| Dr Faisal Khan |
On the heels of World Hepatitis Day, observed on July 28, the exponentially high global burden of this disease continues to be a growing public concern. In 2012, the WHO revealed an alarming set of global statistics. A whopping 2000 million people were estimated to have fallen prey to hepatitis B infection globally with chronic infections documented in 240 million cases. Hepatitis B-associated deaths were estimated to be around 500000 to 700000 worldwide. Approximately 150 million individuals were estimated to suffer from hepatitis C infection; with an estimate of 350,000 hepatitis C-related deaths all over the world.
Statistics put forth by the WHO project that five million hepatitis-related deaths could occur in South East Asia alone, in the coming decade. This region is home to approximately 100 million hepatitis B and 30 million hepatitis C patients; 65 per cent and 75 per cent of these respectively, are unaware of their hepatitis status owing to the silent nature of the disease. The WHO has confirmed that hepatitis prevalence has superseded HIV infection in this part of the world. Greater than 50 per cent of the global burden of hepatitis E is from South East Asia alone.1 The number of chronic hepatitis B carriers in India alone was estimated to be around 40 million in 2006, which increased from 36 million reported in 1996. 2,3
Changing diagnostic landscape of viral hepatitis
Dr B R Das President, Research and Innovation, SRL |
July 28, regarded by the WHO as World Hepatitis Day, indeed presents an apt occasion to delve deeper into the various facets and nitty-gritty of this infectious disease; its diagnosis being one of the most extensively researched areas. ‘Screening’, ‘diagnosis’ and ‘diagnostic monitoring’ are crucial parameters in the clinical management of viral hepatitis. The key to reducing the burgeoning morbidity and mortality associated with this disease lies in adequate screening measures coupled with the use of modern molecular approaches to diagnose and monitor. The diagnostic landscape of viral hepatitis testing has witnessed a notable change. In the recent past, molecular diagnostic approaches have received phenomenal acceptance within the medical fraternity; for the diagnosis and monitoring of viral hepatitis. Emphasising the importance of these molecular assays, Dr BR Das, President – Research and Innovation, SRL said, “Molecular assays represent a highly precise and sensitive diagnostic tool with growing acceptance within the medical fraternity. The realm of molecular diagnostics holds great clinical promise and is the backbone of the diagnostic work up for viral hepatitis.”
Growing acceptance of molecular assays: A new diagnostic paradigm
The exponentially high rates of prevalence and mortality associated with viral hepatitis, present a dire and urgent unmet medical need: the need to beef up diagnostic facilities, diagnostic measures and clinical intervention based on sound diagnosis. Diagnostic measures for hepatitis B and C can be broadly divided into serologic tests and molecular assays. Enzyme-linked immunosorbent assay (ELISA) or immonoblot-based serologic tests detect antibodies to hepatitis virus or its antigens; their clinical utility being mainly limited to screening and initial diagnosis. Though serological methods can be employed for periodic monitoring of virologic response, they lack the superior precision, sensitivity and specificity offered by newer molecular diagnostic methods. Several crucial questions necessary for robust diagnosis and treatment planning; remain unanswered in a purely serology-based diagnostic menu: What is the load of the infection? What is the genotype of the virus involved? Is the genotype a mutant or a known drug resistant one? What are the patient’s best possible therapeutic options based on viral load and genotype? Clinicians often grapple with these queries during confirmatory diagnosis and treatment planning phases in the management of viral hepatitis. Molecular assays provide the answer to these key questions and represent a confirmatory diagnostic plus monitoring aid in viral hepatitis. They score over serologic tests in terms of superior precision, sensitivity and specificity.
Qualitative molecular assays are employed to determine the presence or absence of the hepatitis virus; a task that can also be performed with serological testing. However, due to high sensitivity and specificity of polymerase chain reaction (PCR)-based qualitative HBV DNA and HCV RNA assays; the medical fraternity is showing a lot of inclination towards qualitative molecular assays for confirmation of the diagnosis of viral hepatitis.
