Perspectives of fixed daily dose of sofosbuvir and ledipasvir for the treatment of chronic hepatitis C

Abstract

The fixed dose combination of sofosbuvir and ledipasvir (SOF/LDV) has marked a new era for patients with chronic HCV because it is the first drug to be approved by the FDA that does not include peginterferon or ribavirin. The results of three clinical studies show that SOF/LDV has sustained virologic response of approximately 96% when given as once a day pill for 3 months to both treatment naive and treatment-experienced HCV-1 patients with the exception of prior null responder patients with cirrhosis. Moreover, emerging data in special populations (patients with decompensated cirrhosis, with post-transplant recurrence, with prior SOF-based therapy failure, and with HIV co-infection) show a good tolerance and high sustained virological profile. Many other emerging therapies are now available. Actually, the recommendations of the international guidelines are applicable only for selected patients followed-up by dedicated specialists, including hepatologists and infectologists, and are specifically individualized for patients with advanced fibrosis. We will expect that the landscape for management of HCV will include direct-acting antivirals for treatment of patients with different genotypes and low-grade fibrosis in order to interrupt the progression to late stage of disease and the complications of the infection, including renal disease, thyroid dysfunction, and some cancers.

Keywords:

• hepatitis C
• ledipasvir
• sofosbuvir
• therapy

Therapy for hepatitis C is undergoing a revolution, and as we begin 2015, the guidance for hepatitis C management in adults is changing constantly, due to the enormous research and production of a large number of antiviral drugs, including direct-acting antiviral (DDA) and host-targeted agents. According to the AASLD/DSA/IAS-USA guidelines, immediate treatment is recommended for patients with advanced fibrosis (Metavir F3), with compensated cirrhosis (Metavir F4), liver transplant recipients, and patients with severe extra-hepatic hepatitis C (http://www.hcvguidelines.org). Moreover, the recent approval of the fixed dose combination (FDC) of the NS5B polymerase inhibitor sofosbuvir and the NS5A inhibitor ledipasvir (SOF/LDV) has marked a new era for patients with chronic HCV with genotype 1a, 1b, and 4 because it is the first drug to be approved by the FDA that does not include peginterferon or ribavirin (RBV). All studies with the fixed combination were only performed in the US.

The synopsis by Kumari et al. [1] describes outcomes of naive and experienced patients with HCV-1 infection treated with an interferon-free combination of SOF and LDV. The results clearly show that the combination of SOF (400 mg) and LDV (90 mg) has sustained virologic response (SVR) of approximately 96% when given as once a day pill for 3 months to both treatment naive and treatment-experienced HCV-1 patients with the exception of prior null responder patients with cirrhosis. The latter group of patients also achieves high SVR of 95% but with therapy for 24 weeks.

In the ION-1 study (Clinical Trials.gov number NCT01701401), 865 naive patients with HCV-1 were randomly assigned to receive SOF/LDV for 12 weeks, SOF/LDV plus RBV for 12 weeks, SOF/LDV for 24 weeks, and SOF/LDV plus RBV for 24 weeks. SVR in all four groups was higher, 97 – 99% than the historical rate of 60% irrespective of treatment duration or addition of RBV [2]. Interestingly, there was no significant difference in the SVR 12 between genotype 1a and genotype 1b.

In the ION-2 study (Clinical Trials.gov number NCT01768286), a total of 440 treatment-experienced US HCV-1 patients were randomly assigned to receive SOF/LDV for 12 weeks, SOF/LDV plus RBV for 12 weeks, SOF/LDV for 24 weeks, and SOF/LDV plus RBV for 24 weeks [3]. SVR rates among the four groups ranged 94 – 99%. As in ION-1, addition of RBV did not have any increased effect on SVR; however, in patients prior null responders with cirrhosis, 24 weeks of treatment were more effective than 12 weeks treatment (100 vs 82 – 86%).

