HIV and ID Observations

One of the things that keeps me on Twitter — besides cute dog videos — is the periodic realization that the platform can help patients.

Which is, after all, why most of us do this doctor thing — to help people get better.

Example:

Several months ago we had a challenging patient. I asked twitter if anyone had ever used compassionate use cefiderocol. #IDtwitter responded and help Dr. Clancy and I save this gentleman’s life. So pleased to finally share the case back where it started! https://t.co/sStAqf0xFS

— Ryan Stevens (@Stevens_AK) September 26, 2019

So let’s consider this case from the energetic and amusing Canadian ID doctor Sebastien Poulin, which he posted a couple of weeks ago.

He was kind enough to share a few more details of the case with me via email (certain details slightly changed):

Middle-aged man admitted with fatigue and weight loss. Evaluation notable for oropharyngeal candidiasis, moderate pancytopenia, intra-abdominal lymphadenopathy (mesenteric and perihepatic), homogeneous hepatomegaly without splenomegaly.

HIV test positive. CD4 13; HIV RNA 2 million. Started on TDF/FTC, dolutegravir. Also TMP/SMX for PCP prophylaxis.

Three weeks later, blood culture turns positive for M avium complex.

Two questions immediately occurred to me with this challenging case:

Question #1:  Is this this TDF/FTC plus DTG regimen the optimal choice, or should we add (or use) boosted darunavir?

Certainly TDF/FTC plus DTG is a guidelines-endorsed first-line regimen, and the clinical trials of DTG as first-line therapy demonstrate good activity across a broad range of baseline viral loads and CD4 cell counts.

But consider the three case reports of treatment failure with emergent DTG resistance in initial treatment with three-drug therapy:

1. Fulcher, et al, Clin Infect Dis 2018;67(5):791-4:  HIV RNA — 1,970,000. CD4 — 78. Active infection — PCP.  Relevant concomitant medications — None.
2. Pena MJ, et al. Open Forum Infect Dis 2019;6(1):ofy332:  HIV RNA — 457,000. CD4 — 39. Active infection — Staph aureus.  Relevant concomitant medications — rifampin (DTG dosed twice-daily).
3. Lübke N, N Engl J Med 2019; 381(9):887-9:  HIV RNA — 1,400,000. CD4 — 22. Active infection — TB.  Relevant concomitant medications — rifabutin (DTG dosed once-daily). [Special note from me: got to love when OFID scoops the NEJM!]

All of these cases involved people with HIV who had advanced HIV disease, high viral loads, and active infections. All ultimately achieved viral suppression with inclusion of darunavir-based therapy.

Remember, patients like this, or the case posted by Sebastien, did not qualify for the registrational clinical trials of dolutegravir. Even stable patients with severe immunosuppression and high viral loads were uncommon. The same limitation applies to studies of bictegravir/FTC/TAF.

In contrast, consider the NAMSAL study — 66% of entrants had a viral load of ≥100,000, and 31% had a viral load of ≥500,000. Responses to both the efavirenz and DTG-based strategies was notably lower in these participants.

So how comfortable should we be using DTG or BIC-based regimens in someone with a baseline viral load of 2 million and a CD4 cell count of 13? An ongoing clinical trial might help us answer the question, but until results are available, what to do?

Question #2:  Should rifabutin be part of the treatment for MAC?

In a prospective, comparative clinical trial of treatment for HIV-related disseminated MAC, the three-drug regimen of clarithromycin, ethambutol, and rifabutin improved survival compared with either clarithromycin plus ethambutol or clarithromycin plus rifabutin.

So the answer to this Question #2 seems pretty obvious. Yes!

But we might wonder whether these data are still relevant to Sebastien’s case. Only 14% of the participants in that study were receiving PI-based ART. Plus, the study enrolled from 1994-1998, when combination ART was markedly less effective and more toxic than today — and was especially difficult to tolerate for patients with advanced HIV disease and active opportunistic infections.

As a result, the current OI guidelines say the following about adding a third drug for disseminated MAC:

Some experts would recommend addition of a third or fourth drug for people with HIV with high mycobacterial loads (i.e., >2 log CFU/mL of blood), or in the absence of effective ART.

You know that whenever the “Some experts” phrase makes an appearance, there are no strong data to direct us one way or another. And who these days knows a patient’s quantitative “mycobacterial load”?

Let’s look again at our cases of dolutegravir failure with resistance — two out of three received rifamycin drugs. Rifampin strongly induces DTG metabolism, which requires doubling the dose to 50 mg twice daily (the clinicians did this in case #2). Rifabutin has much less of an effect, so no change in dose is required. Still, experience with rifabutin and dolutegravir in clinical practice must be quite limited.

So back to our questions:

1. Is this this TDF/FTC plus DTG regimen enough, or should we add (or use) boosted darunavir?
2. Should rifabutin be part of the treatment for MAC?

Let’s do a poll on #1. Please use the comments section to let us know why you made your choice, as well as your thoughts on the rifabutin quandary in question 2.

As for cute dog videos, there’s this:

“Difficulties strengthen the mind as labour does the body.”
Seneca the Younger, Roman Stoic philosopher (4BC-66AD.) pic.twitter.com/7tnxzWbX48

— Dick King-Smith HQ (@DickKingSmith) September 10, 2019