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Keywords:

  • genotype 2;
  • genotype 3;
  • HCV;
  • IL28B;
  • response-guided therapy;
  • SVR

Abstract

  1. Top of page
  2. Abstract
  3. Standard of care for patients with G2 and G3 chronic hepatitis C
  4. Strategies of optimization therapy in patients with genotype 2 and 3 chronic hepatitis C: are they effective?
  5. Factors affecting the likelihood of a virological response in G2 and G3 patients
  6. Do IL28B polymorphisms affect sustained virological response in G2 and G3 patients?
  7. Conclusions
  8. Conflicts of interest
  9. References

Current guidelines recommend that patients with genotype 2 (G2) and 3 (G3) chronic hepatitis C be treated with pegylated interferon (PEG-IFN) plus low doses of ribavirin (800 mg/day) for 24 weeks, resulting in a sustained virological response (SVR) rate of approximately 80%. Considering these high response rates, several recent randomized trials have assessed whether shorter treatment (12–16 weeks) could be cost-effective in these patients. The results of these studies vary but suggest better responsiveness in G2 patients, and overall, do not strongly support reducing treatment to <24 weeks in all patients. On the other hand, the presence of a rapid virological response (RVR) (defined as an undetectable hepatitis C virus-RNA at 4 weeks of treatment) was always reported to be the best positive predictor of achieving SVR in both G2 and G3 patients. These results suggest that in a subgroup of subjects with RVR (G2>G3, viral load <400 000 IU, low fibrosis, no metabolic cofactors), shorter treatment is as effective as standard regimens, and that it can be proposed mainly if problems of poor tolerance or adherence are foreseen. It is possible that the SVR rate in non-RVR patients and non-responder patients could also be improved by prolonging therapy, but this must be specifically investigated in other studies along with the role of IL28B polymorphisms.


Abbreviations
CHC,

chronic hepatitis C;

HVL,

high viral load;

LVL,

low viral load;

PEG-IFN,

pegylated interferon;

RCT,

randomized-controlled trial;

RVR,

rapid viral response;

SOC,

standard of care

SVR,

sustained virological response.

Standard of care for patients with G2 and G3 chronic hepatitis C

  1. Top of page
  2. Abstract
  3. Standard of care for patients with G2 and G3 chronic hepatitis C
  4. Strategies of optimization therapy in patients with genotype 2 and 3 chronic hepatitis C: are they effective?
  5. Factors affecting the likelihood of a virological response in G2 and G3 patients
  6. Do IL28B polymorphisms affect sustained virological response in G2 and G3 patients?
  7. Conclusions
  8. Conflicts of interest
  9. References

In the late 1990s, trials of standard interferon (IFN) plus ribavirin (RBV) (1) showed that 24 weeks of treatment in patients with genotypes 2 (G2) and 3 (G3) chronic hepatitis C (CHC) resulted in the same sustained virological response (SVR) rate as 48 weeks of treatment (about 65%). Despite these results, the phase 3 trials by Manns (2) and Fried (3), resulting in the registration of pegylated interferons (PEG-IFN) α-2a and α-2b in combination with RBV for the treatment of CHC, only investigated 48 weeks of combination therapy in these patients. These studies reported an SVR rate of about 80% in these easy-to-treat patients, raising the important issue of potential ‘overtreatment’ in these cases. The study by Hadziyannis et al. (4) was an initial effort to rectify this error, despite its methodological limitations, such as the lack of stratification by genotype. They clearly demonstrated that SVR rates in G2 and G3 patients treated with PEG-IFN α-2a plus RBV at a flat dose of 800 mg/day for 24 weeks were similar to patients treated for 48 weeks with higher doses of RBV of 1 000/1 200 mg/day. Thus, based on these trials, in the 2009 American Association for the Study of Liver Diseases guidelines on the diagnosis, management and treatment of hepatitis C (5), the recommended standard of care (SOC) for patients with G2 and G3 CHC was PEG-IFN α-2b 1.5 μg/kg/week or PEG-IFN α-2a 180 μg/week, combined with low doses (800 mg/day) of RBV for 24 weeks.

