Hepatitis C virus (HCV) genotypes 2 and 3 have previously been classified as easy-to-treat genotypes, because sustained virologic responses (SVRs) up to 80% have been achieved with 24-week peginterferon and ribavirin. More detailed studies have shown differences between HCV genotypes 2 and 3, indicating that genotype 3 has become the most difficult-to-treat genotype. With new drugs, new challenges are emerging regarding relapse rates, the role of ribavirin, and optimal duration of therapy. Sofosbuvir remains the backbone of genotype 3 therapy, whereas this drug is not an option in patients with creatinine clearance lower than 30 mL/min.
Key points
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With the advent of new direct-acting antivirals, sustained virologic response (SVR) rates have dramatically increased, and with fewer adverse effects.
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In genotype 2, SVR rates of 90% are achieved with interferon-free regimens based on sofosbuvir and ribavirin.
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The outlook for genotype 3 is slightly different. Patients without cirrhosis and treatment-naive patients with cirrhosis have high SVR rates, whereas treatment-experienced patients with cirrhosis achieve around 60% with 24-week therapies. As such, new treatments are needed for genotype 3 because these have become the most difficult-to-treat patients.
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New drugs have enabled most of the host and viral factors with decreased SVR rates to be resolved. However, new challenges have emerged, such as ribavirin use and duration of therapy, and special populations, such as patients with chronic renal failure.
Introduction
Hepatitis C virus (HCV) is a pandemic affecting more than 150 million people worldwide. Genotype 3 is the most common in east Asian countries like Pakistan and northern Europe, whereas genotype 2 is the most common on the West Africa coast. In the past, HCV genotypes 2 and 3 have been classified as easy-to-treat genotypes because sustained virologic response (SVR) has been achieved in 75% to 80% of cases with a 24-week therapy period using peginterferon and ribavirin. However, recent studies have shown relevant differences between HCV genotypes 2 and 3. Therapy for hepatitis C virus infection is evolving rapidly, with direct-acting antivirals (DAAs) transforming the treatment of hepatitis C such that interferon-free regimens have become a new reality. Serious side effects have been substantially reduced. This article reviews the currently available therapies for HCV genotypes 2 and 3, and summarizes the special features of these genotypes.
Introduction
Hepatitis C virus (HCV) is a pandemic affecting more than 150 million people worldwide. Genotype 3 is the most common in east Asian countries like Pakistan and northern Europe, whereas genotype 2 is the most common on the West Africa coast. In the past, HCV genotypes 2 and 3 have been classified as easy-to-treat genotypes because sustained virologic response (SVR) has been achieved in 75% to 80% of cases with a 24-week therapy period using peginterferon and ribavirin. However, recent studies have shown relevant differences between HCV genotypes 2 and 3. Therapy for hepatitis C virus infection is evolving rapidly, with direct-acting antivirals (DAAs) transforming the treatment of hepatitis C such that interferon-free regimens have become a new reality. Serious side effects have been substantially reduced. This article reviews the currently available therapies for HCV genotypes 2 and 3, and summarizes the special features of these genotypes.
Hepatitis C virus genotype 2
HCV genotype 2 represents around 13% of all HCV infections, with a major prevalence in sub-Saharan African countries and Asia. This genotype has been strongly associated with acupuncture using nondisposable material. Until 2013, the standard of care for HCV-2 treatment-naive as well as treatment-experienced patients was a combination of peginterferon plus ribavirin for 24 weeks. With this combination, SVR rates up to 80% could be achieved. More recently, the launch of DAAs has resulted in treatments that have been shorter as well as better tolerated ( Table 1 ).
