Research

HFM/P is supporting research on Hepatitis B and C in Malaysia

HFM/P is undertaking research on Hepatitis C in Malaysia, particularly to address practical and operational issues that will arise in planning and executing public screening and treatment campaign. The cogent ones are:

  • Lab based screening test is too costly and logistically impractical when one is targeting to screen 100,000 people in Temerloh alone. Does low cost point-of-care test based on lateral flow immune-chromatography technology perform acceptably (in terms of accuracy and reliability) for screening use?
  • Epidemiology of Hepatitis C in Malaysia remains uncharacterized. Epidelmiologic data such as prevalence, persons at risk are necessary to inform operational planning and resourcing for the screening and treatment campaign. We are taking the opportunity presented by the first screening campaign to be conducted in Temerloh district to do this work.

For Investigators and sites participating in HFM/HFP research, click here
For synopsis on theon the "DIAGNOSTIC ACCURACY STUDY OF POCT SEROLOGICAL AND NUCLEIC ACID SCREENING TESTS FOR USE IN PUBLIC SCREENING CAMPAIGN AND IN HEMODIALYSIS SETTING" evaluation, click here
For synopsis on the "Epidemiology of Hepatitis C" research, click here
For synopsis on the "Registry Of Patients With Chronis Hcv And Hbv Treated With Imported Generic Anti-Virals" , click here
To view MOH approval for this research, click here
To download the research protocol, click here
To view MOH approval for this research, click here

Investigators and sites participating in HFM/HFP research

sub-study on Cross sectional case study to determine the false positive (FP) rates of current serology based tests among patients on HD (hemodialysis)

Table 1: List of investigators participating the Diagnostic accuracy test as well as the registry

No. Site conducted State Investigator
01. HOSPITAL BENTONG Pahang Darul Makmur Investigator Name
Dr Alif Adlan Mohd Thabit
Dr Wan Mohd Rasis Wan Ahmad Kamil
Role
Principal Investigator at the site
Principal Investigator at the site
02. HOSPITAL SELAYANG Selangor Darul Ehsan Investigator Name
Dr Tan Soek Siam
Dr Wong Hin Seng
Dr Suryati Yakob
Ms Lee Fei Yee
Role
Principal Investigator at the site
Principal Investigator at the site
Co / Sub Investigator at the site
Co / Sub Investigator at the site
03. HOSPITAL SULTAN HAJI AHMAD SHAH, TEMERLOH Pahang Darul Makmur Investigator Name
Dr Lim Ee Keng
Dr Rafidah Abdullah
Role
Principal Investigator at the site
Principal Investigator at the site
04. HOSPITAL SULTANAH BAHIYAH, ALOR SETAR Kedah Darul Aman Investigator Name
Dr Ching Chen Hua
Dato' Dr Muhammad Radzi Abu Hassan
Role
Principal Investigator at the site
Principal / Coordinating Investigator
05. HOSPITAL TENGKU AMPUAN AFZAN, KUANTAN Pahang Darul Makmur Investigator Name
Dr Fariz Safhan bin Mohamad Nor
Dato' Dr Mohd Ramli Seman
Dr Kiren Kaur A/P Bhajan Singh
Ms Lim Bee Chiu
Ms Fatihah Mahmud
Role
Principal Investigator at the site
Principal Investigator at the site
Co / Sub Investigator at the site
Co / Sub Investigator at the site
Co / Sub Investigator at the site
06. HOSPITAL SUNGAI BULOH Selangor Darul Ehsan

