HIV and ID Observations

A couple of months ago, I presented these three clinically stable, virologically suppressed patients — and asked if they should switch treatment:

1. 50 year old man on ABC/3TC, EFV since 2000.  No renal disease.  Hyperlipidemia, on atorvastatin 80 mg a day.  Father died of an MI age 48.
2. 63 year old man, on EFV + LPV/r for years; past history of neuropathy on d4T and 3TC.  Needs to go on inhaled steroids (preferably fluticasone) to help manage increasingly refractory asthma.
3. 35 year old woman, on ABC/FTC, FPV/r BID — doing ok but missing some PM doses.

We also published them in AIDS Clinical Care, inviting both reader and and formal “expert” opinion.

Not surprisingly, there was disagreement from both the readers and the experts — some electing to change, some to switch, with various suggested new regimens.  It makes interesting reading, as all perspectives are defensible.

So what actually happened?  I switched them all:  Patient 1 is now on TDF/FTC/EFV, and Patient 3 on ABC/3TC, DRV/r.  They are both doing great.

Patient 2, um, not so much:  After switching to TDF/FTC/EFV, he almost immediately noted marked worsening in neuropathic symptoms — reminding me that in the bad old days of d4T and ddI, some patients did seem to experience worsening on 3TC.  So he went back on EFV + LPV/r, and the neuropathy returned to baseline over a month or so.

But — since he still needed the inhaled steroids for asthma treatment, and the fluticasone/PI interaction can be troublesome, I tried the combination of etravirine and raltegravir as a novel “NRTI- and PI-sparing” approach.  Almost immediately after this switch, he developed fevers, rigors, and malaise, and actually needed to be hospitalized overnight.

His current regimen?  Back to EFV + LPV/r — again doing well from the HIV perspective.  The pulmonologist managing his asthma is trying to get by with low dose beclomethasone, with some success.

Humbled, I’m reminded that this antiretroviral business can be tricky — and that sometimes, it’s better to do nothing than something.

A couple of years ago, an ID-colleague of mine told me about a tough case:  While working in the ICU, an anesthesiologist sustained a pretty severe needle stick.  Approached for HIV testing, the source of the exposure felt threatened by the providers in the ICU, and refused to sign the consent.

The patient then deteriorated and required intubation.  The intensivist, understandably in something of a panic, contacted my colleague for advice.

We’re about to post this case — actual details of which are slightly changed to protect anonymity — in AIDS Clinical Care.   We’ve asked some experts (MD, lawyer, ethicist) on the matter a few key questions, including:

• How would you manage the intensivist who sustained the injury?
• Would you give post-exposure prophylaxis? If so, what specifically would you give, and for how long?
• How would you determine if the source patient has HIV? Would you perform surrogate testing (for example, obtain a CD4-cell count) to assess this? Would you consider testing him without written informed consent?
• If he is tested, would you give him the results after he recovers if the test is negative? If the test is positive?

This case is different from the this one, but many of the issues are related.  (Different from this one too, obviously.)

And it’s a reminder that amidst all the controversy over “opt-out” testing and HIV screening, there’s another big issue out there regarding HIV testing that’s hardly been settled.

With first-line therapy for HIV being so astonishingly successful, much of what we do in practice is tweak regimens that are by virologic and immunologic standards, working just fine:  Viral load undetectable, CD4 stable.

But not so fast — while one of my colleagues said that if he didn’t change his patients’ regimens, then he’d have nothing to do, the other said he NEVER changed a regimen that was working unless he absolutely had to.

Who’s right?  Both of them, of course.  The regimen might improve in convenience, tolerability, safety, etc, but new side effects could also occur, as well as virologic failure.

So consider these virologically suppressed, clinically stable patients (all recently seen) — would you switch?

1. 50 year old man on ABC/3TC, EFV since 2000.  No renal disease.  Hyperlipidemia, on atorvastatin 80 mg a day.  Father died of an MI age 48.
2. 63 year old man, on EFV + LPV/r for years; past history of neuropathy on d4T and 3TC.  Needs to go on inhaled steroids (preferably fluticasone) to help manage increasingly refractory asthma.
3. 35 year old woman, on TDF/FTC, FPV/r BID — doing ok but missing some PM doses.

Keep in mind, all are doing fine — would you switch?  If so, to what?  Thanks in advance* for the consult.

(*ahem.)

