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October 2008  
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Home - Knowledge - Article


NAT: Safe Blood, Safe India

NAT is the latest and safest technology available to reduce the risk of the HIV transmission through blood. Nancy Singh stresses on the need for adopting this technology

To avoid HIV practice safe-sex. To avoid HIV, Hepatitis B, C assure that you have been transfused blood that is certified 'safe'. Chances are high that you might have read statement number one, thousands of times, but winds of doubts loom large when it comes to concept of safe-blood. Thanks to the one-sided awareness campaigns on HIV, we all know the concept of safe sex, but when it comes to safe blood, there still exists half-baked or complete lack of knowledge - not only amongst the masses but the medical fraternity as well. "Protection of our country's blood supply is of critical importance. Such efforts are especially required in India where the prevalence of these infections is high and the risk of Transfusion Transmitted Infections (TTI) continues to increase," states Sumit Bagaria, President, Hemogenomics.

The numbers say it all. India is the second most populous nation in the world, with a population of more than 1.2 billion that includes 2.5 million HIV, 43 million Hepatitis B (HBV) and 15 million Hepatitis C (HCV) infected persons. All this just warrants the use of Nucleic Acid Testing Technology (NAT) - the safest and latest mode of blood screening technology.

Advantage NAT

NAT is a recently developed technology that allows detection of very small amounts of genetic material (DNA or RNA) by a process of massive copying (amplification) of a gene fragment. Since 1997, Food and Drug Administration (FDA) has encouraged the investigation of NAT technology through the use of experimental protocols, in the hope of improving the safety of plasma derivatives and further reducing the risk of an infectious unit of blood being transfused.

Currently, donors of blood and plasma are tested for antibodies to HCV, antibodies to HIV, and HIV-1 antigens, which are the virus' own proteins. However, there is still a 'window period' during which a donor can be infected, but will show negative screening tests. With the use of NAT for HCV, the 'window period' for detection of HCV is reduced by 67 days (from an average of 72 days to 5 days). For HIV-1, the average window period with conventional antibody tests is 22 days. Antigen testing cuts down the window period to approximately 16 days and NAT further reduces this period to 5.6 days.

NAT is used for the screening of HIV-1, HBV and HCV virus in donated blood. This test is the first simultaneous, single tube NAT solution for HIV-1, HCV and HBV. It is a direct test where it actually detects the viral nucleic acid (RNA/DNA). Being a direct test it reduces the window period of detection for all these three viruses from the current available serological (ELISA) tests.

NAT combines the advantages of direct detection of the organism with sensitivity several orders of magnitude higher than that of traditional methods. Currently, the screening of blood for infectious markers (anti HIV 1 and 2, anti HCV and HBsAg) is done using Government approved test kits like Elisa or Rapid kits.

In these tests, residual risk of TTI remains because of donors in the pre-seroconversion (window period), viral variants, non-seroconverting (immunosilent) or delayed seroconverting carriers (atypical seroconversion). "NAT along with conventional serological testing can reduce this residual risk to a great extent because it involves highly specific detection of an infectious agent with much higher sensitivity," says Bagaria.

NAT has been reported to detect infections earlier than serological testing by reducing the window period for HIV by 10-15 days, for HCV by 41-60 days, and by 17 -20 days in case of HBV. "Given the high rate of sero-positivity of HIV, HCV and HBV in India and keeping in mind the high percentage of first time and replacement donors, it is likely that adding NAT to the current screening tests will have a very significant reduction in TTI - making our blood safer," says Bagaria.

The Safest

NAT is a method of testing blood that is more sensitive than conventional tests. Whilst the conventional methods depend on antibodies to produce a positive result NAT is based on the genetic material. When an infection occurs, NAT is able to detect the low levels of viral genetic material present in the body. This happens before the body begins producing antibodies in response to a virus, giving the ability to detect a disease at an earlier stage.

The test begins with a number of blood samples, normally five to eight being 'pooled' collectively in the laboratory. If this pool contains a viral genetic material like HIV-RNA, it is amplified million of times in the molecular biology laboratory, so that it becomes detectable.

