SEARCH

SEARCH BY CITATION

Keywords:

  • HCV;
  • hepatitis C;
  • protease inhibitor;
  • response guided therapy

Abstract

  1. Top of page
  2. Abstract
  3. Genotype 1
  4. Genotype 2 and genotype 3
  5. Genotype 4
  6. Summary
  7. Conflicts of interest
  8. References

Over time, HCV therapy with pegylated interferon and ribavirin has evolved from a fixed duration strategy to one of response guided therapy and this has enabled us to optimize treatment duration. With the evolution of protease inhibitor based therapy, the paradigm of response guided therapy has further helped in decreasing treatment duration in greater number of patients and which then translates into shorter duration of adverse events. However, several population groups have done better with extended duration therapy as opposed to response guided therapy despite early viral clearance. These include the Black population, and those with cirrhosis, decreased interferon sensitivity, and unfavorable IL28B genotypes. The proper identification of those who might benefit from extended duration HCV therapy will undoubtedly lead to optimal care and outcomes.

Abbreviations
cEVR

complete EVR

DAA

direct acting antivirals

eRVR

extended rapid virological response

EVR

early virological response

HCV

hepatitis C virus

PEG-IFN

pegylated interferon

pEVR

partial EVR

RAVs

resistance associated variants

RBV

ribavirin

RGT

response-guided therapy

RVR

rapid virological response

SOC

standard of care

SVR

sustained virological response

Up until recently, the standard of care (SOC) for chronic hepatitis C genotype 1 was a combination of pegylated interferon (PEG-IFN) and ribavirin (RBV). In the year 2011, a new paradigm has evolved which combines a protease inhibitor (boceprevir or telaprevir) with PEG-IFN/RBV as the treatment of choice for these patients. This combination dual therapy regimen achieved a sustained virological response (SVR) in approximately 42–52% of genotype 1 and 67–84% of genotype 2 and 3 patients [1-4]. The treatment duration was usually 48 weeks for HCV genotype 1 infection [1-3, 5-12] and 24 weeks for HCV genotypes 2 and 3 [1-4, 13-17]. A significant effort has been made to shorten the duration of treatment in patients with favourable baseline host and viral characteristics and with on-treatment virological responses because of the cost and adverse effects of treatment, although they do not affect response rates [8-10, 13, 14, 18, 19]. An extended duration of therapy has also been assessed to optimize the outcome in patients with slow on-treatment virological responses, [5-8, 11, 12, 19, 20].

In the context of PEG-IFN/RBV treatment, response-guided therapy (RGT) is an approach based on on-treatment milestones of a rapid virological response (RVR: viral clearance by week 4 of therapy), a complete early virological response (cEVR: viral clearance at week 12) and a partial early virological response (pEVR: at least 2 log10 reduction of viral load at week 12). However, with protease inhibitor based therapy, new virological on-treatment definitions have evolved to determine the RGT strategy (Table 1). An RVR while on PEG-IFN/RBV is the best on-treatment predictor of SVR. It is a better predictor than other factors such as cirrhosis, genotype, baseline viral load and race/ethnicity [8, 9, 13, 14, 21, 22]. In a retrospective analysis of 1383 patients with HCV genotypes 1–4, RVR was achieved in 16% of patients with genotype 1, 71% of patients with genotype 2 and 60% with genotype 3 [22]. Of those who achieved an RVR, 88–100% attained SVR regardless of genotype, which has thus made the predictive value of RVR a focus of many studies to tailor therapy [22].

Table 1. Definition of virological response on treatment
AcronymTermDefinition
Peginterferon and ribavirin
SVRSustained virological responseHCV RNA negative at 6 months of cessation of therapy
RVRRapid virological responseNegative HCV RNA levels by week 4
EVREarly virological response< 2 log10 decrease at 12 weeks
pEVRPartial EVR≥ 2 log10 decrease at 12 weeks
cEVRComplete EVRClear at 12 weeks
Protease inhibitor, peginterferon and ribavirin
eRVRExtended rapid virological responseClearing of HCV RNA levels by weeks 4 and 12 for TPV regimen
eVREarly virological responseRapid viral clearance at week 8 maintained through week 24 for BOC regimen
Treatment-experienced patients
 RelapsersCleared virus on treatment but reappeared subsequent to treatment cessation
 Null-responders< 2 log10 decline in HCV RNA 12 weeks
 Partial responders≥ 2 log10 decrease in HCV RNA at week 12

