HIV and ID Observations

Thanks to our mail person for taking this portrait of our pets Louie and Otto. You can tell by their expressions that they miss us.

Here’s a most entertaining email about a tricky case (some details changed for the usual reasons), with my annotations in brackets:

Subject: Regimen intensification?

Hi Paul:

Long-time reader, first time caller. [Love that intentional mixed metaphor — should we start a radio talk show?]

We have a pt who was on TDF/FTC/EFV for a decade. He was undetectable the whole time. [He must have been difficult for his friends and family to find! Ha ha ha.]

He agreed to modernize, and another doc switched him to TDF/FTC/RPV, then TAF/FTC/RPV. He suddenly had a viral load that hovered just above the threshold of detectable — e.g. 59, 86, 101 — and it refused to go away. [Bad viral load!] So, we switched him to ABC/3TC/DTG. But he still has a persistent low viral load… like 95, 81, 72. [There is clearly no trend. Isn’t my statistical acumen impressive?] He says his adherence is virtually 100% and his partner confirms it. We were suspicious, but pharmacy also said he’s picking up his meds on time.

Interestingly, he admits he took TDF/FTC/EFV on weekdays only and stayed undetectable (grrrrr), so of course he wants to switch back! [Hey, that strategy probably works fine for that regimen.] He has no major mutations on a genotype run during the TDF/FTC/RPV phase, and no major mutations on an archive genotype either.

*{#%*$, Paul?! Do we switch him to a PI regimen, or just intensify by adding another agent. If so, which one? Do we check blood levels? Who does that? Or is he just not taking his meds every day, like before?

I know you’re a very busy man, Paul. [Nah. Just sitting here writing this blog post.] If you could take a moment to link me to any discussions, posts, or articles on this topic, I would be forever grateful.

With high hopes you can help! […which I am about to disappoint.]

Dorabella [I wanted to put her real name here, as she had aspirations to be detected on Google searches. But it’s a no-no for patient queries.]

Oh my, so much to unwrap here! Because when it comes to persistent low-level viremia in treated HIV patients, there’s much agony, gnashing of teeth, and confusion.

This is not the isolated low-level result preceded and followed by an undetectable one, the entertainingly termed “blip.” The blipologists of the world all agree blips mean essentially nothing (hence putting themselves out of business).

This patient’s situation is much tougher. So here, in a lazy bulleted list, are a bunch of things we know — and mostly don’t know — about this tricky situation of persistent low-level viremia.

• These patients have a higher HIV “reservoir.” If you look back, they often a history of advanced HIV disease, and/or very high pre-treatment HIV RNA.
• There are at least two types of low-level viremia patients. The first are those who are fully adherent to their meds, and their HIV RNA has been persistently detectable since we started using the more sensitive RT-PCR assays, especially compared to the bDNA, may it R.I.P. The second type are practicing “white coat adherence” — that is, not taking their medications very much, then remembering to do so again a few weeks before coming in for an appointment. A quick call to the pharmacy for a refill frequency check can sort this out.
• Some studies show low-level viremia is more likely to happen on boosted PI-containing regimens. The smart virologist Carlo Federico Perno from Italy has a nice theory why this is the case. It’s some combination of the mechanism of action of the PIs, where they act in viral replication, the defective virions, and the resistance barrier. So I wouldn’t switch to a boosted PI; this might make things worse.
• Several (but not all) studies suggest they are at greater relative risk of eventually developing true virologic failure, compared to those with undetectable HIV RNA.  For example, in this study, a viral load between 50–200 was OK, but not 201–499. In this one, even 50-200 wasn’t benign — more failures. Regardless, the absolute risk is still quite low, especially if adherence is good. And they do not appear to be slowly developing resistance to their regimens.
• Intensification won’t work. Throwing more drugs at this low-level viremia on treatment doesn’t lower the viral load further. We know this from studies and from anecdotal clinical experience.
• They are not sick. Their CD4 cell counts remains stable, and they don’t get opportunistic infections. Data are mixed whether this low-level viremia is associated with higher levels of inflammation and immune activation markers, but you can’t do much about that even if it’s true.
• Hey, what about “undetectable = uninfectious”? Does this still count? Hmmm, tough one. We simply don’t know if they are more likely to transmit HIV to others compared to those with undetectable HIV RNA. Reassuringly, the viral load thresholds in the major HIV transmission studies were all higher than most patients with low-level viremia, including the one in this case. This query forced me to look it up, so here they are:  Rakai (1500 cop/mL, untreated); 052 (400 cop/mL); PARTNERS (200 cop/mL); and Opposites Attract (200 cop/mL). (You’re welcome.) Isn’t that at least somewhat reassuring?

