Oncologic Treatment of HIV-Associated Kaposi Sarcoma 40 Years on

Abstract

The observation in 1981 of the emergence of Kaposi sarcoma (KS) among young men who had sex with men was one of the first harbingers of the HIV epidemic. With advances in HIV care, the incidence of HIV-associated KS (HIV⁺KS) has decreased over time in the United States. However, it remains a persistent malignancy among some HIV-infected populations and is one of the most common tumors in sub-Saharan Africa. Because of the relapsing and remitting nature of this cancer, patients with HIV⁺KS can experience significant, long-term, morbidity. Patients with severe HIV⁺KS may also have concurrent lymphoproliferative syndromes, malignancies, and/or infections that can contribute to mortality. Several chemotherapy agents were explored in clinical trials for HIV⁺KS during the early stage of the epidemic. As HIV⁺KS emerges with CD4 lymphopenia and immunodysregulation, T-cell–sparing options are important to consider. Here, we explore the pathogenesis of HIV⁺KS and the current evidence for immunotherapy and therapies that potentially target KS pathogenesis. This review provides the current landscape of therapies for HIV⁺KS and highlights management issues for patients with HIV and cancer.

INTRODUCTION

In July 1981, the CDC reported the emergence of an aggressive form of Kaposi sarcoma (KS) among 26 young men who had sex with men, which was in contrast to the known epidemiologic characteristics of KS at the time.¹ KS was previously a rare tumor found predominantly among elderly men of Mediterranean origin (classic KS). A more aggressive form of KS was also seen in sub-Saharan Africa (endemic KS), and KS was known to develop in immunosuppressed patients (iatrogenic KS). KS in the setting of HIV infection and AIDS is known as epidemic KS (HIV⁺KS).² KS rates are elevated 500-fold among people living with HIV (PLWH) compared with the general population,³ and from the beginning of the HIV epidemic, KS was considered an AIDS-defining tumor.² Epidemiologic studies suggested that KS was caused by a second transmissible agent, but for some time, this agent remained elusive. In 1994, the causative agent of KS, Kaposi sarcoma herpesvirus (KSHV, also known as human herpesvirus 8), was identified.⁴ KSHV has since been shown to cause primary effusion lymphoma (PEL), a form of multicentric Castleman disease (MCD) and an inflammatory cytokine syndrome (KICS).^5-8

CONTEXT

• Key Objective

• Forty years ago, physicians were battling the unusual emergence of Kaposi sarcoma (KS) among young individuals subsequently diagnosed with HIV. Over time, there have been significant advances in the management of HIV worldwide with corresponding decreases in the rates of KS.

• Knowledge Generated

• We present the evidence of cancer therapies studied for HIV-associated KS (HIV⁺KS). Despite available US Food and Drug Administration–approved chemotherapies, there are immediate and long-term toxicities that need to be considered. We address investigations and treatments where HIV⁺KS occurs with other KS herpesvirus–associated diseases. We address the rationale for chemotherapy-sparing agents that are subject to ongoing clinical trials for participants with HIV⁺KS.

• Relevance

• In the 21st century, HIV⁺KS remains persistent and severe and can contribute to morbidity and mortality among young individuals worldwide who face health disparities. Moreover, it can occur concurrently with other diseases caused by KS herpesvirus and they can complicate the diagnosis and management of KS.

Over the past 40 years since the original report from the CDC, advances in HIV therapy with prompt initiation of antiretroviral therapy (ART) at HIV diagnosis have led to decreases in the rates of KS among PLWH in the United States and other countries.^9-12 Between 2008 and 2016, the HIV⁺KS incidence rates decreased 3.2% per year in data from a US cancer registry.¹³ However, KSHV prevalence remains high in men who have sex with men and KS remains persistent, particularly among young Black men with HIV in the United States.¹⁴ Furthermore, in sub-Saharan Africa, KS continues to be a leading cause of morbidity and mortality because of high rates of HIV and endemic KSHV infection. KS is the most common tumor in men overall in certain countries in sub-Saharan Africa.^15,16

This narrative review specifically focuses on management of HIV⁺KS, as it may have a more aggressive course than HIV-negative forms. HIV⁺KS can occur with concurrent KSHV-associated conditions, which can present diagnostic challenges as these diseases can mimic infections in an immunocompromised population. We address evidence for the current therapies, management of KS with concurrent KSHV-associated processes, and ongoing studies for HIV⁺KS.

