HIV Guidelines: Some Evolve; Some Don't. What's Up With That? Part One

Among the most common questions cramming their way into my inbox at the HIV Prevention and Safer Sex Expert Forum are an impressively wide spectrum of concerns about HIV-diagnostic testing. Everything from the very basic -- "to test or not to test; that is the question" (a favorite of Shakespeare aficionados) -- to the ridiculous -- "Grandma farted getting out of the barcalounger. I think I smelled an HIV-charged fart. Should I get an AIDS test?" In between these extremes are HIV-diagnostic-testing conundrums, such as:

"Is the three-month window period calculated as 90 days (three months x 30 days per month) or 84 days (12 weeks x seven days per week)?"

"Which test should I take -- ELISA, EIA, Rapid, Western Blot, qualitative PCR DNA or quantitative PCR RNA?"

"What is pooled NAAT testing and how does it work?"

"Should I test using blood, urine or oral fluids?"

"What's the difference between confidential and anonymous HIV testing?"

"Do I have to worry about delayed seroconversion, and what about rare or emerging strains?"

"What causes false-positive, false-negative and indeterminate results?"

"What is the difference between older HIV-antibody tests and the newer generation assays?"

Needless to say confusion abounds on many levels! It is not feasible for me to address all these topics in detail in this blog without totally congesting the information superhighway and getting carpal tunnel syndrome from excessive keyboarding. (Note to readers: Most of the above topics I've discussed at length by responding to questions now posted in the archives of the HIV Prevention and Safer Sex Expert Forum.) What I will attempt to address here are some of the evolving technologies that are guiding emerging new strategies in the field of HIV-diagnostic testing and how these emerging new strategies affect HIV guidelines.

Let's begin with a rather startling fact: The United States Public Health Service HIV-testing-algorithm guidelines have not changed substantially since they were first devised in the late 1980s, even though new and improved diagnostic-testing technologies have been developed and are currently in widespread use. It's interesting to compare the static HIV-testing guidelines to the guidelines for when to start antiretroviral therapy, another field of HIV medicine in which there has been significant development and now widespread use of new-and-improved technologies (new and novel antiretroviral agents). While there has been no substantial change in the testing guidelines, the when-to-start guidelines have changed rather dramatically multiple times over the past 25 years. When the first effective antiretroviral drugs were discovered, our initial treatment mantra was "hit early; hit hard." Highly active antiretroviral therapy (HAART) showed great promise. However, we soon learned more about HIV-drug resistance leading to treatment failure. HAART (rather embarrassingly) became FAART (fairly active antiretroviral therapy).

Complicating matters further was the gradual recognition of unexpected and bizarre drug-related side effects and toxicities. This led the treatment-guidelines pendulum to swing in the opposite direction, and the mantra became "treat when CD4 counts drop to dangerous levels." Next, new antiretrovirals were added to the drug armamentarium that provided additional and safer treatment options. Our treatment mantra evolved to "hit wisely." Today we have over 30 antiretroviral drugs or fixed-dose combinations from six classes, each class having its own unique mechanism of action to battle HIV.

As new and novel, better-tolerated therapies have come online and we have learned more about the natural history and immunopathology of HIV disease, our mantra is now "hit earlier (CD4 of 500 or less) and hit wisely (use resistance testing to guide therapy)." The treatment pendulum has swung back toward early intervention. Many HIV specialists, including your author, have evolved beyond the most current federal guidelines and now recommend starting antiretroviral therapy as soon as the diagnosis of HIV positive is made, even if the CD4 count is above 500, in order to preserve immune function and decrease damaging immune activation/inflammation. The point here is that federal guidelines that address when to start treatment have changed dramatically over the years, based on our improved understanding of HIV coupled with the development of new and novel antiretroviral therapies.

So why are the HIV-diagnostic testing guidelines still stuck in the Reagan Era? Excellent question!

So that this blog doesn't become a tome rivaling War and Peace in length, let me focus on just a few aspects of HIV-diagnostic testing -- the so-called window period and the detection of acute HIV infection.

Window-period confusion is a great source of frustration and anxiety when getting HIV tested. The window period is defined as the time during which markers of HIV infection are not detectable in a person infected with the virus. In other words it's the time between becoming infected with HIV and being able to detect that infection with HIV-diagnostic tests: HIV antibodies, p24 antigen or NAAT/PCR/RNA. The window-period length for each of these tests (and different generations of these tests) varies based on sensitivity and specificity and which component or marker of HIV they are measuring (i.e., direct measurement of the virus with NAAT/PCR/RNA versus an indirect measurement of infection via detection of anti-HIV antibodies). Adding to the confusion is a natural variation in the time it takes for different individuals to produce detectable antigen and/or antibodies and complications arising from concurrent illnesses and the use of certain medicines that can affect some of the diagnostic tests. It should become apparent that making definitive statements about the exact length of "the window period" is extremely challenging, if not completely impossible! Making this situation even more murky is the fact that guidelines and recommendations defining the window period are not consistent or clearly communicated. Some take into account the newer realities of the improved testing assays; others do not.

I can just about hear many of the anxious folks in the throes of their "window pain" who are reading this blog begin frantically typing questions to me, such as "but Dr. Bob, why can't scientists just determine the precise duration of the window period for each type of test?" Okay, let me try to explain. To be calculated accurately, researchers would have to know the precise date that person was exposed to HIV, and then have multiple serial blood samples to test with different testing assays (NAAT/PCR/RNA, p24 antigen, anti-HIV antibodies). Even if we had this data, the best we could come up with would be an average number of days during which specific tests were not able to detect infection.

The key variables remain:

  1. Individual variations in immune response to the virus;
  2. Rarely known precise dates of exposure; and
  3. Confounding factors, such as concurrent illnesses, the use of certain medications and possible variations due to viral strain and route of exposure.

Even designing research studies to try to definitively answer the question of the exact duration of the window period would be challenging, due to the scope and number of these variables and the need to have multiple serial blood samples.

What we know for certain is that HIV RNA is the first measurable marker of HIV infection. The gap between acquiring HIV and the first detection of HIV RNA is sometimes referred to as the "eclipse phase." Viral replication during this period occurs principally at the site of infection.

Early diagnosis of HIV disease is of particular public health importance, because recently infected positively charged folks who aren't aware of their HIV-positive status often have sky-high HIV viral loads, because they obviously are not on antiretroviral treatment. High viral loads are associated with high infectiousness. This explains the disproportionate number of new HIV infections traced to HIVers who have acquired the virus very recently.

Stay tuned for part two of this blog in which I discuss the various HIV-diagnostic tests currently available and the evolving guidelines for diagnosing recent HIV infection, and make some summary comments on window periods.

Want to get in touch with Dr. Bob? You can reach him through his "Ask the Experts" forum, by sending a message to the Robert James Frascino AIDS Foundation, or by leaving a comment for him below. (If it's a private message, or if it includes personal info such as your e-mail address or phone number, we won't post the comment, but we will send it along to him.)