indinavir-sulfate and Sarcoma--Kaposi

Topics: Abdominal Abscess; Acquired Immunodeficiency Syndrome; Adult; Aged; AIDS-Associated Nephropathy; Erectile Dysfunction; Humans; Indinavir; Kidney; Kidney Calculi; Lymphoma; Male; Male Urogenital Diseases; Middle Aged; Prostatic Diseases; Prostatitis; Sarcoma, Kaposi; Testicular Diseases; Urination Disorders

A reduced incidence or the regression of Kaposi's sarcoma (KS) has been described in HIV-infected patients treated with HIV-protease inhibitors (PI). We have recently demonstrated that PI block the angiogenesis and the development of KS lesions induced experimentally in vivo by the inoculation of angiogenic factors or human primary KS cells. These effects of PI occur at the same drug concentrations in plasma of treated individuals, and they are due to the inhibition of cell invasion and of the activation of matrix metalloprotease-2, an enzyme that is key to angiogenesis and tumor growth and invasion. Since PI also block the production of cytokines involved in KS initiation and maintenance, this anti-inflammatory activity of PI may also contribute to the anti-KS effects observed in treated individuals. Thus, by direct and indirect activities PI can simultaneously block several pathways involved in tumor growth, invasion or metastasis. These data indicate that PI should also be investigated and exploited for the therapy of KS and tumors of different histology occurring in non infected individuals.

Topics: Antiretroviral Therapy, Highly Active; Enzyme Activation; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Matrix Metalloproteinase 2; Neovascularization, Pathologic; Saquinavir; Sarcoma, Kaposi

Lymphomas are a well-known malignancy in individuals with human immunodeficiency virus type 1 (HIV-1) infection. Most lymphomas are of B-cell lineage and cutaneous involvement is rare. Cutaneous T-cell lymphomas have been previously described in adults with HIV-1 infection but are exceptional in HIV-1 infected-children. The authors report here the extremely rare case of a large-cell cutaneous lymphoproliferation of T-cell lineage expressing Epstein-Barr virus (EBV) antigens in a 15-year-old boy with AIDS and his uncommon clinical presentation. The atypical clinical evolution with a nonaggressive treatment emphasizes that for immunosuppressed patients, the diagnosis of immunosuppression-related lymphoproliferative disorder should be considered before giving the diagnosis of malignant lymphoma when tumoral lymphoid cells express EBV antigens.

Topics: Acquired Immunodeficiency Syndrome; Adolescent; Anti-HIV Agents; Antigens, CD; Antiretroviral Therapy, Highly Active; Combined Modality Therapy; Diagnosis, Differential; Epstein-Barr Virus Infections; Gene Rearrangement, T-Lymphocyte; Herpesvirus 4, Human; HIV Protease Inhibitors; Humans; Immunophenotyping; Indinavir; Lamivudine; Lymphoma, AIDS-Related; Lymphoma, T-Cell, Cutaneous; Male; Reverse Transcriptase Inhibitors; RNA, Viral; Sarcoma, Kaposi; Skin Neoplasms; Stavudine; Transfusion Reaction; Viral Matrix Proteins

HIV protease inhibitors have been shown to exert antiangiogenic and antitumor actions independently from their antiretroviral effect. Based on these studies, HIV-seronegative patients with classic Kaposi's sarcoma were treated with indinavir and followed for clinical evolution, drug pharmacokinetics and Kaposi's sarcoma biomarkers. A favorable clinical course was associated with high drug plasma levels, reduced production of basic fibroblast growth factor, lower numbers of circulating endothelial cells, and a decrease in antibody titers against human herpesvirus 8.

