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Recently published near full-length KSHV genomes from a Cameroon Kaposi sarcoma case-control study showed strong evidence of viral recombination and mixed infections, but no sequence variations associated with disease. Using the same methodology, an additional 102 KSHV genomes from 76 individuals with KSHV-associated diseases have been sequenced. Diagnoses comprise all KSHV-associated diseases (KAD): Kaposi sarcoma (KS), primary effusion lymphoma (PEL), KSHV-associated large cell lymphoma (KSHV-LCL), a type of multicentric Castleman disease (KSHV-MCD), and KSHV inflammatory cytokine syndrome (KICS). Participants originated from 22 different countries, providing the opportunity to obtain new near full-length sequences of a wide diversity of KSHV genomes. These include near full-length sequence of genomes with KSHV K1 subtypes A, B, C, and F as well as subtype E, for which no full sequence was previously available. High levels of recombination were observed. Fourteen individuals (18%) showed evidence of infection with multiple KSHV variants (from two to four unique genomes). Twenty-six comparisons of sequences, obtained from various sampling sites including PBMC, tissue biopsies, oral fluids, and effusions in the same participants, identified near complete genome conservation between different biological compartments. Polymorphisms were identified in coding and non-coding regions, including indels in the K3 and K15 genes and sequence inversions here reported for the first time. One such polymorphism in KSHV ORF46, specific to the KSHV K1 subtype E2, encoded a mutation in the leucine loop extension of the uracil DNA glycosylase that results in alteration of biochemical functions of this protein. This confirms that KSHV sequence variations can have functional consequences warranting further investigation. This study represents the largest and most diverse analysis of KSHV genome sequences to date among individuals with KAD and provides important new information on global KSHV genomics.
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Genoma Viral , Herpesvirus Humano 8 , Sarcoma de Kaposi , Humanos , Herpesvirus Humano 8/genética , Sarcoma de Kaposi/virología , Sarcoma de Kaposi/genética , Masculino , Femenino , Persona de Mediana Edad , Adulto , Polimorfismo Genético , Anciano , Infecciones por Herpesviridae/genética , Infecciones por Herpesviridae/virología , Etnicidad/genética , Enfermedad de Castleman/virología , Enfermedad de Castleman/genética , FilogeniaRESUMEN
Kaposi sarcoma herpesvirus (KSHV)-associated disorders include Kaposi sarcoma (KS), primary effusion lymphoma (PEL), KSHV-associated multicentric Castleman disease (MCD) and KSHV-inflammatory cytokine syndrome (KICS). PEL, MCD, and KICS are associated with elevated circulating inflammatory cytokines. However, activation of the inflammasome, which generates IL-1ï¢ and IL-18 via active caspase-1/4/5, has not been evaluated in patients with KAD. Here we report that patients with HIV and one or more KAD present with higher plasma levels of IL-18 and increased caspase-1/4/5 activity in circulating monocytes as compared to HIV-negative healthy volunteers (HV) or people with HIV without KAD (PWH). Within KAD subtypes, KICS and MCD shared enhanced caspase-1/4/5 activity and IL-18 production when compared to HV and PWH, while patients with PEL showed remarkably high levels of inflammasome complex formation (known as apoptosis-associated speck-like protein containing a caspase recruitment domain (CARD) (ASC)-speck). Moreover, caspase-1/4/5 activity and IL-18 plasma levels correlated with KSHV viral load, indicating KSHV-driven inflammasome activation in KAD. Accordingly, factors released by KSHV-latently infected cells triggered inflammasome activation and cytokine production in bystander monocytes, in vitro. Finally, both supervised and unsupervised analyses with inflammasome measurements and other inflammatory biomarkers demonstrate a unique inflammatory profile in patients with PEL, MCD, and KICS as compared to KS. Our data indicate that detrimental inflammation in patients with KAD is at least partially driven by KSHV-induced inflammasome activation in monocytes, thus offering novel approaches to diagnose and treat these complex disorders.
