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Your very creative use of resistance testing
Apr 28, 2004

Dear Dr. Conway, I would like to echo what someone wrote about your more precise knowledge on diagnostic tests for HIV and to express my respect for how you creatively used plasma resistance testing to diagnose a rare strain of HIV when most doctors would have quit on that patient.

While the ELISA test is of course the gold standard and as sensitive as the best test in medicine, no diagnostic test can achieve 100 % sensitivity. So, if ELISA is 99.8% sensitive after the six month window period, is it accurate to state that approx 2/1000 people will get a false negative...and the ratio of false negatives would likely be higher where rarer strains of HIV are involved. And there presumably are also some false negatives due to blood specimens not being properly handled...waiting too long at a doctor's office, not being properly refrigerated etc.?

Yet,because HIV triggers a high proportion of "worried wells", those 2/1000 (80,000 plus worldwide if one goes on a 40 million infected number) would/have been told by almost every doctor that they are definitely HIV negative...the number is probably higher because of more variant strains worldwide. So, while 99.8% sensitivity is great, for the 0.2% HIV positives who slip through the cracks, it's a problem: they will get sicker and sicker and presumably unknowingly infect thousands of others...

Are rare cases of HIV simply undiagnosable? What to do for those in that situation...repeatedly negative ELISA tests, yet suspicion of HIV? Your creative approach..sending a plasma sample for resistance testing is very interesting and I must say that the patient was lucky to have you as his/her physician, because most doctors would have told him that HIV was definitively ruledout. Your persistence and creative approach also was lucky for the people s/he would otherwise have unknowingly infected after being told hIV was not the problem. My questions (and I apologize for a bunch of them, but I think a lot of readers would find your answers on these important issues to be very interesting and helpful) are:

a. did that patient test ELISA negative repeatedly after the six month window period?...was this possibly a case of agammaglobulinemia or some other metabolic reason for not producing HIV antibodies?

b.what made you convinced that this patient was in fact HIV positive when all highly sensitive diagnostic tests had said the opposite and you would have been justified in not taking the HIV possibility further?

c. What strain of HIV did this person have that was so rare and where were they infected?..Canada, Europe, West Africa?

d. Did you send the plasma to a commercial or research Lab for the resistance testing that found the virus or is all resistance testing the same?...roughly how sensitive/accurate and specific would resistance testing be as a diagnostic test?

e. Had that patient tested negative on bDNA, DNA PCR as well?

f. Did the patient ever develop HIV antibodies later and how is s/he doing now..was the HIV strain more virulent and resistant to certain classes of HAART drugs?

g. Is that RT enzyme test ("PERT"?) very reliable and is its sensitivity undiminished by genetic mutations/diversity of HIV...so it will find this enzymatic activity at the RT level for every genetic form of retrovirus? In the US the PERT test is I think used to test vaccines for traces of retorviruses..if it solves the problem of HIV genetic diversity...rare strains that can elude ELISA or bDNA, why is it not used more often as an HIV diagnostic test?

Finally - and I apologize for all these questions - but you raise some compelling issues...are diagnostic tests being worked on to overcome the unique genetic diversity challenge posed by HIV? Or will some cases (rare situations of course) always exist where some unlucky few are infected with undiagnosable strains of HIV? Or would the plasma resistance test you used always find every genetic form of HIV?

Again, my apologies for all these questions, but I think the issues are important. Thank you for sharing your invaluable insights and for being obviously a clinician who knows a lot about a subject where there is so much wrong information and assumptions.

Best regards.

Response from Dr. Conway

The rate of false negative ELISA tests actually includes all the issues of samples being improperly processed, test failure, etc Thus, the true rate of false negative tests is vanishingly low, so very few slip through the cracks, either because of repeat testing, the results of other tests (such as the CD4 count or viral load). In the final analysis, it is rare for people to slip through the cracks.

Rare cases are just thatrare. They require an individualized approach and the input of people who have dealt with rare cases and have figured them out in the past. The rare case we had developed antibodies to HIV with a positive ELISA and Western blot, and had a lowered CD4 count and inverted CD4/CD8 ratio. It is just that the viral load was undetectable, that didn't make sense. The standard commercial resistance test picked up the virus. We are still trying to figure out what the source of the virus was and why this happened.

The PERT test is looking for porcine endogenous retroviruses and may or may not be useful for figuring out difficult cases. Hence, the importance of an individualized approach and the input of an expert.

Let me end on a positive note. People who develop tests are always trying to make sure their diagnostic tests pick up the rarest strains of HIV (or whatever else they are looking for) to make sure that the occurrence of undiagnosable diseases is kept to a minimum, making the lives of patients and doctors alike less stressful.


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