HIV-associated Multicentric Castleman Disease Research Articles

Clinical Features and Outcome in HIV-Associated Multicentric Castleman's Disease

To describe clinical features, treatment outcomes and relapse rates in HIV-associated multicentric Castleman's disease (MCD) in a sizeable mature cohort. From a prospective database, we identified 61 HIV-seropositive patients with histologically confirmed MCD (median follow-up, 4.2 years). Since 2003, 49 patients with newly diagnosed MCD have been treated with rituximab with (n = 14) or without (n = 35) etoposide. At MCD diagnosis, 55 (90%) of 61 patients met proposed clinical criteria defining an attack. Four patients (7%) had histologic evidence of coexisting lymphoma, and one developed lymphoma 2 years after treatment. The incidence of lymphoma is 28 per 1,000 patient years. With rituximab-based treatment, the overall survival was 94% (95% CI, 87% to 100%) at 2 years and was 90% (95% CI, 81% to 100%) at 5 years compared with 42% (95% CI, 14% to 70%) and 33% (95% CI, 6% to 60%) in 12 patients treated before introduction of rituximab (log-rank P < .001). Four of 49 rituximab-treated patients have died; three died as a result of MCD within 10 days of diagnosis, and one died as a result of lymphoma in remission of MCD. Eight of 46 patients who achieved clinical remission suffered symptomatic, histologically confirmed MCD relapse. The median time to relapse was 2 years, and all have been successfully re-treated and are alive in remission. The 2- and 5-year progression-free survival rates for all 49 patients treated with rituximab-based therapy were 85% (95% CI, 74% to 95%) and 61% (95% CI, 40% to 82%), respectively. HIV-associated MCD is a remitting-relapsing disease. The outlook has improved dramatically in recent years with the introduction of rituximab-based therapy and yields high overall survival rates.

How I treat HIV-associated multicentric Castleman disease

HIV-associated plasmablastic multicentric Castleman disease is an increasingly frequent diagnosis. Kaposi sarcoma herpesvirus is found in the monotypic polyclonal plasmablasts that characterize this disease. Unlike Kaposi sarcoma, the incidence does not correlate with CD4 cell count or use of highly active antiretroviral therapy. It is a relapsing and remitting illness, and diagnostic criteria are emerging that define disease activity based on the presence of a fever and raised C-reactive protein coupled with a list of clinical features. Treatment protocols increasingly stratify therapy according to performance status and organ involvement. I advocate rituximab monotherapy for good performance status patients without organ involvement and rituximab with chemotherapy for more aggressive disease. The success of antiherpesvirus agents in controlling active disease is limited, but valganciclovir may have a role as maintenance therapy in the future.

Protective Effect of Rituximab Against Lymphoma Risk In HIV-Associated Multicentric Castleman Disease

