REVIEW URRENT C OPINION

Facing up to the ongoing challenge of Kaposi’s sarcoma Rebecca C. Robey a and Mark Bower a,b

Purpose of review Kaposi’s sarcoma is a mesenchymal tumour caused by infection with human herpesvirus 8, usually in the context of immunodeficiency. The global incidence of Kaposi’s sarcoma rose dramatically with the outbreak of HIV and AIDS. Although the introduction of combined antiretroviral therapy (cART) has seen a dramatic decline in Kaposi’s sarcoma incidence, it remains a significant burden of morbidity and mortality, especially in sub-Saharan Africa. This review considers the most recent evidence regarding the prevalence, current treatment strategies and future therapies for Kaposi’s sarcoma. Recent findings In the post-cART era, the epidemiology of acquired immunodeficiency syndrome-related Karposi sarcoma (AIDS-KS) is changing, with a rising incidence in the context of immune reconstitution inflammatory syndrome, and this has important implications for cART rollout initiatives. The current best-available treatment strategies use cART either alone or in combination with systemic chemotherapy, and there is new evidence for a stage-stratified treatment algorithm to guide their use. In addition, a number of new, targeted therapies for Kaposi’s sarcoma are under investigation. Summary The introduction of cART has not entirely removed the challenge of AIDS-KS. It is, however, an increasingly manageable disease, although issues of drug availability in sub-Saharan Africa remain to be addressed. Keywords human herpesvirus 8, immune reconstitution inflammatory syndrome, Kaposi’s sarcoma, paclitaxel, pegylated liposomal doxorubicin

INTRODUCTION Kaposi’s sarcoma is a multifocal mesenchymal neoplasm characterized by neoangiogenesis, inflammatory infiltration and endothelial-derived, spindleshaped tumour cells. It is associated with infection with human herpesvirus 8 (HHV8; also known as Kaposi’s sarcoma-associated herpesvirus), which is necessary, but not sufficient, to cause disease. HHV8 infection in immunocompetent hosts usually results in latent infection. The development of Kaposi’s sarcoma involves a complex interaction of reactivated HHV8 infection, immunosuppression and, paradoxically, some level of systemic and localized immune activation, which initiates proinflammatory angiogenesis, culminating in Kaposi’s sarcoma lesion formation. HHV8 is a large, double-stranded DNA virus that encodes over 90 open reading frames (ORFs) and has developed several complex strategies for evading the host’s immune system. For example, a large number of viral ORFs encode homologues of cellular genes

that have been ‘pirated’ from the host genome during the course of the virus’s evolution [1]. Many of these ORFs also have roles in driving oncogenesis, often through the same molecular pathways that are employed in immune evasion. Figure 1 illustrates some of the factors in the pathogenesis of Kaposi’s sarcoma. Until the 1980s, Kaposi’s sarcoma was a relatively rare neoplasm [1]. Two forms were seen: ‘classic Kaposi’s sarcoma’, an indolent, chronic form usually confined to the skin and mostly affecting elderly men of Mediterranean, Eastern European or Middle Eastern origin, and ‘endemic Kaposi’s a

Imperial College and bChelsea and Westminster Hospital, London, UK

Correspondence to Mark Bower, PhD, FRCP, FRCPath, Professor, National Centre for HIV Malignancy, Chelsea and Westminster Hospital, 369 Fulham Road, London SW10 9NH, UK. Tel: +44 208 237 5054; fax: +44 208 746 8863; e-mail: [email protected] Curr Opin Infect Dis 2015, 28:31–40 DOI:10.1097/QCO.0000000000000122

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KEY POINTS  The post-cART era has not seen, as hoped, a total decline in AIDS-KS, but a changing pattern of epidemiology has emerged. The issue of Kaposi’s sarcoma in the context of immune reconstitution inflammatory syndrome (IRIS) and its impact on cART rollout initiatives have become increasingly apparent.  The increased incidence of Kaposi’s sarcoma-IRIS and its higher mortality rates in sub-Saharan Africa in particular need to be addressed.  AIDS-KS is an increasingly manageable disease in the developed world. Excellent outcomes can be achieved when using optimal cART alone, or cART in combination with liposomal anthracyclines, according to a simple treatment algorithm. Paclitaxel is an effective rescue therapy in many anthracyclineresistant cases.

sarcoma incidence, particularly in North America and Western Europe [2]. Nonetheless, it continues to represent a considerable burden of morbidity and mortality in PLWHA in these countries [3 ,4 ,5 ]. Recent data reveal some thought-provoking disparities in Kaposi’s sarcoma incidence in different populations in the United States. In adolescents and young adults, Kaposi’s sarcoma incidence is significantly higher in black and Hispanic men compared with white men [6 ]. In an interesting analysis of the relationship between cancer incidence and socioeconomic status in the USA, Kaposi’s sarcoma was the tumour most strongly associated with higher levels of poverty [7 ]. In sub-Saharan Africa, Kaposi’s sarcoma remains one of the most common cancers, representing a staggering 27, 35 and 24% of total cancer burden in Uganda, Zimbabwe and Mozambique, respectively [8 –10 ]. This is in part because of the high seroprevalence of HHV8 in these countries [11], which predates the emergence of HIV, and in part because of lack of access to cART and other drugs. In Uganda and Zimbabwe, data indicate a recent decline in Kaposi’s sarcoma incidence; however, data from Mozambique report a continuing rise in Kaposi’s sarcoma incidence [8 –10 ]. In South Africa, Kaposi’s sarcoma was not endemic before the emergence of HIV, and cases were rare prior to 1995. A recent retrospective study of cancers in HIV-positive children found that Kaposi’s sarcoma was the most common neoplasm, with most cases occurring after 2000. Moreover, cases of Kaposi’s sarcoma in children continue to rise despite the drive to make cART available nationwide since 2004 [12 ]. A separate prospective multicohort study looked at the impact of this cART rollout initiative on Kaposi’s sarcoma incidence in adults [13 ]. Incidence rates were 138 per 100 000 person-years for those on cART and 1682 per 100 000 person-years in cART-naı¨ve individuals. This not only supports a case for the timely initiation of cART in order to reduce the burden of Kaposi’s sarcoma, but also, importantly, illustrates that, as in North America and Western Europe, the introduction of cART has not completely removed the challenge of Kaposi’s sarcoma. &&