Topics: Aged; Aged, 80 and over; Antibodies, Viral; Antineoplastic Agents; Biomarkers, Tumor; Herpesvirus 8, Human; HIV Protease Inhibitors; HIV Seronegativity; Humans; Indinavir; Middle Aged; Sarcoma, Kaposi; Treatment Outcome

To investigate the pharmacokinetics of liposomal daunorubicin (DaunoXome) administered alone or in combination with antiviral therapy including protease inhibitors (PI) to HIV-positive patients affected by Kaposi's sarcoma (KS).. A group of 18 patients with extensive or rapidly progressing AIDS-related KS received DaunoXome at a dose of 40 mg/m2 alone or in association with a triple combination therapy consisting of one PI plus two nucleoside reverse transcriptase inhibitors (NRTI). Daunorubicin pharmacokinetics were determined in a total of 23 cycles, 6 with DaunoXome alone, 9 in combination with indinavir, 6 with ritonavir and 2 with saquinavir. Plasma samples were obtained at different times during the 72 h after DaunoXome administration. Daunorubicin and daunorubicinol plasma levels were determined by high-performance liquid chromatography.. After the DaunoXome infusion, daunorubicin was rapidly cleared from the body following, in most cases, a one-compartment open kinetic model. The daunorubicin peak concentrations, clearances and elimination half-lives were (means +/- SD): 16.3 +/- 2.8 microg/ml, 0.3 +/- 0.1 l/h per m2 and 5.6 +/- 2.6 h after DaunoXome alone; 15.1 +/- 4.9 microg/ml, 0.5 +/- 0.3 l/ h per m2 and 5.8 +/- 2.1 h after the combination with indinavir; and 14.5 +/- 2.8 microg/ml, 0.4 +/- 0.2 l/h per m2 and 6.5 +/- 3.9 h after the combination with ritonavir. In all groups, daunorubicinol plasma levels were approximately 25-30 times lower than those of the parent drug.. Our data show that there are no significant differences in the pharmacokinetic parameters of daunorubicin in patients receiving DaunoXome in combination with indinavir and ritonavir compared with those in patients not receiving PIs. Therefore in patients affected by AIDS-related KS treated with Highly Active AntiRetroviral Therapy (HAART) there is no pharmacokinetic justification for reducing the doses of DaunoXome.

Topics: Adult; AIDS-Related Opportunistic Infections; Anti-HIV Agents; Antibiotics, Antineoplastic; Daunorubicin; Drug Interactions; Drug Therapy, Combination; Female; HIV Protease Inhibitors; Humans; Indinavir; Liposomes; Male; Middle Aged; Ritonavir; Saquinavir; Sarcoma, Kaposi

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Daunorubicin; Didanosine; Drug Therapy, Combination; Herpesvirus 8, Human; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Reverse Transcriptase Inhibitors; Sarcoma, Kaposi; Stavudine; Viremia

Given that HIV-protease inhibitors (HIV-PIs) are substrates/inhibitors of the multidrug transporter ABCB1, can induce ABCB1 expression, and are used in combination with doxorubicin for AIDS-Kaposi's Sarcoma (KS) treatment, the role that ABCB1 plays in mediating multidrug resistance (MDR) in a fully transformed KS cell line (SLK) was explored.. The KS cells were exposed to both acute and chronic treatments of physiological concentrations of different HIV-PIs (indinavir, nelfinavir, atazanavir, ritonavir, or lopinavir), alone or together with doxorubicin. The ABCB1 mRNA and protein expression levels were then assessed by qRT-PCR and western blotting, flow cytometry, and immunofluorescence.. Chronic treatment of SLK cells with one of the five HIV-PIs alone or together resulted in increased resistance to doxorubicin. Co-treatment with one of the HIV-PIs in combination with doxorubicin resulted in a synergistic increase in resistance to doxorubicin, and the degree of resistance was found to correlate with the expression of ABCB1. The SLK cells were also revealed to be cross-resistant to the structurally unrelated drug paclitaxel.. These studies suggest that ABCB1 is primarily responsible for mediating MDR in SLK cells selected with either HIV-PIs alone or in combination with doxorubicin. Therefore, the roles that ABCB1 and drug cocktails play in mediating MDR in KS in vivo should be evaluated.

