Therapy with atazanavir plus saquinavir in patients failing highly active antiretroviral therapy: a randomized comparative pilot trial

Haas, David W.; Zala, Carlos; Schrader, Shannon; Piliero, Peter J.; Jaeger, Hans; Nunes, Danilo Henrique; Thiry, Alexandra; Schnittman, Steven M.; Sension, Michael

doi:10.1097/00002030-200306130-00008

Cited by 89 publications

(65 citation statements)

References 21 publications

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“…In order to set up an experimental model to study the HAART-associated lipodystrophy, control mice were compared to mice receiving two long-term intraperitoneal treatments: treatment with the classical combination of LPV/r, which is strongly involved in HAART, and treatment with the new compound ATV, which induces rare metabolic disorders in patients (12,19).…”

Section: Resultsmentioning

confidence: 99%

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

Prot

Héripret

Cardot‐Leccia

et al. 2006

Antimicrob Agents Chemother

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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.Highly active antiretroviral therapy (HAART) combines various protease inhibitors (PIs), nucleoside analogue reverse transcriptase inhibitors (NRTIs), and nonnucleoside analogue reverse transcriptase inhibitors (NNRTIs). Whereas HAART efficiently suppresses human immunodeficiency virus (HIV) replication, long-term treatment of HIV-infected patients has been associated with a lipodystrophic syndrome and metabolic complications, with one of the most common complications being hypertriglyceridemia (6). The HAART-associated lipodystrophy is characterized by peripheral fat wasting in the face and limbs and the accumulation of visceral fat, breast hypertrophy, and cervical fat pads (buffalo hump) (7-9). Metabolic complications are preferentially associated with PI treatment and appear much more rapidly than lipodystrophy (20). It is not known whether the latter is a long-term consequence of the metabolic disorder or whether it corresponds to distinct molecular mechanisms. Because of the lack of a pertinent experimental model, the pathogenesis and physiopathological mechanisms by which PIs, NRTIs, and NNRTIs cause HAARTassociated lipodystrophy and metabolic disorders remain to be elucidated.PIs, NRTIs, and NNRTIs can interfere with adipocyte differentiation and adipocyte-specific gene expression (16,18,22,(26)(27)(28)(29). However, the reported effects are quite variable, positive or negative, depending on the molecule and on the experimental model studied. Furthermore, these cellular studies do not explain why HAART leads, in one case, to peripheral lipoatrophy and, in the other case, to abdominal...

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Section: Resultsmentioning

confidence: 99%

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

Prot

Héripret

Cardot‐Leccia

et al. 2006

Antimicrob Agents Chemother

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“…Recent clinical studies in patients (Woerle et al, 2003;Calza et al, 2004) and in normal subjects (Purnell et al, 2000;Noor et al, 2002Noor et al, , 2004 have confirmed a direct connection between some protease inhibitors and metabolic effects, despite the complexity of multidrug therapy and virological and immunological responses during HAART. The recent emergence of a newer generation of protease inhibitor that exhibits antiviral efficacy without adverse affects on lipid or glucose parameters in the clinic (Haas et al, 2003;Murphy et al, 2003;Sanne et al, 2003;Cahn et al, 2004;Noor et al, 2004;Squires et al, 2004) provided an opportunity to reexamine the molecular pharmacology and toxicology of the protease inhibitor class.…”

mentioning

confidence: 99%

Endoplasmic Reticulum Stress Links Dyslipidemia to Inhibition of Proteasome Activity and Glucose Transport by HIV Protease Inhibitors

