HCV: Epidemiology, Screening and Diagnosis

Table of Content

Disease Overview

Viral hepatitis caused by HCV (hepatitis C virus) has been found to be an important cause of liver disease and remains a major public health problem worldwide. HCV, first identified in 1989, belongs to the Flaviviridae family, genus Hepacivirus,and is a highly heterogeneous blood-borne virus.

HCV: Virus Structure

HCV infects predominantly hepatocytes and has the ability to evade the host immune response in multiple ways. It is a small single-stranded RNA virus with a lipid envelope (E) containing glycoproteins (E1 and E2) and a core (C) with the HCV genome (Fig. 1).

The HCV genome consists of 9.6-kb single-stranded RNA of positive polarity and a single open reading frame of 9033–9099 nucleotides flanked by a conserved 5’ and 3’ noncoding region (NCR) at the ends. The genome codes for a long polyprotein of approximately 3,000 amino acids, which is processed by co-translational and post-translational ways to yield structural proteins (core, envelope glycoproteins E1 and E2) and non-structural (NS) proteins (NS1/p7, NS2, NS3, NS4A, NS4B, NS5A and NS5B 6 (Fig. 1).

Structural proteins (core, E1 and E2): The two envelope glycoproteins, E1 and E2 are targets of host antibody response and the core protein interacts with progeny viral genomes for assembly of the virus.

Non-structural proteins: NS1/p7, NS2, NS3, NS4A, NS4B, NS5A and NS5B form a complex with viral RNA to initiate viral replication in a cytoplasmic membranous structure. The HCV NS5B gene encodes a polymerase, which is responsible for virus replication and is a potential target for the development of antiviral agents.

Fig. 1: Structure of HCV

Transmission

HCV is most often spread by direct blood-to blood contact. HCV is usually spread when blood from a person infected with the hepatitis C virus enters the body of someone who is uninfected. The HCV can live in dried blood and on environmental surfaces for days. HCV is most commonly transmitted through the following routes:

  • Sharing needles, syringes, or other equipment to inject drugs
  • Transmission of HCV is possible when poor infection-control practices are used during tattooing or piercing, or if the tattoo or piercing instruments are inadequately sterilized
  • In healthcare settings due to the reuse or inadequate sterilization of medical equipment, especially syringes and needles
  • Transfusion of unscreened blood and blood products
  • Occupational exposure in healthcare workers: Needlestick injuries in health care settings
  • Perinatal transmission: can be passed from an infected mother to her baby; however, this mode is less common
  • Sharing personal care items that may have come in contact with another person’s blood, such as razors or toothbrushes- less common
  • Having sexual contact with a person infected with the hepatitis C - less common

Healthcare-Associated Transmission

Nearly 8 and 12 billion injections are administered annually around the world and 50% of these are considered to be unsafe (mainly in Sub-Saharan Africa and Asia). Persons who received untested blood products prior to the introduction of screening of blood for HCV are also at risk.

Universal access to safe blood transfusion requires implementation of 100% voluntary blood donation and 100% quality-assured testing of donated blood.

People Who Inject Drugs (PWID)

An estimated 16 million people actively inject drugs among which 10 million are infected with HCV. PWID infected with HCV are at increased risk of all-cause mortality, owing to chronic drug abuse, low socioeconomic status, poor access to healthcare and environmental factors.

Mother-to-Child Transmission

The risk of transmission of HCV from a mother to her child occurs in 4–8% of births to women with HCV infection and in 17–25% of births to women with HIV and HCV co-infection.

Sexual Transmission

Sexual transmission of HCV occurs infrequently in heterosexual couples. It is more common in HIV-positive persons, particularly in men who have sex with men (MSM) and HIV-infected heterosexual partners of HCV-infected people who are at increased risk.

Hepatitis C is not spread through breast milk, food or water or by casual contact such as hugging, kissing and sharing food or drinks with an infected person.

Co-infections

HIV and HCV Co-infection

HIV and HCV have common routes of transmission, and it is estimated that, globally,

4–5 million persons are co-infected with these two viruses.

HBV and HCV Co-infection

Hepatitis B virus (HBV) and HCV co-infection is commonly found in HBV-endemic countries in Asia, Sub-Saharan Africa and South America. Up to 25% of HCV infected persons may be co-infected with HBV in some areas.