Reducing the duration of dual therapy from 48 to 24 weeks in genotype 1-infected patients results in similar SVR rates predominantly in patients who achieve RVR and with low baseline viral load (< 800 000 IU/ml) [8-10]. The data in patients with genotypes 2 and 3 generally support the reduction of treatment duration in patients who achieve an RVR, except in those who are over 40, have advanced fibrosis, or have a high baseline viral load [13-15, 17, 23]. The rate of RVR is influenced by host and viral factors that include age, race, degree of fibrosis, insulin resistance, HCV genotype, baseline viral load and IL28 B status, which in turn translates into achieving SVR [13-15, 17, 20, 24-26]. However, although RGT is appropriate for most patients, certain populations such as those with cirrhosis, decreased interferon sensitivity, unfavourable IL28 B genotypes and Black ethnicity may benefit from extended therapy [13-15, 17, 20, 24-26]. With the recent introduction of protease inhibitors, there are now more options to tailor therapy in genotype 1 disease. It should be noted that these new treatments have limited activity outside of genotype 1 infection [27].

Genotype 1

  1. Top of page
  2. Abstract
  3. Genotype 1
  4. Genotype 2 and genotype 3
  5. Genotype 4
  6. Summary
  7. Conflicts of interest
  8. References

Pegylated interferon and ribavirin therapy

A pooled analysis of several studies in HCV genotype 1 concluded that SVR rates for patients with RVR who receive a short duration of therapy were lower than those for the standard treatment duration (79.7% for 24 weeks vs. 94.1% for 48 weeks) and similar results were only found in patients with low baseline viral loads < 400 000 IU/ml (95.5% for 48 weeks vs. 90.6% for 24 weeks) (Table 2) [23]. Overall, relapse rates tended to be higher in patients who received 24 weeks of therapy than in those receiving 48 weeks (34–37% vs. 12–24%) [10, 26, 27] and they are especially high in those with high viral loads or without RVR (50.8% vs. 15.7% respectively) [9, 10, 28, 29]. Finally, even after achieving RVR, SVR rates were suboptimal in patients with advanced fibrosis [8].

Table 2. Duration of treatment, SVR, and response-guided therapy in genotype 1 patients following PEG-IFN and RBV
General Variable durationStandard durationP
 Weeksn%n%
  1. a

    RVR with baseline viremia ≥ 400 000 IU/ml, higher SVR for 48 weeks vs. 24 weeks (87% vs. 73%).

  2. b

    Low baseline viral load < 800 000 IU/ml and RVR, comparable rates for individualized and fixed duration therapy.

  3. c

    P value for non-inferiority.

  4. d

    Historical control for standard duration [6].

Mangia 2008aSVRRGT24, 48, 72 vs. 48224/45949107/23745ns
Berg 2009bSVRRGT18–48 vs. 4872/20835105/225480.005
Relapse rates   33 14< 0.0005
Sarrazin 2011cSVR: overallRGT24–72 vs. 48217/39855108/22548< 0.0001
SVR: with RVR 24–30 vs. 48 86–88 93–100 
SVR: slow responders 62–72 vs. 48 60–68 43–44 
  Shortened durationStandard duration 
 Weeksn%n%P
Sanchez-Tapias 2006SVR: with RVRnon-RGT24 vs. 48 64 79 
Zeuzem 2006dSVR: ≤ 600 000 IU/mlnon-RGT24 vs. 48117/2355027/3871 
Relapse rates  69/185371/284 
Yu 2008SVR: overallnon-RGT24 vs. 4859/1005979/100790.002
SVR: with RVR  40/458942/421000.056
SVR: with no RVR  19/553537/58640.002
Liu 2008SVR: overallnon-RGT24 vs. 48 56 76< 0.001
SVR: with RVR + < 800 000 IU/ml   94 100ns
SVR: with no RVR   16 390.01
  Extended durationStandard duration 
 Weeksn%n%P
Buti 2010SVR: slow respondersnon-RGT72 vs. 4834/704836/8543 
Relapse rates   33 47ns
Ferenci 2010SVR: slow responders with EVRnon-RGT72 vs. 4888/1505971/13951ns
Relapse rates  20/1081936/107340.0115
Sanchez-Tapias 2006SVR: non-RVRnon-RGT72 vs. 4863/1654441/161280.003
Pearlman 2007SVR: with EVRnon-RGT72 vs. 4820/52389/49180.026

