Failure of cidofovir in HIV-associated multicentric Castleman disease

Multicentric Castleman disease (MCD) is a distinct lymphoproliferative disorder characterized by lymphadenopathy with angiofollicular hyperplasia and plasma cell infiltration. Patients typically have fever associated with lymphadenopathy, hepatosplenomegaly, respiratory symptoms, peripheral edema, cytopenia, hypergammaglobulinemia, hypoalbuminemia, and high levels of serum C reactive protein (CRP).¹  In the context of HIV infection, MCD is associated with Kaposi sarcoma-associated herpesvirus (KSHV). Clinical symptoms correlate with an important increase of KSHV DNA in peripheral blood mononuclear cells (PBMCs).^2,3  Vinca alkaloids produce frequent but short-lived responses, and most patients remain dependent upon chemotherapy. Rituximab has been reported to be effective.⁴  Besides cellular targets, viral targets could be considered for intervention. In vitro, KSHV replication can be inhibited by some antiherpesvirus drugs such as ganciclovir, foscarnet, and cidofovir.⁵ 

We have read with interest the article by Casper et al⁶  on the treatment of HIV-associated MCD with ganciclovir. This study, showing a response to ganciclovir in 3 patients, suggested that antiviral agents against KSHV could be used in the management of MCD. However, clinical remission was short lived for patient 2, and patient 1 died with fungal infection after 12 days of ganciclovir. Only the third patient had a long-lasting remission after a 21-day course of valganciclovir. In contrast, our experience with cidofovir (CDV), the most potent anti-KSHV drug in vitro,⁵  was disappointing. There were 5 HIV-infected patients with histologically proven and chemo-dependent MCD treated prospectively with CDV (5 mg/kg per dose) weekly for 3 weeks and then every other 2 weeks (Table 1). The treatment period was scheduled for 60 days. Chemotherapy was discontinued at entry but was permitted during the study period in case of severe recurring flares. All of the patients had controlled HIV replication on antiretroviral therapy.

Patients received 3 to 6 CDV infusions over 21 to 60 days. All 5 patients experienced repeated recurrence of MCD symptoms during the study and remained dependent upon chemotherapy. Clinical symptoms were correlated with high serum CRP values and high KSHV copy numbers in PBMCs without any demonstrable impact of cidofovir on these parameters. Patient 5 had no response with an increase of KSHV DNA in PBMCs and was splenectomized, as a diagnosis of lymphoma was suspected. The treatment was prematurely interrupted in 4 patients because of evident failure (Figure 1).

Anecdotal reports of Kaposi sarcoma (KS) responding to antiherpes drugs⁷  and studies showing that treatment of AIDS patients with ganciclovir or foscarnet for cytomegalovirus disease reduced the risk of KS⁸  could suggest that antiherpes drugs might be effective against KSHV-associated diseases. Moreover, MCD differs from KS not only in the infected cell type, but also in the pattern of viral gene expression as infected cells from MCD express both latent and lytic proteins.⁹  This point could argue for a possible direct efficacy of antiviral drugs in KSHV-associated MCD. However, the pathologic features, the frequent evolution of MCD toward KSHV⁺ non-Hodgkin lymphoma,¹⁰  the failure of CDV, and the effectiveness of chemotherapy and rituximab suggest that the profile of this disease remains closer to that of a virus-associated lymphoproliferative disorder.