Tuberculosis and HCV Co-infection

Groups at increased risk of infection with HCV are also at risk of infection withtuberculosis (TB). PWID are more at risk of developing TB, regardless of their HIV status. Among PWID who develop TB, two out of three will have HCV antibodies. People who live with HIV and inject drugs have a two- to six-fold increased risk of developing TB compared with non-injectors.

Epidemiology of Hepatitis C

Globally, an estimated 130–170 million people (translates to 2–3% of the world’s population), are living with HCV infection. The most recent estimates of disease burden show an increase in seroprevalence over the last 15 years to 2.8%, equating to >185 million infections worldwide.

More than 350,000 deaths are attributed to HCV infection each year, most of which are caused by liver cirrhosis and hepatocellular carcinoma (HCC). An estimated 27% of cirrhosis and 25% of HCC can be linked to hepatitis C worldwide.

Country-specific hepatitis C data published by the World Health Organization (WHO) reveal that rates of HCV infection vary widely throughout the world. HCV prevalence is categorized as “high” prevalence (>3.5%), “moderate” prevalence (1.5–3.5%) or “low” prevalence (<1.5%) based on the prevalence of the anti-HCV antibody.

The hepatitis C burden in many developed countries (e.g., Australia and most countries in WesternEurope) and the United States, is similar at <2%. HCV infection rates are, however, higher in many countries in Eastern Europe and Latin America, countries of the former Soviet Union and certain countries in Africa, the Middle East and South Asia. Egypt has been reported to have the highest rate of hepatitis C in the world, estimated at >10%.

According to the WHO, as many as 2–4 million persons may be chronically infected in theUnited States, 5–10 million in Europe, and about 12 million in India.

HCV Genotypes

There are seven major HCV groups or genotypes, numbered 1 to 7, although some experts believe that there may be as many as 11 types. These genotypes differ by about 30–35% in their nucleotide sequence. The worldwide distribution, transmission and disease progression of these genotypes varies across the world.

HCV genotype 1 was found to be the most prevalent worldwide, comprising 83.4 million cases (46.2% of all HCV cases), approximately one-third of which were found to be in East Asia. Genotype 3 is the next most prevalent globally (54.3 million, 30.1%); genotypes 2, 4 and 6 are responsible for a total 22.8% of all cases; genotype 5 comprises the remaining <1%.

The Indian Scenario

There is a paucity of large population-based studies assessing the prevalence of hepatitis C in the general population. The few published studies have found a potentially large reservoir of asymptomatic subjects harboring HCV infection.

The prevalence of HCV infection in India is estimated at between 0.5% and 1.5%. It is higher in the northeastern part, tribal populations and Punjab, and is lower in the western and eastern parts of the country. Since India has one-fifth of the world’s population, this percentage accounts for a large proportion of the worldwide HCV infection burden.

Among the genotypes, genotype 3 is the most common HCV genotype in India accounting for 54–80% of cases, followed by genotype 1. Genotype 1 has been reported more commonly from southern India. There are also increasing reports of genotype 4 from India.

Fig. 2: Global HCV genotype distribution

Natural History and Clinical Presentation of Hepatitis C

Natural History of Hepatitis C

Acute hepatitis C is a short-term infection of the HCV during the first 6 months after exposure to HCV. Annually, upto 4 million people are newly infected with HCV.The acute illness is clinically mild and is typically unrecognized and undiagnosed characterized by high liver enzymes such as serum alanine aminotransferase (ALT) levels and jaundice, which appears in about 25% of cases. Between 10 and15% of acutely infected individuals spontaneously clear HCV.

Approximately 55–85% of those with an acute infection are unable to clear the virus within 6 months of infection without any therapeutic intervention and are referred to as chronic hepatitis C patients.

Even in the chronic stage, however, most infected persons may be asymptomatic until serious complications such as cirrhosis, liver failure, and HCC arise, although this often does not occur until 20 years after infection. More prominent symptoms such as swelling of the abdomen, fatigue, dark urine, fluid retention, jaundice, ascites, muscle weakness, itching, and weight loss are observed.