 Alternative new treatments against Kaposi’s sarcoma, including immunomodulatory drugs and targeted therapies, have shown promise in the early-phase trials.

sarcoma’, a more aggressive form, often with lymph node involvement, affecting both adults and children in sub-Saharan Africa [1]. In 1981, an unusual cluster of Kaposi’s sarcoma cases in young men from New York City and California was a harbinger of the outbreak of AIDS [1], and in 1982 Kaposi’s sarcoma was listed as an AIDS-defining illness by the United States Center for Disease Control and Prevention. ’Acquired immunodeficiency syndrome-related Karposi sarcoma’ (AIDS-KS) is a more aggressive disease, often affecting the mouth, genitalia and internal organs, most commonly the lungs and gastrointestinal tract. Its global incidence rose dramatically in conjunction with the rise of the AIDS epidemic in the 1980s and 1990s. Despite a decline in incidence since the introduction of combined antiretroviral therapy (cART), it remains the most common cancer in people living with HIV/AIDS (PLWHA).

KAPOSI’S SARCOMA EPIDEMIOLOGY: A CHANGING PATTERN IN THE POSTCOMBINED ANTIRETROVIRAL THERAPY ERA The introduction of cART, and the continued improvement in its efficacy, tolerability and availability, has seen a substantial decline in Kaposi’s 32

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 Access to the most effective chemotherapeutic agents, pegylated liposomal doxorubicin and paclitaxel, is extremely limited in sub-Saharan Africa, and the use of older, suboptimal agents remain the mainstay of treatment.

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Kaposi’s sarcoma in the context of immune reconstitution inflammatory syndrome The phenomenon of immune reconstitution inflammatory syndrome (IRIS) in patients initiating cART is well recognized and takes two forms. There is either a paradoxical clinical worsening of opportunistic infections and malignancies diagnosed before cART initiation or an ‘unmasking’ effect, with Volume 28  Number 1  February 2015

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The ongoing challenge of Kaposi’s sarcoma Robey and Bower

Targeted T-cell activity enhancers Anti-CTLA4 mAbs (ipilimumab) PD1/PDL1 inhibitors

Immunomodulators

Lenalidomide Pegylated IFNα2a IL12 Rapamycin

CD8 CD8 CD8

KS spindle cells surround slit-like neovasculature containing erythrocytes

Targeted therapies Anti-IL6 or IL6R mAbs (siltuximab, tocilizumab)

Anti-angiogenics Anti-VEGF mAbs (bevacizumab) VEGF and PDGF inhibitors (imatinib, sorafenib, sunitinib) Matrix metalloprotease inhibitors (COL-3)

HHV8 encodes genes involved in immune evasion, for example, a viral homologue of IL6

FIGURE 1. Schematic illustration of some of the factors in the pathogenesis of Kaposi’s sarcoma and the new therapeutic approaches that target them. In immunocompetent individuals, human herpesvirus 8 (HHV8) infection is kept in check, predominantly by the CD8 T lymphocytes. When T-cell-mediated control declines, for example, in AIDS, HHV8-infected cells proliferate and transformation to tumour spindle cells occurs. HHV8 encodes several genes involved in immune evasion, further contributing to the immunosuppressive tumour microenvironment. New therapies are under investigation that act by enhancing the immune response against HHV8 (immunomodulators and targeted T-cell activity enhancers), inhibiting angiogenesis, or directly targeting molecular pathways employed by HHV8 in immune evasion and oncogenesis. IFN, interferon; IL, interleukin; mAb, monoclonal antibody; PD1, programmed death 1; PDL1, programmed death ligand 1; VEGF, vascular endothelial growth factor; PDGF, platelet derived growth factor.

previously subclinical diseases becoming apparent de novo. Both occur during the initial weeks of therapy and are temporally related to successful immune reconstitution. The scale of this problem in relation to Kaposi’s sarcoma and its impact on universal cART rollout in resource-limited settings is only just beginning to become apparent. Until recently, the literature on Kaposi’s sarcoma in the context of IRIS (KS-IRIS) was limited to approximately 50 cases, described in case reports, case series or small cohort studies. A recent prospective study investigated the incidence and outcomes of paradoxical KS-IRIS in three cohorts in subSaharan Africa and one from the UK [14 ]. Out of 417 PLWHA with Kaposi’s sarcoma initiating cART (213 in London and 204 in Africa), 58 developed KSIRIS: 18 in London and 40 in Africa, representing 8.5 and 19.6% of cases, respectively. It should be noted that the treatment strategy in Africa and London differed for patients with advanced-stage (T1) Kaposi’s sarcoma, who were routinely treated with systemic chemotherapy in London. The risk factors for KS-IRIS were initial Kaposi’s sarcoma treatment with cART alone, more advanced Kaposi’s sarcoma &&

tumour stage at cART initiation, and higher HIV viral load at cART initiation. Outcomes for KS-IRIS were better in London: 22% of patients had a complete response to treatment and the remaining 78% had a partial response. In Africa, 23% had partial responses, 18% had stable Kaposi’s sarcoma, 53% had progressive disease, including 19 deaths (48% of patients), and the remaining 8% were lost to followup. Overall, this study illustrates that KS-IRIS is a significant problem, both in the UK and Africa, but rates are approximately 2.5-fold higher in subSaharan Africa and outcomes are considerably worse, likely because of more severe disease at presentation and limited access to chemotherapy. This is supported by the additional studies reporting similar rates of incidence and mortality for KS-IRIS in sub-Saharan Africa [15 ,16 ]. True unmasked KS-IRIS must begin within 6 months of initiating therapy, and the rates remain unclear. A large European cohort study estimated that the relative risk of developing Kaposi’s sarcoma de novo was 3.94 times higher in the first 3 months after starting cART than in those not receiving cART [17 ]. A U.S.-based prospective study found that &

