Running head: RAPID POINT-OF-CARE TESTING FOR HEPATITIS C 1

Rapid Point-of-Care Testing for Hepatitis C

Student’s Name

Institutional Affiliation

CHAPTER ONE: INTRODUCTION

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1.1 Background of the Study

1% of the world’s population is infected with hepatitis C and is at a high risk of

developing cirrhosis, liver failure, and hepatocellular carcinomai. The largest demographic of

people who are adversely being affected by this condition are individuals who are exposed to

the poor or deplorable healthcare outcomes, have low healthcare system engagements and are

highly socioeconomically deprived. With the advancement of medical technology, such as

the increased availability of curative antiviral therapy, the World Health Organization (WHO)

has stated that it plans to eliminate HCV infection as a common public health threat by 2030

(WHO, 2019).

The transmission of HCV can take place via multiple means such as sexual, blood-blood

contact or even vertically such as mother-to-child. Also, there are several high-risk groups for

acquiring HCV such as people who require blood transfusion or organ transplant, people who

work in prisons, individuals who use needles to inject drugs, people who have multiple sexual

partners, new-borns from chronic HCV infected mothers and migrants from HCV endemic

regions. The initial infection of HCV is relatively asymptomatic or mild in 70-90% of the

cases. 50-80% of the people infected will develop a chronic infection at later stages of their

lives and can eventually lead to the development of liver cirrhosis in 50% and liver cancer in

up to 5% of the infected people after approximately 20-30 years. According to WHO, there

are between 30-150 million people worldwide who have chronic hepatitis C, out of which

350,000 to 500,000 die each year from hepatitis C-related liver diseasesii.

According to the New Zealand Ministry of Health, there are more than 50,000 people in

the country. However, only 50% of the estimated number of people have currently been

diagnosed. As has been stated before, although the condition can remain asymptomatic for

decades, in situations whereby the diagnosis is made early, an individual can be able to
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undertake lifestyle changes to avoid or delay the onset of complications related to the disease

or follow a treatment plan to cure the disease. The New Zealand Ministry of Health identified

the people in the following groups as being at an increased risk of being diagnosed with

HCV. These are:

 Individuals who inject drugs via needles into their bloodstream.

 People who have received a tattoo or a body piercing using equipment that has not

been properly sterilized.

 Individuals who had a blood transfusion before 1992

 People who have received medical treatment such as surgery or a dental procedure in

a high-risk country.

 Individuals who have worked or served time in prison

 Children or infants who have been born to a mother who has hepatitis C

The development and availability of the oral direct-acting antiviral (DAA) therapies that

can cure HCV infections within a period of two to three months have drastically

revolutionized the HCV care approach and increased the calls for the elimination of this virus

such as has been the case for smallpox, rinderpest, and poliomyelitis (polio). It is estimated

that the DAA offers a cure rate of 95% with little or no side-effects and the duration for the

treatment is only 12 weeks. It is a contrast from the interferon-based treatments that were

used in the past as they had poorer outcomes, side-effect problems, which led to a majority of

individuals who had been diagnosed with the condition to opt not to follow the medical

procedure as it made them feel worse.

Until 2016, the DAA treatment uptake was low. For instance, in Australia, 1 to 2% of the

people who had been diagnosed with HCV had access to treatment and in New Zealand, less
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than 10% had access to treatment of the condition by 2014. As of 2016, the treatment uptake

in the two countries had drastically improved. According to the 2017 Pharmac report, in New

Zealand, 2,000 people had been treated with the new DAAs and in Australia, more than

32,000 people had initiated their treatment with DAAs in 2017. However, achieving the

objective that has been set by the WHO requires that 90% of the people who are estimated to

be living with HCV be diagnosed and 80% of the diagnosed people be treated. The

achievement of these targets is highly probable in countries that offer unrestricted access to

DAA therapy, such as is the case in Australia and New Zealand. However, there is a need to

undertake more proactive approaches in countries where a high number of people are at a

high risk of HCV infection.

Studies by Jones et al. (2014) and Islam, Topp, Day, Dawson and Conigrave (2012) show

that previously the type of tests used for HCV required a multi-step process for diagnosisiii.

