Paul E. Sax, M.D.
(Disclosure: The following post represents personal opinion, and is in conflict with treatment guidelines. Proceed at your own risk.)
E-mail recently from one of our outstanding first-year fellows:
I've heard you recommended against the use of MAC [M. avium complex] prophylaxis in most settings in the modern HAART era. We admitted a 21yo F patient, non-compliant with meds, with a CD4 of 2. She has poor tolerance of pills in general which has been a major obstacle to her care. Would you recommend against the use of MAC ppx in this patient? Even with a CD4 of 2?
It's a great question, notwithstanding the use of the term "HAART". (I think she did that just to bug me).
In general, I'm not recommending MAC prophylaxis anymore, and here's why:
- It's never been proven necessary in the modern ART era. For the record, this is the most relevant placebo-controlled trial, and it enrolled patients from 1992-1994 -- eons ago, ART-wise (only available HIV therapies were NRTIs). There's certainly no controlled clinical trial since 1996, when effective ART became widely available. This observational study from the HIV Outpatient Study (too bad it wasn't the MACs cohort, ha ha) didn't find any benefit, and this one from the early ART era was conducted in 1996-1997, a time when virologic suppression rates in clinical cohorts was 20-30%. Please tell me if I'm wrong and there are other more relevant studies.
- Effective HIV therapy reduces MAC risk much more than azithromycin ever did. Disseminated MAC was, along with CMV retinitis, one of those dreaded "final common pathway" OIs that occurred late in HIV disease, almost exclusively in patients with longstanding severe immunosuppression. The incidence of both of these conditions -- especially if you limit diagnoses to non-IRIS cases -- has dropped dramatically.
- Some of these advanced disease patients may have undiagnosed MAC. It could be clinical or subclinical, and you wouldn't want to give low-dose "monotherapy" to them anyway. They might develop MAC IRIS, but do we have any evidence that MAC prophylaxis prevents MAC IRIS?
- High-dose, weekly azithromycin has side effects. These are mostly GI side effects, and I'd argue anything that might make it tougher for someone with a CD4 < 50 to take ART is a bad thing.
- Any antibiotic administered chronically selects for resistance, will alter the "microbiome." Although clinical studies of MAC prophylaxis didn't find much macrolide resistance in M avium, resistance to macrolides among other bacteria is widespread. And one dose of an antibiotic can alter the microbiome.
- It costs money. Not a lot, but something. And if it's not doing any good, or even worse, distracting someone from taking ART, it's bad value.
So could there be anyone in whom I'd still recommend MAC prophylaxis? I suppose -- but without much enthusiasm, and only if all the following criteria were met:
- Newly diagnosed with HIV, or newly ready to take ART.
- CD4 < 50.
- No clinical symptoms or signs consistent with MAC.
- Expresses strong commitment to taking ART now that he/she has this serious diagnosis (AIDS).
In these cases, one could argue that it's possible that giving it would provide some benefit during this very vulnerable period. If the patient takes ART, furthermore, the CD4 will soon be above the threshold allowing discontinuation of primary MAC prophylaxis,
But I'd have a very low threshold for stopping it (any GI toxicity in particular) even before the CD4 cell count is > 100, and would make it abundantly clear that this patient's true lifeline to health is HIV therapy.
So what about a controlled clinical trial? It's never going to happen -- the incidence of MAC is too low these days, so the sample size would need to be untenably large. Additionally, finding and enrolling patients who meet the CD4 entry criteria would be an enormous challenge. These are not the easiest patients to get into clinical trials.
So what say you, ID/HIV specialists -- should we still be prescribing MAC prophylaxis?
Paul E. Sax, M.D., is director of the HIV Program and Division of Infectious Diseases at Brigham and Women's Hospital in Boston.