Hepatitis C virus: how to provide the best treatment with what I have

Background

The therapeutic landscape for the treatment of chronic hepatitis C virus (HCV) infection has been rapidly evolving since the approval of the first direct-acting antiviral agents (DAAs), telaprevir and boceprevir, in 2011. In 2013, sofosbuvir became the first nucleoside NS5B polymerase inhibitor to be approved and offered a potent DAA with a high genetic barrier that led the transformation of HCV treatment to all-oral regimens. Over the last 2 years, the US Food and Drug Administration (FDA) approved five all-oral regimens: (i) sofosbuvir plus ribavirin (RBV); (ii) sofosbuvir plus simeprevir, an NS3 protease inhibitor; (iii) the fixed-dose combination of sofosbuvir with the NS5A inhibitor ledipasvir; (iv) sofosbuvir plus daclatasvir; and (v) a 3 DAA (3D) ± RBV regimen [paritaprevir (NS3/4A protease inhibitor) boosted with ritonavir, ombitasvir (NS5A inhibitor) and dasabuvir (non-nucleoside NS5B polymerase inhibitor)]. Recent data also suggest that 12 weeks of 2 DAA (2D) therapy with just ombitasvir/paritaprevir/ritonavir led to SVR rates of 95% in a cohort of Japanese, genotype 1b patients 1. This same regimen received FDA approval in July 2015 to treat genotype 4 infected patients (100% SVR with RBV, 91% SVR without). In January 2016, another 2D regimen of grazoprevir (NS3/4A protease inhibitor) plus Elbasvir (NS5A inhibitor) is also expected to receive approval, adding a new genotype 1 treatment option and filling an unmet need for patients with end-stage renal disease. As highlighted in Table 1, there are now many DAA-based treatment regimens available to treat chronic HCV. Despite these advances with interferon-free therapy, few persons in low- and middle-income countries have been treated for HCV infection. The availability and cost of DAAs vary globally and the high cost of treatment, the need for expensive laboratory equipment and tests to evaluate the eligibility for and response to the treatment, and the lack of healthcare workers trained in administering treatment for HCV infection often limit treatment options outside of the USA and Western Europe.

Hepatitis C therapy is evolving so quickly that the need to make policy and treatment decisions is far outpacing the typical timeline for real-world comparative data collection, analysis and publication. While the phase III clinical trials inform clinicians about optimizing therapy with these drugs, not all patient scenarios can be anticipated and often a more nuanced interpretation of Phase III trial results, coupled with rapidly evolving data from ongoing Phase II and Phase IV clinical trials, also provide important information to guide practice. In the absence of comparative data for new treatments, the choice of a particular regimen will be influenced by cost, insurance coverage, pill burden, disease severity/comorbid conditions, potential drug interactions and the use of RBV. However, as many as patient populations face limited access to new DAA regimens, patients and physicians are often faced with the question ‘Does the end justify the means?’ In other words, can I build a regimen that cures my patient based on the drug regimens that I have at my disposal? An example of this paradigm can be highlighted by a few hypothetical case scenarios.

Case 1: a 24year-old Asian female, with baseline HCV RNA levels of 650,000 IU/ml and genotype 1b, who has mild fibrosis and the IL28B CC genotype

Each of these approved regimens would offer this patient a >95% chance for a SVR 4, 5. It is difficult to recommend one of these regimens over another as the only available data for DAAs are from drug registration trials; thus, there are no studies directly comparing the outcomes of one medicine vs. another. With global regional income and health insurance system diversity, treatment choice for this patient will vary widely depending on the country and region where this patient is living. If she lives in the USA and has commercial insurance, she would probably be treated with either Sofosbuvir/Ledipasvir (Harvoni) for 8–12 weeks or Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir (Viekira Pak) for 12 weeks. If she lived in Japan, she will probably receive Asunaprevir (not approved in either USA or Europe) and Daclatasvir for 24 weeks 6. Recognizing limited treatment access because of cost and resource limitations in some regions, the EASL HCV treatment recommendations also include IFN-containing options. In the EASL guidelines, this patient could be considered for treatment with Peg-IFN/RBV plus a DAA (either protease inhibitor – simeprevir or nucleoside inhibitor – sofosbuvir) and also have a >90% SVR. Since she has a favourable IL28B CC genotype and if she lived in Eastern China, she would probably receive 24–48 weeks of a generic IFN and RBV without DAA 7.