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Kaposi’s sarcoma incidence in the first 6 months after cART initiation was 1342 per 100 000 personyears [18 ]. Several studies have shown that the risk of KS-IRIS development is increased with lower CD4 counts before starting cART, reflecting the importance of timely cART initiation [13 ,17 ,18 ]. &

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Kaposi’s sarcoma in the context of competent immunity In addition to KS-IRIS, another new pattern of Kaposi’s sarcoma in cART-treated patients is emerging. In resource-rich countries, there has been an increase in the Kaposi’s sarcoma cases in patients with high CD4 counts and low HIV viral load, both in cART-naı¨ve patients, and those established on successful cART [18 ,19,20 ,21 ,22 ,23,24 ]. Although the incidence rate of Kaposi’s sarcoma declines with increasing CD4 count [22 ], there is still a substantially increased risk of developing Kaposi’s sarcoma in patients with fully restored immunity compared with the general population [3 ]. This is in contrast to non-Hodgkin’s lymphoma, another AIDS-defining cancer, which shows no statistical difference in the incidence between HIV-infected patients with restored immunity and the general population [3 ]. In some patients developing Kaposi’s sarcoma in the context of restored immunity, it has been suggested that the disease appears to run a more indolent course, more akin to classic Kaposi’s sarcoma [21 ,24 ]. &

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directly inhibit HHV8 replication and shedding [26,27], clinical data from nonrandomized cohort studies do not show clear superior efficacy for either protease-inhibitor-based or NNTI-based regimes in the prevention or treatment of Kaposi’s sarcoma [19,28]. A randomized controlled trial to address this question specifically is under way in Uganda (NCT00444379) and the results are pending. On balance, current evidence indicates that the primary antitumour effect of cART remains the successful suppression of HIV and restoration of immunity, and the specific choice of regime is less significant. This is particularly relevant as most widely available cART regimes in sub-Saharan Africa are NNRTI based.

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Chemotherapy The use of cytotoxic chemotherapy to treat AIDS-KS requires a complex balance of risk and benefit, most notably to achieve an anticancer effect without causing further immunocompromise. Drug interactions between cART and chemotherapeutic agents are also a major consideration, largely because of the convergence on the cytochrome P450 enzyme system. In particular, protease inhibitors and NNRTIs alter the pharmacokinetics of CYP3A4, which is involved in the metabolism of many chemotherapeutic agents [29]. A number of chemotherapeutic agents are effective, and the current first-line therapy is pegylated liposomal doxorubicin (PLD) or other liposomal anthracyclines [30 ]. In randomized trials conducted in the pre-cART era, PLD achieved greater response rates and less toxicity than the previously widely used combination regimes of bleomycin and vincristine as dual therapy or with the addition of adriamycin (doxorubicin) in triple therapy (ABV). Paclitaxel also has significant activity against Kaposi’s sarcoma as a single agent. Randomized trials of paclitaxel versus PLD showed slightly higher response rates and longer progression-free survival (PFS) with the former, but with significantly increased toxicity. This, together with its proven efficacy as a rescue therapy for anthracycline-refractory Kaposi’s sarcoma, has established paclitaxel as the second-line agent of choice [25,30 ,31]. A major issue that remains, however, is identifying at presentation which patients require systemic chemotherapy in addition to cART. In a large prospective study, a staging system was used, for the first time, to define a treatment algorithm for the use of chemotherapy in addition to cART to treat Kaposi’s sarcoma [20 ]. Kaposi’s sarcoma is not staged using the standard tumour, node, metastasis system used for most solid tumours, as the &

CURRENT TREATMENT FOR KAPOSI’S SARCOMA cART is key to Kaposi’s sarcoma treatment, and as sole therapy can achieve remission in between 60 and 90% of patients with limited-stage (T0) disease [19,25]. However, this usually follows the recovery of cell-mediated immunity and can take several months. Therefore, in more advanced-stage or aggressive Kaposi’s sarcoma, or in those who present established on cART with reasonable CD4 counts and undetectable plasma HIV viral load, systemic chemotherapy in combination with cART is the established treatment strategy.

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Antiretroviral therapy Current cART regimes are based on either a protease inhibitor or a nonnucleoside reverse-transcriptase inhibitor (NNRTI) or, more recently, an integrase inhibitor, in combination with two nucleoside reverse-transcriptase inhibitors. Despite evidence that some protease inhibitors have direct antiangiogenic and antitumourigenic properties, and may 34

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The ongoing challenge of Kaposi’s sarcoma Robey and Bower

multifocal nature of Kaposi’s sarcoma makes it difficult to describe in these terms, and other AIDS-related factors contributing to disease burden must also be considered. Instead, a system developed in the pre-cART era by the AIDS Clinical Trials Group (ACTG) is used (Table 1). Over a 15-year period, 469 consecutive patients presenting with Kaposi’s sarcoma were staged at diagnosis according to the ACTG system [20 ]. Those presenting with T0 (early-stage) disease were routinely treated with cART alone except in cases of severely cosmetically disfiguring lesions, which were treated by surgical excision, localized radiotherapy or chemotherapy. Those presenting with T1 (advanced-stage) disease were routinely treated with cART and PLD. Results are summarized in Fig. 2. Ninety percent of ART-naı¨ve patients who presented with T0 disease received cART alone, and achieved 5-year and 10-year overall survival (OS) rates of 95 and 91%, and PFS rates of 77 and 76%, respectively. Eighty-four percent of patients presenting with T1 disease received cART with liposomal anthracycline chemotherapy and achieved 5-year and 10-year OS rates of 85 and 83%, respectively. This study demonstrated excellent outcomes for the treatment of T0 disease with cART alone, and validated the use of a simple treatment algorithm for new presentations of Kaposi’s sarcoma in ART-naı¨ve patients based on the ACTG staging system. However, it also showed that this algorithm may not be so applicable to patients presenting with Kaposi’s sarcoma whilst established on cART, as nearly half of these patients required additional therapy even if they presented with T0 disease. &&