METHODS

We searched PubMed for clinical trials, meta-analyses, and guidelines of major professional societies on the management of HIV⁺KS. Response rates from seminal prospective clinical trials investigating oncologic treatments (including chemotherapy, targeted therapy, and immunotherapy) of HIV⁺KS were highlighted. Studies that are open for enrollment for HIV⁺KS were identified from ClinicalTrials.gov.

DISCUSSION/OBSERVATIONS

Pathophysiology

KSHV is a linear double-stranded DNA gammaherpesvirus.¹⁷ KSHV can infect a wide variety of cell types, including B cells, monocytes, and endothelial cells. KS consists of KSHV-infected vascular or lymphatic endothelial cells; there is still uncertainty as to the exact cell of origin.

Like other herpesviruses, KSHV has latent and lytic replication programs. During latency, a few genes are expressed, including those encoded by open reading frame (ORF)71 (v-FLIP), ORF72 (v-cyclin), and ORF73 (latency-associated nuclear antigen) and several microRNAs.^18-20 During lytic replication, all genes are expressed, resulting in production and release of progeny virions and death of the host cell. In KS, only a small proportion of infected cells express lytic genes. However, there is evidence that expression of one lytic gene, ORF74, that encodes a constitutively active viral G-protein–coupled receptor (vGPCR) is particularly important in KS pathogenesis.^21,22 vGPCR is constitutively active and leads to production of vascular endothelial growth factor (VEGF), interleukin (IL)-6, IL-8, and tumor necrosis factor alpha, which promote KS through autocrine and paracrine pathways.^21-23

Various KSHV-encoded genes promote proliferation of infected cells and dysregulate host innate immune pathways, including apoptosis and cell cycle arrest. Some KSHV-encoded genes are mimics of human genes with angiogenic and inflammatory properties. KSHV-encoded K3 and K5 ubiquinate surface MHC-1 and contribute to downregulation, making infected cells invisible to effector T cells.^24-26 A homolog of human IL-6, known as viral IL-6, encoded by K2, induces the JAK and STAT pathway, leading to increased expression of angiogenic markers.^27-29 Several KSHV genes also upregulate human IL-6, which contributes to the systemic symptoms and multiorgan dysfunction seen in MCD and PEL.^30,31 KSHV v-FLIP activates the nuclear factor–κB, which contributes to the pathogenesis of KS, PEL, and MCD.¹⁹

Although many human cancers are considered clonal, the question whether KS is a clonal neoplasm, an oligoclonal process, or a multifocal vascular proliferation is still not completely resolved. One group of investigators studying women with advanced KS concluded that KS was a clonal cancer on the basis of the patterns of methylation in different KS lesions in the same individual.³² However, another group using a similar technique noted that clonality was noted in some lesions but not others.³³ A more recent study investigating KSHV transcripts in KS lesions from both sexes concluded that most individual KS lesions were either oligoclonal or monoclonal and that different lesions in the same patient represented different oligoclonal or clonal expansions.³⁴ This study is consistent with KS being a multifocal disease in which individual lesions arise separately rather than by metastases. However, additional research is needed to address these issues. Whatever the resolution, from a clinical perspective, KS acts like other neoplastic processes with its invasion of various organs and the devastating outcome of HIV⁺KS if untreated.

Clinical Presentation

Although HIV⁺KS is typically observed in PLWH who have < 200 CD4⁺ T cells/µL, some patients present with or experience a recurrence of KS at higher CD4⁺ T-cell counts.³⁵ Patients with HIV⁺KS, like those with other epidemiologic forms of KS, often present with pigmented cutaneous KS lesions. There may be a spectrum of clinical presentations. Patients may initially present with a small focus of lesions that can be managed as an outpatient, but patients can also present with severe manifestations of cutaneous and visceral diseases with systemic symptoms or laboratory abnormalities requiring hospitalization. The nature of initial presentation influences additional investigations and management.