| Population | Study | Combination | SVR (%) |
|---|---|---|---|
| Treatment naive | PROTON | SOF + IFN + RBV 12 wk | No cirrhosis: 96 |
| FISSION | SOF + RBV 12 wk | Overall: 95 No cirrhosis: 97 Cirrhosis: 83 | |
| POSITRON | SOF + RBV 12 wk | Overall: 93 No cirrhosis: 92 Cirrhosis: 94 | |
| VALENCE | SOF + RBV 12 wk | Overall: 99 No cirrhosis: 97 Cirrhosis: 100 | |
| PHOTON-1 | SOF + RBV 12 wk | Overall: 88 | |
| Japanese trial | SOF + RBV 12 wk | Overall: 98 No cirrhosis: 97 Cirrhosis: 100 | |
| AI444-40 | SOF + DCV 24 wk SOF + DCV + RBV 24 wk | No cirrhosis: 96 | |
| Treatment experienced | LONESTAR-2 | SOF + IFN + RBV 12 wk | Overall: 96 No cirrhosis: 100 Cirrhosis: 93 |
| FUSION | SOF + RBV 12 wk | Overall: 82 No cirrhosis: 90 Cirrhosis: 60 | |
| SOF + RBV 16 wk | Overall: 88 No cirrhosis: 92 Cirrhosis: 78 | ||
| VALENCE | SOF + RBV 12 wk | Overall: 90 No cirrhosis: 91 Cirrhosis: 88 | |
| PHOTON-1 | SOF + RBV 12 wk | Overall: 92 | |
| Japanese trial | SOF + RBV 12 wk | Overall: 96 No cirrhosis: 95 Cirrhosis: 89 |
Treatment Options for Hepatitis C Virus Genotype 2
Treatment-naive patients: direct-acting antivirals in combination with peginterferon/ribavirin
Sofosbuvir is a potent nucleotide polymerase inhibitor analogue that acts at the catalytic site of Nonstructural protein 5B (NS5B) polymerase. The PROTON trial evaluated the combination of sofosbuvir with peginterferon and ribavirin treatment over 12 weeks. A SVR rate of 96% (25 out of 26) was achieved. Daclatasvir is a NS5A inhibitor that shows pangenotypic activity. Eighty patients with HCV genotype 2 (23% with cirrhosis) were enrolled randomly to 3 treatment arms: (1) daclatasvir, peginterferon, and ribavirin over 12 weeks (n = 24); (2) the same combination over 16 weeks (n = 23); (3) placebo, peginterferon, and ribavirin over 24 weeks (n = 24). SVR, 24 weeks after treatment has ended (SVR24) was higher in groups receiving daclatasvir (83% [20 out of 24] and 82% [19 out of 23], respectively) compared with placebo (63%; 15 out of 24). Simeprevir is a second-wave NS3/4A protease inhibitor with potent antiviral activity in HCV genotypes 1, 4, 5, and 6. A phase 2a study closed early and prevented further development of simeprevir, with or without peginterferon and ribavirin in HCV genotype 2. The study included 6 treatment-naive patients receiving simeprevir in monotherapy (200 mg/d for 7 days); only half of the patients showed antiviral activity.
Treatment-naive patients: interferon-free regimen with direct-acting antivirals
Most studies have evaluated the combination of sofosbuvir plus ribavirin. The FISSION study was a phase 3 trial that compared sofosbuvir plus ribavirin for 12 weeks (n = 73) versus peginterferon plus ribavirin for 24 weeks (n = 67) in 140 previously untreated patients with HCV infection. Patients receiving sofosbuvir plus ribavirin achieved 95% (69 out of 73) SVR compared with 78% (52 out of 67) in those receiving peginterferon plus ribavirin. Patients with cirrhosis had lower SVR rates than those without in both treatment groups (sofosbuvir plus ribavirin, 83% [10 out of 12] vs 97% [59 out of 61]; peginterferon plus ribavirin, 62% [8 out of 13] vs 81% [44 out of 54]). POSITRON was a randomized trial that included patients chronically infected with HCV genotype 2 and for whom treatment with peginterferon was not an option. They were assigned to receive sofosbuvir plus ribavirin (n = 109) or placebo (n = 34) for 12 weeks. Those treated with sofosbuvir plus ribavirin achieved SVR of 93% (101 out of 109), whereas the rate was 0% in those receiving placebo, regardless of the presence of liver cirrhosis (94% [16 out of 17] vs 92% [85 out of 92], respectively). The VALENCE trial evaluated sofosbuvir plus ribavirin or placebo for 12 weeks in treatment-naive patients (n = 32). The treated patients achieved SVR of 97% (29 out of 30) in those who did not have cirrhosis and 100% (2 out of 2) in those with cirrhosis. In the PHOTON-1 study, the combination of sofosbuvir plus ribavirin was evaluated in treatment-naive patients with HCV genotype 2 and concurrent Human immunodeficiency virus (HIV). The SVR achieved was 88% (23 out of 26). In addition, a phase 3 study conducted in Japan assessed the efficacy and safety of sofosbuvir plus ribavirin in treatment-naive patients with chronic genotype 2 HCV infection. The SVR obtained was 97% (80 out of 82) in patients without cirrhosis and 100% (8 out of 8) in those with cirrhosis. Sofosbuvir was also evaluated in combination with daclatasvir, with or without ribavirin, over 24 weeks in 26 HCV-2 treatment-naive patients. Overall, 96% achieved SVR (24 out of 26). Other combinations have been addressed but efficacy has continued to be suboptimal. A combination of ombitasvir and paritaprevir with ritonavir, with or without ribavirin, has been evaluated in treatment-naive patients and adults without cirrhosis with chronic HCV genotype 2. HCV RNA was undetectable from week 4 to 12 in 90% (9 out of 10) receiving the ribavirin-containing regimen and 80% (8 out of 10) receiving the ribavirin-free regimen, whereas SVR12 was achieved by 80% (8 out of 10) receiving the ribavirin-containing regimen, and 60% (6 out of 10) receiving the ribavirin-free regimen.
