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HELP! subtypes of group M and also group O
Dec 21, 2006

Hi Doc,

My understanding is that standard testing (i.e. ELISAs) and Roche PCR & bDNA do not necessarily detect ALL subtypes of HIV-1 group M and also group O.

In a clinical setting suggestive of HIV infection AND where there is progressive decline in CD4 counts (absolute, percentage and ratio) - which is admittedly a VERY RARE case - what further tests would you recommend?

My understanding is that sending a plasma sample off for resistance testing might shed some light on the case because it uses different amplification primers.

Would you advice this / anything else?

Response from Dr. Sherer

Many questions and issues lend themselves well to this internet forum, and most HIV clinicians believe that people living with HIV infection and at risk of infection should be as well informed as possible about their risk and/or their illness. While the subject of the management of suspected HIV infection in the presence of a negative HIV antibody test is no exception, it is a good example of a situation in which no lay person should venture independently, i.e. without the ongoing active participation of a knowledgeable HIV clinician.

One reason that I stress the above is that the circumstances that you have described, i.e. in which HIV infection is present but not detectetd by standard assays in the current era - is quite rare, as you suggest. For every one of such patients - and most HIV clinicians may have never seen such a case - there are scores, or perhaps hundreds, of individuals who are at risk of HIV infection and who are unable to accept a repeatedly negative HIV antidbody test, for a variety of reasons.

As a general rule, following a possible exposure to HIV, I encourage patients to follow the current recommendations for HIV testing at 3 and 6 months, and to consider the 6 month test to be definitive. For patients who seek a higher level of certainty, another test at 12 months can be done, but thereafter, without an additional reason to repeat testing, I encourage them to accept the test result that they are not HIV infected. I and many HIV clinicians have had experience with patients for whom the anxiety about the possibility of infection is overwhelming and long lasting; such patients may undergo years of repeated HIV testing. I try to help such patients with more frequent visits and referral for counseling.

To return to the question; the actual frequency of negative HIV antibody tests due to non-type M and sub-type O tests in this era is rare, as the latest generations of HIV antibody tests do detect these antibodies. Even in a study in the US in 1996, four of five commercial assays detected O strain infections during a small outbreak in the US.

Two other clinical diagnoses should be considered in such a circumstance. First, HIV-2 can mimic some features of HIV-1 infection, and 20-30% of cases may be missed by some standard assays. There is also a rare 'T-lymphocyte depletion syndrome' that has been described in the absence of documented HIV infection which would also be a consideration in such a circumstance.

Options available to clinicians if HIV infection is strongly suspected in the presence of repeatedly negative ELISAs are to request a repeat HIV antibody test with an alterate ELISA kit than is usually used in the reference lab; this is a simple, inexpensive step that may eliminate the need for more elaborate activities. A standard HIV PCR should also be done with the latest generation tests, since acute HIV infection may occassionally explain this clinical circumstance.

If these tests are also negative, and the suspicion strongly remains, then the caveats above apply, i.e. you, your clinician, and an experienced HIV physician should assess the clinical situation and proceed accordingly. Options then should include a genotype resistance test, and a sequencing of the virus to determine the clade; in most cases, this further testing and investigation should be done collaboratively with the CDC or state health department or a reference HIV virology laboratory. CDC would also perform a wider range of antibody and HIV PCR tests to determine the HIV sub-type IF HIV infection is indeed found to be present.

Let me emphasize again that these suggestions should only be considered and acted upon with a physician, and that the actual number of such instances is very infrequent; for example, in the type O outbreak mentioned above in the US, a review noted 91 type O cases out of 590,000 HIV cases in the US in 1996.

I will end by quoting the MMWR recommendations in the event that such cases are suspected: "The recognition of this case of HIV-1 group O infection and the potential for emergence of other highly divergent strains underscore the importance of maintaining active surveillance for HIV variants at local, national, and global levels (6,7). To improve surveillance for and characterization of divergent HIV strains, CDC has established a domestic and global monitoring program for divergent HIV strains that are not reliably detected by the FDA-licensed tests.

Patients who present with clinical or laboratory findings suggestive of HIV disease, but for whom HIV screening tests are negative or equivocal, should be evaluated with further diagnostic tests to rule out HIV infection. Physicians evaluating such patients should consult with their state or local health department for assistance in characterizing risks for HIV exposure, defining prior history of blood donation, confirming the diagnosis of HIV infection, contacting sex partners, and, if necessary, characterizing the HIV strain."

Fluctuating CD4
Viral loads

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