Hello Dear Readers-
Sorry it has been awhile since I posted. The night is dark and full of terrors.
Before we go any further…I want you to know I’m not only posting about articles where the ratio means something. Today I’m posting about an article in which the ratio was not helpful. I’ll also warn you now that alas again this is an HIV centric post about a “hot area” in the world of HIV clinical decision-making, but perhaps not as relevant to people that don’t think about antiviral regimens for People Living With HIV (PLWH). What is this “hot area” you ask? Well it is about how much a PLWH who is suppressed can “deescalate their regimen”. For more background I posted about this in issue 5 “Are two dragons enough or are 3 truly needed.” There is now more evidence that some PLWH can be safely switched from a 3 drug regimen to a 2 drug regimen. For resistance and other reasons though not everyone can or should be switched. My point with the earlier post was to highlight some data suggesting some of those PLWH who switch may maintain virologic control at undetectable, but not recover their immune system as fast (in this case the CD4/CD8 might not ratio recover as fast) if they stayed on 3 drugs. This would not be good because evidence continues to pile up that a low ratio that doesn’t “revert” to normal is bad. Still that post was over a year ago and having ratio rises “stall” due to switching to fewer drugs has not been widely reported so it is not likely a common scenario. This is all as recap to the earlier post…so what is new?
Well what is new is published literature (1) on dolutegravir monotherapy (the DOMONO trial; NCT02401828). Now dolutegravir monotherapy was probably always wishful thinking (some would say an “unwise” idea) but to be fair even in this study of 95 patients there were “only” 8 patients with dolutegravir monotherapy failure. In retrospect there were some features that associated with failure and some make sense. One was CD4 nadir, and another was 4 fold higher HIV DNA (an imperfect measure of the reservoir)*.
One surprising thing though was that some of these failures occurred in fairly high CD4/CD8 ratio PLWH (range .74-2.0) and as a group these 8 actually had a slightly higher average ratio than the 87 who didn’t fail. Clea
rly a medium high ratio is not protective against future viremia. There is a lot of variation in the data that we don’t understand. Since my last post I realized while multiple studies have demonstrated the effect of smoking on raising the ratio, some reasonably large studies have failed to find it.
While some of these patients had a history of low CD4 nadirs, there was an attempt to find very well controlled patients and a past viral load of >100,000 was an exclusion criteria. Argueably, even more surprisingly then the ratio not correlating is that, the 8 failures had also had a longer time on suppressive antivirals on average (57 vs 31 months) which perhaps implies not everyone’s reservoir decreases by half every 4 years as current QVOA reservoir data suggests. The 8 failures did have a longer time between HIV diagnosis and starting therapy (49 vs 15 months) suggesting not only early but also late events contribute to reservoir size. Now we don’t know lots of things about these 8 including adherence and side effects. By itself these results don’t argue the ratio has no meaning. They do argue though that for the ratio to be used in isolation as a reservoir marker…it better be quite high, maybe even above 2.0 which is rare in practice at this point in the epidemic. As more people start right after diagnosis at higher CD4 counts and higher ratios, we will see more people with ratios over 2.0. Two papers that studied treatment interruption specifically in the population of PLWH who were treated during acute infection (which is rare) have found that ratios >1 are associated with slightly longer times to viral rebound (Hurst et al 2015 and Colby DJ et al 2018) but rebound still occurred. The ratio can still be useful on a population basis and at least in extreme lows at predicting PLWH at risk for nonAIDS events and complications. Clearly though like Game of Thrones, what the ratio really tells us is cryptic and more chapters will follow (hopefully).
*Yes we are using our symbol for house QVOA+CD4 cells as a “generic” symbol of the reservoir. The Siliciano group has published a PCR based assay now for reservoir measurement (Feb 2019).
- Predictors of virological failure in HIV-1-infected patients switching to dolutegravir maintenance monotherapy. 2019 HIV Medicine, Wijting IEA et. Al.