Cutaneous KS often presents in the lower extremities as flat, ulcerated, and/or fungating lesions that are frequently associated with edema (Fig 1). Patients may develop woody edema that can persist even after KS treatment, and long-standing edema can lead to recurrent skin infections and issues with mobility. Cutaneous lesions are often disseminated in patients with profound CD4⁺ T-cell lymphopenia; however, even a few isolated cutaneous lesions can cause significant morbidity if they are on the feet, face, or eye. In severe cases, KS lesions may also present in the oral cavity as nodular lesions, lymph nodes, or any visceral organ, most commonly the GI tract or pulmonary systems. In some cases, bone lesions are seen on imaging that may be intermittently symptomatic. Patients who report respiratory or GI symptoms or present with anemia may benefit from bronchoscopy and/or endoscopy in visualizing lesions, staging the disease, and investigating for opportunistic infections, especially if they are severely immunosuppressed. Cross-sectional imaging such as computed tomography, where available, showing visceral KS may be useful to determine the stage of disease. However, these tests should not delay treatment of HIV⁺KS in the presence of cutaneous KS. Biopsies may be obtained from the skin or GI system to confirm KS. Diagnostic characteristics of KS on biopsy include the presence of endothelial markers, spindle cells, and positive KSHV latency–associated nuclear antigen staining on immunohistochemistry.¹⁷ KS lesions are vascular and prone to bleeding, and biopsy of the airways is not advisable.

FIG 1.

KS lesions in selected clinical trial participants at study entry. The images are nonidentifiable to protect patient privacy. KS, Kaposi sarcoma.

Diagnosis of Concurrent KSHV-Associated Processes and KS-Immune Reconstitution Inflammatory Syndrome

The presence of systemic symptoms such as fevers, night sweats, effusions, adenopathy, and laboratory abnormalities such as low albumin, elevated C-reactive protein, or pancytopenia should also prompt concern for concurrent KSHV-associated processes (MCD and/or PEL) that are often underdiagnosed and can occur in tandem with HIV⁺KS.⁶ This can pose a diagnostic challenge as these conditions can mimic infection in an immunocompromised host and can affect treatment and outcomes. Up to 50% of patients with MCD may have concurrent KS,³⁶ but the prevalence of other KSHV-associated diseases among patients presenting with HIV⁺KS is unknown. Circulating markers concerning for a concurrent KSHV-associated process include elevated KSHV levels and IL-6 and IL-10 cytokine levels.^6,8,31 KSHV viral load levels in the blood in patients with HIV⁺KS alone are often not elevated as compared with other KSHV-associated diseases.³⁷ A large study among PLWH and KSHV-associated diseases demonstrated that an undetectable KSHV viral load excludes a diagnosis of MCD.³⁸ Imaging in these cases should include a positron emission tomography-computed tomography to assess avid lymph nodes or splenomegaly that is suggestive of MCD.³⁹ Diagnosis of concurrent KSHV-associated processes may require expert pathology review. Lymph nodes should be evaluated for MCD, and effusions should be sent for cytology and flow cytometry to diagnose PEL (Fig 2). In the absence of these histologic diagnoses, patients with KS who have symptoms of inflammation may have KICS.

FIG 2.

Oncologic and HIV workup of patients with HIV-associated KS. Patients who present with systemic symptoms or multiorgan dysfunction may have other concurrent KSHV-associated conditions. Therefore, in addition to an infectious workup, additional diagnostic procedures may be required depending on the extent of symptoms and degree of immunosuppression as this will influence management. Created using BioRender.⁴⁰ CT, computed tomography; KS, Kaposi sarcoma; KSHV, Kaposi sarcoma herpesvirus; MCD, multicentric Castleman disease; PEL, primary effusion lymphoma; PET, positron emission tomography; VL, viral load.

A proportion of patients with HIV⁺KS may experience KS immune reconstitution inflammatory syndrome (KS-IRIS) within the first 12 weeks after ART initiation, resulting in worsening of HIV⁺KS or the onset of undiagnosed KS.^41,42 However, this is a diagnosis of exclusion as the inflammatory symptoms may mimic infections or other KSHV-associated disorders, which if not appropriately diagnosed can result in high mortality. There is no standard therapy for KS-IRIS; continuation of ART and initiation of chemotherapy may result in improved outcomes.⁴² Although steroids are known to treat tuberculosis-IRIS, there have been cases where steroids led to the unmasking of KSHV-associated conditions, including KS, and steroids should probably be avoided when possible in patients with KS-IRIS.⁴³

Treatment

Staging and principles of therapy.

