ritonavir and Sarcoma--Kaposi

Kaposi's sarcoma (KS) is the most prevalent malignant neoplasia in human immunodeficiency virus positive (HIV+) patients for which the primary mode of management was chemotherapy.. We have presented the case of a newly diagnosed HIV+ male patient who was diagnosed with a pedunculated nodule in the anterior region of the hard palate, measuring 3.5 cm in diameter and with 2 months of evolution.. Histopathological examination confirmed the clinical hypothesis of KS. Soon after the diagnosis, the patient started using combined antiretroviral therapy (Biovir and Kaletra), presenting a significant reduction of the lesion after 4 weeks. With 1.5 cm in diameter, the lesion was surgically removed. The patient was followed-up for 10 years without any recurrence.. In antiretroviral-naive patients with a well-preserved immune system, the use of cART may be efficient in reducing the progression of the KS lesions, thus avoiding the use of chemotherapeutic agents.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Drug Combinations; HIV Infections; Humans; Lamivudine; Lopinavir; Male; Middle Aged; Mouth Neoplasms; Ritonavir; Sarcoma, Kaposi; Zidovudine

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: Acquired Immunodeficiency Syndrome; AIDS-Related Opportunistic Infections; Anti-HIV Agents; Double-Blind Method; HIV Protease Inhibitors; Humans; Male; Middle Aged; Ritonavir; Sarcoma, Kaposi; Treatment Outcome

Immune reconstitution inflammatory syndrome (IRIS) represents paradoxical immune-mediated inflammation in response to an infecting pathogen, occurring after initiation of antiretroviral therapy (ART), concomitantly with immune system recovery. It has also been described in Kaposi's sarcoma (KS). We report a case of a 9-year-old Guinean girl, who developed Kaposi's sarcoma, following introduction of ART. KS associated with immune reconstitution inflammatory syndrome is rare, especially in children, but with the increased use of ART is becoming more prevalent.

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Child; Dideoxynucleosides; Drug Therapy, Combination; Female; Humans; Immune Reconstitution Inflammatory Syndrome; Lamivudine; Lopinavir; Ritonavir; Sarcoma, Kaposi

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

Topics: Adult; Antineoplastic Agents; Contraindications; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Docetaxel; Drug Interactions; Drug Therapy, Combination; Eyelid Neoplasms; HIV Infections; HIV Protease Inhibitors; Humans; Male; Neutropenia; Ritonavir; Sarcoma, Kaposi; Taxoids

A 39-year-old man with human immunodeficiency virus infection and Kaposi sarcoma on HAART therapy and doxorubicin presented in 2007 with a hyperpigmented tongue. Physical examination also showed hyperpigmented patches on the mucosal aspects of the lips and longitudinal dark bands on multiple nails. A skin biopsy specimen showed pigmentary alteration. Such hyperpigmentation has been described in numerous case reports and case series and has been reported to resolve within weeks to months of cessation of doxorubicin.

Topics: Acquired Immunodeficiency Syndrome; Adult; Anti-HIV Agents; Antineoplastic Agents; Antiretroviral Therapy, Highly Active; Carbamates; Doxorubicin; Drug Combinations; Furans; Humans; Lamivudine; Lip Diseases; Male; Melanosis; Nails, Malformed; Organophosphates; Ritonavir; Sarcoma, Kaposi; Sulfonamides; Tongue Diseases; Zidovudine

The coadministration of protease inhibitors with anticancer drugs in the management of human immunodeficiency virus-related malignancies can cause potential drug-drug interactions. The effect of lopinavir/ritonavir (LPV/RTV) on the pharmacokinetics of irinotecan (CPT11) has been investigated in seven patients with Kaposi's sarcoma. Coadministration of LPV/RTV reduces the clearance of CPT11 by 47% (11.3+/-3.5 vs 21.3+/-6.3 l/h/m(2), P=0.0008). This effect was associated with an 81% reduction (P=0.02) of the AUC (area under the curve) of the oxidized metabolite APC (7-ethyl-10-[4-N-(5-aminopentanoic-acid)-1-piperidino]-carbonyloxycamptothecin). The LPV/RTV treatment also inhibited the formation of SN38 glucuronide (SN38G), as shown by the 36% decrease in the SN38G/SN38 AUCs ratio (5.9+/-1.6 vs 9.2+/-2.6, P=0.002) consistent with UGT1A1 inhibition by LPV/RTV. This dual effect resulted in increased availability of CPT11 for SN38 conversion and reduced inactivation on SN38, leading to a 204% increase (P=0.0001) in SN38 AUC in the presence of LPV/RTV. The clinical consequences of these substantial pharmacokinetic changes should be investigated.