G2 and G3 CHC patients are therefore collectively referred to as easy to treat. However, this is an oversimplification since substantial evidence has accumulated to show that G2 and G3 patients may respond differently to treatment. Zeuzem et al. (6) evaluated the efficacy and safety of PEG-IFN α-2b plus weight-based RBV for 24 weeks in 224 patients with G2 and G3 CHC and showed that the SVR rate was higher in G2 than in G3 patients (93 vs 79% respectively) because of a high relapse rate in the latter (14 vs 7% respectively). This study also showed that a high viral load (HVL) at baseline [hepatitis C virus (HCV)-RNA>600 000 IU/ml] was an important predictive factor of lower SVR and higher relapse rates in G3, but not in G2 patients. A retrospective analysis of data from the WIN-R trial (7) of PEG-IFN α-2b also found higher SVR rates and lower relapse rates in G2 than in G3 patients (72 vs 63% and 5 vs 10% respectively). Finally, a recent meta-analysis (8) confirmed higher SVR rates in G2 than in G3-infected patients treated for 24 weeks (74 vs 69% respectively).

Strategies of optimization therapy in patients with genotype 2 and 3 chronic hepatitis C: are they effective?

  1. Top of page
  2. Abstract
  3. Standard of care for patients with G2 and G3 chronic hepatitis C
  4. Strategies of optimization therapy in patients with genotype 2 and 3 chronic hepatitis C: are they effective?
  5. Factors affecting the likelihood of a virological response in G2 and G3 patients
  6. Do IL28B polymorphisms affect sustained virological response in G2 and G3 patients?
  7. Conclusions
  8. Conflicts of interest
  9. References

Based on phase 3 trial results of SVR in G2 and G3 patients treated for 24 weeks, several studies have evaluated the treatment response and cost effectiveness of shorter treatment regimens according to virological response and the probability of achieving SVR. In particular, recent studies have investigated the efficacy of shorter treatment regimens based on the presence of a rapid virological response (RVR) defined as an undetectable HCV-RNA at week 4 of treatment), which is the best predictor of SVR in both difficult and easy-to-treat genotypes. Because RVR can be achieved in more than 60% of G2 and G3 patients, this design seemed especially appealing.

Earlier studies did not randomize patients with RVR to standard or shorter therapy, but directly assigned a shorter treatment to patients with RVR and longer to those without, therefore adding a bias to the data. The study by Dalgard et al. (9) in 122 patients who were mostly G3 with PEG-IFN α-2b plus weight-based RBV, showed that an SVR rate of 90% was obtained in patients with a virological response at week 4 or 8 compared with only 56% in patients without. Interestingly, the relapse rate was higher in G3 patients treated for 14 weeks with bridging fibrosis or cirrhosis as well as in those with a high viral load (HVL) at baseline. In particular, in G3 patients with negative HCV-RNA at week 4 or 8, an SVR was obtained in 98% of patients with a pretreatment viral load of <600 000 IU/ml compared with 72% of those with ≥600 000 IU/ml.

A similar methodological bias also limited the results of an Italian randomized trial by Mangia et al. (10), including 283 mostly G2 patients treated with PEG-IFN α-2b plus weight-based RBV. Patients were randomized into a control arm and treated for 24 weeks or into a variable-duration group, which received treatment for 12 or 24 weeks, depending on RVR. Overall, RVR was achieved in 63% of cases and SVR in 76%. The SVR rate in G2 patients who achieved RVR was 89%, independent of the treatment duration (12 or 24 weeks). In contrast, SVR was only achieved in about 50% of G2 patients treated for 24 weeks who did not achieve RVR. Interestingly, in G3 subjects with RVR, a trend towards higher SVR rates was observed in patients treated for 24 weeks (100%) compared with those treated for 12 weeks (77%). However, the small number of G3 patients limits the significance of these findings. Another study (11) in 150 G2 CHC Asian patients randomized to 16 or 24 weeks of PEG-IFN α-2a plus weight-based RBV showed no difference in SVR rates in patients with RVR after 16 or 24 weeks of treatment (100 vs 98% respectively).

