An ongoing dialogue on HIV/AIDS, infectious diseases,
November 13th, 2016
Poll: Should We Be Starting HIV “Elite Controllers” On Antiretroviral Therapy?
(Note to readers: This will have nothing to do with the election — for obvious reasons. Yes, there’s a poll at the end, but your political views will not matter one bit. There, I feel better.)
Just received this email from a longstanding leader in HIV care and research:
I would like to ask for you a favor. I am preparing an elite controllers talk for the next GESIDA meeting that will take place in Madrid on December 2nd 2016 and I am doing a very short survey to international experts [thanks very much, Jose!]. I would appreciate very much if you can answers these 2 questions:
1) Would you treat with ART elite controllers (patients with CD4>500 and longstanding HIV VL<50 copies/mL)?
2) Please, explain your answer in 1-2 short sentences
Thanks again for considering my proposal and for your time.
This is a tough question, and if you’re wondering why, let me provide a bit of background for those who don’t do ID/HIV medicine regularly.
“HIV controllers” are those rare individuals who have HIV infection, but their immune systems somehow “controls” viral replication without the need for antiretroviral medications. How common is it? Estimates vary, but it’s certainly no more than 1% of those with HIV. (Here’s one representative study from France.) Rarity notwithstanding, every experienced HIV/ID clinician has seen at least one of these patients, and those of us doing this for a while have several, most of whom we’ve been following for years.
At the extreme end of the controller phenotype are people sometimes termed “elite” controllers, meaning we can’t detect HIV in their blood using even our current highly sensitive viral load assays — their results always come back “Target not detected” (in other words, “undetectable”), and their CD4 cell counts remain normal.
Not surprisingly, these elite controllers are the source of immense interest to researchers, who have long believed that these patients’ immunologic response to HIV — a usually progressive, lethal infection — might hold the clue for immunotherapy, or an effective vaccine, or both. Not only that, but their “elite” status allows them to board the plane first even when traveling coach, and grants them free WiFi and an automatic room upgrade when checking into fine hotels.
(Just wanted to see if you were listening.)
Back to the science: But all is not completely normal in these lucky HIV controllers. Some have elevated levels of immune activation and inflammation — perhaps a marker that their immune systems are working overtime to control HIV. Might this insalubrious inflammatory milieu cause lymphoid fibrosis? Or increase the risk of cardiovascular disease? One provocative study showed that HIV controllers were admitted to the hospital more often than HIV infected patients who were on antiretroviral therapy.
Ultimately, this raises the question Jose posed in his email — should we start HIV controllers on antiretroviral therapy? Ten years ago, the answer was easy — NO — and we told them this repeatedly. Your immune system is doing what our antiretrovirals set out to do, which is control viral replication. Not only that, it’s doing so without side effects. You’re lucky — you don’t need treatment.
But times most definitely have changed. In addition to the above data on immune activation and inflammation, HIV treatment is now so much safer. Plus, we have the results of the START study and HPTN 052, showing that HIV treatment is beneficial even to those with CD4 > 500, and that suppressive therapy makes people with HIV essentially non-contagious. As a result, all guidelines now explicitly state that HIV treatment is indicated for all people with HIV. Doesn’t that include HIV controllers?
The reason this isn’t so clear comes down to three remaining issues, all of them significant. Two are uncertainties from clinical science, the third an emotional one from our patients.
- For elite controllers, there’s no proof of clinical benefit or reduction in transmission risk. The START study showed that those with CD4 > 500 benefited from starting therapy rather than waiting until the CD4 fell to < 350. However, the median HIV RNA of study participants was 13,000, and while it’s not in the primary paper, only a small fraction of participants could have had HIV RNA < 500. Imagine how few (if any?) were “elite controllers”. Similarly, would HPTN 052 demonstrate a reduction in the risk of HIV transmission even among those who started the study with undetectable viral loads? Doubtful.
- Patients who start ART often have some residual abnormalities in immune activation and inflammation — will the same hold true for elite controllers? In patients on long-term suppressive ART, abnormalities in inflammatory and immunologic markers persist in many patients. Moreover, the number of elite controllers who have been treated with ART and studied intensively is very small, limiting our ability to make firm conclusions. This study looked at 4 such patients treated with TDF/FTC and raltegravir, showing a non-significant trend downward over 24 weeks of therapy. More such patients are being studied in ACTG A5308, which is an ongoing prospective clinical study of ART in HIV controllers (I’m on the study team) — but until we have those results, the benefits of ART even on surrogate markers for this population are unknown.
- Most HIV controllers don’t want to start treatment. We’ve been telling some of them for years — even decades — that they are special, and that they don’t need treatment since their immune systems are doing all the work. Not surprisingly, after hearing this for so long, it’s hard for them to hear otherwise, in particular since they still feel fine. It’s difficult to convey the benefits of HIV therapy by using the concepts of “T-cell activation” or (even worse), “%CD38+HLA-DR+ CD4+ T cells”.
Our experience with A5308 when we approached HIV controllers about participating was fascinating — even those who have been enormously generous to the research community, providing blood and tissue samples to numerous investigators for years, simply didn’t want to take HIV meds. One even told me he would prefer something more experimental than ART, such as an HIV vaccine or novel combination of cytokines.
OK, that’s enough — much more than the 1-2 sentences requested by Jose, sorry about that!
But it’s time to decide, please take the poll below (all are encouraged to participate). And this time (ahem), there’s no wrong answer.