As shown in Table 2, there are many regimens that could generate a >90% SVR for this type of patient. While there are clearly preferred all-oral regimens that have the highest efficacy and the lowest adverse event profiles (Tier 1), there are also reasonable alternatives (Tier 2) that have similar efficacy but have some trade-offs in terms of viral resistance or adverse event profiles. It is critical to ensure the highest SVR for each patient since treatment failure is often associated with the selection and enrichment of resistant associated variants (RAVs). A recent analysis of combination of grazoprevir (NS3 inhibitor) and elbasvir (NS5A inhibitor) showed that the presence of baseline NS5A resistance, which occurs in about 12% of genotype 1a patients, led to marked decrease in SVR compared to those without baseline resistance (69% vs 96% respectively) 8. Although regulatory approval for grazoprevir/elbasvir is pending, regulatory authorities may recommend pretreatment viral resistance testing and avoidance of this regimen in the genotype 1a population with baseline resistance. Fortunately, for this ‘easy to treat’ genotype 1b patient, it is fairly simple to build a reasonable treatment regimen that minimizes harm (side effects and treatment failure with selection of resistance-associated variants) and provides a high chance for cure. Other than an IFN, RBV or first-generation protease inhibitor (e.g, Telaprevir) containing regimens (Tier 3), which would be associated with significant side effects and pregnancy issues for RBV, the DAA containing regimens would all offer a favourable risk/benefit decision.

Case 2: a 68-year-old male having genotype 3, cirrhosis and failed prior therapy with pegylated interferon and ribavirin

Patients with genotype 3, compared to HCV non-genotype 3, have relatively faster rates of the progression of fibrosis, a higher prevalence of significant steatosis and a higher incidence of hepatocellular carcinoma 9. Genotype 3 infection has emerged as the most challenging of all HCV genotypes to treat in this IFN-free era, particularly in patients with prior treatment failure and cirrhosis. This patient would be considered a ‘difficult to treat’ patient where the risk/benefit considerations for treatment lead to a much narrower range of options. The best chance for SVR in an all-oral regimen would probably be 24 weeks of sofosbuvir plus daclatasvir (with or without RBV) and approach 90% 10, 11. If the patient was a candidate to again receive IFN, then sofosbuvir plus pegylated interferon with RBV for 12 weeks would result in an SVR of approximately 80–85% 12. A less attractive option would include sofosbuvir plus RBV for 24 weeks, which would lead to a SVR of 40–60% because of a high rate of relapse 13. One could also consider the ‘off-label’ use of ledipasvir/sofosbuvir plus RBV, which, when given for 12 weeks to treatment experienced genotype 3 patients in a Phase II trial, resulted in a SVR of 77% in those with cirrhosis 14. While there are numerous other regimens under study for genotype 3 infection (GS-5816 plus sofosbuvir, ABT493-protease inhibitor plus ABT-530-NS5a inhibitor), the fact that this patient has cirrhosis and is at a high risk of developing HCC15 suggests that he should undergo therapy now and not to wait for future regimens. In contrast to case 1, this patient has an increased risk of treatment failure, which has significant implications for the development of resistant-associated variants (especially NS5A resistance) which may influence the choice and response to future regimens.

Case 3: a 54-year-old Egyptian male with genotype 4, stage 2 fibrosis and treatment naive

Several factors influence the optimal treatment regimen in patients with chronic genotype 4 infection: naïve or treatment experienced, whether the patient is eligible to receive IFN and the presence or absence of cirrhosis. Three all-oral options with similar overall efficacy are recommended for treatment-naive patients with HCV genotype 4 infection: (i) a daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks; (ii) a daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) and weight-based RBV for 12 weeks; and (iii) daily sofosbuvir (400 mg) and weight-based RBV for 24 weeks. There is also real world data to support a very high SVR and excellent safety with the combination of sofosbuvir (400 mg) and simeprevir (150 mg) for 12 weeks 16. The EASL HCV guidelines also recommend a combination of sofosbuvir (400 mg) and daclatasivir (60 mg) for 12 weeks with the addition of weight-based RBV in the setting of cirrhosis. Although there are very limited data on this regimen (100% SVR in a small cohort; N = 18), there is also evidence of in vitro antiviral activity in both treatments 3. An alternative regimen for a patient eligible to receive IFN includes daily sofosbuvir (400 mg) and weight-based RBV plus weekly pegylated interferon (PEG-IFN) for 12 weeks. Recent data from an Egyptian observational registry have reported a high SVR (88%) in naïve patients treated with PEG-IFN/RBV plus sofosbuvir for 12 weeks 17. Another promising all-oral regimen that is under development is grazoprevir plus elbasvir for 12 weeks, which had a 100% SVR in a small number of genotype 4 patients 18.

Summary

In summary, there are now many regimens that can be used to treat HCV patients that provide very high cure rates. Based on availability and access, great flexibility exists to combine oral agents from different classes and to consider the use of IFN in eligible patients. The opportunity to create individualized treatment regimens should only expand as new DAAs become more accessible to patients throughout the world.