Kaposi's sarcoma in the age of highly active antiretroviral therapy

In the age of HAART, KS generally responds well to therapy.1 KS often significantly improves and blood levels of HHV-8 drop dramatically when HAART is commenced. This clinical improvement is thought to be due to the drugs' restoration of immune function, rather than any direct anti-KS effects.2 Although protease inhibitor- and non-nucleoside reverse transcriptase inhibitor-based HAART regimens have similar efficacy in causing KS regression,3 there is some evidence that HIV protease inhibitors may have direct anti-HHV-8 effects. If the drugs start to fail and HIV viral load increases, KS is likely to progress again.

The widespread use of anti-HIV therapy has produced a reduction in the number of KS cases. In a study of 6700 HIV-positive gay men in the United States, no new cases of KS were seen in 1996. This was a dramatic reduction from 1993 to 1995 that coincided with the widespread introduction of protease inhibitors. In another large study of over 5000 gay and bisexual men in the United States, incidence of KS peaked in 1985 at 26 cases per 1000 person-years, dropping to 7.5 cases per 1000 person-years in 1996 to 1997. The EuroSIDA study has reported a similar fall in incidence in its study of over 7000 individuals from Europe, Israel and Argentina, decreasing further to an incidence of two cases per 1000 person-years in 2002.4

Although KS is rarer in women than in men, a similar drop in incidence has been observed in women since the introduction of HAART.5

A study in the US military found that new cases of KS were 72% lower in 2002-2008 than in 1985-1990. While higher CD4 cell counts were still protective against KS overall, more than a third of recent cases were occurring in patients with CD4 cell counts above 350 cells/mm3.6

A small Italian study found that HAART caused a complete resolution of KS in seven of nine people, while a larger British study found that HAART was an effective and durable treatment for KS. A study of 53 people diagnosed with KS at a mean CD4 cell count of 174 cells/mm3 showed that the magnitude of the CD4 cell count increase after commencing HAART predicted the likelihood that KS would disappear. In total, 72% of those who started HAART after a KS diagnosis had a complete or partial remission of their KS within 48 weeks.7 However, these results have not been replicated in other studies, which have failed to show an effect of CD4 cell count on KS remission, although sustained suppression of HIV viral load did show an association with regression.3

Patients taking HAART are likely to develop KS if they fail to have good virological or immunological response to antiretroviral treatment. Furthermore, despite the dramatically reduced incidence of the disease, gay men taking HAART are still more likely to develop KS than individuals from other risk groups.4

Studies have shown that it may take more than a year for an effective HAART regimen to lead to loss of HHV-8 in HIV-positive patients, whether they have symptomatic KS or not.8 However, in nearly all patients in a prospective study of 22 HIV-positive gay and bisexual men with KS in the Swiss HIV Cohort, KSHV antibodies significantly increased and KSHV viral load became undetectable within 24 months of starting ART.9

HAART regimens have also been shown to reduce the shedding of HHV-8 in saliva, with regimens containing drugs from the three major classes being the most effective.10

In the era of HAART, the prognosis of people with KS is worst when they have both advanced tumours and advanced systemic disease.11

The development of multicentric Castleman's disease (MCD) is associated with increased risk of KS disease progression, particularly if lymphoma develops.12 13 1 A cluster of rapidly progressing MCD has been reported among people taking antiretroviral therapy in the United States. Three people with a history of KS and HHV-8 infection developed symptoms of MCD after initiation of HAART, and two died within a week of diagnosis.14 However, many people with MCD can be managed in the long-term with the use of chemotherapy.15 12

Rapid progression, development and spread of cancerous lesions or tumours have been reported in patients responding to HAART. It is postulated that these growths are an immune reconstitution response to HHV-8, leading to worsening or new appearance of KS or MCD.16

References

  1. Thirlwell C et al. Kaposi's sarcoma in the third millenium. Second International AIDS Society Conference on HIV Pathogenesis and Treatment, Paris (Antiviral Therapy 8:1), abstract 933, 2003
  2. Leao JC et al. Effect of human immunodeficiency virus-1 protease inhibitors on the clearance of human herpesvirus 8 from blood of human immunodeficiency virus-1-infected patients. Journal of Medical Virology 62: 416-420, 2000
  3. Martinez V et al. Prognostic factors of Kaposi's sarcoma in the HAART era. Eleventh Conference on Retroviruses and Opportunistic Infections, San Francisco, abstract 779, 2004
  4. Mocroft A et al. The changing pattern of Kaposi's sarcoma in patients with HIV, 1994-2003: the EuroSIDA study. Cancer 100: 2644-2654, 2004
  5. Hessol NA et al. Cancer risk among participants in the Women's Interagency HIV Study. J Acquir Immune Defic Syndr 36: 978-985, 2004
  6. Crum-Cianflone NF et al. Is Kaposi’s sarcoma occurring at higher CD4 cell counts over the course of the HIV epidemic? AIDS, advance online publication, September 4, 2010. DOI: 10. 1097/QAD.0b013e32833f9fb8., 2010
  7. Renato M et al. Effects of HAART regimens as exclusive treatment of slow proliferating Kaposi's sarcoma. Thirteenth International AIDS Conference, Durban, abstract TuOrB302, 2000
  8. Bourboulia D et al. Short- and long-term effects of highly active antiretroviral therapy on Kaposi sarcoma-associated herpes virus immune responses and viraemia. AIDS 18: 485-493, 2004
  9. Sullivan SG et al. Kaposi sarcoma herpes virus antibody response and viremia following highly active antiretroviral therapy in the Swiss HIV Cohort study. AIDS, advance online publication: DOI: 10. 1097/QAD. 0b013e32833b7830, 2010
  10. Casper C et al. Differential reduction of human herpesvirus 8 oropharyngeal shedding rats with specific antiretroviral agents. Eleventh Conference on Retroviruses and Opportunisitic Infections, San Francisco, abstract 780, 2004
  11. Nasti G et al. AIDS-related Kaposi's sarcoma in 211 patients: assessment of the AIDS Clinical Trial Group staging classification prognostic value in the era of HAART. Tenth Conference on Retroviruses and Opportunistic Infections, Boston, abstract 815, 2003
  12. Oksenhendler S et al. Multicentric Castleman's disease in 70 HIV-infected patients: a prospective cohort study. Second International AIDS Society Conference on HIV Pathogenesis and Treatment, Paris (Antiviral Therapy 8:1), abstract 74, 2003
  13. Martinez V et al. Prognostic factors of Kaposi's sarcoma in the era of HAART. Second International AIDS Society Conference on HIV Pathogenesis and Treatment, Paris (Antiviral Therapy 8:1), abstract 78, 2003
  14. Zietz C et al. An unusual cluster of cases of Castleman's disease during highly active antiretroviral therapy for AIDS. Correspondence, 1999
  15. Neuville S et al. Failure of anti-CD20 monoclonal antibody (rituximab) to control exacerbation of HIV-associated multicentric Castleman's disease in HIV-infected patients. Second International AIDS Society Conference on HIV Pathogenesis and Treatment, Paris (Antiviral Therapy 8:1), abstract 926, 2003
  16. Hosseinipour M et al. Experience with treatment of Kaposi's sarcoma patients in Lilongwe, Malawi. Eleventh Conference on Retroviruses and Opportunistic Infections, San Francisco, abstract 782, 2004