tretinoin and AIDS-Related-Opportunistic-Infections

Kaposi's sarcoma (KS) is the most common malignancy associated with HIV infection and is considered an AIDS defining condition by the US Centers of Disease Control Guidelines. Several advances in the treatment of AIDS-related KS have been achieved over the past few years, even though a gold standard therapy for KS has not yet been defined and treatment must be tailored to individual needs. Since the availability of highly active antiretroviral therapy (HAART), a dramatic clinical response has been documented in patients with KS, making HAART an essential approach in the management of KS in most, if not all, patients with AIDS-related KS. However, in case of aggressive, visceral, and/or life-threatening KS, more complex therapeutic schedules have to be taken into account, including chemotherapy, radiotherapy, and/or immunotherapy. In general, systemic treatment for KS is limited to widespread, symptomatic disease, whereas local interventions are indicated for minimal, cosmetically troublesome lesions. Among new cytotoxic agents, liposomal anthracyclines and paclitaxel are highly effective molecules for KS and have been approved by the US Food and Drug Administration (FDA) as first-line and second-line monotherapy, respectively, for advanced KS. Furthermore, a greater understanding of the pathogenesis of KS has lead to the development of an array of new experimental agents. Many antiangiogenic agents such as AGM 1470 (TNP 470), thalidomide, and glufanide disodium (IM 862) have produced encouraging responses in patients with KS and large clinical trials are in progress. Retinoic acids may also block neoangiogenesis as well as proliferation of KS cells in vitro, and they have been used either systemically or topically with a high response rate. Thus, a topical compound 0.1% alitretinoin gel was approved in 1999 by the FDA for the treatment of skin lesions associated with KS. Human chorionic gonadotropin, a hormonal agent, has shown a strong inhibitory activity in KS cells, but its role in the regression of KS lesions is not clear. Finally, the identification of a novel gamma-herpesvirus, human herpesvirus-8, as a causative agent for KS, together with novel antiangiogenic compounds, such as metalloproteinase inhibitors, may offer promising targets for the therapy of KS.

Topics: AIDS-Related Opportunistic Infections; Angiogenesis Inhibitors; Antineoplastic Agents; Antiretroviral Therapy, Highly Active; Antiviral Agents; Humans; Interferons; Paclitaxel; Sarcoma, Kaposi; Tretinoin

Kaposi's sarcoma (KS) is an opportunistic tumor that develops with increased frequency (100,000-fold) after HIV infection. KS causes significant morbidity from mucocutaneous involvement and mortality from complications of visceral sites of disease such as the lungs, gastrointestinal tract, and the liver. Progressive unraveling of the KS pathogenesis has lead to the development of novel therapeutic approaches. Newest therapies are first evaluated in patients with limited tumor burden. These include: 1) inhibitors of angiogenesis such as vascular endothelial growth factor signaling inhibitor (SU 5416), and several other inhibitors of angiogenesis such as the dipeptide IM 862, TNP-470, Col-3, and thalidomide; 2) topical and systemic retinoids; 3) antiviral agents specific for Kaposi's sarcoma herpesvirus and human herpesvirus-8, or HIV; and 4) pregnancy-related factors. Patients with advanced disease such as widespread mucocutaneous disease, lymphedema, and visceral disease are treated most effectively with cytotoxic agents. The most active agents include liposomal anthracyclines, paclitaxel, vinca alkaloids, and bleomycin. The combination of liposomal anthracyclines and paclitaxel, with and without the most promising biologicals, should now be studied to further reduce the toxicity, and enhance the antitumor effects. Furthermore, identification of risk factors for KS should serve to explore prophylactic therapies.

Topics: Acquired Immunodeficiency Syndrome; AIDS-Related Opportunistic Infections; Angiostatins; Antineoplastic Agents; Antiviral Agents; Chorionic Gonadotropin; Collagen; Drug Therapy, Combination; Endostatins; Herpesvirus 8, Human; HIV-1; Peptide Fragments; Plasminogen; Sarcoma, Kaposi; Tissue Inhibitor of Metalloproteinases; Tretinoin

To evaluate the efficacy and safety of topical alitretinoin gel (9-cis-retinoic acid [LGD1057], Panretin gel; Ligand Pharmaceuticals, Inc, San Diego, Calif) in cutaneous Kaposi sarcoma (KS).. Open-label, within-patient, controlled, dose-escalating phase 1 and 2 clinical trials. In all patients, 1 or more cutaneous KS lesions were treated with alitretinoin gel, and at least 2 other lesions served as untreated controls for up to 16 weeks. Alitretinoin (0.05% or 0.1% gel) was applied twice daily for the first 2 weeks and up to 4 times daily thereafter, if tolerated.. Nine academic clinical centers.. One hundred fifteen patients with biopsy-proven acquired immunodeficiency syndrome (AIDS)-related KS.. AIDS Clinical Trials Group response criteria.. Statistically significant clinical responses were observed in 31 (27%) of 115 patients for the group of treated index lesions compared with 13 (11%) for the group of untreated control lesions (P<.001). Responses occurred with low CD4(+) lymphocyte counts (<200 cells/microL) and in some patients with refractory response to previous systemic anti-KS therapy. The incidence of disease progression was significantly lower for treated index lesions compared with untreated control lesions (39/115 [34%] vs 53/115 [46%]; P =.02). Alitretinoin gel generally was well tolerated, with 90% of treatment-related adverse events confined to the application site and only mild or moderate in severity.. Alitretinoin gel has significant antitumor activity as a topical treatment for AIDS-related KS lesions, substantially reduces the incidence of disease progression in treated lesions, and is generally well tolerated.

