The direct-acting antivirals (DAAs) telaprevir and boceprevir have revolutionized hepatitis C virus (HCV) therapy by improving therapeutic outcomes for many patients. Although DAA-based therapy is a great leap forward, it is not a panacea, and many patients will not be appropriate candidates for this treatment. This review defines the patients who will remain untreated and explores emerging challenges in the era of triple therapy.
Patients with Contraindications to Pegylated Interferon (PEG) and Ribavirin (RBV)
PEG and RBV remain part of the current DAA-based therapy; therefore, patients with contraindications to the previous standard-of-care treatment are unlikely to be candidates for triple therapy (Table 1). This includes patients with previous adverse reactions to PEG or RBV and patients with uncontrolled autoimmune disease.1 In addition, interferon-induced bone marrow suppression, in combination with the hemolytic effects of RBV, can result in significant anemia and pancytopenia, and this makes patients with preexisting cytopenias, severe peripheral vascular disease, pulmonary disease, or coronary artery disease potentially unsuitable candidates for treatment.1 Finally, depression has been reported to occur in 23.2% of patients undergoing interferon therapy.2 Although patients tend to respond well to antidepressants during HCV therapy, severe uncontrolled depression remains a contraindication to treatment.1
|Prior intolerance of PEG or RBV|
|Severe autoimmune disease|
|Severe cardiopulmonary disease|
|Uncontrolled psychiatric disease (including depression)|
|Baseline anemia or pancytopenia|
Patients with Contraindications or Limited Responses to DAA Therapy
Boceprevir and telaprevir have significant interactions with both cytochrome P450 3A and p-glycoprotein, and these result in significant drug-drug interactions (Table 2).3, 4 A thorough medication history should be taken before treatment, and it is possible in many cases to substitute or hold a contraindicated drug during HCV therapy. However, in rare instances, patients who are taking a contraindicated medication that cannot be modified may not be candidates for current DAA-based therapy.
|Calcium channel blockers|
|Endothelin receptor antagonists|
|HIV antiviral agents|
|Phosphodiesterase type 5 inhibitors|
Although triple therapy is highly effective in most patients, response rates among patients with cirrhosis (especially previous null responders) remain relatively low. In the Sprint (Serine Protease Inhibitor Therapy) 2 study, cirrhosis was a significantly negative predictor of sustained virological response (SVR) in patients treated with boceprevir [odds ratio = 2.5 (1.4–4.6), P = 0.003].5 Furthermore, in the REALIZE study, investigators performed a subgroup analysis of patients with cirrhosis who were treated with telaprevir-based therapy and were previous null responders, and they found an SVR rate of only 29%.6 Clearly, many patients with HCV-related cirrhosis (especially previous nonresponders) will have limited success with the current therapy and will require treatment beyond what is currently available.
HCV affects many patients who have unique characteristics that are beyond the scope of currently published phase 3 registration trials of DAAs. These patients may benefit from DAA therapy but will pose a significant challenge to clinicians because there are limited data (if any) for guiding their care (Table 3).
|Patients with decompensated cirrhosis|
|Liver transplant recipients|
|Patients coinfected with HIV|
|Patients more than 65 years old|
|Patients with previous DAA exposure|
Patients Coinfected With Human Immunodeficiency Virus (HIV)
At least 17% of patients with HIV are coinfected with HCV.7 Progression to cirrhosis is more rapid in coinfected patients, and hepatic failure is an increasingly common cause of death in this patient population.8 The treatment of HCV in the setting of HIV is a longstanding clinical challenge because previous standard-of-care therapy with PEG/RBV has resulted in suboptimal SVR rates. In 2004, the AIDS Pegasys Ribavirin International Co-Infection Trial study group performed a multicenter, international study of HCV therapy in 868 patients coinfected with HIV. In genotype 1 patients, the SVR rate was 29%, which is lower than the published rates for PEG/RBV-based therapy in the non–HIV-infected population.9, 10 Currently, there are no available data describing DAA-based therapy in the HIV/HCV-coinfected population, and although improved treatment outcomes are anticipated, safety concerns (primarily involving drug-drug interactions) must first be addressed.
Liver Transplant Recipients
Patients with chronic HCV who undergo liver transplantation universally experience HCV recurrence in the transplanted liver. This leads to inferior posttransplant patient and graft survival in comparison with many other indications for liver transplantation.11 HCV therapy with PEG/RBV after liver transplantation has been largely unsuccessful because of poor SVR rates and significant adverse events, which include acute rejection.12, 13 Theoretically, direct-acting agents should be ideal in an immunocompromised host because there is less reliance on the host immune system for antiviral activity. Telaprevir and boceprevir are strong inhibitors of the enzyme cytochrome P450, which also plays a key role in the metabolism of the immunosuppressants commonly used in liver transplantation: cyclosporine and tacrolimus. Pharmacokinetic studies investigating the interaction between telaprevir and cyclosporine yielded extremely high drug concentrations of immunosuppressants when they were tested in healthy controls (a 70-fold increase in the tacrolimus concentration and a 4.6-fold increase in the cyclosporine concentration).14 Further prospective studies will be needed to determine safe and efficacious dosing strategies when these medications are used together.
