Virology, Natural History, and Treatment for HCV Genotype 3
Virology, Natural History, and Treatment for HCV Genotype 3
Multiple targets are being developed for DAA therapy against HCV-1 but many of these particularly the protease inhibitors have limited activity against HCV-3. There are some novel 2nd-generation NS5A inhibitors such as Achillion ACH-3102, IdenixIDX-719 and Gilead GS-5816 that have potent in vitro activity against HCV-3 and are moving into early-phase clinical trials in combination with other DAAs or IFN. The class with the broadest pangenotypic activity to date is the NS5B nucleotide polymerase inhibitors, which includes merimepodib and sofosbuvir, which are in advanced clinical development and early-phase compounds such as Vertex VX-135. These compounds have the potential to be backbone agents for all oral DAA therapy for HCV-3 in combination with RBV or some of the newer NS5A or disease-modifying agents such as the cyclophilin inhibitors.
Mericitabine (also known as RG7128) is a nucleoside analogue with pangenotypic antiviral activity in vitro. Mericitabine was evaluated in HCV-2 and HCV-3 patients with prior PEG-RIBA treatment failure. After a 4-week triple combination, mericitabine at a twice-daily dose of 1500 mg was discontinued and PEG-RBV was resumed for 20–44 weeks. RVR was achieved in 95% of the mericitabine-treated patients versus 60% in the pegylated interferon ribavirin group. 68% of patients with RVR achieved SVR. SVR was higher in those treated for 48 weeks (90%) than in those treated for 24 weeks (67%). Overall, SVR rates did not differ between HCV-2 and HCV-3 patients (63% and 67%, respectively). Unfortunately, this strategy still requires IFN use for up to 48 weeks and will likely be replaced by all oral therapies.
Sofosbuvir, formerly GS-7977, is a uridine nucleotide analogue that inhibits the NS5B HCV polymerase with in vitro pangenotypic activity. The ELECTRON trial randomly assigned previously untreated, noncirrhotic patients with HCV-2 or HCV-3 to 6 groups receiving sofosbuvir at a daily dose of 400 mg. Five of these groups received 12 weeks of therapy, 4 of which also received weight-based ribavirin and 3 of which received pegylated interferon (alpha-2a). These groups included 6 to 7 HCV-3 and 3–4 HCV-2-infected patients. A final 6th group of 10 HCV-3-infected patients received 8 weeks of sofosbuvir-PEG-RBV. All (100%) of the 50 previously untreated patients with chronic HCV-2 or HCV-3 infection who received 8 or 12 weeks of treatment with sofosbuvir and ribavirin, with or without peginterferon-alpha 2a, had a SVR at 24 weeks after therapy. Of the 10 patients treated with sofosbuvir monotherapy, 6 achieved SVR, while 4 (including two of the seven patients with HCV-3) had relapsed after the end of treatment.
Jacobson et al. reported the results of two much larger trials of sofosbuvir in HCV-2 and HCV-3 patients: POSITRON (interferon intolerant/ineligible patients) and FUSION (interferon treatment failures). POSITRON randomized 207 patients to 12 weeks of sofosbuvir at a daily dose of 400 mg and weight-based ribavirin to be compared to 71 patients on placebo. SVR was achieved in 78% of treated patients, in 92.7% in HCV-2 and 61.2% of 98 HCV-3 patients. The superior performance of this therapy in HCV-2 compared to HCV-3 was also seen in patients without cirrhosis with a 92% SVR rate in HCV-2 and 68% in HCV-3. In a multivariate regression, genotype was the strongest predictor of response. Beyond that, it appears that cirrhotic patients with chronic HCV-3 fare particularly poorly, with an SVR rate of only 21%. FUSION randomized patients to receive sofosbuvir 400 mg once daily and weight-based RBV for either 12 (100 patients) or 16 weeks (95 patients). SVR was achieved in 50% after 12 weeks and 73% after 16 weeks. Again, genotype played a significant role. For patients with HCV-2, SVR was achieved in 86.1% after 12 weeks and 93.8% after 16 weeks of therapy. By contrast, HCV-3-infected patients achieved SVR in 29.7% and 61.9% after 12 and 16 weeks, respectively. In a multivariate regression, genotype was again the most significant predictor of response to sofosbuvir therapy. The only other predictor was the presence of cirrhosis where patients with HCV-3 cirrhosis achieved SVR in only 19.2% of cases.