Topics: Adenine; Adult; Aged; Anti-HIV Agents; Antineoplastic Agents, Phytogenic; Antiretroviral Therapy, Highly Active; Area Under Curve; Camptothecin; Drug Therapy, Combination; HIV Infections; Humans; Irinotecan; Lamivudine; Lopinavir; Male; Middle Aged; Organophosphonates; Pyrimidinones; Ritonavir; Sarcoma, Kaposi; Tenofovir; White People

This case report describes an exacerbation of AIDS-associated Kaposi sarcoma (KS) in the setting of iatrogenic Cushing syndrome caused by an interaction between ritonavir-boosted atazanavir and fluticasone. Discontinuation of fluticasone resulted in resolution of the cutaneous KS. Clinicians should be aware of this potential drug-drug interaction that can result in increased corticosteroid levels. Inhaled corticosteroids should be used cautiously in persons with HIV/AIDS who have a history of KS and are being treated with a boosted atazanavir regimen because this can potentially exacerbate KS.

Topics: Androstadienes; Anti-Inflammatory Agents; Atazanavir Sulfate; Cushing Syndrome; Drug Interactions; Fluticasone; HIV Infections; HIV Protease Inhibitors; Humans; Iatrogenic Disease; Male; Middle Aged; Oligopeptides; Pyridines; Ritonavir; Sarcoma, Kaposi

Topics: Administration, Oral; Adult; Antineoplastic Agents, Phytogenic; Antiretroviral Therapy, Highly Active; Camptothecin; Drug Interactions; HIV Infections; HIV Protease Inhibitors; Humans; Irinotecan; Lopinavir; Male; Pyrimidinones; Ritonavir; Sarcoma, Kaposi

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

We report a case of rapidly progressive solid lymphoma with anaplastic large cell morphology, followed by systemic Kaposi sarcoma in an adult patient with AIDS. The lymphoma cells expressed human herpesvirus 8 (HHV-8)-encoded latent and lytic proteins and Epstein-Barr virus-encoded small RNA, suggesting that this case could be categorized into HHV-8-associated solid lymphoma, a recently identified disease entity.

Topics: Acquired Immunodeficiency Syndrome; Adult; Anti-HIV Agents; Antineoplastic Combined Chemotherapy Protocols; Antiretroviral Therapy, Highly Active; Cyclophosphamide; Disease Progression; Doxorubicin; Epstein-Barr Virus Infections; Fatal Outcome; Gastrointestinal Neoplasms; Herpesviridae Infections; Herpesvirus 4, Human; Herpesvirus 8, Human; HIV-1; Humans; Lamivudine; Lymphoma, AIDS-Related; Lymphoma, Large B-Cell, Diffuse; Male; Neoplasms, Second Primary; Prednisone; Ritonavir; Saquinavir; Sarcoma, Kaposi; Skin Neoplasms; Stavudine; Tumor Virus Infections; Vincristine

Treatment of patients with human immunodeficiency virus (HIV) protease inhibitors such as ritonavir can result in increases in CD4(+) T-cell counts that are independent of a reduction in HIV-1 viral load. This lack of correlation between the 2 has led to the identification of additional effects of ritonavir that potentially alter HIV disease pathogenesis. Our previous studies indicated that ritonavir directly affects immune cell activation, proliferation, and susceptibility to apoptosis. We show here that ritonavir inhibited the activation and proliferation of primary endothelial cells and decreased the production of tumor necrosis factor alpha (TNF-alpha) interleukin 6 (IL-6), IL-8, and vascular endothelial growth factor, factors that all contribute to tumor neovascularization and to the development of Kaposi sarcoma (KS) lesions. Ritonavir also suppressed the expression of vascular cell adhesion molecule 1, intercellular adhesion molecule 1, and E-selectin, which correlated with a functional decrease in leukocyte adhesion. Transcriptional activation of nuclear factor-kappaB, as induced by the KS-promoting factor TNF-alpha, the HIV-1 Tat protein, or the human herpesvirus 8 protein ORF74, was inhibited by ritonavir. KS-derived cell lines underwent apoptosis in vitro after treatment with ritonavir at concentrations that are obtained in clinical therapy (3-15 microM). In a KS mouse xenotransplantation model, ritonavir inhibited tumor formation and progression by KS-derived cells. Taken together, these data suggest that ritonavir has antineoplastic effects that are independent from its ability to inhibit the HIV protease.