The first well-designed study to evaluate whether RVR can be used as an indicator to prescribe shorter therapy in patients with easy-to-treat genotypes was performed by von Wagner et al. (12). In this study cohort of 162 mostly G3 patients with RVR were randomized into 16 or 24 weeks of treatment with PEG-IFN α-2a plus weight-based RBV. A similar SVR rate was found in both groups (82 vs 80%), and their findings were confirmed in subgroups of G2 patients and G3 low viral load (LVL) patients. However, in G3 patients with HVL, a course of 24 weeks appeared to be more effective for SVR than 12 weeks, although the difference was not statistically significant (67 vs 55%). Although these studies have shown that shorter treatment is effective in patients with easy-to-treat genotypes, especially those with G2, the results of other studies are conflicting.

For example the ACCELERATE study (13) of a large cohort of 1469 G2 and G3 patients showed that a 24-week regimen was better than a 16-week regimen. In this study, with a low dose of RBV (800 mg/day), the SVR rate was lower in the 16-week than that in the 24-week arm (62 vs 70%), because of an increase in the relapse rate (31 vs 18%). A standard course was also found to be more effective in patients who achieved RVR (85% for 24 weeks vs 79% for 16 weeks). However, there was no difference in SVR rates between the 16- and 24-week arms in subjects with baseline HCV RNA <400 000 IU.

Similar results have been found in two recent northern European studies. One study by Dalgard et al. (14) only randomized RVR patients while the other by Lagging et al. (15) randomized patients at baseline. In the latter trial (NORDynamIC study), 382 patients with G2 and G3 (72%) CHC were treated with PEG-IFN α-2a plus a flat dose of RBV (800 mg/day) for 12 or 24 weeks. These results showed that 12 weeks of therapy was less effective than 24 weeks (SVR: 59 vs 78%), regardless of HCV genotype and stage of fibrosis. The NORTH-C trial (14) by Dalgard et al. included 428 G2 and G3 (80%) patients, randomized by RVR to 14 or 24 weeks of treatment, and showed that a duration of 14 weeks was less effective than 24 weeks for obtaining SVR. In that study, the lower SVR rate (81 vs 91%) was mostly because of a higher relapse rate (19 vs 9%). A cumulative analysis (16) was performed of this latter study and a non-randomized Scandinavian pilot trial in which all patients with RVR were treated for 14 weeks. The results of this analysis showed that in G2 and G3 patients with RVR, 14 weeks of treatment were not as effective as 24 weeks. A recent Italian study (17) including 210 G2 and G3 CHC patients assigned to 12 or 24 weeks of PEG-IFN α-2a plus weight-based RBV depending on RVR showed that 12-week combination therapy was as effective as a 24-week regimen.

The contrasting conclusions of these studies, summarized in Tables 1 and 2, are probably because of the different study designs, ethnicities of the study populations, differences in the prevalence of advanced fibrosis and different schedules of RBV. However, a recent meta-analysis (8), including all the above-mentioned studies, found that 24 weeks of therapy should remain the standard duration for G2 and low-viraemic G3 patients. The subgroup analysis of these results also suggested that SVR rates were similar in patients who achieved RVR independent of basal viral load whether they had received standard or short-term treatment. Another recent meta-analysis (18) also compared the results of short therapy and standard therapy in G2 and G3 patients. This study concluded that short therapy does not reduce the efficacy of treatment in G2 and G3 CHC patients who achieve RVR, while patients who do not should consider 24 weeks of treatment. However, overall, the results of these meta-analyses as well as the individual studies need to be confirmed in large studies before being applied to clinical practice, especially in patients with G3, HVL, obesity and advanced fibrosis. Mangia et al. (19) recently reported that both G2 and G3 patients with RVR who relapsed after 12 weeks of treatment achieved SVR in 70% of cases when retreated for 24 weeks.