Topics: Antibiotics, Antineoplastic; Atazanavir Sulfate; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Blotting, Western; Cell Line, Tumor; Doxorubicin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drug Synergism; Flow Cytometry; Fluorescent Antibody Technique; Gene Expression Regulation, Neoplastic; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lopinavir; Nelfinavir; Oligopeptides; Pyridines; Pyrimidinones; Reverse Transcriptase Polymerase Chain Reaction; Ritonavir; Sarcoma, Kaposi; Treatment Outcome

Angiogenesis is thought to play a major role in the development of Kaposi's sarcoma (KS), considered by many to be a hyperplastic disorder caused in part by local production of inflammatory cytokines. The antiangiogenic effects of protease inhibitors, in particular ritonavir, have been suggested in laboratory work to lead to regression of KS, and recent data have shown the importance of ritonavir as a model of pharmaceutical development. As our clinical cohort data has shown that non-nucleoside reverse transcriptase inhibitor-based regimens are not inferior to protease inhibitor-based therapy in the prevention of KS, we investigated the specific contribution of ritonavir to chemoprevention of this AIDS-defining illness. In a logistic regression analysis, we found that ritonavir-based therapy confers no advantages compared to other regimens in the prevention of KS. This is consistent with data suggesting that regression of KS is mediated by an overall improvement in immune function and not by the effects of specific antiretrovirals.

Topics: Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Reverse Transcriptase Inhibitors; Ritonavir; Sarcoma, Kaposi; Treatment Outcome

Treatment with HIV-1 protease inhibitors (PI) is associated with a reduced incidence or regression of Kaposi sarcoma (KS). Here we show that systemic administration of the PIs indinavir or saquinavir to nude mice blocks the development and induces regression of angioproliferative KS-like lesions promoted by primary human KS cells, basic fibroblast growth factor (bFGF), or bFGF and vascular endothelial growth factor (VEGF) combined. These PIs also block bFGF or VEGF-induced angiogenesis in the chorioallantoic membrane assay with a potency similar to paclitaxel (Taxol). These effects are mediated by the inhibition of endothelial- and KS-cell invasion and of matrix metalloproteinase-2 proteolytic activation by PIs at concentrations present in plasma of treated individuals. As PIs also inhibit the in vivo growth and invasion of an angiogenic tumor-cell line, these data indicate that PIs are potent anti-angiogenic and anti-tumor molecules that might be used in treating non-HIV KS and in other HIV-associated tumors.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents, Phytogenic; Disease Models, Animal; Endothelial Growth Factors; Endothelium, Vascular; Extraembryonic Membranes; Female; Fibroblast Growth Factor 2; HIV Protease Inhibitors; Humans; Indinavir; Lymphokines; Matrix Metalloproteinase 2; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Neovascularization, Pathologic; Paclitaxel; Saquinavir; Sarcoma, Kaposi; Skin; Tumor Cells, Cultured; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

Combination therapy with protease inhibitors and nucleoside analogues dramatically suppresses plasma HIV-1 RNA and delays progression to AIDS, but the impact on HIV-associated malignancy remains to be established. We therefore examined incidence trends of Kaposi's sarcoma and non-Hodgkin's lymphoma in patients with advanced HIV infection in nine AIDS Clinical Trial Group studies of antiviral therapies for HIV and cytomegalovirus infections. Among a total of 6587 patients enrolled between November 1987 and February 1997, there were 280 cases of Kaposi's sarcoma and 68 cases of non-Hodgkin's lymphoma. Incidence rates per 100 person-years of both malignancies declined in concert with decreases in mortality, but the decreases in Kaposi's sarcoma were more profound and consistent than the decreases in non-Hodgkin's lymphoma. These data suggest that current therapies have ameliorated the incidence of Kaposi's sarcoma, but may not have had an equal effect on non-Hodgkin's lymphoma.

Topics: AIDS-Related Opportunistic Infections; Anti-HIV Agents; Antiviral Agents; Clinical Trials as Topic; Cytomegalovirus Retinitis; Foscarnet; Ganciclovir; HIV Infections; Humans; Incidence; Indinavir; Lymphoma, AIDS-Related; Lymphoma, Non-Hodgkin; Retrospective Studies; Sarcoma, Kaposi