The polymorphisms in the Interleukin-28B gene (IL28 B) have also been shown to correlate with achieving an SVR after combination therapy. Patients with genotype variant C/C at rs12979860 achieved an SVR two to three times more frequently than those with C/T or T/T variants [30, 31]. Furthermore, the RVR and SVR rate was significantly higher in Caucasians with a C/C variant (28% for C/C vs. 5% for C/T vs. 5% for T/T) and (69% for C/C vs. 33% for C/T vs. 27% for T/T) respectively [31]. The IL28B variants also appear to be important in patients who do not achieve RVR as SVR rates were twice as high in Caucasians with C/C alleles than in those with non-C/C alleles (66% for C/C vs. 31% for C/T vs. 24% for T/T) [31]. The IL28B polymorphisms may explain some of the differences in virological responses between Blacks and Caucasians [32] as the Black populations have a lower prevalence of C/C than Caucasians (16% in Blacks vs. 39% in Caucasians) [30]. However, the response to treatment by Black population was poorer across all IL28B genotypes, suggesting that there may be other viral and host factors influencing SVR [30, 31].

Despite the different definitions of slow on-treatment response and the associated confounding treatment outcomes [5, 6, 8, 11, 12], the SVR rate following 72 weeks of extended therapy was shown to be higher in slow responders (≥ 2 log10 decrease in HCV RNA levels by week 12 as compared with baseline, but clear HCV RNA by week 24) than that after 48 weeks of therapy (38% for 72 weeks vs. 18% for 48 weeks) with lower relapse rates (20% vs. 59%) [7]. A pooled analysis of slow responders (defined as detectable HCV RNA at week 12) found that 39.4% of patients who received 72 weeks of therapy achieved SVR compared with only 30.3% of patients who received 48 weeks of therapy [23]. In contrast, patients who had undetectable HCV RNA levels at week 12 did not benefit from extended therapy [23].

Protease inhibitor, pegylated interferon and ribavirin

Because of the suboptimal response rates with PEG-IFN/RBV in hepatitis C genotype 1, a significant effort has been made to develop additional treatment options (Tables 3 and 4) [20, 24-27, 33]. The first direct-acting antiviral agents (DAA), boceprevir and telaprevir were recently approved for the treatment HCV genotype 1. Both treatments are linear inhibitors of the HCV NS3/4A protease, an enzyme that is important in post-translational processing of the viral polyprotein [20, 25]. Combined with PEG-IFN and RBV these protease inhibitors have been shown to significantly improve SVR rates and shorten the duration of therapy [20, 24-26, 33].

Table 3. Response-guided therapy and predictors of response following PEG-IFN/RBV combination therapy and triple therapy with boceprevir
Genotype 1 – boceprevirDual therapyResponse guidedResponse unguidedPa
n%n%n%
  1. a

    P values are with control.

General
Poordad 2011SVR137/36338233/36863242/36666< 0.001
Bacon 2011SVR: treatment experienced  95/16259107/16166< 0.001
High baseline viral load
Bacon 2011SVR: > 800 000 IU/ml11/651783/1475691/14165 
SVR: ≤ 800 000 IU/ml6/154012/158016/2080 
Age
Bacon 2011Age: > 539/402242/735855/7970 
Age: ≤ 538/402053/896052/8263 
Fibrosis
Poordad 2011SVR: Metavir fibrosis score ≥ 39/243814/344122/4252ns
Bacon 2011SVR: metavir fibrosis score ≥ 32/151314/324421/3168 
SVR: Cirrhosis0/1006/173517/2277 
Interferon response
Poordad 2011SVR: decrease by < log103/83427/972836/9538< 0.001
SVR: decrease by ≥ log10133/25051203/25281200/25479< 0.001
Race
Poordad 2011SVR: blacks12/522322/524229/5553< 0.001
SVR: non-Blacks125/31140211/31667213/31168< 0.001
Bacon 2011SVR: blacks1/12811/186110/1953 
SVR: non-Blacks16/682484/1445897/14268 
Prior treated
Bacon 2011SVR: prior non-response2/29723/574030/5852 
SVR: Prior relapse15/512972/1056977/10375 
Table 4. Response-guided therapy and predictors of response following PEG-IFN/RBV combination therapy and triple therapy with telaprevir
Genotype 1 – telaprevirDual therapyProtease therapy overalleRVR therapy (T12PR24)non-eRVR therapy (T12PR48)
n%n%n%n%
  1. a

    Study did not have a response-guided component.