Cirrhosis is the most well-known consequence of chronic hepatitis C, and is seen in about 20% of patients. Of those with chronic HCV infection, the risk of cirrhosis of the liver is 15–30% within 20 years. The risk of HCC in persons with cirrhosis is approximately 2–4% per year.

Fig. 3: Natural history of hepatitis C

Clinical Presentation

The spectrum of HCV is varied and has a long and relatively symptom-free incubation period. The severity ranges from mild, short-term symptoms to complicated, life-long chronic liver disease (CLD), which has increased mortality. The incubation period for hepatitis C is 2 weeks to 6 months. Approximately 75% of people are asymptomatic.Those who are acutely symptomatic may exhibit fever, fatigue, decreased appetite, nausea, vomiting, abdominal pain, dark urine, gray-colored feces, joint pain and jaundice (yellowing of skin and the sclera of the eyes).

Table 1: Symptoms and signs of chronic hepatitis C by stage of disease

 

Chronic hepatitis C

 

Symptoms

Signs

Early and/or

slowly

progressive

liver disease

  • Often none
  • Lethargy
  • Loss of appetite
  • Nausea
  • Abdominal discomfort
  • Intolerance to alcohol and fatty foods
  • Often not present

 

  • Hepatomegaly

Progressive

liver disease

  • Often none
  • Lethargy
  • Loss of appetite
  • Nausea
  • Abdominal discomfort
  • Intolerance to alcohol and fatty foods
  • Often not present
  • Hepatomegaly
  • Peripheral signs of CLD* (palmar erythema, spider naevi, leuchonychia) if cirrhosis

Advanced

liver

disease

 

 

 

  • Increasing lethargy
  • Fluid retention
  • Bruising
  • Prolonged bleeding

Peripheral signs of CLD*

  • Gynecomastia
  • Ascites/edema
  • Splenomegaly
  • Distended abdominal veins
  • Bruising
  • Hepatic encephalopathy
  • Jaundice (poor prognostic sign)

*CLD – chronic liver disease

Screening and Diagnosis

Screening

The WHO recommends that HCV serology testing be performed on individuals who are part of a population with high HCV seroprevalence or who have a history of HCV risk exposure and/or behavior rather than at the time of presentation with symptomatic disease.

The American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA), in collaboration with the International Antiviral Society–USA (IAS–USA), recommend screening certain groups of people for hepatitis C. In India, the Indian Association for the Study of the Liver (INASL) has also defined similar risk groups for HCV.

Screening Recommendations for HCV Infection

  • CDC recommends that HCV testing be performed in all persons born between 1945 and 1965
  • Persons who:
    • Currently inject drugs or have a prior history of injection drug use; and/or
    • Have certain medical conditions:
      • Received clotting factor concentrates produced before 1987
      • On long-term hemodialysis/thalassemics
      • Persistently abnormal ALT levels/unexplained chronic liver disease
      • HIV infection
  • Prior recipients of transfusions or organ transplants, including persons who
    • were notified that they received blood from a donor who later tested positive for HCV infection; and/or,
    • received a transfusion of blood or blood components or an organ transplant before July 1992 (for India—all persons who received blood transfusions before 2001, when mandatory HCV testing in blood banks was introduced)
  • HCV-testing based on recognized exposure recommended for
    • Occupational exposure : healthcare, emergency medical, and public safety workers after needle sticks, sharps, or mucosal exposures to HCV-positive blood
    • childrenborn to HCV-positive mothers

Note: For individuals who may have been exposed to HCV within the past 6 months, testing for HCV RNA or follow-up testing for anti-HCV antibody is recommended.

Diagnosis

Diagnosis of hepatitis C involves confirmation of the diagnosis of HCV infection and assessment of the severity of liver disease.

Virological Tests

Investigations for patients with HCV infection include serological assays for antibodies to hepatitis C (anti-HCV) and molecular assays for detection of viral RNA. In addition, investigations for staging or assessment of hepatic fibrosis may also be considered.

After acute exposure, HCV RNA is usually detected in serum before antibody; HCV RNA can be identified as early as 2 weeks following exposure, whereas anti-HCV is generally not detectable before 8–12 weeks.

