Kaposi-Sarcoma Herpesvirus Associated Cancers and Related Diseases

Abstract

Purpose of the review

To discuss the pathogenesis and recent advances in the management of KSHV-associated diseases.

Recent findings

KSHV, a gammaherpesvirus, causes several tumors and related diseases, including Kaposi sarcoma (KS), a form of multicentric Castleman disease (KSHV-MCD), and primary effusion lymphoma (PEL). These most often develop in patients infected with human immunodeficiency virus (HIV). KSHV-associated inflammatory cytokine syndrome (KICS) is a newly described syndrome with high mortality that has inflammatory symptoms like MCD but not the pathologic lymph node findings. KSHV-associated diseases are often associated with dysregulated human interleukin-6, and KSHV encodes a viral interleukin-6, both of which contribute to disease pathogenesis. Treatment of HIV is important in HIV-infected patients. Strategies to prevent KSHV infection may reduce the incidence of these tumors. Pomalidomide, an immunomodulatory agent, has activity in KS. Rituximab is active in KSHV-MCD but can cause KS exacerbation; rituximab plus liposomal doxorubicin is useful to treat KSHV-MCD patients with concurrent KS.

Summary

KSHV is the etiological agents of all forms of KS and several other diseases. Strategies employing immunomodulatory agents, cytokine inhibition and targeting of KSHV-infected cells are areas of active research.

1-Introduction

Kaposi sarcoma herpesvirus (KSHV), a gammaherpesvirus, was discovered in 1994 by Yuang Chang, Patrick S. Moore and colleagues, as the causative agent of AIDS-associated Kaposi sarcoma (KS)[1]. It is also called human herpesvirus-8 (HHV-8). KSHV has been implicated as the etiologic agent of all forms of KS and several other diseases, including multicentric Castleman disease (MCD), primary effusion lymphoma (PEL) and a newly described syndrome, KSHV-associated inflammatory cytokine syndrome (KICS)[2–4]. KSHV is a necessary but insufficient etiological agent for these diseases.

2-KSHV Life Cycle

KSHV is a double stranded DNA gammaherpesvirus. After infection, the genome is maintained as an episome in the host cell nucleus. KSHV can infect a variety of cells including endothelial cells, B-cells, and monocytes. Figure 1 depicts the circularized KSHV genome. Upon infection of a cell, KSHV establishes latency, where only a few genes are expressed. Most reside in a cluster in the latency locus, and include: ORFK12 (kaposins), ORF71 (vFLIP), ORF72 (vCyclin), ORF73 (latency-associated nuclear antigen, LANA), and various viral microRNAs. These help maintain the viral episome, deter host immune responses, and promote survival and proliferation of infected cells[5–8].

Figure 1. Kaposi sarcoma herpesvirus genome.

The circular KSHV episome is shown with protein-encoding genes. Non-coding RNAs are not shown. ORF: open reading frame; LANA: latency-associated nuclear antigen; vIRF: viral interferon regulatory factor. Gene names starting with "K" are unique to KSHV.

Certain physiological signals cause the virus to enter the lytic phase, where all viral genes are expressed, progeny virions are produced and released, and the infected cell dies. The switch from latency to lytic replication is set in motion by ORF50 (replication and transcription activator protein, RTA). In addition to physiologic stressors such as hypoxia, various chemicals (sodium butyrate, valproic acid) can induce the lytic cycle[9]. Additional genes may be expressed in a more selective manner in otherwise latently infected cells and these are partially dependent on the specific cell type[10–12]. Latent infection is observed in the majority of tumor cells in KS lesions. However, around 1% of infected cells in KS express lytic genes, while a higher percentage express lytic genes in PEL and even more in MCD.

3- KSHV Transmission

KS prevalence and new infections remain high in men who have sex with men (MSM) in the US. KSHV is secreted in saliva, and there is evidence that common modes of transmission in MSM are through oral-anal contact, oral-penile contact, or use of saliva as a lubricant[13–17]; thus education regarding these practices may be useful in reducing its spread in this population. In Sub-Saharan Africa (SSA), transmission often occurs during childhood, and may be in part through food premastication[18].