Patients With Decompensated Cirrhosis
Successful HCV treatment in patients with cirrhosis has been shown to increase survival and decrease the development of ascites, esophageal varices, and hepatic encepaholpathy.15 Unfortunately, few decompensated patients with genotype 1 or 4 who undergo HCV treatment with PEG/RBV will achieve SVR (7%); therapy is often poorly tolerated, and frequent dose reductions and discontinuations are required.16 Current guidelines from the American Association for the Study of Liver Diseases recommend that for patients with decompensated cirrhosis, attempts at treatment should be “administered by experienced clinicians with vigilant monitoring for adverse events preferably in patients who have already been accepted as candidates for liver transplantation.”1 The risk of further decompensation along with the low SVR rates means that the previous standard-of-care treatment with PEG/RBV is rarely a viable option. With the use of more potent antiviral agents, SVR rates may increase; however, DAA metabolism appears to be different in patients with advanced cirrhosis versus patients with earlier stages of disease, and the tolerability and safety in this population remain largely unknown. Decisions to treat these patients with triple therapy rely solely on anecdotal accounts, and they should be made with extreme caution and should be based on physician experience and unique patient characteristics.
Pediatric and Elderly Populations
Recent National Health and Nutrition Examination Survey data suggest that approximately 0.2% to 0.4% of children up to 14 years old are infected with HCV.17 The majority of pediatric HCV infections occur as a result of maternal-fetal transmission. Because of the shorter period of chronic infection, pediatric patients usually have earlier stage disease at the time of diagnosis in comparison with adults; however, progression to cirrhosis and hepatocellular carcinoma has been reported.18, 19 In a pilot study of 62 patients between the ages of 2 and 17 years who were treated with PEG and RBV, 48% of the patients with genotype 1 achieved SVR.20 Although the results are based on limited data, the treatment outcomes appear to be similar to those of the adult population, and so are the adverse events during therapy, with the exception of spastic diplegia, which is a severe form of neurotoxicity seen in infants treated with interferon-α.17 The pediatric population would very likely tolerate and benefit from more potent agents; however, to date, there are no data on the use of telaprevir, boceprevir, or other new HCV therapies in this population. The current Food and Drug Administration treatment for patients who are 18 or less years old remains interferon plus RBV three times a week (3–18 years old) or PEG plus RBV once a week (5–18 years old).
In upcoming years, the highest prevalence of HCV infection will be seen in patients who are 65 years old or older.21 Older patients with HCV have a faster rate of progression to cirrhosis and have a higher incidence of hepatocellular carcinoma; this indicates a significant therapeutic need in this understudied population.22, 23 Patients more than 65 years old are more likely to be cirrhotic and have comorbidities that make treatment with PEG/RBV less effective. This was shown by Huang et al.24 in a study of 70 HCV patients older than 65 years who were treated with PEG/RBV. In comparison with younger cohorts, older patients had significantly inferior SVR rates and higher rates of dose reduction and therapy discontinuation. DAAs may improve response rates; however, there are significant concerns about the tolerability of triple therapy in this population and especially in patients who have been unable to tolerate PEG/RBV in the past. The consideration of alternate dosing schedules and treatment algorithms may be key to the use of DAA-based therapy in this population.
Patients With Previous DAA Exposure
Unlike dual-therapy treatment with PEG/RBV, treatment failure with DAAs is complicated by the emergence of resistant variants. Pawlotsky25 defined three major factors that influence the clinical ramifications of resistance: the genetic barrier to resistance, the fitness of the resistant variant, and the attainable drug exposure. First-generation protease inhibitors such as telaprevir and boceprevir have a low genetic barrier to resistance; however, after the discontinuation of therapy, the wild-type virus typically regains dominance, possibly to the point of the complete eradication of the resistant variants over time. Patients who develop resistant variants while they are being treated with one protease inhibitor will not likely be candidates for treatment with the other available protease inhibitor because boceprevir and telaprevir have been shown to share cross resistance in vitro. In addition, the emergence of resistance is also related to interferon insensitivity, which would hinder successful therapy with any DAA that requires interferon as part of the therapeutic regimen. As more DAAs become available, the treatment of patients who develop resistant variants may become similar to HIV treatment, in which combinations of agents are selected on the basis of viral resistance profiles.
Overcoming Current Challenges with DAA Therapy
This review describes many groups of patients who are underserved by currently available DAA therapy (Fig. 1). Fortunately, there are robust basic, translational, and clinical investigations aimed specifically at addressing these shortcomings. For those with limited responses or contraindications to telaprevir- or boceprevir-based treatment, ongoing clinical trials are evaluating the safety and efficacy of the next generation of protease inhibitors, polymerase inhibitors, and other novel agents such as cyclophilin inhibitors and short interfering RNA. In addition, many new agents are being investigated in interferon-free combinations that are targeted at patients who have deferred interferon-based treatment because of their own preference or medical contraindications. Finally, active research is taking place through both sponsored trials and investigator-initiated studies evaluating current DAA-based therapy in many of the understudied populations mentioned in this review.
Chronic HCV progresses slowly, and most patients do not develop advanced liver disease until at least 2 to 3 decades after the time of infection. Within understudied and difficult-to-treat populations, patients with early-stage disease will have the luxury of waiting for safer or more effective therapies; however, patients who already have advanced disease will have limited options and will remain a challenge, even in the era of DAA therapy.