General
Jacobson 2011SVR158/36144271/36375189/2128982/15154
Relapse rates64/2292827/3149    
Sherman 2011SVR   72149/1629276/11864
Zeuzem 2011aSVR: previous relapse16/6824121/14583 n/a n/a
With lead-in  124/14188 n/a n/a
SVR: previous partial response6/64929/4959 n/a n/a
With lead-in  26/4854 n/a n/a
SVR: no previous response2/37521/7229 n/a n/a
With lead-in  25/7533 n/a n/a
High baseline viral load
Jacobson 2011SVR: ≥ 800 000 IU/ml101/27936207/28174    
SVR: < 800 000 IU/ml57/827064/8278    
Age
Jacobson 2011Age: ≤ 4574/14352118/14283    
Age: > 45 to ≤ 6582/21638150/21470    
Fibrosis
Jacobson 2011SVR: bridging fibrosis or cirrhosis24/733345/7362    
SVR: No or minimal fibrosis134/28847226/29078    
Sherman 2011SVR: bridging fibrosis or cirrhosis    31/388223/4255

Although initially a significant reduction in HCV RNA can be achieved with protease inhibitor monotherapy, the low barrier of resistance leads to the emergence of viral resistance associated variants (RAVs) [34, 35]. RAVs of the hepatitis C virus can emerge within a few days with resistance to both boceprevir and telaprevir [34, 35]. Moreover, the relapse rate following treatment with a protease inhibitor and PEG-IFN is significantly higher than with PEG-IFN/RBV and a protease inhibitor [36]. Thus, both PEG-IFN and RBV are critical components in an effective triple therapy regimen for chronic hepatitis C.

Treatment-naïve patients

Boceprevir

The SPRINT-2 trial included a lead-in period of 4 weeks of treatment with PEG-IFNα-2b and RBV in all patients. This was followed in two groups by either 44 additional weeks of placebo, PEG-IFN/RBV or boceprevir, PEG-IFN/RBV for a total of 48 weeks. A third RGT group received an additional 24 weeks of triple therapy if patients cleared the virus at week 8 and maintained this status while patients with detectable HCV RNA at week 8 who cleared the virus later were given a placebo, PEG-IFN/RBV for an additional 20 weeks for a total of 48 weeks of treatment [25].

Telaprevir

The aim of the two telaprevir trials (ADVANCE and ILLUMINATE) was to evaluate the safety and efficacy of telaprevir, PEG-IFN α-2a and RBV in previously untreated HCV genotype 1 infections. In the ADVANCE study, unlike in the SPRINT-2 trial, telaprevir was administered simultaneously with PEG-IFN/RBV without a lead-in phase. This study had three treatment arms in which the control group had PEG-IFN/RBV and placebo for 12 weeks followed by PEG-IFN/RBV for 36 weeks for total of 48 weeks of treatment. The T12PR group received telaprevir, PEG-IFN/RBV for 12 weeks. Patients who cleared HCV RNA at weeks 4 and 12 (eRVR) received an additional 12 weeks of PEG-IFN/RBV, whereas those with undetectable HCV RNA levels at either point were treated for an additional 36 weeks with PEG-IFN/RBV. Another telaprevir group only received 8 weeks of telaprevir (T8PR) plus 4 weeks of placebo/PEG-IFN/RBV with a similar response-guided strategy as T12PR group [20].

The ILLUMINATE trial directly evaluated telaprevir based response-guided therapy. Treatment with telaprevir and PEG-IFN/RBV was administered for 12 weeks followed by only PEG-IFN/RBV. Patients who cleared HCV RNA by weeks 4 and 12 (eRVR) were randomly assigned at week 20 to a total of 24 weeks or 48 weeks of treatment. Patients without an extended RVR were assigned to 48 weeks of total treatment [24]. There were strict stopping rules for virological failure in all treatment-naïve and treatment-experienced boceprevir and telaprevir trials [1, 18, 20, 22-26, 32, 33].