Topics: Administration, Cutaneous; Adult; AIDS-Related Opportunistic Infections; Alitretinoin; Antineoplastic Agents; Dose-Response Relationship, Drug; Drug Administration Schedule; Gels; Humans; Male; Middle Aged; Sarcoma, Kaposi; Skin Neoplasms; Treatment Outcome; Tretinoin; United States

Kaposi's sarcoma (KS) is the most frequent malignancy in patients with HIV. Given the promise that retinoids show in the treatment of various hyperproliferative skin disorders and in vitro evidence of inhibition of proliferation of KS cells, a randomized, controlled clinical trial was conducted.. A 12-week, multicenter, randomized, double-blind, vehicle-controlled safety and efficacy evaluation of topical alitretinoin 0.1% gel applied to cutaneous KS lesions was conducted in HIV-infected patients. The primary efficacy endpoint was the patient's response rate, as determined by evaluating six index lesions representative of the patient's overall KS cutaneous disease using AIDS Clinical Trials Group (ACTG) response criteria applied to topical therapy. Of 268 patients entered in the blinded treatment phase of the study (alitretinoin group, n = 134; vehicle group, n = 134), 47 patients (35%) treated with alitretinoin 0.1% gel had a positive response, compared with 24 patients (18%) treated with vehicle gel. Of 184 patients receiving open-label alitretinoin treatment following the blinded phase of the trial, 90 patients (49%) met criteria for a positive response. This superior efficacy of alitretinoin gel over vehicle gel was maintained when the data were adjusted or analyzed for age, race, Kamofsky scores, baseline CD4+ lymphocyte counts, number of raised lesions at baseline, and aggregate area of index lesions. Alitretinoin 0.1% gel was superior to vehicle gel regardless of the number of concurrent antiretroviral therapies. Most adverse events were mild to moderate in severity, limited to the application site, and reversible on reduction in frequency or suspension of application. Relatively few patients (7%) discontinued alitretinoin therapy because of to related adverse events.. The results show that alitretinoin gel application is safe and generally well tolerated, and they indicate the superiority of alitretinoin 0.1% gel over vehicle gel in the treatment of cutaneous AIDS-related KS lesions.

Topics: Administration, Topical; Adult; Aged; AIDS-Related Opportunistic Infections; Alitretinoin; Anti-HIV Agents; Antineoplastic Agents; Double-Blind Method; Drug Therapy, Combination; Female; Gels; Humans; Male; Middle Aged; Sarcoma, Kaposi; Tretinoin

Human immunodeficiency virus (HIV) causes disease by infecting lymphocytes and progressively destroying critical regulatory and effector cells of the immune system, leaving patients vulnerable to a number of bacterial, fungal, and viral infections. Facial herpes (herpes simplex virus-1 [HSV-1]), genital herpes (HSV-2), herpes zoster (varicella zoster virus), oral hairy leukoplakia (Epstein-Barr virus), Kaposi's sarcoma (HHV-8), molluscum contagiosum, condyloma acuminata (human papillomavirus [HPV-6, HPV-11]), plantar warts (HPV-1), and facial warts and flat warts (HPV-5) are some of the cutaneous viral diseases most commonly seen in HIV-infected patients. Two immunomodulatory agents, imiquimod (Aldara), shown to be safe and effective in the management of genital warts, and alitretinoin gel, shown to be safe and effective in the treatment of Kaposi's sarcoma, may offer a new therapeutic approach to treatment of cutaneous viral diseases. There is a strong scientific rationale to suggest that imiquimod and alitretinoin gel may be useful in the treatment of a variety of cutaneous viral diseases that have been shown to respond to immunomodulatory drugs. This represents a new approach in the therapeutic treatment paradigm for treatment of cutaneous viral diseases at their site of infection.

Topics: Adjuvants, Immunologic; AIDS-Related Opportunistic Infections; Alitretinoin; Aminoquinolines; Antiviral Agents; Condylomata Acuminata; Gels; Humans; Imiquimod; Molluscum Contagiosum; Skin Diseases, Viral; Tretinoin

Topics: Administration, Cutaneous; AIDS-Related Opportunistic Infections; Alitretinoin; Anti-HIV Agents; Dermatologic Agents; Drug Administration Schedule; Humans; Sarcoma, Kaposi; Skin Neoplasms; Treatment Outcome; Tretinoin

Topics: Administration, Topical; AIDS-Related Opportunistic Infections; Alitretinoin; Antineoplastic Agents; Clinical Trials as Topic; Drug Approval; Gels; Humans; Sarcoma, Kaposi; Tretinoin; United States; United States Food and Drug Administration