Table 1.   Studies assessing the role of rapid virological response in the achievement of sustained virological response in genotype 2 patients
StudyTypeRandomizationPatientsF3–F4RVRSVRSVR rate in pts with RVR underwent short-duration therapySVR rate in pts with RVR underwent standard-duration therapyTherapy
  1. HCV, hepatitis C virus; NA, not available; PEG-IFN, pegylated interferon; RBV, ribavirin; RVR, rapid virological response; SVR, sustained virological response.

Dalgard et al. (9)RandomizedRVR (HCV-RNA – at week 4 or 8)[RIGHTWARDS ARROW] 14 weeks No RVR [RIGHTWARDS ARROW] 24 weeks2323%91%86.9%90.4%50% (1/2)PEG-IFN α-2b 1.5 RBV 800/1400
Mangia et al. (10)RandomizedStandard group: 24 weeks Variable group: RVR [RIGHTWARDS ARROW]12 weeks NO RVR [RIGHTWARDS ARROW]24 weeks21323.5%64%80%87%89%PEG-IFN α-2b 1.0 RBV 1000/1200
von Wagner et al. (12)RandomizedRVR[RIGHTWARDS ARROW] 16 weeks [RIGHTWARDS ARROW]24 weeks38NA97%92%94%94%PEG-IFN α-2a RBV 1000/1200
Shiffman et al. (13)Randomized16 weeks 24 weeks72826.5%69.2%68.6%78%85%PEG-IFN α-2a RBV 800
Yu et al. (11)Randomized16 weeks 24 weeks15020.6%86.6%94.6%100%98%PEG-IFN α-2a RBV 1000/1200
Dalgard et al. (14)RandomizedRVR [RIGHTWARDS ARROW]14 weeks [RIGHTWARDS ARROW] 24 weeks85NA75%95%93%97%PEG-IFN α-2b 1.5 RBV 800/1400
Lagging et al. (15)Randomized12 weeks 24 weeks10439%NA68.0%NANAPEG-IFN α-2a RBV 800
Mecenate et al. (17)RandomizedRVR[RIGHTWARDS ARROW]12 weeks [RIGHTWARDS ARROW] 24 weeks116NA79%67.2%NANAPEG-IFN α-2a RBV 800/1200
Table 2.   Studies assessing the role of rapid virological response in the achievement of sustained virological response in genotype 3 patients
StudyTypeRandomizationPatientsF3–F4RVRSVRSVR rate in pts with RVR underwent short- duration therapySVR rate in pts with RVR underwent standard- duration therapyTherapy
  1. HCV, hepatitis C virus; NA, not available; PEG-IFN, pegylated interferon; RBV, ribavirin; RVR, rapid virological response; SVR, sustained virological response.

Mangia et al. (10)RandomizedStandard group: 24 weeks Variable group: RVR [RIGHTWARDS ARROW] 12 weeks NO RVR [RIGHTWARDS ARROW] 24 weeks7023.5%59%66%77%100%PEG-IFN α-2b 1.0 RBV 1000/1200
Dalgard et al. (9)RandomizedRVR (HCV-RNA – at week 4 OR 8)[RIGHTWARDS ARROW] 14 weeks No RVR [RIGHTWARDS ARROW] 24 weeks9923%74.7%79.7%89%56%PEG-IFN α-2b 1.5 RBV 800/1400
von Wagner et al. (12)RandomizedRVR[RIGHTWARDS ARROW]16 weeks[RIGHTWARDS ARROW]24 weeks113NA91%85%76.4%75%PEG-IFN α-2a RBV 1000/1200
Shiffman et al. (13)Randomized16 weeks 24 weeks72621.4%61.8%64%80%85%PEG-IFN α-2a RBV 800
Dalgard et al. (14)RandomizedRVR[RIGHTWARDS ARROW]14 weeks [RIGHTWARDS ARROW] 24 weeks343NA70.3%88.4%84%92%PEG-IFN α-2b 1.5 RBV 800/1400
Lagging et al. (15)Randomized12 weeks 24 weeks27639%NA68.0%NANAPEG-IFN α-2a RBV 800
Mecenate et al. (17)RandomizedRVR[RIGHTWARDS ARROW]12 weeks [RIGHTWARDS ARROW]24 weeks94NA68.1%72.3%NANAPEG-IFN α-2a RBV 800/1200