Both here and on the AIDS Clinical Care site, we posted a case of a 50-year-old HIV+ man in need of a screening colonoscopy.  What sedation could he receive while on tenofovir/FTC and ritonavir-boosted atazanavir?  Specifically, would midazolam and fentanyl (”contraindicated” in the ritonavir package insert) be ok?

(Same issue for efavirenz, by the way.)

We solicited responses from two PharmD’s and a gastroenterologist, and also received a bunch of comments.

The comments vary in specifics, but the most common is similar to this one, echoing what Brian Fennerty wrote:

These sedative drugs are always titrated to effect for individual patients. We are aware that responses are variable and I think it completely unnecessary to alter an HIV patient’s drug regimen to allow them to receive the discussed drugs. In my experience, I have never noticed a marked exaggeration in clinical effects in this scenario anyway. Bolus doses should be reduced and given with more caution, in the same manner that we approach any patient with altered metabolism, such as the elderly, or those known to have hepato-renal failure.

Or said another way, by a clinician receiving ART himself: Read more of this post »

Here’s a problem we’re grappling with:

A patient with HIV needs a colonoscopy, but is on either a ritonavir-boosted protease inhibitor or an efavirenz-based regimen.

(This must be something like 90% of HIV patients as of March 1, 2009, based on my extremely unscientific gut impression.)

For efavirenz, midazolam is contraindicated; for ritonavir, same story — or “consider therapy modification”, according to one source I found.  Ditto fentanyl.

So what should be given for sedation?  (Important side note: if you told me pre-1996 that this would be a critical management question for my HIV patients, I would have thought you were out of your mind.)

Lots of different views here in Boston, including:

• Give the usual meds, titrate to effect
• NEVER give midazolam with either efavirenz or ritonavir; instead, use lorazepam, etc
• Stop HIV meds 1 day in advance, then give midazolam and fentanyl

Does anyone know?  Or does anyone have sufficient experience to share?

Fresh back from lovely Montreal, where the temperature (I’m glad to report) climbed into the balmy 40’s …

Here’s a rapid-fire listing of the Greatest Hits.  As I’m sure to be leaving something off this list, happy to accept other suggestions:

1. Interleukin-2 does not work.  The ESPRIT and SILCAAT studies are over. Yes, the CD4’s increase, but compared to antiretroviral therapy alone, there’s absolutely no clinical benefit, and plenty of side effects.
2. Should we be starting antiretroviral therapy at even higher CD4s? At ICAAC, the NA-ACCORD group said starting before 350 improved survival; here they said it was 500!  The ART-CC disagreed, slightly (their estimate was around 350).
3. Switching from lopinavir/r to raltegravir increases the risk of virologic failure in suppressed patients. Likely explanation:  undetected NRTI resistance at baseline.  This study should have no bearing on the use of raltegravir in either treatment-naive or treatment-experienced patients — essentially, the drug must be used with at least one other fully active agent.  (Oh yeah, the lipids improved, not surprisingly.)
4. Treating HIV during TB treatment increases survival compared with waiting until TB therapy is completed. One of the most interesting things about this study is that TB treatment outcomes were similar — but those who delayed therapy obviously had HIV disease progression.  By contrast, a small study of cryptococcal meningitis from Zambia suggested that early ART was harmful — the first time early ART has been associated with worse outcomes.
5. Treating HIV significantly reduces the risk of HIV transmission to a seronegative partner. This study from Zambia and Uganda involved nearly 3000 discordant couples (!), and the effect was dramatic — especially when one considers that HIV therapy was only given if clinically indicated (i.e., not to prevent transmission).
6. …But the risk of transmission is not zero. Some studies showed persistent HIV shedding in semen despite effective antiretroviral therapy.  No surprise — but this doesn’t diminish my enthusiasm for #5 above, as the reduction in risk from treatment is huge.
7. Antivirals and cardiovascular disease. D:A:D is updated, and continues to implicate abacavir, and a French Hospital Database study does the same — and both now cite lopinavir/r as associated with increased risk as well.  An ACTG database study does not find an association with abacavir, but a prospective randomized switch trial (to ABC/3TC or TDF/FTC) does — in the updated analysis, the difference was statistically significant.  Regarding abacavir, pathogenesis studies were all over the place — split about evenly whether positive or negative.  Peter Reiss gave a sensational summary on this complex issue — web cast highly recommended if you have 15 minutes to spare.
8. Lopinavir/r is better than nevirapine for women who previously received single-dose nevirapine. This might seem intuitively obvious, but it answers an important question that has generated enormous controversy over the years.  (Plus the first author is a beloved colleague.)
9. Two non-ritonavir boosters are introduced. (Details here and here.)  Yes, data are early, but something without the GI and lipid effects would be welcome indeed.  Whether we really will need PK boosters at all remains an open question, but for now they clearly are needed for PIs and the investigational integrase inhibitor elvitegravir.
10. A microbicide works.  Sort of.