Response guided

The protease inhibitors trials provide robust data on the effectiveness of RGT in treatment-naïve patients. There is compelling evidence that 24–28 weeks of therapy is as effective as 48 weeks of therapy in patients with early viral clearance. The boceprevir-based regimen achieved SVR rates of 42–53% in Black and 67–68% in non-Black treatment naïve patients respectively with a response guided and fixed duration strategy. Forty-four per cent of patients qualified for 28 weeks of dual therapy [25]. Telaprevir (12 weeks duration) based treatment also resulted in high overall SVR rates of 72–75% in treatment-naïve patients [20, 24]. The SVR with the telaprevir-based regimen in patients who achieved an eRVR (58–65% of patients), ranged from 89 to 92% with 24 weeks of therapy compared with 54–64% in patients who did not achieve an eRVR and also received 48 weeks of therapy [20, 26].

Response unguided

Although RGT was a successful strategy overall, several populations appeared to benefit from longer treatment. The SPRINT-2 trial included a limited number of patients with stage 3–4 fibrosis whose results were worse with RGT (41% for RGT vs. 52% for fixed-duration). That study also showed that Black patients were significantly less likely to achieve SVR with RGT (42% for RGT vs. 53% for fixed-duration) [25]. Further, patients with a poor response to IFN (< 1 log10 IU/ml decrease at week 4) had lower SVR with RGT when evaluated by race/ethnicity (overall 28% vs. 38%; non-Blacks 29% vs. 39%; Blacks 25% vs. 31%) [25]. Thus, identifying the appropriate treatment duration with a boceprevir-based regimen for Blacks, Caucasians with suboptimal sensitivity to IFN, and those with advanced fibrosis, should optimize outcomes [25].

The ILLUMINATE study showed that results after 24 weeks of therapy in patients with eRVR, was not less effective than 48 weeks of therapy (92% for T12PR24 vs. 88% for T12PR48)[26]. However, SVR rates were lower with 24 weeks of therapy in patients with an eRVR and bridging fibrosis/cirrhosis than in those without bridging fibrosis/cirrhosis, (82% vs. 95%) respectively, whereas rates were similar (88% vs. 87%) with 48 weeks of treatment [26].

Treatment-experienced patients

RESPOND-2, a phase III study, assessed boceprevir and PEG-IFN α-2b/RBV in previously PEG-IFN/RBV-treated genotype 1 unsustained virological responders and noted that triple therapy resulted in significantly higher rates of SVR than in the PEG-IFN/RBV control group. Three groups in RESPOND-2 received a 4 week lead-in phase of PEG-IFN/RBV after which the control group received 44 weeks of PEG-IFN/RBV and a second group received 44 weeks of boceprevir and PEG-IFN/RBV. After the lead-in phase, patients in the RGT arm (HCV RNA negative at week 8 and thereafter) only received 32 weeks of boceprevir and PEG-IFN/RBV whereas those with detectable HCV RNA levels at week 8, but negative by week 12, received a placebo and PEG-IFN/RBV for another 12 weeks for a total of 48 weeks of therapy [24].

Similarly, the REALIZE study assessed telaprevir without an RGT paradigm in previously treated unsustained virological responders. There were two cohorts of telaprevir-based regimens as well as a control group of 48 weeks of PEG-IFN/RBV. Although one cohort had received telaprevir and PEG-IFN/RBV directly for 12 weeks followed by 36 weeks of PEG-IFN/RBV, the other cohort received a 4 week lead-in of PEG-IFN/RBV then triple therapy for 12 weeks followed by 32 weeks of PEG-IFN/RBV for a total of 48 weeks of treatment [33].

Response-guided therapy

The SVR rates with boceprevir, PEG-IFN/RBV in treatment-experienced patients were 59 and 66% in RGT and fixed duration treatment groups respectively compared with 21% in the control arm [24, 25]. In patients who achieved an EVR, 86% of the 36-week treatment group and 88% of the 48-week group achieved SVR respectively [24]. Evaluation of prior relapsers and partial responders showed that SVR rates in the prior relapse population were 69% and 75% (RGT vs. fixed duration respectively) and 40% and 52% in those with a prior partial response [24].

Overall SVR rates in the telaprevir study with treatment-experienced patients were 64%, 66% and 17% for simultaneous telaprevir, PEG-IFN, lead-in and delayed telaprevir and the control arm, respectively [20, 33]. The SVR rates with the telaprevir-based regimens in patients with a prior non-response for the simultaneous telaprevir and delayed telaprevir cohorts were; relapsers 81% and 83%; partial responders 59% and 54% and non-responders 29% and 33% respectively.

