Original Article

The management of patients positive to hepatitis C

virus antibody in Malta
Anthea Brincat, Neville Azzopardi, Maria Deguara, Kelly Mifsud
Taliana, Marilyn Rogers, James Pocock
Abstract Only 56% of patients found to be HCV Ab positive
Hepatitis C virus (HCV) infection is one of the main had a scheduled appointment with an infectious diseases
causes of chronic liver disease and hepatocellular specialist or gastroenterologist documented on the MDH
carcinoma worldwide and is an important public health online appointment system. 58% of patients had HCV
concern. A retrospective analysis of the demographics and RNA testing done and 45% had genotype testing. 7.3%
management of patients who had a positive anti-HCV with HCV infection were given treatment, of which 43%
detected by enzyme immunoassay test done at Mater Dei had a Sustained Virological Response (SVR).
Hospital was carried out to analyse the epidemiology of
HCV infection in Malta and assess our management when Keywords
compared to the European Association for the Study of Hepatitis C virus, EASL guidelines, management,
the Liver (EASL) guidelines. 72% of patients were male. treatment
The majority of patients were aged 21-50 years. The main
mode of infection was via intravenous drugs use, Introduction
accounting for 68% of cases. The Management of Patients Positive to Hepatitis C
Virus Antibody in MaltaHepatitis C virus (HCV) infection
Anthea Brincat M.D. *
Department of Medicine, is one of the main causes of chronic liver disease
Mater Dei Hospital worldwide.1 WHO estimates that about 150 million people
Msida are chronically infected with HCV and that every year
anthea.brincat@gov.mt more than 350 000 people die from HCV-related liver
diseases.2
Neville Azzopardi M.D. MRCP(UK) HCV is a single-stranded enveloped RNA virus
Department of Gastroenterology, belonging to the Flaviviridae family. The outcome of
Mater Dei Hospital, HCV infection on the liver may range from minimal
Msida changes to acute or chronic hepatitis, cirrhosis and
hepatocellular carcinoma. 75-85% of patients infected
Maria Deguara M.D.
with HCV will not clear the virus by 6 months, thus
Affiliations: Department of Medicine, developing chronic HCV infection. Cirrhosis develops in
Mater Dei Hospital, approximately 10- 15% of individuals with chronic HCV
Msida infection over twenty years.3 The European Association
for the Study of the Liver (EASL) has issued guidelines
Kelly Mifsud Taliana M.D. MRCP(UK)
on the management of patients infected with HCV. In this
Department of Oncology and Haematology, study we have audited the management of chronic HCV
Sir Paul Boffa Hospital with respect to the EASL guidelines.

Method
Marilyn Rogers M.D. MRCP(UK) The audit is a retrospective analysis of the demographics
Affiliations: Department of Medicine, and management of patients who had a positive HCV Antibody
Mater Dei Hospital, detected by EIA test done at the Virology Laboratory at Mater
Msida
Dei Hospital. The time period studied was between January
2008 and May 2012, during which there were a total of 1,074
James Pocock M.D. FRCP(UK) unique positive tests. Of these, 538 patients could not be
Department of Gastroenterology, identified as the tests were coded and 25 patients never had a
Mater Dei Hospital, file created or their file was misplaced. The remaining 506 files
Msida were viewed at medical records. This is a limiting factor of the
study since not all the files could be traced. The following data pertains to
*Corresponding author these 506 patients.

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Results Table 2: Highest Ranking Relative Prevalence Rates

Demographics according to localities
72% (363) of patients were male. The age No. of Relative
distribution of the patients with a positive HCV antibody people Prevalence
Rank Locality with HCV Population4 No./Populati
test is shown in Graph 1. 77.7% of patients who tested
in the on
positive were aged 21-50 years. This model of infection locality X106
suggests that the risk for HCV infection was greatest in 1 COSPICUA 30 5658 530
the relatively recent past and primarily affects young
2 VALLETTA 23 6966 330
adults. Table 1 describes the nationality of individuals
with a positive HCV antibody test, with 81% of patients 3 ST.VENERA 18 6939 259
being Maltese. 4 FLORIANA 5 2335 214
5 ST.JULIANS 22 10573 208
Figure 1: Age distribution of patients 6 HAMRUN 18 9649 187
7 VITTORIOSA 5 2758 181
8 GZIRA 15 8392 178
9 MSIDA 16 9227 173
10 KALKARA 5 2999 167

Mode of Infection
Chart 1 shows the alleged mode of infection. 68% of
patients were known IVDU. In 2% of cases, the alleged
mode of infection was via blood transfusions infected with
HCV prior to the introduction of blood screening. In these
cases, blood transfusions were the only risk factor
documented in the notes. Vertical and sexual transmission
Table 1: Nationality of individuals with a positive HCV accounted for 1% each whilst there was only one case
antibody test (0.2%) of a needle stick injury resulting in infection. In
Nationality Percentage 27% of cases, no risk factors were documented.