4-Pathogenesis of KSHV-Associated Malignancies

KSHV has evolved strategies to evade innate and specific immunity, induce proliferation, and prevent apoptosis of infected cells. These strategies can promote oncogenesis. KSHV also has pleotropic effects on cell signaling that contribute to oncogenesis and angiogenesis, a hallmark of KS. For example, the KSHV protein vFLIP stimulates activation of NF-kB and is implicated in KS, KSHV-MCD and PEL[19–21]. Various KSHV proteins promote activation of the AKT and mechanistic target of rapamycin (mTOR) pathways, which promote survival and growth and are upregulated in many cancers[12, 22–24]. Importantly, sirolimus, an inhibitor of mTOR, can treat KS in transplant patients[25, 26]. Expression of latent viral proteins is necessary for survival of PEL cell lines, and repression of specific KSHV latent genes can induce apoptosis[6, 27]. Also, KSHV-encoded miRNAs can increase B cell proliferation in an animal model and promote survival of infected cells[28–31]. p53 is wild-type in KSHV-infected cells; however LANA can inhibit p53 activity[32]. Activation of p53 induces apoptosis in KSHV-infected cells, suggesting that repression of p53 is important for survival of these cells[33]. Human interleukin 6 (hIL-6) is up regulated upon KSHV infection; this is mediated by several KSHV genes, such as vFLIP, kaposin B and a KSHV G protein coupled receptor (encoded by open reading frame 74 [ORF74])[34]. Also, KSHV encodes a homologue of hIL-6, viral IL-6 (vIL-6). It is believed that increased IL-6 expression benefits KSHV infection in part by inducing proliferation of B lymphocytes[35, 36]. Additionally, vIL-6 signaling can lead to increased VEGF expression to stimulate angiogenesis[37]. By contrast to other oncogenic viruses, there is evidence that certain lytic KSHV genes are important in oncogenesis. In particular, several studies have shown vGPCR (ORF74) is important in the pathogenesis of KS[38].

5- Kaposi Sarcoma

Kaposi sarcoma is the most common KSHV-associated tumor. There are four major epidemiologic subtypes: classic; iatrogenic or transplant-associated; endemic or African; and AIDS-related or epidemic. KS was first described in elderly men in Mediterranean or Eastern European regions and this form is called “classic” KS. Later on, a high incidence of KS in SSA was described[39]. In the 1970s, association of KS with immunosuppressive therapies such as steroids and cyclosporin was reported, providing initial evidence that immunossupression is an important cofactor[40]. In 1981, the development of KS in young gay men was one of the harbingers of the AIDS epidemic. MSM have a much higher incidence than other HIV risk groups, suggesting that another etiologic agent was causal; in 1994, KSHV was identified as the etiologic agent. The prevalence of KSHV parallels the incidence of KS in various populations. In AIDS, a low CD4⁺ count, lack of KSHV T-cell immunity and HIV viremia are associated with the highest KS risk[41–43]. In the combination anti-retroviral therapy (ART) era, KS incidence decreased by approximately 80%, but has since stabilized [44]. KS incidence in HIV patients remains substantially greater than the general population, even in those on ART with controlled HIV viremia and relatively preserved CD4⁺ counts. The number of HIV-infected persons in the United States is increasing and ageing, and it is possible that this may lead to an increase in the incidence of AIDS KS. The incidence of KS is particularly high in SSA because of the high prevalence of both HIV and KSHV infection; in some SSA countries, KS is the most common tumor in men [45].

