Lamivudine monotherapy in HIV-1-infected patients harbouring a lamivudine-resistant virus: a randomized pilot study (E-184V study)

Castagna, Antonella; Danise, Anna; Menzo, Stefano; Galli, Laura; Gianotti, Nicola; Carini, Elisabetta; Boeri, Enzo; Galli, Andrea; Cernuschi, Massimo; Hasson, Hamid; Clementi, Massimo; Lazzarin, Adriano

doi:10.1097/01.aids.0000218542.08845.b2

Cited by 142 publications

(99 citation statements)

References 22 publications

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“…However, tenofovir preserved at least some degree of activity, and the presence of M184V could have an additional effect on viral fitness. 26 In addition, the selection of PI resistance-associated mutations accompanying M184V while receiving lamivudine and unboosted PIs cannot be ruled out. In that case, the IC 50 for lopinavir might be higher, the genetic barrier of resistance lower, and simplification to lopinavir/ritonavir could facilitate viral escape and accumulation of PI resistance mutations in the CSF, whereas plasma concentrations could suffice to maintain HIV-1 RNA under the detection level.…”

Section: Discussionmentioning

confidence: 99%

Short Communication: Focal Encephalitis Related to Viral Escape and Resistance Emergence in Cerebrospinal Fluid in a Patient on Lopinavir/Ritonavir Monotherapy with Plasma HIV-1 RNA Suppression

ImazArkaitz

CayuelaNuria²,

NiubóJordi³

et al. 2014

AIDS Research and Human Retroviruses

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Monotherapy with boosted protease inhibitors has emerged as an antiretroviral therapy simplification alternative for selected patients, endorsed by the results of some randomized clinical trials. However, there are some concerns about the efficacy of such a strategy in achieving successful viral suppression in those anatomic compartments or reservoirs in which antiretroviral drug penetration is lower, such as the central nervous system (CNS). Several studies have demonstrated better neurocognitive performance in patients receiving antiretroviral drugs with better cerebrospinal fluid (CSF) penetration. Nevertheless, cases of CSF viral escape accompanied by moderate or severe neurological symptoms have been reported with both standard triple therapy and boosted protease inhibitor (PI) monotherapy, and it is not well established whether ritonavir-boosted protease inhibitor (PI/r) monotherapy is associated with a higher risk of symptomatic CSF viral escape or not. Herein, we present a case of viral rebound and resistance emergence exclusively in CSF associated with an unusual clinical manifestation of focal encephalitis in a patient with plasma HIV-1 RNA suppression while receiving lopinavir/ ritonavir monotherapy. Clinical resolution and CSF viral suppression were observed after switching to a genotype-guided combined antiretroviral regimen with good CSF penetration.

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Section: Discussionmentioning

confidence: 99%

Short Communication: Focal Encephalitis Related to Viral Escape and Resistance Emergence in Cerebrospinal Fluid in a Patient on Lopinavir/Ritonavir Monotherapy with Plasma HIV-1 RNA Suppression

ImazArkaitz

CayuelaNuria²,

NiubóJordi³

et al. 2014

AIDS Research and Human Retroviruses

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“…Interruption of nucleoside analogues, including 3TC, in patients with multiple drug resistance and stable plasma viral load results in a significant increase in viremia (21). In the same type of patients, treatment maintenance with 3TC alone results in a better virological and clinical outcome than complete treatment interruption (17), again suggesting that some residual benefit is retained in the prescription of 3TC in spite of genotypic resistance to this drug.…”

Section: Vol 81 2007mentioning

confidence: 99%

Human Immunodeficiency Virus Type 1: Resistance to Nucleoside Analogues and Replicative Capacity in Primary Human Macrophages

