ritonavir and Hodgkin-Disease

A 60-year-old HIV-1 infected woman on antiretroviral therapy (emtricitabine/tenofovir, and ritonavir-boosted atazanavir) developed Hodgkin's lymphoma. The patient initiated ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) chemotherapy and presented with neutropenia and severe hypokalemia. Hypokalemia was considered as part of a proximal tubular renal dysfunction, and other causes of hypokalemia were excluded. Due to suspicion of drug--drug interactions between antiretrovirals and vinblastine, ritonavir-boosted atazanavir was switched to dolutegravir and the patient continued emtricitabine/tenofovir. In the subsequent ABVD cycles, no neutropenia or hypokalemia were observed. Vinblastine is metabolized by the hepatic P450 cytochrome isoenzyme CYP3A4, therefore, concomitant administration with protease inhibitors may increase plasma levels of vinblastine. Vinblastine is also a substrate and inhibitor of multidrug resistance-associated protein 2 (MRP2) transporter in the proximal renal tubule. Inhibition of this renal transporter could increase tenofovir renal toxicity. Our hypothesis is that the hypokalemia could be a result of a tenofovir-mediated tubular damage triggered by the increased vinblastine serum levels secondary to a CYP3A4 inhibition by ritonavir. To the best of our knowledge, this is the first report of severe hypokalemia and proximal tubular renal dysfunction as a result of a possible drug-drug interaction between vinblastine, tenofovir and ritonavir-boosted atazanavir.

Topics: Adenine; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Dacarbazine; Doxorubicin; Drug Interactions; Emtricitabine; Female; HIV Infections; HIV Protease Inhibitors; Hodgkin Disease; Humans; Hypokalemia; Middle Aged; Ritonavir; Tenofovir; Treatment Outcome; Vinblastine

The incidence of Hodgkin lymphoma (HL) is rising among individuals infected with human immunodeficiency virus (HIV). Standard treatment regimens include vinblastine, which is known to cause neurotoxicity (NT) and is metabolized by cytochrome 3A4 (CYP3A4). This is inhibited by protease inhibitors (PIs), possibly increasing vinblastine exposure. There is little information on how interactions affect clinical outcome. A retrospective review of 32 patients with HIV-HL receiving chemotherapy with curative intent was performed to identify the frequency and risk factors for NT, hematologic toxicity (HT) and lung toxicity (LT). Treatment was: ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) in 90%, MOPP/ABV (mechlorethamine, vincristine, procarbazine, prednisone/doxorubicin, bleomycin, vinblastine) in 10% and HAART (highly active anti-retroviral therapy) in 63%. Seventeen potential risk factors and 18 individual anti-retroviral (ARV) agents were examined, and only ritonavir or lopinavir use was found to have a significant association with toxicity. Grade 3-4 NT occurred in five patients, grade 3-4 HT in 17, infectious complications in 10 and bleomycin LT in three. Ritonavir and lopinavir use was associated with grade 3-4 NT (p = 0.03 and p = 0.01, respectively), and ritonavir with any HT (p = 0.04). Patients with HIV-HL experienced an increased incidence of NT and possibly HT. The use of ritonavir or lopinavir was associated with NT, suggesting a clinically significant interaction with vinblastine. Prospective pharmacokinetic studies to devise a rational dosing strategy for vinblastine in patients receiving ritonavir/lopinavir are warranted.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Antiretroviral Therapy, Highly Active; Bleomycin; Dacarbazine; Doxorubicin; Female; Hematologic Diseases; HIV Infections; HIV Protease Inhibitors; Hodgkin Disease; Humans; Incidence; Kaplan-Meier Estimate; Lopinavir; Lung Diseases; Male; Mechlorethamine; Middle Aged; Nervous System Diseases; Prednisone; Procarbazine; Prognosis; Retrospective Studies; Ritonavir; Vinblastine; Vincristine

In order to analyze the clinical relevance of the pharmacokinetic interactions between vinblastine and antiretrovirals described in literature, we evaluated all HIV-infected patients with Hodgkin's lymphoma treated with vinblastine-containing regimens and combination antiretroviral therapy, in a single clinical center. The use of protease inhibitors was independently associated with WHO grade III-IV neutropenia. Moreover, an inverse correlation between dosage of ritonavir and mean nadir neutrophil count was found. The concomitant administration of vinblastine-containing chemotherapy regimens with protease inhibitors can lead to higher levels of neutropenia than those of different classes of drugs such as nonnucleoside reverse transcriptase inhibitors or integrase inhibitors.

Topics: Adult; Aged; Drug Interactions; Female; HIV Infections; HIV Protease Inhibitors; Hodgkin Disease; Humans; Male; Middle Aged; Ritonavir; Vinblastine