The most common presentation of KS is multifocal cutaneous macules or nodules commonly involving the lower extremities. Edema, ulceration, bleeding, pain and secondary infection may cause significant morbidity, and patients often have psychological distress from visible stigmata of AIDS. Nodal, lung, gastrointestinal (GI), bones and other visceral KS may occur. Diagnosis is established with a biopsy showing KSHV-infected spindle cells. Staging requires evaluation of the skin and oral mucosa, while evaluation for visceral disease is generally limited to a chest X-ray and stool occult blood test, with additional evaluations prompted by symptoms or abnormal initial tests. KS patients were initially staged following the AIDS Clinical Trials Group (ACTG) Oncology Committee criteria, where T stands for tumor burden (T₀ or T₁), I for immune status (I₀ or I₁) and S for systemic illness (S₀ or S₁)[46]. Subscripts 0 and 1 denote good and poor risk respectively. Criteria for poor-risk parameters are as follows: T₁ includes tumors with tumor-associated edema or ulceration, extensive oral or GI KS and KS in other non-nodal viscera; I₁ includes CD4⁺ cell <150/uL; and S₁ includes history of opportunistic infections and/or thrush, B symptoms, Karnofsky performance status <70 or other HIV related illnesses. In patients receiving ART, CD4⁺ cell counts are less important prognostically, and the ACTG classification has been modified, with T₁S₁ patients considered poor risk and all others (T₀S₀; T₁S₀, or T₀S₁) good risk[47]. Nonetheless, in patients with T₁ KS, advanced immunosuppression, as measured by CD4 count <100/uL, remains an important predictor of death in some regions[48].

The natural history of KS varies. KS may worsen or improve spontaneously, often in tandem with changes in underlying immune function. Some patients have an indolent pattern while others present with aggressive growth. Patients with rapidly progressive KS should be evaluated for concurrent KSHV-MCD, PEL or KICS (see below). There is no evidence that KS can be “cured”, although long term remissions without continued specific therapy are possible. Initial KS treatment should be aimed at correcting the underlying immunodeficiency where feasible. In HIV patients, this includes ART. In transplant-related KS, replacing cyclosporine with sirolimus may lead to disease remission[26]. If KS is indolent and not affecting quality of life, patients may be followed with a “watch and wait” approach. Criteria for systemic treatment, i.e., treatment over and above improving immune status, include KS-related symptoms, rapidly growing KS, or psychological distress from cosmetic disfigurement or stigmatization[47]. Localized treatment is generally avoided, due to its systemic nature and local toxicities. Table 1 summarizes the main systemic treatment options [49–67]. For patients requiring systemic treatment, most physicians now use Food and Drug Administration (FDA)-approved liposomal anthracyclines as initial therapy[49–53]. Paclitaxel is approved by the FDA for patients who fail or do not tolerate this initial approach[54, 55]. Patients with KS often require treatment for many years, and current therapies are limited by toxicity or the risk of cumulative anthracycline cardiotoxicity. Effective and less toxic approaches are thus an unmet need. In addition, it will be important to develop effective oral agents for resource-limited settings. Pomalidomide has recently been shown to have promising activity in a Phase I/II trial[56].

Table 1.

Select Prospective Studies of Systemic Therapies for the Treatment of Kaposi Sarcoma