To evaluate the clinical and biological impact of protease inhibitors on HIV-associated Kaposi's sarcoma.. A cohort of 10 patients included prospectively from April 1996 to June 1997 were studied in one institutional centre after initiation of protease inhibitors.. All patients but one (stable disease) had progressive Kaposi's sarcoma. Three out of 10 patients had stopped specific chemotherapy for Kaposi's sarcoma for more than 4 weeks, three were still under chemotherapy, and four had never received specific treatment of Kaposi's sarcoma. Plasma HIV viral load, human herpesvirus (HHV)-8 viraemia in peripheral blood mononuclear cells (PBMC), and CD4 cell count were sequentially assessed from the beginning of therapy. For six patients, a semiquantitative evaluation of HHV-8 viral load in the Kaposi's sarcoma lesions was performed during treatment using polymerase chain reaction.. After initiation of HIV triple therapy with protease inhibitors, we observed six complete responses, two partial responses, and two patients with progressive disease. All patients had undetectable plasma HIV viral load within 2 months of treatment. Undetectable HHV-8 viraemia in PBMC occurred in seven out of eight patients with partial or complete response and in none of the progressive patients. A decrease or negation of HHV-8 viral load in Kaposi's sarcoma lesions was observed in two complete responders.. Our results suggest that antiviral therapy with protease inhibitors are clinically efficient in HIV-associated Kaposi's sarcoma and that there exists a correlation between clinical response and negation of HHV-8 viraemia.

Topics: Adult; AIDS-Related Opportunistic Infections; Anti-HIV Agents; Didanosine; Dideoxynucleosides; Drug Therapy, Combination; Female; Herpesvirus 8, Human; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Male; Middle Aged; Prospective Studies; Reverse Transcriptase Inhibitors; Ritonavir; Saquinavir; Sarcoma, Kaposi; Stavudine; Treatment Outcome; Viral Load; Viremia; Zalcitabine; Zidovudine

To study the relationship between effective antiretroviral therapy, monitored by CD4 counts, and it s influence on the clinical course of AIDS associated Kaposi's sarcoma.. Four representative cases with AIDS and advanced Kaposi's sarcoma (KS) showed improvement of histologically proven KS s in various sites, including pulmonary disease, treated with liposomal doxorubicin. CD4 counts increased significantly during administration of triple antiretroviral therapy. In three cases chemotherapy cycles were extended and subsequently discontinued for 4, 14 and 4 months, respectively, without any relapse. In one other case interferonalpha therapy has been started overlapping with doxorubicin prior to permanent discontinuation of doxorubicin.. Data of those patients suggest that in patients with increasing CD4 counts KS's chemotherapy intervals should be extended or even discontinued. In some patients change of therapy to interferon alpha can be considered. A potent combined antiretroviral therapy may enhance efficiency of KS treatment even in patients with high CD4 counts.

Topics: Adult; Anti-HIV Agents; Antibiotics, Antineoplastic; Doxorubicin; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Interferon-alpha; Lamivudine; Liposomes; Male; Remission Induction; Reverse Transcriptase Inhibitors; Sarcoma, Kaposi; Stavudine

Topics: AIDS-Related Opportunistic Infections; Anti-HIV Agents; Bisexuality; Didanosine; Drug Therapy, Combination; Herpesvirus 8, Human; HIV Seroprevalence; HIV-1; Homosexuality, Male; Humans; Indinavir; Male; Middle Aged; Saquinavir; Sarcoma, Kaposi; Stavudine; Viral Load

Topics: Acquired Immunodeficiency Syndrome; HIV Protease Inhibitors; Humans; Indinavir; Male; Middle Aged; Remission Induction; Sarcoma, Kaposi; Viral Load

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; CD4 Lymphocyte Count; DNA, Viral; Herpesvirus 8, Human; HIV-1; Humans; Indinavir; Leukocytes, Mononuclear; Male; Polymerase Chain Reaction; Protease Inhibitors; Sarcoma, Kaposi

Topics: AIDS-Related Opportunistic Infections; Follow-Up Studies; Herpesvirus 8, Human; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Middle Aged; Remission Induction; Sarcoma, Kaposi

Topics: Acquired Immunodeficiency Syndrome; Antineoplastic Agents; Drug Approval; Drug Therapy, Combination; HIV Protease Inhibitors; Humans; Indinavir; Sarcoma, Kaposi; United States; United States Food and Drug Administration