An initial HCV antibody test, followed by an RNA test was considered laborious and a

majority of people felt that they were being discriminated against for taking this test based on

its prevalence association with drug addictsiv. The utilization of the point-of-care test may

assist in overcoming this barrier. In a study by Grebely, Applegate, Cunningham, and Feld

(2017) showed that when using this test, it led to an increase in the entry points and also

avoided delays in HCV carev. Beckwith et al. (2016) noted that the use of point-of-care tests

for the detection of HCV antibodies had been implemented and tested in multiple settingsvi.

Coats and Dillon (2015) noted that there has been limited research about the impact of the

HCV point-of-care tests on the impact of the tests and the treatment outcomes. This is an

indicator that there is a need for more tests to be undertaken to assess the feasibility and

acceptability of this testvii.

Different point-of-care tests can be used for HCV testing such as a serum, plasma,

whole blood or oral fluid. Out of these four tests, conducting HCV tests using a swab of oral
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fluid is considered to be the easiest to administer for the providers and patients. The results

for this form of the test are available in 20 to 30-minute duration. The test has high sensitivity

and specificity duration. For instance, Ora-Quick has a sensitivity of 95.9% and a specificity

of 99%, which is considered to be the highest sensitivity and specificity in comparison to the

other point-of-care tests that are used for HCV testing.

CHAPTER 2: AIMS AND OBJECTIVES

 Assess the feasibility of the point-of-care HCV testing in the general practice setting

in New Zealand

 To gain insights into the experience of the participants and health-care providers with

this test

 Assess patient uptake of further investigations after a positive point-of-care HCV test

 Assess patient adherence to the treatment of hepatitis C after a positive point-of-care

test.

CHAPTER 3: LITERATURE REVIEW

3.1 The Origins of Hepatitis C

Feinstone et al. in 1975 discovered the existence of a third hepatitis virus when they

identified that in a majority of the cases of the transfusion-associated hepatitis were not from

hepatitis-A or hepatitis-B virus infections. They labeled the new virus as non-A, non-B

hepatitis. Choo et al. (1989) in their study noted that there was scientific evidence that

showed that the blood-borne NANBH agent could be a small, enveloped virus that could be

transmissible to the chimpanzeesviii. Choo et al. (1989) highlighted that one of the obstacles

for identifying this ‘new’ virus at that time, despite researching this issue for more than ten

years was that the conventional methods that were applied at that time had failed to identify
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the specific viral antibodies and antigens. There were suggestions that the identified failure

could be interpreted or assumed to be a lack of viral antibody, however, Choo et al. (1989)

stated that the reason for this was mainly insufficient concentrations of the viral antigen in

NANBH infections. The solution to this problem was to increase the viral antigen

concentrations that were derived from the infectious material.

Houghton et al. in 1989 managed to clone and sequence the genome of the HCV using

the high-titer samples that had been collected from a chimpanzee that was intentionally

infected with the NANBH virus and later developed through conducting diagnostic tests

(Houghton, 2009)ix. Choo et al. (1989) noted that the HCV infection led to the development

of acute and chronic hepatitis and liver cancer at later stages of the people who had this virus.

It is important to point out that, shortly after the cloning of the HCV, it was determined that

this virus was the cause of 90% of the NANBH diagnoses in the United States alone.

Hepatitis C virus is categorized as an RNA virus, which belongs to the family

Flaviviridae. Although it replicates in the cytoplasm of hepatocytes, it is not cytopathic. The

high rate of infection among individuals is a result of the rapid production of the virus and

continuous cell-to-cell spread. In addition to that, a lack of vigorous T-cell immune response

to the HCV antigens is considered to be one of the causes of the high rate of HCV infections

that have been reported globally. HCV turnover rate is estimated to range between 1010 to

1012 virions per day, and the viral half-life is estimated to be between 2 to 3 hours. It is

important to point out that the reasons why the HCV genome RNA mutates at a frequent rate

are because of the rapid viral replication and lack of error proofreading by the viral RNA

polymerase. Studies have identified six HCV genotypes, which are numbered 1 to 6 and there

are more than 50 known subtypes of this virus.