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SUMMARYWithin weeks of the first report of acquired immunodeficiency syndrome (AIDS) in 1981, it was observed that these patients often had Kaposi sarcoma (KS), a hitherto rarely seen skin tumor in the USA. It soon became apparent that AIDS was also associated with an increased incidence of high-grade lymphomas caused by Epstein-Barr virus (EBV). The association of AIDS with KS remained a mystery for more than a decade until Kaposi sarcoma-associated herpesvirus (KSHV) was discovered and found to be the cause of KS. KSHV was subsequently found to cause several other diseases associated with AIDS and human immunodeficiency virus (HIV) infection. People living with HIV/AIDS continue to have an increased incidence of certain cancers, and many of these cancers are caused by EBV and/or KSHV. In this review, we discuss the epidemiology, virology, pathogenesis, clinical manifestations, and treatment of cancers caused by EBV and KSHV in persons living with HIV.
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An estimated 38 million people live with human immunodeficiency virus (HIV) worldwide and are at excess risk for multiple cancer types. Elevated cancer risks in people living with HIV (PLWH) are driven primarily by increased exposure to carcinogens, most notably oncogenic viruses acquired through shared transmission routes, plus acceleration of viral carcinogenesis by HIV-related immunosuppression. In the era of widespread antiretroviral therapy (ART), life expectancy of PLWH has increased, with cancer now a leading cause of co-morbidity and death. Furthermore, the types of cancers occurring among PLWH are shifting over time and vary in their relative burden in different parts of the world. In this context, the International Agency for Research on Cancer (IARC) and the US National Cancer Institute (NCI) convened a meeting in September 2022 of multinational and multidisciplinary experts to focus on cancer in PLWH. This report summarizes the proceedings, including a review of the state of the science of cancer descriptive epidemiology, etiology, molecular tumor characterization, primary and secondary prevention, treatment disparities and survival in PLWH around the world. A consensus of key research priorities and recommendations in these domains is also presented.
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Fármacos Anti-VIH , Infecciones por VIH , Neoplasias , Estados Unidos/epidemiología , Humanos , VIH , National Cancer Institute (U.S.) , Neoplasias/tratamiento farmacológico , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/epidemiología , Fármacos Anti-VIH/uso terapéuticoRESUMEN
BACKGROUND: Human herpes virus 8 (HHV-8) or Kaposi sarcoma herpesvirus (KSHV) is an opportunistic oncovirus that causes multiple pathologic entities. METHODS: We present a case of fatal HHV-8-associated multisystem illness with disseminated Kaposi sarcoma and HHV8-associated lymphoproliferative disorder with systemic inflammation. We conducted a narrative review of the literature on HHV-8 in transplantation with a goal of illuminating the spectrum of HHV-8-associated diseases in this vulnerable population, modes of disease transmission, and the potential role for donor and recipient screening. RESULTS: HHV-8-associated KS, primary effusion lymphoma (PEL), multicentric Castleman disease (MCD), and KSHV inflammatory cytokine disorder (KICS) may affect transplant recipients; with the exception of KS, these conditions are rare but carry high morbidity and mortality. CONCLUSION: HHV-8-associated diseases have diverse and protean manifestations in transplant recipients, with potentially fatal outcomes. HHV-8 seroprevalence among organ donors and the magnitude of risk for donor-derived HHV-8 infection or clinically significant disease remain unknown and require further study.