Maltese 81% Investigations

Diagnosis of ongoing HCV infection requires the
African & Eastern countries 11% presence of HCV RNA, which is detected by molecular
assays such as PCR. In our study, only 58% of patients
West Europe 6% had HCV RNA checked with 46% being positive and 11%
negative. A negative HCV RNA in a patient who has a
Other 2% positive HCV Ab could be due to previous successful
treatment, neonates who received the HCV Ab via
transplacental transfer of the antibody, spontaneous
The residing locality of the patients was documented clearance of the virus, a low viral load that is below the
to analyze the distribution of HCV in Malta. The limit of detection of the laboratory or a false positive HCV
population estimate for each locality was obtained from Ab.
The Malta Government Gazette (Number 18,789 HCV is divided into six genotypes with numerous
published on Tuesday 9th August, 2011).4 The number of subtypes. Genotype 1, with subtypes 1a and 1b is the most
patients infected with HCV living in a particular locality prevalent genotype worldwide. Genotype 3a is highly
was multiplied by 106 and divided by the population living prevalent among European IVDU5 whilst genotype 1b is
in that location thus allowing us to compare localities associated with blood transfusions.6 In our study, it was
(Table2). shown that genotype testing was done in 20.5% of
patients, with genotype 1a accounting for 45% of cases.
The highest ranking localities are mainly Harbour or (Chart 2). HCV genotype testing should be assessed in
Inner Harbour areas or localities associated with patients prior to starting antiviral therapy as it is important
recreation. to decide treatment duration and dose of ribavirin.

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Figure 2: Alleged mode of Infection

Figure 3: Distribution of Genotype Table 3: Blood Tests

Percentage of Number of
Value
patients patients tested
Platelets
21% n=499
< 150 x109/L
INR > 1.3 10.5% n=416
Albumin
14.5% n=343
< 35g/dL
Bilirubin
10% n=454
> 30µmol/L

An ultrasound was done in 51% of patients. The

finding of a nodular liver (suggestive of liver cirrhosis)
was present in 9%. Ascites, which is indicative of liver
failure, was found in 9%. Splenomegaly (suggestive of
portal hypertension) was found in 18%.
HCV infection is associated with a 15 to 20-fold
EASL guidelines recommend that assessment of increase in hepatocellular carcinoma (HCC). The rate of
liver disease should include alanine aminotransferase, HCC among patients with HCV infection ranges from 1-
aspartate aminotransferase, gamma-glutamyl 3% over 30 years.7 In our study, HCC was found in 4% of
transpeptidase, alkaline phosphatase, bilirubin, INR, patients who underwent an US abdomen, 80% of who
albumin, gammaglobulins, full blood counts and an were male.
abdominal ultrasound.1 Having low platelet counts, high A liver biopsy is done locally to assess the severity
INR, low albumin and high bilirubin is highly suggestive of liver disease, unless the patient is already has
of underlying cirrhosis. (Table 3) established liver cirrhosis. EASL guidelines state that a
liver biopsy is regarded as the reference method to assess
the degree of inflammation and fibrosis.1 A standardized
scoring system is used to report the grade, which is the

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degree of inflammation and stage, which is the degree of Referrals

fibrosis. Both values range from 0 being no inflammation 56% of patients found to be HCV Ab positive had a
or fibrosis, progressively worsening with a higher grade or scheduled appointment with an infectious diseases
stage until 4 is severe inflammation or fibrosis (termed specialist or gastroenterologist documented on the MDH
liver cirrhosis). Assessment of the severity of hepatic online appointment system.
disease is important in decision making with regards to
treatment as patients with cirrhosis are less likely to
respond to therapy and have a worse prognosis post- Treatment
treatment1. In this study, 47 patients (9%) underwent a Prior to the introduction of combination therapy,
liver biopsy (Charts 3 and 4). 80% of patients have either monotherapy with alpha interferon (IFN) was used. When
no, minimal or mild inflammation and fibrosis which a combination therapy of pegylated interferon IFN-α (PEG
good prognostic factor for treatment. Alternative non- IFN) and ribavirin was introduced, it became the standard
invasive methods such as transient elastography can also treatment. Single therapy is nowadays only used if the
be used to assess liver fibrosis in patients with chronic patient cannot tolerate dual therapy due to side-effects.
HCV1; however this non-invasive test is not available 37 out of the 506 patients audited (7.3%) were treated
locally. with either both PEG IFN and ribavirin or else with IFN
alone. 55 patients (10.9%) were HCV RNA negative, and
Figure 4: Distribution of Grade of liver biopsies therefore treatment was not needed whilst 44 patients
(8.7%) were in liver cirrhosis, so treatment was not given
due to the risk of decompensation. 24 patients had an
uncontrolled psychiatric condition and thus treatment was
contraindicated. Chart 5 describes all patients who were
deemed ineligible for treatment.

Figure 6: Ineligibility for treatment

Figure 5: Distribution of the Stage of liver biopsies

Sustained virological response (SVR) is defined as an

undetectable HCV RNA level (<50 IU/mL) 24 weeks after
cessation of treatment. Null response is defined as failure
to achieve a decline of 2 logs HCV RNA IU/mL after 12
weeks of treatment or failure to achieve undetectable
HCV RNA during treatment of a minimum duration of 24
weeks. Relapse is defined as having achieved undetectable
HCV RNA at the end of treatment but HCV RNA is
detected after stopping treatment1.
Out of the 37 patients who were treated with either
PEG IFN and ribavirin or IFN alone, 43% went into SVR,
8% were Null responders, 8% relapsed, 8% were lost to
follow-up and 11% had to stop treatment due to side-
effects (Chart 6).

