Treatment And Survival Of Ks

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Treatment is guided by the extent of symptomatic and extracutaneous KS, immune system conditions, and concurrent complications of HIV infection since KS is not considered curable by standard therapies.

Local Treatment

Localized KS lesions can be treated with alitretinoin gel, intralesional chemotherapy, radiation therapy, laser therapy, cryotherapy, and surgical excision.90,110 With intralesional therapy, vinblastine is likely the most used and yields a response rate of 70%.191 Radiotherapy, whether given as whole-body electron beam therapy, fractionated focal radiation therapy, and single treatments have produced CRs in 50-80% of patients.192-194

Chemotherapy

Systemic chemotherapy is used with individuals with progressive, widespread disease, and in particular with visceral involvement. Large randomized studies have established liposomal anthracyclines (doxorubicin, daunorubicin) as first line singleagent chemotherapy agents with promising results compared with combination chemotherapy treatment.195-197 Paclitaxel has also been recently used as a cytotoxic agent against KS. Compared with other regimens, the median duration of response ranged from 7.4 to 10.4 months, among the longest observed.198-201 Although well tolerated, paclitaxel has many adverse effects, including neutropenia and toxic interactions with HAART due to both being metabolized by the cytochrome P-450 pathways.202,203

Interferon

For HIV-infected individuals who have appropriate immune reconstitution with antiretrovirals, but still have disseminated cutaneous KS, interferon-alpha may be a favorable option. Response rates from 20 to 40% have been observed in patients.168 Adverse side effects from interferon-alpha encompass fever, chills, neutropenia, hepatotoxicity, and cognitive impairment.

Anti-HHV-8 Therapy

The discovery of HHV-8 in all forms of KS has raised the possibility of using antiviral agents to target this virus. HIV-infected individuals that used foscarnet instead of ganciclovir to treat cytomegalovirus disease had a considerably longer time of their existing KS progressing to a more severe form.204 In another trial, the use of ganciclovir for treatment of cytomegalovirus disease reduced the risk of developing KS.205 A pilot study using cidofovir for the treatment of AIDS-associated and classic KS showed no effect on disease progression, no decrease in viral load of HHV-8 among seven patients, and no change in expression of early lytic and latent gene expressions from cutaneous KS lesions. Only one of seven patients demonstrated decreased production of a late lytic gene.206

Most KS tumor cells are latently infected with HHV-8 and thus more resistant to antiherpesvirus drugs that rely on lytic replication. This resistance can be overcome by inducing HHV-8 to reenter the lytic cycle during antiviral therapy, leading to destruction of virally infected cells. Another way would be to disrupt the maintenance and replication of HHV-8 during the latency, via glycyrrhizic acid or hydroxyurea, and thus interrupt the role of the virus in tumor formation.207

Other Potential Targets

Potential targets based on KS pathogenesis are the focus of many current trials. Angiogenesis inhibitors including fumagillin, thalidomide, MMP inhibitor COL-3, and Imatinib mesylate are all agents being tested on individuals with AIDS-associated KS.187,208-212 Further, platelet-derived growth factor213 and c-kit214 have a role in active tumor formation. In one small study, the use of Imatinib mesylate, a c-kit and platelet-derived growth factor (PDGF) receptor inhibitor, resulted in regression of AIDS-related KS lesions.211

Impact of HAART

It is essential for tumor control for the majority of individuals now with HIV and concurrent KS to be treated with HAART.187,215 The inhibition of HIV replication, decreased production of the Tat protein, restored immunity to HHV-8 and the direct antiangiogenic activity of some protease inhibitors are among the benefits of antiretroviral therapy.216,217

HAART has been associated with a lengthening of time to treatment failure with either local or systemic therapy for KS. Bower and colleagues218 reported in a retrospective study a median time of 1.7 years from the initiation of HAART versus 0.5 years with no antiretroviral therapy to detect treatment failure among HIV-infected individuals with KS.

It has also been shown that antiretroviral therapy alone is linked with regression in size and number of existing KS lesions.219-221 Nasti et al.222 demonstrated that HIV-infected individuals who were already receiving HAART at KS diagnosis had a less aggressive presentation versus individuals who were naive to HAART at time of KS diagnosis.

Tam et al.,223 in a retrospective analysis from 1990 to 1999, demonstrated improved survival, an 81% risk reduction of death among HIV-infected individuals, with the initiation of HAART after the diagnosis of KS.

Thus, HAART taken along with chemotherapy extends the time to treatment failure of anti-KS therapies218 and patients are able to sustain extended course of chemotherapy without relapse at its discontinuation.224

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