Anti-Human Immunodeficiency Virus Drug Combination Strategies

1998 ◽  
Vol 9 (3) ◽  
pp. 187-203 ◽  
Author(s):  
A-M Vandamme ◽  
K Van Vaerenbergh ◽  
E De Clercq
Keyword(s):  
Human Immunodeficiency Virus ◽  
Drug Resistance ◽  
Salvage Therapy ◽  
Highly Active Antiretroviral Therapy ◽  
Term Treatment ◽  
New Drugs ◽  
Resistance Testing ◽  
Long Term Treatment ◽  
Immunodeficiency Virus

It is now generally accepted that mono- and bitherapy for human immunodeficiency virus type 1 (HIV-1) infection are only transiently efficient mainly due to virus drug resistance. To obtain a sustained benefit from antiviral therapy, current guidelines recommend at least triple-drug combinations, or the so-called highly active antiretroviral therapy (HAART). In some patients, HAART can be problematic, either because it is difficult to remain compliant or because previous suboptimum therapies have limited the choice of drugs. For compliant drug-naive patients, HAART should be able to offer long-term virus suppression, when changing from first- to second- to third-line HAART at drug failure. Long-term treatment might ultimately result in multi-drug resistant virus leaving few options for salvage therapy. HIV drug resistance testing to guide this salvage therapy and the development of new drugs to allow new options will therefore remain priorities in anti-HIV drug research.

scholarly journals Long-Term Treatment with Lopinavir-Ritonavir Induces a Reduction in Peripheral Adipose Depots in Mice

2006 ◽  
Vol 50 (12) ◽  
pp. 3998-4004 ◽  
Author(s):  
Matthieu Prot ◽  
Laurence Heripret ◽  
Nathalie Cardot-Leccia ◽  
Christophe Perrin ◽  
Myriam Aouadi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Highly Active Antiretroviral Therapy ◽  
Fold Increase ◽  
Term Treatment ◽  
Long Period ◽  
Highly Active ◽  
Long Term Treatment ◽  
Immunodeficiency Virus ◽  
Lipodystrophic Syndrome

ABSTRACT Highly active antiretroviral therapy (HAART) of human immunodeficiency virus-infected patients is associated with adverse effects, such as lipodystrophy and hyperlipidemia. The lipodystrophic syndrome is characterized by a peripheral lipoatrophy and/or fat accumulation in the abdomen and neck. In order to get insights into the physiopathological mechanisms underlying this syndrome, we treated mice with protease inhibitors (PIs) over a long period of time. Although atazanavir-treated mice presented the same circulating triglyceride concentration as control mice, lopinavir-ritonavir-treated mice rapidly became hypertriglyceridemic, with triglyceride levels of 200 mg/dl, whereas control and atazanavir-treated animals had triglyceride levels of 80 mg/dl. These results obtained with mice reproduce the metabolic disorder observed in humans. White adipose tissue (WAT) was analyzed after 8 weeks of treatment. Compared to the control or atazanavir treatment, lopinavir-ritonavir treatment induced a significant 25% weight reduction in the peripheral inguinal WAT depot. By contrast, the profound epididymal WAT depot was not affected. This effect was associated with a 5.5-fold increase in SREBP-1c gene expression only in the inguinal depot. Our results demonstrate that the long-term treatment of mice with PIs constitutes an interesting experimental model with which some aspects of the lipoatrophy induced by HAART in humans may be studied.

scholarly journals Genotype and Phenotype Patterns of Human Immunodeficiency Virus Type 1 Resistance to Enfuvirtide during Long-Term Treatment

2004 ◽  
Vol 48 (9) ◽  
pp. 3253-3259 ◽  
Author(s):  
Stefano Menzo ◽  
Antonella Castagna ◽  
Alessia Monachetti ◽  
Hamid Hasson ◽  
Anna Danise ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Term Treatment ◽  
Heptad Repeat ◽  
Long Term Treatment ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT The human immunodeficiency virus type 1 (HIV-1) fusion inhibitor enfuvirtide has recently been introduced into clinical practice and has exhibited efficient anti-HIV-1 activity in combination with other antiretroviral agents. In the present study, we addressed the effect of long-term treatment with enfuvirtide on the intrahost evolution of HIV-1. The genotype and phenotype patterns and the relative replication capacity (rRC) of enfuvirtide-resistant HIV-1 mutants were evaluated in samples from 11 subjects (7 virological nonresponders and 4 responders) who received the compound for more than 1 year in combination with different regimens. Selection of one or more mutations clustering in a sequence (amino acids 36 to 45) of the gp41 N-terminal heptad repeat was observed in samples from the seven virological nonresponders but not in those from responders. In two subjects who discontinued enfuvirtide, reversion of the resistant genotype was detected within 3 months. Recombinant clones bearing mutated gp41 sequences displayed reduced susceptibilities to enfuvirtide, with the 50% inhibitory concentrations (IC50s) ranging from 0.6 to 12.8 μg/ml, whereas the IC50 for isolates with baseline sequences was 0.013 ± 0.010 μg/ml. Interestingly, long-term monitoring of resistant variants provided evidence that ongoing adaptation to the drug is paralleled by phenotypic changes. A limited drop in the rRC in the absence of drug was observed for clones from four of the seven nonresponders bearing mutations associated with resistance. Overall, the data indicate that the different genotype patterns associated with a detectable degree of HIV-1 resistance to enfuvirtide generated during long-term treatments are characterized by a substantially low genetic barrier, possible ongoing adaptation with increased degrees of resistance, and limited influence on the viral rRC.

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