June 2nd, 2023

Continued Activity of NRTIs Despite Resistance Is a Real Thing

I don’t think many orthopedists are reading this post.

In our last post, we reviewed a case of a person with longstanding HIV with extensive multi-class resistance, but now a decade of viral suppression. They’re currently on an HIV treatment regimen of fully active raltegravir, partially active etravirine, and barely active (or not active at all!) darunavir. There are no NRTIs in the regimen, presumably because a resistance genotype showed four thymidine-associated mutations plus M184V.

They are taking a lot of large pills (four twice daily), with significant drug interactions and metabolic adverse effects, and the challenge is whether or not to simplify — and to what.

Based on the poll results, the comments, and the conversation online, there was hardly unanimity. But here’s what I would have voted:

It’s OK to simplify to bictegravir/emtricitabine/tenofovir AF (BIC/FTC/TAF) — or, if you don’t have it, tenofovir/lamivudine/dolutegravir (TLD).

This isn’t the only effective choice. There are other active drugs from newer drug classes (ibalizumab, fostemsavir, lenacapavir), one of which could be added to BIC/FTC/TAF or to TLD.  And of course they could just stay on what they’re on — if it ain’t broke, right?

(Quick aside — some recommended regimens with doravirine or continued darunavir. Based on our understanding of genotypic correlates of drug resistance in these two drug classes, I strongly doubt these two drugs will do much of anything — with the Y188L mutation, I’m especially dubious about doravirine.)

The BIC/FTC/TAF or TLD options are highly likely to maintain viral suppression, plus they offer several obvious advantages — simplicity, relatively low cost, fewer adverse effects or drug interactions. The reason why they will work is the focus of this post.

First, it’s because bictegravir and dolutegravir have a much higher resistance barrier than raltegravir. There’s no SWITCHMRK study in their profile — just the opposite, with switch studies in suppressed patients consistently showing maintenance of suppression, and no emergent integrase inhibitor resistance. To get resistance to DTG or BIC, you really need to put them through a stress test, often a combination of high baseline viral load, low CD4-cell count, suboptimal adherence, monotherapy, or drug interactions.

None of those apply here.

Second, and sometimes not well appreciated, the NRTIs continue to exert substantial antiviral activity even in the setting of significant genotypic resistance. In other words, despite that nasty-looking genotype with all NRTIs characterized as showing “high-level resistance,” we still get something from this drug class.

I’ve linked below a bunch of studies that directly or indirectly prove that this phenomenon is clinically important. Some were done in eras when treatment options were much more limited, and hence maintenance of the NRTI class was a high priority. Each one shows that ongoing NRTI activity in the setting of genotypic resistance is the real deal, not just some laboratory phenomenon:

This last study, called 2SD, deserves further description; from the IAS-USA guidelines:

In the 2SD study conducted in Kenya, participants receiving second-line regimens consisting of a boosted PI plus nRTIs were randomly assigned to continue their current treatment or switch to dolutegravir plus 2 nRTIs. At 48 weeks, dolutegravir plus 2 nRTIs was noninferior to the continued therapy. Although no prior resistance assessments were performed in that trial, other studies of second-line boosted PI regimens in Africa have shown extensive nRTI resistance, including high rates of M184V and K65R mutations, and such resistance would be expected in the population enrolled in the 2SD trial.

Note also that the investigator presenting these data said that there was no INSTI resistance detected among those randomized to TLD. Awaiting the publications of this trial, we can also take some comfort in the fact that to date, I’m not aware of a single published report of the dolutegravir or bictegravir-based switch strategy failing in cases like this one, provided that adherence is good:

Importantly, I’m not saying that bictegravir or dolutegravir resistance cannot happen. In the NADIA and DAWNING studies of second-line treatment comparing DTG plus NRTIs versus boosted PI plus NRTIs, although the DTG strategy turned out to be noninferior (and with DAWNING, even superior), a small number of participants did develop INSTI resistance. But remember, these were patients who were viremic on study entry, not virally suppressed; furthermore, baseline NRTI resistance did not appear to influence the outcomes.

One multinational cohort study does show that NRTI resistance is indeed a risk factor for development of DTG resistance, but there is insufficient data from the preprint to assess whether it occurred in people virologically suppressed or viremic when they started DTG. Nor does this preprint address medication adherence.

Fortunately, we should have more data to inform this decision shortly. A huge number of people on second-line treatment globally will be switching to TLD, and BIC/FTC/TAF is by far the most popular HIV regimen here in the USA, both for initial treatment and stable-switch.

Stay tuned!

And watch this wonderful video, which includes asking an orthopedist Are you an infectious diseases doctor? His response is priceless.

2 Responses to “Continued Activity of NRTIs Despite Resistance Is a Real Thing”

  1. Jake Lazarus says:

    Paul, thank you for this. I have a patient (on 3TC/DTG + r/DRV BID for reasons you’d guess) who I now am reassured is appropriate for simplification!

  2. Ashraf Khan says:

    For someone like me working outside the US setup, thanks for make it all very simple that INSTI-based combined pills are really the saviours for people with HIV.

    And you diligently provide the studies, also as a simple list to prove it. Thank you!

HIV Information: Author Paul Sax, M.D.

Paul E. Sax, MD

Contributing Editor

NEJM Journal Watch
Infectious Diseases

Biography | Disclosures | Summaries

Learn more about HIV and ID Observations.