Service des Maladies Infectieuses et Tropicales, Hôpital Saint Louis, Paris, France.
Received: 15 January 2003; accepted: 18 February 2003.
Kaposi's sarcoma (KS) is the most common malignancy associated with HIV infection. In recent years, several studies have reported a steady decline in the incidence of KS, coinciding with the increasing use of combination potent antiretroviral agents, such as HIV-1 protease inhibitors (PI) . Furthermore, a number of reports have documented tumour regression after the initiation of highly active antiretroviral therapy (HAART) that includes at least one PI [2,3]. We describe here five patients in whom a relapse of KS was documented a few months after the switch from a PI, to a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based HAART regimen.
The characteristics of the five patients are summarized in Table 1. At the diagnosis of KS, all five patients presented with widespread skin lesions, three also had mucosal involvement, and one had multicentric Castleman's disease. All had been treated with cytotoxic chemotherapy for a median duration of 30 months (range 2–51 months). Three patients had received major chemotherapy such as adriamycin–bleomycin–vincristine and docetaxel. The other two had been treated with bleomycin and radiotherapy or bleomycin alone. Before the switch from a PI to a NNRTI-based HAART regimen, the median duration of complete KS remission was 32 months (range 16–33 months). At the time of the switch, the median duration of the PI-based HAART regimen was 29 months (range 10–37 months). Two patients had received indinavir, two nelfinavir, and one ritonavir. The decision to switch treatment from PI to NNRTI was made because of a virological failure in three cases and a wish to simplify the regimen in the remaining two cases. All patients received a combination of two nucleoside reverse transcriptase inhibitors and efavirenz (four patients) or nevirapine (one patient). The KS relapse was diagnosed within a median of 11 months (range 4–28 months) after the switch, despite a sustained high CD4 cell count in four cases. Overall, the median CD4 cell count did not change significantly from the time of the switch to the relapse of KS: 658 cells/mm3 (range 165–814 cells/mm3) versus 499 cells/mm3 (range 157–1319 cells/mm3), respectively. The relapse of KS was not associated with virological failure from the new antiretroviral combination. Before the switch, the HIV-RNA level was below 20 copies in two out of five cases, and in four out of five cases after the switch.
Although the precise mechanism by which PI-based HAART modifies the clinical course of KS has not been elucidated, it has been suggested that an improvement in KS is largely caused by the recovery of the immune system [2,3]. However, clinical studies and in-vivo models have indicated a lack of association between the suppression of HIV-1 replication and KS [3,4]. The patients described here presented with a relapse of KS after a switch from PI to NNRTI, despite having a long-term remission of their KS under PI-based HAART. Of significance is the fact that the KS relapse was not explained by the immunological or virogical failure of NNRTI-based HAART. Two reports using in-vitro and in-vivo models [4,5] have recently demonstrated that PI, such as ritonavir, indinavir or saquinavir, have direct anti-angiogenic, anti-KS and anti-tumour effects. Notably, PI block angiogenesis mediated by basic fibroblast growth factor and vascular endothelial growth factor, the two key factors for KS lesion formation. PI not only block the development of KS in mice treated with the drugs before KS cell inoculation, but they are also effective when given at the time of cell inoculation . This suggests that PI can both directly prevent the development and induce the regression of KS. These data are in agreement with the observed lower incidence and the regression of KS seen in patients treated with a PI-based HAART regimen. Our case se series, therefore, illustrates the fact that KS can relapse after the withdrawal of PI, despite successful antiretroviral therapy. This relapse may be explained by the antineoplastic effects of PI, which are independent of their ability to inhibit HIV protease or induce CD4 cell recovery.
A switch from PI to NNRTI should be performed with caution in patients with a history of KS, even though the new regimen is fully active in maintaining HIV viral suppression and high CD4 cell counts.
1.Grulich AE, Li Y, McDonald AM, Correll PK, Law MG, Kaldor JM. Decreasing rates of Kaposi's sarcoma and non-Hodgkin's lymphoma in the era of potent combination anti-retroviral therapy. AIDS
2.Lebbé C, Blum L, Pellet C, Blanchard G, Verola O, Morel P, et al. Clinical and biological impact of antiretroviral therapy with protease inhibitors on HIV-related Kaposi's sarcoma. AIDS
3.Dupont C, Vasseur E, Beauchet A, Aegerter P, Berthe H, de Truchis P, et al. Long-term efficacy on Kaposi's sarcoma of highly active antiretroviral therapy in a cohort of HIV-positive patients. AIDS
4.Sgadari C, Barillari G, Toschi E, Carlei D, Bacigalupo I, Baccarini S, et al. HIV protease inhibitors are potent anti-angiogenic molecules and promote regression of Kaposi sarcoma. Nat Med
5.Pati S, Pelser CB, Dufraine J, Bryant JL, Reitz MS, Weichold FF. Antitumorigenic effects of HIV protease inhibitor ritonavir: inhibition of Kaposi sarcoma. Blood
© 2003 Lippincott Williams & Wilkins, Inc.