Hepatitis — Diagnostic Advances Help Guide New Therapies

Chou, Peter P., PhD, D(ABCC)
Director of Scientific Affairs
Quest Diagnostics Nichols Institute, Chantilly, VA
Also by this Author 

An estimated 4.4 million Americans are living with chronic hepatitis - the majority unaware they are infected. Approximately 30% have chronic Hepatitis B (HBV) infection, and 70% have chronic Hepatitis C (HCV). It is estimated that about 80,000 new infections occur each year but only a small proportion are reported since many of those newly infected are asymptomatic. Viral hepatitis is the leading cause of liver cancer and the most common reason for liver transplantation.1

Approximately 79% of newly acquired cases of HBV infection are associated with high-risk sexual activity or injection-drug use; other known exposures (i.e., occupational, household, travel, and healthcare-related) account for 5% of new cases.2

Those at increased risk for HCV infection include:3

  • Current or former injection drug users
  • Recipients of clotting factor concentrates made before 1987
  • Recipients of blood transfusions or solid organ transplants before July 1992
  • Chronic hemodialysis patients
  • Persons with known exposures to HCV
  • Persons with HIV infection
  • Children born to HCV-positive mothers

Dr. Peter Chou, Director of Scientific Affairs and Dr. Thomas Huard, Scientific Director, Infectious Molecular Diagnostics, Quest Diagnostics Nichols Institute discuss trends in HBV and HCV treatment and review advances in diagnostics to predict and monitor therapy response, and guide clinicians in selecting treatment options.

A Breakthrough In HCV Therapy

Last year’s approval of two protease inhibitors (PIs), boceprevir and telaprevir, represents a significant advance in treating chronic HCV patients, says Dr Chou: “Adding one of these direct acting agents (DAAs) to standard therapy achieves a significant increase in sustained virologic response. Data show a response rate of 67% for genotype 1 HCV when combining DAAs with the standard regimen of peginterferon-αplus ribavirin, compared with a response rate of 41% for standard therapy alone.”4

An important aspect of the new regimen using PIs is the need for regular monitoring using quantitative HCV RNA testing to determine therapy efficacy. “You need to look at the viral load at various intervals to assess whether or not it has dropped below the detection limit,” notes Dr. Chou. “This gives guidance on how to proceed with treatment, providing a basis for response-guided therapy.” Testing at Weeks 8 and 24 determine the duration of treatment for boceprevir and at Weeks 4 and 12 for telaprevir.5, 6

With the advent of DAAs, researchers are working to understand the nature of resistance to these drugs7 and tests are becoming available to help assess potential resistance. A nucleic acid sequencing assay that identifies NS3 and NS4A mutations and NS3 associated resistance to these therapies is now available8 and others are in development. With studies underway to assess interferon-sparing therapy using different combinations of DAAs9 it will be all the more important to gain a better understanding of, and have the means to predict, resistance to these agents.

Challenges in HBV Therapy

With HBV there are fewer chronically infected patients than with HCV. The challenge is identifying them. “A whole battery of serology tests are available to help predict those who are more likely to be chronically infected,” says Dr. Huard. “These include relatively new tests, such as E antigen and E antibody tests.”

Drug resistance can also be a challenge in treating HBV, especially in relation to long-term treatment with lamivudine.10 Polymerase chain reaction (PCR) testing detects HBV mutations associated with resistance to antiviral drugs, helping predict and monitor response to therapy.11 The recent development of a line probe assay for detection of mutations or polymorphisms in the B-C Domains of the HBV polymerase gene will offer another option for HBV genotyping.  This test will enable the classification of the viral subtype (genotypes A-H) by analysis of sequences at codons 80, 173, 180, 181, 204, and 236. The assay uses hybridization of PCR amplicons generated from patient samples with probes embedded in solid-phase strips for detection of HBV Genotypes. Genotype determination can be useful for assessing the prognosis of the infection. Analysis of the basal core promoter (BCP) and the pre-Core (PC) region of the viral genome for polymorphisms at nt1762 and nt1764 are also useful for predicting whether the virus will be affected by the most common antiviral treatment modalities. Another challenge is the increase in patients with occult HBV. As Dr. Huard explains: “These are patients who are Hepatitis B surface antigen positive but don’t have circulating DNA, or vice versa. One aspect of this is that there is over-production of the antigen in infected liver cells without viral replication. These patients are more likely to relapse and much less likely to respond to treatment. They are also more likely to be chronically infected.”

The Promise Of Future Developments

Looking ahead, Dr. Chou anticipates a move to interferon-sparing therapy with different combinations of DAAs, as well as the introduction of alternatives to protease inhibitors to inhibit viral replication. These include nucleotide polymerase inhibitors, non- nucleotide polymerase inhibitors, and NS5A inhibitors.  As new drugs are introduced developments in testing will aim to help predict response and assess potential resistance based on their pharmacokinetics and metabolism.

The hope is that the emergence of new therapies will provide increased options to treat non-responsive patients and offer better-tolerated regimens.


  1. Viral Hepatitis. Centers for Disease Control and Prevention. www.cdc.gov/hepatitis Page last reviewed: November 18, 2009Page last updated: February 10, 2012 Page accessed: March 19, 2012.  Content source: Division of Viral Hepatitis and National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention
  2. A Comprehensive Immunization Strategy to Eliminate Transmission of Hepatitis B Virus Infection in the United States. Recommendations of the Advisory Committee on Immunization Practices (ACIP) Part II: Immunization of Adults. MMWR. December 8, 2006 / 55(RR16);1-25 www.cdc.gov/mmwr/preview/mmwrhtml/rr5516a1.htm?s_cid=rr5516a1_e
  3. Hepatitis C Information for Health Professionals. Centers for Disease Control and Prevention.
    Page last reviewed: July 21, 2008 Page last updated: August 4, 2011. Page accessed: March 20, 2012
  4. McHutchison J, Everson G, Gordon S, et al for the PROVE1 Study Team. Telaprevir with Peginterferon and Ribavirin for Chronic HCV Genotype 1 Infection. N Engl J Med 2009;360:1827-38.
  5. Prescribing information for VICTRELISTM (boceprevir) (Schering Corporation, a subsidiary of Merck & Co., Inc.)
  6. Prescribing information for INCIVEKTM (telaprevir) (Vertex Pharmaceuticals Incorporated)
  7. Halfon P, Locarnini S, Hepatitis C Virus Resistance To Protease Inhibitors. Journal of Hepatology 2011; 55:1192–206
  8. Monogram Biosciences. www.monogrambio.com/pdf/HCV_GS_NS34A.pdf
  9. Gane E. Future hepatitis Cvirus treatment: interferon-sparing combinations Liver International 2011; 31(s1): 62–67
  10. Lai C-L, Dienstag J, Schiff E. Prevalence and Clinical Correlates of YMDD Variants during Lamivudine Therapy. Clinical Infectious Diseases. 2003; 36(6): 687-696
  11. Hepatitis B Virus Genotype Test Summary. Quest Diagnostics.

Released on Tuesday, May 22, 2012