Anti-HCV Antibody  

Detection of anti-HCV by ELISA is the initial step in the diagnosis/screening test for HCV and it is more than 99% sensitive and specific. This is followed by HCV RNA testing for confirmation of viremia if the anti-HCV test is positive. While the presence of anti-HCV antibodies indicates prior exposure to HCV infection, the assay may be negative in the early stage of acute HCV infection, in immunosuppressed individuals or years after resolution of HCV infection. In such cases, HCV RNA testing should be done to confirm the presence.

HCV RNA (viral load) Tests

A viral load test measures the amount of HCV RNA in the blood and is used to confirm active HCV infection and also used to guide treatment. There are two types of viral load tests:

Qualitative: Measures the presence of the virus in the blood. This type of test is usually used to confirm initial and chronic infection with HCV.

Quantitative: Measures the amount of virus in the blood and is generally used for HCV treatment to determine if a patient is responding or has responded to treatment.

Table 2: Interpretation of HCV test results

The approach to hepatitis C diagnosis is mentioned in Fig.4 below.

Fig. 4: Flowchart for diagnosis of hepatitis C

HCV Genotyping HCV genotype/subtype test is generally offered to someone who is considering HCV medical treatment.These tests are pivotal to determine the duration and dosage of therapy with pegylated-interferon (peg)-IFN alfa and RBV therapy and in predicting the likelihood of response.

Liver Function Profile

The serum ALT level may be a marker of hepatic inflammation although levels may be normal despite progressive liver disease. People with chronic HCV who have consistently normal ALT levels are at low risk of progression to cirrhosis. Although people with abnormal ALT levels are at increased risk of progressive liver disease, the level of ALT in chronic hepatitis C is a relatively poor predictor of disease stage or disease progression.

An “inverted”aspartate aminotransferase (AST)/ALT ratio (higher AST than ALT) may indicate underlying cirrhosis in chronic HCV infection.

Albumin level (along with the prothrombin time) gives an indication of the synthetic function of the liver. Hypoalbuminemia and prolonged prothrombin time indicate decompensated cirrhosis.

Liver Fibrosis Assessment

The severity of disease can be assessed by the stage of liver fibrosis, which plays an important role in clinical management and in determining a patient's prognosis. Percutaneous liver biopsy is the gold standard test to assess liver fibrosis. The biopsy sample is then graded and staged as per the Metavir scoring system, developed for use in patients with HCV infection,which consists of a grade (indication of the activity or amount of inflammation) and a stage (amount of fibrosis or scarring).

The grade score range is 0–4: 0 = no activity and 3 or 4 = severe activity. The fibrosis score range is also 0–4: F0 = no fibrosis; F1 = enlargement of the portal areas; F2 = fibrosis extending out from the portal areas with rare bridges between portal areas; F3 = many bridges of fibrosis that link up the portal and central areas of the liver (bridging fibrosis); and, F4 = cirrhosis.

Non-invasive methods for assessing disease progression or prognosis are promising and may reduce the need for liver biopsy. These approaches include serum biomarkers and ultrasound-based imaging techniquessuch as transient elastography.

Others Abdominal ultrasound is used to assess the liver and biliary tree, and helps to screen for HCC and to assess for small amounts of ascites where doubt exists. However, a normal ultrasound does not exclude cirrhosis.

Alpha-fetoprotein (AFP) level should also be measured at baseline, and monitored every six months, especially in people with chronic hepatitis C and those with cirrhosis, since this is a useful marker of HCC.

Goals of Therapy

All patients with compensated liver disease due to chronic hepatitis C, who have evidence of HCV replication and no contraindications to therapy, should be considered for treatment. The goal of therapy for chronic hepatitis C is eradication of the virus, which, in turn, will limit or prevent the development of complications. The endpoint of successful therapy is a sustained virologic response (SVR), defined as undetectable HCV RNA in serum for at least 12 weeks after treatment has been stopped.

Short-term outcomes can be measured using the following:

  • Biochemically
  • Virologically (absence of HCV RNA from serum by a sensitive PCR-based assay)
  • Histologically (>2 point improvement in the necroinflammatory score with no worsening in the fibrosis score)

Conclusion

Thus, the overall 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 HCC, by the achievement of virologic cure as evidenced by an SVR.

In conclusion,HCV infection, previously known as blood-borne non-A, non-B infection is a serious public health problem worldwide. Hence, it is a necessity to promote early diagnosis and timely treatment of HCV infection.

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