AbstractAbstract 2869Human Immunodeficiency Virus (HIV)-associated multicentric Castleman disease (HIV-MCD) is a rare lymphoproliferative disorder occurring in patients co-infected with HHV-8. Long-term prognosis remains severe mainly because of the high incidence of aggressive HHV-8 associated non-Hodgkin lymphoma (NHL). Chemotherapy is usually the first line therapy in active HIV-MCD. Most patients remain dependent on chemotherapy. Recent studies have demonstrated that rituximab allows to resume chemotherapy in most patients. However, effect of rituximab on long-term incidence of lymphoma is unknown.All consecutive patients with HIV-MCD from the national HIV-lymphoproliferative cohort (Clinical site, Saint-Louis Hospital, Paris, France) were enrolled in combination antiretroviral therapy (cART) era. Patients with NHL within the 2 months prior or following rituximab were excluded from analysis. Patients treated with rituximab received 4 infusions, 375 mg per m2 at weekly intervals. Primary objective of the study was to compare incidence of NHL between patients who received rituximab (rituximab group) and who did not received rituximab (control group). Secondary objectives were to compare overall survival and to describe tolerance to rituximab. Survival and NHL incidence was estimated using Kaplan-Meier method and tested with log-rank test.115 patients with HIV-MCD were included in the HIV-lymphoproliferative cohort until november, 2009. Patients were followed for a mean period of 3 years. 7 patients received rituximab as part of LNH therapy and were excluded from analysis. 33 patients (29%) received rituximab as part of MCD therapy. In rituximab group at MCD diagnosis, mean age was 41 years, 24 patients (73%) received antiretroviral therapy, HIV viral load was undetectable (< 500 c/ml) in 10 patients (30%), median CD4 cell count was 233 × 106/L [IQR, 101–368], median nadir CD4 was 160 × 106/L [IQR, 61–194], 14 patients (42%) had an history of Kaposi sarcoma (KS) before rituximab therapy, which was in complete remission or stable at time of rituximab therapy. All 33 patients received chemotherapy as first line MCD treatment: etoposide (n=27), vinblastine (n=4), anthracyclines (n=2). The median period from MCD diagnosis to rituximab therapy was 7.7 months [IQR, 4.6–23.8]. All but 2 patients received the 4 scheduled infusions. These 2 patients discontinued rituximab after the second infusion; one died at day 15 from progressive MCD and the other one discontinued for investigation of rectal tumor. 4 patients received a second course of 4 rituximab infusions for MCD relapse, after a median period of 19.5 months (IQR, 15 to 23).The 3-years probability of developing lymphoma was 0.04% [95%CI,0.01-0.99] in rituximab group (n=33) and 23% [95%CI,14-34] in control group (n=74) (P=0.001). The only lymphoma in rituximab group occurred 22 months after rituximab therapy and patient died. In rituximab group, the median overall survival was 15.7 years compared to 5.2 years in control group (P=0.0007). During total follow-up, 5 patients (15%) died in rituximab group and 28 patients (38%) died in control group. Causes of death in rituximab group was MCD attack (n=1), lymphoma (n=1), acute myeloid leukemia (n=1), infection (n=1), cardiovascular disease (n=1).No severe adverse event was observed during rituximab infusions. Within the first year following rituximab therapy, 9 patients (27%) developed mild to moderate infections; pneumonia (n=2), herpes reactivation (n=2), enterocolitis (n=2), dacryocystitis (n=1), folliculitis (n=1), staphylococcus catheter-related infection (n=1). Transient grade 3 neutropenia occurred in 2 patients (6%). Exacerbation of KS was observed in 4 out of the 15 patients with prior history of KS (4, 4, 7, 36 months after rituximab therapy, respectively), and required specific treatment in 2 patients.Despite improvement in overall survival of HIV-MCD in cART era, risk for developing lymphoma remains high (23% at 3 years). Rituximab seems to induce long-term protection against lymphoma risk, with only one patient developing lymphoma during the 3-year follow-up period in our cohort. Disclosures:No relevant conflicts of interest to declare.

Clinical Presentation, Treatment and Outcome of HIV-Associated Multicentric Castleman Disease