Investigator Name
Dr Suryati Yakob

Role
Principal Investigator at the site
07. HOSPITAL RAJA PERMAISURI BAINUN Perak Darul Ridzwan Investigator Name
Dr Lee Yee Yan
Dr Senamjit Kaur
Dr Loh Chek Loong
Dr Sridhar Ramanaidu
David Chang
Role
Principal Investigator at the site
Principal Investigator at the site
Co / Sub Investigator at the site
Co / Sub Investigator at the site
Co / Sub Investigator at the site
08. HOSPITAL KUALA LUMPUR Wilayah Persekutuan Kuala Lumpur Investigator Name
Datuk Dr. Ghazali Ahmad Kutty
Dr Korina Koh
Dr Izzaty Binti Dalawi
Dr Murnilina Binti Abdul Malek
Dr Nurul Asyiqin
Role
Principal Investigator at the site
Co / Sub Investigator at the site
Co / Sub Investigator at the site
Co / Sub Investigator at the site
Co / Sub Investigator at the site
09. HOSPITAL SULTANAH AMINAH, JOHOR BHARU Johor Darul Takzim Investigator Name
Dr Liu Wen Jiun
Dr Tee Shin Kuan
Role
Principal Investigator at the site
Co / Sub Investigator at the site
10. AMPANG HOSPITAL, SELANGOR Selangor Darul Ehsan Investigator Name
Dr Hajah Rosaida Hj Md Said
Dr Sattian Koilanthavelu
Role
Principal Investigator at the site
Principal Investigator at the site
11. JABATAN KESIHATAN NEGERI PAHANG, KUANTAN Pahang Darul Makmur Investigator Name
Dr. Mohd Rahim bin Sulong
Role
Principal Investigator at the site

Table 2: Listing of investigators participating in the sub-study on Cross sectional case study to determine the false positive (FP) rates of current serology based tests among patients on HD (haemodialysis) as the registry
Sub-study on Cross sectional case study to determine the false positive (FP) rates of current serology based tests among patients on HD (hemodialysis)

No. Site conducted Investigator Co-Investigator
01. Pusat Dialisis NKF - Yayasan Dialisis Pertubuhan Pendidikan Akhlak, Taiping (Moral Uplifting Society(MULS) - NKF Taiping, Perak) Dr Anita Bhajan Manocha  
02. Pusat Dialisis NKF - Nanyang  Dr Bee Boon Cheak  
03. Pusat Dialisis NKF - Fungates Superflow  Dr Bee Boon Cheak  
04. Pusat Dialisis NKF - Good Health  Dr Bee Boon Cheak  
05. Pusat Rawatan Dialisis MUIS - NKF  Dr Bharathan A/L Theva Rajah  
06. Pusat Dialisis NKF - Kelab Lions Alor Star Dr Ching Chen Hua  
07. Pusat Rawatan Dialisis Tuanku Syed Putra - NKF  Dr Eason Chang  
08. Pusat Dialisis NKF - Superkids Trinity Dr Eason Chang  
09. Pusat Dialisis NKF - Rotary Damansara Dr Goh Bak Leong  
10. Pusat Dialisis NKF - Dato Dr. G.A.Sreenevasan Dr Goh Bak Leong  
11. Pusat Dialisis NKF - Yayasan Sultanah Bahiyah  Dr Lam Swee Win  
12. Pusat Dialisis Amal FOYI - NKF (Unit I )  Dr Liew Yew Fong  
13. Pusat Dialisis NKF - Yayasan Buah Pinggang Kemaman Dr Zawawi Bin Nordin  
14. Nobel Dialysis Centre (KK) Dr Morris Wo Chee Yuen  
15. Nobel Dialysis Centre Cawangan Tuaran Dr Morris Wo Chee Yuen  
16. Prima Dialysis Kluang Dr Ahmad Fauzi Mr. Chee Fook Wah
17. Pusat Hemodialysis Darul Ta'zim Dr Zulkifli Bin Mohd Shah  

This Research incorporates 3 sub-studies:

  1. EPIDEMIOLOGY OF HEPATITIS C IN MALAYSIA
  2. DIAGNOSTIC ACCURACY STUDY OF POINT-OF-CARE (POC) SEROLOGICAL AND NUCLEIC ACID SCREENING TESTS FOR USE IN PUBLIC SCREENING CAMPAIGN AND IN HEMODIALYSIS SETTING.
    • Cross sectional case-control study to determine the sensitivity and specificity of point of care serology tests (POCT) and Nucleic Acid Tests (NAT)
    • Cross sectional case-only study to determine the sensitivity and lower limit of detection (LOD) of Nucleic Acid Test (HCV RNA and HBV DNA only) from public or clinical sites screening
    • Cross sectional case only study to determine the false positive (FP) rates of current serology based tests among patients on HD (hemodialysis)
    • Non-randomized self-controlled Cohort study to compare 2 approaches (current vs POCT_NAT) to monitoring for HBV, HCV and HIV transmission on patients on hemodialysis to be monitored over 2 years
  3. REGISTRY OF PATIENTS WITH CHRONIS HCV AND HBV TREATED WITH IMPORTED GENERIC ANTI-VIRALS