FISSION was a randomized, open label, active-control noninferiority study of 12 weeks of sofosbuvir plus ribavirin versus PEG-RIBA in an international cohort of untreated patients with HCV-2 and HCV-3. This trial included 183 HCV-3-infected patients in the sofusbuvir-RIBA arm and 176 HCV-3-infected patients in the PEG-RIBA arm. RVR was achieved in all but one patient in the sofusbuvir-RIBA arm compared with 67% in the PEG-RIBA arm. Both arms achieved SVR in 67% of cases. However, response rates in the sofosbuvir–ribavirin group were again lower amongst patients with HCV-3 infection than amongst those with HCV-2 infection (56% vs 97%).
How can we best interpret these responses in HCV-3? Certainly with over 90%, SVR HCV-2 is now truly an easy-to-treat genotype with a simple all oral DAA regimen of sofosbuvir and RBV. However, this same combination was not superior to PEG-IFN and RBV for treatment-naïve HCV-3 patients and the SVR was somewhat disappointing at 67% in all HCV-3 groups studied but still very acceptable as a treatment for our patients in clinical practice. We need to also realize that in the presence of RBV as the 2nd agent, duration may be a critical factor. The studies were designed with 12-week treatment arms except for FUSION, which had a 16-week arm. Just increasing treatment by 4 weeks more than doubled SVR including patients with cirrhosis, where it went from 19% to 61% with just a 4-week increase in duration. Because all patients had RVR and all were negative at the end of treatment, the issue with sofosbuvir/RBV is clearly one of relapse, and as in prior studies with IFN, increasing duration prevented that relapse. The aetiology of the relapse is unclear, but its response so dramatically to duration does suggest that it is a reservoir effect. This level of relapse is not seen in therapies with sofosbuvir for genotype 1 and suggests that there may be something unique about the ability of genotype 3 to avoid complete eradication. To answer the relapse question, there is a large European trial that is looking both at 24 weeks of sofosbuvir and RBV and also combining these two agents with IFN for 12 weeks. An alternative is to add a 2nd more powerful genotype 3 active NS5A to sofosbuvir to see whether that can replace RBV and improve SVR rates.
An alternative approach has been taken with alisporivir, a host-targeting antiviral (HTA) with pangenotypic anti-HCV activity and high barrier to viral resistance. VITAL-1 randomized 340 treatment-naïve HCV-2 and HCV-3 patients (ratio 3:7) to five arms: alisporivir monotherapy (1 g daily), alisporivir (600 or 800 mg) and weight-based ribavirin, alisporivir (600 mg) and pegylated interferon, or PEG-RBV. Patients in alisporivir-containing arms that achieved RVR continued on their initial treatment for 24 weeks. Those without RVR continued with alisporivir and rescue PEG-RBV from week 6 to week 24. Of the interferon-free treatments, alisporivir and ribavirin achieved greater early HCV clearance at week 6 than alisporivir monotherapy: 49% (600 mg and ribavirin), 46% (800 mg and ribavirin) and 32% (1 g monotherapy). Of the 70 patients receiving any interferon-free alisporivir/ribavirin regimens, 88% achieved SVR. Of 177 patients receiving combined regimen – interferon-free alisporivir/ribavirin from baseline and alisporivir/ribavirin/interferon add-on, 90% had SVR versus 72% with standard pegylated interferon and ribavirin. There was no difference in HCV-2 and HCV-3 responses to alisporivir treatment. Host-targeting agents with their high-resistance barrier and efficacy have more potential in combination with other DAAs for treatment of HCV-3.