AbstractAbstract 3897 Background:Multicentric Castleman disease (MCD) is a monotypic but non-clonal lymphoproliferation with increased incidence in HIV infection. It is characterized by human herpes virus 8 (HHV-8) infection of the lymphocytes. Signs and symptoms (sx) are largely mediated by HHV-8 induced production of IL-6. Although life expectancy in MCD appears to have improved in the era of highly active antiretroviral therapy (HAART), it remains poor, and the optimal treatment approach in patients (pts) not responding to HAART is undefined due to few large series in which to evaluate management. Contributing to poor outcome is a concomitant increased incidence of other HHV-8 related disorders such as Kaposi sarcoma (KS) and non-Hodgkin lymphoma (NHL), particularly primary effusion lymphoma and plasmablastic lymphoma (PBL). We report the clinical presentation, treatment and outcome of 8 pts with HIV associated MCD diagnosed and treated at our center since 2005. Methods:Pts with HIV-associated MCD were identified from the clinical database of the hematology practice. Charts were reviewed and the following data was extracted: baseline characteristics such as prior opportunistic infections or neoplasms, HAART received and response (CD4 count, HIV viral load [VL]), clinical and laboratory features (including HHV-8 in tissues and plasma HHV-8 VL), MCD course as well as treatment and outcome. Results:Median age at onset of MCD sx was 43 (range 31–63) years (y) and all pts were male. HIV risk was men who have sex with men (MSM) in all and 1 pt had a history of KS. Seven pts were receiving HAART at MCD presentation and the median CD4 count was 385 (140-950) cells/mL and HIV VL 318 (<40-2080) copies/mL. The most common MCD presenting sx were: drenching sweats, n=7; fever, n=6; fatigue, n=4; shortness of breath, n=4; nausea, vomiting and diarrhea, n=3. Signs included: lymphadenopathy, n=8; splenomegaly, n=8; edema, n=4; ascites, n=3; hepatomegaly, n=3; jaundice, n=3; maculopapular rash, n=3; cutaneous KS, n=2. The most striking feature was the waxing and waning course in all pts. Pts were moderately to severely ill for up to several weeks (3 pts required ICU admission; total 6 episodes). Near complete recovery lasting up to several weeks followed after which signs and sx recurred. Common findings on investigation were: anemia, n=8; thrombocytopenia, n=7; hyperbilirubinemia, n=6; and interstitial pulmonary infiltrates, n=5. The median hemoglobin and platelet counts at MCD dx were 89 (67-114) G/L and 128 (34-199) × 109/L, respectively, and 4 pts each required transfusion support. MCD dx was made in the presence of characteristic morphologic features and demonstration of tissue HHV-8 staining on biopsy (excisional lymph node, n=7; splenectomy, n=1; clinical probability plus HHV-8 plasma VL [7 ×106 HHV-8 copies/mL] with positive stains for HHV-8 in the bone marrow, n=1). The median interval from onset of MCD sx to diagnosis (dx) was 7.5 (2-13) months and the time to MCD dx following HIV dx was a median of 9 (0.2-20) y. Concomitant conditions were: KS, n=5 (limited to lymph nodes, n=3; extensive cutaneous, n=2); hemophagocytic lymphohistiocytosis (HLH), n=2; PBL, n=1; Henoch-Schonlein purpura (HSP), n=1. One or more plasma HHV-8 VL measurements were obtained in 5 pts, and 5 were started on valgancyclovir (VGCV) as anti-HHV-8 therapy with a 6th pre-treatment. The median follow-up from MCD dx is 2.6 (0.1-66) months. VGCV was well tolerated. One pt receiving VGCV after not responding to HAART sustained a long term remission of both MCD and KS and remains clinically well 6 y from the onset of sx (5.25 y from starting VGCV). One pt developed tumor lysis syndrome following the initiation of VGCV and is currently improving clinically, 3 are early in VGCV treatment (1-10 weeks). Two pts died, including the pt with PBL, before MCD could be confirmed and treatment started. Conclusions:MCD can be challenging to diagnose due to its waxing and waning nature and frequently poor accessibility of tissue for biopsy. Simultaneous diagnoses such as KS, NHL, HLH and HSP further compound these difficulties. Anti-HHV-8 therapy is a potentially promising treatment for MCD and possibly other HHV-8 mediated conditions, with a long term remission achieved in OUR first pt treated with VGCV. The diagnosis and management of MCD requires a multi-disciplinary approach. To our knowledge, this is one of the largest single institution experiences with HIV-associated MCD reported. Disclosures:No relevant conflicts of interest to declare.

Highly active antiretroviral therapy alone may be an effective treatment for HIV-associated multi-centric Castleman's disease

Highly active antiretroviral therapy alone may be an effective treatment for HIV-associated multi-centric Castleman's disease

Rituximab Therapy for Hiv-Associated Multicentric Castleman Disease

HIV-associated multicentric Castleman disease (MCD) is a rare lymphoproliferative disorder with marked systemic symptoms attributed to cytokine disarray. Many therapeutic approaches conducted in small series of patients have often proved unsuccessful. Rituximab is a chimeric monoclonal antibody that has been extensively used for B-cell lymphomas and autoimmune disorders. The use of rituximab for HIV–MCD now derives from a collection of case reports, case series and two clinical trials, which has led to rituximab being considered as the gold standard therapy for HIV–MCD. Rituximab infusions have been reported to be well tolerated in most patients with mild-to-moderate infectious complications being the most commonly reported toxicity. The most significant adverse event of rituximab therapy for HIV–MCD is Kaposi sarcoma progression. Further work is required to increase our understanding of the disease process to help refine the optimal therapy for this aggressive disease.