The ION-3 study (Clinical Trials.gov number NCT01851330) was conducted in 58 sites in the US in naive HCV-1 patients without cirrhosis [4]. A total of 647 patients were randomly assigned to receive SOF/LDV for 8 weeks, SOF/LDV plus RBV for 8 weeks, and SOF/LDV for 12 weeks. SVR was 93 – 95% among the three treatment groups. The addition of RBV to the 8-week regimen of SOF/LDV or the extension of therapy from 8 weeks to 12 weeks did not result in improved rates of SVR. There was no significant difference in the SVR rates among the various ethnic groups or genotype subtypes 1a versus 1b.

The pooled data of these three studies showed a high profile of tolerance for SOF/LDV combination. Moreover, emerging data in special populations (patients with decompensated cirrhosis, patients with post-transplant recurrence, patients with prior SOF-based therapy failure, and patients with HIV co-infection) show a good tolerance and high SVR profile. A total of 108 patients with decompensated cirrhosis (HCV-1 and HCV-4) and with MELD score > 15 were randomized to receive either 12 or 24 weeks of SOF/LDV with escalating RBV doses (SOLAR study). The SVR rate was similar in both groups (86 vs 89%). A study including 223 post-liver transplant naive and treatment-experienced patients with HCV-1 and HCV-4 is still ongoing, but preliminary results are encouraging: the 4 week SVR is 94 – 96% in those without cirrhosis and 82 – 92% in those with cirrhosis [5]. SOF/LDV plus RBV for 12 weeks was well tolerated and effective for re-treatment of patients who previously failed SOF-based regimens with 100% of SVR [6].

Finally, an excellent SVR (98%) has been reported in patients co-infected with HIV either on antiretroviral (ARV)-naive or taking ARV combination [7].

Given that the free direct-acting antivirals (DAAs) are highly effective in treating HCV chronic hepatitis, the landscape of management of chronic hepatitis C is rapidly changing. Up to now two other DDA regimens have been approved from the US FDA. The first one is the combination with SOF and simeprevir (SMP), the second one is the NS3/4A protease inhibitor of hepatitis C. In the COSMOS study, the combination of 150 mg SMP and 400 mg SOF once a day for 12 weeks resulted in SVR rates of 86 – 91% in previous non-responders with METAVIR 4 [8]. SMP has been also proved to be useful in combination with SOF for patients with genotype 1 enrolled in the TARGED cohorts [9]. An advantage of SOF/LDV combination is the practical administration with one pill once a day, whereas SMP/SOF is administered as two separate pills also once a day. In addition, the cost of SOF/LDV combination is lower than SMP/SOF combination. A drawback of SOF/LDS combination is the risk for drug interaction with proton pump inhibitors, which may result in decreased absorption of LDV; thus, if possible, acid-suppressing medications should be held prior to and during the HCV treatment period to optimize LDV exposure. Another limitation of the SOF/LDV regimen is the possible occurrence of the adverse drug events (ADEs). Patients treated with SOF/LDV experienced headaches, fatigue, insomnia, nausea, and diarrhea with a frequency ranging between 67 and 82%. The rates of ADEs varied by length of therapy and were higher in those receiving RBV than those that did not. However, the rates of serious ADEs were up to 8% (total of 34 patients of 1952 treated). Mild ADEs were reported in patients treated with other DAA regimens. In the interferon-free regimen of ABT-450 with ritonavir (ABT-450/r), ombitasvir, and dasabuvir with or without RBV ADEs occurred in up to 92% of cases, and the serious ADEs occurred in up to 3% of cases (in those taking RBV) [10,11]. A further limitation of SOF/LDV is the potential NS5A-resistant variants. In fact, of patients who failed treatment in the ION-2 trial, 57% had NS5A variants at baseline. However, LDV is active against the NS5B variant, which is known to reduce response to SOF [12]. Another molecule, daclatasvir is being clinically evaluated in IFN-free combination therapies, to prevent and suppress the emergence of resistant viruses. Finally, another limitation of the SOF/LDV regimen is the reduced activity on genotype 3; however, very limited Phase II data are available from a single-center study (ELECTRON-II) on 104 treatment-naive non-cirrhotic patients with genotype 3 randomized to receive SOF plus GS-5816 with or without RBV [11]. Actually, a Phase III trial is ongoing with GS-5816, a new highly potent and pan-genotypic NS5A inhibitor.