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A biopsy of lymphoid tissue is currently required to diagnose Kaposi sarcoma-associated herpesvirus (KSHV)-associated multicentric Castleman disease (KSHV-MCD). Patients showing clinical manifestations of KSHV-MCD but no pathological changes of KSHV-MCD are diagnosed as KSHV inflammatory cytokine syndrome. However, a lymph node biopsy is not always feasible to make the distinction. A pathognomonic feature of lymph nodes in KSHV-MCD is the expansion of KSHV-infected, lambda-restricted but polyclonal plasmablasts. To investigate whether these cells also reside in extra-nodal sites, effusion from 11 patients with KSHV-MCD and 19 with KSHV inflammatory cytokine syndrome was analysed by multiparametric flow cytometry. A distinct, lambda-restricted plasmablastic population (LRP) with highly consistent immunophenotype was detected in effusions in 8/11 patients with KSHV-MCD. The same population was also observed in 7/19 patients with KSHV inflammatory cytokine syndrome. The detection of LRP stratified KSHV inflammatory cytokine syndrome into two clinically distinct subgroups; those with detectable LRP closely resembled KSHV-MCD, showing similar KSHV viral load, comparable severity of thrombocytopenia and hypoalbuminaemia, and similar incidences of hepatosplenomegaly. Collectively, the detection of LRP by flow cytometry can serve as a valuable tool in diagnosing KSHV-MCD. KSHV inflammatory cytokine syndrome with LRP in effusions may represent a liquid-form of KSHV-MCD.
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Enfermedad de Castleman , Herpesvirus Humano 8 , Sarcoma de Kaposi , Humanos , Enfermedad de Castleman/patología , Ganglios Linfáticos/patología , CitocinasRESUMEN
BACKGROUND: Kaposi sarcoma (KS) is a multicentric tumor caused by Kaposi sarcoma herpesvirus (KSHV) that leads to morbidity and mortality among people with HIV worldwide. KS commonly involves the skin but can occur in the gastrointestinal tract (GI) in severe cases. METHODS: RNA sequencing was used to compare the cellular and KSHV gene expression signatures of skin and GI KS lesions in 44 paired samples from 19 participants with KS alone or with concurrent KSHV-associated diseases. Analyses of KSHV expression from KS lesions identified transcriptionally active areas of the viral genome. RESULTS: The transcript of an essential viral lytic gene, ORF75, was detected in 91% of KS lesions. Analyses of host genes identified 370 differentially expressed genes (DEGs) unique to skin KS and 58 DEGs unique to GI KS lesions as compared to normal tissue. Interleukin (IL)-6 and IL-10 gene expression were higher in skin lesions as compared to normal skin but not in GI KS lesions. Twenty-six cellular genes were differentially expressed in both skin and GI KS tissues: these included Fms-related tyrosine kinase 4 (FLT4), encoding an angiogenic receptor, and Stanniocalcin 1 (STC1), a secreted glycoprotein. FLT4 and STC1 were further investigated in functional studies using primary lymphatic endothelial cells (LECs). In these models, KSHV infection of LECs led to increased tubule formation that was impaired upon knock-down of STC1 or FLT4. CONCLUSIONS: This study of transcriptional profiling of KS tissue provides novel insights into the characteristics and pathogenesis of this unique virus-driven neoplasm.
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Herpesvirus Humano 8 , Sarcoma de Kaposi , Neoplasias Cutáneas , Humanos , Sarcoma de Kaposi/genética , Células Endoteliales , Herpesvirus Humano 8/genética , Piel , Interleucina-6RESUMEN
Primary effusion lymphoma (PEL) is an aggressive HIV-associated lymphoma with a relatively poor prognosis in the era of effective HIV therapy. Kaposi sarcoma herpesvirus (KSHV) is the etiologic agent, and â¼80% of tumors are coinfected with Epstein-Barr virus (EBV). A better understanding of how KSHV-related immune dysregulation contributes to the natural history of PEL will improve outcomes. Twenty patients with PEL diagnosed between 2000 and 2013, including 19 treated with modified infusional etoposide, vincristine, and doxorubicin with cyclophosphamide and prednisone (EPOCH), were identified. We compared their clinical, virologic, and immunologic features vs 20 patients with HIV-associated diffuse large B-cell lymphoma and 19 patients with symptomatic interleukin (IL)-6 related KSHV-associated multicentric Castleman disease. Survival analyses of treated patients with PEL were then performed to identify prognostic factors and cancer-specific mortality. Compared with HIV-associated diffuse large B-cell lymphoma, PEL was associated with significant hypoalbuminemia (P < .0027), thrombocytopenia (P = .0045), and elevated IL-10 levels (P < .0001). There were no significant differences in these parameters between PEL and KSHV-associated multicentric Castleman disease. Median overall survival in treated patients with PEL was 22 months, with a plateau in survival noted after 2 years. Three-year cancer-specific survival was 47%. EBV-positive tumor status was associated with improved survival (hazard ratio, 0.27; P = .038), and elevated IL-6 level was associated with inferior survival (hazard ratio, 6.1; P = .024). Our analysis shows that IL-6 and IL-10 levels contribute to the natural history of PEL. Inflammatory cytokines and tumor EBV status are the strongest prognostic factors. Pathogenesis-directed first-line regimens are needed to improve overall survival in PEL.