Successful treatment of HIV-associated multicentric Castleman's disease and multiple organ failure with rituximab and supportive care: a case report

IntroductionMulticentric Castleman's Disease (MCD), a lymphoproliferative disorder associated with Human Herpes Virus-8 (HHV-8) infection, is increasing in incidence amongst HIV patients. This condition is associated with lymphadenopathy, polyclonal gammopathy, hepato-splenomegaly and systemic symptoms. A number of small studies have demonstrated the efficacy of the anti-CD20 monoclonal antibody, rituximab, in treating this condition.Case presentationWe report the case of a 46 year old Zambian woman who presented with pyrexia, diarrhoea and vomiting, confusion, lymphadenopathy, and renal failure. She rapidly developed multiple organ failure following the initiation of treatment of MCD with rituximab. Following admission to intensive care (ICU), she received prompt multi-organ support. After 21 days on the ICU she returned to the haematology medical ward, and was discharged in remission from her disease after 149 days in hospital.ConclusionRituximab, the efficacy of which has thus far been examined predominantly in patients outside the ICU, in conjunction with extensive organ support was effective treatment for MCD with associated multiple organ failure. There is, to our knowledge, only one other published report of its successful use in an ICU setting, where it was combined with cyclophosphamide, adriamycin and prednisolone. Reports such as ours support the notion that critically unwell patients with HIV and haematological disease can benefit from intensive care.

Cytokine changes during rituximab therapy in HIV-associated multicentric Castleman disease

AbstractRecent data highlight the importance of inflammatory markers during human immunodeficiency virus type 1 (HIV) infection. HIV-associated multicentric Castleman disease (HIV-MCD) presents with systemic symptoms attributed to cytokine disarray, and we have previously shown that the use of the anti-CD20 monoclonal antibody rituximab induces clinical remissions. Before and during successful rituximab therapy, 15 plasma cytokines were measured as were adaptive (CD4, CD8, CD19) and innate (CD16/56) immune cell populations and HIV-1 viral loads. A significant reduction from baseline of the CD19 B-cell count, consistent with rituximab’s mechanism of action, was observed. Markedly elevated cytokine levels were observed before rituximab therapy, and a reduction from baseline values with rituximab therapy was observed for interleukin (IL)-5, IL-6, and IL-10. Therapies that reduce the inflammatory cytokine response are likely to be successful in a range of diseases, including HIV-MCD, and in the future may be used to guide therapeutic strategies.

HIV-associated multicentric Castleman disease

In this review we will discuss the recent findings in HIV-associated multicentric Castleman disease. On the basis of current knowledge on pathophysiology, we will illustrate different therapeutic approaches and try to provide guidelines at least for the initial care of the disease. On the basis of pathological and virological data, pathophysiology appears to conjugate both proliferation of human herpesvirus (HHV-8) infected plasmablasts and replication of HHV-8. Therefore, recent therapies have targeted the infected cells using chemotherapy or rituximab, an anti-CD20 monoclonal antibody or both, and the virus replication by using valganciclovir, a potent antiviral drug usually used against cytomegalovirus. Etoposide is the most effective first-line therapy for active multicentric Castleman disease. Rituximab can be used after an initial control of the attack and provides a 1-yearremission rate above 70%. Exacerbation of Kaposi sarcoma lesions, observed in half of the patients with previous Kaposi sarcoma lesions, may represent a limitation.Valganciclovir effectively suppresses HHV-8 replication both in vitro and in vivo, and reduction in HHV-8 viremia associated with clinical improvement has been suggested in short series of patients with multicentric Castleman disease treated with valganciclovir.

FDG-PET/CT imaging in the management of HIV-associated multicentric Castleman’s disease

To evaluate the role of FDG-PET/CT scanning in the management of HIV-associated multicentric Castleman's disease (MCD) a rare lymphoproliferative disorder associated with infection by human herpesvirus 8 (HHV8). Nine patients with histologically confirmed MCD underwent fused FDG-PET/CT scans at initial MCD diagnosis (n = 3), at MCD relapse (n = 4), or during remission (n = 2). All seven patients with active MCD had markedly elevated plasma HHV8 viral loads, but the patients in remission had no HHV8 viraemia. The three patients with newly diagnosed MCD were not on antiretroviral therapy at the time of imaging, but the other six were all on fully suppressive antiretroviral regimens. In the seven patients with active MCD (newly diagnosed or relapse) 33/91 lymph node groups (36%) included radiologically enlarged nodes on the CT scan, whilst 57/91 lymph node groups (63%) showed enhanced FDG uptake on the PET scan. In scans from patients in remission, there were no enlarged lymph nodes on the CT scan but 3 lymph nodes (11%) demonstrated enhanced FDG uptake. The median SUV recorded for the seven patients with active MCD was 4.8 (range 2.6-9.3) which was significantly higher than the median value of 2.5 recorded for the patients in remission (Mann-Whitney U test, p = 0.011). Despite the small number of patients, in HIV-positive individuals with active MCD, FDG-PET scans more frequently detected abnormal uptake than CT scans detected enlarged lymph nodes. FDG-PET scanning has a useful role in the management of HIV-associated MCD in selecting appropriate sites for biopsy, and in staging and monitoring these lymphoproliferations.

