No. 5 Are two dragons enough, or are 3 needed to truly subdue HIV?

Rheagar Strange here, and as any follower of Thrones (show or book) knows there is an element of history repeating itself. The original Targaryen invasion was led not by Aegon the Conqueror riding a dragon alone, but also by his two sister-wives each also with their own Dragons. Hence the Targaryen sigil has a three-headed dragon. The new would be Conqueror Daenerys Stormborn also has three dragons. For awhile, much speculation existed on who will ride them and does there need to be 3 “heroes” saving Westeros from the White Walkers. (Spoiler for season 7 skip over the yellow if you are not caught up on the show)

 

Then the show threw a curveball (by allowing one dragon to be not only killed, but also resurrected to fight for the evil side).

 

So too in the fight against HIV from 1995 on, it was clear that we needed 3 HIV drugs to cause a durable suppression. When people infected with HIV got only 2 antivirals, therapy would work, but the treatment would lose efficacy after a few months or even weeks. Three drugs if taken regularly seemed to almost always work though, (unless the virus is resistant). For the most part even 3 drugs from one class of agent, such as 3 nucleosides (Trizivir) would work, as would 3 drugs from different classes. This is why so many HIV medications have “tri” in their name…..Atripla, Trizivir, Triumeq. This is also why when people take Pre-exposure prophylaxis (PreP) they are required to get multiple HIV tests/ year, because the PreP med only has 2 not 3 medications inside the pill and is enough to prevent but not treat HIV. Despite many attempts by Pharma companies and academics there have not been convincing demonstrations that 4 was better than 3. This is even true for late stage patients near death, although 4 drugs are still sometimes used, because it is hard to know for sure that there might be some benefit. Both in the “Thrones” world and in the HIV world, 3 seemed to be a magical number.

So it seemed till relatively recently when some of the newer HIV drugs such as dolutegravir and darunavir seemed to be so powerful that curious minds wondered if we could get away with only two drugs. Data on this concept was just presented at a recent virology meeting and both proponents of 2 drug regimens as well as defenders of “3 drug orthodoxy” can find something to “cheer” about in the results. This data is from the International AIDS Society conference 2017 and was presented by C. Mussini of the ICONA Foundation Study Group. The abstract is available online. I’m afraid I don’t have the exact details of the regimens in the study (sorry), but I think it still makes an interesting point.

Mussini IAS2017 2vs3

 

 

Briefly, even though 104 patients switched from 3 drugs to an unorthodox 2 or even 1 drug Maintenance regimen (no patients were initially treated with less than 3 drugs) there were no virologic breakthroughs (that’s a relief). That said the less than 2 drug party can’t really celebrate because compared to the 801 patients that stayed on triple therapy the mono/dual group actually had no change in their CD4/CD8 ratio, while the triple group continued to improve their ratio more towards a “healthy” normal immune system moving up 0.12 in the 3 drug arm and only .04 in the dual at 24 months. This effect was mainly seen through the 3 drug arm achieving a lower CD8 which is more normal.  To be clear getting to virally undetectable in the blood is important for a person to not transmit the virus, and necessary for the immune system to heal, but if the goal is a healthy immune system, perhaps a more stringent viral control is needed. To my knowledge this in one of the first studies to show that virologic suppression is critical but perhaps “not enough” at least in some patients. This is certainly something to keep an eye on as long acting injectable medications or other regimens try to “dethrone” the 3 drug dogma.

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