Emerging mutations at virological failure of HAART combinations containing tenofovir and lamivudine or emtricitabine

Maserati, Renato; Silvestri, Annalisa De; Uglietti, Alessia; Colao, G; Biagio, Antonio Di; Bruzzone, Bianca; Pietro, Massimo Di; Re, Maria Carla; Tinelli, Carmine; Zazzi, Maurizio

doi:10.1097/qad.0b013e328336e962

Cited by 33 publications

(21 citation statements)

References 19 publications

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“…A difference was seen between 3TC and FTC in the development of M184V, which is potentially due to the different pharmacokinetics of the two agents, with FTC being more forgiving of intermittent adherence. 11 However, this difference might also be due to shifts in other antiretrovirals given concurrently, as regimens containing 3TC (and especially the use of the combination pill combivir or AZT/3TC) tended to occur on average between 2003-2004, while regimens containing FTC (and especially the combination pill Truvada, or TDF/ FTC) tended to occur between [2007][2008]. Following initiation of a SLR, the majority of patients achieved VS in approximately 179 days irrespective of the regimen.…”

Section: Discussionmentioning

confidence: 99%

Development of the M184V Mutation in HIV-1 Infection and Subsequent Treatment Outcomes

Wilson¹,

Cross²,

Nurutdinova³

et al. 2015

HIV/AIDS Res Treat Open J

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CitationThe purpose of this study was to describe the occurrence of the M184V mutation in a single clinic setting over a period of 10 years. We examined the combination Antiretroviral Therapy (cART) being taken at the time of first identification of the M184V mutation as well as Second Line Regimens (SLR) started immediately after the documentation of M184V. SLR were evaluated for frequency and time to Virologic Suppression (VS) as well as frequency and time to subsequent Virologic Failure (VF). Prevalence of the M184V mutation, ART regimen leading to M184V acquisition, and outcomes of SLR in patients with M184V (as measured by time to initial VS and subsequent VF on SLR) were analyzed in a retrospective cohort study of all HIV-infected persons receiving care at a university clinic. Results: Of 2500 screened clinic patients, 220 had an acquired MI184V mutation (8.8%). There were 158(72%) male and 171(78%) African-American patients. The mean time from the start of a regimen to the documented M184V mutation was 575(0-3253) days. Independent of Nucleoside Reverse Transcriptase Inhibitor (NRTI) backbone, the mean time to development of M184V in Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) (n=109) and Protease Inhibitor (PI) based (n=84) regimens was 538(+/-556) and 622 (+/-620) days, respectively (p=0.325) approximately, 78% of patients achieved VS on a SLR in a mean of 179 days. Of the 122(57%) of patients whose SLR retained FTC/3TC, VS was achieved in 80% compared to 74% without FTC/3TC (p=0.285) with no significant difference in time to VS (152(+/-187) and 181(+/-257) days respectively, p=0.406). There were no significant differences in achievement of VS in PI (n=158) and NNRTI (n=27) -based SLRs independent of the NRTI backbone, 76% vs. 78%, respectively (p=0.837) with a similar time to VS (180(+/-228) vs. 128(+/-158) days, p=0.313). All patients on PI+Raltegravir (RAL) (n=10) and PI+NNRTI (n=12) -based regimens achieved VS (vs. 76% in PI+2NRTI (p=0.078 and p=0.054, respectively). Regardless of SLR, about 50% of each group experienced VF after VS with a similar time to failure. Conclusions: M184V mutation developed in 9% of patients in a mean of 575 days with no significant differences between ART regimens. Following initiation of an SLR, the majority of patients achieved VS in approximately 179 days irrespective of the regimen. The addition of 3TC/FTC did not significantly affect VS. Although numbers were small, 100% of patients on two fully active non-NRTI-backbone-based regimens attained VS. Approximately half of all patients subsequently failed on SLR, regardless of regimen used, suggesting that the development of M184V is a marker of noncompliance to therapy.

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Section: Discussionmentioning

confidence: 99%

Development of the M184V Mutation in HIV-1 Infection and Subsequent Treatment Outcomes

Wilson¹,

Cross²,

Nurutdinova³

et al. 2015

HIV/AIDS Res Treat Open J

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“…According to UNAIDS, 99% of Wrst-line regimens in developing countries contain either lamivudine or emtricitabine, whereas only 47% of second-line regimes still contain these drugs. Genotypic resistance testing reveals a prevalence of the M184V mutation in 64-100% of resistant viruses in diVerent populations [22][23][24]. Therefore, lamivudine and emtricitabine are frequently used drugs, but treatment failure arises quickly.…”

Section: Discussionmentioning

confidence: 99%

“…The reasons for choosing this mutation were the following: (1) It is the most common DRM in several studies [22][23][24]. (2) Lamivudine/emtricitabine are frequently used antiretroviral compounds and are available in developing countries (UNAIDS).…”

Section: Cd8 T-cell Responses Toward Regions Of Drm Within Pol Are Comentioning

confidence: 99%

Control of M184V HIV-1 mutants by CD8 T-cell responses

Vollbrecht

Eberle²,

Roider

et al. 2011

Med Microbiol Immunol

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Antiretroviral treatment directed against HIV is highly effective, yet limited by drug resistance mutations. We hypothesized that CD8 T cells targeting drug-resistant HIV mutants are able to inhibit viral replication in the setting of a failing therapeutic regimen. We evaluated CD8 T-cell responses and mapped epitopes in HIV-infected patients by interferon-gamma Elispot and intracellular cytokine staining. Autologous virus was sequenced by RT-PCR. Viral replication inhibition assays were performed using M184V mutant virus and CD8 T cell lines. CD8 T-cell responses toward the regions of viral drug resistance mutations in Pol are frequent. Focusing on the M184V mutation, A*02:01-YQYVDDLYV and A*02:01-VIYQYVDDLYV were identified as optimal epitopes for the majority of study subjects. Viral replication of M184V HIV mutants was inhibited by CD8 T cell lines in vitro. In case of a failing lamivudine/emtricitabine containing regimen, individuals with a CD8 T-cell response toward M184V had a significant lower viral load than those without a CD8 response (p = 0.005). Two study subjects even achieved an undetectable viral load. Our data suggest that control of M184V mutant virus by CD8 T-cell responses is possible in vitro and in vivo. This control has important implications for therapeutic vaccination strategies.

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“…Another recent study [43] retrospectively evaluated treatmentnaïve and treatment-experienced patients who underwent genotypic resistance testing within 1 month after having a documented virological failure whilst receiving TDF/3TC-containing or a TDF/FTC-containing combination therapy after ≥6 months of virological suppression (i.e. an HIV-RNA level <50 copies/mL).…”

Section: Emergence Of Resistancementioning

confidence: 99%

Cytosine deoxyribonucleoside anti-HIV analogues: a small chemical substitution allows relevant activities

Scaglione

Berrino²

2012

International Journal of Antimicrobial Agents

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Emerging mutations at virological failure of HAART combinations containing tenofovir and lamivudine or emtricitabine

Abstract: Despite their close structural similarity, 3TC and FTC are associated with a significantly different rate of drug resistance at treatment failure when combined with TDF in HAART regimens independently of the third drug used.

Cited by 33 publications

References 19 publications

Development of the M184V Mutation in HIV-1 Infection and Subsequent Treatment Outcomes

Development of the M184V Mutation in HIV-1 Infection and Subsequent Treatment Outcomes

Control of M184V HIV-1 mutants by CD8 T-cell responses

Cytosine deoxyribonucleoside anti-HIV analogues: a small chemical substitution allows relevant activities

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