Lymph Nodes Involved by Multicentric Castleman Disease Among HIV-positive Individuals are Often Involved by Kaposi Sarcoma

Multicentric Castleman disease (MCD), a lymphoproliferative disorder and Kaposi sarcoma (KS), a vascular tumor, both occur at a higher frequency among patients with human immunodeficiency virus (HIV) infection. Human herpes virus 8 (HHV8), with an ability to infect and persist in B-lymphoid cells and endothelial cells, is causally associated with both MCD and KS. The coexistence of these HHV8-associated diseases in the same tissue samples has hitherto not been investigated. In this report, we compile the histologic and immunohistochemical findings in 24 lymph node (LN) and 5 spleen samples from 26 patients documented to have HIV-associated MCD. In addition to MCD, 15 of 24 LN samples (63%) showed evidence of coexisting KS. The involvement by KS was typically "microscopic" and involved the LN capsule, trabeculae, or hilum. Examination of 5 spleens involved by MCD did not show any evidence of KS. These were compared with LN biopsies from HIV patients with neither granulomatous diseases, metastatic carcinomas nor lymphoproliferative disorders. Among 20 LN biopsies from 19 individuals without MCD, 5 LNs showed involvement by KS (25%); an association significantly lower than LNs with MCD (Pearson chi 2: 6.2, 2-sided significance: 0.013). Coexistence of MCD and KS in the same tissue sample is a common phenomenon and we hypothesise that the association is due to lytic HHV8 infection of B-lymphoid cells exposing susceptible endothelial cells at vulnerable subsites within the LNs to extremely high levels of HHV8 resulting in formation of KS tumorlets in MCD-LNs.

Complete regression of HIV-associated multicentric Castleman disease treated with rituximab and thalidomide

Complete regression of HIV-associated multicentric Castleman disease treated with rituximab and thalidomide

HIV‐associated multicentric Castleman's disease

Multicentric Castleman's disease (MCD), a relatively rare lymphoproliferative disorder that presents with heterogenous symptoms including fevers, anemia, and multifocal lymphadenopathy, is today most commonly observed in individuals infected with human immunodeficiency virus type-1 (HIV). In such individuals, a lymph node biopsy typically identifies cells that stain for Kaposi's sarcoma-associated herpesvirus proteins, and most HIV-associated MCD features can be attributed to the presence of this gamma-herpesvirus. Surgery and antiviral therapies including highly active antiretroviral therapy, interferon-alpha, foscarnet, ganciclovir, and antibodies to interleukin-6 have proved largely ineffective, and chemotherapy in HIV positive individuals is complicated by limited efficacy and pronounced toxicity. While no randomized trials have been performed, more recently the use of the anti-CD20 monoclonal antibody rituximab in large single center cohorts has been associated with prolonged remissions, radiologic responses, as well as hematologic and serum chemistry normalization of the inflammatory picture observed, at the expense of B cell depletion and flare of Kaposi's sarcoma. MCD represents a model of disease at the interplay between tumor biology, infection, and immunology.