For the record, there’s a reason “Dorabella” didn’t just go to the HIV treatment guidelines for guidance, as there is ready acknowledgement that we just don’t know exactly what to do. Here are the blunt assessments from DHHS and IAS-USA, respectively:

“There is controversy regarding the clinical implications of persistent HIV RNA levels between the lower limit of detection and <200 copies/mL in patients on ART.”
and:
“Data are inconsistent about long-term effects of persistent HIV RNA between 50 and 200 copies/mL, and current data are insufficient to guide clinical management.”

Given this uncertainty, here’s what I wrote back:

Hi Dorabella,

Tough one! First, is it possible that you switched from the bDNA assay to the RT-PCR right around the time his regimen changed? That’s important, because if so, it would explain why he went from “undetectable” (<75 copies/mL) to low-level detectable — it’s not the regimen, it’s that the RT-PCR is more sensitive.

Second, we don’t really know what to do with these patients who have persistent low-level viremia. They have a higher viral reservoir, and some might eventually fail therapy (probably those with poor adherence), but intensification doesn’t seem to work. So keep him on a high resistance barrier regimen, like the one he’s on — or theoretically even better, switch to TAF/FTC, DTG.

Third, can I steal this case for the blog?

Thanks,

Paul

She obviously said yes to that last query!

(Inspired by various unvalidated, non-FDA approved lab tests.)

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Once upon a time, I used being on service as a convenient excuse for not writing very much — or certainly, not writing very much of importance — on this site.

The on-service time also allowed me to poke gentle fun at my colleagues, several of whom always turn on an “out-of-office” message when they attend on the inpatient ID consultation service.

I’m talking about this thing that responds instantly when you email them:

I am currently attending on the inpatient consult service. During this busy time, I may not be able to respond to email in a timely fashion. If you need to reach me urgently, please page me by calling xxx-xxx-xxxx, or leave a non-urgent message here and I will respond shortly.
Thank you,
Rudolph

Reminding me of this post, my friend Carlos Del Rio sent me this email earlier this year:

Going on service April 1st. Should I put my “Rudolph” message up?

I’d advised Carlos to check Emory’s Policies and Procedures — am sure it’s in there somewhere.

Now, having just completed a couple of weeks doing inpatient ID consults — and falling behind on emails — I thought it time to add a few additional observations about this practice:

1. Who is most likely to do it? Let’s call people who do this “OOODS.” (Pronounced like the first syllable of “noodle,” and standing for “out-of-office during service” types.) My anecdotal impression is that OOODS are predominantly academic physicians, people who know patient care is important but don’t do it on a day-to-day basis. Hence they want to “clear the decks” of other pressing responsibilities. A minority might be full-time outpatient clinicians who only rarely do inpatient work.
2. When not on service, they are generally very responsive to email. OOODS are often “inbox zero” types who wouldn’t think of allowing the sun to set on a critical research or administrative query. So when busy consult days happen, and the long hours on the wards make it impossible for them to keep up, they want to reassure their colleagues and friends that they haven’t suddenly decided to abandon academic medicine for more frivolous activities. Imagine the speculation!
   

   “Hey, I emailed Dr. Smith 12 hours ago, and he hasn’t  gotten back to me yet — that’s weird, he’s usually so quick to respond. Plus, no out-office-message.”

   “Yes, that’s weird. But he’s a pretty big Phish Phan — maybe seeing all their summer concerts?”

