Virological and immunological effects of treatment interruptions in HIV-1 infected patients with treatment failure

Miller, Veronica; Sabin, Caroline; Hertogs, Kurt; Bloor, Stuart; Martínez-Picado, Javier; D’Aquila, Richard T.; Larder, Brendan A.; Lutz, Thomas; Gute, Peter; Weidmann, Eckhart; Rabenau, Holger F.; Phillips, Andrew; Staszewski, Schlomo

doi:10.1097/00002030-200012220-00007

Cited by 198 publications

(126 citation statements)

References 21 publications

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“…After treatment interruption, a higher rate of viral replication and a rapid decline in CD4 ϩ cells was observed in this study, in concordance with previous reports (10,12,16,26,45,59). In order to determine if these changes in viral replication and cytopathogenicity were caused by the emergence of variants with a syncytium-inducing/CXCR4 phenotype, the coreceptor usage by HIV-1 was inferred from V3 loop sequences.…”

Section: Discussionsupporting

confidence: 90%

“…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%

“…ϩ cell count and plasma viral load at study entry (26), baseline CD4 ϩ cell count and baseline viral load/CD4 ϩ cell count ratio (45), viral suppression during ARV therapy (10), and duration of treatment interruption (12).…”

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.…”

mentioning

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: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

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 present findings evoke an argument regarding continuation of incomplete HAART. When HAART results in incomplete suppression of virus replication due to emergence of variants resistant to the available drugs, some clinical trials currently recommend continuation of therapy, because any interruption could result in increased plasma viral load and low CD4 cell counts (3,9,19). In general, it is believed that continuation of HAART under such circumstances can still produce some clinical benefits because of the reduced replication capacity of the PI-resistant virus (9).…”

Section: Table 3 Amino Acid Substitutions In Gag P17mentioning

confidence: 99%

Isolation and Molecular Characterization of a Nelfinavir (NFV)-Resistant Human Immunodeficiency Virus Type 1 That Exhibits NFV-Dependent Enhancement of Replication

Matsuoka-Aizawa

Sato

Hachiya

et al. 2003

J Virol

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Structured Treatment Interruptions for the Management of HIV Infection

Friedman

Lisziewicz²

2001

JAMA

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Antiretroviral drugs constitute a milestone in the treatment of human immunodeficiency virus (HIV) infection; however, emerging problems limit their long-term use, and an increasing number of patients interrupt the prescribed continuous drug therapy for short or long periods. Some patients appear to benefit from structured treatment interruptions (STI), involving monitored repetition of on-and-off cycles of drugs; however, it is unclear whether patients and/or physicians should consider STI as a treatment option. This review is intended to provide a comprehensive update on the use of STI in clinical settings, and to carefully evaluate the advantages and potential risks for patients infected with HIV. We used a MEDLINE search to find all English-language articles published January 1999 to August 2001 regarding patients treated with highly active antiretroviral therapy for whom treatment interruption was investigated. Priority was assigned to peer-reviewed sources, when available. Otherwise, abstracts from authoritative international conferences were selected through the AIDSLINE database. Results from various studies with respect to type of drug treatment, baseline patient status, number of treatment interruptions, duration of treatment and interruption, changes in viral load, and immune system parameters were analyzed. Patients could be categorized into 3 distinct clinical scenarios: acute infection, chronic drug-suppressed infection and virological drug failure. The STI approach may offer more benefit during acute infection when the patient's immune system remains nearly intact. It is yet to be determined whether STI will facilitate the long-term management of chronic infection by decreasing drug-associated toxicity and improving quality of life without jeopardizing the efficacy of the treatment. Results from randomized controlled trials and more definitive means of gauging the status of the patient's immune system must be available before this treatment method is extended beyond the research setting. Ultimately, a safer approach using therapeutic immunization or vaccination would be preferable for stimulating vigorous T-cell-mediated immune responses and control of HIV during treatment interruption.

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Virological and immunological effects of treatment interruptions in HIV-1 infected patients with treatment failure

Cited by 198 publications

References 21 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

Isolation and Molecular Characterization of a Nelfinavir (NFV)-Resistant Human Immunodeficiency Virus Type 1 That Exhibits NFV-Dependent Enhancement of Replication

Structured Treatment Interruptions for the Management of HIV Infection

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