September 28th, 2019

What Is the Best Treatment for Advanced HIV Disease?

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:

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 infectionStaph 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.

What would you use for intial HIV therapy in this case?

View Results

As for cute dog videos, there’s this:

6 Responses to “What Is the Best Treatment for Advanced HIV Disease?”

  1. Jose Arribas says:

    This is really a situation where we lack evidence. In the Reality trial (https://journals.plos.org/plosmedicine/article/file?id=10.1371/journal.pmed.1002706&type=printable) adding a 4th drug (raltegravir) to standard triple therapy did not improve outcomes. Would Darunavir added to DTG or BIC be different?

    • Paul Sax says:

      Good point about the REALITY trial. As you note, it was RAL on top of EFV (plus TDF/3TC), so that’s a bit different. With DRV/r, we’d trying to prevent emergence of resistance with another high barrier resistance drug. But who knows whether it would be worth it, the road is littered with 4-drug strategies that have been no better than 3 (ACTG 5095 immediately comes to mind).

  2. Christian Weaver says:

    Thank you Drs. Sax and Poulin for the interesting question. As a recently graduated fellow, I had an experienced attending who touted “if you’re worried about resistance, nothing in our arsenal compares to the protease inhibitors.” While I think that interactions will have to be watched closely in a patient with such a high viral load and co-existent OI (and potential for baseline resistance), a PI would be my first choice.

  3. Sébastien Poulin says:

    Follow up;

    1- VL 2 million —> 6000 in ~3-4w

    2- Multiple ulcerative lesions showed up (picture) Bx AFB (+)

    3- Progressive lymphadenopathy (mesenteric-perih) and now hilar/mediastinal+new pulmonary nodules

    4- Yes, I started Azi/Eth + Rifabutin

    Clinically ‘very well’ (!)

    To be continued..(IRIS)

  4. David K says:

    As a fellow at Maryland, for patients with baseline high viral load (>1M) we often did dual-PI induction, usually with DRV/r + ATV, and then switched to a standard regimen when the viral load had come down to something more reasonable. Usually it fell to the hundreds to thousands by 1 month. I have used this approach from time to time, in maybe a half dozen patients since then. All had high baseline viral loads, and all of them have achieved a nondetectable viral load. I would love to see some clinical data on this approach.

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HIV Information: Author Paul Sax, M.D.

Paul E. Sax, MD

Contributing Editor

NEJM Journal Watch
Infectious Diseases

Biography | Disclosures | Summaries

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