New Direct-Acting Antivirals
Multiple targets are being developed for DAA therapy against HCV-1 but many of these particularly the protease inhibitors have limited activity against HCV-3. There are some novel 2nd-generation NS5A inhibitors such as Achillion ACH-3102, IdenixIDX-719 and Gilead GS-5816 that have potent in vitro activity against HCV-3 and are moving into early-phase clinical trials in combination with other DAAs or IFN. The class with the broadest pangenotypic activity to date is the NS5B nucleotide polymerase inhibitors, which includes merimepodib and sofosbuvir, which are in advanced clinical development and early-phase compounds such as Vertex VX-135. These compounds have the potential to be backbone agents for all oral DAA therapy for HCV-3 in combination with RBV or some of the newer NS5A or disease-modifying agents such as the cyclophilin inhibitors.
Mericitabine (also known as RG7128) is a nucleoside analogue with pangenotypic antiviral activity in vitro. Mericitabine was evaluated in HCV-2 and HCV-3 patients with prior PEG-RIBA treatment failure. After a 4-week triple combination, mericitabine at a twice-daily dose of 1500 mg was discontinued and PEG-RBV was resumed for 20–44 weeks. RVR was achieved in 95% of the mericitabine-treated patients versus 60% in the pegylated interferon ribavirin group. 68% of patients with RVR achieved SVR. SVR was higher in those treated for 48 weeks (90%) than in those treated for 24 weeks (67%). Overall, SVR rates did not differ between HCV-2 and HCV-3 patients (63% and 67%, respectively). Unfortunately, this strategy still requires IFN use for up to 48 weeks and will likely be replaced by all oral therapies.
Sofosbuvir, formerly GS-7977, is a uridine nucleotide analogue that inhibits the NS5B HCV polymerase with in vitro pangenotypic activity. The ELECTRON trial randomly assigned previously untreated, noncirrhotic patients with HCV-2 or HCV-3 to 6 groups receiving sofosbuvir at a daily dose of 400 mg. Five of these groups received 12 weeks of therapy, 4 of which also received weight-based ribavirin and 3 of which received pegylated interferon (alpha-2a). These groups included 6 to 7 HCV-3 and 3–4 HCV-2-infected patients. A final 6th group of 10 HCV-3-infected patients received 8 weeks of sofosbuvir-PEG-RBV. All (100%) of the 50 previously untreated patients with chronic HCV-2 or HCV-3 infection who received 8 or 12 weeks of treatment with sofosbuvir and ribavirin, with or without peginterferon-alpha 2a, had a SVR at 24 weeks after therapy. Of the 10 patients treated with sofosbuvir monotherapy, 6 achieved SVR, while 4 (including two of the seven patients with HCV-3) had relapsed after the end of treatment.
Jacobson et al. reported the results of two much larger trials of sofosbuvir in HCV-2 and HCV-3 patients: POSITRON (interferon intolerant/ineligible patients) and FUSION (interferon treatment failures). POSITRON randomized 207 patients to 12 weeks of sofosbuvir at a daily dose of 400 mg and weight-based ribavirin to be compared to 71 patients on placebo. SVR was achieved in 78% of treated patients, in 92.7% in HCV-2 and 61.2% of 98 HCV-3 patients. The superior performance of this therapy in HCV-2 compared to HCV-3 was also seen in patients without cirrhosis with a 92% SVR rate in HCV-2 and 68% in HCV-3. In a multivariate regression, genotype was the strongest predictor of response. Beyond that, it appears that cirrhotic patients with chronic HCV-3 fare particularly poorly, with an SVR rate of only 21%. FUSION randomized patients to receive sofosbuvir 400 mg once daily and weight-based RBV for either 12 (100 patients) or 16 weeks (95 patients). SVR was achieved in 50% after 12 weeks and 73% after 16 weeks. Again, genotype played a significant role. For patients with HCV-2, SVR was achieved in 86.1% after 12 weeks and 93.8% after 16 weeks of therapy. By contrast, HCV-3-infected patients achieved SVR in 29.7% and 61.9% after 12 and 16 weeks, respectively. In a multivariate regression, genotype was again the most significant predictor of response to sofosbuvir therapy. The only other predictor was the presence of cirrhosis where patients with HCV-3 cirrhosis achieved SVR in only 19.2% of cases.