KS is a vascular multicentric tumor, and therefore, the standard nomenclature from other cancer subtypes is not helpful, including the term metastases. HIV⁺KS is staged according to the extent of disease, CD4 count, and presence of systemic illness.⁴⁴ Patients with HIV⁺KS limited to the skin and/or lymph nodes and/or minimal oral disease are considered as having T0 disease, and patients with edema, ulceration, extensive oral disease, or visceral KS are considered as having T1 disease (Fig 3). A stage-stratified approach to the treatment of HIV⁺KS is feasible where patients with minimal disease receive ART alone and those with T1 disease and extensive cutaneous disease or who otherwise require rapid disease resolution receive ART and chemotherapy.⁴⁵

FIG 3.

Staging and treatment strategy for KS and other KSHV-associated diseases. With respect to staging, I stage may have less prognostic value than T or S stages in the current era with ART. B symptoms are unexplained fever, night sweats, or > 10% weight loss. KS can occur with MCD, PEL, and KICS. Patients with PEL may also meet criteria for KICS. Diagnosis of a concurrent KSHV-associated diseases will affect therapy and long-term outcomes. First- and second-line therapies for KS are from FDA approval and NCCN guidelines. Treatments noted for PEL and MCD with concurrent KS are based on NCCN guidelines. ^aOverall good risk is defined as T0S0, T1S0, and T0S1, whereas overall poor risk is T1S1. ^bSystemic therapy includes treatment approved for HIV⁺KS such as chemotherapy (liposomal doxorubicin, paclitaxel) or immunomodulatory therapy (pomalidomide). ^cFor patients with recurrent and/or persistent disease, consider evaluation for concurrent KSHV-associated processes. Created using BioRender.⁴⁰ ART, antiretroviral therapy; CHOP, cyclophosphamide, doxorubicin, vincristine and prednisone; EPOCH, etoposode, prednisone, vincristine, cyclophosphamide, doxorubicin; FDA, US Food and Drug Administration; HIV⁺KS, HIV-associated Kaposi sarcoma; IL, interleukin; KICS, KSHV-associated inflammatory cytokine syndrome; KS, Kaposi sarcoma; KSHV, Kaposi sarcoma herpesvirus; LD, liposomal doxorubicin; MCD, multicentric Castleman disease; NCCN, National Comprehensive Cancer Network; PEL, primary effusion lymphoma.

In the early studies of paclitaxel and liposomal doxorubicin (LD) in HIV⁺KS, only between 40% and 70% of participants were on concurrent ART (Table 1). With current management guidelines, all patients with HIV⁺KS should be initiated on ART. Most patients will be started a once-a-day pill of an integrase-inhibitor based therapy for HIV care, which generally will not interact with standard chemotherapy agents. Where possible, a multidisciplinary approach including oncologists, HIV specialists, and pharmacists from both disciplines should be involved to coordinate concomitant medications to avoid drug-drug interactions and manage opportunistic infections or other complications.

TABLE 1.

Therapies Approved for HIV⁺KS and Therapies With Other Improved Indications Trialed in HIV⁺KS

KSHV cannot be eradicated, patients with KS cannot be cured, and the goal of therapy is long-term control. There are no set number of cycles of systemic treatment for HIV⁺KS management.⁶⁹ The duration of therapy is determined by the response to therapy. Cutaneous lesions can be evaluated by the total number, area of lesions, and number of nodular lesions. If there are a small number of lesions, six cycles or less of treatment may be sufficient. For those with many lesions or involvement of visceral disease, the number of cycles will depend on the response. Patients may require intermittent therapy for years. Repeat imaging, bronchoscopy, and/or endoscopy may be required to determine the response of visceral lesions. Physicians experienced in treating KS rarely use local approaches, such as panretin gel or radiotherapy. Although radiotherapy may play a role in obstructive KS lesions or cases where there are no systemic options available, it can delay wound healing and cause long-lasting induration and fibrosis.⁶⁹ Except for biopsy, there is no role for surgical intervention or amputation in the management of HIV⁺KS.

Chemotherapy.