Synopsis: DIAGNOSTIC ACCURACY STUDY OF POCT SEROLOGICAL AND NUCLEIC ACID SCREENING TESTS FOR USE IN PUBLIC SCREENING CAMPAIGN AND IN HEMODIALYSIS SETTING

Synopsis:DIAGNOSTIC ACCURACY STUDY OF POINT-OF-CARE (POC) SEROLOGICAL AND NUCLEIC ACID SCREENING TESTS FOR USE IN PUBLIC SCREENING CAMPAIGN AND IN HEMODIALYSIS SETTING

Screening Test performance evaluation has been completed at the study sites (see table above); this is necessary prelude to using the test for large scale screening in the population.

Protocol number: HR2017-01
The study protocol was approved by the Medical Review and Ethics Committee (MREC), Ministry of Health Malaysia on the 21st February 2017.

Public screening for Hepatitis B and C

Public screening for Hepatitis B and C which entails testing hundreds of thousands of people in the community of necessity must employ robust low cost Point of Care (POC) tests which are simple to perform (minimal training and no equipment required) and provide results on the spot [1]. Many such test for HBsAg, ant-HCV and anti-HIV are now available in the market. Validation study was performed to evaluate the performance of these tests from variety of manufacturers on both finger-stick capillary as well as venepuncture whole-blood samples. Data from the validation then provide the basis for selecting the tests for subsequent use in large scale public screening campaign. Subjects who are screened positive from the above-mentioned public campaign will require confirmatory testing as well as assessment of disease activity to inform treatment decision. This is currently based on Nucleic Acid Tests (NAT) for HCV RNA and HBV DNA. Validation study to evaluate the performance of HCV RNA and HBV DNA tests is currently ongoing.

Public screening for Hepatitis B and C

Public screening for Hepatitis B and C which entails testing hundreds of thousands of people in the community of necessity must employ robust low cost Point of Care (POC) tests which are simple to perform (minimal training and no equipment required) and provide results on the spot [1]. Many such test for HBsAg, ant-HCV and anti-HIV are now available in the market. Validation study was performed to evaluate the performance of these tests from variety of manufacturers on both finger-stick capillary as well as venepuncture whole-blood samples. Data from the validation then provide the basis for selecting the tests for subsequent use in large scale public screening campaign. Subjects who are screened positive from the above-mentioned public campaign will require confirmatory testing as well as assessment of disease activity to inform treatment decision. This is currently based on Nucleic Acid Tests (NAT) for HCV RNA and HBV DNA. Validation study to evaluate the performance of HCV RNA and HBV DNA tests is currently ongoing.

Study Design

This is a cross sectional diagnostic accuracy study to determine the tests' sensitivity and specificity. This study shall employ a case control design. Cases shall consist of 450 subjects who currently have the target conditions (ie 150 each of anti-HCV+, HBsAg+ and anti-HIV+). Both cases and controls will be enrolled from participating Gastroenterology/Hepatology and Infectious Disease clinics as well as Dialysis centres. Validation of HCV RNA and HBV DNA tests among subjects who are POCT anti-HCV or HBsAg positive from public screening. This sub study consist of 300 subjects who are screened positive (based on POCT) from a pubic Hepatitis screening campaign or known cases on follow up visits from the clinical sites in Malaysia

Screening (monitoring) patients on regular dialysis for Hepatitis B and C transmission