FISSION was a randomized, open label, active-control noninferiority study of 12 weeks of sofosbuvir plus ribavirin versus PEG-RIBA in an international cohort of untreated patients with HCV-2 and HCV-3. This trial included 183 HCV-3-infected patients in the sofusbuvir-RIBA arm and 176 HCV-3-infected patients in the PEG-RIBA arm. RVR was achieved in all but one patient in the sofusbuvir-RIBA arm compared with 67% in the PEG-RIBA arm. Both arms achieved SVR in 67% of cases. However, response rates in the sofosbuvir–ribavirin group were again lower amongst patients with HCV-3 infection than amongst those with HCV-2 infection (56% vs 97%).
How can we best interpret these responses in HCV-3? Certainly with over 90%, SVR HCV-2 is now truly an easy-to-treat genotype with a simple all oral DAA regimen of sofosbuvir and RBV. However, this same combination was not superior to PEG-IFN and RBV for treatment-naïve HCV-3 patients and the SVR was somewhat disappointing at 67% in all HCV-3 groups studied but still very acceptable as a treatment for our patients in clinical practice. We need to also realize that in the presence of RBV as the 2nd agent, duration may be a critical factor. The studies were designed with 12-week treatment arms except for FUSION, which had a 16-week arm. Just increasing treatment by 4 weeks more than doubled SVR including patients with cirrhosis, where it went from 19% to 61% with just a 4-week increase in duration. Because all patients had RVR and all were negative at the end of treatment, the issue with sofosbuvir/RBV is clearly one of relapse, and as in prior studies with IFN, increasing duration prevented that relapse. The aetiology of the relapse is unclear, but its response so dramatically to duration does suggest that it is a reservoir effect. This level of relapse is not seen in therapies with sofosbuvir for genotype 1 and suggests that there may be something unique about the ability of genotype 3 to avoid complete eradication. To answer the relapse question, there is a large European trial that is looking both at 24 weeks of sofosbuvir and RBV and also combining these two agents with IFN for 12 weeks. An alternative is to add a 2nd more powerful genotype 3 active NS5A to sofosbuvir to see whether that can replace RBV and improve SVR rates.
An alternative approach has been taken with alisporivir, a host-targeting antiviral (HTA) with pangenotypic anti-HCV activity and high barrier to viral resistance. VITAL-1 randomized 340 treatment-naïve HCV-2 and HCV-3 patients (ratio 3:7) to five arms: alisporivir monotherapy (1 g daily), alisporivir (600 or 800 mg) and weight-based ribavirin, alisporivir (600 mg) and pegylated interferon, or PEG-RBV. Patients in alisporivir-containing arms that achieved RVR continued on their initial treatment for 24 weeks. Those without RVR continued with alisporivir and rescue PEG-RBV from week 6 to week 24. Of the interferon-free treatments, alisporivir and ribavirin achieved greater early HCV clearance at week 6 than alisporivir monotherapy: 49% (600 mg and ribavirin), 46% (800 mg and ribavirin) and 32% (1 g monotherapy). Of the 70 patients receiving any interferon-free alisporivir/ribavirin regimens, 88% achieved SVR. Of 177 patients receiving combined regimen – interferon-free alisporivir/ribavirin from baseline and alisporivir/ribavirin/interferon add-on, 90% had SVR versus 72% with standard pegylated interferon and ribavirin. There was no difference in HCV-2 and HCV-3 responses to alisporivir treatment. Host-targeting agents with their high-resistance barrier and efficacy have more potential in combination with other DAAs for treatment of HCV-3.