Dynamics of NRTI Resistance Mutations during Therapy Interruption

Trignetti, Maria; Sing, Tobias; Svicher, Valentina; Santoro, Maria Mercedes; Forbici, Federica; D’Arrigo, Roberta; Bellocchi, Maria Concetta; Santoro, Mario; Marconi, P; Zaccarelli, Mauro; Trotta, Maria Paola; Bellagamba, Rita; Narciso, Pasquale; Antinori, Andrea; Lengauer, Thomas; Perno, Carlo Federico; Ceccherini‐Silberstein, Francesca

doi:10.1089/aid.2008.0159

Cited by 10 publications

(9 citation statements)

References 39 publications

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“…Using a survival analysis model, Trignetti et al did not find a pattern in the reversion of RT mutations during treatment interruption [21]. The difference in results may be due to the nature of the cohort data.…”

Section: Discussionmentioning

confidence: 96%

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

et al. 2011

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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.

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Section: Discussionmentioning

confidence: 96%

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

et al. 2011

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“…For example, K65R, which is thought to emerge more readily in patients with subtype C virus [41], was detected in only 3 of 115 patients. K65R and M184V/I disappear rapidly (<4 months) after treatment interruptions, whereas TAMs, Q151M, and NNRTI mutations persist longer [17–19]. …”

Section: Discussionmentioning

confidence: 99%

“…Studies indicate that only 17%–53% of patients have switched regimen 12 months following virological failure [9, 15]. Although resistance patterns on identification of virological failure are well described, few data exist on resistance patterns on switching regimens [6, 14, 16] and the influence of nonadherence on such patterns [17–19]. Also, few studies have explored the impact of NRTI mutations and the resultant loss of regimen activity on empirically prescribed second-line ART [4, 16].…”

mentioning

confidence: 99%

Viral Suppression Following Switch to Second-line Antiretroviral Therapy: Associations With Nucleoside Reverse Transcriptase Inhibitor Resistance and Subtherapeutic Drug Concentrations Prior to Switch

Johnston

Cohen

Wiesner

et al. 2013

The Journal of Infectious Diseases

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Background. High rates of second-line antiretroviral treatment (ART) failure are reported. The association with resistance and nonadherence on switching to second-line ART requires clarification.Methods. Using prospectively collected data from patients in South Africa, we constructed a cohort of patients switched to second-line ART (1 January 2003 through 31 December 2008). Genotyping and drug concentrations (lamivudine, nevirapine, and efavirenz) were measured on stored samples preswitch. Their association with viral load (VL) <400 copies/mL by 15 months was assessed using modified Poisson regression.Results. One hundred twenty-two of 417 patients (49% male; median age, 36 years) had genotyping (n = 115) and/or drug concentrations (n = 80) measured. Median CD4 count and VL at switch were 177 cells/µL (interquartile range [IQR], 77–263) and 4.3 log10 copies/mL (IQR, 3.8–4.7), respectively. Fifty-five percent (n = 44/80) had subtherapeutic drug concentrations preswitch. More patients with therapeutic vs subtherapeutic ART had resistance (n = 73): no major mutations (3% vs 51%), nonnucleoside reverse transcriptase inhibitor (94% vs 44%), M184V/I (94% vs 26%), and ≥1 thymidine analogue mutations (47% vs 18%), all P = .01; and nucleoside reverse transcriptase inhibitor (NRTI) cross-resistance mutations (26% vs 13%, P = .23). Following switch, 68% (n = 83/122) achieved VL <400 copies/mL. Absence of NRTI mutations and subtherapeutic ART preswitch were associated with failure to achieve VL <400 copies/mL.Conclusions. Nonadherence, suggested by subtherapeutic ART with/without major resistance mutations, significantly contributed to failure when switching regimen. Unresolved nonadherence, not NRTI resistance, drives early second-line failure.

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“…The replicative compromise conferred by K65R is reflected by the strong selective pressure driving its rate of disappearance/reversion upon treatment interruption – K65R (1 month) > M184I/V (3 months) > TAMs (4–6 months) and Q151-NAMs (5.6 months) [27]. The low incidence and rapid disappearance of K65R is important with respect to second-line and salvage treatment options.…”

Section: Barrier To K65r Selection Is Dependent On Nrti and Nnrti Regimensmentioning

confidence: 99%

The K65R Mutation in HIV-1 Reverse Transcriptase: Genetic Barriers, Resistance Profile and Clinical Implications

Brenner¹,

Coutsinos²

2009

HIV Ther.

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Resistance to antiviral therapy is the limiting factor in the successful management of HIV. In general, the K65R mutation is rarely selected (1.7-4%) with tenofovir disoproxil fumarate (TDF), abacavir (ABC), didanosine (ddI), and stavudine (d4T), as compared with the high incidence (>40%) of thymidine analog mutations associated with zidovudine and d4T. The high barrier to the development of K65R may reflect a combination of factors, including the high potency of K65R-selecting drugs, including recommended TDF/emtricitabine and ABC/lamivudine (ABC/3TC) combinations; the partial (low-intermediate level) profile of cross-resistance conferred by K65R to TDF, ABC and 3TC; the favorable viral fitness constraint imposed by K65R and the 3TC/emtricitabine-associated M184V mutations; the bidirectional antagonism between the K65R and thymidine analog mutation pathways; and unique RNA structural considerations in the region surrounding codon 65. Nevertheless, surprisingly high levels of treatment failures and K65R resistance may be associated with triple nucleoside analog regimens. The use of TDF + ABC, TDF + ddI and ABC + d4T in combination with 3TC or emtricitabine should be avoided. This selection of K65R may be reduced by the inclusion of zidovudine in two-four nucleoside reverse-transcriptase regimens. Clinical studies have demonstrated an increased frequency of K65R in association with suboptimal d4T and ddI regimens, as well as nevirapine and its resistance mutations Y181C and G190A. The potential for the development of the K65R mutation in subtype C is particularly problematic wherein a signature KKK nucleotide motif, at codons 64, 65 and 66 in reverse transcriptase, appear to lead to template pausing, facilitating the selection of K65R. Optimizing regimens may attenuate the emergence of K65R, leading to better long-term treatment management in different geographic settings. TDF-based regimens are the leading candidates for first-and second-line therapy, microbicides and chemoprophylaxis strategies.

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Dynamics of NRTI Resistance Mutations during Therapy Interruption

Cited by 10 publications

References 39 publications

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

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

Viral Suppression Following Switch to Second-line Antiretroviral Therapy: Associations With Nucleoside Reverse Transcriptase Inhibitor Resistance and Subtherapeutic Drug Concentrations Prior to Switch

The K65R Mutation in HIV-1 Reverse Transcriptase: Genetic Barriers, Resistance Profile and Clinical Implications

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