Brief Communication: Rituximab in HIV-Associated Multicentric Castleman Disease

HIV-associated multicentric Castleman disease is a rare lymphoproliferative disorder with marked systemic symptoms attributed to cytokine disarray. Many therapeutic approaches in small series of patients have proved largely unsuccessful to date. To investigate the efficacy and clinicopathologic variables associated with first-line treatment for HIV-associated multicentric Castleman disease with the anti-CD20 monoclonal antibody rituximab. Single-group, open-label, phase II trial. 3 teaching hospitals in England. Previously untreated patients with histologically proven HIV-associated multicentric Castleman disease. 4 infusions of rituximab, 375 mg per m2 of body surface area, at weekly intervals. Response was evaluated clinically and radiologically and by measuring plasma Kaposi sarcoma-associated herpesvirus viral load. 21 consecutive patients (18 men) with plasmablastic multicentric Castleman disease were recruited. The median follow-up was 12 months (range, 1 to 49 months). One patient died before completing therapy, 20 achieved remission of symptoms, and 14 (67%) achieved a radiologic response. The overall and disease-free survival rates at 2 years were 95% (95% CI, 86% to 100%) and 79% (CI, 49% to 100%), respectively. Plasma acute-phase proteins, immunoglobulins, and Kaposi sarcoma-associated herpesvirus viral load decreased after rituximab therapy. The main adverse effect was reactivation of Kaposi sarcoma. The study had no comparison group. Rituximab may be clinically valuable as initial therapy for HIV-associated multicentric Castleman disease.

Prospective Study of Rituximab in Chemotherapy-Dependent Human Immunodeficiency Virus–Associated Multicentric Castleman's Disease: ANRS 117 CastlemaB Trial

Single-agent chemotherapy is usually effective in HIV-associated multicentric Castleman's disease (MCD). However, in most patients, chemotherapy cannot be discontinued. To evaluate the efficacy of four weekly rituximab infusions (375 mg/m(2)) after discontinuation of chemotherapy in HIV-associated MCD, 24 patients were enrolled onto a prospective open-label trial. At study entry, the median time from MCD diagnosis was 21 months. All patients had stable disease on chemotherapy and were dependent on chemotherapy for a median time of 13 months. The median CD4 cell count was 270 x 10(6)/L, and the plasma HIV RNA was less than 50 copies/mL in 18 patients. One patient died with progressive disease at day 15, and 23 patients completed the four cycles of rituximab. Sustained remission (SR) off treatment at day 60 (primary end point) was achieved in 22 patients (92%). From day 60 to day 365, one patient died with acute respiratory failure of undetermined origin, and four patients experienced relapse. Seventeen patients (71%) were alive in SR at day 365 without specific treatment, and the overall survival rate was 92% (95% CI, 71% to 98%). Rituximab was well tolerated, and the majority of adverse events were mild to moderate infections. Mild exacerbation of Kaposi's sarcoma (KS) lesions was observed in eight of 12 patients with previous KS. Rituximab was both effective and safe in HIV-infected patients with chemotherapy-dependent MCD.

Rituximab induces long-term remissions in patients with HIV-associated multicentric Castleman's disease

8049 Background: HIV associated multicentric Castlemans (MCD) is rare lympohproliferative disorder and most treatment options to date, have proved largely unsuccessful. This study investigated the efficacy of the anti CD20 monoclonal antibody rituximab in patients with this disease. Methods: Between 2003 and 2006, patients with histological proven HIV related MCD received a course of 4 infusions of rituximab 375mg/m2 at weekly intervals. Results: Twenty one consecutive patients (18 male) were recruited into this study and the median follow-up is 12 months (range 1–49). The median age was 37 years and all patients were either on highly active antiretroviral therapy (HAART) (62%) or started HAART at the time of MCD diagnosis (38%). The median CD4 cell count at MCD diagnosis was 275/mm3 (range 77–725). One died within 2 weeks of starting rituximab (not evaluable); 20 evaluable patients all achieved clinical remission of symptoms and 71% achieved a radiological response according to RECIST criteria. Rituximab lead to a significant fall in anaemia, thrombocytopenia, CRP, ESR, serum HHV8 viral load and IL-10. Rituximab caused transitory fall in the CD19 count, but had no effect on the CD4, CD8 and NK cell counts or plasma HIV viral load. The disease free survival at 2 years is 79% (95%CI: 49–100%) and overall survival is 95% (95%CI: 86–100%). Two patients have relapsed after 1.6 &amp; 2.8 years and were successfully retreated with rituximab therapy. Conclusions: Rituximab therapy results in a sustained clinical, radiological and biochemical remission in patients with HIV related MCD. No significant financial relationships to disclose.