Perez-Bercoff

Wurtzer

Compain

et al. 2007

J Virol

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Antiretroviral treatment failure is associated with the emergence of resistant human immunodeficiency virus type 1 (HIV-1) populations which often express altered replicative capacity (RC). The resistance and RC of clinical HIV-1 strains, however, are generally assayed using activated peripheral blood mononuclear cells (PBMC) or tumor cell lines. Because of their high proliferation rate and concurrent high deoxynucleoside triphosphate (dNTP) content, both resistance and RC alterations might be misestimated in these cell systems. We have evaluated the resistance of HIV-1 clones expressing a variety of RT resistance mutations in primary human macrophages using a single cycle system. Our experiments indicate that d4T, ddI, and 3TC are more potent in macrophages than in HeLa-derived P4 tumor cells. Mutant viruses bearing thymidine analogue mutations (TAMs) or the K65R mutation had similar resistance levels in the two cell types. Strikingly, however, the M184V mutant, although fully resistant to 3TC in P4 cells, maintained some susceptibility to 3TC in macrophages from 8 of 11 donors. Using the same system, we found that the impact of resistance mutations on HIV RC was minimal in activated PBMC and in P4 cells. In contrast, mutant viruses exhibited strongly impaired RC relative to the wild type (WT) in macrophages, with the following RC order: WT > two TAMs > four TAMs ‫؍‬ M184V > K65R. In undifferentiated monocytes, WT virus replication could be detected in three of six donors, but replication of all mutant viruses remained undetectable. Altogether, our results confirm that nucleoside reverse transcriptase inhibitors (NRTIs) are powerful antiviral agents in differentiated macrophages, reveal that HIV resistance to some NRTIs may be less efficient in these cells, and indicate that resistance-associated loss of RC is more pronounced in macrophages than in high-dNTP content cell systems.Nucleoside analogues, also referred to as nucleoside reverse transcriptase inhibitors (NRTIs) are one of the main drug classes used in the treatment of human immunodeficiency virus type 1 (HIV-1) infection. After phosphorylation into their active triphosphate form by cellular kinases, these compounds, which lack a 3Ј-hydroxyl group, inhibit reverse transcription through termination of viral DNA synthesis. HIV-1 resistance to NRTIs is achieved via two distinct and generally exclusive mechanisms: (i) decreased incorporation of the triphosphorylated NRTI or (ii) excision of the triphosphorylated NRTI and primer unblocking. Decreased NRTI incorporation is mediated by mutations such as the M184V substitution, which induces high-level resistance to ␤-L-2Ј,3Ј-dideoxy-3Ј-thiacytidine (3TC or lamivudine) (24,35,61,64), as well as other mutations such as K74V, K65R, or the Q151M complex. These mutations promote resistance through impairment of the correct positioning of triphosphate NRTIs within the RT active site (19,67). In contrast, thymidine analogue mutations (TAMs), such as the M41L, the D67N, the K70R, the L210W, the T215F/Y, and the K219Q...

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“…Studies show that reverse transcriptase (RT) inhibitors (RTIs) continue to exert antiviral activity in the presence of resistance mutations (8,21). In particular, continuation of lamivudine (3TC) or emtricitabine in the presence of the M184V mutation may provide clinical benefit (3,4). We previously showed that M184V is lost at a median of 20 weeks following interruption of 3TC together with other RTIs while the use of protease (PR) inhibitors (PIs) was continued in viremic subjects with MDR HIV-1 (8).…”

mentioning

confidence: 99%

In Vivo Fitness Cost of the M184V Mutation in Multidrug-Resistant Human Immunodeficiency Virus Type 1 in the Absence of Lamivudine

Paredes

Sagar

Marconi

et al. 2009

J Virol

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Lamivudine therapy selects for the M184V mutation. Although this mutation reduces the replicative capacity of human immunodeficiency virus in vitro, its impact on viral fitness in vivo has not been well defined. We used quantitative allele-specific PCR to precisely calculate the fitness differences between the mutated M184V virus and one that had reverted to the wild type in a cohort of patients by selectively interrupting reverse transcriptase inhibitor therapy, and we found that the M184V variants were consistently 4 to 8% less fit than the wild type in the absence of drug. After a lag phase of variable duration, wild-type variants emerged due to continued evolution of pol and back mutation rather than through emergence of an archived wild-type variant.Despite recent advances, the management of multidrug-resistant (MDR) human immunodeficiency virus type 1 (HIV-1) remains a major clinical problem. One strategy to avoid immune deterioration while minimizing toxicity in viremic patients infected with MDR HIV-1 is to prevent the emergence of wild-type (WT) HIV-1 by continuing selected drugs in a failing antiretroviral regimen. Studies show that reverse transcriptase (RT) inhibitors (RTIs) continue to exert antiviral activity in the presence of resistance mutations(8, 21). In particular, continuation of lamivudine (3TC) or emtricitabine in the presence of the M184V mutation may provide clinical benefit (3, 4). We previously showed that M184V is lost at a median of 20 weeks following interruption of 3TC together with other RTIs while the use of protease (PR) inhibitors (PIs) was continued in viremic subjects with MDR HIV-1(8). In this study, we performed a detailed analysis of the decay of the M184V-carrying mutants in these individuals.(

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Lamivudine monotherapy in HIV-1-infected patients harbouring a lamivudine-resistant virus: a randomized pilot study (E-184V study)

Abstract: In HIV-1-infected patients harbouring a lamivudine-resistant virus, lamivudine monotherapy may lead to a better immunological and clinical outcome than complete therapy interruption.

Cited by 142 publications

References 22 publications

Short Communication: Focal Encephalitis Related to Viral Escape and Resistance Emergence in Cerebrospinal Fluid in a Patient on Lopinavir/Ritonavir Monotherapy with Plasma HIV-1 RNA Suppression

Short Communication: Focal Encephalitis Related to Viral Escape and Resistance Emergence in Cerebrospinal Fluid in a Patient on Lopinavir/Ritonavir Monotherapy with Plasma HIV-1 RNA Suppression

Human Immunodeficiency Virus Type 1: Resistance to Nucleoside Analogues and Replicative Capacity in Primary Human Macrophages

In Vivo Fitness Cost of the M184V Mutation in Multidrug-Resistant Human Immunodeficiency Virus Type 1 in the Absence of Lamivudine

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