So what’s missing?  Not a single phase III study of a novel agent, nor a phase IV comparative trial of existing drugs done in the developed world.

Yes, it’s a very “quiet” phase in HIV drug development — too quiet.  If this poster is a harbinger of what’s coming with integrase resistance, let’s hope it’s not quiet for long.

We recently published a case in AIDS Clinical Care entitled “Too Many Options”, describing a patient with longstanding HIV infection, virologic failure, and resistance to NRTIs, NNRTIs, and PIs.

Fortunately, resistance and tropism testing gave him several options for a new drug regimen — including darunavir, etravirine, maraviroc, enfuvirtide, and — if one believes phenotypic NRTI susceptibility with multiple TAMs — several NRTIs.

And what did our three experts suggest?  Three different regimens:

• Sharon Walmsley:  darunavir/r, maraviroc, and etravirine (three drugs — not counting ritonavir)

• Tim Wilkin:  darunavir/r, raltegravir, maraviroc, and tenofovir/FTC (five drugs)

• Graeme Moyle: darunavir/r, raltegravir, and maraviroc (three drugs, but different from Sharon’s selection)

Now these are smart, highly-experienced clinicians, physicians who are active in clinical research, know the literature extremely well, and actually see patients.  (Funny how that last part is sometimes left out.)   Each of them provided sound reasons for their (varying) choices.

And what did we do with this patient?  (Or one very much like him … obviously some details changed as per HIPAA mandate.)

We offered him the chance to enroll in the clinical study ACTG 5241 (mentioned by Tim), which takes patients like this, gives them an optimal regimen — then randomizes them to receive or not to receive NRTIs.

(I don’t think it will ruin the study to mention that the “flip of the coin” gave him the “No Nukes” option.)

I sure hope we learn something from this study.  While we know that regimens should contain “two (preferably three)” active agents, beyond that there’s plenty of uncertainty out there.

As part of our regular series “Antiretroviral Rounds” in AIDS Clinical Care, today we post a case of a highly treatment-experienced patient with dreaded “triple class” resistance — that is, resistance to NRTIs, NNRTIs, and PIs.

The good news now, of course, is that we have more than these three drug classes.

The tough part is choosing what to use, as often with so many new options we’re designing regimens that have not been extensively tested in prospective studies.  (Or tested at all — for example, no patient in the maraviroc MOTIVATE studies received darunavir; today I’d suspect nearly every patient on this drug is on darunavir.)

We asked three highly-experienced HIV specialists what they’d do for a patient like this with “too many options” — raltegravir-naive, R5 tropic virus, susceptibility to both etravirine and darunavir — and perhaps not surprisingly, we got three different answers.

Further input to management of this case is welcome, of course.

After a lecture on HIV for Primary Care Providers in our course last week, the most controversial topic was, not surprisingly, the use of post-exposure prophylaxis (PEP) for both occupational and non-occupational exposures.  And today, after an entire lecture on PEP to a group of HIV providers in our AIDS course, again the subject drew numerous questions — and strong opinions — from the audience.

Since this is a relatively data-free zone, one turns to the guidelines for advice.  But not surprisingly, they offer tons of wiggle room for a clinician to do pretty much anything he or she wants in all but the most florid exposures or non-exposures.

(Can there be a florid non-exposure?)

So here’s a case we just posted on AIDS Clinical Care. (Drawn from real life, of course.)  Emergency room resident sticks herself with a needle while suturing a patient’s wound, a patient who’s HIV positive with an undetectable viral load on treatment. Oh, and the resident is pregnant.

To give PEP or not to give PEP?

A few things have been guaranteed to get widely divergent views among HIV specialists — and one of them was when to start antiretroviral therapy in someone presenting with an acute OI.  However, in the latest Antiretroviral Rounds, our two experts (Raphy Landovitz and Phil Grant/Andrew Zolopa) kind of agreed.  They’d start immediately.  

At least that’s what they said.   What do we do?  What do you do?