Treatment	Dosage	Design	Response Rate	Comments
Pegylated liposomal anthracycline (doxorubicin and daunorubicin)	20–40mg/m2 every 3 weeks	1) PLDa × DBV [49]* 2) PLD × BV [50]* 3) PLD × PLDa [51] 4) PLD × Paclitaxel [52] 5) PLD × DBV [53]*	25–59% (CR+PR)	Usually given as first line treatment due to similar RR to paclitaxel and better toxicity profile. Single agent pegylated liposomal anthracyclines yields similar RR to drug combination with a less toxic profile. FDA approved drug.
Paclitaxel	100 mg/m2 every 2 weeks and 135 to 175mg/m2 every 3 weeks	Phase 2 trials [54]* [55]	56–71% (CR+PR)	Needs to be given with steroids, which may exacerbate KS in HIV patients. FDA approved drug.
Pomalidomide	5mg daily for 21 out of 28 days	Phase 1/2 [56, 57]	68% (CR+PR)	Well tolerated, increases in CD4+ and CD8+ T cells. Effective in HIV infected and classic KS.
Vinorelbine	30mg/2 every 2 weeks	Phase 2 trial [58]*	43% (CR+PR)	Anti-tubulin agent; usually reserved for patients that failed previous pegylated liposomal anthracycline (PLD) and/or paclitaxel therapy.
Etoposide	50mg once a day for 7 out of 21 days	Phase 2 trial [59]	36% (CR+PR)	Risk of secondary myelodysplastic syndrome and leukemia with long term therapy.
Nab-paclitaxel	Nab-paclitaxel 100mg IV on days 1,8 and 15 of each 4-week cycle	Phase 2 [60]	100% (CR+PR)	Well tolerated. Steroid sparing. Evaluated in a small number of HIV-negative patients.
Bevacizumab	15mg/kg every 3 weeks	Phase 2 trial [61]	31% (CR+PR)	Relatively low anti- tumor effect as monotherapy, but may improve tumor associated edema.
Imatinib	400–600mg daily	Phase 2 trial [62]	33% (CR+PR)	Activating mutations in PDGF-R and c-kit did not correlated with responses.
COL-3	MTD: 25 mg/m2/day	Phase 1 trial [63]	44% (CR+PR)	MMPs are involved in tumor invasion and are overexpressed in KS. COL-3 is a MMP inhibitor.
Interferon-alfa	Low dose (1million IU) or high dose (8– 10million IU) once a day	Low dose or high dose with DDI [64]*or AZT [65]*	Low dose group: DDI-40% and AZT- 8% (CR+PR) High dose group: DDI-55% and AZT- 31% (CR+PR)	Unfavorable toxicity profile. FDA-approved drug.
ART	Three drug regimen following DHHS Guidelines	Description of a prospective stage- stratified approach. T0 disease: ART alone T1 disease: ART + liposomal anthracycline [66]	No RR described. 5-year OS: T0- 95% T1- 85%	Patients with T1 KS treated with specific KS therapy in addition to ART still have a worse 5-year OS when compared to T0 patients treated with ART alone.
ART	Three drug regimen	Summary of several studies of ART alone [67]	T0 patients: 39/48 (81%) with (PR+ CR) T1 patients: only 4 patients identified in clinical trials that were treated with ART alone, of which 3 responded (PR+CR)	In review of entire literature up until 2004, only 5 documented cases were identified in which patients with T1 KS responded to ART alone.
ART	Three drug regimen following DHHS Guidelines	Randomized controlled trial of patients with T1 disease in SSA: ART vs. ART + CXT [48]	ART alone: 39% (CR+PR) ART +CXT: 66% (CR+PR)	CXT regimen in SSA trial reported in 2012: DBV or oral etoposide when DBV not available.

PLDa: pegylated liposomal daunorubicin; PLD: pegylated liposomal doxorubicin; DBV: doxorubicin, bleomycin, vincristine; BV: bleomycin, vincristine; KS: Kaposi Sarcoma; HIV: human immunodeficiency virus; ART: anti-retroviral therapy; SSA: Sub-Saharan Africa; CXT: chemotherapy; OS: overall survival; RR: response rate; FDA: Food and Drug Administration; DHHS: The US Department of Health and Human Services; PR: partial response; CR: complete response; SD: stable disease; DDI: didanosine; AZT: zidovudine; PDGF-R: platelet derived growth factor receptor; MMP: matrix metalloproteinases; MTD: maximum tolerated dose;

^*: studies conducted in the pre-ART era; ORR: overall response rate.

6 – Multicentric Castleman Disease

KSHV-associated MCD is a B-cell lymphoproliferative disorder most common arising in HIV-infected patients. It appears to be more common in the ART era[68]. It is rarely reported in SSA, but this is likely because of substantial under-diagnosis. KSHV-MCD presents with intermittent inflammatory symptoms such as fever, night sweats, weight loss, fatigue, and non-specific respiratory and GI symptoms, along with hepatosplenomegaly, lymphadenopathy and edema. KSHV viral load (VL) is elevated during symptomatic flares, and decreases with disease treatment and remission[69]. Laboratory abnormalities include elevated C-reactive protein, hypoalbuminemia, anemia, thrombocytopenia, hyponatremia, and elevated immunoglobulins[69, 70]. There is no consensus definition of a KSHV-MCD flare; different groups use combinations of the symptoms and laboratory abnormalities[71, 72]. KSHV-MCD-associated symptoms are believed to be caused by an excess of cytokines, especially vIL-6, hIL-6 and human interleukin-10 (IL-10)[69, 73]. Patients with flares can have increased serum levels of vIL-6, hIL-6, or both[73]. There is evidence that vIL-6 can activate hIL-6, and may be the most important driving force[74].