Several chemotherapy options were investigated in HIV⁺KS during the early stage of the HIV epidemic. Initially, combination chemotherapy regimens including doxorubicin, bleomycin, and vincristine were used. These combination regimens identified doxorubicin as the mainstay of treatment. Pegylated LD is doxorubicin encapsulated in long-circulating stealth liposomes. This formulation is thought to reduce uptake within the reticuloendothelial system and prolong circulation times. One study noted higher doxorubicin levels in KS lesions in those receiving LD as compared with those administered standard doxorubicin.⁷⁰ Randomized controlled trials in the late 1990s comparing doxorubicin, bleomycin, and vincristine with LD at a dose of 20 mg/m² once every 2 or 3 weeks demonstrated higher overall response rates and lower toxicity among those receiving LD^46-50 (Table 1).

Paclitaxel was approved for use in HIV⁺KS in 1997. Overall response rates from phase II studies were between 56% and 71%.^52-54 One randomized study compared paclitaxel administered every 2 weeks and LD every 3 weeks in 73 participants.⁵⁰ The overall response rate was not statistically different between these agents (56% in paclitaxel and 46% in LD, P = .49). In general, paclitaxel is associated with more side effects such as fatigue, alopecia, and neuropathy and is generally used after LD. An important recent randomized study from 11 resource-limited settings in Brazil and sub-Saharan Africa highlighted the superiority of paclitaxel to etoposide or bleomycin plus vincristine in patients receiving ART.⁵⁵

LD and paclitaxel remain the most used first-line chemotherapy options in HIV⁺KS. If patients have the re-emergence of KS after cessation of these therapies, patients can be retreated with the same agent. LD has a US Food and Drug Administration black box warning for cardiotoxicity at cumulative doses > 550 mg/m². This is extrapolated from patients with advanced breast cancer; however, a study using endomyocardial biopsy of 10 patients with HIV⁺KS did not identify myocardial damage at cumulative LD doses of 440-840 mg/m².⁷¹ Nonetheless, physicians considering cumulative doses above 550 mg/m² should be aware of the potential for cardiotoxicity and weigh the potential risks against the benefits.

Other chemotherapy agents, such as vinorelbine, gemcitabine, and etoposide, have been investigated in HIV⁺KS^56-58 in single-site phase II studies with none or only a proportion of participants on ART. These agents are less effective than LD or paclitaxel but can be considered in specific situations for persistent or relapsed HIV⁺KS per the National Comprehensive Cancer Network guidelines.⁶⁹

Immunomodulatory agents and targeted therapies.

Initially on the basis of studies showing that thalidomide had antiangiogenic activity, other immunomodulatory agents, such as pomalidomide and lenalidomide, have been investigated in HIV⁺KS.^59-61 We now know that this class of agents target cereblon, an E3 ubiquitin ligase,^72,73 and downstream effects include enhancement of CD4⁺ and CD8⁺ T-cell costimulation, enhancement of natural killer cell activity, and modulation of tumor necrosis-α, IL-6, and VEGF. Preclinical studies have also shown that pomalidomide reverses the virus-induced downregulation of immune surface markers including MHC-1, ICAM-1, and B7-2 in several PEL cell lines, rendering cells more visible to the immune system. In two prospective trials, the response rate to pomalidomide among HIV+ participants was 60% and the response rate to lenalidomide among HIV+ participants was 40% (Table 1).^59,60 There were increases in CD4⁺ T-cell counts from baseline to the first 4 weeks in the pomalidomide study. Data from this study led to approval of pomalidomide by the US Food and Drug Administration for the treatment of HIV+ and HIV-negative KS. The US National Center Institute–funded AIDS Malignancy Consortium (AMC) has initiated a trial of pomalidomide to assess its feasibility in sub-Saharan Africa and is planning a confirmatory study within the United States.

KS is notable for its aberrant angiogenesis with components of the VEGF pathway expressed in KS lesions; therefore, several agents that target angiogenesis have been investigated. Results so far have been mixed. Bevacizumab alone led to response rates of 31% and a 1-year progression-free survival of 70%.⁶³ Bevacizumab in combination with LD led to a response rate of 56%, but side effects such as hypertension and bleeding events were noted and led to treatment cessation in several participants.⁷⁴ Tyrosine kinase inhibitors that target angiogenesis and other proliferative pathways that are involved in KS pathogenesis have also been investigated. A small study of sorafenib demonstrated a poor response rate of 29%.⁶⁵ Imatinib, an inhibitor of c-kit and platelet-derived growth factor receptor signaling, led to a response rate of 50% in 10 participants.^66,75 However, in a larger phase II study, a partial response was seen in only 33% of participants.

