The Evolution of Antiretroviral Therapy for HIV - Episode 7
Peter L. Salgo, MD: This is all very encouraging. When you’re talking about all these things, I get a sense that you’re kind of down in the noise. You think about them, but there aren’t all that many people. What about the HIV-positive patients with the opportunistic infections—the ones that I would call tuberculosis (TB), cryptococcal meningitis, PCP (pneumocystis pneumonia), and all these things? We used to say that, “It isn’t the HIV that’s killing them, it’s all these other things.” How do you balance the ART (antiretroviral) therapy with the therapy for the opportunistic infections?
Paul E. Sax, MD: It turns out that the patients who benefit the most from ART are just the people you described—the ones with opportunistic infections. So, there’s a sense of urgency we have of getting them on to ART as soon as feasible—much more so for those patients than for any other group.
We recently had a woman in our hospital who was newly diagnosed with cerebral toxoplasmosis. Her CD4 cell count was 14. Yes, we treat the cerebral toxoplasmosis, but the clock is ticking to get them on antiretroviral therapy. Now, you have to put up with some possible drug—drug interactions, some polypharmacy, and maybe some immune reconstitution inflammatory syndrome (IRIS), but those are trade-offs we’re willing to make in exchange for the improved outcome that’s been proven in randomized clinical trials for people who start ART early rather than waiting.
Eric S. Daar, MD: And that’s really what’s amazing with HIV. We’re so fortunate in that there have been so many large randomized controlled trials that inform all of our decision making. In particular, we have large randomized controlled trials that tell us that people who present with advanced immune suppression and opportunistic infections actually benefit, not just from early therapy, but if you start them within 2 weeks (somebody with PCP), they’ll do better than if you wait 6 weeks. And the same thing is true for people with TB with advanced immune suppression (CD4 less than 50). We have a lot of great data. One of the conundrums has always been cryptococcal meningitis, which is probably one of the most common opportunistic infections people present with in our hospital nowadays. And that’s hard because of this IRIS issue.
Peter L. Salgo, MD: You need to define that. What’s an IRIS?
Eric S. Daar, MD: This immune reconstitution inflammatory syndrome, where you enhance their immune response and then they have an inflammatory reaction to the antigen. And, unfortunately, the antigen, in this case, is residing in a fixed compartment in the central nervous system.
Peter L. Salgo, MD: So they get cerebral edema?
Eric S. Daar, MD: They develop cerebral edema, and not only is it a bad place to develop inflammation, but it’s also really common. About 25%, 30% of the people develop cryptococcal meningitis.
Peter L. Salgo, MD: Cryptococcal meningitis is that common. And really, their best hope is a competent immune system. Yet, it’s their immune system that may kill them. What do you do as doctors?
Eric S. Daar, MD: It’s a delicate balancing act. What I always love to talk to the residents and fellows about, when we have a case like this, is, I say, “Why don’t you read the paragraph in the guidelines?” Because it basically says, “Well, you could start early, but then you might not want to start early, and you could wait until it’s kind of late, but that might not be good either.”
Joseph Eron, MD: The biggest waffle in the guidelines is, what do we do then? And we still fight about it because the best randomized data comes from a resource-limited setting; it comes from Africa. And those data suggest that if you start it early, you actually increase mortality.
Eric S. Daar, MD: They don’t suggest it. They definitively demonstrated it in the clinical trial.
Joseph Eron, MD: Yes, they demonstrated it.
Peter L. Salgo, MD: So, what are you saying? Do you go after the cryptococcal meningitis first with an anti-cryptococcal drug and knock the burden down?
Joseph Eron, MD: The question is, when in that process do you start? And I think that in a first-world setting (resource rich setting), that you should start early. You don’t start day 1 or day 2, but you start around 2 weeks in. That’s what I do. You get ready for this IRIS, you prepare for it, and you prepare the patient for it.
Paul E. Sax, MD: I agree with that.
Eric S. Daar, MD: I wait 4 to 6 weeks.
Peter L. Salgo, MD: Four to 6 weeks on anticryptococcal therapy?
Eric S. Daar, MD: Right.
Paul E. Sax, MD: There is an analysis of timing of ART in resource-rich settings that suggests that early is probably okay. It’s not randomized. It was only a small number of randomized patients in one study. Can I mention about tuberculosis?
Peter L. Salgo, MD: Please do. I was going to go there.
Paul E. Sax, MD: Tuberculosis is decreasingly common in the United States, but it still happens. It is extremely challenging to treat because TB treatment includes rifampin, and rifampin is the biggest pain in the world when it comes to drug interactions. So, a lot of the drugs that we commonly use for ART don’t get along well with rifampin. And so it’s sort of this separate world of people with HIV and TB—they get a slightly different antiretroviral approach than people without TB.
Joseph Eron, MD: You can see some serious IRIS with someone that actually has a temperature for days on end. You have to give them steroids.
Peter L. Salgo, MD: Oh great. You’re going to give somebody who’s immunocompromised steroids?
Eric S. Daar, MD: You have to.
Peter L. Salgo, MD: But I guess the saving grace is that it’s not a closed compartment?
Joseph Eron, MD: Yes, right.
Peter L. Salgo, MD: Unless it’s cerebral TB.
Joseph Eron, MD: TB meningitis—that’s as bad as cryptococcal meningitis, perhaps even worse. We just never see it.
Paul E. Sax, MD: Yes.
Peter L. Salgo, MD: But there, too, you have at least a static therapy. I’m not sure if anything is really cidal against TB at the end of the day. But you can knock it down.
Paul E. Sax, MD: Yes, definitely.
Peter L. Salgo, MD: My early infectious disease professor said, “Antibiotics, shmantibiotics. It’s the white cells that kill everything.” And all you’re doing is holding everything in check for the body to go after it. You’re putting that in steroids when you give them the ART therapy.
Paul E. Sax, MD: You have to treat bad IRIS with something because, as Joe was alluding to, these are patients who are very sick. They have really hectic fevers. If they have mesenteric adenitis, they have terrible abdominal pain. If they have lymph nodes in the chest, they’re coughing. It can be very difficult.
Joseph Eron, MD: And we’ve certainly all seen abdominal rupture from mesenteric nodes in the IRIS. So, it’s not just about treating fever.
Transcript edited for clarity.