KSHV-MCD diagnosis generally requires an excisional lymph node biopsy showing expansion of reactive plasma cells interspersed with KSHV-infected plasmablasts, as well as hyalinization of lymphoid follicles and increased capillary proliferation. A substantial subset express vIL-6, and a smaller subset also express other KSHV lytic antigens. Maturing B cells have high levels of X-box binding protein 1 (XBP-1), and there is evidence that that this can contribute to KSHV-MCD pathogenesis by inducing KSHV lytic activation and directly inducing expression of vIL-6[10].

KSHV-MCD can wax and wane, but untreated, is generally fatal within 2 years. There is no FDA-approved treatment. ART is indicated in HIV-associated KSHV-MCD but is generally insufficient. However, control of HIV viremia may reduce the likelihood of recurrence[75]. Treatment with rituximab or the combination of rituximab and liposomal doxorubicin often leads to clinical remission; prolonged remissions are observed, and this therapy and can improve survival[71, 76–78]. Patients may present with concurrent KS, and rituximab alone can cause KS exacerbation; rituximab plus liposomal doxorubicin can be particularly useful in such patients[76]. High-dose zidovudine in combination with valganciclovir targets KSHV-infected cells expressing lytic proteins, and has demonstrated activity in KSHV-MCD, although remissions appear more common with rituximab[79]. Table 2 summarizes the evidence for selected therapeutic options for KSHV-MCD.

Table 2.

Select Treatment Strategies for KSHV-MCD

Therapy	Dosage	Rationale	Outcomes	Special Considerations
Rituximab	375mg/m2 weekly × 4 weeks [71,76]	Rituximab eliminates CD20+ B cells	92% SR rate at day 60, 71% at one year. Patients should have been treated with chemotherapy for at least 3 months with clinical response and should have experienced at least one recurrence of MCD attack after attempt to discontinue chemotherapy prior to initiating rituximab [71] 95% had remission of symptoms; 67% had a radiological response. 79% disease-free survival at 2 years [76]	KS progression may occur (National Comprehensive Cancer Network Guidelines version 1.2015 (NCCN Guidelines)
Rituximab + liposomal doxorubicin	Rituximab 375mg/m2 + liposomal doxorubicin 20mg/m2 every 3 weeks [78]	Rituximab may lead to worsening of KS lesions. Rituximab alone may be inadequate as single agent to treat KSHV-MCD. LD can target CD20-KSHV infected MCD plasmablasts and KS spindle cells	Clinical response: 94% major clinical response (PR or better); 88% CR Biochemical response: 88% major response; 76% CR	Well-tolerated, rapid clinical improvement. Listed as preferred line of treatment in patients with KSHV-MCD and concomitant KS (NCCN Guidelines)
High dose AZT + valganciclovir	AZT 600mg orally every 6h + valganciclovir 900mg orally every 12h for 7 out of 21 days [79]	ORF21 (KSHV lytic gene) can phosphorylate AZT and ganciclovir to toxic moieties; ORF36 (KSHV lytic gene) can phosphorylate ganciclovir	Clinical responses: 86% major clinical response Biochemical responses: 50% major response; 21% CR; 29% PR	Decrease in C-reactive protein and viral IL-6 noted from baseline to time of best clinical response (NCCN Guidelines)

SR: sustained remission; KS: Kaposi Sarcoma; PR: partial response; CR: complete response; KSHV: Kaposi-sarcoma herpes virus; MCD: multicentric Castleman’s disease; FDA: Food and Drug Administration; AZT: zidovudine; IL-6: interleukin-6; NCCN: National Comprehensive Cancer Network.