3.2 Global Burden of the Disease

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Averhoff, Glass, and Holtzman (2012) in their study established that there were 130-

170 million people or 2%-3% of the world’s population that were living with the hepatitis C

virus (HCV) as of 2012x. The researchers observed that there are 350,000 deaths as a result of

chronic HCV, which are mainly caused by liver cirrhosis and hepatocellular carcinoma

(HCC). Averhoff, Glass, and Holtzmann (2012) added that 27% of cirrhosis and 25% of HCC

cases that are reported worldwide can be attributed to HCV infections. In addition to that,

these researchers observed that the disease rates in some countries are highly substantial than

in others, which creates a high burden of infection. For instance, in Japan, up to 90% of all

the reported HCC cases were caused by HCV infection. Furthermore, Averhoff, Glass, and

Holtzman (2012) added that while the statistics of HCV infection varies considerably by

country and region, the true burden of the disease cannot be established because in a majority

of the countries there is limited available data on the rate of infection.

According to a 2016 WHO report, HCV infections between 1990-2013 have led to the

rate of disability-adjusted-life-years (DALYs) to increase by 43%. Morbidity and mortality

rates that have been caused by hepatitis C infections have increased by 97%. The WHO

reported highlighted that mortality rates from HCV infections were high in Oceania, western

sub-Saharan Africa, and central Asiaxi. However, when putting into consideration, the

absolute numbers of the people who have died because of HCV infections, it was noted that

east and south Asia had the highest rates (52% of the total number of deaths). Also, it was

noted that, unlike the HIV infections, which primarily affect people from the low-income

countries mainly in Africa, 58% of the reported hepatitis deaths that have been reported

globally have occurred in the upper-middle and high-income countriesxii.

WHO (2019) stated that there are an estimated 71 million people who have chronic

HCV globally. Also, 99,000 people die annually from HCV mainly from cirrhosis and

hepatocellular carcinoma. It is important to point out that new HCV infections are
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asymptomatic, which means that for some people who have been diagnosed with acute HCV,

it does not result in life-threatening disease. Approximately 30% of the infected people will

spontaneously clear the virus within the first 6 months of infection without requiring any

form of treatment. On the other hand, 70% of the people will develop chronic HCV infections

at the later stages of their lives, which is within the next 20 years after infection.

According to 2019 WHO report, it was established that the most affected regions

globally are the WHO Eastern Mediterranean and WHO European regions, which have a

prevalence rate of 2.3% and 1.5% respectivelyxiii. The prevalence rate in the other WHO

regions varies from 0.5% to 1.0%. In a majority of the countries, new HCV infections can be

attributed to the use of injections during drug use and it is therefore mainly concentrated

among the drug users than any other sociodemographic population in the regionxiv. However,

in countries where there have been no, or the history of infection control practices is

insufficient, HCV infections are widely distributed in the general population. It is important

to point out that although there are multiple strains or genotypes of the HCV virus and that

their distribution varies from one region to another, in a majority of the countries the actual

genotype distribution is unknown (Jefferies, Rauff, Rashid, Lam, & Rafiq, 2018).

Natural History of Hepatitis C Infection

The natural history of chronic HCV infection has not been properly described in the

previous research work. The reason for this is that the researchers that are conducting this

study are facing challenges in the design of studies that will effectively show the natural

history of this condition for a variety of reasons such as being unable to accurately establish

the initial acquisition of the infection and accurate follow-up of the patients. The available

data of the progression of chronic HCV indicates that the stages of the disease from acute to

HCC or other serious liver diseases can take a period of twenty years after the initial
 RAPID POINT-OF-CARE TESTING FOR HEPATITIS C 9

infection. There are other studies that indicate that the diseases such as cirrhosis, end-stage

liver disease (ESLD) and HCC are highly likely to emerge after 30-40 years after the initial

infection of an individual.