Bortezomib, a proteosome inhibitor that inhibits the nuclear factor–κB pathway, is licensed for use in multiple myeloma. Additionally, bortezomib has been shown to result in KSHV lytic activation, which may lead to direct tumor killing by viral-mediated lysis. In a recent dose-escalation study of bortezomib by the AMC of 17 participants, the overall response rate was 60%.⁶⁴ Five of six participants at the highest dose experienced a partial response (83%). Although bortezomib is known to increase KSHV lytic replication and increases in circulating KSHV plasma DNA were noted at the highest dose level, there were no associated inflammatory symptoms.

Immunotherapy.

Among PLWH, CD4⁺ T-cell loss may lead to depletion of virus-specific T cells and allows for proliferation of virus-infected cells, leading to virus-associated cancers. Chronic T-cell stimulation by HIV, oncogenic viruses, and tumor neoantigens can lead to an increase in immune checkpoint markers on T cells, leading to loss of cytotoxic responses and eventual T-cell exhaustion.⁷⁶ Immune checkpoint markers include programmed death-1, and in the past 10 years, checkpoint inhibitors have revolutionized cancer therapy. However, exclusion of PLWH from cancer clinical trials because of concerns of toxicity, HIV activation, and potentially poor responses have led to a lag in their study and use in PLWH.⁷⁷ Checkpoint inhibitor therapy may offer a promising chemotherapy-sparing option that avoids treatment-related decreases in CD4⁺ T-cell counts that may perpetuate HIV⁺KS. A retrospective case series identified nine patients with HIV⁺KS treated with immunotherapy (eight received nivolumab and one received pembrolizumab), resulting in a response rate of 67% and others experiencing stable disease.⁷⁸ Responses were seen in those with low CD4⁺ T-cell counts and visceral disease, including a complete response in one patient with GI disease.

The first prospective study of pembrolizumab in PLWH and cancer included participants with CD4⁺ T-cell counts > 100 cells/µL. Six participants with HIV⁺KS were enrolled,⁶⁸ and some tumor regression was noted in five of the six; however, no response met the threshold for a partial response. One participant with heavy pretreatment for HIV⁺KS and a history of elevated peripheral blood mononuclear cell–associated KSHV developed significant anasarca, effusions, and substantial KSHV viremia after two cycles of pembrolizumab, leading to the participant's death. Autopsy findings showed substantial KSHV activation, but not pathologic findings of MCD. The trial investigators were concerned about the emergence of KSHV lymphoproliferation possibly attributed to pembrolizumab. In the ongoing prospective KS cohort within this study, participants with active MCD or KICS, anemia, or thrombocytopenia are excluded because of safety concerns.

Treating KS with concurrent KSHV-associated processes.

When HIV⁺KS occurs in the presence of another KSHV-associated disease or diseases, it is important to treat the concurrent KSHV processes in tandem (Fig 3). Among patients with MCD and KS, rituximab and LD lead to remission of both conditions.^79,80 Rituximab, which is used to treat KSHV-MCD, is known to exacerbate KS and LD can thwart this. After resolution of MCD symptoms, LD can be continued alone for KS. KICS is an IL-6 syndrome that occurs in patients with KS and KSHV infection without MCD pathology. Although tocilizumab, an anti–IL-6 receptor antibody, has been studied in patients with MCD and shown to induce transient improvement in the majority of patients,⁸¹ its use and the role of other IL-6 inhibitors in KICS are unknown. The optimal therapy for KICS and KS has not been identified, and patients should be referred for clinical trials. In patients who do not respond to therapy of KS, KICS, or MCD, physicians should consider undiagnosed PEL. In patients with a diagnosis of PEL and KS with or without MCD, treatment should include treatment of the PEL with curative intent, generally with combination anthracycline–based chemotherapy regimens used for other B-cell non-Hodgkin lymphomas.⁷ Clinical trial options should be considered, especially for patients experiencing relapsed or refractory disease.