Response guided therapy of viral hepatitis represents a widely accepted treatment approach in clinical practice. Dose titrations, treatment durations and stopping criteria for treatment are based upon the virologic response elicited by treatment. This virologic response can be measured with utmost precision and sensitivity, through quantitative molecular assays performed at pre-specified time points during treatment.4
Achieving prolonged and sustained suppression of the virus, at least six months from discontinuation of therapy, a concept termed as ‘sustained virologic response’ (SVR) has emerged as one of the cornerstones of hepatitis treatment. This further increases the demand and significance of quantitative molecular assays, which are performed not only during treatment but also during follow up, to measure treatment efficacy in achieving SVR. Such quantifiable, objective and tangible monitoring of treatment can be easily achieved through quantitative estimation of HBV DNA and HCV RNA by PCR-based methods.5
Commenting on the role played by quantitative molecular assays in response guided therapy and SVR estimation, Dr Das stated, “Novel commercial real-time PCR assays like Roche Cobas Taqman and Abbott Real Time assay are highly sensitive techniques for viral quantification, and present a much broader and dynamic range of quantification than routine methods. The advent of such new technologies will give a major impetus to the monitoring of hepatitis cases.”
Deciphering viral blueprint: Genotyping hepatitis virus
Mounting clinical evidence supports the fact that different genotypic strains of the hepatitis virus respond differently to antiviral therapy. Also the course of the disease and its severity is largely impacted by the genotype of the infecting virus. Hence, identifying the genotype of the virus provides a very useful insight into planning the correct and the most sensitive anti viral regimen for a patient. This, in turn improves overall prognosis. HCV and HBV genotyping are diagnostic tests that reveal the genotypic strain of the causative organism and play a cardinal role in therapy decision making.2,6 “Genotyping of the viral strain along with a real time PCR-based quantitative estimation of the viral load; can be very instrumental in treatment planning and monitoring,” Das added.
Besides, identifying genotypes on large samples of patients at a community level provides insights into the prevalence of the most common strains in a given geographical area or ethnicity. Thus, genotyping of HBV and HCV is not only an effective tool in treatment planning but is also a promising epidemiological marker. 2,3
The current mainstay and gold standard of treatment for HCV is a combination of pegylated-interferon (peg-IFN) and ribavirin (RBV). However, response to this therapy can be influenced by genetic polymorphisms. Highlighting the impact of genetic polymorphism on treatment outcomes, Das infomed, “Patients with a particular type of genetic polymorphism in the IL28 B region have higher viral replication rates and are thus poor responders to treatment. These patients require a longer duration of treatment and a higher RBV dose.”
Given this rationale, the IL28B genotype test can be used to predict response to peg-IFN and RBV in HCV genotype 1 and 4 patients. The test result indicates whether the patient has an IL28B CC, CT, or TT genotype. Patients who have the IL28B CC genotype are more likely to have an SVR with peg-IFN and RBV treatment, whereas patients who have the TT genotype are more likely to be non-responders. This information can prove useful for clinicians in tailoring the peg-IFN/RBV regimen as per the patient’s IL 28B genotype, targeting to obtain SVR.7
Tackling drug resistance and mutation testing
Drug resistance has been a daunting challenge in the treatment of hepatitis B. A notably high level of drug resistance has been associated with older anti-virals like lamivudine. Resistance has been reported towards newer anti viral agents to a lesser extent. Such drug resistance compromises the efficacy of the treatment and often precipitates breakthrough hepatitis. Therefore, timely detection of mutation in HBV cases, through PCR and direct sequencing; can assist in therapy decision making, prevent the occurrence of resistance and save the patient from the agony of breakthrough hepatitis. Upon identification of the mutant through PCR-based assays, the patient can be switched over to a drug therapy other than the resistant one, early during the course of the treatment.8
