Last month, I wrote a post inviting responses to our Antiretroviral Rounds case in AIDS Clinical Care, and inviting you to respond. It was a case of someone with (mostly) undetectable HIV RNA levels, but lots of resistance detected when he had to stop meds due to pancreatitis.
I also promised to tell you how the case was actually handled.
First, some of your responses:
From Helmut Albrecht, MD: Good arguments on either side but I would come to the same conclusion that Joe arrived at. We should always treat the patient and not the lab value, especially if the lab report makes no sense. The current regimen should not be able to suppress a viable virus with this genotype. Either the virus is not viable or the report is wrong. Neither of these scenarios require a change of therapy.
From Ellen Koenig, MD: I would not change the meds at this point. His low viral load could be due to changes in his replicative capacity and we might get a period of sustained response. This gives time to see what new drugs come on the market and to learn about the newer more recently approved ones.
From Elizabeth Jenny-Avital, MD: The paradigm that resistance causes virologic failure is based mostly on observations of genotypic resistance that coincides with virologic failure. Our inability to measure “below the radar” resistance in patients who are virologically suppressed prevents us from knowing exactly how much resistance exists even in patients who are doing well. If we use a two-inch net to catch fish, we erroneously conclude that all fish are bigger than two inches. Same with most of our understanding of resistance—since we look for it in patients who are failing, we only find it in patients who are failing and perhaps erroneously believe that it does not occur in patients who are succeeding. When we do not find resistance in patients who are failing, we blame it on poor adherence, or as in the case of the enhanced trophile story with the CCR5 inhibitors, we develop better tests to look for resistance in failures, but not in suppressors. The same is true for adherence—we look poor adherence in failures but do not as vigilantly count pills or check refill dates in those who are doing well.
I have similar examples to that in the case described. One patient, for example, was on trizivir for years with intial VL> 100,000/ml. He maintained a good CD-4 count but only took the trizivir daily at best and as a result, he had accumulated many TAMs and M184V. Rather than salvage him, given his clinical stability and lack of commitment to HAART, I continued the trizivir. At some point, he decided to mend his ways, and suppressed while adherent to BID trizivir.
Exactly how much poor adherence and resistance jeopardizes outcomes is not altogether clear. Let us not forget that prognostic interpretation of resistance tests is validated by virologic observations in patients over fairly short periods. The meaning of resistance in myriad of clinically nuanced situations is by no means well established.
I applaud the clinician for doing the resistance test just to learn. Only more time on the same regimen will tell us whether that regimen is prematurely doomed.
How did I actually manage this case? First, I have the advantage of actually knowing this guy, and he simply never misses a dose of his medications. He’s the kind of person who obsesses about East-West travel, because the time zone shifts force him to alter his every-12-hours routine. (Note to adherence experts: despite the abundant evidence that we health care providers often get it wrong about whether our patients are taking their medications, sometimes we’re right. Like this time.)
Second, I truly believe that he has the resistance he had on his genotype report. I was his doctor during the years of “serial monotherapy”, where I had to add whatever new drug came along to his regimen because there was simply nothing else available. Frankly, I’m shocked he’s been able to maintain the degree of viral suppression he’s had, so when the genotype came back with such extensive resistance, I was not surprised.
So I changed his treatment to darunavir, raltegravir, and continued the tenofovir/FTC. Not suprisingly, the viral load remained undetectable.
But then something funny happened. Despite the continued excellent blood test results, he didn’t feel so great on this new treatment — he was irritable, had trouble concentrating, and just became (in his words), “not the kind of person you want to spend time with.”
I stopped the raltegravir, and all the side effects resolved. So he’s now on darunavir/r, tenofovir/FTC. Viral load (still) undetectable.
My conclusion? Based on clinical trials and my own experience, raltegravir is an extraordinary advance in HIV therapy. It has remarkable antiviral activity, and is extremely well tolerated.
Except for those who can’t tolerate it. There’s a lesson in there someplace.
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