Clinical trial approaches and future directions.

Building on existing evidence from clinical trials, many of the ongoing studies in HIV⁺KS include chemotherapy-sparing options. Confirmatory studies are planned in the United States and sub-Saharan Africa for pomalidomide to determine feasibility and efficacy. The HIV and AIDS Malignancy Branch of the US National Cancer Institute is conducting an ongoing study of pomalidomide in combination with LD in severe cases of KS among HIV-positive and HIV-negative participants (Table 2). This study also explores the use of pomalidomide and LD where KS occurs with other KSHV-associated processes such as KICS or MCD as a rituximab-sparing alternative. The HIV and AIDS Malignancy Branch is also initiating a study of pomalidomide in combination with nivolumab in virus-associated cancers, including HIV⁺KS. Other combination immunotherapy studies that investigate advanced cancers in PLWH include cabozantinib and nivolumab as well as nivolumab and ipilimumab.

TABLE 2.

Ongoing Studies in KS Registered in ClinicalTrials.gov

Following the data from the bortezomib study in HIV⁺KS, there is an ongoing AMC trial using ixazomib, an oral proteasome inhibitor, in HIV⁺KS. Also, on the basis of an in vitro study, sEphB4-HSA, a soluble human receptor tyrosine kinase ephrin type-B receptor 4 fused to human serum albumin, which targets blood vessel maturation, cell migration, and adhesion, is being investigated by the AMC in HIV⁺KS. Cytokines that are involved in T-cell development and proliferation (IL-7 and interleukin 12 fused to NHS76 antibody [NHS-IL12], a congener of IL-12) are also the subject of ongoing studies. IL-12 has antiangiogenic effects mediated through the induction of interferon-γ, which may lead to an increase in interferon-inducible protein 10 (IP-10). IP-10 can downregulate KSHV-encoded vGPCR, which is important in KS pathogenesis. Studies of IL-12 alone and in combination with LD have previously shown safety and activity in HIV⁺KS.^82,83 NHS-IL12 is a novel immunocytokine that is composed of two IL-12 heterodimers, each fused to an NHS76 antibody, which targets regions of tumor necrosis where DNA has become exposed. The study of NHS-IL12 also investigates it in combination with bintrafusp-alfa, a programmed cell death ligand-1 inhibitor fused to the soluble extracellular domain of human transforming growth factor β receptor II.

Prognosis and Health Disparity Issues

HIV⁺KS is a cancer that now often presents at the time of an initial HIV diagnosis.^14,84 Data from a UK specialist center have demonstrated good outcomes in HIV⁺KS with a 5-year overall survival of 85% even in poor-risk disease.⁴⁵ Even so, the prognosis of HIV⁺KS is often poor in resource-poor regions or in individuals with poor access to health care. In sub-Saharan Africa, KS continues to be a leading cause of mortality among patients diagnosed with HIV.¹⁶ Within the United States, projecting current HIV diagnosis rates in the future, it is expected that one in two Black men who have sex with men and one in four Latino men who have sex with men will be diagnosed with HIV during their lifetime.⁸⁵ These populations also have a high prevalence of KSHV infection and are at risk for KS. Such individuals face stigma related to their HIV status, race, and sexual orientation. As a result, they also experience significant challenges in access to health care and are under-represented in cancer clinical trials. Efforts are ongoing to ensure inclusion of PLWH in cancer clinical trials. Where possible, patients should receive multidisciplinary care among oncology and HIV specialists including nurses, social workers, and outreach staff who are aware of the complexity and stigma that PLWH and cancer face.

In conclusion, in the past 40 years, there have been substantial advances in the understanding of HIV, KSHV, and HIV⁺KS. Moreover, systemic therapies for HIV⁺KS with ART have led to improvements in care of patients worldwide. However, HIV⁺KS continues to occur in the modern age, causing significant morbidity and mortality particularly among populations experiencing cancer health disparities.

AUTHOR CONTRIBUTIONS

Conception and design: All authors

Financial support: Robert Yarchoan

Administrative support: Robert Yarchoan

Collection and assembly of data: Ramya Ramaswami

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Oncologic Treatment of HIV-Associated Kaposi Sarcoma 40 Years on

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