Treatment-experienced patients: direct-acting antivirals in combination with peginterferon/ribavirin
The LONESTAR-2 trial evaluated sofosbuvir plus peginterferon and ribavirin in combination over 12 weeks in 23 treatment-experienced patients. SVR was 100% (9 out of 9) in patients without cirrhosis and 93% (13 out of 14) in those with cirrhosis. Daclatasvir plus peginterferon and ribavirin combination has been tested in HCV genotype 2. Patients were enrolled into 3 arms: (1) daclatasvir and peginterferon plus ribavirin over 12 weeks (n = 26); (2) the same combination over 16 weeks (n = 27); (c) placebo, peginterferon plus ribavirin over 24 weeks (n = 27). SVR24 was higher in groups receiving daclatasvir (69% [18 out of 26] and 67% [18 out of 27] for 16 and 12 weeks of therapy, respectively) compared with those receiving placebo (59%; 16 out of 27).
Treatment-experienced patients: interferon-free regimen with direct-acting antivirals
All studies described thus far were also conducted in treatment-experienced patients having genotype 2. The treatment regimens were with sofosbuvir and were interferon free. The FUSION trial included patients who had not had a response to previous interferon therapy. Patients received sofosbuvir plus ribavirin for 12 weeks (n = 39) or 16 weeks (n = 35). SVR rates were 90% (26 out of 29) in patients without cirrhosis receiving treatment over 12 weeks, and 92% (24 out of 26) in those treated for 16 weeks; lower SVR was observed in those with cirrhosis (60%; 6 out of 10) and 78% (7 out of 9), respectively. The VALENCE trial evaluated sofosbuvir plus ribavirin or placebo for 12 weeks in patients with HCV who were treatment experienced (n = 41). In patients receiving treatment, the SVR rate was 91% (30 out of 33) in patients without cirrhosis and 88% (7 out of 8) in those patients with cirrhosis. In the PHOTON-1 study, sofosbuvir plus ribavirin was evaluated in treatment-experienced patients with HCV genotype 2, and with concurrent HIV. The SVR rate was 92% (22 out of 24). The Japanese study evaluating sofosbuvir plus ribavirin was also performed in treatment-experienced patients. The SVR12 was 95% (52 out of 54) in patients without cirrhosis and 89% (8 out of 9) in those with cirrhosis.
