Protease inhibitors and Kaposi’s sarcoma (KS): KS relapse seen after switch from PI to NNRTI
Paul Blanchard, HIV i-Base
Kaposi’s sarcoma (KS) is the most common malignancy experienced in the context of HIV-infection. Although the aetiology and pathogenesis of KS remains ill defined it is known to be an angio-proliferative disease characterised by angiogenesis, endothelial spindle-cell growth, inflammatory cell infiltration and oedema. KS in HIV-infection is also associated with coinfection with human herpesvirus 8 (HHV8), KS development and aggressivity is highly associated with reactivation and viral load of this particular herpesvirus.
Chemotherapy of KS with cytostatic drugs as well as radiotherapy has been found to have variable response rates and has also been associated with an increase in the frequency of opportunistic infections. Recent reports have described both a reduced incidence and regression of KS in HIV-infected patients treated with combination antiretroviral therapy including at least one HIV protease inhibitor (PI).  It is unclear, however, if PIs are an essential component of combination antiretrovirals required to bring about such protection or regression of KS. There remains a lack of evidence to conclude if alternative regimens such as those based on non-nucleoside reverse transcriptase inhibitors (NNRTIs) or triple nucleoside analogue (NA) alone offer the same benefits as PIs in terms of KS regression or protection. A single study did, however, identify three patients whose HHV8 viral load and KS showed a reduction after initiation of NNRTI-based regimens. 
The KS regression observed with the use of PI based antiretroviral regimens is thought to occur primarily due to the immune reconstitution that occurs after such regimens are initiated. Other studies have indicated that the evolution of AIDS-related KS is greatly dependent on the HIV-1 burden, and the ensuing degree of immunodeficiency. However, both in vitro and animal model studies have also shown that PIs may have a direct anti-KS and/or anti-angiogenic effect that may enhance their potency against KS when used in this setting over and above other classes of antiretroviral agents. Recently Sgadari and colleagues reported data showing that PIs have direct anti-angiogenic, anti-KS and anti-tumour effects. 
A report in the journal AIDS by doctors from the Hospital Saint Louis, Paris, appears to be the first publication to identify a relapse of KS in five HIV-infected patients switching from a PI to an NNRTI based antiretroviral regimen.  All five patients had experienced widespread KS prior to the use of PI based antiretroviral regimens and had all received treatment with various regimens of cytotoxic chemotherapy and/or radiotherapy. Under PI treatment they had experienced a median duration of complete KS remission of 32 months.
PIs were discontinued due to virological failure in three cases and a wish to simplify therapy in the other two. Substituted therapy consisted of two nucleoside analogues and efavirenz in four patients and two nucleosides and nevirapine in one patient. Overall the median CD4 count did not change significantly after the switch and HIV viral load remained well suppressed. KS relapse was diagnosed within a median of 11 months post-switch and at a median CD4 cell count of 499 cells/mL.
Bani-Sadr and colleagues comment: “Of significance is the fact that the KS relapse was not explained by the immunological or virological failure of NNRTI-based HAART.” They go on to suggest that the relapse may be explained by the antineoplastic effects of PIs, which are independent of their ability to inhibit HIV protease or induce CD4 cell recovery.
A final caution is given that: “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.”
- Cattelan AM, Calabro ML, Aversa SM et al. Regression of AIDS-related Kaposi’s sarcoma following antiretroviral therapy with protease inhibitors: biological correlates of clinical outcome. Eur J Cancer. 1999 Dec;35(13):1809-15.
- Gill J, Bourboulia D, Wilkinson J et al. Prospective study of the effects of antiretroviral therapy on Kaposi’s sarcoma-associated herpesvirus infection in patients with and without Kaposi’s sarcoma. J Acquir Immune Defic Syndr. 2002 Dec 1;31(4):384-90.
- Sgadari C, Barillari G, Toschi E et al. HIV protease inhibitors are potent anti-angiogenic molecules and promote regression of Kaposi’s sarcoma. Nat Med. 2002 Mar;8(3):225-32.
- Bani-Sadr F, Fournier S, Molina JM. Relapse of Kaposi’s sarcoma in HIV-infected patients switching from a protease inhibitor to a non-nucleoside reverse transcriptase inhibitor-based highly active antiretroviral therapy regimen. AIDS. 2003 Jul 4;17(10):1580-1.