Approach to salvage antiretroviral therapy in heavily antiretroviral-experienced HIV-positive adults

Temesgen, Zelalem; Cainelli, Francesca; Poeschla, Eric M.; Vlahakis, Stacey; Vento, Sandro

doi:10.1016/s1473-3099(06)70550-3

Cited by 29 publications

(24 citation statements)

References 105 publications

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“…The distinct group of patients, who started treatment already in the pre-cART era and survived, has now been on cART for more than 10 years. Most of these patients were only on partially suppressive treatments before cART [11], which influenced the course of their HIV infection [12], [13]. Many of them also experienced virological failure on cART regimens taken thereafter.…”

Section: Discussionmentioning

confidence: 99%

Impact of Previous Virological Treatment Failures and Adherence on the Outcome of Antiretroviral Therapy in 2007

et al. 2009

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BackgroundCombination antiretroviral treatment (cART) has been very successful, especially among selected patients in clinical trials. The aim of this study was to describe outcomes of cART on the population level in a large national cohort.MethodsCharacteristics of participants of the Swiss HIV Cohort Study on stable cART at two semiannual visits in 2007 were analyzed with respect to era of treatment initiation, number of previous virologically failed regimens and self reported adherence. Starting ART in the mono/dual era before HIV-1 RNA assays became available was counted as one failed regimen. Logistic regression was used to identify risk factors for virological failure between the two consecutive visits.ResultsOf 4541 patients 31.2% and 68.8% had initiated therapy in the mono/dual and cART era, respectively, and been on treatment for a median of 11.7 vs. 5.7 years. At visit 1 in 2007, the mean number of previous failed regimens was 3.2 vs. 0.5 and the viral load was undetectable (<50 copies/ml) in 84.6% vs. 89.1% of the participants, respectively. Adjusted odds ratios of a detectable viral load at visit 2 for participants from the mono/dual era with a history of 2 and 3, 4, >4 previous failures compared to 1 were 0.9 (95% CI 0.4–1.7), 0.8 (0.4–1.6), 1.6 (0.8–3.2), 3.3 (1.7–6.6) respectively, and 2.3 (1.1–4.8) for >2 missed cART doses during the last month, compared to perfect adherence. From the cART era, odds ratios with a history of 1, 2 and >2 previous failures compared to none were 1.8 (95% CI 1.3–2.5), 2.8 (1.7–4.5) and 7.8 (4.5–13.5), respectively, and 2.8 (1.6–4.8) for >2 missed cART doses during the last month, compared to perfect adherence.ConclusionsA higher number of previous virologically failed regimens, and imperfect adherence to therapy were independent predictors of imminent virological failure.

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Section: Discussionmentioning

confidence: 99%

Impact of Previous Virological Treatment Failures and Adherence on the Outcome of Antiretroviral Therapy in 2007

et al. 2009

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“…It is currently unknown if IL-2 treatment would eventually enhance the survival of patients; in particular, IL-2 treatment at high or low doses did not result in enhanced immunological responses (77). The efficacy of IL-2 was addressed in larger phase III studies (126). The effect of IL-2 was more profound on CD4 than CD8 T cells because, although IL-2 enhances the proliferation of both CD4 ϩ T and CD8 ϩ T cells, it prolongs the survival of expanded CD4 ϩ but not CD8 ϩ T cells (116).…”

Section: Foxp3 In Human Cells Similar To Results With Scurfy and Foxp3mentioning

confidence: 99%

Natural Regulatory T Cells and Persistent Viral Infection

Gowans

Chougnet

et al. 2008

J Virol

139

116

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“…Therapy typically consists of a combination of three to four drugs in therapeutic regimens known as highly active antiretroviral therapy (HARRT) (Chen, Hoy, and Lewin, 2007; Simon, Ho, and Abdool Karim, 2006). The simultaneous use of multiple drugs is required because of the ease with which HIV-1 can acquire drug resistance to any single inhibitor (Emini and Fan, 1997; Simon, Ho, and Abdool Karim, 2006; Temesgen et al, 2006). Resistance arises due to the high degree of HIV-1 genetic diversity within an individual patient, a consequence of a rapid rate of viral replication combined with the error-prone nature of RT and frequent recombination events (Hu et al, 2003; Simon, Ho, and Abdool Karim, 2006; Svarovskaia et al, 2003).…”

Section: A Introductionmentioning

confidence: 99%

Novel approaches to inhibiting HIV-1 replication

2010

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Considerable success has been achieved in the treatment of HIV-1 infection, and more than twodozen antiretroviral drugs are available targeting several distinct steps in the viral replication cycle. However, resistance to these compounds emerges readily, even in the context of combination therapy. Drug toxicity, adverse drug-drug interactions, and accompanying poor patient adherence can also lead to treatment failure. These considerations make continued development of novel antiretroviral therapeutics necessary. In this article, we highlight a number of steps in the HIV-1 replication cycle that represent promising targets for drug discovery. These include lipid raft microdomains, the RNase H activity of the viral enzyme reverse transcriptase, uncoating of the viral core, host cell machinery involved in the integration of the viral DNA into host cell chromatin, virus assembly, maturation, and budding, and the functions of several viral accessory proteins. We discuss the relevant molecular and cell biology, and describe progress to date in developing inhibitors against these novel targets.Keywords virus entry; virus assembly; retrovirus; drug resistance; HIV-1 drug therapy A. Introduction A1. Overview of HIV-1 ReplicationThe replication cycle of human immunodeficiency virus type 1 (HIV-1) is a complex multistep process that depends on both viral and host cell factors (Figs. 1 and 2) . Replication begins with viral entry into the target cell. Entry proceeds by fusion of the viral lipid envelope and the cellular plasma membrane (Doms, 2000;Melikyan, 2008). The viral component that mediates fusion is the envelope (Env) glycoprotein spike, which is composed of a trimeric, non-covalently associated complex of the surface glycoprotein gp120 and the transmembrane glycoprotein gp41 (Roux and Taylor, 2007). Fusion is initiated by binding of gp120 to the cellular receptor CD4 and a subsequent interaction with the CCR5 or CXCR4 coreceptor (Berger, Murphy, and Farber, 1999;Doms, 2000). Coreceptor binding triggers a series of conformation changes in both gp120 and gp41 that mediate membrane fusion (Doms, 2000;Melikyan, 2008). Fusion delivers the viral core into the cytoplasm of the target cell. The viral core is composed of a capsid (CA) protein shell that encapsidates the single-stranded, dimeric viral RNA genome in complex with the viral nucleocapsid (NC) protein and the viral Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. (Adamson and Freed, 2007;GanserPornillos, Yeager, and Sundquist, 2008). The core uncoats (Warrilow and Harrich, 2007) and RT copies the RNA genome into a ...

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Approach to salvage antiretroviral therapy in heavily antiretroviral-experienced HIV-positive adults

Cited by 29 publications

References 105 publications

Impact of Previous Virological Treatment Failures and Adherence on the Outcome of Antiretroviral Therapy in 2007

Impact of Previous Virological Treatment Failures and Adherence on the Outcome of Antiretroviral Therapy in 2007

Natural Regulatory T Cells and Persistent Viral Infection

Novel approaches to inhibiting HIV-1 replication

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