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Enfermedad de Castleman/virología , Linfoma de Células B Grandes Difuso/virología , Linfoma de Efusión Primaria/patología , Sarcoma de Kaposi/virología , Adulto , Anciano , Citocinas/sangre , Citocinas/inmunología , Femenino , Herpesvirus Humano 4 , Herpesvirus Humano 8 , Humanos , Interleucina-10/sangre , Interleucina-6/sangre , Linfoma de Efusión Primaria/complicaciones , Linfoma de Efusión Primaria/inmunología , Linfoma de Efusión Primaria/virología , Masculino , Persona de Mediana Edad , Pronóstico , Sarcoma de Kaposi/patología , Análisis de Supervivencia , Adulto JovenRESUMEN
Noncoding RNAs have substantial effects in host-virus interactions. Circular RNAs (circRNAs) are novel single-stranded noncoding RNAs which can decoy other RNAs or RNA-binding proteins to inhibit their functions. The role of circRNAs is largely unknown in the context of Kaposi's sarcoma herpesvirus (KSHV). We hypothesized that circRNAs influence viral infection by inhibiting host and/or viral factors. Transcriptome analysis of KSHV-infected primary endothelial cells and a B cell line identified human circRNAs that are differentially regulated upon infection. We confirmed the expression changes with divergent PCR primers and RNase R treatment of specific circRNAs. Ectopic expression of hsa_circ_0001400, a circRNA induced by infection, suppressed expression of key viral latent gene LANA and lytic gene RTA in KSHV de novo infections. Since human herpesviruses express noncoding RNAs like microRNAs, we searched for viral circRNAs encoded in the KSHV genome. We performed circRNA-Seq analysis with RNase R-treated, circRNA-enriched RNA from KSHV-infected cells. We identified multiple circRNAs encoded by the KSHV genome that are expressed in KSHV-infected endothelial cells and primary effusion lymphoma (PEL) cells. The KSHV circRNAs are located within ORFs of viral lytic genes, are up-regulated upon the induction of the lytic cycle, and alter cell growth. Viral circRNAs were also detected in lymph nodes from patients of KSHV-driven diseases such as PEL, Kaposi's sarcoma, and multicentric Castleman's disease. We revealed new host-virus interactions of circRNAs: human antiviral circRNAs are activated in response to KSHV infection, and viral circRNA expression is induced in the lytic phase of infection.
