Treatment of Kaposi Sarcoma in the Highly Active Antiretroviral Therapy Era
- 1Service de Dermatologie, Pavillon Tarnier, Hôpital Cochin, Assistance Publique des Hôpitaux de Paris and unité propre de recherche de l'enseignement supérieur-Equipe d'Acceuil 1833, Faculté de Médecine René Descartes, Paris
- 2Service de Dermatologie et d'Infectiologie, Hôpital Bonnet, Fréjus, France
- Reprints or correspondence: Dr. Pascal Del Guidice, Dept. of Dermatology and Infectious Diseases, Centre Hospitalier Intercommunal de Frej, Ave. Andre Leotard, Frejus, 83608, France (del-giudice-p{at}chi-frejus-saint-raphael.fr).
The introduction of HAART in the United States and Europe has resulted in a dramatic decrease in the incidence of opportunistic infections and tumors associated with AIDS, including Kaposi sarcoma (KS) (see Krown [1] for review). In the French Hospital Database on HIV, the KS incidence rate decreased from 32 cases per 1000 person-years during the period 1993–1994 to 3 cases per 1000 person-years after 1999 [2]. The prognosis associated with some visceral KS locations (notably, that associated with lung KS) has dramatically improved with the use of HAART in combination with chemotherapy [1]. HAART has been reported to prolong time to treatment failure in KS, and complete remissions of both cutaneous and visceral KS have been reported in patients treated with HAART alone [1].
The remission of KS observed in patients with AIDS who are treated with HAART is quite similar to the resolution of KS observed in patients with iatrogenic KS after treatment with immunosuppressors is modulated or stopped, confirming the opportunistic nature of KS [3]. In patients with AIDS who are treated with HAART, immune restoration appears to be the main factor associated with KS remission. It has been shown that remission of KS in patients who receive a HAART regimen is associated with a significant increase in total CD4+ cell count [4]. Studies of cellular immunity have demonstrated that KS is associated with a lack of immune response to human herpesvirus 8 (HHV-8) epitopes, whereas HHV-8-infected patients without KS have a cellular response to HHV-8 epitopes [5]. However, longitudinal studies have shown that HHV-8-specific immune restoration is delayed >24 months after the initiation of HAART [6], suggesting that control of KS may be attributable to a combination of immune restoration and inhibition of HIV replication. Indeed, in a retrospective study, it was shown that an undetectable HIV load was the best marker of KS response at 6, 12, and 24 months after the introduction of HAART and that patients with an undetectable HIV load experienced the best response [7]. Although some authors have suggested that protease inhibitors may have a proper anti-KS effect via an anti-angiogenic action [8], longitudinal studies showed no difference in both the incidence of KS and the response of KS in patients who received an antiretroviral combination containing protease inhibitors, compared with patients who received a regimen that did not contain protease inhibitors [7].
In addition to remission of KS, paradoxical exacerbations of preexisting KS have been reported among severely immunocompromised patients at the introduction of HAART. Such exacerbations were considered to be manifestations of an immune reconstitution inflammatory syndrome [9–10].