The overall 10-year survival of the entire cohort was 84%, which is considerably higher than that reported by similar cohorts over the same time period. In a large, multicentre study in Italy, 10-year survival was only 73% [32], and a study in California reported 1-year survival of only 75% [33]. Although neither of these studies provided information regarding tumour stage or treatment strategies, this nonetheless illustrates the advantage of treating patients by following a stage-stratified algorithm for optimal care.

Chemotherapy in the developing world Although recent drives have made cART increasingly available in the developing world, the low availability of chemotherapy remains a significant problem. PLD and paclitaxel remain prohibitively expensive for routine use in most resource-poor settings. A U.S.-based study estimated that it costs $18 125 to treat a patient with PLD and $12 347 to treat a patient with paclitaxel, taking into account the wholesale costs of the drugs, and the cost of adverse events including neutropenia, hypersensitivity and discontinuation of therapy [34 ]. Furthermore, the infrastructure and expertise necessary to safely reconstitute and deliver intravenous chemotherapy is not available in most hospitals in Africa. The prohibitive cost of liposomal anthracyclines and taxanes is reflected by the recent trials investigating the use of older, cheaper chemotherapy agents for Kaposi’s sarcoma in sub-Saharan Africa [15 ,35 ,36 ]. In general, the data support a role for early chemotherapy in combination with &

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Table 1. The ACTG staging system for Kaposi’s sarcoma Parameter

Good risk (0)

Poor risk (1)

Tumour (T)

Kaposi’s sarcoma confined to skin and lymph nodes

Tumour-associated oedema or ulceration

Minimal oral disease: nonnodular Kaposi’s sarcoma confined to palate

Extensive oral Kaposi’s sarcoma Gastrointestinal Kaposi’s sarcoma Kaposi’s sarcoma in other nonnodal viscera

Immune status (I)

CD4 count >200 cells/ml

Systemic illness (S)

No history of opportunistic infection or thrush

CD4 count 2 weeks

Lymphoma

Performance status >70 (Karnofsky score) The multifocal nature of Kaposi’s sarcoma makes it difficult to stage using the standard tumour, node, metastasis (TNM) system used for most solid tumours, and other AIDS-related factors contributing to disease burden must also be considered. Therefore, a system developed in the pre-cART era by the AIDS Clinical Trials Group (ACTG) is used instead and is summarized in this table.

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Consecutive KS patients N = 469

T0 disease n = 303

cART-naïve n = 237

On cART > 3 mths at presentation n = 66

Rx cART alone n = 213 (90%)

Rx cART alone n = 35

T1 disease n = 166

cART alone n = 14

cART + PLD n = 140 (84%)

OS: 5yr = 85% 10yr = 83%

OS: 5yr = 95% 10yr = 91% PFS: 5yr = 77% 10yr = 76%

FIGURE 2. Results of a large prospective study testing an algorithm for the treatment of KS based on the AIDS Clinical Trials Group’s staging system. Flow diagram summarizing the treatments received and the outcomes achieved in a large prospective study testing a stage-stratified algorithm for the treatment of KS. A total of 469 consecutive KS patients were treated. Those presenting with T0 disease routinely received optimal cART alone as therapy. Those presenting with T1 disease routinely received cART in combination with systemic chemotherapy [19]. Overall and PFS rates refer to patients who were treated as per algorithm protocol. Chemo, systemic chemotherapy; CI, contraindicated; KS, Kaposi’s sarcoma; PLD, pegylated liposomal doxorubicin; OS, overall survival; PFS, progression-free survival.

cART in advanced-stage Kaposi’s sarcoma, but reinforce the suboptimal nature of the available agents, which include oral etoposide, and intravenous vincristine, bleomycin and adriamycin, as either single, double or triple therapies. A randomized trial of agents to treat Kaposi’s sarcoma in children found that survival was significantly better with bleomycin and vincristine or etoposide compared with vincristine alone, and etoposide was associated with slightly greater improvement in the quality of life measures [36 ]. Other reports have highlighted the limited availability of even these older cheaper agents [28,37 ]. &&

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NOVEL THERAPEUTIC STRATEGIES Despite the success of the latest chemotherapeutic agents against Kaposi’s sarcoma, a proportion of cases remain refractory to these treatments. Moreover, toxicity and immunosuppression remain a significant issue with these agents, as does their delivery in resource-limited countries. Therefore, a number of novel agents are under investigation, including immunomodulatory drugs and targeted therapies using monoclonal antibodies (mAbs) 36

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and small-molecule inhibitors [38 ,39 ,40–42,43 , 44–47] (Fig. 1 and Table 2).