Hepatitis C virus genotype 3
This genotype represents around 20% of overall HCV infections worldwide. The probable origin of HCV genotype 3 has been placed in Asia, where it is more prevalent (south and east Asia, and India). From molecular studies, HCV genotype 3, in particular subtype 3a, is significantly associated with transmission via intravenous drug abuse in industrialized countries (especially North and South America and Europe). HCV genotype 3 has some special features that differ from the other viral genotypes ( Fig. 1 ). First, it is associated with the highest rate of steatosis, including a morphologic expression of a viral cytopathic effect. The magnitude of HCV-3 infection–related steatosis correlates with the level of viral replication, and is independent of other well-documented steatogenic factors such as PNPLA3. Second, genotype 3 is associated with a more accelerated fibrosis progression. The mechanism of accelerated fibrogenesis in patients infected with HCV genotype 3 is under debate because some investigators have failed to identify steatosis as an independent factor of fibrosis in these patients. There may be genotype-dependent fibrogenetic effects with respect to proinflammatory cytokines or the hepatic stellate cells. Third, HCV genotype 3 has been found to increase the risk of developing hepatocellular carcinoma, relative to other viral genotypes. Steatosis and fibrosis attributed to the genotype are, perhaps, the main factors explaining this association. Fourth, genotype 3 seems to interact with the immune response, compared with other HCV genotypes. Haplotype BTN3A3 rs13220495 CC plus IL28B genotype CC were observed to be universally present in patients with genotype 3a. This interaction could explain the 2 critical aspects of the genotype: higher rates of spontaneous viral clearance and higher rates of disease progression.
Treatment Options for Hepatitis C Virus Genotype 3
Treatment-naive patients: direct-acting antivirals in combination with peginterferon/ribavirin
Sofosbuvir has been evaluated in combination with peginterferon and ribavirin over 12 weeks in the PROTON trial. SVR rate was achieved in 96% (38 out of 39) ( Table 2 ). The BOSON study also evaluated this combination. This study included 94 (overall SVR, 95%) treatment-naive patients, with SVR rates of 96% (68 out of 71) in noncirrhotic and 91% (21 out of 23) in cirrhotic patients. Daclatasvir together with peginterferon and ribavirin has been used in genotype 3. Seventy-one patients (1% with cirrhosis) were enrolled and randomly assigned to groups to receive 12 or 16 weeks of daclatasvir, or 24 weeks of placebo, all in combination with peginterferon and ribavirin. SVR24 rates were 69%, 67%, and 59%, respectively.
| Population | Study | Combination | SVR (%) |
|---|---|---|---|
| Treatment naive | PROTON | SOF + IFN + RBV 12 wk | No cirrhosis: 96 |
| FISSION | SOF + RBV 12 wk | Overall: 56 No cirrhosis: 61 Cirrhosis: 34 | |
| POSITRON | SOF + RBV 12 wk | Overall: 61 No cirrhosis: 68 Cirrhosis: 21 | |
| VALENCE | SOF + RBV 24 wk | Overall: 93.3 No cirrhosis: 94 Cirrhosis: 92 | |
| BOSON | SOF + IFN + RBV 12 wk | Overall: 95 No cirrhosis: 96 Cirrhosis: 91 | |
| SOF + RBV 16 wk | Overall: 77 No cirrhosis: 83 Cirrhosis: 57 | ||
| SOF + RBV 24 wk | Overall: 88 No cirrhosis: 90 Cirrhosis: 82 | ||
| PHOTON-1 | SOF + RBV 12 wk | Overall: 67 | |
| AI444-40 | SOF + DCV 24 wk SOF + DCV + RBV 24 wk | No cirrhosis: 89 | |
| ALLY-3 | SOF + DCV 12 wk | Overall: 90 No cirrhosis: 97 Cirrhosis: 58 | |
| ELECTRON-2 | SOF + LDV 12 wk | No cirrhosis: 64 | |
| SOF + LDV + RBV 12 wk | No cirrhosis: 100 | ||
| Treatment experienced | LONESTAR-2 | SOF + IFN + RBV 12 wk | Overall: 83 No cirrhosis: 83 Cirrhosis: 83 |
| FUSION | SOF + RBV 12 wk | Overall: 30 No cirrhosis: 37 Cirrhosis: 19 | |
| SOF + RBV 16 wk | Overall: 62 No cirrhosis: 63 Cirrhosis: 61 | ||
| VALENCE | SOF + RBV 24 wk | Overall: 70 No cirrhosis: 85 Cirrhosis: 60 | |
| BOSON | SOF + IFN + RBV 12 wk | Overall: 91 No cirrhosis: 94 Cirrhosis: 86 | |
| SOF + RBV 16 wk | Overall: 64 No cirrhosis: 76 Cirrhosis: 47 | ||
| SOF + RBV 24 wk | Overall: 80 No cirrhosis: 82 Cirrhosis: 77 | ||
| ELECTRON-2 | SOF + LDV + RBV 12 wk | Overall: 82 No cirrhosis: 89 Cirrhosis: 73 |
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