expression, particularly of genes involved in the IFN pathway compared with the upregulation observed in subsequent responders to therapy (35). These findings would suggest that the innate IFN system cannot respond to exogenous IFN in non-responders because it is already maximally upregulated. The cause is uncertain but may be because of upregulation of other genes that are important in this pathway. It is not known whether this pattern of gene expression can be reversed with the new STAT-C agents.

Approaches to achieving a sustained virological response in prior non-responders to treatment for chronic hepatitis C

  1. Top of page
  2. Abstract
  3. Definitions of non-response ()
  4. Causes of non-response ()
  5. Viral factors
  6. Type and dose of interferon α/dose of ribavirin
  7. Host factors
  8. Approaches to achieving a sustained virological response in prior non-responders to treatment for chronic hepatitis C
  9. New therapies for the treatment of hepatitis C
  10. Therapeutic vaccines and other potential immune modulators
  11. Preventive strategies in non-responders
  12. Conflicts of interest
  13. References

The above review of factors that are known to influence response to the current standard of care guides our assessment of prior non-responders for their suitability for retreatment.

Address compliance issues with past therapy

In routine clinical practice, the most common reason for failure to eradicate hepatitis C is incomplete compliance with therapy. The importance of taking full-dose, continuous therapy as prescribed may not have been appreciated either by the patient and/or by the treating physician or nurse. Hence, the need for compliance needs to be emphasized before and throughout retreatment. Gaps in treatment with either or both drugs leads to lower response rates than when only dose reductions occur.

In a population of former drug users, daily marijuana use was shown to improve SVR significantly (37). Mood stabilizers may enhance compliance in those with treatment-related anxiety or depression (38). Adjunctive therapies used to reverse treatment-induced cytopaenias, which may have meant gaps in therapy in the past, increase the chance of SVR because they allow maintenance of full-dose therapy (14, 39).

Retreatment with pegylated interferon and ribavirin

Individuals who did not respond or who relapsed following previous standard IFN therapy or standard IFN therapy in combination with ribavirin may achieve SVR if retreated with PEG IFNα and ribavirin (12). For those with genotype 1 given previous standard IFN monotherapy, an SVR upon retreatment with PEG IFNα-2a plus Ribavirin ranges from 22 to 47% depending on whether they were a prior non-responder or relapser. When PEG IFNα-2a is given to prior non-responders or relapsers to standard IFN plus ribavirin, SVR rates in those with genotype 1 range between 20 and 31%. The SVR rates for those with genotype 2 and 3 retreated in this manner are considerably higher: in those who received prior monotherapy, SVR rates ranged from 44 to 63%, depending on whether they were a non-responder or relapser to monotherapy, and 37–52%, depending on whether they were a non-responder or a relapser to standard IFN therapy in combination with ribavirin. In another study, SVR following retreatment was seen more often in prior relapsers without cirrhosis (40).

Would longer treatment enhance the likelihood of an SVR in prior non-responders?

The strongest predictor of response to antiviral therapy is an RVR but this is only observed in fewer than a third of patients (8, 10). Thus, a sustained response to ‘combination’ therapy depends on the time it takes to reach viral clearance. In a study of treatment-naïve genotype 1 patients, Berg et al. (19) showed that when using methodology where the lower limit for detection of HCV RNA was 50 IU/ml, if HCV RNA was still detected at 12 weeks into therapy (pEVR), the relapse rate was less after 72 weeks rather than 48 weeks of therapy. Subsequently, another study showed that if HCV RNA remained >50 IU/L at 4 weeks into treatment (no RVR), the relapse rate after 48 weeks of therapy could be reduced if patients were given a full 72 weeks of therapy (20). The benefit of prolonging antiviral therapy up to 72 weeks was subsequently observed in the REPEAT study, where prior non-responders to PEG IFNα-2b were retreated with PEG IFN α-2a with or without induction dosing (360 mcg PEG IFNα-2a for the first 12 weeks). Patients were randomized to treatment for 48 or 72 weeks (41). No benefit from induction dosing was seen but there was benefit from prolonging therapy to 72 weeks in these patients, who had previously failed PEG IFNα-2b plus ribavirin. Because of side effects, compliance deteriorated markedly between 48 and 72 weeks and so the full benefit of prolonged therapy may go unappreciated. However, those patients who choose to undergo retreatment tend to be very committed to complying fully with their treatment.

