[Question #868] 3rd or 4th Generation Window Period Studies/Publications

74 months ago
My question has pertains to the inconsistent information on window periods online. I'm well aware of the various national guidelines across the world, most of which state 3 months. On the other hand, many specialists claim 28 days or 6 weeks for >99% reliability, presumably for good reason. (I imagine they're basing this off published studies.)  

Would you be willing to direct me to some published window period studies? What are the names of some of the published studies? They're surprisingly hard for me to find. 

Thanks for any help with this.

H. Hunter Handsfield, MD
73 months ago
Welcome to the forum. Thanks for your question. It's an important one, and although we have addressed it previously on this forum, this provides an opportunity for a blog-like response that we can use in response to similar questions in the future. I apologize in advance for its length; it may be more information than you need. But here goes.

The data are "surprisingly hard to find" because they don't exist or have not been published. The best available data often are buried in the studies done by test manufacturers prior to FDA approval and don't necessarily see the light of day in scholoarly publications. But even these data are not precise. Scientifically rigorous research to determine exact window periods is essentially impossible from practical, ethical, and cost perspectives. It would require a large number of persons known to be exposed at a particular time, not treated with PEP (in some cases despite very high risk exposures), then regular testing (at least once a week) for 2-3 months. And it would have to account for all the different types of exposure:  different sexual practices, with and without condoms, with and without ejaculation, duration of penetration, viral load in the infected partner, and so on. So we should expect that scientifically rigorous studies will never be done.

Further, this is not considered a very important topic among most experts. For the large majority of HIV testing, the time since last exposure is not an important consideration, i.e. in people generally at risk (or not at risk at all, i.e. routine testing regardless of risk) but with no particular exposure in mind either by the person being tested or the doctor or clinic doing the testing. Serious concerns about window period occur in a small minority of all HIV testing, although it can seem otherwise based on the kinds of concerns that are common on this and other forums or online resources.  So even if accurate research were practical, it wouldn't be a priorty.

In the absence of definitive data, window period advice is based primiarly on biological principles, which is our tendency on this forum. We have good data on time after exposure when HIV antigen or RNA are detectable, and when measurable antibodies appear. On this basis, the 4th generation tests are virtually always positive within 4 weeks and remain positive thereafter for the life of the infected person. It is also the case that there are few if any published case reports of people with negative test results at 4+ weeks who were later found to have HIV; and all the HIV/AIDS experts we know also say they have never seen this in any of their patients. The same sorts of considerations apply to combinations of tests, such as when an RNA test is done at say 2 weeks and a standalone antibody test is done at 4 weeks.

On the other hand, some experts and agencies are unfortable standing only on these biological principles and hold out for more definitive data, without which they take consiervative stances. Often there also is a tendency to not change previous guidelines unless and until new data conclusively prove that information was wrong, which explains why 3 months remains a commonly accepted standard, based on older standalone antibody tests. And health departments and other governmental agencies also tend to take conservative stances, preferring to err on the side of longer advice about window periods. CDC is in this category.

I hope this has helped. Let me know if anything isn't clear.


73 months ago
Thank you for taking the time to give such a detailed (and incredibly helpful) response. This all makes a lot of sense.

After *countless*, and I mean countless, hours of research, I have come across a few studies that may be helpful both to others and myself on this matter. (These studies don't have the exactitude of type you're talking about--I imagine for the very reasons you give, impracticality, impossibility, etc.--but they may still be useful.) Furthermore, they seem fairly consistent with the 28 day figure you and other specialists quote. I'd be curious to get your thoughts, should they be taken seriously, etc.?




Anyway, I apologize if this is too involved for a follow-up question, I was just curious what a specialist on the matter thought of these. 

Thank you again for your help.

H. Hunter Handsfield, MD
73 months ago
Thanks for the follow-up comments.

The first study is very good, from highly respected investigators, and quite relevant, having included the Ag/Ab combo test (4th generation). The second was well done, but 20 years old, looking at older (1st or maybe 2nd gen) testing and iof marginal relevance to most HIV testing today. Both are based on "seroconversion panels" of blood specimens, usually 1 to 3 specimens on particular patients who had negative HIV testing at some point in time then later became positive, usually (I believe) with a stated date of probable exposure. The intervals of follow-up testing are quite variable, nowhere near the standard I suggested above, such as weekly testing for several weeks. And most people with new HIV infections have had several possible exposure often inaccurately judge which one was the source. Sometimes the exposure is known with certainty, such as new infection following blood transfusion, but I suspect that in most seroconversion panels these are a small minority. The bottom line is that a lot of statistical extrapolation is necessary to come up with the results. The results aren't necessarily unreliable, but they are less precise than might be assumed, especially if you read only the abstract or a one-line summary of the work.

The third citation is simply a policy statement from Sweden's national public health agency, describing why they now recommend 6 weeks as the recommended window period on which to counsel patients undergoing Ag/Ab HIV testing. Not 4 weeks as some experts would recommend, but very different than CDC's continued advice about 3 months.

Regards--  HHH, MD

73 months ago
Thank you again for your helpful reply. 
I had one more question I was hoping you could help with: 
I took both a 4th generation lab test and a PCR RNA test at 28 days, both were negative.
I planned on taking a follow-up 4th generation at 6 weeks. 

I understand many experts factor in risk when assessing the reliability of a test. However, would you say these tests will conclusively rule out HIV, regardless of risk? 

H. Hunter Handsfield, MD
73 months ago
There is no point in having another 4th generation blood test at 6 weeks. The combination of tests you had is absolutely conclusive evidence you don't have HIV. It simply is not possible to be infected and not have HIV RNA detectable in the blood by PCR; and the combination of that, plus negative HIV antigen and antibody at 4 weeks, makes it impossible you caught HIV 4 weeks earlier. Of course you are free to be tested as many additional times as you like. But if somehow I were in your situation, I would not do it and by now would have resumed unprotected sex with my wife without worry I could infect her.

That completes the two follow-up questions and replies included with each new question, and so ends this thread. Thanks again for your confidence in our services. Best wishes and stay safe.