Response-unguided therapy

An analysis of the RESPOND-2 trial suggested that patients who respond less well to RGT than to fixed-duration therapy included those with a high baseline viral load > 800 000 IU/ml (56% vs. 65%), who are older than 53 (58% vs. 70%), with a body mass index (BMI) > 30kg/m2 (56% vs. 65%), a fibrosis score ≥ 3 (44% vs. 68%) and those with cirrhosis (35% vs. 77%) [24]. That study also showed that results of RGT in prior partial responders were poorer than with fixed duration therapy (40% vs. 52%). This study was limited in that it excluded prior non-responders [24].

Genotype 2 and genotype 3

  1. Top of page
  2. Abstract
  3. Genotype 1
  4. Genotype 2 and genotype 3
  5. Genotype 4
  6. Summary
  7. Conflicts of interest
  8. References

Pegylated interferon and ribavirin therapy

Two landmark studies established 24 weeks of therapy with PEG-IFN/RBV as the SOC in hepatitis C genotypes 2 and 3 (Table 5) [3, 15]. Hadziyannis and colleagues assessed the efficacy of 24 or 48 weeks of treatment with PEG-IFN, plus a low-dose or standard-dose of RBV. Patients were randomized into four treatment groups, 24LD (low-dose RBV, 800 mg/day), 24SD (standard-dose RBV, weight-based 1000 or 1200 mg/day), 48LD and 48SD. The study found that in genotypes 2 and 3 all four groups attained similar SVR rates, (84% 24-LD, 81% 24-SD, 79% 48-LD, and 80% 48-SD) and thus concluded that 48 weeks of therapy and high dose RBV were unnecessary for the treatment of HCV genotype 2 or 3 infections [3].

Table 5. Duration of treatment, SVR, and response-guided therapy in genotype 2 and 3 patients following PEG-IFN and RBV
  Response guidedResponse unguided 
 Weeksn%n%P
General
Mangia 2005SVR: with RVRRGT12,24 vs. 24164/2137753/7076 
Relapse rates: with RVR  n/a9n/a3 
  Shortened durationStandard duration 
   Weeksn%n%P
General
Shiffman 2007SVR: all patientsnon-RGT16 vs. 24455/73262515/73170<0.001
SVR: with RVR  387/48979400/47085 
Relapse rates   31 18<0.001
Lagging 2008SVR: all patientsnon-RGT12 vs. 24 59 78<0.0001
SVR: with RVR  85/12071101/111910.0001
SVR: without RVR  28/684144/71620.014
Relapse rates   33 12<0.0001
Dalgard 2008SVR: with RVRnon-RGT14 vs. 24120/14881136/15091 
von Wagner 2005SVR: with RVRnon-RGT16 vs. 2457/708257/7180 
Mecenate 2010SVR: with RVRnon-RGT12 vs. 2453/717560/7283 
Baseline viral load
Shiffman 2007SVR: > 400 000 IU/mlnon-RGT16 vs. 24323/57157393/58168ns
Lagging 2008SVR: > 400 000 IU/mlnon-RGT12 vs. 24 51 74 
von Wagner 2005SVR rates: > 800 000 IU/ml  24/356930/4075 
Age
Lagging 2008SVR: ≥ 40 yearsnon-RGT12 vs. 2453/1184584/11275< 0.0001
Relapse rates: > 40 years  53/1184517/11215< 0.0001
Fibrosis
Shiffman 2007SVR: cirrhosis  88/1854895/16558ns
Lagging 2008SVR: bridging fibrosisnon-RGT12 vs. 2436/705153/70760.0051
SVR: Cirrhosis  7/303013/2357 
Relapse rates: bridging fibrosis  26/703710/70140.002
Relapse rates: cirrhosis  10/23437/2330 

Shiffman et al. evaluated whether a shorter duration of 16 weeks of therapy was as effective as 24 weeks and showed that reducing the duration significantly lowered the chances of achieving SVR. Patients who received the traditional 24 weeks of therapy had a 70% chance of achieving SVR and only an 18% relapse rate, whereas patients who received 16 weeks of therapy had a lower SVR (62%) and significantly higher relapse rates (31%) [15].

Shortened and standard duration therapy

Most studies in genotypes 2 and 3 have evaluated a treatment duration of 12–16 weeks compared with a fixed duration of 24 weeks, rather than assessing a response-guided strategy [4, 13-15, 17, 37, 38]. Several studies retrospectively addressed the effectiveness of a shorter duration in patients who achieved an RVR and they generally found that SVR rates were similar to those with a fixed duration. However, the degree of significance of these studies is the subject of debate [4, 13-15, 17, 37, 38].

