Hepatitis C virus: Here comes all-oral treatment
ABSTRACTTreatment for chronic hepatitis C virus (HCV) infection is evolving rapidly. The approval in 2013 of two new direct-acting antivirals—sofosbuvir (a polymerase inhibitor) and simeprevir (a second-generation protease inhibitor)—opens the door for an all-oral regimen, potentially avoiding interferon and its harsh side effects. Other direct-acting antivirals are under development.
KEY POINTS
- In clinical trials of treatment for chronic HCV infection, regimens that included a direct-acting antiviral agent were more effective than ones that did not.
- Sofosbuvir is approved in an oral dose of 400 mg once daily in combination with ribavirin for patients infected with HCV genotype 2 or 3, and in combination with ribavirin and interferon in patients infected with HCV genotype 1 or 4. It is also recommended in combination with ribavirin in HCV-infected patients with hepatocellular carcinoma who are awaiting liver transplantation.
- Simeprevir is approved in an oral dose of 150 mg once daily in combination with ribavirin and interferon for patients with HCV genotype 1.
- The new drugs are expensive, a potential barrier for many patients. As more direct-acting antiviral agents become available, their cost will likely decrease.
- Combinations of direct-acting antiviral agents of different classes may prove even more effective and could eliminate the need for interferon entirely.
THE FUTURE
The emergence of all-oral regimens for HCV treatment with increasingly sophisticated agents such as sofosbuvir and simeprevir will dramatically alter the management of HCV patients. In view of the improvement in sustained virologic response rates with these treatments, and since most HCV-infected persons have no symptoms, the US Centers for Disease Control and Prevention29 recently recommended one-time testing of the cohort in which the prevalence of HCV infection is highest: all persons born between 1945 and 1965. This undoubtedly will increase the detection of this infection—and the number of new patients expecting treatment.
Future drugs promise further improvements (Table 6).30–35 Advances in knowledge of the HCV molecular structure have led to the development of numerous direct-acting antiviral agents with very specific viral targets. A second wave of protease inhibitors and of nucleoside and nonnucleoside polymerase inhibitors will soon be available. Inhibitors of NS5A (a protein important in the assembly of the viral replication complex) such as daclatasvir and ledipasvir, are currently in phase 3 clinical trials. Other viral proteins involved in assembly of the virus, including the core protein and p7, are being explored as drug targets. In addition, inhibiting host targets such as cyclophilin A and miR122 has gained traction recently, with specific agents currently in phase 2 and 3 clinical trials.
Factors that previously were major determinants of response to treatment, such as IL28B genotype, viral load, race, age, extent of fibrosis, and genotype 1 subtypes, will become much less important with the introduction of highly potent direct-acting antiviral agents.
Many all-oral combinations are being evaluated in clinical trials. For example, the open-label, phase 2 LONESTAR trial tested the utility of combining sofosbuvir and ledipasvir (an NS5A inhibitor) with and without ribavirin for 8 or 12 weeks in previously untreated patients with HCV genotype 1, and for 12 weeks in patients with HCV genotype 1 who did not achieve a sustained virologic response after receiving a protease inhibitor-based regimen (half of whom had compensated cirrhosis).36 Sustained virologic response rates were very high (95% to 100%) in both previously treated and previously untreated patients, including those with cirrhosis. Similar rates were achieved by the 8-week and 12-week groups in noncirrhotic patients who had not been previously treated for HCV. The typical hematologic abnormalities associated with interferon were not observed except for mild anemia in patients who received ribavirin. These results suggest that the combination of sofosbuvir and ledipasvir could offer a very effective, short, all-oral treatment for patients with HCV genotype 1, including those with cirrhosis, who up to now have been difficult to treat.
Challenges remaining
The success of sofosbuvir and simeprevir paves the way for interferon-free regimens.37 For a long time, the treatment of HCV infection required close monitoring of patients while managing the side effects of interferon, but the current and emerging direct-acting antiviral agents will soon change this practice. Given the synergistic effects of combination therapy—targeting the virus at multiple locations, decreasing the likelihood of drug resistance, and improving efficacy—combination regimens seem to be the optimal solution to the HCV epidemic. Lower risk of side effects and shorter treatment duration will definitely improve the acceptance of any new regimen. New agents that act against conserved viral targets, thereby yielding activity across multiple genotypes, will be advantageous as well. Table 7 compares the rates of sustained virologic response of the different currently approved HCV treatment regimens.
Clinical challenges remain, including the management of special patient populations for whom data are still limited. These include patients with cirrhosis, chronic kidney disease, renal failure, and concurrent infection with human immunodeficiency virus, and patients who have undergone solid organ transplantation. Clinical trials are under way to evaluate the treatment options for these patients, who will likely need to wait for the emergence of additional agents before dramatic improvement in sustained virologic response rates may be expected.38
As the treatment of HCV becomes simpler, safer, and more effective, primary care physicians will increasingly be expected to manage it. Difficult-to-treat patients, including the special populations above, will require specialist management and individualized treatment regimens, at least until better therapies are available. The high projected cost of the new agents may limit access, at least initially. However, the dramatic improvement in sustained virologic response rates and all that that implies in terms of decreased risk of advanced liver disease and its complications will undoubtedly make these therapies cost-effective.39