The study by Martin-Carbonero et al. [11], published in this issue of Clinical Infectious Diseases, reports on the long-term prognosis of 98 patients with AIDS who received pegylated liposomal doxorubicin for KS. They show that, within a median follow-up period of 28 months, one-third of the patients died, with a high proportion of patients having non-Hodgkin lymphoma. The increasing risk of non-Hodgkin lymphoma among patients with KS has already been reported, even for HIV-negative patients with KS [12]. Indeed, in addition to KS, HHV-8 infection has been implicated in at least 2 rare lymphoproliferative disorders: the multicentric form of Castleman disease, and primary effusion lymphoma. Because HHV-8 is implicated in lymphomagenesis, the excess of non-Hodgkin lymphoma among such patients is not completely surprising; the presence of HHV-8 DNA in all cases and the types of non-Hodgkin lymphoma (including 3 cases of primary effusion lymphoma) further illustrated this hypothesis [11]. However, the unexpected findings of this study [11] concern both the high incidence of non-Hodgkin lymphoma and the high proportion of death during a relative short period of observation. One could hypothesize that the high rate of mortality in this cohort reflects the high proportion of patients with markers of poor KS prognosis, because 50% of the patients were classified as having T1 stage KS and were heavily immunocompromised (median CD4+ cell count at study inclusion was 150 cells/mL). The negative impact of doxorubicin itself may be a factor and requires additional studies, because we know that patients who have been treated with anthracyclins may later develop non-Hodgkin lymphoma and leukemia [13]. The important message conveyed by the high number of patients with non-Hodgkin lymphoma reported in this study should be the importance of avoiding excessive exposure to chemotherapeutic drugs that could favor the development of non-Hodgkin lymphoma or other neoplasms in population that are at risk for developing such complications.
So, how should we treat patients with AIDS and KS in the HAART era? Any therapeutic choice should take into consideration several parameters, such as the extension of mucocutaneous KS lesions, the presence of visceral involvement that may be life-threatening (e.g., symptomatic lung KS), KS involvement at a location that could compromise a specific organ function, and the intensity of immunosuppression. We must also remember that most patients with KS will respond to HAART, even if the response may be delayed by several months or years.
For limited disease, defined as <10 skin lesions with no proximal edema and no mucosal involvement, HAART alone should be preferred, with a strict clinical monitoring to detect progression of KS, which is rare but has been reported in both patients with immune restoration and patients without immune restoration. Adjuvant local therapies can be used to treat patients who experience such progression.
Although Martin-Carbonero et al. [11], comparing HAART alone with HAART plus pegylated doxorubicin in the treatment of moderately advanced KS, report a better response rate in the HAART plus chemotherapy group at 48 weeks of follow-up, it seems reasonable to evaluate the risk and the benefit of HAART alone versus HAART with an adjuvant therapy. In patients who receive HAART alone, immunoresponse should be followed by strict clinical monitoring. In such patients, monochemotherapy, such as treatment with bleomycin, could be proposed for a short period (3–6 months). When lymphoedema is predominant, taxanes could be an option but, again, they should be administered for a limited number of cycles. The role of IFN in the treatment of patients with AIDS and KS seems to be limited in the HAART era.
For life-threatening KS or extensive KS compromising an organ function, Krown [1], who analyzed the literature on the effects of HAART in KS, concluded that “although HAART is an important component of treatment for all patients with KS, there is scant evidence that HAART induces regression of advanced, symptomatic KS without concomitant KS therapy” [1, p. 401]. Therefore, in these patients, HAART should be associated with adjuvant therapy, such as taxanes or liposomal anthracyclins chemotherapies. Evaluation of the response to therapy should be performed regularly to prevent both early and late complications of chemotherapy and to avoid excessive dosages of chemotherapy in this population, which is at risk of developing lymphoproliferative disorders.
Monitoring HHV-8 levels in peripheral blood may provide interesting data that can assist, not only in following the response to nonspecific or specific treatment, but also in detecting the development of non-Hodgkin lymphoma or Castleman disease. It has been demonstrated that patients with those lymphoproliferative disorders have high levels of HHV-8 in this compartment [14].
Despite recent descriptions of patients with KS associated with low or undetectable HIV loads and high CD4+ cell counts (>300 cells/µL) [15, 16], we must keep in mind that the efficacy of the best specific chemotherapy for patients with AIDS and KS depends on a stable and high level of immunorestoration, associated with a strong control of HIV load, which remains the main prognosis criteria for long-term regression and control of KS.
Acknowledgments
Potential conflicts of interest. P.D.G. has served as a consultant to Galderma and on the Speakers' Bureaus of GlaxoSmithKline and 3M. N.D.: no conflicts.
- Received April 22, 2007.
- Accepted April 23, 2008.
- © 2008 by the Infectious Diseases Society of America
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