Someone recently alerted me to a 2006 paper comparing adverse events on “continuous” vs. “interrupted” ARV therapy:
“CD4+ Count-Guided Interruption of Antiretroviral Treatment: The Strategies for Management of Antiretroviral Therapy (SMART) Study Group”, NEJM, Volume 355:2283-2296, November 30, 2006, Number 22
The study was trumpeted in the media as the death knell for so-called “interrupted” or “intermittent” ARV therapy, following the conclusion:
“Episodic antiretroviral therapy guided by the CD4+ count, as used in our study, significantly increased the risk of opportunistic disease or death from any cause, as compared with continuous antiretroviral therapy, largely as a consequence of lowering the CD4+ cell count and increasing the viral load. Episodic antiretroviral therapy does not reduce the risk of adverse events that have been associated with antiretroviral therapy.”
The original study was intended to last 6-9 years:
“We calculated that 6000 patients would need to be enrolled for the study to have a statistical power of 80% to detect a 17% relative reduction in the rate of opportunistic disease or death from any cause in the drug conservation group as compared with the viral suppression group, with a two-sided alpha level of 0.05. Follow-up was to continue until 910 primary end points had occurred (estimated to be at least 6 years for each participant), assuming an event rate in the viral suppression group of 1.3% in each of the first 2 years and 2.6% per year thereafter.”
but was stopped short after a mean patient follow-up of just 16 months, for “ethical reasons”:
“On January 10, 2006, at its sixth meeting, the board recommended stopping enrollment in the SMART trial because of a safety risk in the drug conservation group and because it appeared to be very unlikely that superiority of the drug conservation treatment would be shown. On January 11, 2006, investigators and participants were notified of these findings, enrollment was stopped, and participants in the drug conservation group were advised to restart antiretroviral therapy.
What I found most revealing about this study was:
“Only 8% of deaths were due to opportunistic disease.”
The cognitive dissonance here is astounding.
Among all patients, grade 4 events occurred about 3.5 times as often as opportunistic disease: a total of 89 patients experienced any type of opportunistic disease; by contrast, a whopping 321 patients experienced grade 4 events.
Even more shocking is the following: out of all 85 patients who died, more than 5 times as many experienced grade 4 events as compared to opportunistic diseases, because 37 of the 85 patients who died experienced grade 4 events, compared to only 7 who experienced opportunistic diseases.
Opportunistic diseases did occur about 3.5 times as often in the DC (drug conservation) group as in the VS (viral suppression) group (69:20), but only 7 of these 89 patients died (8%), 4 from the DC group and 3 from the VS group. By contrast, grade 4 events occurred slightly more often in the DC group as in the VS group (173:148), but 37 of these 321 patients died (12%).
This also means that out of all patients who died, between 41 and 48 patients (48-56%) died due to causes that were either unknown or not related to either opportunistic diseases or grade 4 events. I wonder why the researchers didn’t stop to ponder this incredibly bizarre finding.
Let’s put these numbers into perspective: We have a study on giving ARV to HIV patients, and 5 times as many have drug reactions as AIDS defining illnesses, and this fact doesn’t even register with the authors of the paper? HALF of all deaths have nothing to do with AIDS or ARVs, and this bizarre fact doesn’t register with the researchers either?
The half of all deaths having nothing to do with AIDS or ARVs is several times higher than the average national mortality rate for all Americans among that age group. Why are they dying so much? They can’t blame their low CD4 counts, because their deaths weren’t AIDS related. They can’t even blame the drugs! Obviously, simply being told you’re HIV positive and have a low CD4 count greatly increases your probability of dying from things that have absolutely nothing to do with HIV or CD4 counts… very strange.
Never mind that the whole explanation why this study supports “continuous” therapy is prima facie absurd. The reasoning goes something like this: After controlling for other factors, lower CD4 counts and higher viral load were associated with higher risk of adverse events, and so the reason the patients on “interrupted” therapy had more adverse events was because they weren’t getting enough ARVs to keep HIV viral load in check, to keep their CD4 counts high enough to stave off the adverse events caused by the ARVs in the first place.
Try wrapping your mind around that one!