Life‐threatening interaction between antiretroviral therapy and vinblastine in HIV‐associated multicentric Castleman's disease

HIV-infected patients still present a high risk of developing lymphoproliferative malignancies, despite the fact that their prognosis has been considerably improved by highly active antiretroviral therapy (HAART). Potential interactions exist between antiretroviral drugs, in particular protease inhibitors, and anti-neoplastic ones, but their impact in terms of clinical and haematological adverse events remains unclear. We report a case of potentially life-threatening interaction between vinblastine and antiretroviral therapy in a patient presenting with HIV-associated multicentric Castleman's disease (MCD). A 55-year-old HIV-1 infected patient was diagnosed with MCD while being treated with a salvage HAART regimen consisting of zidovudine, lamivudine, abacavir, nevirapine and ritonavir-boosted lopinavir. Vinblastine was prescribed as a monotherapy at the usual dose of 6 mg/m2 (i.e. 10 mg) every 3 weeks. The first vinblastine course was performed without HAART with no adverse event. Antiretroviral therapy was resumed for the two following courses which were associated with unexpected severe digestive and haematological toxicities, and moderate renal failure. Vinblastine was then administered alone at increasing doses without toxicity. HAART was finally resumed and we assessed that a decreased vinblastine dose of 2 mg/m2 was well tolerated, with a complete response of MCD. HAART regimen comprising protease inhibitors, which are potent inhibitors of cytochrome P450 and P-gp, could interfere with anti-neoplastic drugs, as demonstrated with vinblastine in our case report.

Use of rituximab as a salvage therapy for HIV-associated multicentric Castleman disease

Several approved therapies for multicentric Castleman disease (MCD) cannot be uniformly applied due to intolerable side effects. There is also a high percentage of recurrence of this disease despite treatment. Rituximab may be effective in controlling MCD in a subset of patients. This paper includes a brief case report and an extensive review of previously published cases. We observed an aggravation of concomitant cutaneous Kaposi sarcoma, and hypothesize that rituximab could have exacerbated it.

Pulmonary manifestations of multicentric Castleman's disease in HIV infection: a clinical, biological and radiological study

The aim of the present study was to report clinical, radiological and bronchoalveolar lavage (BAL) findings in patients with pulmonary manifestations of HIV-associated multicentric Castleman's disease (MCD). This was a retrospective study of 12 patients with histologically proven MCD. Clinical manifestations were as follows: dyspnoea (nine out of 12 cases), cough (n = 10), bilateral crackles (n = 10), together with high fever, malaise, peripheral lymphadenopathy (n = 12), and hepatosplenomegaly (n = 10). Two patients developed acute respiratory distress syndrome. Chest radiographs and computed tomography scans showed reticular (n = 7) and/or nodular (n = 7) interstitial patterns, with mediastinal lymphadenopathy (n = 9), and bilateral pleural effusion (n = 3). Fibreoptic endoscopy was normal in all cases. BAL analysis showed hypercellularity (n = 6) and/or lymphocytosis (n = 6), and human herpesvirus-8 DNA was detected in two out of two cases. Specific stains and cultures for pathogens were negative. All patients received etoposide and/or vinblastine, and improved after 2-4 days. Relapses were frequent (50 attacks in 12 patients). Six patients developed a non-Hodgkin's lymphoma, and five died. In conclusion, the pulmonary manifestation of HIV-related multicentric Castleman's disease is an acute reticulo-nodular interstitial pneumonitis, associated with severe systemic symptoms and peripheral lymphadenopathy. In bronchoalveolar lavage fluid, cellularity is not specific and human herpesvirus-8 DNA is detected. The clinical course is specific due to a rapid onset and regression, frequent relapses and a high occurrence of non-Hodgkin's lymphoma.

Remission of HHV-8 and HIV-associated multicentric Castleman disease with ganciclovir treatment

AbstractMulticentric Castleman disease (MCD) is a lymphoproliferative disorder associated with human herpesvirus 8 (HHV-8) infection among persons with human immunodeficiency virus (HIV) infection. Treatment often includes chemotherapy, and progression to non-Hodgkin lymphoma frequently occurs. MCD is characterized in part by active HHV-8 replication, and many of the symptoms of MCD may be attributable to viral gene products. We describe the effect of ganciclovir on the clinical and virologic course of MCD in a series of 3 case reports. Two patients experienced a reduction in the frequency of episodic flares of MCD and detectable HHV-8 DNA with intravenous or oral ganciclovir, whereas the third patient recovered from an acute episode of renal and respiratory failure with intravenous ganciclovir therapy. These data provide in vivo evidence for the utility of antiviral agents against HHV-8 in the management of MCD.