7- Primary Effusion Lymphoma

Primary effusion lymphoma (PEL) is a KSHV–associated aggressive mature monoclonal B-cell lymphoma with a poor outcome[80]. Most cases arise in HIV patients. While relatively rare, PEL is likely under-diagnosed[81]. PEL presents with lymphomatous effusions, most commonly pleural, but also peritoneal, pericardial and even joint[82]. Extra-cavitary forms can involve the skin, lymph nodes, GI and central nervous system (CNS)[83]. PEL should be considered in any HIV patient with effusions, especially if they have KS and/or inflammatory symptoms similar to MCD and laboratory criteria for KICS (described below). Even small effusions should be evaluated. PEL cells generally have immunoglobulin gene rearrangement, but often lack surface immunoglobulin or common B-cell surface markers such as CD19, CD20, or CD79a. A diagnosis of PEL requires the presence of KSHV in the malignant cells; about 80% are coinfected with EBV. The immunophenotypic profile may include CD45, CD30, CD38, CD138, and interferon regulatory factor 4 (IRF4)[83–85].

In addition to imaging of the chest, abdomen and pelvis, staging should include brain MRI and lumbar puncture to look for CNS involvement. Serial evaluation of KSHV VL may provide additional information. Currently, there is no standard therapy. Administration of ART is key component for HIV infected patients, but is insufficient in itself. Dose-adjusted (DA) EPOCH (infusional cyclophosphamide, doxorubicin, etoposide, vincristine and prednisone) or CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) with ART can yield 2-year survival rates of approximately 30–40% [80, 86]. Preclinical studies of pomalidomide or lenalidomide show activity in PEL cells, due in part to a reduction of IRF4 [87, 88]. Interestingly, both lenalidomide and pomalidomide have been shown to inhibit KSHV-induced downregulation of MHC class I expression in PEL cells[88]. A prospective trial using lenalidomide combined with rituximab and DA-EPOCH is being developed. Elevated cytokines such as IL-6 have been shown to correlate with poor prognosis in PEL patients and a substantial proportion meet criteria for KICS (described below)[86]. Even though PEL cells do not express CD20, rituximab should be used to treat PEL in patients with concurrent MCD, and may also be useful in other PEL patients by targeting cytokine production by KSHV-infected non-tumor B cells.

8 – KSHV Inflammatory Cytokine Syndrome (KICS)

Our group observed that some KSHV-infected patients manifested inflammatory symptoms similar to those in KSHV-MCD but did not have KSHV-MCD pathology. We described six such patients in a retrospective analysis [4]. Serum vIL6, hIL-6, IL-10 and serum KSHV VL were significantly higher than control patients with KS and no MCD-like symptoms. Based on this initial study, we have developed a working definition of KICS and have undertaken a prospective study of this condition[89, 90]. Our current understanding is that as in KSHV-MCD, the symptoms in these patients are caused by cytokine excess directly or indirectly caused by KSHV infection and not attributable to uncontrolled HIV[89]. KICS patients have a high risk of death, and anemia and hypoalbuminemia were poor prognostic indicators[89]. Many have KS and/or PEL. Unrecognized KICS may be an important cause of death in certain patients with AIDS-associated KS. Our findings highlight the importance of recognizing KICS in critically ill patients with HIV/KSHV co-infection and stress the unmet need to develop treatment strategies for this patient population. Table 3 displays the working criteria for KICS. The National Cancer Institute is currently evaluating several strategies to treat KSHV-associated diseases, including KICS (Table 4).

Table 3.

Working Definition of the KSHV-Inflammatory Cytokine Syndrome (KICS)

1- Clinical manifestations
a- Symptoms	Fever, fatigue, edema, cachexia, respiratory symptoms, GI disturbance, arthralgia and myalgia, altered mental state, neuropathy	b- Laboratory abnormalities	Anemia Thrombocytopenia Hypoalbuminemia Hyponatremia	c- Radiographic abnormalities	Adenopathy Splenomegaly Hepatomegaly Body effusions
2- Systemic Inflammation	Elevated C- reactive protein
3- KSHV viral activity	KSHV VL in plasma (≥1000 copies/mL) or PBMC ((≥100 copies/106 cells)
4- No evidence of KSHV MCD	If adenopathy present, requires histopathologic assessment of nodes
For a diagnosis of KICS to be made, must have at least 2 clinical manifestations from at least 2 categories (symptoms, laboratory abnormalities and radiographic abnormalities) IN ADDITION to each of the criteria in 2, 3, and 4