In addition, all of the above studies and the meta-analysis showed that only about 50% of G2 and G3 patients who did not achieve RVR achieved SVR even after 24 weeks of treatment, suggesting that longer treatment could be indicated. However, randomized-controlled trials (RCT) are needed before suggesting prolonged treatment in this cohort of patients.

Factors affecting the likelihood of a virological response in G2 and G3 patients

  1. Top of page
  2. Abstract
  3. Standard of care for patients with G2 and G3 chronic hepatitis C
  4. Strategies of optimization therapy in patients with genotype 2 and 3 chronic hepatitis C: are they effective?
  5. Factors affecting the likelihood of a virological response in G2 and G3 patients
  6. Do IL28B polymorphisms affect sustained virological response in G2 and G3 patients?
  7. Conclusions
  8. Conflicts of interest
  9. References

Predictive factors of achieving SVR and RVR are of major relevance to identify G2 and G3 CHC patients who could benefit from a shorter regimen. The results of published studies are summarized in Table 3.

Table 3.   Factors associated with rapid virological response, and with sustained virological in studies comparing shortened vs standard duration therapy in patients with genotype 2 and 3 chronic hepatitis C
StudyFactors associated with RVRFactors associated with SVR
  1. ALT, alanine aminotransferase; BMI, body mass index; HCV, hepatitis C virus; γ-GT, γ-glutamyl transferase; RVR, rapid virological response; SVR, sustained virological response.

Dalgard et al. (9)Not reportedAbsent or minimal fibrosis, age <40 years, HCV-RNA<600 000 IU/ml
Mangia et al. (10)Low viral load, high ALTNot reported
von Wagner et al. (12)Not reportedLow viral load, genotype 2, low γ-GT
Shiffman et al. (13)Not reportedAbsence of severe fibrosis, younger age, HCV-RNA<600 000 IU/ml, lower body weight, high ALT, genotype 2
Yu et al. (11)Not reportedYounger age
Dalgard et al. (14)Male sex, low viral load, age <40 yearsNot reported
Lagging et al. (15)Not reportedAge <40 years, HCV-RNA<1000 IU/ml at day 7, undetectable HCV-RNA at day 29
Mecenate et al. (17)Not reportedLow viral load, high ALT, absence of severe fibrosis
Mangia et al (19)Not reportedPlatelets≥140 000, BMI<30 (only RVR patients)
Diago et al. (20)Not reportedAbsence of advanced fibrosis, low viral load, lower body weight, standard duration therapy (only RVR patients)

As expected, most of the predictive factors of SVR with standard treatment have been revalidated for shorter therapies. Dalgard et al. (9) showed that absent or minimal fibrosis was strongly predictive of achieving SVR in all patients treated for 12 or 24 weeks, even if 29 patients were excluded from the analysis because of a lack of histological data. Interestingly, the authors found that age <40 years old and HCV-RNA <600 000 IU were the strongest independent baseline predictors of SVR when considering all patients, without evaluating histological data. Similar data have been reported in the other studies. In particular, the ACCELERATE study (13) found that younger age, LVL and the absence of severe fibrosis were independent baseline predictors of SVR in the entire population, but also found that other factors played a role such as lower body weight, higher ALT levels and G2 infection. Mecenate et al. (17) also identified LVL, higher ALT levels and the absence of severe fibrosis as positive predictors of achieving SVR in patients treated for 12 or 24 weeks. In an Asian study of G2 patients by Yu et al. (11), older age was found to be a negative predictor of SVR. The study by von Wagner et al. (12) confirmed that G2 infection and LVL were independent predictors of SVR, and like the ACCELERATE study, found that metabolic factors, in particular GGT levels, could negatively affect achieving SVR. Finally, Lagging et al. (15) found that HCV-RNA <1000 IU/ml at day 7, age <40 years old and undetectable HCV-RNA at day 29 were independently associated with SVR in patients who received 12 weeks of therapy, while undetectable HCV-RNA at day 29 and older age were predictive of achieving SVR in the 24-week arm.

