HIV: resistance mutations

Let’s start with a case:

49M with 25yr h/o HIV and intermittent compliance establishing care after PCP retired. Most recent regimen was TDF/FTC/EFV; he has been taking this 2-3 times a week to make it last. VL 12500, CD4 321. Genotype w/M184V. What would you prescribe?

Let’s talk #HIV Mutations! The M184V mutation is an NRTI mutation that is selected for by exposure to 3TC or FTC. The result is phenotypic resistance to both agents (susceptibility can drop by > 100-fold). There is also low-level resistance to ddI and ABC.

As a reminder, NRTI = nucleoside reverse transcriptase inhibitor. They function by being incorporated into the growing HIV DNA chain in place of a normal nucleotide – however, they are missing the hydroxyl group that allows chain continuation.

The M184V mutation promotes some interesting physiology – it reduces overall viral fitness resulting in decreased replication in cells. The figure below (from PMID 10482597) compares several mutants to wild type (pNL4-3). Met184Val = M184V

Even when resistance develops, it seems that lamivudine (and presumably emtricitabine) continue to exert effects. Castagna et al demonstrated that even in M184V mutated viruses, lamivudine monotherapy (dark line) still reduced clinical failure. PMID: 16549962.

Interestingly M184V promotes increased susceptibility to tenofovir. This leads many experts to suggest continuing pressure with FTC or 3TC as a way to decrease fitness and promote increased susceptibility to TDF or TAF. Also, removing 3TC or FTC complicates many regimes

The wonderful @PaulSaxMD has two great M184V blog posts on HIV and ID observations which sum this up nicely! 👍
Pt 1: https://blogs.jwatch.org/hiv-id-observations/index.php/the-curious-case-of-m184v-part-2-and-more/2019/09/08/
Pt 2: https://blogs.jwatch.org/hiv-id-observations/index.php/the-curious-case-of-m184v-part-2-and-more/2019/09/08/

What should be done in patients with M184V mutations? There are a few options.

Based on DHHS guidelines (https://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-arv/15/virologic-failure) – it depends on what regimen they have failed. Our patient failed a regimen of NNRTI plus two NRTIs.

Guiding evidence comes from the DAWNING trial (PMID: 30732940) which evaluated those who failed NNRTI + 2 NRTI regimens. They were given either DTG or LPV/r plus 2 NRTIs. In this analysis, the DTG regimen was superior even though 85% of regimens contained FTC or 3TC!

Here is a question – do you feel comfortable extrapolating this to mean BIC/TAF/FTC is a reasonable regimen in this circumstance?

In summary, M184V is an HIV mutation that:
⬇️ Susceptibility to FTC and 3TC
⬇️ Viral Fitness
⬆️ Susceptibility to tenofovir

While multiple possible regimens exist, DTG + 2 NRTIs likely has the best evidence, followed by boosted PI + INSTI or 2 NRTIs.

Thank you to @MDdreamchaser and Dr. E.P. Barrette for providing review and feedback on this #tweetorial and @PaulSaxMD for his excellent M184V overview at HIV and ID Observations.

Originally tweeted by Infectious Diseases Fellows Network (@ID_fellows) on 20 August, 2020.

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