Immunotherapy for Kaposi’s sarcoma In the pre-cART era, the antiangiogenic immunomodulator thalidomide was used in AIDS-KS with limited success. Recent case reports describe partial responses to lenalidomide, a thalidomide analogue, in aggressive chemotherapy-refractive AIDS-KS [38 ]. A phase I/II trial is ongoing in the United States. Interferon-alpha is another immunomodulatory and antiviral drug previously investigated for use in AIDS-KS. Although 40% of patients responded, frequent significant side-effects led to a decline in its use. However, new pegylated formations of interferon-alpha 2a show superior efficacy and less toxicity. An observational study of 10 cART-treated patients with T1-stage AIDS-KS (six of whom had failed previous chemotherapy) reported an overall response rate of 90% and median PFS of 645 days [39 ]. Somewhat paradoxically, rapamycin (sirolimus), an immunosuppressant, has been used to &

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Anti-CTLA4 mAb

Ipilimumab

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[47]

[47]

[47]

[46]

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[43 ]

[45]

[42]

[44]

[41]

[40]

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Reference(s)

A number of novel therapeutic agents are under investigation for the treatment of Kaposi’s sarcoma, including immunomodulatory drugs and targeted therapies such as monoclonal antibodies small-molecule inhibitors. This table summarizes the mechanism of action of these therapies, the current evidence for their use in Kaposi’s sarcoma and the currently listed clinical trials. CTLA4, cytotoxic T-lymphocyte-associated protein 4, HHV8, human herpesvirus 8; mTOR, mammalian target of rapamycin; PD1, programmed death 1; PD1L, programmed death 1 ligand; PDGF, platelet-derived growth factor; PLD, pegylated liposomal doxorubicin; PLWHA, people living with HIV/AIDS; mAb, monoclonal antibody; RAF, rapidly accelerated fibrosarcoma; VEGF, vascular endothelial growth factor.

Not yet investigated for Kaposi’s sarcoma

Trials show efficacy in multicentric Castleman’s disease

Siltuximab

HHV8 encodes a viral homologue of IL6 which may be important in Kaposi’s sarcoma tumourigenesis

Trials show efficacy in multicentric Castleman’s disease Not yet investigated for Kaposi’s sarcoma

Anti-IL6R mAb HHV8 encodes a viral homologue of IL6 which may be important in Kaposi’s sarcoma tumourigenesis Anti-IL6 mAb

CD20 is a B-cell surface marker

Tocilizumab

Current standard of care for Kaposi’s sarcoma with concurrent multicentric Castleman’s disease, a lymphoproliferative disorder associated with HHV8 in PLWHA

Anticancer effect by restricting tumour blood flow Anti-CD20 mAb

In trial in the USA (NCT00020683)

Matrix metalloprotease inhibitor

COL-3

Rituximab

Phase II trial showed safety and efficacy

PD1/PDL1 pathway is involved in downregulation of T-cell functionality Inhibitors lead to T-cell activation

Not currently in trial

Not currently in trial

Phase II trial showed safety and efficacy

In phase II trial (NTC00521092)

Under clinical trial (NCT0030412)

Case reports of efficacy

PD1/PDL1 inhibitors

Anti-CTLA4 leads to T-cell activation

CTLA4 inhibits T cells

Small-molecule inhibitor of VEGF and PDGF and other tyrosine kinases Small-molecule inhibitor of PDGF and c-kit

Sunitinib

Imatinib

Small-molecule inhibitor of VEGF and PDGF and other tyrosine kinases and RAF kinases

Phase II trial showed safety and efficacy Ongoing trials (NCT00055237, NCT00923936)

Anti-VEGF mAb

Phase II trial (NCT00020449) showed safety and efficacy in combination with PLD

Under clinical trial (NCT00450320)

Antiangiogenic

Antiviral and antiangiogenic

Sorafenib

Bevacizumab

Targeted agents

Interleukin-12

Efficacy recognized in iatrogenic Kaposi’s sarcoma Pilot study showed safety and efficacy in AIDS-KS

Immunosuppressant, inhibits mTOR mTOR is overexpressed in Kaposi’s sarcoma and may be important in tumourigenesis

Rapamycin

Observational study of efficacy in 10 patients

In phase I/II trial in the USA (NCT01057121) Immunomodulatory and antiviral

Pegylated interferon-alpha 2a

Case reports of efficacy

Current evidence and clinical trials

Immunomodulatory and antiangiogenic

Mechanism of action

Lenalidomide

Immunomodulatory agents

Agent

Table 2. Novel therapeutic agents under investigation for the treatment of Kaposi’s sarcoma

The ongoing challenge of Kaposi’s sarcoma Robey and Bower

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induce regression in posttransplant iatrogenic Kaposi’s sarcoma whilst preserving graft function [40]. Its target, mammalian target of rapamycin, is activated in Kaposi’s sarcoma and may play an important role in tumourigenesis. In a pilot study in seven individuals with AIDS-KS receiving cART, rapamycin pharmacokinetics were dramatically different in protease-inhibitor-treated patients compared with NNRTI-treated patients, the latter requiring 200-fold higher maintenance doses [41]. Despite this, rapamycin was well tolerated and three patients with higher levels of rapamycin exposure showed partial responses.

Targeted therapies Kaposi’s sarcoma is characterized by angioproliferation, and vascular endothelial growth factor A (VEGF-A) is an important autocrine and paracrine growth factor in Kaposi’s sarcoma. In a phase II trial, 17 patients with AIDS-KS, including 13 with chemotherapy-refractive T1-stage disease, were treated with bevacizumab, an anti-VEGF-A mAb [42]. Three patients had a complete response and two had a partial response (overall response rate of 31%). Four of the five responders had previously failed chemotherapy. In general, bevacizumab was well tolerated and, importantly, did not appear to interfere with immune reconstitution, in contrast to most cytotoxic agents. Imatinib, a tyrosine kinase receptor, has also been trialled in Kaposi’s sarcoma. It inhibits platelet-derived growth factor (PDGF), another important cytokine in Kaposi’s sarcoma tumour development that induces the expression of VEGF, and c-kit, a receptor that is upregulated in HHV8infected cells. In a phase II trial, 30 patients with AIDS-KS were treated with imatinib, 10 (33%) had a partial response and 6 (20%) had stable disease. Five patients (17%) discontinued the use because of toxicity [43 ]. Two other new agents with both anti-VEGF and anti-PDGF activity are the oral small-molecule inhibitors sorafenib and sunitinib, both of which are currently in trial against Kaposi’s sarcoma. The importance of T-cell control of HHV8 infection and Kaposi’s sarcoma provides a strong case for the use of two other new targeted therapies: ipilimumab (an anti-CTLA4 mAb) and agents targeting the programmed death 1 (PD1)–PD1 ligand (PDL1) pathway, which is implicated in downregulating T-cell function. These therapies both essentially reduce T-cell inhibition, thereby activating the surveillance defences against cancer. They have shown remarkable effect against some of the more immunogenic solid tumours, in particular melanoma and