The predictors of SVR after short or standard treatment were assessed in the above studies by pooling patients with or without RVR. Other studies and retrospective analyses of previous trials have evaluated the baseline factors associated with SVR and with relapse in the subgroup of patients with RVR. Mangia et al. (19) found that in 496 G2 and G3 CHC patients with RVR who underwent 12 weeks of PEG-IFN α-2b plus weight-based RBV therapy, only platelet count <140 000/mm3 (a surrogate of fibrosis) and body mass index >30 kg/m2 (often associated with the metabolic syndrome) were associated with relapse. In addition, they showed that patients without these negative factors had SVR and relapse rates of 92.0 and 8.0%, respectively, compared with 72.5 and 27.5% in patients with one or two of these negative factors. An analysis (20) of the 863 patients who reached RVR in the ACCELERATE study showed that the absence of advanced fibrosis, LVL, lower body weight and 24 weeks of therapy were independently linked to achieving SVR. Severe fibrosis, HVL, being overweight, 16 weeks of therapy and male sex were predictive of relapse.

Because of the relevance of RVR in predicting the achievement of SVR in easy-to-treat genotypes, some studies have also investigated baseline factors predictive of RVR. In particular, Dalgard et al. (14) identified male gender, LVL and age <40 years as positive predictive factors of achieving RVR. Mangia et al. (10) also confirmed LVL and higher baseline ALT levels as positive predictors of RVR.

The above results all confirm that severe fibrosis is a strong predictive factor of non-SVR in G2 and G3 CHC patients whatever the length of treatment. Furthermore, the presence of cirrhosis further reduces the likelihood of SVR in G2 and G3 patients. For example a retrospective analysis of the Hadziyannis study (21) showed that the chance of achieving SVR in patients with G2 and G3 cirrhosis was 70 and 46% respectively. In a RCT by our group (22), in patients with HCV cirrhosis and portal hypertension who received PEG-IFN α-2b (1.0 μg/kg/week) with RBV (800 mg/day) for 52 weeks, SVR was achieved in 83% of G2 and G3 CHC patients.

Other studies have evaluated the role of adherence to treatment and drug dosage in achieving SVR in G2 and G3 patients with or without RVR. The results of these trials are conflicting and these studies used different RBV schedules. Some studies suggest that high RBV doses are beneficial in patients with G2 and G3 CHC. In particular, Yu et al. (11) and Dalgard et al. (9) have shown that there is a relationship between RBV dose/adherence and both SVR and relapse rates in these patients. A retrospective analysis of the data by Fried et al. (3), and Hadziyannis et al. (4) found that combining higher doses of RBV with a longer treatment resulted in better SVR rates in non-RVR patients (23). A subanalysis of 355 patients from the NORDynamiC study (24) showed that plasma RBV concentrations at day 29 are a strong independent predictor of SVR, suggesting that the flat dose of RBV 800 mg/day may have been insufficient, resulting in a loss of SVR and supporting the role of higher RBV doses in achieving SVR in G2 and G3 CHC patients. However, other results do not support the dose-dependent role of RBV in easy-to-treat patients. In fact, the results were similar in a recent study of a 24-week regimen of low-dose RBV 400 and 800 mg/day, while in another study (25) in G2 patients, no correlation was found between the mean dose of PEG-IFN and RBV, and either RVR or SVR.