The other clinically significant mutated viral strains are the core and pre core mutants. These strains cause hepatitis E surface antigen negative hepatitis (HBeAg negative). This form of the disease is more severe, long standing and with a high risk of cirrhosis. It requires more aggressive and prolonged treatment. A recently promulgated widely accepted treatment guideline has recommended very specific anti viral therapy (adefovir, entecavir or peginterferon) for the treatment of HBeAg
negative hepatitis.9 Molecular assays can effectively detect core and pre-core mutants, therapy can be customised to meet the needs of these high risk cases and prognosis can be improved.8
Market perspective: A bird’s eye view
As per a market analysis report by BCC Research, the demand for hepatitis-based diagnostics is expected to witness a major upward leap in countries like India and China which have higher rates of viral hepatitis.10 RNCOS released a market research report last year, projecting substantial growth for the ‘infectious diseases’ segment of the global molecular diagnostics market during 2012-2015.11 Another market report published by Renub Research, reiterated the substantial growth prediction for the global molecular diagnostics market. As per the findings of this report, the global molecular diagnostics market is set to grow at a swift pace of a CAGR of 19 per cent with a prediction to touch the $15 billion mark by 2014. The most notable finding of this report is the fact that ‘diagnostics of infectious diseases’ is the fastest growing segment of this market with a robust 21 per cent share.12
The findings of these various reports can be further extrapolated to infer that a sizeable market share of the infectious diseases diagnostic market will certainly come from the large prevalence of viral hepatitis cases. This is a robust pointer towards the fact that the demand for more advanced and more economical diagnostic tools will continue to rise in this domain. Thus, it lays unprecedented responsibility on large diagnostic firms in the global market to constantly keep reinventing technology and keep upgrading the spectrum of their diagnostic services for infectious diseases like viral hepatitis; while striving to offer competitive pricing as well. The diagnostics industry will have to meet this challenge to converge medical advancements, patient welfare and commercial growth.
References:
1. Prevention and control of hepatitis infection: A framework for global action. WHO publication 2012 available at http://www.who.int/csr/disease/hepatitis/GHP_Framework_En.pdf
2. Acharya SK, Madan K, Dattagupta S and Panda SK. Viral hepatitis in India. The National medical Journal of India. Volume 19, Number 4, July/August 2006
3.Tandon BN, Acharya Sk and Tandon A. Epidemiology of hepatitis B virus infection in India. Gut 1996; 38 (suppl 2): S56-S59
4. Ferenci P Best Pract Res Clin Gastroenterol. 2012 Aug;26(4):463-9. Response guided therapy in patients with chronic hepatitis C – yesterday, today and tomorrow
5. Chen J, Florian J, Carter W, Fleischer RD, Hammerstrom TS, Jadhav PR et al. Earlier sustained virologic response end points for regulatory approval and dose selection of hepatitis C therapies. Gastroenterology 2013 Jun; 144(7):1450-1455
6. Lin CL and Kao JH. The clinical implications of hepatitis B virus genotype: Recent advances. J Gastroenterol Hepatol. 2011 Jan;26 Suppl 1:123-30
7. Christine M. Nguyen, Margaret Mendes, Shirley Tsunoda, Joseph D. Ma et al. Interleukin-28B genotype testing to determine response to the combination of pegylated-interferon and ribavirin for the treatment of hepatitis C virus. PLoS Curr. 2011 January 8; 3: RRN1207
8. S. O’shea R. Hepatitis B. Accessed at http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/hepatology/hepatitis-B/
9. Lok and McMahon. AASLD practice guidelines on chronic hepatitis B. Hepatology (Feb 2007); Volume 45, Issue 2, pages 507–539
10. BCC Research market report on: Global market for infectious disease diagnostics, vaccine and treatment products (2013). Accessed on 3rd June 2013 at http://www.prweb.com/releases/2013/5/prweb10742989.htm
11. RNCOS market report: Global infectious diseases molecular diagnostics market to remain strong (2012). Accessed on 3rd June 2013 at http://www.rncos.com/Press_Releases/Global-Infectious-Diseases-Molecular-Diagnostics-Market-to-Remain-Strong.htm
12. Renub market research report: Global molecular diagnostic s market and future forecast 2010-2014. Accessed on 3rd June 2013 at http://www.marketresearch.com/Renub-Research-v3619/Global-Molecular-Diagnostics-Future-Forecast-6444055/