Topics: Animals; Antineoplastic Agents; Apoptosis; Caspases; Cell Adhesion; Cell Adhesion Molecules; Cell Division; Cells, Cultured; Cytokines; Dose-Response Relationship, Drug; Endothelium, Vascular; Growth Substances; HIV Protease Inhibitors; Humans; Kinetics; Male; Mice; NF-kappa B; Ritonavir; Sarcoma, Kaposi; Xenograft Model Antitumor Assays

The effect of human immunodeficiency virus-1 protease inhibitors on the frequency of human herpesvirus 8 DNA detection from peripheral blood of human immunodeficiency virus-positive persons was evaluated. Thirty-three human immunodeficiency virus-seropositive male patients were studied longitudinally. DNA from open reading frame 26 of the human herpesvirus 8 genome was amplified by the polymerase chain reaction from the CD45+ fraction of peripheral blood before and after the introduction of protease inhibitor therapy. Human herpesvirus 8 IgG status, CD4+ cell counts, and human immunodeficiency virus-1 plasma viral load were also assessed before and after therapy. When both reverse transcriptase inhibitor and protease inhibitor treatment were introduced at the same time, there was an increase in CD4+ T cell counts (P=0.0041), a decrease in human immunodeficiency virus plasma load (P=0.0584), and a decrease in the detection rate of human herpesvirus 8 DNA (P=0.0077). Introducing protease inhibitor to patients already receiving reverse transcriptase inhibitor treatment was associated with an increase in CD4+ T cell counts (P=0.0003), a decrease in human immunodeficiency virus plasma viral load (P=0.0911), and a decrease in the human herpesvirus 8 detection rate (P=0.0412). No significant changes in the titters of anti-human herpesvirus 8 IgG were observed. Treatment with human immunodeficiency virus-1 protease inhibitors is therefore associated with the clearance of human herpesvirus 8 DNA from peripheral blood of human immunodeficiency virus-infected patients. The concomitant decrease in the human immunodeficiency virus plasma load and increase in the peripheral CD4+ cell count suggest that an amelioration in the immune defect following reduction in the burden of human immunodeficiency virus-1 infection is responsible for the clearance of human herpesvirus 8 by protease inhibitors.

Topics: Adult; Aged; Antibodies, Viral; CD4 Lymphocyte Count; DNA, Viral; Herpesvirus 8, Human; HIV Infections; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Immunoglobulin G; Longitudinal Studies; Male; Middle Aged; Ritonavir; Saquinavir; Sarcoma, Kaposi; Viral Load

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

This paper describes a case report of an HIV-infected patient with mucocutaneous Kaposi's sarcoma (KS) with oral involvement, which presented complete clinical resolution of lesions on antiretroviral treatment with ritonavir, an HIV-1 protease inhibitor. Although it has still not been demonstrated that ritonavir has a specific antiviral action against HHV-8, a gamma herpesvirus probably involved in KS aetiopathogenesis, it has been proven that it reduces the HIV load significantly. This affects certain growth factors of KS, such as Tat protein and cytokines, and favours recovery of immune function, which correlates with protection against AIDS-defining conditions.

Topics: Adult; HIV Infections; HIV Protease Inhibitors; Humans; Male; Palatal Neoplasms; Ritonavir; Sarcoma, Kaposi

Topics: Acquired Immunodeficiency Syndrome; Adult; AIDS-Related Opportunistic Infections; Anti-HIV Agents; Antiviral Agents; DNA, Viral; Herpesvirus 8, Human; HIV Protease Inhibitors; Humans; Male; Mouth Neoplasms; Ritonavir; Sarcoma, Kaposi; Skin Neoplasms

Topics: Adult; AIDS-Related Opportunistic Infections; Anti-HIV Agents; HIV Protease Inhibitors; Humans; Male; Mouth Mucosa; Mouth Neoplasms; Ritonavir; Saquinavir; Sarcoma, Kaposi