HCV Treatment: What Can I Do Now? What's Coming Next?

Treating an Underdiagnosed Disease

Approximately 170-200 million persons worldwide are infected with hepatitis C virus (HCV), including 3.2 million in the United States.^[1] Many lack symptoms and are clinically unrecognized.^[2]

Outcomes of HCV infection include chronic hepatitis; cirrhosis; hepatocellular carcinoma; and a need for orthotopic liver transplantation owing to complications, such as cirrhosis or cancer.^[3] Estimating the quantity of fibrosis in a liver biopsy specimen from patients with HCV may help determine the risk for decompensation^[4] and the need for HCV therapy. Approximately 40% of patients awaiting liver transplantation have underlying HCV infection, and recurrent HCV infection of the transplant allograft is virtually assured.^[5] Eradication of HCV from infected patients improves survival of all patients, even if they have advanced liver disease.^[6,7]

There are six major genotypes of HCV.^[8] Genotype 1 accounts for approximately 75% of HCV infections in the United States, of which two thirds are genotype 1a and one third are genotype 1b. Genotype 1b is less likely to develop resistance during therapy, resulting in better cure rates with treatment than genotype 1a. Approximately 16% of HCV-infected patients have genotype 2; 12% have genotype 3; and 1% each have genotype 4, 5, and 6.

The development of direct-acting antivirals represents a significant improvement in HCV treatment. New combinations of drugs have led to improved response rates, even in patients with characteristics previously associated with having lower response rates: African American, high viral load, concomitant cirrhosis, infection with genotype 1a, and failed treatment with other anti-HCV drugs.^[9]

The four classes of direct-acting antivirals are:

NS3/4A protease inhibitors (boceprevir, telaprevir, simeprevir, paritaprevir, and grazoprevir);
NS5B nucleoside inhibitors (sofosbuvir);
NS5B non-nucleoside inhibitors (dasabuvir, beclabuvir); and
NS5A inhibitors (daclatasvir, ledipasvir, ombitasvir, and elbasvir).

Other direct-acting antivirals are under development.

Currently, no single drug produces a 100% cure rate for all genotypes of HCV, and questions remain about the best drugs for use in patients with associated renal failure, concomitant HIV infection, and advanced cirrhosis.^[10]

Understanding Whom to Treat

The availability of new, more effective therapies also raises the question of whether we should be more aggressive and screen for HCV in all persons in the United States.^[11] Projections indicate that universal screening could identify as many as 1 million additional cases, and widespread treatment could result in the elimination of HCV over the next 22 years.

However, the relatively high cost of new therapies also raises questions about who should be treated.^[12,13,14] Should we limit treatment only to patients who have advanced or potentially progressive disease? If so, how can we best determine those at greater risk of developing progressive disease? Or should we simply recommend immediate treatment for all patients, given the long-term, overall cost-effectiveness of these treatments even at their current costs?^[15]

The website HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C, from the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America,^[16] suggests the following regarding the goals of and options for patient treatment:

"The goal of treatment of HCV-infected persons is to reduce all-cause mortality and liver-related health adverse consequences, including end-stage liver disease and hepatocellular carcinoma, by the achievement of virologic cure as evidenced by an SVR [sustained viral response]."
"Treatment is recommended for patients with chronic HCV infection."
"Immediate treatment is assigned the highest priority for those patients with advanced fibrosis (Metavir F3), those with compensated cirrhosis (Metavir F4), liver transplant recipients, and patients with severe extrahepatic hepatitis C."
"Based on available resources, immediate treatment should be prioritized as necessary so that patients at high risk for liver-related complications and severe extrahepatic hepatitis C are given high priority."

Patients at higher risk for future complications from HCV include those with advanced liver fibrosis, HIV-1 coinfection, hepatitis B virus coinfection, diabetes mellitus, or porphyria cutanea tarda, and patients with severe extrahepatic manifestations, such as mixed cryoglobulinemia with end-organ complications, nephrotic syndrome, or membranous glomerulonephritis.

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