HIV and ID Observations

We got some bad news about our dog Louie, the world’s greatest dog. Writing his story here is therapeutic, so forgive the oversharing.

In January, 2013, my wife forwarded me this email:

She doesn’t usually use 5 exclamation points or 6 question marks, and the unusual punctuation betrayed her excitement. The answer to “What do we do??????”, of course, was to claim one of these puppies; this would be her first dog.

The father of these pups — Asher was his name — was a special dog, a little guy who reigned supreme at the local gift shop, Wild Goose Chase. He greeted visitors with kindness, bright eyes, and a wagging tail, easily claiming his title as The World’s Cutest Dog. His owners even printed up his own card, one my wife kept in her wallet just for this opportunity.

A couple of months later, after Asher’s pups had grown up a bit, we met the very tired mom and the whole gang of her offspring at their home in western Massachusetts. We chose our favorite — a spotted little guy we called Louie, and brought him home to join our family.

Love at first sight.

Louie was no purebred, as the black spots gave away the unfancy part of his genetic lineage. Embark (yes, we checked) told us he was half Coton du Tulear, and half “super mutt,” a term I particularly like. Since this was always cumbersome to explain, when others asked what kind of dog he was, I often just said he was a mix, or a Havanese, since that’s what he looked like and “Havanese” was easier to say.

Over the years, we’ve bonded with Louie in a way that only dog lovers can understand — it’s nothing unusual, but it’s magic nonetheless. Here’s what happened:

• He immediately learned his name, and responded to it instantly. Of course his name is Louie.
• He excelled at eye contact, melting your heart. Stare your way to bigger meals.
• His sleep cycle gradually fell in sync with ours.
• We learned his loves and hates, based solely on the barking and yipping sounds he’d make at the door when he spotted a favorite (the mailperson who always brought him a Pup-peroni) or an enemy (a black lab that somehow embodied pure evil to him).
• His tail and bright eyes gave away excitement for every adventure (We’re going to the park!) or incoming snack (Would you like a treat?).
• Most importantly: He exuded love and adoration for us with zero ambivalence, expressing it regularly without ever, for a moment, getting tired of our company.

The years of love flowing from him made us utterly smitten. Someone came to my office recently, and noted that though the pictures of my family outnumbered the pictures of Louie, the biggest one in size was the painting my son’s friend made of our doggie, in exchange for a contribution we made to an animal services organization. Guilty as charged.

And yes, I’ve featured him here on this site, probably too much, and probably to the annoyance of those who just don’t get the dog thing. A sampling:

1. There was a post about dog-related infections used as an excuse to post pictures about cute dogs, including Louie.
2. How about this one about the importance of eye contact in clinical medicine? A perfect chance to show-off Louie’s super skill.
3. Or another one, about the time he was attacked. He recovered quickly and harbored no hard feelings, what a good dog.
4. I featured him with my brother’s and sister’s dogs, Zelda and Zoe. Why not?
5. Here he posed with his favorite dessert plates, the china picked up by my wife in the bargain bin at local store. Yes, we bought a full set.

So lots of Louie here, the Star of the Show on this ID blog.

When I threw his toy or a ball, and he chased after it, he came romping back in a way perfectly embodied by the Charles Barsotti cartoon with the caption, And the crowd roars!

Wow, he learned to wag his tail in exchange for a treat! What a genius! He can even ride a bike!

To the non-animal lovers, I understand this post might not be your cup of tea. This kind of relationship is not for everyone, nor does it have much logic behind it. Why do we grow to love these animals so much? What causes us to generate endorphins when we pet them and stare into their eyes? Why do some people cry more at the death of their dogs than their family members? Makes zero sense.

We thought we had many more years of these tricks, and eye contact, and tail wags ahead.

But for those of us who have experienced it — this deep love for our pets that is returned by them more than a thousand-fold in exchange — I can assure you that watching them get seriously ill is utterly heartbreaking.

Which is why I’m writing this with tears streaming down my cheeks.

Let’s hope you rally, Louie, and that this is just some minor thing from a random scrap you picked up off the street, or a transient viral illness that just gets better with time.

But I am not optimistic. The unspoken messages conveyed by the vet as she told us of the ultrasound findings (we’re doctors, after all), and that she insisted he be admitted to the animal hospital for further workup — these do not engender hope.

I miss you already. ♥

Three-drug therapy has been the standard of care for HIV therapy for so long it’s difficult to shake the view that it must be more effective than two drugs. This is particularly the case for those with advanced, HIV-related immunosuppression or very high viral loads, as they provide an important stress test for all regimens.

Remember the pivotal GEMINI studies, comparing initial two-drug treatment with DTG/3TC with three-drug regimens of TDF/FTC plus DTG? Overall, they found that the two-drug arm was noninferior in virologic response. But because of concerns about inadequate activity of using fewer drugs, the trial excluded participants with HIV RNA >500,000. Plus, in the small number of those who started with CD4 <200, the results hinted at a suboptimal response in the DTG/3TC arm.

Now, along comes the DOLCE study, which had an entry criterion that required a CD4 <200, limiting the study population to people with advanced HIV disease — a bold move. Conducted in Argentina and Brazil, DOLCE enrolled treatment-naive participants who then were randomized 2:1 to receive open-label DTG/3TC (given as a single pill) or TDF/XTC plus dolutegravir (DTG). Concomitant chronic hepatitis B was exclusionary.