GI: gastrointestinal; KSHV: Kaposi Sarcoma herpes virus; VL: viral load; MCD: Multicentric Castleman’s disease; PBMC: peripheral mononuclear cells; GI: gastrointestinal; KSHV: Kaposi Sarcoma herpes virus; MCD: Multicentric Castleman’s disease; PBMC: peripheral mononuclear cells.

Adapted from [89].

Table 4.

Select On-going or Recently Completed Therapeutic Studies Open to Patients with KSHV-Associated Diseases

Therapy	Disease	Rationale	Clinical Trials.gov Identification (https://clinicatrials.gov)
Selumetinib	KS	MEK 1/2 inhibitor	NCT01752569
Nelfinavir	Gamma herpes virus- related tumors including KS	Nelfinavir may activate lytic gene expression in gamma herpes virus tumors	NCT02080416
Pembrolizumab	Patients with HIV and refractory/advanced malignancies, including KS and PEL	PD-1 inhibitor	NCT02595866
Nivolumab+ Ipilimumab	HIV- associated malignancies, including KS and PEL	PD-1 inhibition combined with CTLA4 inhibition	NCT02408861
Pomalidomide + liposomal doxorubicin	KS, MCD, KICS	Unmet need to treat patients with KSHV- MCD and KS as single agents alone are not usually sufficient	NCT02659930
DS-8895a	Advanced or metastatic EphA2 cancers	EphA2 is an entry receptor for KSHV	NCT02252211
Tocilizumab	HIV positive MCD	IL-6 overproduction plays a role in MCD. Tocilizumab is a humanized anti-IL6 receptor antibody. Blocking human IL-6 may be sufficient to treat MCD by blocking paracrine and autocrine stimulation	NCT01441063
Sirolimus	HIV positive MCD	Rapamycin is directly toxic to KSHV infected cells [91]. Tumor responses in KS were associated with recovery of T cell memory responses against KSHV latent ORF73 and lytic K8.1 antigens [92]	NCT01441063
DA-EPOCH + lenalidomide	KSHV-associated lymphomas (including PEL)	Lenalidomide has in vitro direct antitumor effect in KSHV- lymphomas as well as immunomodulatory and anti-angiogenic effects	Anticipated opening in 2016
Lenalidomide	KS	Thalidomide has shown activity in KS. Lenalidomide is a more potent thalidomide derivative.	NCT01057121

MEK: mitogen-activated protein kinase; HIV: human immunodeficiency virus; PEL: primary effusion lymphoma; KS: Kaposi sarcoma; MCD: Multicentric Castleman; KICS: Kaposi Sarcoma Inflammatory Cytokine Syndrome; PD1: programmed cell death protein 1; CTLA4: cytotoxic T-lymphocyte protein 4; IL-6: interleukin-6; EphA2: ephrin receptor tyrosine kinase A2; DA-EPOCH: dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin.

9- Conclusions

KSHV-associated diseases represent a heterogeneous group of disorders. The principal manifestations are from tumor formation (KS and PEL) and from cytokine excess (MCD and KICS). A better understanding and recognition of this cluster of entities is essential for the development of improved prevention and treatment approaches. It will be useful to understand the factors leading to these different diseases in different KSHV-infected patients. Promising efforts to develop effective therapies include targeting specific viral genes, targeting dysregulated cellular pathways, inhibiting abnormal cytokine expression, and immunomodulatory approaches.

Key points.

• KSHV-associated diseases include KS, KSHV-MCD, PEL and KICS

• KICS is a newly described high mortality syndrome of KSHV-infected patients

• There are few FDA-approved therapies to treat KSHV-associated diseases

• KSHV-associated diseases are an important cause of morbidity and mortality in HIV patients

• Treatment options likely include inhibition of abnormal cytokine expression and immunomodulatory agents