NAT testing (HBV DNA, HCV RNA and HIV RNA) offers considerable advantages over above serology tests. NAT tests enable diagnosis of active infection (which provides the basis for initiating treatment) while antibody tests indicate only previous exposure. NAT not only eliminates transmission risk during window period, it is also more sensitive than serological tests and thus identifies more false negatives (besides occult infection). No less significantly, NAT will also identify false positives among those tested positive for HBsAg and ant-HCV. This could arise because patients may clear their infections spontaneously over time or because of cross-reactivity. The objective of this sub-study is to compare the performance of the use of bi-annual Lab based serological tests versus POCT and bi-annual NAT tests for monitoring patients on regular dialysis. Bi-annual instead of quarterly NAT is necessary to ensure the adoption of NAT will be relatively cost neutral to dialysis providers, an important consideration in our low reimbursement resource limited setting.

Study Design

The study comprises 2 parts as follows:

  1. The first part is a cross sectional diagnostic accuracy study to determine the false positive (FP) rates of serology based tests among current patients. Cases shall consist of 250 subjects on regular hemodialysis (HD) who currently have the target conditions (100 ach of anti-HCV+ and HBsAg+, and 50 anti-HIV+) as ascertained by prior positive labs. Cases will be enrolled from participating Dialysis centres in Malaysia.
  2. The second part is non-randomized self-controlled cohort study designed to compare current approach (lab based serological tests only) versus a novel approach using combination of POCT and NAT to monitor for HIV, HBV and HCV transmission. The study cohort shall comprise of 1000 patients enrolled from HD centres who shall undergo monitoring for 2 years using a combination of bi-annual lab based versus POCT anti-HCV, HBsAg and anti-HIV tests, and bi-annual NAT tests (HBV DNA, HCV RNA, HIV RNA).

This is a cross sectional diagnostic accuracy study to determine the tests' sensitivity and specificity.
This study shall employ a case control design. Cases shall consist of 450 subjects who currently have the target conditions (ie 150 each of anti-HCV+, HBsAg+ and anti-HIV+). Both cases and controls will be enrolled from participating Gastroenterology/Hepatology and Infectious Disease clinics as well as Dialysis centres. Validation of HCV RNA and HBV DNA tests among subjects who are POCT anti-HCV or HBsAg positive from public screening. This sub study consist of 300 subjects who are screened positive (based on POCT) from a pubic Hepatitis screening campaign or known cases on follow up visits from the clinical sites in Malaysia


Screening (monitoring) patients on regular dialysis for Hepatitis B and C transmission

NAT testing (HBV DNA, HCV RNA and HIV RNA) offers considerable advantages over above serology tests. NAT tests enable diagnosis of active infection (which provides the basis for initiating treatment) while antibody tests indicate only previous exposure. NAT not only eliminates transmission risk during window period, it is also more sensitive than serological tests and thus identifies more false negatives (besides occult infection). No less significantly, NAT will also identify false positives among those tested positive for HBsAg and ant-HCV. This could arise because patients may clear their infections spontaneously over time or because of cross-reactivity. The objective of this sub-study is to compare the performance of the use of bi-annual Lab based serological tests versus POCT and bi-annual NAT tests for monitoring patients on regular dialysis. Bi-annual instead of quarterly NAT is necessary to ensure the adoption of NAT will be relatively cost neutral to dialysis providers, an important consideration in our low reimbursement resource limited setting.

Study Design

1. The first part is a cross sectional diagnostic accuracy study to determine the false positive (FP) rates of serology based tests among current patients. Cases shall consist of 250 subjects on regular hemodialysis (HD) who currently have the target conditions (100 ach of anti-HCV+ and HBsAg+, and 50 anti-HIV+) as ascertained by prior positive labs. Cases will be enrolled from participating Dialysis centres in Malaysia.

2. The second part is non-randomized self-controlled cohort study designed to compare current approach (lab based serological tests only) versus a novel approach using combination of POCT and NAT to monitor for HIV, HBV and HCV transmission. The study cohort shall comprise of 1000 patients enrolled from HD centres who shall undergo monitoring for 2 years using a combination of bi-annual lab based versus POCT anti-HCV, HBsAg and anti-HIV tests, and bi-annual NAT tests (HBV DNA, HCV RNA, HIV RNA).

