Use of cidofovir for the treatment of HIV-negative human herpes virus-8-associated primary effusion lymphoma.
Year: 2010
Type: article
Abstract: Stingaciu, Ticchioni et al. report a case of an elderly HIV-negative Mediterranean woman diagnosed with primary effusion lymphoma (PEL) resistant to conventional chemotherapy. In addition to bilateral pleural effusion and decreased breath sounds, the patient also exhibited reactive changes in axillary and retroperitoneal lymph nodes. Cytologic and histologic analyses of the pleural fluid were consistent with a diagnosis of PEL. Human herpesvirus-8 (HHV-8) DNA was present in pleural fluid and antibodies to HHV-8 were detected in serum. The patient underwent two rounds of CHOP chemotherapy (cyclophosphamide, vincristine, doxorubicin and prednisone) with no improvement in her effusions or performance scor e. However, she exhibited complete and sustained remission after three doses of intracavitary cidofovir.
While the presence of HHV-8-infected lymphocytes is essential for diagnosis of PEL, malignant cells are commonly co-infected with the closely related Epstein Barr virus (EBV)1,2 as in this case study. The effect of dual herpesvirus infection is not well-defined with respect to either disease progression or response to treatment. Although this case report is on HIV-negative PEL, more is known about PEL arising in the setting of HIV infection, which results in a poor prognosis. The average survival in HIV-positive patients with PEL is 6 months after diagnosis, despite conventional chemotherapy treatment3–5. Non-compliance with HAART therapy has proven to be a poor prognostic factor in HIV-positive patients with PEL4, 5. Furthermore, patients with HIV and PEL may be less likely to tolerate the systemic side effects of conventional chemotherapies based on multiple co-morbidities and poor performance score4.
The mainstay of treatment in PEL continues to be systemic conventional combinatorial chemotherapeutic regimens such as CHOP5, 6 as attempted in this case study. However, standard cytotoxic regimens are suboptimal for several reasons. First, toxicity from effects on normal cells, including bone marrow suppression, gastrointestinal toxicity, and neurotoxicity can limit the benefit of these agents. Second, patients with PEL tend to have poorer immune function and performance status than other lymphoma patients, making them less likely to tolerate these side effects. Most importantly, systemic chemotherapy works very poorly in PEL, improving survival by a few months at best, with quick relapses even if there is an initial response. This poor response may be partially due to the sequestration of malignant cells within the body cavity where it may not experience high enough levels of cytotoxic agents to have a major direct effect. Newer strategies using radiation therapy or immunotherapy have also been attempted with only marginal improvement in outcomes4, 7–10.
The prospect of a specific antiviral agent is enticing as it presumably would have fewer side effects caused by off-target effects. Cidofovir selectively inhibits the herpesviral DNA polymerase, thereby inhibiting viral DNA replication11. HHV-8 exists in both a latent and lytic lifecycle in the infected host. The majority of HHV-8 tumors, including PEL, contain latent virus with a small percentage of the tumor cells undergoing lytic replication12. The expression of lytic viral genes is thought to play a significant role in the tumorigenesis through the upregulation of paracrine and autocrine growth factors which augment tumor proliferation and survival. While cidofovir does not affect viral latency, it does inhibit the lytic phase of the virus, and thus may repress the expression of lytic viral genes that contribute to tumor survival13–15.
Cidofovir has been shown to have direct cytotoxic effects on PEL cells in vitro 16. Although initial trials with intravenous cidofovir for the treatment of cutaneous Kaposi sarcoma, another HHV-8-associated malignancy, appeared successful17, a larger, more recent report evidenced progression of disease in all seven patients with intravenous administration of cidofovir for AIDS-related and classical KS18. The data on intravenous administration of cidofovir (cidofovir-IV) for PEL are scant and also mixed. Complete remission has been documented with two HIV-positive patients with PEL when cidofovir-IV was combined with antiretroviral and interferon administration, while another patient achieved only partial remission and died after six months2, 19. The authors of this case study postulated that high enough concentrations of cidofovir were not achieved in the pleural fluid to affect direct cell killing when the drug was administered intravenously. Including this case report, four studies report achieving durable remission in HIV-negative patients with PEL with intracavitary cidofovir after conventional chemotherapy failure20-22. No reports were identified in which HIV-positive patients with PEL were treated with intracavitary cidofovir.
The main side effects of intravenous cidofovir include nephrotoxicity, neutropenia, and decreased intraocular pressure and thus it is not a totally benign drug23, 24. However, it is possible that these ill effects may be lessened by the intracavitary route of administration, assuming systemic concentrations are lower, while still achieving concentrations in the effusion high enough to kill PEL cells and reduce the effusion. Indeed in this case study, minimal side effects were noted by the patient. In summary, treatment of PEL with intracavitary cidofovir has the potential to be a more effective treatment strategy than standard chemotherapy regimens, and clinical trials using it in combination with front-line chemotherapy regimens are warranted.
Source: PubMed
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funder: National Cancer Institute
OpenAlex ID: W1922379132