Overall, all these studies confirm that factors such as older age, severe fibrosis or cirrhosis, HVL, metabolic factors and perhaps RBV dose, affect RVR and SVR rates in both G2 and G3 CHC patients.

Do IL28B polymorphisms affect sustained virological response in G2 and G3 patients?

  1. Top of page
  2. Abstract
  3. Standard of care for patients with G2 and G3 chronic hepatitis C
  4. Strategies of optimization therapy in patients with genotype 2 and 3 chronic hepatitis C: are they effective?
  5. Factors affecting the likelihood of a virological response in G2 and G3 patients
  6. Do IL28B polymorphisms affect sustained virological response in G2 and G3 patients?
  7. Conclusions
  8. Conflicts of interest
  9. References

Besides the well-known factors affecting SVR, other unconventional variables have recently been identified that may help optimize the therapeutic strategy in CHC patients. Several highly correlated single nucleotide polymorphisms (SNPs) on a linkage disequilibrium blocking chromosome 19 in the vicinity of three IFN-λ genes (IL29, IL28A and IL28B) have been strongly associated with response to PEG-IFN plus RBV in three genome-wide association studies of G1 CHC patients (26–28), also suggesting a relationship between these SNPs and spontaneous clearance of HCV (31, 32). In this emerging area of research, SNP rs12979860 (C>T), located 3 kb upstream from IL28B, has the strongest association, as patients with its CC genotype are more than twice as likely to respond to SOC than those with non-CC genotypes (26). The exact mechanisms underlying this association are unknown (27).

Also, it has been shown that in non-responders, some IFN-stimulated genes were highly expressed; thus, preactivation of the IFN system in patients appears to limit the effect of IFN antiviral therapy (28–31).

There are very little data for G2 and G3 patients. Rauch et al. (33) found no significant association between genetic variations in IL28B (rs8099917 G-risk allele) and response to therapy in individuals infected with HCV G2 or 3. In fact, they found that treatment failure occurred in 20% (17/83) of G2 and G3 patients with the at-risk allele compared with 14% (20/147) in those without. On the other hand, in a study on the rs12979860 SNP in CHC of all genotypes (45 G2 and G3), McCarthy et al. (34) showed that there was no difference in the effect of this SNP on tSVR in Caucasians with HCV G1 and 2/3. In addition, in a cohort of 649 CHC patients (84 G2 and 60 G3), they also found that the CC genotype was more frequent in G2 and G3 (46 and 55% respectively) patients than in G1 (33.5%) patients. The overexpression of the CC genotype in non-G1 genotypes compared with G1-infected patients was also confirmed in a Spanish study (35) (66.7 vs 39.1%). However, in 58 non-G1 patients in that study, the SVR rate was similar in patients with the CC genotype and those with the CT and TT genotypes (87.2 vs 84.2%). Similarly, in a cohort of 164 HCV/HIV co-infected patients (31% G3), Rallon et al. (36) found that the SNP rs12979860 had no effect on SVR in the subgroup of G3 patients. A large-scale Italian study (37) on 268 easy-to-treat patients (G2, 213; G3, 55) undergoing a standard (24 weeks) or a variable duration of treatment depending on RVR (12 or 24 weeks) re-evaluated these conflicting data. The authors showed that the CC genotype, present in 37% of the cases, was an independent predictor of SVR in this cohort of patients. Interestingly, the IL-28B genotype was found to be an independent positive predictor of SVR in G2 and G3 patients without RVR (SVR rates: CC, 87%; CT, 67%; and TT, 29%), but not in those with RVR who achieve SVR in more than 70% of cases in all IL-28 genotypes. These results suggest that combining standard and new predictors of SVR could allow individualized assignment to short, standard or even prolonged courses of therapy in virtually all patients with G2 or G3.

