Hello,
I was hoping I could get input regarding this unusual resistance pattern:
63 y.o. man, long-term survivor, CKD stage 2-3 on Dovato (dolutegravir-lamivudine). Virologically suppressed on Dovato since 2020. Had a tiny blip in 2023, but suppressed again all 2024 and 2025. Had an MI in May/2025 requiring angioplasty. During that hospital stay his VL was 193. The patient denied missing any doses and was taking meds consistently. On discharge follow up June/2025 VL was 19,900. We sent a genotype and the results reported:
HIV-1 Drug Resistance by NGS -
○ INSTI drug resistance mutations: G140S
○ INSTI additional mutations: D41N, G47R, G70R, T112A, T124A, T125A, W131*, W132*, G134K, E152K, E157K, G163H, R166K, Y194C, V201I, I208M, K211R, N222K, A265V
○ *INSTI uncalled sites identified: V75
V75I would be associated with potential low-level CAB resistance
The following 7 APOBEC-associated mutations were present in the sequence IN: G47R, G70R, W131*, W132*, E152K, E157K, R166K.
Interpretation: --> potential low-level resistance to BIC and DTG; low level resistance to CAB; intermediate resistance to EVG and RAL
○ PI drug resistance mutations: None
○ PI accessory mutations: L63Q, V77I
○ NRTI drug resistance mutations: None
○ NNRTI drug resistance mutations: V106I
○ RT additional mutations: V118I, K122E, I135T, K166R, E194A, G196E, T200I, I202V, H208Y, R211K, F214L
○ *RT uncalled sites identified: Y318, N348
Y318F would be associated with high-level DOR resistance
N348I would be associated with low-level NVP resistance
*In HIV resistance testing, "uncalled sites identified" refers to known locations within the HIV genome where drug resistance mutations are expected to occur, but the sequencing process was unable to definitively determine if mutations were present at those specific locations. This is usually because there wasn't enough high-quality sequencing data for those sites.
We discussed with Merck MSL (very helpful) and they explained that the V106I should not have much of an impact on doravirine activity. And that they think a 5-fold decrease in activity or more is what it usually takes to knock out doravirine as an option, which usually takes 2 or more mutations. They did say though, that the Y188L and the Y318F appear to be exceptions to that rule, with Y318F causing an 11-fold reduction in activity on its own (and the Y318 site was one of the uncalled sites on his genotype that we have, meaning we don't know if there is a mutation there or not).
We decided to obtain a phenotype, but they couldn't run it because the repeat VL is now 31.
The sudden loss of viral suppression is hard to explain. The patient denies any missed ART doses, changes prescribed or OTC medications/supplements/herbal products, or changes in diet that would help explain. Patient does have significant past NNRTI exposure pre-2014, but no recent exposure around the time of genotype collection, and susceptibility to the newer NNRTI doravirine not able to be determined.
Questions:
--Thoughts regarding these APOBEC-associated mutations? It is the first time I see this in a genotype results.
--VL is now significantly better, but not fully suppressed, would you feel inclined to switch based on this genotype?
--CrCL hovers around 40-50 so we were hoping to avoid Tenofovir containing regimens, would want to Avoid ABC after recent MI, odd that he has possible resistance to DRV with minimal NNRTI experience (EFV remotely) and he is now on brilinta which is contraindicated with PIs making this complicated. Any suggestions?
Thanks for your thoughts.
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Ruth Serrano
San Antonio TX
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