renal cell carcinoma. Moreover, upregulation of PDL1 is seen in chronic HIV infection, even in aviraemic patients on successful cART. Investigation of these agents in Kaposi’s sarcoma is therefore warranted, although a recent report failed to detect PDL1 expression in nine cases of Kaposi’s sarcoma [48].

CONCLUSION Although AIDS-KS is, in many cases, an increasingly manageable disease, there remain a number of important clinical issues that need to be addressed. A greater understanding of the disease and optimal treatment of KS-IRIS is needed, especially in resource-poor settings, in which it carries a mortality of nearly 50%. Likewise, a greater understanding of Kaposi’s sarcoma in the context of restored immunity may become increasingly important as the population of PLWHA on long-term cART increases. Furthermore, although the current chemotherapeutic agents produce excellent remission rates, AIDS-KS is still considered an incurable disease, and issues remain of systemic toxicity, worsening of immunosuppression and, most importantly, access in resource-poor environments. The novel agents currently under investigation may eventually provide a solution to these problems. Acknowledgements The authors wish to thank Dr S.J. Kelly for her support in the preparation of this article. Financial support and sponsorship None. Conflicts of interest The authors declare no conflicts of interest.

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REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Robey R, Bower M. Kaposi sarcoma herpesvirus. In: Gupta S, Kumar B, editors. Sexually transmitted infection, 2nd ed. Delhi, India: Elsevier; 2012 . pp. 418–426. 2. Rubinstein PG, Aboulafia DM, Zloza A. Malignancies in HIV/AIDS: from epidemiology to therapeutic challenges. AIDS 2014; 28:453–465. 3. Hleyhel M, Belot A, Bouvier AM, et al., French Hospital Database on HIV– && ANRS CO4 Cohort. Risk of AIDS-defining cancers among HIV-1-infected patients in France between 1992 and 2009: results from the FHDH-ANRS CO4 cohort. Clin Infect Dis 2013; 57:1638–1647. A very large cohort study showing patterns in the incidence of Kaposi’s sarcoma in France over a 20-year period. This study illustrates that, although there was a dramatic decline in the incidence with the introduction of cART, Kaposi’s sarcoma nonetheless remains a significant problem and incidence rates have been relatively stable over the last 10 years.

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The ongoing challenge of Kaposi’s sarcoma Robey and Bower 4. Calabresi A, Ferraresi A, Festa A, et al., Brescia HIV Cancer Study Group. & Incidence of AIDS-defining cancers and virus-related and nonvirus-related non-AIDS-defining cancers among HIV-infected patients compared with the general population in a large health district of Northern Italy, 1999–2009. HIV Med 2013; 14:481–490. A smaller cohort study illustrating the continuing challenge of Kaposi’s sarcoma in Italy. 5. Yanik EL, Tamburro K, Eron JJ, et al. Recent cancer incidence trends in an & observational clinical cohort of HIV-infected patients in the US, 2000 to 2011. Infect Agent Cancer 2013; 8:18. This study shows stable Kaposi’s sarcoma incidence rates over the last 10 years in North Carolina, USA. 6. Hsieh MC, Wu XC, Andrews PA, Chen VW. Racial and ethnic disparities in & the incidence and trends of soft tissue sarcoma among adolescents and young adults in the United States, 1995–2008. J Adolesc Young Adult Oncol 2013; 2:89–94. This study demonstrates the ethnic disparities in the incidence rates of Kaposi’s sarcoma in the USA. 7. Boscoe FP, Johnson CJ, Sherman RL, et al. The relationship between area & poverty rate and site-specific cancer incidence in the United States. Cancer 2014; 120:2191–2198. An interesting study which shows that Kaposi’s sarcoma is the cancer most strongly associated with higher levels of poverty in the USA. 8. Wabinga HR, Nambooze S, Amulen PM, et al. Trends in the incidence of & cancer in Kampala, Uganda 1991–2010. Int J Cancer 2014; 135:432–439. An update on cancer incidence from one of the most comprehensive cancer registries in sub-Saharan Africa, which shows Kaposi’s sarcoma is still one of the most common cancers in the population as a whole in Uganda. 9. Chokunonga E, Borok MZ, Chirenje ZM, et al. Trends in the incidence of & cancer in the black population of Harare, Zimbabwe 1991–2010. Int J Cancer 2013; 133:721–729. An update on cancer incidence from one of the most comprehensive cancer registries in sub-Saharan Africa, which shows Kaposi’s sarcoma is still one of the most common cancers in the population as a whole in Zimbabwe. 10. Carrilho C, Ferro J, Lorenzoni C, et al. A contribution for a more accurate & estimation of the incidence of Kaposi sarcoma in Mozambique. Int J Cancer 2013; 132:988–989. Data from Mozambique shows Kaposi’s sarcoma is one of the most common cancers and indicates that rates are continuing to rise. 11. Stolka K, Ndom P, Hemingway-Foday J, et al. Risk factors for Kaposi’s sarcoma among HIV-positive individuals in a case control study in Cameroon. Cancer Epidemiol 2014; 38:137–143. 12. Davidson A, Wainwright RD, Stones DK, et al. Malignancies in South African & children with HIV. J Pediatr Hematol Oncol 2014; 36:111–117. This study shows that Kaposi’s sarcoma has relatively recently (in the last 15 years) become one of the most common cancers in HIV-infected children, and the rates continue to rise despite cART rollout initiatives. 13. Bohlius J, Valeri F, Maskew M, et al. Kaposi’s sarcoma in HIV-infected patients && in South Africa: multicohort study in the antiretroviral therapy era. Int J Cancer 2014; 135:2644–2652. A very up-to-date study which shows that although the antiretroviral rollout initiative in South Africa has reduced the incidence of Kaposi’s sarcoma, it has not eliminated the problem. 14. Letang E, Lewis JJ, Bower M, et al. Immune reconstitution inflammatory && syndrome associated with Kaposi sarcoma: higher incidence and mortality in Africa than in the UK. AIDS 2013; 27:1603–1613. A multicohort study investigating the incidence and outcomes of KS-IRIS in subSaharan Africa and the UK. This study highlights the growing problem of KS-IRIS, and also its higher rate and worse outcomes in sub-Saharan Africa. 15. Mosam A, Shaik F, Uldrick TS, et al. A randomized controlled trial of highly & active antiretroviral therapy versus highly active antiretroviral therapy and chemotherapy in therapy-naive patients with HIV-associated Kaposi sarcoma in South Africa. J Acquir Immune Defic Syndr 2012; 60:150–157. A randomized trial of older, cheaper chemotherapeutic agents to treat Kaposi’s sarcoma in South Africa. This study not only demonstrates the efficacy of chemotherapy in combination with cART, but also highlights the suboptimal nature of the available agents. This study also illustrates the incidence and mortality rates of KS-IRIS in sub-Saharan Africa. 16. Cox CM, El-Mallawany NK, Kabue M, et al. Clinical characteristics and & outcomes of HIV-infected children diagnosed with Kaposi sarcoma in Malawi and Botswana. Pediatr Blood Cancer 2013; 60:1274–1280. This study demonstrates high rates of KS-IRIS incidence and related mortality in children in sub-Saharan Africa. 17. Lacombe JM, Boue F, Grabar S, et al. Risk of Kaposi sarcoma during the & first months on combination antiretroviral therapy. AIDS 2013; 27:635– 643. A large European cohort study demonstrating increased risk of Kaposi’s sarcoma in the first few months after the initiation of ART compared with cART-naı¨ve individuals. 18. Yanik EL, Napravnik S, Cole SR, et al. Incidence and timing of cancer in HIV& infected individuals following initiation of combination antiretroviral therapy. Clin Infect Dis 2013; 57:756–764. This study provides an estimate of the risk of developing unmasked KS-IRIS in a U.S.-based cohort.

