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False Negative HIV ELISA test

3rd generation ELISAThere are such things as False Negative HIV ELISA tests but they are very rare.

I have been pondering whether or not to write this article for a long time.

I finally decided to do it in the name of scientific truth and complete transparency.

What I do not want to happen is for this article to feed the unreasonable fear and paranoia that is already out there.

I want to state categorically that I still believe the HIV Combo test is 100% conclusive at 28 days post exposure and the HIV 3rd Gen ELISA Antibody test is 100% conclusive at 3 months post exposure.

Click here for more info on the HIV testing Window Period.

Note that the cases mentioned in this article are extremely rare, literally 1 in a million.

With all that in mind, let’s get into the topic proper.

Introduction

In the 1980’s when HIV was first discovered, we needed a way to determine if a patient was infected with HIV or not.

Out of this need was born the first generation ELISA test which tested for the presence of HIV specific antibodies in the blood. Over the years, these ELISA tests became more and more accurate. However, they all depended on one thing: the assumption that a patient who is infected with HIV will develop antibodies to HIV so that it can be detected in the first place.

Click here for more info on the Different Generations of ELISA tests

It was soon discovered that this was not always a valid assumption. There were instances where a person was infected with HIV but yet the ELISA test showed that he was not. This so called ‘False Negative’ ELISA test was initially blamed on the HIV Testing Window Period – the time from when a person is infected with HIV to when antibodies to HIV become detectable in the blood. However, we soon discovered that there were other, albeit extremely rare, causes of a False Negative HIV ELISA test.

Causes: 1. Window period  2. Non-Clade B Hypogammaglbulinaemia  3. End Stage AIDS  4. Hep C co-infection 5. Unkown (Sero-Negative HIV Infection)

The commonest cause of a False Negative ELISA – the testing Window Period

Initially, all cases of false positive ELISA tests were blamed on the testing window period. Till today, testing within the window period is still the commonest cause of a false negative ELISA.

The newer generation ELISAs can detect IgM antibodies which are produced much earlier than the IgG antibodies detected by older generation ELISA tests. This has significantly brought down the window period but it still hovers between 6 weeks to 3 months.

Click here for more info on the HIV testing Window Period.

Newer tests including the P24 and RNA PCR has made the testing Window Period even shorter. Furthermore, these 2 tests are not dependent on the presence of antibodies and therefore will still be positive in people infected with HIV but do not develop antibodies (sero-negative infections).

Click here for more info on the HIV Combo test
Click here for more info on the HIV PCR test

Non-Clade B HIV virus

Once the issue with the testing window period was worked out, another problem arose.

As most tests were developed in North America and Europe, most of the focus was on detecting Clade B viruses which were the most commonly found subtype in these areas.

As such, some HIV ELISA tests that were developed were not so sensitive in detecting non-Clade B viruses.

This problem was quickly picked up and nowadays, HIV tests are all designed to detect non-Clade B viruses.

Hypogammaglobulinaemia, Agammaglobulinaemia

This is an extremely rare cause of sero-negative HIV infection (i.e. infected with HIV but with no detectable antibodies in the blood).

Hypogammaglobulinaemia in itself is a very rare condition in which patients have a (frequently genetically induced) inability to develop antibodies. It is rarer still to find such a patient and infected with HIV.

To date, I know of only 1 reported case in the NEJM in 2005.

Sero-reversion in End-Stage AIDS

We all know that HIV destroys the immune system and eventually leads to AIDS.

At the very late stages of AIDS, the patient’s immune system may be so poor that he/she is unable to produce antibodies anymore.

The antibodies that were present in the blood then disappear. This is what we call sero-reversion (the disappearance of antibodies) as opposed to sero-conversion (the appearance of antibodies).

Patients in these situations are always extremely ill and the diagnosis of a HIV infection is made by RNA PCR viral load test.

Click here for more info on the HIV PCR test

Interestingly enough, when some of these patients are given HAART, their immune system comes back to life and they start producing antibodies again, leading to sero-conversion and positive ELISA tests.