The ACCELERATE study, which was the largest of all genotype 2 and 3 studies, retrospectively evaluated the impact of RVR on SVR. Seventy-nine per cent of patients who achieved an RVR achieved an SVR with 16 weeks of treatment and 85% of patients who underwent 24 weeks of treatment achieved an SVR [15]. Lagging et al. noted that treatment for 12 weeks was less effective than 24 weeks of therapy (59% vs. 78%). Moreover, the SVR was lower and the relapse rate was higher in patients who achieved an RVR after 12 weeks compared with 24 weeks of treatment (SVR 71% vs. 91%, relapse rate 26% vs. 4% respectively) [14]. NORTH-C, another large trial, compared therapy for 14 and 24 weeks and found that shorter treatment resulted in SVR rates of 81% compared with 91% after 24 weeks of therapy. Although there was a numerical difference of 10% in SVR rates, the study concluded that SVR rates were similar between the two treatments and that the decrease in side effects and cost made shorter therapy an economically rational approach [13].

Because of the differences in demographics, geographical areas, host and viral characteristics and treatment durations among the studies, a meta-analysis of shortened treatment duration in genotype 2 or 3 was performed. In nine trials, the SVR rate with standard duration therapy for 24 weeks was higher in genotypes 2 and 3 than shorter therapy (87.5% vs. 79.9% respectively) [21]. In six trials, patients achieving an RVR also had a higher rate of relapse following shorter therapy (12.3% vs. 3.6%) [23].

Response-guided therapy and -unguided therapy

The use of RVR alone as an indicator for shorter therapy has been questioned in several studies suggesting that this approach may not be optimal in certain populations. Groups that tend to respond less well to shorter therapy are those with a high baseline viral load, age older than 40 and an advanced stage of fibrosis/cirrhosis [13-15, 17].

In the clinical trial by Lagging et al., patients who had similar results after 12 weeks and 24 weeks of therapy were under the age of 40 and had an RVR (86% for 12 weeks vs. 93% for 24 weeks), or were ≥ 40 of age, but had low HCV RNA levels (below 1000 IU/ml) on day 7 of treatment and undetectable HCV RNA by day 29 (89% vs. 91%). These data suggest that patients who do not meet these criteria will tend to have poorer outcomes with shorter therapy [14].

The Interleukin 28B genotype does not appear to be an important factor in genotype 2 and 3 patients as it does not appear to influence SVR overall. However, differences in SVR have been found in patients who do not achieve an RVR; patients with C/C alleles had SVR rates of 87%, whereas those with C/T alleles and T/T alleles had SVR rates of 67% and 29% respectively [39]. Although data on the impact of different treatment durations in relation to the IL28B genotype are limited, results suggest that SVR rates are similar in those with C/C alleles, but lower in those with C/T or T/T alleles who receive shorter therapy [39].

Genotype 4

  1. Top of page
  2. Abstract
  3. Genotype 1
  4. Genotype 2 and genotype 3
  5. Genotype 4
  6. Summary
  7. Conflicts of interest
  8. References

Although genotype 4 is much more common in Africa and the Middle East and includes up to 90% of HCV infections in those regions, there are fewer studies on treatment outcome than in genotypes 1–3 [12, 38-41]. Although the most appropriate therapy has not been extensively studied, the SOC for genotype 4 is typically PEG-IFN/RBV for 48 weeks, resulting in SVR rates of more than 60% [40]. One study showed that 36 weeks was the ideal treatment duration with PEG-IFN/RBV based on RGT [41]. Patients were randomly assigned to three groups to be treated for 24, 36 or 48 weeks of therapy respectively. The study found that 48 and 36 weeks of therapy were more effective than 24 weeks (69% for 48 weeks vs. 66% for 36 weeks vs. 29% for 24 weeks) and that there was no significant difference between 36 and 48 weeks of therapy [41]. However, the study also showed that 48 weeks of therapy might be effective in patients with high pretreatment HCV RNA viral loads of > 2 million copies/ml based on SVR rates of 25% in the 36 week treatment group compared with 65% in the 48 week treatment group [41].