If you’re new to this HIV treatment business, allow me this geeky digression: “XTC” here doesn’t refer to the 1980s New Wave band, but to lamivudine (3TC) or emtricitabine (FTC), which are interchangeable from a safety and virologic perspective. The names come from their chemical structures — 3TC from one of the 3’s in 2′,3′-dideoxy-3′-thiacytidine, FTC from its fluoro group. And yes, confusingly, lamivudine is “L” in TLD, the abbreviation for tenofovir-lamivudine-dolutegravir. Got it? There will be a quiz.

Ok, back to the study. DOLCE enrolled 229 participants, 152 assigned to DTG/3TC, and 77 to TDF/XTC + DTG. At baseline, the median CD4 cell count was 116, and the viral load was 151,000. Fully a third of the participants would not have qualified for the GEMINI trials, as 23% had viral loads >500,000, and 10% greater than 1 million.

At week 48, 82% in the DTG/3TC arm and 81% in the triple-therapy group achieved viral suppression (<50 copies/mL). Time to virologic suppression and CD4 outcomes were similar, with no hint that three drugs performed better. Notably, responses remained comparable with both strategies even in the group with very high viral loads (>500,000). No treatment-emergent resistance occurred.

All studies have limitations, and this one is no exception — each acknowledged by the authors. The DOLCE trial was relatively small and not powered in its primary analysis to make specific claims about noninferiority (though a post-hoc analysis suggested it would meet standard noninferiority criteria). Plus, as an open-label trial, the DTG/3TC arm had the benefit of a single-pill formulation, which was not the case in the three-drug arm. With only two South American countries participating and the study being predominantly men, the results might not be applicable in other settings, though there is no obvious reason to doubt effectiveness in broader populations.

Limitations notwithstanding, credit to the investigators for filling this gap in knowledge about DTG/3TC with a challenging patient population. The astute (and always quite witty) Dr. Laura Waters wrote a fine accompanying editorial, appropriately stating that the data are reassuring from the virologic and safety perspective — and noting that the underperformance of DTG/3TC in GEMINI was likely unrelated to its antiviral activity.

But she also noted that still missing is a clear benefit of two drugs over a regimen that contains TAF (not TDF)/FTC plus either DTG or BIC — none of the studies to date have found evidence that “less is more” when it comes to this comparison, which was not done here. It may turn out that the true advantage of the three-drug regimens with DTG or BIC is not that they’re three drugs with greater anti-HIV activity — but that they contain tenofovir, which has a happy additional effect of being a highly effective treatment and preventive strategy for hepatitis B.

Now take it away, XTC! And this time I don’t mean 2′,3′-dideoxy-3′-thiacytidine.

Image by Jackson Moccelin from Pixabay

Throughout my career as an infectious diseases doctor, the CDC has been a rock-solid source.

• Need reliable data on an outbreak? The CDC.
• Need thoughtful, evidence-based guidelines? The CDC.
• Need an authoritative reference for a consult question or to steer a colleague or trainee to the right place? The CDC.
• Need the latest, most accurate surveillance information on HIV or influenza or dengue or you-name-it? The CDC.
• Need advice for your friend doing anthropology research in rural Bolivia and wondering whether they should take malaria prophylaxis (yes), and what it should be (multiple options)? The CDC.

Did I always agree with every word? Of course not. Show me an ID doctor who always agrees with every guideline, and I’ll show you a cephalosporin that covers enterococcus.

For example, for years I’ve thought we’re too aggressive with “bat in bedroom, no bite” postexposure prophylaxis, preferring the Canadian approach. But I never doubted the people making the U.S. guidelines had done their homework with integrity; they weren’t part of some sinister rabies vaccine/immunoglobulin cabal. It was a difference in opinion, that’s all.

And I trusted the people. The ones I’ve known who have worked at the CDC are mission-driven and incredibly hard-working. They’re not looking for fame or fortune, to cultivate a brand, or to make a splash in the media. You don’t expect to see a TikTok video from a CDC official. They’re the kind of colleagues who disappear into data sets, surveillance reports, and fieldwork, all in the service of preventing disease and saving lives.

So what happened?

In a word: COVID. The pandemic was the public health earthquake of our lives, and the aftershocks continue. The CDC is one of its casualties. Instead of learning from missteps and strengthening the institution, we’re watching it be weakened — deliberately, in some cases, and it seems with pointless vengeance. The critics who scream the loudest treat it as if every imperfect COVID recommendation, every adjustment of guidance in real time, every policy now viewed as incorrect with 20-20 hindsight, was a betrayal and not a best effort to help us cope with this new, tricky virus.

Let’s acknowledge that perfection was impossible in the face of an unprecedented global crisis. Guidance had to evolve, sometimes rapidly. To punish the agency now is like telling tennis star Carlos Alcaraz he can’t compete in the U.S. Open because he lost in the Wimbledon finals.

Yes, the stakes were high during COVID, but nobody — NOBODY — got it 100% right.

The result? One of our most reliable public health institutions is being destroyed by non-experts in medicine and public health. People with disturbing beliefs about infectious diseases in general and vaccines in particular. And who knows what the next year or years will bring? Who will we turn to then?

For those of us who have leaned on the CDC our entire careers, watching its destruction at the hands of non-experts is not just disorienting — it’s heartbreaking, and makes me very, very sad.