AIDS drugs: when resistance is futile

 

“Resistance is futile” – the Borg

In nearly every conversation I’ve had with Affecteds who are experimenting with ways to reduce the toxicity of antiretroviral (ARV) regimens, questions about “AIDS drug resistance” comes up. Resistance is often raised as a boogeyman in research trials of monotherapy and intermittent treatment options. While drug resistance—especially bacterial antibiotic resistance to staphylococcus or tuberculosis, for example—is increasingly a problem in modern medicine, one is unlikely to hear drug resistance discussed quite the way it is with AIDS. No other pathogen is described as “sneaky”, “clever”, or more mutable than HIV, despite the fact that retroviruses do not even meet most definitions for being a living entity, let alone have a brain.

There is little question that ARV drugs can stop working; that is they can cease to accomplish the objectives of reducing so-called viral load to undetectable levels, or that sick people may get sicker or even die, despite (and sometimes because of) taking their drugs. The guidelines for treatment suggest changing the drugs in an attempt to “outsmart” the virus. For too many patients, this game of drug switching proves to be an exercise in futility, until their health is so far gone that the only options left are called “salvage therapy”. The language of AIDS drug treatments itself can be quite telling.

In my last post, I wrote about a new strategy—unfortunately not yet well known to most patients and many practitioners—to shift away from NRTIs and NNRTIs, the oldest and most toxic classes of AIDS drugs. The fear of resistance has been so deeply drummed in the AIDS treatment community’s psyche that a critically important shift in thinking is having difficulty gaining traction where it is most needed: in doctors’ offices.

A recent article in the NEJM Journal Watch’s blog HIV and ID Observations reported, with some surprise, that Janssen Diagnostics will cease offering its vircoType HIV1 “resistance test”.

 

Announcing the end of vircoTYPE HIV resistance testing on Janssen DIagnostic’s website.

If resistance is such a problem in managing HIV drug treatment, why in the world would a test for resistance be dropped? It’s no surprise to the NEJM blogger Paul Sax, MD:

But am I surprised it’s disappearing? Not if you think about it for a moment. As is plainly obvious to anyone doing HIV care, the incidence of new patients with the sort of HIV drug resistance for which the test was developed has plummeted. There simply aren’t many new patients out there who have multiple mutations, especially in the PI-drug class, and who will need the computational black-box firepower provided by a vircoTYPE. A regular genotype does just fine for those who are newly diagnosed, or have virologic failure on a first-line regimen due to poor adherence.

So there are other tests for “resistant mutations”, but note the explanation given for the passing of vircoTYPE: the incidence of certain “resistance” has plummeted. Why?

What about the existing patients with this sort of resistance? Most are virologically suppressed right now, and hence don’t need resistance tests anymore.

And in a nice irony, it’s in part the antiretrovirals made by the therapeutics branch of this company — darunavir in particular, etravirine as well — that have made the vircoTYPE obsolete.

I’ve seen and read Dr. Sax in other venues, and he’s quite the promoter of ARV drugs. This is not the first time he’s addressed “resistance”. In another blog post, Sax makes some fascinating assertions about who develops resistance (edited for brevity, emphasis added):

I actually don’t think expanding treatment will significantly increase drug resistance, ironically for the exact reasons she cites in her piece — the same people who don’t take their medications and don’t show up for clinic visits usually don’t get resistance, or at least not much of it.

No meds = no selective pressure.

Just look at the people in HIV clinics today with horribly multi-drug resistant virus. They are predominantly the highly adherent, aggressively treated patients from the 1990s/early 2000s who received “serial monotherapy”, that inadvertent adding-on of a single active drug to a failing regimen.

Sometimes the serial monotherapy was out of clinical necessity — we had to do something when our patients were about to die of AIDS even if we didn’t have two active drugs — and sometimes it was the result of incomplete understanding HIV drug resistance. For example: did we really once think that d4T resistance was uncommon? Yikes…

And diagnosing a new case of high-level resistance to NRTIs, NNRTIs, and PIs — or even worse, to all six drug classes — has become incredibly rare. I strongly suspect it’s likely to stay that way, at least in settings with access to viral load monitoring, resistance testing, and the full range of antiretroviral drugs.

Here’s my take. These resistance tests are expensive, so they are not likely to be used in so-called resource poor countries. The vircoTYPE test was probably used mostly in the U.S., and perhaps Canada and Western European countries. These are the same countries that have moved away from—or at least reduced the dosages of—the early classes of NRTIs and other drugs that are most susceptible to failure (another word for resistance). For example, stavudine, one of the oldest and most toxic NRTIs, is rarely prescribed in wealthier countries, but is still being forced down the throats of patients in poorer countries¹:

On Monday 30 November 2009, the World Health Organisation stated that “[The WHO] recommends that countries phase out the use of Stavudine, or d4T, because of its long-term, irreversible side-effects. Stavudine is still widely used in first-line therapy in developing countries due to its low cost and widespread availability.

It is embarrassing to the human race, and the United States in particular, that drugs found to be unacceptable here are still being promoted in other countries.

Stop it. Just STOP IT.

Note too, the reference in the article to darunavir in particular. This particular protease inhibitor was designed—based on a naturally occurring PI—to resist resistance, if you will. While etravirine is also mentioned as being less prone to resistance, it has far too many toxic and adverse effects to be considered a first line option, imho.

Add this information to the balance scale of recently published information favoring the elimination of NRTIs everywhere.