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Once a patient is then referred to the appropriate

Figure 7: Response to Treatment specialist, the management is then of high standards and
success rates are good. In clinical trials, SVR was
achieved in 40-54% of patients infected with HCV
genotype 1 who were given PEG IFN and ribavirin
combination therapy and in 65-82% of patients infected
with genotype 2 or 3.1 SVR rates with monotherapy are
lower. In the study population, 43% of patients (all
genotypes included) went into SVR when treated with
either combination therapy or IFN alone. IFN was used
prior to the introduction of combination therapy. Thus,
especially taking into account that both monotherapy and
combination therapy are included, SVR rates for patients
with HCV in Malta are favourable when compared to
SVR rates in clinical trials.
Trials have shown that relapse rate after treatment
with combination therapy varies between 15-25%.1 In our
study, 8% of patients relapsed on either monotherapy or
combination therapy. In clinical trials, 32-53% of patients
Discussion who relapsed after being given IFN alone then responded
HCV is one of the leading causes of liver disease, to combination therapy with PEG IFN and ribavirin.1
cirrhosis and HCC and one of the most common Thus, patients who relapsed should be reassessed with an
indications for liver transplantation.3 It is estimated that aim to give combination therapy.
the prevalence of HCV infection is approximately 2.2-3% 4-14% of treated patients will not respond to
worldwide.9 combination therapy.1 In our study population, 8% of
Presently the main mode of transmission of HCV is patients treated with monotherapy or combination therapy
via sharing of devices used for illegal drug use. These were non-responders.
include both IVDU and nasal drug use. Measures have Recent studies have shown that boceprevir or
been instituted to attempt to decrease the risk of HCV telaprevir in combination with PEG IFN and ribavirin
transmission by providing free new syringes from health (triple therapy) result in substantially higher sustained
centres. It is of utmost importance to draw attention of the virological response rates in both treatment-naïve as well
risks of sharing needles and apparatus to drug users at as in previous non responders with genotype 1 HCV
every visit and to educate the general public via national chronic hepatitis. Triple therapy is however associated
education campaigns. This study indicated the highest with increased side effects, increased drug interactions,
ranking localities where patients resided and these areas increased cost and reduced cost effectiveness.8
should be particularly targeted. This article highlights the need to refer all patients with
Some of the reasons for shortcomings in HCV positive HCV antibody tests to a gastroenterologist or an
management in Malta are due to the fact that the patient infectious disease physician for assessment of hepatic
population can be difficult to work with as most patients function and suitability for treatment. Management of
are IVDU and there is stigma associated with both drug these patients at Mater Dei Hospital mirrors the results
use and HCV infection. The disease is also clinically obtained from international studies and therefore this
silent and so patients will present late unless the infection treatment offers the best hope of a cure for these patients.
is picked up by screening blood tests. Inadequate referrals
to appropriate specialists may occur because of lack of References
awareness amongst doctors of the rapid advances in 1. European Association for the Study of the Liver. EASL Clinical
management of HCV over the past years and the current Practice Guidelines: Management of hepatitis C virus infection.
Journal of Hepatology. 2011;55(1):245-64.
success rates. Patients should also be encouraged by their 2. Global surveillance and control of hepatitis C. Report of a WHO
GPs to attend Outpatients appointments and undergo the consultation organized in collaboration with the Viral Hepatitis
necessary investigations. In order to receive treatment Prevention Board, Antwerp, Belgium. J Viral Hepat. 1999
patients frequently depend on funding from NGOs since Jan;6(1):35–47.
3. Chen SL, Morgan TR. The Natural History of Hepatitis C Virus
the medications are not available on the NHS and are (HCV) Infection. Int J Med Sci. 2006;3(2):47–52.
relatively expensive. This might also partly account of the 4. Estimated Population by Locality 31st March 2001. Article 73 of
small percentage of patients who were treated. Part VII of the Local Councils Act. Malta Government Gazette.
2011 Aug 9;18789:9657.

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5. Muhlberger M, Schwarzer R, Lettmeier B, Scroczynski G,

Zeuzem S, Siebert U. HCV-related burden of disease in Europe:
a systematic assessment of incidence, prevalence, morbidity, and
mortality. DMC Public Health. 2009 Jan;34(9).
6. Esteban JI, Sauleda S, Quer J. The changing epidemiology of
hepatitis C virus infection in Europe. J Hepatol. 2008
Jan;48(1):148-62.
7. El-Seraq HB. Epidemiology of Viral Hepatitis and
Hepatocellular Carcinoma. Gastroenterology. 2012
May;142(6):1264-1273.
8. Perlman BL. Protease inhibitors for the treatment of chronic
hepatitis C genotype-1 infection: the new standard of care.
Lancet Infect Dis. 2012 Sept;12(9):717-28.

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