Parker

Flint²,

Mulvey³

et al. 2005

Mol Pharmacol

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The lipid and metabolic disturbances associated with human immunodeficiency virus (HIV) protease inhibitor therapy in AIDS have stimulated interest in developing new agents that minimize these side effects in the clinic. The underlying explanation of mechanism remains enigmatic, but a recently described link between endoplasmic reticulum (ER) stress and dysregulation of lipid metabolism suggests a provocative integration of existing and emerging data. We provide new evidence from in vitro models indicating that proteasome inhibition and differential glucose transport blockade by protease inhibitors are proximal events eliciting an ER stress transcriptional response that can regulate lipogenic pathways in hepatocytes or adipocytes. Proteasome activity was inhibited in vitro by several protease inhibitors at clinically relevant (micromolar) levels. In the intact cells, protease inhibitors rapidly elicited a pattern of gene expression diagnostic of intracellular proteasome inhibition and activation of an ER stress response. This included induction of transcription factors GADD153, ATF4, and ATF3; amino acid metabolic enzymes; proteasome components; and certain ER chaperones. In hepatocyte lines, the ER stress response was closely linked to moderate increases in lipogenic and cholesterogenic gene expression. However, in adipocytes where GLUT4 was directly inhibited by some protease inhibitors, timedependent suppression of lipogenic genes and triglyceride synthesis was observed in coordination with the ER stress response. These results further link ER stress to dyslipidemia and contribute to a unifying mechanism for the pathophysiology of protease inhibitor-associated lipodystrophy, helping explain differences in clinical metabolic profiles among protease inhibitors.The development and clinical use of HIV protease inhibitors have contributed greatly to treatment of HIV-AIDS as a critical component of highly active antiretroviral therapy (HAART) regimens. With this efficacy has come recognition of an associated syndrome of metabolic side effects that is relevant in evaluating the long-term risk/benefit of treatment options (Calza et al., 2004). The constellation of metabolic problems with protease inhibitors includes hyperlipidemia, insulin resistance, peripheral lipoatrophy, central fat accumulation, and hepatic steatosis. Despite several hypotheses to explain clinical findings, the cellular and molecular mechanisms underlying this lipodystrophy-like syndrome are incompletely understood. Recent clinical studies in patients (Woerle et al., 2003;Calza et al., 2004) and in normal subjects (Purnell et al., 2000;Noor et al., 2002Noor et al., , 2004 have confirmed a direct connection between some protease inhibitors and metabolic effects, despite the complexity of multidrug therapy and virological and immunological responses during HAART. The recent emergence of a newer generation of protease inhibitor that exhibits antiviral efficacy without adverse affects on lipid or glucose parameters in the clinic (Haas et al

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“…Reports of adverse effects were similar when ATV plus SQV was compared to SQV plus low-dose RTV. 43 Yet, significantly more patients discontinued treatment early due to adverse reactions in the SQV plus low-dose RTV group. Atazanavir's most notable laboratory abnormality is indirect hyperbilirubinemia, which is reversible upon discontinuation.…”

Section: Adverse Drug Reactionsmentioning

confidence: 97%

“…One study in treatment-experienced adults showed similar efficacy between once-daily ATV plus saquinavir (SQV) compared to twice-daily SQV plus low-dose RTV when administered as part of combination therapy. 43 Information regarding the antiretroviral efficacy of ATV is not yet available in pediatric patients < 16 years of age.…”

Section: Efficacymentioning

confidence: 99%

New Antiretroviral Therapies for Pediatric HIV Infection

Morris¹,

Kraus

2005

The Journal of Pediatric Pharmacology and Therapeutics

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Human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome affect millions of children worldwide. The development of antiretroviral therapy has significantly improved the morbidity and mortality of pediatric patients infected with HIV. Currently, 4 classes of antiretroviral agents exist: nucleoside / nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, and entry inhibitors. A total of 21 single-entity antiretroviral agents and 4 co-formulated antiretroviral products hold Food and Drug Administration (FDA) approval for treatment of HIV-1 infection. However, not all of these agents are indicated for use in patients less than 18 years of age. Since the year 2000, 7 new antiretroviral agents (atazanavir, emtricitabine, enfuvirtide, fosamprenavir, lopinavir/ritonavir, tenofovir, and tipranavir) have been approved by the FDA for use in adult patients as part of combination therapy for the treatment of HIV-1 infection. Although only 3 of these newer agents (emtricitabine, enfuvirtide, and lopinavir/ritonavir) are currently FDA approved for use in pediatric patients, pediatric clinical studies of the other 4 new agents are currently underway. The purpose of this article is to review these 7 new antiretroviral agents and describe their roles in the treatment of pediatric HIV infection. For each drug, the following information will be addressed: FDA-approved indication and age groups, clinical efficacy, pharmacokinetics, adverse drug reactions, clinically relevant drug interactions, pediatric and adult dosing, dosage forms, administration, and place in the treatment of pediatric HIV infection.

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Therapy with atazanavir plus saquinavir in patients failing highly active antiretroviral therapy: a randomized comparative pilot trial

Cited by 89 publications

References 21 publications

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

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

Endoplasmic Reticulum Stress Links Dyslipidemia to Inhibition of Proteasome Activity and Glucose Transport by HIV Protease Inhibitors

New Antiretroviral Therapies for Pediatric HIV Infection

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