Statistical Analysis

For each POC screening test included in the sub-study on diagnostic accuracy, we shall construct 2X2 contingency tables in which all subjects are classified as having positive or negative POC screening test and as having known chronic HCV or HBV. The table is used to evaluate the test diagnostic accuracy. For each POC test included, we estimate the test sensitivity, specificity, positive and negative Likelihood Ratio and diagnostic odds ratio (DOR). Sensitivity is the proportion of people with disease who have a positive POC screening test result [3], specificity is the proportion of people without disease who have a negative test result[3], the positive LR is the ratio of the likelihood of a positive test result when the disease is present to the likelihood when it is absent, which tells us how much more often a positive test result occurs in those with the condition than in those without [4], the negative LR is the ratio of the likelihood of a positive test result when the disease is absent to the likelihood when it is present, which tells us how much more often a negative test result occurs in those with the condition than in those without [4]. A positive LR higher than 5 and a negative LR less than 0.2 provide strong diagnostic evidence [5].

We also estimate the DOR which is the ratio of the odds of a positive result when the disease is present to the odds of a positive result when the disease is absent [6]. The DOR is a measure of diagnostic test performance that accounts for the fact that sensitivity and specificity are negatively correlated. We estimate the 95% confidence intervals (CIs) for the sensitivity, specificity, LR and DOR based on normal or Poisson approximations to the binomial distribution, as appropriate [7].

References

  • Malaysia National Renal Registry. Annual Reports of the Malaysian Dialysis and Transplant Registry 2010. Available at: http://www.msn.org.my/fwbPagePublic.jsp?fwbPageId=pPublications
  • Commission decision of 7 May 2002 on common technical specifications for in vitro-diagnostic medical devices (notified under document number C (2002-1344) 2002/364/EC. Official J Eur Commun 2002:L131/17- 30.
  • Altman DG, Bland JM. Diagnostic tests 1: sensitivity and specificity. BMJ. 1994;308:1552.
  • Deeks JJ, Altman DG. Diagnostic tests 4: likelihood ratios. BMJ. 2004;329: 168-9.
  • Jaeschke R, Guyatt GH, Sackett DL. Users' guides to the medical literature. III. How to use an article about a diagnostic test. B. What are the results and will they help me in caring for my patients? The Evidence-Based Medicine Working Group. JAMA. 1994;271:703-7
  • Glas AS, Lijmer JG, Prins MH, Bonsel GJ, Bossuyt PM. The diagnostic odds ratio: a single indicator of test performance. J Clin Epidemiol. 2003;56: 1129-35
  • Fleiss J. Statistical Methods for Rates and Proportions. 2nd ed. New York, NY: John Wiley & Sons Inc; 1981

Synopsis: Epidemiology of Hepatitis C in Malaysia

Protocol number: HR2017-01

The study protocol was approved by the Medical Review and Ethics Committee (MREC), Ministry of Health Malaysia on the 21st February 2017

Title: Community screening and Prevalence of Hepatitis C and B in Malaysia based on low cost Point of Care Screening tests.

Number of subjects for Hepatitis prevalence study 100,000
Anticipated dates: Study initiation March 2017
Prevalence study closeout March 2020
Screening Test performance study closeout Sept 2017
Planned duration of study: 40 months

Objectives

The objective of this community based cross sectional survey is to determine the prevalence of HCV and HBV in Pahang and other states of Malaysia in conjunction with a Hepatitis screening campaign to be organized by Hepatitis Free Pahang Foundation (HFP) and Hepatitis Free Malaysia Society (HFM).

The screening shall utilize low cost Point of Care screening tests. These tests will be subject to a diagnostic performance evaluation to be implemented within this protocol. Results from the POC tests' performance will determine whether a test is suitable for use when scaling up the mass screening campaign.

Study Design

The study shall be based entirely on secondary data which will become available from a Hepatitis screening campaign to be conducted throughout Pahang and other states of Malaysia between 2017 and 2020.