It is developed primarily from a molecular biology technique known as Polymerase Chain Reaction (PCR). It is a simple technique that is based on amplifying a template DNA (sample) using primers - a set of small DNA sequences. The design of the primers and additional factors like fluorescence, modifications etc determine the sensitivity and specificity of the PCR. "In NAT, the viral particles are lysed and then the viral nucleic acids are captured. The captured nucleic acids are then amplified to create billions of copies and specially prepared chemiluminescent probes get attached to the amplified products (amplicons). The chemiluminescent signal is measured by a luminometer and is reported as relative light units and shows the presence or absence of a particular viral nucleic acid," explains Bagaria. The presence or absence of the genetic material determines the infection and the amount of amplification signifies the extent or seriousness of the infection. Hence, it becomes an important tool for doctors to adjust the dosage of the medication depending on the extent of viral presence.

Apart from diagnosing infectious diseases like HIV, HCV, STDs, NAT also plays a major role in detecting tuberculosis and even in emerging tests for MRSA and respiratory viral infections. "NAT aids in identifying microbacterial, bacterial and fungal pathogens. This facilitates timely treatment of these diseases," says Wendy Bao, Regional Marketing Manager, Asia-Pacific, Chiron. In case of tuberculosis, the PCR technique has been designed such that it not only detects the bacilli but also determines the type of tuberculosis.

NAT is further useful in cancer and genetic testing. The PCR technique is instrumental in determining whether an HIV positive mother has infected her baby.

NAT Benefits
  • The India Multi-Centre study shows that NAT would pick up 1 in 1528 infected units which were cleared by Serology.
  • 1 year in Apollo Delhi shows a yield of 1 in 2700.
  • Based on this approximately 1 in 2400 units in India are still infected.
  • With 1 unit being transfused to up to 3 patients, NAT could interdict 7500 infections of HIV and Hepatitis B & C annually in India.

NAT vis-à-vis Traditional Tests

NAT which is categorically a nucleic acid assay, is helpful in monitoring a single cancer cell, microorganism, with as less as 50 copies of RNA /DNA (viral load). As compared to cultures or patient response, NAT provides a faster turnaround time which can be instrumental in starting the therapy early. Traditional diagnostic modes based on cell culture, antibody tests as well as symptom diagnosis take longer in contrast to NAT. When it comes to early diagnosis NAT is the answer. "The window period can be as short as two weeks to a few months. Not only it is highly specific but is sensitive as well and can pick up early infections," says N Vaghul, Board of Directors, Hemogenomics. Normally, in some cases, such as with the HCV, this "window period" could be on the average of 70 days.

Furthermore, antibody testing have a very high rate of false-positives which meant that even completely healthy donors sometimes are tested positive for these tests, as test manufacturers compromised test specificity to gain test sensitivity. The USP of NAT is that it is specific as well as sensitive at the same time! Hence, while HCV can be detected on average 60 days earlier and HIV can be identified on an average five days sooner.

NAT also has an edge in terms of throughput, cost and time. Automated NAT systems are available today that trigger very high throughput. "However, semi-automated modular systems are more cost-effective in the Indian context and have very few manual steps. One can test around 180 samples in less than seven hours with one set of instruments. The automated systems can do up to 1,000 tests per day," informs Bagaria. Another prime advantage of NAT is the Individual Donor Testing (IDT). According to Bagaria, pool testing reduces the sensitivity of a particular test.

IDT NAT has the advantage of highest possible sensitivity, minimum manpower, less capital cost and high throughput for releasing blood and blood products.

However, the catch is that NAT cannot act as a substitute for conventional tests but can only supplement or synergise with the existing ones to make the blood safer than ever.

Hard Facts
  • Population 1.2 billion includes 5.7(reduced to 2.5) million with HIV, 15million with HCV, and 43 million with HBV.
  • High blood donor seroprevalence of 0.5 per cent, 0.4 per cent, and 1.4 per cent for anti- HIV-1, anti-HCV, and HBsAg, respectively increases transfusion transmission risk of these viruses.
  • High percentage (50 per cent) of replacement donors compared to volunteer donors.
  • Fragmented Blood Banking System: Over 2200 government and private blood collection agencies, many of which have poorly regulated practices, collect 6 million donations annually.