Sero-reversion with HAART

Many people also ask about and are worried about sero-reversion with HAART.

This is extremely rare. There are 2 known case reports of such a phenomenon. This refers to months on HAART and should not be confused with PEP. So far, there have been no case reports of delayed sero-conversion or sero-reversion with PEP.

HIV and Hepatitis C Co-Infection

Co-infection with Hepatitis C can prolong the HIV testing window period up to 12 months.

Click here for more info on the effect of Hep C co-infection on the HIV testing window period

Unknown – Sero-Negative HIV Infections

This is what science cannot explain.

There are a group of people in this world, albeit extremely rare, who seem apparently normal in all ways but just do not develop antibodies against HIV when infected with HIV.

These people often progress rapidly into AIDS and are only diagnosed when they are in AIDS stage.

It is theorized that the problem is with the patients rather than the virus. This is because a genetically identical virus in a different patient can illicit an antibody response. In other words, if the same virus infects 2 different people, one will develop antibodies against it and not the other.

It has been theorized that this has something to do with the HLA make up of a person which determines how his/her immune system works. But to date, we do not really know what causes these patients to remain persistently sero-negative.

Although such cases has been described, they are very rare. Less than 1 in a million of HIV cases diagnosed.

How do we overcome this problem?

That is the golden question.

Unfortunately, many of these patients present in late stage AIDS because their diagnosis of a HIV infection has been missed all this while.

The 2 solutions we have are:

  1. P24 testing or Combo Test

These patients who do not develop antibodies against HIV will have a persistently high P24 level in their blood. So doing a P24 test will identify the infection.

This is very inline with the new HIV diagnostic testing Guidelines published in June 2014 by the US CDC which states that everyone should get a Combo test and not just an antibody test.

Click here for more info on the HIV Combo test
  1. RNA PCR (Viral Load) Testing

These patients who do not develop antibodies against HIV will have a very high HIV viral load. Often greater than 100,000 copies per ml.

There are 2 drawbacks with this test in Singapore:

  1. It is expensive ($600 to $700) in most clinics
  2. It cannot be done anonymously
Click here for more info on the HIV PCR test

In Summary

There are cases of people in this world who get infected with HIV but do not develop any antibodies. They therefore have persistently false negative ELISA tests.

These cases are very very rare.

There is no reason for you to doubt the ELISA tests that you have done. If your doctor tells you that your tests are conclusive and you do not have HIV, please accept that happy fact and move on.

If you cannot let go and require that added measure of reassurance, get a P24 test and/or an RNA PCR test.

If you still cannot let go, it is more likely you need psychological help rather than virological help.

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Related Articles:

HIV Window Period

HIV CMIA Test Accuracy

How long can HIV live outside the body

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Rapid Anonymous HIV Combo test at our Clinic

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About Dr. Tan
Dr. Tan graduated from the National University of Singapore in 2001. His residency was in the two largest public hospitals in Singapore; Tan Tock Seng Hospital and Singapore General Hospital.

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334 Comments

  1. Hi Dr.

    I had a risky contact on the 1st of October 2017 and tested on the 26th of November 2017, which is exactly 8 weeks after the exposure. The test type was ELISA, which was negative.

    From the 14th of October i have been having general illness, such as sore throat, which subsided after 2 sets of antibiotics, however, i developed white patches at the very back of the throat, which are still there today even after taking 2 sets of antifungal medication.

    I also had skin peeling on the hands, which subsided. There was no pain. The skin peeling then moved to the feet. It also almost gone there.

    Currently feeling mild leg muscle pains (on and off).

    Another woman sucked my penis on the 12th of November, now she has nausea and missed her period by 10 days, although a condom was correctly used on vaginal sex.

    Its reall confusing, please help.

    • I would consider your HIV tests conclusive. For your other symptoms, I would recommend you visit us for a proper consult and evaluation.

      • Thank you. Week 12 is approaching and will do the test as a formality and report back here if there’s abnormal results, so that it can be used further somehow.