As has been mentioned before, HCV exists in two forms in the body of human beings-

acute and chronic HCV. Individuals who have chronic HCV are the ones who have HCV in

their blood system for more than 6 months after the onset of acute infection. It is estimated

that approximately 55-85% of the patients who have been diagnosed with acute HCV will

transition to chronic HCV diagnosis. It is important to point out that once the infection

transitions from acute to chronic, then spontaneous resolution is rare. It has been observed

that chronic HCV can lead to patients developing fibrosis and later on cirrhosis,

hepatocellular carcinoma and end stage liver disease. Lingala and Ghany (2015) stated that

there are approximately 20-30% of the patients that have been diagnosed with chronic HCV

will progress to cirrhosisxv. However, they also noted that this estimation is highly variable

and it is dependent on the methodology that is undertaken by different researchers to define

the natural history of the disease.

Lingala and Ghany (2015) highlighted this in their analysis of 57 studies that were

conducted to provide an estimation of the progression from chronic HCV to cirrhosis. The

studies were undertaken from tertiary care liver clinics, blood donors, community-based

cohorts and post-transfusion cohorts. The estimation of the progression from chronic HCV to

cirrhosis after a period of 20 years varied. In the post-transfusion studies it was determined to

be 24%, in tertiary care liver clinic studies, it was determined to be 22%, in community based

cohorts, it was 7% and for blood donors, it was 4%. In an earlier study by Freeman, Law,

Kaldor and Dore (2003), they stated that factors such as selection bias, recall bias and short

duration during the follow-up period could be the reason for the differences in the estimated

rates in different studies. Freeman et al. (2003) highlighted that the use of the community-
RAPID POINT-OF-CARE TESTING FOR HEPATITIS C 10

based cohort studies was the best or most appropriate option for estimation of disease

progression at a population level.

Lingala and Ghany (2015) argued that monitoring the progress of fibrosis can be an

effective way of estimating the outcome of HCV. The reason for this is that the advanced

stages of fibrosis are considered to be a precursor of cirrhosis and therefore can be considered

as an indicator to the course of this disease. Evidence from previous studies have shown that

individuals with HCV who are at the Fibrosis state are highly likely to be diagnosed with

cirrhosis, may require liver transplantation at the later stages of their lives or experience liver-

related deaths. Therefore, this can be considered an important stage (fibrosis) in determining

the outcome of chronic HCV.

Cross-sectional biopsy studies provide an estimation period of 30 years from chronic

HCV to the development of cirrhosis. However, it is important to point out that the

progression of fibrosis varies for different patients. Therefore, the best or most appropriate

option is to conduct repeated liver biopsies in the subjects of a study to provide an accurate

determination of the progression rate of fibrosis. Boccato et al. (2006) in their study

established that the progression to cirrhosis takes 30 to 40 years after conducting paired liver

biopsy studiesxvi.

Cirrhosis development in patients who have been diagnosed with chronic HCV

represents an important stage in their lives. The reason for this is that these patients are at a

high risk of developing ascites, spontaneous bacterial peritonitis, variceal haemorrhage and

hepatic encephalopathy. These conditions increase the likelihood of a patient to require

urgent liver transplantation or risk death by complications in his or her liver. The information

concerning the natural history of hepatitis C after the development of cirrhosis has been

gotten mainly from the studies that have been conducted in the tertiary referral centers and
RAPID POINT-OF-CARE TESTING FOR HEPATITIS C 11

this does not represent the people or populations that have been diagnosed. The survival of

the patients who have been diagnosed with cirrhosis in the short-and medium term has been

determined to be good. For instance, the five year survival rate is between 85-91% and 10-

year has been determined to be 60-79%.

HALT-C trial provided crucial information on the natural history of the patients that

have been diagnosed with advanced fibrosis and cirrhosis. The results showed that Ascites

was the most common form of clinical decompensation for the participants of the study as it

occurred in 59 of the patients, representing 5.6% of the study participants. 29 participants or

2.8% were diagnosed with Hepatocellular carcinoma and 16 with cirrhosis. Planas et al.

(2004) conducted a study with 200 patients who had been diagnosed with HCV-related

cirrhosis without known HCC after hospitalization for their first hepatic decompensation. In a

follow-up study after 3 years, it was determined that HCC developed in 33 of the patients and

death occurred in 85 of the patientsxvii. The researchers established that the chances of

survival after the diagnosis of decompensated cirrhosis was 82% and 51% at one and five

years respectively. If the patients develop HE or Ascites as the first hepatic decompensation,

then they have a low survival rate.

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