Alternative interferons

Consensus interferons

There have been small reports that indicate that higher doses of treatment with alternate IFNs given to prior non-responders may lead to SVR in some. Cornberg et al. (42) showed that when high-dose consensus IFN was given to prior non-responders to either standard IFN or standard IFN and Ribavirin, SVR rates as high as 30% were observed. A more recent study using a slightly lower dose of consensus IFN given to prior non-responders to the current standard of care, namely PEG IFN plus ribavirin, showed that the SVR rate was 10% (43). However, the patients recruited into this study were clearly defined and most were prior ‘null’ responders (80%) and 60% had advanced hepatic fibrosis (i.e. patients who could be anticipated would respond poorly to any IFN-based therapy with or without ribavirin).

Albuferon

The high-molecular-weight (85.7 kDa) Albuferon comprises IFNα-2b genetically fused with human albumin. Viral kinetic studies indicate that when high-dose (1200 mcg) Albuferon is given, IFN remains detectable in serum for up to 1 month; hence, the possible benefit of this treatment may be the need for less frequent injections (44). One small study of Albuferon and oral ribavirin given to prior non-responders suggests that SVR rates ranging between 15 and 17% are achievable (45). As is the case for all these studies conducted in non-responders, the likelihood of response depends on the kind of non-responder being treated, usually impossible to ascertain reliably.

Other interferons

No advantage of using IFN-γ (46) as therapy to reduce hepatic fibrosis in non-responders with CHC has been observed.

Higher dose ribavirin and/or interferon and adjunctive therapies

The SVR rate increases as more ribavirin is administered until the dose is >15 mg/kg, when haemolysis becomes too troublesome. One very small pilot study showed that 90% (nine of 10 cases) of treatment-naïve patients with genotype 1 and a high viral load were able to achieve an SVR when treated with PEG IFN and 3600 mg of ribavirin daily but all 10 patients required blood transfusions and remained extremely fatigued (13). A recent study by Shiffman et al. has shown that high-dose ribavirin (15.2 mg/kg) when given with erythropoietin 40 000 U weekly yields a significantly higher rate of SVR in treatment-naïve patients with genotype 1 than that seen with ribavirin 10.3 mg/kg given also with erythropoietin (14). The degree to which these data can be translated to prior non-responders really depends on the cause for non-response – but if dose reduction or cessation of ribavirin had been a major issue, it is reasonable to anticipate that adjunctive therapy with erythropoietin may enhance responsiveness by allowing full-dose therapy to be used. In the same vein, if prior treatment had been stopped in the past because of thrombocytopaenia, then supplementation with the thrombopoietin receptor agonist, Eltrombopag, may be beneficial (39).

Reducing insulin resistance

A recent study where patients with insulin resistance were treated with triple therapy, Metformin was added to the antiviral treatment, did not show higher SVR rates (47). It is reasonable to assume that this treatment would also be ineffective in prior non-responders who are insulin resistant. It is not known whether regular exercise and/or weight loss reduces insulin resistance in hepatitis C. It is noticeable that obesity is common in those who fail to achieve a response to antiviral therapy and weight loss in patients with chronic liver disease does diminish hepatic steatosis (48).

Maintenance interferon therapy

To date, there have been two large studies that have reported the results of prolonged PEG IFN for the treatment of prior non-responders to the standard of care in patients with advanced fibrosis (F3/F4) (49, 50). Unfortunately, a beneficial outcome was not observed in either study. During a relatively short period of follow-up (<5 years), the rates for hepatocellular carcinoma (HCC) and hepatic decompensation were no different between those who received PEG IFNα and controls.