Kamal et al. performed a four arm PEG-IFN/RBV clinical trial in Egypt in which patients with undetectable HCV RNA at week 4 were assigned to 24 weeks of treatment, those with undetectable HCV RNA at week 12 were assigned to 36 weeks of treatment and the rest were assigned to 48 weeks of treatment. There was also a group treated with a fixed duration of 48 weeks regardless of on-treatment virological response. The SVR rates in the four groups were 86% (24 weeks treatment), 76% (36 weeks treatment), 56% (48 weeks treatment for slow responders) and 58% for fixed duration group [42]. The study concluded 24 and 36 weeks of treatment was as effective in patients who cleared HCV RNA by weeks 4 and 12 [42].

A small population of genotype 4 patients evaluated outside of Egypt received extended therapy and those without an RVR achieved similar SVR rates to standard duration therapy (50% for 48 weeks vs. 44% for 72 weeks) [12]. However, when patients who achieved an RVR were treated with only 24 weeks of therapy, the SVR rate was high (87%) [43].

More recently in a unique well-characterized cohort of HCV-4 patients, the association between IL28B polymorphism and response to treatment or severity of liver disease was assessed [44]. In 164 HCV-4 patients from different ethnic groups (Egyptian, European and Sub-Saharan African), 82 were studied for response and 160 for disease severity. IL28Brs12979860 CC genotype was associated with better treatment response rates and was 81.8%, 46.5% and 29.4% for genotype CC, CT and TT respectively. There was no significant relationship between IL28B status and the severity of the disease. Thus, pretreatment determination of IL28B genotype may help determine probability of response and help guide treatment decisions in genotype 4 patients.

Summary

  1. Top of page
  2. Abstract
  3. Genotype 1
  4. Genotype 2 and genotype 3
  5. Genotype 4
  6. Summary
  7. Conflicts of interest
  8. References

In the past two decades, considerable progress has been made in HCV therapy. Until recently, PEG-IFN/RBV has been the SOC for patients with genotype 1 chronic hepatitis C. In these patients, treatment began with 48 weeks of treatment until results showed that achieving an SVR depended upon time to on-treatment virological clearance and that RVR was the best predictor of SVR. This then led to strategies assessing treatment duration based upon on-treatment virological response; so-called response-guided therapy. Efforts to shorten the duration of therapy to 24 weeks in patients with RVR and extend the duration of therapy to 72 weeks in slow responders seem to have optimized outcomes. Similarly, some of the patients with genotypes 2 and 3 with favourable characteristics of low viral load and RVR, absence of cirrhosis and younger age may respond well to 12–16 weeks of treatment whereas those without an RVR and poor baseline characteristics may benefit from more than 24 weeks of treatment, although the latter must be systematically assessed in clinical trials. The approval of two protease inhibitors for genotype 1 patients has ushered in a new era of hepatitis C therapy. Triple therapy with a protease inhibitor, PEG-IFN/RBV has improved SVR rates and introduced the new dimension of shorter therapy. Once again, the paradigm of RGT for triple therapy is dictated by the on-treatment virological response. Although an RGT strategy is beneficial for most patients with triple therapy, it is limited in certain patient populations. The RGT strategy is not appropriate in patients with advanced fibrosis, those with poor interferon sensitivity or in Black patients as they have consistently lower SVR rates when treated with RGT than with fixed-duration therapy. Although Black populations have been shown to respond significantly better to fixed-duration therapy than non-Black populations, ethnic studies are limited and Blacks are usually under-represented in clinical trials. Current data suggest that the RGT strategy with triple therapy is inadequate in patients with advanced fibrosis, Black/African ethnicity or previous failure to IFN-RBV therapy. Additional host factors probably play a role in the poor response to RGT in these patient populations. As progress continues to be made with new therapies, patients can be more specifically characterized to develop new algorithms based on baseline host and viral characteristics, for response-guided and -unguided treatments and durations.

Conflicts of interest

  1. Top of page
  2. Abstract
  3. Genotype 1
  4. Genotype 2 and genotype 3
  5. Genotype 4
  6. Summary
  7. Conflicts of interest
  8. References

KRR is on the Advisory Boards for Genetech-Roche, Merck, Tibotec, Vertex and Gilead and is an Investigator for Genetech-Roche, Merck, Gilead, Tibotec, Vertex, FL declares no conflicts of interests; FZ has not declared any conflicts of interests.

References

  1. Top of page
  2. Abstract
  3. Genotype 1
  4. Genotype 2 and genotype 3
  5. Genotype 4
  6. Summary
  7. Conflicts of interest
  8. References