HIV and ID Observations

Mostly, HIV testing works great. It’s long been so accurate that we can strongly support HIV testing even in relatively low-risk people.

The 2014 revised lab testing guidelines made it even better, recommending a combined antigen/antibody screening test (called the 4th generation test), and replacing the Western blot with the HIV-1/2 differentiation immunoassay as the preferred confirmatory test.

However, if you’re a primary care, ID/HIV, or OB/GYN clinician who sends a lot of HIV tests, you’ve no doubt received the following perplexing result::

4th Generation Human Immunodeficiency Virus (HIV) Combination Antigen/Antibody:  Repeatedly Reactive

HIV-1/2 Antibody Differentiation Immunoassay:  Negative

Interpretation:  INDETERMINATE for HIV-1/2.

There are many problems with this outcome, which is common enough that it turns out to be the most common question about HIV testing by far. But three years have passed since I last addressed it, so let’s explore again and figure out how to fix it.

First, the reasons it’s so problematic:

1. In patients at high risk for HIV, this is a critical result that should prompt rapid action. An indeterminate result with a positive HIV screen and negative HIV-1/2 differentiation assay could be acute HIV — patients may be in the “window” period before they have developed a sufficient antibody response. Why? It’s worth remembering that when we moved from the 3rd- to the 4th-generation screening test, we shortened the window period by adding p24 antigen to the screening test only. It’s now around 14 days after HIV acquisition. By contrast, the confirmatory differentiation test still only detects antibody. Window period for this test? A median of 33 days. And that difference may occur exactly when people with acute HIV are most symptomatic. Bad.
2. In patients at low risk for HIV, this is a confusing result that almost never means anything and prompts only worry. Since we appropriately do a lot of HIV testing in low-risk people — especially pregnant women — the prior probability that they actually have acute HIV is extraordinarily low, especially if they are asymptomatic. The screening test’s 99.6% specificity is great (Lyme testing is jealous). But this means that around 4/1000 times, the HIV test will be positive even in a person without HIV — the prevalence of acute HIV in most screened populations is way lower than that. As a result, in many centers (including ours), most of the reactive HIV screens with negative confirmatory tests ultimately end up being false-positive screens.
3. Sorting out what your patient has — acute HIV or a false-positive HIV screen — is straightforward medically, but far from easy from a logistical perspective. Sure, a subsequent negative quantitative HIV viral load means it’s a false positive, and a positive one (at pretty much any value) indicates acute HIV — simple to interpret medically. But try explaining that to a worried patient on the other end of your notification phone call, or telling them they have to come back in for another test to just be sure that your impression (whatever it may be) is correct. With so much testing done today as a matter of routine screening, we might end up having to do some of the risk assessment over the telephone, a distinctly uncomfortable scenario — especially tricky in an era when lots of our communication is via “patient portals” or some other non face-to-face method. Notably, some labs will “reflex” their indeterminate tests to a qualitative HIV nucleic acid test (NAT), but in discussion with my colleagues around the country, this is far from routine.
4. Most medical centers can offer turnaround on a quantitative HIV viral load far faster than the HIV differentiation assay. This is particularly true if the screening test is done at your hospital’s lab, with reactive tests then sent to a reference laboratory. In our hospital, for example, when clinicians suspect acute HIV — patient may be at risk, or have symptoms — they often appropriately send an HIV viral load at the time of initial presentation. We then have this bizarre outcome where the HIV screen returns positive, the viral load comes back very high within a couple of days, and then — after a 3 or 4 day further delay — the differentiation assay return negative. In one such case, the HIV resistance genotype was also ordered at baseline, and it came back before the (negative) differentiation test!
5. The tests are a nonsense word salad smothered with Thousand Island dressing. Read that result at the top in its entirety — what a bunch of gobbledygook. Look, we ID/HIV specialists know what these words mean, but ask some primary care clinicians or obstetricians, they will have no idea. Or ask them what it’s like to enter “HIV” in the order box of their electronic medical record. Chaos! (See image on the right — click on it for the full effect.) It’s completely understandable why they might be confused — this isn’t their specialty. So read the tests again, and pity the non-ID specialists: 4th Generation Human Immunodeficiency Virus (HIV) Combination Antigen/Antibody.  HIV-1/2 Antibody Differentiation Immunoassay. Good grief. How about just, “HIV screening test” and “HIV confirmatory test”?

How can we fix this? As usual when it comes to HIV testing, we turn to the top expert in this area, Dr. Bernie Branson. Fortunately for all of us, he just wrote a sensational review of HIV testing for Infectious Disease Clinics.

Here’s what Bernie says:

With current technology, it would be more efficient to reverse the current confirmatory testing sequence and, after a reactive Ag/Ab combination assay, perform a quantitative HIV-1 RNA viral load test to both confirm the diagnosis and contribute to immediate clinical management.

Of course! Confirm the reactive screen with an HIV-1 viral load! How sensible! This will give us the most critical result much more rapidly.

A detectable (at almost any level) HIV-1 viral load would prompt immediate HIV therapy, important for reducing HIV transmission, preserving immune function, and possibly providing our best candidates for HIV cure strategies when they become available.

With a negative HIV-1 viral load, the HIV-1/2 antibody assay (done next) would pick up the small proportion of those who are elite controllers, or are on ART and haven’t told you (HIV-1 antibody positive, viral load negative); have HIV-2 (HIV-2 antibody positive); or just had a false-positive HIV screen (HIV-1/2 antibody negative).

And those worried about a (slight) delay in diagnosis for HIV-2? This will occur rarely — with the prevalence of HIV-2 in this country exceedingly low, a CDC scientist recently described the routine use of this test as “High Burden, Low Yield”. 

So what are the barriers to making this change a reality?

• There is no FDA-approved quantitative viral load test for HIV diagnosis. There is a qualitative HIV viral load test approved, but it is not widely available, requires plasma (see below), and a positive result would still warrant doing the quantitative test. According to Bernie’s paper, some are available internationally. Time to bring them here!
• Many labs draw serum, not plasma, when doing HIV testing. Available quantitative viral load tests have been validated on plasma only. This makes the “reflex” strategy cited above in item #3 impractical. Apparently, serum-based quantitative viral load tests are also available in other countries.
• Viral load testing is much more expensive. Tests considered “molecular” by payers cost a ton, even though the technology to do them has dramatically improved and become more efficient. This progress should theoretically make them more affordable, but some labs may be reluctant to give up the high price and revenues.

The above issues are not insurmountable barriers, but they will take time to overcome. But as an optimist by nature, I’m convinced this will happen — it just makes too much sense. And look, you apparently agree:

In the United States, the confirmatory test for a reactive HIV screen (e.g., a 4th gen antigen/antibody test) should be a quantitative HIV viral load–not an HIV-1/2 differentiation antibody. @HIVMA @IDSAInfo @CDCgov

— Paul Sax (@PaulSaxMD) October 6, 2019

Until then, we’re stuck with this strange situation where the “confirmatory” test ironically may not confirm anything at all — either during acute HIV, or when the screening test is a false positive.

Fortunately, it doesn’t have to be this way — time to make the change!