Conclusions

  1. Top of page
  2. Abstract
  3. Standard of care for patients with G2 and G3 chronic hepatitis C
  4. Strategies of optimization therapy in patients with genotype 2 and 3 chronic hepatitis C: are they effective?
  5. Factors affecting the likelihood of a virological response in G2 and G3 patients
  6. Do IL28B polymorphisms affect sustained virological response in G2 and G3 patients?
  7. Conclusions
  8. Conflicts of interest
  9. References

Current treatment guidelines recommend that patients with G2 and G3 CHC be treated with combination PEG-IFN α-2a or PEG-IFN α-2b and RBV at a flat dose of 800 mg/day for 24 weeks, leading to SVR in approximately 80% of cases. However, there is good reason to believe that this current 24-week duration SOC for G2 and G3 HCV patients is oversimplified, lacks a firm biological basis and can lead to over- or undertreatment in certain cases. SOC will be used in the near future in G2 and G3 patients, because protease inhibitors will be registered first for genotype 1 patients. There is a growing interest in research that would allow individualizing treatment duration by response-guided therapy. This strategy is supported by evidence that patients can be categorized according to early treatment virological kinetics to determine their ‘susceptibility’ to HCV eradication. Many studies have evaluated whether a shorter treatment is as effective as standard-duration therapy in G2 and G3 CHC patients who achieve RVR. A few statements can be made on the basis of the evidence:

  • Patients with G2 and G3 CHC should not be considered a unique group of easy-to-treat patients, because SVR rates are higher in G2.
  • PEG-IFN α-2a (180 mcg/week) or α-2b (1.5 mcg/kg/week) in combination with RBV (preferably weight-based) for 24 weeks is the current SOC for G2 and G3 CHC, resulting in SVR in more than 75% of patients.
  • RVR is achieved in more than 60% of G2 and G3 CHC patients, leading to SVR in about 80% of cases. It therefore represents the strongest predictive factor of SVR.
  • Older age, male gender, advanced fibrosis or cirrhosis, high baseline viral load, and metabolic factors are the most important negative predictive factors RVR and SVR in G2 and G3 CHC patients, whatever the duration of treatment.
  • A response-guided individualized approach considering both the time of virological clearance and the presence of negative predictors of response would favour optimized treatment.
  • In the near future, IL28B and other genetic polymorphisms could further refine the approach to optimized treatment for the individual patient with G2 and G3 CHC.
  • G2 CHC patients with RVR can receive shorter treatment (12–16 weeks), especially if adverse events or poor tolerance during therapy compromise treatment. To reduce the risk of virological relapse, short-term treatment should not be used in patients with advanced fibrosis or cirrhosis, obesity, metabolic risk factors and/or viral co-infections. Adherence to PEG-IFN and RBV in terms of both drug consumption and doses should be optimal.
  • G3 CHC patients with LVL and RVR can receive shorter treatment (12–16 weeks), particularly if adverse events or poor tolerance during therapy compromise treatment. To reduce the risk of virological relapse, short treatment should not be used in patients with high baseline viraemia (≥600 000 IU/ml), advanced fibrosis or cirrhosis, obesity, metabolic risk factors and/or viral co-infections. Optimal adherence to PEG-IFN and RBV in terms of both drug consumption and doses is important.
  • G2 and G3 CHC patients who relapse after a course of short therapy have a 70% chance of achieving SVR when retreated with a standard duration.
  • G2 and G3 CHC patients without RVR receiving a standard duration of therapy have a 40–50% chance of achieving SVR. Although the chances of SVR could be improved by prolonging therapy, there is no firm evidence to support this approach at present.

References

  1. Top of page
  2. Abstract
  3. Standard of care for patients with G2 and G3 chronic hepatitis C
  4. Strategies of optimization therapy in patients with genotype 2 and 3 chronic hepatitis C: are they effective?
  5. Factors affecting the likelihood of a virological response in G2 and G3 patients
  6. Do IL28B polymorphisms affect sustained virological response in G2 and G3 patients?
  7. Conclusions
  8. Conflicts of interest
  9. References
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