The NAT Union

The application of NAT screening to the blood supply appears inevitable and various countries have implemented it. It is currently in use in most of the developed countries. Some of them include USA, Brazil, Canada, Australia, New Zealand, Japan, Singapore, Indonesia and Malaysia.

NAT screening for HIV and HCV is already prevalent. Many countries have also added HBV NAT and others are planning to add it. USA also added West Nile Virus (WNV) NAT to its blood safety programme. While most developed countries and many developing countries have added NAT as a layer of additional safety, other developing countries are now planning to do so.

"A look at the NAT experience of various countries in the SE Asia region shows that every country has been benefited from this technology. In Singapore, among the 466,779 samples tested by NAT since October 2000 were able to pick 9 HCV and 10 HBV NAT yield samples (1 in 24,567). Similarly in Thailand, Hong Kong and in Korea the NAT yield rate is 1 in 11, 676, 1 in 202,500 and 1 in 1, 46,628 respectively," informs Bagaria. Point to be noted is that these countries have a very stringent donor counseling and screening process, a high rate of regular repeat voluntary donation, and use the most sensitive serological tests, but still they were able to identify a significant number of samples which were NAT reactive/positive but sero-negative.

On the other hand, unlike most countries NAT is not mandatory in India. "There is lack of enough awareness about blood safety amongst decision makers in India. The ideal situation would be when the Government makes it mandatory but this is a far-fetched possibility. I believe it is every citizen's right to get safe blood" opines Bagaria.

There are a few institutes in India that have taken a step forward in the positive direction. Indraprastha Apollo Hospital, Delhi was the first one to opt for NAT. However, the adoption of this technology was more out of compulsion instead of choice, as it was sued and asked to compensate Rs18 lakh for a case of a HCV transmission. Nevertheless, in the first nine months of implementing NAT, they were able to detect five (three HBV and two HCV) NAT yield samples among 13,331 samples tested that is one in 2,666 samples.

In another case, a legal case has been filed against AIIMS by the parents of a nine year old cancer patient who was infected with HIV, through blood transfusion. In such a scenario of rising medico-legal cases, the importance of NAT increases manifold, wherein it can become an important tool to reduce HIV transmissions.

Challenges of Blood Screening in India

Blood Transfusion Services (BTS) in India are mainly hospital based and is governed by The Drugs & Cosmetic Act. There are about 2212 licensed blood banks (CDSCO) under different administrative controls i.e. Government 41 per cent, Voluntary 12 per cent, Private Hospital 22 per cent and Private/ Commercial 25 per cent.

"There is a wide gap in the demand and supply of blood as the annual collection is about 6 million against the demand of approximately 9 million. Blood collection from the voluntary blood donors constitutes only 50 per cent," laments Bagaria. Majority of voluntary donors are first time donors, as there is little concept of regular repeat voluntary blood donation. Each and every unit of blood is screened for HBsAg, anti HIV, anti HCV, malaria and syphilis as per Drugs & Cosmetic rules before issuing to patients.

Though paid blood donation is illegal in India, there is no strong monitoring or expert donor counseling in many blood banks. The prevalence of HIV, HCV and HBV among the blood donor population is 0.5 per cent, 0.4 per cent, and 1.4 per cent respectively. Most of the blood banks use serological screening methods for the infectious marker screening. According to Vaghul, most of these serological tests are not sensitive enough and very few blood banks use the more sensitive third or fourth generation serological tests to screen the viral markers. Majority of the blood collected is used as whole blood, as blood component preparation is just 15-20 per cent. "Increased voluntary donation, availability of safe blood, component preparation and optimum utilisation of blood products are the key needs," feels Bagaria.

Experts opine that with increased awareness of patients rights the Government as well as the healthcare community will have to take some stringent steps to assure blood safety and one solution seems to be centralisation. Agrees David Nichols, Senior Director Asia-Pacific -Scientific & Regulatory Affairs, Chiron, "Centralised NAT screening centers are hugely successful all over the world and may as well be the answer for implementing NAT in India. A centralised testing site where all the blood banks of that city will send samples and after testing results can be send electronically to respective blood banks. This model has worked very well in Thailand which has a fragmented blood banking system like India."

If market places like Thailand which have similar models of functioning can afford to improve their quality of blood, then there is probably no reason why India cannot. As they say, where there is a will there's a way.



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