  2. WorriedSick

    Hello Dr Tan,

    I had a p.24 combo test on day 16 and 18 which yielded a negative result. Checked really closely and no faint red line as well. I am now travelling at San Jose where is it pretty cold and i did not bring the adequete clothing so i have been out in the cold on and off.

    Today is the 22nd day since the suspected infection and i have started to develop fever 37.5, alittle backache, coughing with green phlegm.

    Should i be worried or have i just caught a cold?

    • I would not be too worried, as a common cold is infinitely more likely than HIV infection. However, your tests are not yet conclusive so if you are still concerned, best to repeat a test at 28 days or later.

  3. Hi Sir,

    I had a RNA PCR done on 8th day and it was undetectable. I had then the combo test ( antibody + P24 antigen test) on 18th, 22nd and 28th day. All were non-reactive. I then also had an ELISA done on 31st day. It was also negative. Are my results conclusive? Can I move on now? Please advise.

    Thanks

  4. Hi
    How r u sirs???
    Can explain in details Shety questions!!!
    I also find her questios r so so logic!!
    And u did not answer in details

  5. Good Day sir! You have mentioned p24 antigen will remain positive entire life for seronegative people and I know is extremely rare and very unlikely. I need a little more understanding about p24.

    1. If “I might say if” seroconversion(formation of antibodies) were to be delayed by ANY MEAN(any possible way such as HCV) the p24 still STAY DETECTABLE no matter how long it takes until antibodies were produced am I correct?

    2. p24 antigen will NOT disappear by itself no matter how long it takes BUT releasing antibodies in the body will make it disappeared(UNDETECTABLE) am I correct?

    3. Our body need to produce SUFFICIENT amount of antibodies to be detectable to make p24 antigen goes undetectable am I correct?

    Your time will be highly appreciated.

  6. I have heard may said that P24 will disappears once antibodies are formed. If antibodies never develpo I mean persist “seronegative”, will P24 still present in blood for 4th generation test to up after few years for someone who do not develop antibodies? I mean not in late AIDS stage.

  7. Hi Dr Tan I actually have a very confusing question. If let say a person antibody remain seronegative(No antibody develop) in HIV positive person will combo test become positive after many years since no antibody develop now can only rely on the P24 in combo test? I heard HIV antigen start to disappear for antibody develop case, what if no antibody is develop, will still P24 remain there for combo test to give a positive result after many years?

    • Theoretically, the p24 antigen will remain positive. But seronegative cases are extremely rare and there are usually pre-existing comorbidities.

      • Thanks for the reply Dr Jonathan, does p24 still remain positive(in blood) for years if let say HCV “delay” HIV antibody for 4th Generation to pick up the p24?

        Since the antibody was delayed by HCV.

  8. Hello sir..I tried to have anal sex with a woman..I don’t know her status..I put condom in my penis and poured coconut oil in her anus..I tried to insert inside her anus..but I cant..the condom teared..my penis was not inside her anus..is there any risk?? Also if my penis had a slight contact in her anus( for 2 sec) is there any risk..I had poured coconut oil..does it prevented me?..I’m confused.. please reply

    • Sounds like the risk would be negligible, but if you are concerned then just get checked. Coconut oil does not prevent HIV transmission.

      • I’m stressed fully..should I need to get a test compulsory.. because negligible gets me stressed because there is a chance..I’m planning to test a RNA PCR test after 10 days

  9. Saranyan

    Hello sir..I took HIV ab/ag combo test after 34 days post exposure (28 days I took pep)..on the same day I took RNA PCR qualitative test..they were all undetected…after 52 days post exposure (24 days post pep) I took Elisa which is non reactable..the result is test od: 0.045 and ref of: 0.201..result is non reactable..so can I start my normal life?? Stress is killing me

  10. Will P24 still able to detect in the blood for someone who do not develop antibodies? I mean in late AIDS stage will P24 still detechable in late AIDS stage?

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