3. They’re generally pretty important. Many exceptions to this rule, but the academic rank and productivity of OOODS is impressive. One study found that the number of citations for papers published by OOODS was significantly higher than non-OOODS, even when controlling for total RVUs generated on the consult service. NIH grant dollars and the impact factor of their published papers were also significantly higher. If you don’t believe me, the published paper can be found here.
4. One person who inspired the original post identified herself almost immediately. Shortly after I wrote it, I received this email:
   

   Hey, I’m Rudolph aren’t I??? Is that a bad thing?

First, let the record show that this OOODS person who emailed me was only one of several people who sent me a similar query, as I adapted the sample out-of-office message from a bunch of different ones used by friends and colleagues.

Second, it is by no means a bad thing — it’s just a thing some people choose to do; others don’t (I don’t) — as evidenced by the fact that this particular OOODS person was most deservedly just appointed an extremely important leadership position.

Congratulations, Rochelle!

Rabbit or duck?

Two new HCV regimens gained FDA approval recently, bringing us closer to the end of this extraordinary phase of drug development.

Think about it — has there ever been a more spectacularly rapid improvement in treatment of anything? If so, please let me know what that is. Remember, as recently as early 2013, highly toxic interferon-based therapy (with ribavirin and telaprevir or boceprevir) was still standard-of-care.

The recent approvals:  Sofosbuvir-velpatasvir-voxilaprevir (Vosevi) on July 18, indicated for patients who have failed prior treatment with either sofosbuvir or an NS5A inhibitor. Twelve weeks of treatment (one pill daily) will cure 95–96% of patients, and pretreatment presence of NS5A, NS3, or NS5B resistance mutations does not reduce response. A month of sof-vel-vox — which will only be used as a salvage therapy — is priced at $24,900.

Then, glecaprevir-pibrentasvir (Mavyret) was approved on August 3rd. A pan-genotypic regimen that includes both an HCV protease inhibitor and an NS5A inhibitor, “G/P” is 3 pills daily, requiring only 8 weeks of therapy in treatment-naive individuals without cirrhosis. Clinical trial results show cure rates in the high 90s, with a low incidence of treatment-related adverse events requiring drug cessation.

Glecaprevir-pibrentasvir can also be used in patients with renal impairment (including dialysis), prior treatment failure of genotype 1 with either an NS5A inhibitor or PI (but not both), and in compensated cirrhosis. Treatment duration should be increased to 12 weeks in those with prior treatment or cirrhosis.

So where does that leave us in terms of “unmet needs” in HCV therapy?

Let’s review what we currently have:

• Nearly 100% of those who get treated are cured.
• Most regimens are one pill daily.
• Ribavirin is rarely required for treatment-naive patients.
• Side effects leading to drug discontinuation are exceedingly uncommon.
• Treatment duration is only 8–12 weeks.
• Drug interactions are mostly manageable; if not, HCV treatment is so short that temporary discontinuation of the conflicting drug is usually fine.
• Several pan-genotypic options are available.
• Certain therapies are also effective for treatment-experienced patients with resistance.
• Some regimens are safe and effective for those with moderate-severe renal disease — even hemodialysis.

From a medical perspective, this doesn’t leave out a whole lot, does it? Treatment of HCV is so easy there’s a strong push in some circles to move it to front-line providers in primary care — and of course outcomes in their hands are as good as with hepatologists and ID specialists.

Yes, cost of and access to HCV therapy remains an issue, especially in certain regions.

But things have vastly improved in this area too. With prices way down from the crazy days of early 2014 (when the non-FDA approved “sim-sof” regimen was > $100,000/cure), we should anticipate that more payers will stop medically unjustified policies such as fibrosis criteria, negative toxicology screens, and limiting prescribing of HCV therapy to specialists.

And market forces are doing something — note that the wholesale price of G/P is $13,200 per month, very close to the negotiated discounted price for LDV/SOF with the VA and certain state Medicaid programs.

Which brings me back to the title of this post — Have We Reached the End of HCV Drug Development?

If we’re not there yet, we’re certainly close.

Here’s a poll about where we should go with HCV research — please vote!

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