Differences in Reversion of Resistance Mutations to Wild-Type under Structured Treatment Interruption and Related Increase in Replication Capacity

Abstract

BackgroundThe CPCRA 064 study examined the effect of structured treatment interruption (STI) of up to 4 months followed by salvage treatment in patients failing therapy with multi-drug resistant HIV. We examined the relationship between the reversion rate of major reverse transcriptase (RT) resistance-associated mutations and change in viral replication capacity (RC). The dataset included 90 patients with RC and genotypic data from virus samples collected at 0 (baseline), 2 and 4 months of STI.Principal FindingsRapid shift towards wild-type RC was observed during the first 2 months of STI. Median RC increased from 47.5% at baseline to 86.0% at 2 months and to 97.5% at 4 months. Between baseline and 2 months of STI, T215F had the fastest rate of reversion (41%) and the reversion of E44D and T69D was associated with the largest changes in RC. Among the most prevalent RT mutations, M184V had the fastest rate of reversion from baseline to 2 months (40%), and its reversion was associated with the largest increase in RC. Most rates of reversion increased between 2 months and 4 months, but the change in RC was more limited as it was already close to 100%. The highest frequency of concurrent reversion was found for L100I and K103N. Mutagenesis tree models showed that M184V, when present, was overall the first mutation to revert among all the RT mutations reported in the study.ConclusionLongitudinal analysis of combined phenotypic and genotypic data during STI showed a large amount of variability in prevalence and reversion rates to wild-type codons among the RT resistance-associated mutations. The rate of reversion of these mutations may depend on the extent of RC increase as well as the co-occurring reversion of other mutations belonging to the same mutational pathway.

Impaired bortezomib binding to mutant β5 subunit of the proteasome is the underlying basis for bortezomib resistance in leukemia cells

“…It has been established in drug-resistant cancer cells that the mutated gene can revert to WT by an additional mutation event. 41,42 Loss of a mutation can in general also be explained by loss of heterozygosity (losing the mutated gene) or oligoclonality (disappearance of one subclone and emergence of another subclone with a different mutation). Which one of the processes have occurred in this BTZ-resistant cell line remains to be elucidated.…”

Persistence versus Reversion of 3TC Resistance in HIV-1 Determine the Rate of Emergence of NVP Resistance

“…Several studies tested the decay of M184V during salvage therapy as well as treatment interruptions [51,52,53,54]. Resistant variants with impaired fitness disappeared within weeks after discontinuation of highly active antiretroviral therapy (HAART), accompanied by rapid viral load rebound.…”

Resistencias transmitidas del VIH-1 en pacientes sin exposición previa a terapia antirretroviral (Naïve) Cali-Colombia 2008-2015.

“…Del total de mutaciones de la lista de OMS-Bennett 2009, las más frecuentemente encontradas fueron aquellas que generan resistencia del virus a los análogos no nucleosídicos de la transcriptasa reversa (NNRTIs) de primera generación, especialmente efavirenz y nevirapina, específicamente la K103N (n=6, 1.8%), la K103S (n=1, 0.3%) y la Y181C (n=1, 0.3%), esta última con la importancia de afectar, además de efavirenz y nevirapina, a las nuevas generaciones de NNRTIs etravirina y rilpivirina. Con respecto a la mutación K103N, posiblemente una de las más frecuentemente encontradas en pacientes expuestos a efavirenz o nevirapina siempre en compañía de lamivudina y otro NRTI, pero con problemas de cumplimiento con el tratamiento que llevan a falla virológica 19 , a diferencia de la M184V, puede aparecer aún más rápidamente pero perdurar visible sin "archivarse" en el genotipo bien sea de la posible fuente transmisora o en el paciente naïve a quien le sea transmitida, aún en ausencia del efavirenz o la nevirapina; lo anterior tiene la importancia de tener en cuenta que muchas personas que presentan la mutación K103N pueden tener archivada la mutación M184V, con la consecuente afectación de la susceptibilidad del virus tanto a los NNRTIs mencionados como a algunos de los NRTIs de amplio uso dentro del primer tratamiento, tales como lamivudina, emtricitabina y abacavir 30,31 .…”