19. Bower M, Weir J, Francis N, et al. The effect of HAART in 254 consecutive patients with AIDS-related Kaposi’s sarcoma. AIDS 2009; 23:1701–1706. 20. Bower M, Dalla Pria A, Coyle C, et al. Prospective stage-stratified approach to && AIDS-related Kaposi’s sarcoma. J Clin Oncol 2014; 32:409–414. A large prospective study which demonstrates for the first time the use of a simple stage-stratified algorithm based on the tumour stage at presentation for the treatment of Kaposi’s sarcoma. 21. Daly ML, Fogo A, McDonald C, Morris-Jones R. Kaposi sarcoma: no longer an & AIDS-defining illness? A retrospective study of Kaposi sarcoma cases with CD4 counts above 300/mm3 at presentation. Clin Exp Dermatol 2014; 39:7–12. This study illustrates the increasing incidence of Kaposi’s sarcoma in patients on established cART with relatively high CD4 counts in the UK. 22. Mocroft A, Furrer HJ, Miro JM, et al., Opportunistic Infections Working Group && on behalf of the Collaboration of Observational HIV Epidemiological Research Europe (COHERE) study in EuroCOORD.. The incidence of AIDS-defining illnesses at a current CD4 count 200 cells/ml in the postcombination antiretroviral therapy era. Clin Infect Dis 2013; 57:1038–1047. A very large, European-wide cohort study of the incidence of AIDS-defining illnesses at CD4 counts greater than 200 cells/ml. This study demonstrates that Kaposi’s sarcoma is now not uncommon at higher CD4 counts and indicates a changing pattern of epidemiology. 23. Lebari D, Gohil J, Patnaik L, Wasef W. Isolated penile Kaposi’s sarcoma in a HIV-positive patient stable on treatment for three years. Int J STD AIDS 2014; 25:607–610. 24. Unemori P, Leslie KS, Hunt PW, et al. Immunosenescence is associated with & presence of Kaposi’s sarcoma in antiretroviral treated HIV infection. AIDS 2013; 27:1735–1742. This study provides evidence that Kaposi’s sarcoma arising in the context of established cART and high CD4 counts may be associated with immunosenescence, postulated to arise because of an accelerated immunological ageing process that is recognized in HIV infection. 25. Carbone A, Vaccher E, Gloghini A, et al. Diagnosis and management of lymphomas and other cancers in HIV-infected patients. Nat Rev Clin Oncol 2014; 11:223–238. 26. Gantt S, Casper C, Ambinder RF. Insights into the broad cellular effects of nelfinavir and the HIV protease inhibitors supporting their role in cancer treatment and prevention. Curr Opin Oncol 2013; 25:495–502. 27. Gantt S, Cattamanchi A, Krantz E, et al. Reduced human herpesvirus-8 oropharyngeal shedding associated with protease inhibitor-based antiretroviral therapy. J Clin Virol 2014; 60:127–132. 28. Asiimwe F, Moore D, Were W, et al. Clinical outcomes of HIV-infected patients with Kaposi’s sarcoma receiving nonnucleoside reverse transcriptase inhibitor-based antiretroviral therapy in Uganda. HIV Med 2012; 13:166–171. 29. Flepisi BT, Bouic P, Sissolak G, Rosenkranz B. Drug–drug interactions in HIV positive cancer patients. Biomed Pharmacother 2014; 68:665–677. 30. Bower M, Collins S, Cottrill C, et al., AIDS Malignancy Subcommittee. British & HIV Association guidelines for HIV-associated malignancies 2008. HIV Med 2008; 9:336–388. The current UK guidelines for the treatment of Kaposi’s sarcoma. 31. Krell J, Stebbing J. Broader implications of a stage-guided stratified therapeutic approach for AIDS-related Kaposi’s sarcoma. J Clin Oncol 2014; 32:373–375. 32. Gotti D, Raffetti E, Albini L, et al., Master Cohort Group. Survival in HIVinfected patients after a cancer diagnosis in the cART Era: results of an Italian multicenter study. PLoS One 2014; 9:e94768. 33. Mu A, Rutledge J, Mills P, Paul S. Incidence of Kaposi sarcoma and associated mortality in Fresno, California, 1998 to 2012. J Int Assoc Provid AIDS Care 2014. [Epub ahead of print] 34. Raimundo K, Biskupiak J, Goodman M, et al. Cost effectiveness of liposomal & doxorubicin vs. paclitaxel for the treatment of advanced AIDS-Kaposi’s sarcoma. J Med Econ 2013; 16:606–613. This study estimates the cost of treating a single patient with PLD or paclitaxel. 35. Anglemyer A, Agrawal AK, Rutherford GW. Treatment of Kaposi sarcoma in && children with HIV-1 infection. Cochrane Database Syst Rev 2014; 1: CD009826. A Cochrane review of the treatment of Kaposi’s sarcoma in children highlighting the paucity of available data. Only four studies were identified, all of which were retrospective cohort studies. Overall, analysis indicated that the combination of cART and chemotherapy is more effective than either cART or chemotherapy alone, but the quality of evidence was low. 36. Chagaluka G, Stanley C, Banda K, et al. Kaposi’s sarcoma in children: an && open randomised trial of vincristine, oral etoposide and a combination of vincristine and bleomycin. Eur J Cancer 2014; 50:1472–1481. The only randomized trial to date comparing chemotherapeutic agents to treat Kaposi’s sarcoma in children; the use of older, cheaper but suboptimal agents in this trial highlights the problem of lack of access to the best standard of care in sub-Saharan Africa. 37. Molyneux E, Davidson A, Orem J, et al. The management of children with & Kaposi sarcoma in resource limited settings. Pediatr Blood Cancer 2013; 60:538–542. Recommendations for the management of Kaposi’s sarcoma in children in resource-poor settings. This study highlights the lack of trial data and the limited availability of chemotherapeutic agents.

