Clinical Efficacy of the HIV Protease Inhibitor Indinavir in Combination with Chemotherapy for Advanced Classic Kaposi Sarcoma Treatment: A Single-Arm, Phase II Trial in the Elderly.

Kaposi sarcoma is a rare angioproliferative disease associated with human herpes virus-8 (HHV-8) infection. Kaposi sarcoma is frequent and aggressive in HIV-infected people, whereas the classic form (CKS) generally has an indolent course. Notably, all conventional therapies against Kaposi sarcoma have only temporary efficacy. We have previously shown that indinavir, a HIV protease-inhibitor with direct antiangiogenic and antitumor activity, is safe and effective in patients with early CKS, whereas effects are less prominent in advanced disease, probably due to the larger tumor mass. Therefore, the clinical response to indinavir was assessed in patients with advanced CKS after debulking chemotherapy. This was a monocentric phase 2 trial in elderly with progressive/advanced CKS treated with debulking chemotherapy and indinavir combined, followed by a maintenance phase with indinavir alone. Secondary endpoints included safety and Kaposi sarcoma biomarker evaluation.All evaluable patients (22) responded to debulking therapy. Out of these, 16 entered the indinavir maintenance phase. The overall response rate at end of maintenance was 75% (estimated median response-duration 43 months). Moreover, most responders showed further clinical improvements (lesion number/nodularity) during maintenance and post-treatment follow-up. Notably, after relapse, progressors did not require systemic Kaposi sarcoma therapy and showed clinical improvements (including disease stabilization) remaining on study. Responders also showed immune status amelioration with a consistent B-cell increase and positive changes of other biomarkers, including anti-HHV-8 natural killer activity. In advanced CKS a strategy combining indinavir and chemotherapy is safe and associated with high and durable response rates and it could be rapidly adopted for the clinical management of these patients. SIGNIFICANCE: This phase-2 trial showed that the HIV protease inhibitor indinavir may boost and extend the duration of the effects of chemotherapy in elderly with advanced progressive classic Kaposi sarcoma, without additional toxicity. Further, the amelioration of the immune status seen in responders suggests a better control of HHV-8 infection and tumor-cell killing. Thus, indinavir combined with chemotherapy may represent an important tool for the clinical management of classic Kaposi sarcoma in elderly patients.

Litiasis medicamentosa en pacientes Vih+ eb tratamietno con Indinavir / Urinary lithiasis secondary to medication in HIV+patients receiving Indinavir

Objetivo: Los antirretrovirales inhibidores de la proteasa (IP) son fármacos utilizados en el tratamiento de pacientes afectos por el virus de la inmunodeficiencia humana (VIH). Un 20% de la dosis administrada se excreta por el riñón, que en presencia de orina alcalina puede precipitar formando cristales del propio fármaco susceptibles de provocar crisis renoureterales. Métodos: Entre enero del 1998 y junio de 2005 hemos atendido en nuestro centro a 26 pacientes con síntomas de urolitiasis y bajo el tratamiento con antirretrovirales IP. Todos ellos fueron sometidos a exploración física minuciosa, ecografía renoureteral y vesical, urografía intravenosa. Así mismo, se realizó análisis de sangre y anormales y sedimento de orina. Los pacientes fueron tratados ambulatoriamente, salvo aquellos en los que la analgesia con AINEs no fue suficiente para el control del cuadro álgico. Resultados: Todos los pacientes llevaban más de 12 meses de tratamiento con Indinavir. Los 26 pacientes con síntomas de nefrolitiasis representaban un 4% de los sujetos tratados con la dosis recomendada de Crivixan®. La mayoría presentaron dolor en fosa renal casi siempre asociado a microhematuria. De ellos, cinco pacientes requirieron ingreso en nuestra unidad por clínica no controlable de forma ambulatoria. Las pruebas diagnósticas (ecografía y/o UIV) revelaron retraso funcional del riñón (2 casos), ectasia de vía (8 casos) y pequeñas concreciones litiásicas de escasa o nula densidad cálcica (5 casos). El análisis urinario mostró cristaluria sugestiva y un pH alcalino. Todos requirieron tratamiento analgésico e hidratación. En tres casos se redujo la dosis de indinavir, en otro se retiró la medicación y en otro se añadieron 100 mgr de ritonavir. En un caso se intento cateterismo ureteral infructuosamente. La evolución fue satisfactoria en todos ellos. Conclusiones: Es preciso conocer la posibilidad de litiasis medicamentosa en pacientes HIV tratados con IP, si bien, afortunadamente, cada vez se emplean menos. La prevalencia de urolitiasis en los VIH + parece más elevada en función del tiempo de tratamiento con indinavir. Se han observado alteraciones metabólicas en la orina de estos pacientes que contribuyen a una mayor incidencia de litiasis que en la población general (AU)

Objectives: Therapy with protease inhibitors is commonly used in patients infected by human inmunodeficency virus (HIV). 20% of the administered dose is excreted by the kidney, and when alkaline urine is present , indinavir may crystallize forming stones and patients may experience renal colic due to this fact. Methods: Between January 1998 and June 2005, 26 patients receiving antiretroviral treatment with protease inhibitors received care at our hospital because of renal colic or flank pain. All of them underwent physical examination, echography and urography as well as blood and urine analysis. Patients were treated ambulatory excepting those in whom oral analgesics were insufficient to control the pain. Results: All patients had been treated with indinavir for longer than 12 months. They represented 4% of all patients treated with the recommended dose of Crivixan ®. Most of them presented flank pain, associated in most cases to microhaematuria. Five of them required hospitalization because of persistent pain in spite of endovenous analgesia. Imaging tests (echography and urography) showed functional delay of the kidney (2 cases), ureteral stasis (4 cases) and little lithiasic concretions of mild radiologic density (5 cases). Urinalysis revealed suggestive christaluria and alkaline pH. All patients required hidratation and analgesic treatment. In 3 patients indinavir dose was reduced, it was retired in another one, and 100mg of rito-navir were added in another one. Unsuccesfuly ureteral cateterization was tried in one patient. All of them presen-ted symptomatic improvement. Conclusions: We ought to know the capability of indinavir to form urolithiasis in HIV patients treated with protease inhibitors, although its use is decreasing along time. Prevalence of urolithiasis in these patients seems to be higher as length of treatment becomes longer. Metabolic alterations in urine have been proved in these patients, contributing to a higher incidence of lithiasis than in general population (AU)

Toxicidad de dos pautas posológicas de indinavir. Estudio de cohortes retrospectivo / Toxicity of two indinavir dosage regimens. A retrospective cohort study

Indinavir a dosis de 1.200 mg en dos administraciones al día (bid) es una pauta posológica más sencilla que la administración de 800 mg en tres administraciones al día (tid), pero existe riesgo de aumento de toxicidad. Se ha realizado un estudio de cohortes retrospectivo de dieciséis meses de duración con el fin de evaluar si la administración de indinavir 1.200 mg bid se asocia a un mayor número de interrupciones de tratamiento por toxicidad que la administración de 800 mg tid. Se incluyen un total de 127 pacientes que iniciaron tratamiento con indinavir en 1998 (78 con indinavir 800 mg tid y 49 con indinavir 1.200 mg bid). El 32,7 por ciento de los pacientes con indinavir 1.200 mg bid interrumpen tratamiento por toxicidad frente al 15,4 por ciento que tomaban 800 mg tid (p = 0,022) (RR = 2,1; C195 por ciento = 1,1-4,1).Se concluye que indinavir a dosis de 1.200 mg bid se asocia a mayor toxicidad que requiere interrupción de tratamiento que indinavir a dosis de 800 mg tid (AU)