New therapies for the treatment of hepatitis C

  1. Top of page
  2. Abstract
  3. Definitions of non-response ()
  4. Causes of non-response ()
  5. Viral factors
  6. Type and dose of interferon α/dose of ribavirin
  7. Host factors
  8. Approaches to achieving a sustained virological response in prior non-responders to treatment for chronic hepatitis C
  9. New therapies for the treatment of hepatitis C
  10. Therapeutic vaccines and other potential immune modulators
  11. Preventive strategies in non-responders
  12. Conflicts of interest
  13. References

There are a number of STAT-C agents that inhibit either the protease or the polymerase enzyme of the HCV. To date, results from two phase 2 trials in prior non-responders of the two different agents given for different durations have been presented. Telaprevir, in a small study of prior non-responders to PEG IFN and ribavirin, showed that 100% achieved undetectable virus at 1 month into treatment in those who were prior slow responders or relapsers. On retreatment with PEG IFNα, ribavirin and telaprevir in prior ‘null’ responders (defined as <2 log decline in HCV RNA at 4 or 12 weeks into treatment), it was found that the decline in HCV RNA was slower but still occurred in most, although relapse of viraemia occurred in some (51). The pilot study of another protease inhibitor, namely boceprevir, evaluated in prior non-responders, did not yield such good results in that although the likelihood of a virological response depended on the patient's prior response to PEG IFN and ribavirin, if there had been a <1 log decline at 12 weeks (i.e. overt ‘null’ responder) only 20% lost HCV RNA, whereas in those who had previously achieved a >1 log to <2 log decline in HCV RNA at 12 weeks undetectable HCV RNA was achieved in 50% at the end of 24 weeks of therapy (52). Both these studies suggest that there may be differences in the intracellular mechanisms for a ‘null’ responder that are only partially ameliorated by a STAT-C agent. Currently, there are no data on the long-term efficacy off-therapy of the new polymerase inhibitors given to prior non-responders.

Therapeutic vaccines and other potential immune modulators

  1. Top of page
  2. Abstract
  3. Definitions of non-response ()
  4. Causes of non-response ()
  5. Viral factors
  6. Type and dose of interferon α/dose of ribavirin
  7. Host factors
  8. Approaches to achieving a sustained virological response in prior non-responders to treatment for chronic hepatitis C
  9. New therapies for the treatment of hepatitis C
  10. Therapeutic vaccines and other potential immune modulators
  11. Preventive strategies in non-responders
  12. Conflicts of interest
  13. References

There are several ongoing studies of therapeutic vaccines for hepatitis C. Some effects give cause for hope as an increase in CD4 helper T-cell proliferation was induced but, to date, these vaccines have had little effect on HCV RNA viral load (53). A pilot study of CpG 10101, a synthetic oligodeoxynucleotide (a Toll-like receptor 9 agonist), was shown to lower HCV RNA levels but it appears that for the long term this agent is toxic, and further studies are currently not being conducted (54).

Preventive strategies in non-responders

  1. Top of page
  2. Abstract
  3. Definitions of non-response ()
  4. Causes of non-response ()
  5. Viral factors
  6. Type and dose of interferon α/dose of ribavirin
  7. Host factors
  8. Approaches to achieving a sustained virological response in prior non-responders to treatment for chronic hepatitis C
  9. New therapies for the treatment of hepatitis C
  10. Therapeutic vaccines and other potential immune modulators
  11. Preventive strategies in non-responders
  12. Conflicts of interest
  13. References

Many comorbid factors promote liver disease progression and liver cancer in patients with hepatitis C, particularly in those with cirrhosis. These include diabetes (55, 56) and cigarette smoking (57). Regular coffee consumption, however, may reduce the rate of HCC in subjects who have hepatitis C (58). Acute hepatitis may precipitate hepatic decomposition in individuals with cirrhosis, and thus patients with hepatitis C and cirrhosis should have immunity to both hepatitis A and B.

Even though most individuals with cirrhosis remain asymptomatic, it is important that the patient understand the need for 6-monthly screening for liver cancer, regular screening for varices and the need to avoid unnecessary surgery and to have any infection treated rapidly. Most important of all is that such individuals who are non-responders to the current standard of care should maintain contact with research centres as the number of new therapies effective against HCV RNA is escalating.

References

  1. Top of page
  2. Abstract
  3. Definitions of non-response ()
  4. Causes of non-response ()
  5. Viral factors
  6. Type and dose of interferon α/dose of ribavirin
  7. Host factors
  8. Approaches to achieving a sustained virological response in prior non-responders to treatment for chronic hepatitis C
  9. New therapies for the treatment of hepatitis C
  10. Therapeutic vaccines and other potential immune modulators
  11. Preventive strategies in non-responders
  12. Conflicts of interest
  13. References
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