Eligible subjects in this population shall be alerted through communication channels including traditional mass media, social and digital media and advertising, as well as through HFP/M organized events such as campaign launch, public forum, health exhibition, fund raising dinner and so on. Subjects who respond to the campaign and come forward for the screening test therefore constitute a non-random convenient sample for the prevalence study.

The screening test will be conducted opportunistically on eligible subjects who attend the aforementioned campaign related events as well as on those who walk-in to HFP/M screening centres as well as to participating primary care (GP) clinics, pharmacies and dialysis centres. The screening shall primarily target HCV, HBV for those without history of vaccination, and HIV only for individuals at high risk of co-infection such as intravenous drug use (IVDU). The screening shall utilize available low cost Point of Care (POC) anti-HCV, HBsAg and anti-HIV screening tests.

Study population

The study population consists of adults aged 21 or above who come forward for hepatitis screening tests during the Hepatitis Screening campaign to be organized by Hepatitis Free Pahang Foundation and Hepatitis Free Malaysia Society (HFM) between 2017 and 2019.
There are no other eligibility criteria.

Statistical methods

Sample size and power considerations

The sample size calculation has taken into consideration the known values from the literature of the parameters to be estimated (anti-HCV prevalence 2%, HBsAg prevalence 1.5%) and the accuracy and the level of confidence which we are willing to accept.

The table shows the precision to be expected in estimating HCV and HBV prevalence based on given sample sizes. Precision figures were reported in terms of 95% exact binomial confidence intervals. For the sample size of 100,000 subjects to be screened, a prevalence of 2% can be estimated with a 95% confidence interval of 1.9-2.1%.

Statistical Analysis

Continuous variables will be described by summary statistics such as mean, median, standard deviation and cumulative percent. Categorical (nominal/ordinal) variables are summarized by the frequencies of each category.

Logistic regression will be used to estimate the effects of covariates on HCV and HBV prevalence levels. The model shall include age, sex, ethnicity, education level, social class, urban-rural residence and known risk factors (IVDU, family history). The level of significance is set at 0.05.

PATIENT REGISTRY FOR CHRONIC HCV AND HBV

Protocol number: HR2017-01

The study protocol was approved by the Medical Review and Ethics Committee (MREC), Ministry of Health Malaysia on the 21st February 2017 The objectives of the registry are to determine the clinical effectiveness of personally imported generic Anti-Viral drugs which shall be measured by sustained Virological Response (SVR) rates, at 12 and 24 weeks post treatment for HCV and anytime for HBV. A secondary objective of the registry is to serve as an active surveillance system to monitor the safety of generic Anti-Viral drugs through early detection of the occurrence of expected and unexpected adverse events associated with generic drugs

Study Design

This is a multi-centre, observational cohort study designed to evaluate the health outcomes of patients treated with imported generic Anti-Viral drugs for chronic HCV and HBV. All patients treated with generic Anti-Viral drugs who meet eligibility criteria will be enrolled into the registry. The inclusion criteria are deliberately broad and include all treated patients. Patients shall be followed-up for a minimum period of 6 months for HCV and 5 years for HBV


Synopsis: Patient Registry for chronic HCV and HBV.

Protocol number: HR2017-01
The study protocol was approved by the Medical Review and Ethics Committee (MREC), Ministry of Health Malaysia on the 21st February 2017

The objectives of the registry are to determine the clinical effectiveness of personally imported generic Anti-Viral drugs which shall be measured by sustained Virological Response (SVR) rates, at 12 and 24 weeks post treatment for HCV and anytime for HBV. A secondary objective of the registry is to serve as an active surveillance system to monitor the safety of generic Anti-Viral drugs through early detection of the occurrence of expected and unexpected adverse events associated with generic drugs

Study Design

This is a multi-centre, observational cohort study designed to evaluate the health outcomes of patients treated with imported generic Anti-Viral drugs for chronic HCV and HBV. All patients treated with generic Anti-Viral drugs who meet eligibility criteria will be enrolled into the registry. The inclusion criteria are deliberately broad and include all treated patients. Patients shall be followed-up for a minimum period of 6 months for HCV and 5 years for HBV.