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Herpesvirus Humano 8/genética , ARN/genética , Sarcoma de Kaposi/genética , Sarcoma de Kaposi/virología , Linfocitos B/virología , Enfermedad de Castleman/genética , Enfermedad de Castleman/virología , Línea Celular , Células Endoteliales/virología , Perfilación de la Expresión Génica/métodos , Regulación Viral de la Expresión Génica/genética , Genes Virales/genética , Células HEK293 , Células Endoteliales de la Vena Umbilical Humana , Humanos , Linfoma de Efusión Primaria/genética , Linfoma de Efusión Primaria/virología , MicroARNs/genética , Sistemas de Lectura Abierta/genética , ARN Circular , ARN Viral/genéticaRESUMEN
PURPOSE OF REVIEW: Immune checkpoint inhibitors targeting the programmed cell death-1 (PD-1) pathway are a class of anti-cancer immunotherapy agents changing treatment paradigms of many cancers that occur at higher rates in people living with HIV (PLWH) than in the general population. However, PLWH have been excluded from most of the initial clinical trials with these agents. RECENT FINDINGS: Two recent prospective studies of anti-PD-1 agents, along with observational studies and a meta-analysis, have demonstrated acceptable safety in PLWH. Preliminary evidence indicates activity in a range of tumors and across CD4+ T cell counts. Safety and preliminary activity data suggest monoclonal antibodies targeting PD-1 or its ligand, PD-L1, are generally appropriate for PLWH and cancers for which there are FDA-approved indications. Ongoing and future trials of anti-PD-1 and anti-PD-L1 therapy alone or in combination for HIV-associated cancers may further improve outcomes for this underserved population.
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Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Antígeno B7-H1/antagonistas & inhibidores , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias/tratamiento farmacológico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Fármacos Anti-VIH/uso terapéutico , Antígeno B7-H1/inmunología , Infecciones por VIH/tratamiento farmacológico , Humanos , Inmunoterapia/métodos , Receptor de Muerte Celular Programada 1/inmunología , Estudios ProspectivosAsunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Enfermedad de Castleman/tratamiento farmacológico , Infecciones por Herpesviridae/complicaciones , Herpesvirus Humano 8/patogenicidad , Adulto , Fármacos Anti-VIH/uso terapéutico , Enfermedad de Castleman/virología , Femenino , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Infecciones por Herpesviridae/tratamiento farmacológico , Herpesvirus Humano 8/aislamiento & purificación , Humanos , Interleucina-10/sangre , Interleucina-1beta/sangre , Masculino , Persona de Mediana Edad , Sarcoma de Kaposi/complicaciones , Resultado del Tratamiento , Valganciclovir/uso terapéutico , Carga Viral , Zidovudina/uso terapéuticoAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Terapia Antirretroviral Altamente Activa/métodos , Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Infecciones por VIH/complicaciones , Linfoma no Hodgkin/tratamiento farmacológico , Adulto , Neoplasias del Sistema Nervioso Central/patología , Neoplasias del Sistema Nervioso Central/virología , Quimioterapia Combinada , Femenino , Estudios de Seguimiento , VIH/aislamiento & purificación , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , Humanos , Linfoma no Hodgkin/patología , Linfoma no Hodgkin/virología , Masculino , Metotrexato/administración & dosificación , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Rituximab/administración & dosificación , Tasa de SupervivenciaRESUMEN
Blockade of the co-inhibitory receptor PD-1 enhances antitumor responses by boosting the function of antigen-specific T cells. Although rare, PD-1 blockade in patients with cancer can lead to exacerbation of infection-associated pathology. Here, we detail the case of a 38-year-old man who was enrolled in a clinical trial for assessment of the safety and activity of anti-PD-1 therapy for Kaposi sarcoma in people with HIV well-controlled on antiretroviral therapy. Less than a week after receiving the first dose of anti-PD-1 antibody (pembrolizumab), he presented with severe abdominal pain associated with sudden exacerbations of preexisting cytomegalovirus (CMV) enteritis and nontuberculous mycobacterial mesenteric lymphadenitis. Plasma biomarkers of gastrointestinal tract damage were highly elevated compared with healthy controls, consistent with HIV-associated loss of gut epithelial barrier integrity. Moreover, CMV-specific CD8 T cells expressed high levels of PD-1, and 7 days following PD-1 blockade, there was an increase in the frequency of activated CD38+ Ki67+ CMV-specific CD8 T cells. This case highlights the potential for PD-1 blockade to drive rapid exacerbations of inflammatory symptoms when administered to individuals harboring multiple unresolved infections.
