Shift in HIV resistance genotype after treatment interruption and short-term antiviral effect following a new salvage regimen

Izopet, Jacques; Massip, Patrice; Souyris, Corinne; Sandres, Karine; Puissant, Bénédicte; Obadia, Martine; Pasquier, Christophe; Bonnet, É.; Marchou, B.; Puel, J

doi:10.1097/00002030-200010200-00005

Cited by 83 publications

(68 citation statements)

References 35 publications

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“…It was previously reported that not all the patients with treatment failure undergoing STI experienced a reversal in their drug-resistance-associated genotype (10,12,16,26,45,59). Elucidating the factors that could predict which patients would revert from their drug-resistant genotype to a drug- sensitive one after STI would be of great use for the physicians managing patients with ARV treatment failure.…”

Section: Discussionmentioning

confidence: 99%

“…When this selective pressure is removed, the emergence of drug-sensitive quasispecies may be expected, as they would be predicted to have a higher fitness in a drug-free environment (9,15,19,20,22,25,34,40,42,43). This rationale led to the many structured treatment interruption (STI) studies carried out on patients with treatment failure and multidrug-resistant viruses (10,12,16,26,45,59). In those cohorts, a rise in plasma viral load and a concomitant fall in CD4 ϩ cell count was observed after treatment interruption; in approximately half of the patients, drug susceptibility shifted from resistant to sensitive.…”

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confidence: 99%

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Origin of Human Immunodeficiency Virus Type 1 Quasispecies Emerging after Antiretroviral Treatment Interruption in Patients with Therapeutic Failure

Kijak

Simon

Balfe

et al. 2002

J Virol

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The emergence of antiretroviral (ARV) drug-resistant human immunodeficiency virus type 1 (HIV-1) quasispecies is a major cause of treatment failure. These variants are usually replaced by drug-sensitive ones when the selective pressure of the drugs is removed, as the former have reduced fitness in a drug-free environment. This was the rationale for the design of structured ARV treatment interruption (STI) studies for the management of HIV-1 patients with treatment failure. We have studied the origin of drug-sensitive HIV-1 quasispecies emerging after STI in patients with treatment failure due to ARV drug resistance. Plasma and peripheral blood mononuclear cell samples were obtained the day of treatment interruption (day 0) and 30 and 60 days afterwards. HIV-1 pol and env were partially amplified, cloned, and sequenced. At day 60 drug-resistant variants were replaced by completely or partially sensitive quasispecies. Phylogenetic analyses of pol revealed that drug-sensitive variants emerging after STI were not related to their immediate temporal ancestors but formed a separate cluster, demonstrating that STI leads to the recrudescence and reemergence of a sequestrated viral population rather than leading to the back mutation of drug-resistant forms. No evidence for concomitant changes in viral tropism was seen, as deduced from env sequences. This study demonstrates the important role that the reemergence of quasispecies plays in HIV-1 population dynamics and points out the difficulties that may be found when recycling ARV therapies with patients with treatment failure.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Origin of Human Immunodeficiency Virus Type 1 Quasispecies Emerging after Antiretroviral Treatment Interruption in Patients with Therapeutic Failure

Kijak

Simon

Balfe

et al. 2002

J Virol

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“…Two cohorts were evaluated: patients at Hôpital Bichat-Claude Bernard, Paris, France (kinetic studies), and patients participating in a clinical trial of a 3-month STI performed at Centre Hospitalier Universitaire (CHU) Purpan, Toulouse, France. Clinical aspects and outcome of this trial have been presented elsewhere (20). All patients gave informed consent before undertaking STI.…”

Section: Methodsmentioning

confidence: 99%

Changes in Human Immunodeficiency Virus Type 1 Populations after Treatment Interruption in Patients Failing Antiretroviral Therapy

Hance

Lemiale

Izopet

et al. 2001

J Virol

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120

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Mutations in human immunodeficiency virus type 1 (HIV-1) reverse transcriptase and protease that confer resistance to antiretroviral agents are usually accompanied by a reduction in the viral replicative capacity under drug-free conditions. Consequently, when antiretroviral treatment is interrupted in HIV-1-infected patients harboring drug-resistant virus, resistant quasi-species appear to be most often replaced within several weeks by wild-type virus. Using a real-time PCR-based technique for the selective quantification of resistant viral sequences in plasma, we have studied the kinetics of the switch from mutant to wild-type virus and evaluated the extent to which minority populations of resistant viruses not detected by genotyping persist in these individuals. Among 12 patients with viruses expressing the V82A or L90M resistance mutation who had undergone a 3-month interruption of therapy and for whom conventional genotyping had revealed an apparent total reconversion to wild-type virus, minority populations expressing these mutations, representing 0.1 to 21% of total virus, were still detectable in 9 cases. Kinetic studies demonstrated that viruses expressing resistance mutations could be detected for >5 months after the discontinuation of treatment in some patients. Most of the minority resistant genomes detected more than 3 months after the interruption of therapy carried only part of the mutations present in the resistant viruses prior to treatment interruption and appeared to result from the emergence of existing strains selected at earlier stages in the development of drug resistance. Thus, following the interruption of treatment, viral populations containing resistance mutations can persist for several months after the time when conventional genotyping techniques detect only wild-type virus. These populations include viral strains with only some of the resistance mutations initially present, strains that presumably express better fitness under drug-free conditions.

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“…Overall, these adaptations have allowed the programme to scale up from initially few monthly inclusions (mean 16 12 For viral loads greater than 1000 copies per mL, HIV-1 reverse transcriptase genotyping and identifi cation of HIV subtypes were undertaken at the same time. 13,14 The resistance profi les to antiretroviral molecules were defi ned according to National Agency for AIDS Research (ANRS) algorithms. 15 Ethics approval for the survey was obtained from the ethics committee of the Malawi Ministry of Health and written consent was obtained from all participants.…”

Section: Treatmentmentioning

confidence: 99%

Scaling up of highly active antiretroviral therapy in a rural district of Malawi: an effectiveness assessment

Ferradini¹,

Jeannin

Pinoges³

et al. 2006

The Lancet

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405

308

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Shift in HIV resistance genotype after treatment interruption and short-term antiviral effect following a new salvage regimen

Abstract: Suspending treatment for 3 months after multiple failures could be a suitable strategy for optimizing salvage therapy provided it is instituted early, before the HIV disease becomes too advanced.

Cited by 83 publications

References 35 publications

Origin of Human Immunodeficiency Virus Type 1 Quasispecies Emerging after Antiretroviral Treatment Interruption in Patients with Therapeutic Failure

Origin of Human Immunodeficiency Virus Type 1 Quasispecies Emerging after Antiretroviral Treatment Interruption in Patients with Therapeutic Failure

Changes in Human Immunodeficiency Virus Type 1 Populations after Treatment Interruption in Patients Failing Antiretroviral Therapy

Scaling up of highly active antiretroviral therapy in a rural district of Malawi: an effectiveness assessment

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