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HIV infections and AIDS 38. Steff M, Joly V, Di Lucca J, et al. Clinical activity of lenalidomide in visceral human immunodeficiency virus-related Kaposi sarcoma. JAMA Dermatol 2013; 149:1319–1322. A case study showing response to lenalidomide in AIDS-KS. 39. Rokx C, van der Ende ME, Verbon A, Rijnders BJ. Peginterferon alfa-2a for & AIDS-associated Kaposi sarcoma: experience with 10 patients. Clin Infect Dis 2013; 57:1497–1499. An observational study demonstrating superior efficacy and less toxicity of new pegylated formations of interferon alpha-2a for the treatment of Kaposi’s sarcoma. 40. Yaich S, Charfeddine K, Zaghdane S, et al. Sirolimus for the treatment of Kaposi sarcoma after renal transplantation: a series of 10 cases. Transplant Proc 2012; 44:2824–2826. 41. Krown SE, Roy D, Lee JY, et al. Rapamycin with antiretroviral therapy in AIDSassociated Kaposi sarcoma: an AIDS Malignancy Consortium study. J Acquir Immune Defic Syndr 2012; 59:447–454. 42. Uldrick TS, Wyvill KM, Kumar P, et al. Phase II study of bevacizumab in patients with HIV-associated Kaposi’s sarcoma receiving antiretroviral therapy. J Clin Oncol 2012; 30:1476–1483. &

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43. Koon HB, Krown SE, Lee JY, et al. Phase II trial of imatinib in AIDS-associated Kaposi’s sarcoma: AIDS Malignancy Consortium Protocol 042. J Clin Oncol 2014; 32:402–408. A phase II trial demonstrating the safety and efficacy of imatinib in AIDS-KS. 44. Little RF, Aleman K, Kumar P, et al. Phase 2 study of pegylated liposomal doxorubicin in combination with interleukin-12 for AIDS-related Kaposi sarcoma. Blood 2007; 110:4165–4171. 45. Ardavanis A, Doufexis D, Kountourakis P, Rigatos G. A Kaposi’s sarcoma complete clinical response after sorafenib administration. Ann Oncol 2008; 19:1658–1659. 46. Dezube BJ, Krown SE, Lee JY, et al. Randomized phase II trial of matrix metalloproteinase inhibitor COL-3 in AIDS-related Kaposi’s sarcoma: an AIDS Malignancy Consortium Study. J Clin Oncol 2006; 24:1389–1394. 47. Robey RC, Mletzko S, Colley C, et al. The use of monoclonal antibodies to treat Castleman’s disease. Immunotherapy 2014; 6:211–219. 48. Chen BJ, Chapuy B, Ouyang J, et al. PD-L1 expression is characteristic of a subset of aggressive B-cell lymphomas and virus-associated malignancies. Clin Cancer Res 2013; 19:3462–3473.

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Volume 28  Number 1  February 2015

Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Facing up to the ongoing challenge of Kaposi's sarcoma.

Kaposi's sarcoma is a mesenchymal tumour caused by infection with human herpesvirus 8, usually in the context of immunodeficiency. The global incidenc...
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