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OBJECTIVE: Kaposi sarcoma is a vascular tumor that affects the pulmonary system. However, the diagnosis of airway lesions suggestive of pulmonary Kaposi sarcoma (pKS) is reliant on bronchoscopic visualization. We evaluated the role of Kaposi sarcoma herpesvirus (KSHV) viral load in bronchoalveolar lavage (BAL) as a diagnostic biomarker in patients with bronchoscopic evidence of pKS and evaluated inflammatory cytokine profiles in BAL and blood samples. DESIGN: In this retrospective study, we evaluated KSHV viral load and cytokine profiles within BAL and blood samples in patients who underwent bronchoscopy for suspected pKS between 2016 and 2021. METHODS: KSHV viral load and cytokine profiles were obtained from both the circulation and BAL samples collected at the time of bronchoscopy to evaluate compartment-specific characteristics. BAL was centrifuged and stored as cell pellets and KSHV viral load was measured using primers for the KSHV K6 gene regions. RESULTS: We evaluated 38 BAL samples from 32 patients (30 with HIV co-infection) of whom 23 had pKS. In patients with airway lesions suggestive of pKS, there was higher KSHV viral load (median 3188 vs. 0âcopies/10 6 cell equivalent; P â=â0.0047). A BAL KSHV viral load cutoff of 526âcopies/10 6 cells had a sensitivity of 72% and specificity of 89% in determining lesions consistent with pKS. Those with pKS also had higher IL-1ß and IL-8 levels in BAL. The 3-year survival rate for pKS patients was 55%. CONCLUSION: KSHV viral load in BAL shows potential for aiding in pKS diagnosis. Patients with pKS also have evidence of cytokine dysregulation in BAL.
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Líquido del Lavado Bronquioalveolar , Citocinas , Herpesvirus Humano 8 , Sarcoma de Kaposi , Carga Viral , Humanos , Sarcoma de Kaposi/virología , Sarcoma de Kaposi/diagnóstico , Herpesvirus Humano 8/aislamiento & purificación , Masculino , Femenino , Estudios Retrospectivos , Persona de Mediana Edad , Líquido del Lavado Bronquioalveolar/virología , Líquido del Lavado Bronquioalveolar/citología , Adulto , Citocinas/análisis , Broncoscopía , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/virología , Neoplasias Pulmonares/patología , Biomarcadores/análisis , Infecciones por VIH/complicaciones , Infecciones por VIH/diagnóstico , Anciano , Lavado BroncoalveolarRESUMEN
BACKGROUND: Despite a higher risk of classical Hodgkin lymphoma (cHL) in people with HIV and the demonstrated safety and efficacy of PD-1 blockade in cHL, there are limited data on the use of these agents in HIV-associated cHL (HIV-cHL). PATIENTS/METHODS: We retrospectively identified patients with HIV-cHL from the "Cancer Therapy using Checkpoint inhibitors in People with HIV-International (CATCH-IT)" database who received nivolumab or pembrolizumab, alone or in combination with other agents, and reviewed records for demographics, disease characteristics, immune-mediated adverse events (imAEs), and treatment outcomes. Changes in CD4+ T-cell counts with treatment were measured via Wilcoxon signed-rank tests. Overall response rate (ORR) was defined as the proportion of patients with partial or complete response (PR/CR) per 2014 Lugano classification. RESULTS: We identified 23 patients with HIV-cHL who received a median of 6 cycles of PD-1 blockade: 1 as 1st-line, 6 as 2nd-line, and 16 as ≥3rd-line therapy. Seventeen (74%) patients received monotherapy, 5 (22%) received nivolumab plus brentuximab vedotin, and 1 received nivolumab plus ifosfamide, carboplatin, and etoposide. The median baseline CD4+ T-cell count was 155 cells/µL, which increased to 310 cells/µL at end-of-treatment (P = .009). Three patients had grade 3 imAEs; none required treatment discontinuation. The ORR was 83% with median duration of response of 19.7 months. The median progression-free survival was 21.2 months and did not differ between patients with <200 versus ≥200 CD4+ cells/µL (P = .95). CONCLUSION: Our findings support the use of PD-1 blockade in HIV-cHL for the same indications as the general population with cHL.