Many other emerging therapies are now available for treatment of hepatitis C, including the FDC of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) plus twice-daily dosed dasabuvir (250 mg) and weight-based RBV (100 – 1200 mg) for 12 weeks in patients with genotype 1a (no cirrhosis) or 24 weeks (cirrhosis). This regimen was approved by the FDA for genotype 1a infection in treatment-naive patients based on three registration trials: SAPPHIRE-I, PEARL-V, and TURQUOISE-II (http://www.hcvguidelines.org). The same regimen was approved by the FDA for genotype 1b infection in treatment-naive patients based on four registration trials: SAPPHIRE I, PEARL III, TURQUOISE II, and TURQUOISE III (for those with cirrhosis) (http://www.hcvguidelines.org). The Phase III trial (SAPPHIRE-I) included 380 patients with cirrhosis randomly assigned to receive either 12 or 24 weeks of treatment with paritaprevir/rombitasvir (at once daily dose of 150 mg of paritaprevir, 100 mg of ritonavir, and 25 mg of ombitasvir), dasabuvir (250 mg twice daily), and RBV [12]. Patients achieved SVR rates 12 weeks post-treatment of 91.8 and 95.9% in the 12-week and 24-week treatment arm, respectively. The PEARL-III and PEARL-IV studies were specifically designed with the same therapeutic regimens for previously untreated patients with HCV genotype 1 and no cirrhosis [13]. Rates of virological failure were higher without RBV than with RBV among patients with genotype 1a infection (7.8 vs 2.0%, respectively) but not among those with genotype 1b infection. Overall, these combined regimens were well tolerated, with mild or moderate adverse effects occurring more frequently in the 24-week group than in the 12-week group. However, potential serious drug–drug interactions may occur, especially with RBV. Thus, given the excellent results of this combination it would be necessary to investigate if RBV is necessary for obtaining a better SVR. Moreover, patients with concurrent small HCC and/or candidates for liver transplant should be included.

Overall, all the combination trials with SOF/LDV, SMP/SOPF and paritaprevir, ritonavir, and ombitasvir plus dasabuvir and RBV included an impressive number of patients and the safety profile was excellent. However, the FDC SOF/LDV offers the best chance for adherence of the patient as the regimen consists of one pill once a day. Which are the possible scenarios for the treatment regimens for patients with chronic hepatitis C in the near future? First of all, therapy of HCV is rapidly evolving and many pharmaceutical industries will develop new agents for HCV eradication with improvement in efficacy and safety. According to the market rules, we expect that the cost of such agents will fall down. Actually, the recommendations of the international guidelines are applicable only for selected patients followed-up by dedicated specialists, including hepatologists and infectologists. Second, the international guidelines are specifically individualized for patients with advanced fibrosis. We will expect that the landscape for management of hepatitis C will include DDAs for treatment of patients with different genotypes and low-grade fibrosis in order to interrupt the progression to late stage of disease and avoid the complication of infection, including renal disease, thyroid dysfunction, diabetes, and some cancers.

In summary, the FDC of SOF/LDV provides a very attractive and effective one pill once a day option for genotype 1 chronic HCV infection. For treatment of non-cirrhotic patients, the use of shorter 8-week regimen is justified and will provide a major cost savings over the 12-week regimen; moreover, it is less expensive than a 12-week regimen of SOF plus RBV. Patients with HCV/HIV co-infection treated with SOF/LDV combination will have a good expectancy of SVR. Nevertheless, the most important goal of treatment for HCV is to reduce all-cause mortality and liver-related health adverse consequences, including end-stage liver disease and HCC (http://www.hcvguidelines.org). Thus, we will expect to reduce the need for liver transplant for HCV in the short-term and the incidence of HCC in the mid-term.

Declaration of interest

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.