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Are the undetectable viral copies more prone to being drug resistant and spawning many drug resistant viral copies?
Jun 15, 2004

Commercial assays only detec >50 copies of plasma VL. Is it possible/likely (?) that the <50 copies of virus may be the ones that are drug resistant?

What are the reservoirs where dormant HIV resides and does the virus continue to do damage even when VL is <50? Can you please explain this...I wake up each morning, despite a VL <50 and a CD4 >700, wondering if my cognitive abilities might be compromised and/or that the virus may trigger meningitis or some other brain or neurological deficits if it still resides in cells, organs and the central nervous system. Any basis for this, even if a fairly low chance at these VL's and CD4 levels?

Finally, are the CD4's qualitatively the same as those in someone without HIV? Clinical treatment focuses on CD4 numbers and it is rare that anyone has a qualitative assessment on how the various CD4 cells (memory etc) tackle various viruses and other pathogens. Any studies on this?

Thanks for the wonderful service and advice you provide.

Response from Dr. Sherer

Commercial assays only detect the majority species, so we are unaware of the mutations present on minority species, i.e. those with < 10-20% of the population.

More sophisticated techniques have been developed which can detect resistance down to the minority species, but these techniques raise more questions than they answer. In some cases, as you suggest, a small population of resistance has been identified in patients who shortly thereafter go on to show drug resistance in the majority species.

However, in other patients, minority species are identified with resistance mutations that should present problems for the current regimen, and yet this does not happen.

So perhaps there is a critical mass of resistant virus that is required to overcome both wild type and the limited effects of the immune system, in order to replicate rapidly, overgrow, and lead to clinical and virological regimen failure.

To make matters more complex, there is clearly evidence that viral evolution to some degree occurs even in patients with viral loads in their blood below detection, e.g. in 'reservoirs' such as the central nervous system and the gonads.

But its important to keep our feet on the ground here, as these are complex questions raised by sophisticated studies. In spite of the above, ART works remarkable well in the majority of patients who are able to maintain good adherence, and we know they can work this well for many years, i.e. up to 5 or more in the longest lasting studies. This is the central fact that you want to keep in mind.

Finally, CD4s that were once below 200, and are now well above 200, do appear to have differences with CD4 cells in HIV negative patients. Some elements in the immunologic repertoire appear to be lost, and some irreversibly so. Some clinicians use this as an argument for earlier treatment, i.e. around 350 CD4 cells, a position I agree with.

To your issue with neurologic disease: This is a tough issue, as there are uncommon cases where dementia has occurred in individuals with otherwise good responses to HIV therapy. Fortunately, they are very uncommon.

Part of your question seems to be wrestling with co-habitation with HIV, which is part of your daily life. I sometimes remind patients that, well before their cohabitation with HIV, they were co-habitating with bacteria in their colon and other viruses, such as Ebstein Barr virus (the cause of mononucleosis), which in most people lives in our nasopharynx and is shed in the blood stream continuously, only to be picked up and disposed of by lymphocytes. We are all living in this way with many micro-organisms.

One of the most difficult tasks facing a person with HIV is living with these uncertainties. Its useful to remember that worrying about them, like other issues beyond our control, will not change the outcome. While you treat HIV with respect, you also have to go on living your life, and not worry about all of the trouble HIV might yet cause you. Because it also might not, and life is short.

Falling cd4 with undetectable viral load
A bunch of questions about resistance testing

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