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Infecciones por VIH , Enfermedad de Hodgkin , Inhibidores de Puntos de Control Inmunológico , Humanos , Masculino , Enfermedad de Hodgkin/tratamiento farmacológico , Femenino , Persona de Mediana Edad , Adulto , Estudios Retrospectivos , Estados Unidos , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/complicaciones , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Inhibidores de Puntos de Control Inmunológico/farmacología , Nivolumab/uso terapéutico , Nivolumab/efectos adversos , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Anciano , Resultado del Tratamiento , Anticuerpos Monoclonales HumanizadosRESUMEN
The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice.People with HIV (PWH) have an increased lifetime risk of developing certain cancers, even when HIV is well-controlled with antiretroviral therapy. Despite the tremendous advancements in HIV and cancer care over the past several decades, PWH have lower cancer-related survival compared with the general population. Treating HIV-associated cancers requires a multidisciplinary team to manage concurrent opportunistic infections, potential drug-drug interactions, and the co-occurrence of more than one cancer in the same patient. Many factors may lead PWH to receive inappropriate dose adjustments, exclusion from emerging therapies and clinical trials, or no cancer therapy at all. In general, PWH should receive the same standard, full-dose cancer therapy used in the general population unless there are data for specific cancer regimens in PWH. Agents targeting PD-1 and PD-L1 have US Food and Drug Administration (FDA)-approved indications in many HIV-associated cancers, including Hodgkin lymphoma, cervical cancer, head and neck cancer, hepatocellular carcinoma, and non-small-cell lung cancer; however, PWH were excluded from all clinical trials that led to FDA approval of these agents. Several prospective studies and an international retrospective study of PWH with advanced cancer have shown anti-PD-(L)-1 agents to be safe and effective across expected cancer types and CD4+ T-cell counts, supporting their use in PWH for FDA-approved indications. Learning from the experience in anti-PD-(L)-1 agents, future cancer clinical trials should include and seek to actively enroll PWH, so that they have equal and timely access to emerging cancer therapies.
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Carcinoma de Pulmón de Células no Pequeñas , Infecciones por VIH , Neoplasias Hepáticas , Neoplasias Pulmonares , Estados Unidos , Femenino , Humanos , Estudios Prospectivos , Estudios Retrospectivos , Neoplasias Pulmonares/terapia , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológicoRESUMEN
INTRODUCTION: Kaposi sarcoma herpes virus (KSHV) is associated with several diseases including Kaposi sarcoma, a form of multicentric Castleman's disease, primary effusion lymphoma, and an inflammatory cytokine syndrome. These KSHV-associated diseases (KAD) can present with heterogenous signs and symptoms that are often associated with cytokine dysregulation that may result in multiorgan dysfunction. The inability to promptly diagnose and treat these conditions can result in long-term complications and mortality. AREAS COVERED: Existing epidemiological subtypes of existing KSHV-associated diseases, specifically Kaposi sarcoma as well as the incidence of several KSHV-associated disorders are described. We review the KSHV latent and lytic phases as they correlate with KSHV-associated diseases. Given the complicated presentations, we discuss the clinical manifestations, current diagnostic criteria, existing treatment algorithms for individual KAD, and when they occur concurrently. With emerging evidence on the virus and host interactions, we evaluate novel approaches for the treatment of KAD. An extensive literature search was conducted to support these findings. EXPERT OPINION: KSHV leads to complex and concurrent disease processes that are often underdiagnosed both in the United States and worldwide. New therapies that exist for many of these conditions focus on chemotherapy-sparing options that seek to target the underlying viral pathogenesis or immunotherapy strategies.