HIV-associated Kaposi sarcoma and related diseases.
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SUBMITTER: Goncalves PH
PROVIDER: S-EPMC6310482 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:PURPOSE OF REVIEW:This review discusses the pathogenesis and recent advances in the management of Kaposi sarcoma herpesvirus (KSHV)-associated diseases. RECENT FINDINGS:KSHV, a gammaherpesvirus, causes several tumors and related diseases, including Kaposi sarcoma, a form of multicentric Castleman disease (KSHV-MCD), and primary effusion lymphoma. These most often develop in patients infected with human immunodeficiency virus (HIV). KSHV 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 Kaposi sarcoma. Rituximab is active in KSHV-MCD but can cause Kaposi sarcoma exacerbation; rituximab plus liposomal doxorubicin is useful to treat KSHV-MCD patients with concurrent Kaposi sarcoma. SUMMARY:KSHV is the etiological agents of all forms of Kaposi sarcoma and several other diseases. Strategies employing immunomodulatory agents, cytokine inhibition, and targeting of KSHV-infected cells are areas of active research.
| S-EPMC6311702 | biostudies-literature
Project description:Kaposi sarcoma (KS) is an AIDS-defining angio-proliferative malignancy highly prevalent in Sub-Saharan Africa. The main objective of this study was to determine the factors associated with recurrence of HIV-associated KS. We recruited a cohort of individuals on antiretroviral therapy who were in remission for HIV-associated KS after undergoing cytotoxic cancer chemotherapy. Collected variables included sociodemographic and clinical parameters, cytokines and chemokines, HIV viral loads, and CD4 counts. Compared to individuals who had KS recurrence, IL-5 was significantly higher at time of follow-up in individuals who had sustained remission (22.7pg/ml vs. 2.4pg/ml; p = 0.02); IL-6 was significantly higher at baseline and time of follow-up in individuals who had sustained remission, (18.4pg/ml vs. 0pg/ml; p = 0.01) and (18.0pg/ml vs. 0.18pg/ml; p = 0.03) respectively; IP-10 was significantly lower at baseline and at time of follow-up in individuals who had sustained remission, (534pg/ml vs. 920pg/ml; p = 0.04) and (446pg/ml vs.1098pg/ml; p = 0.01) respectively; while HIV viral load was significantly lower at baseline and at time of follow-up in individuals who had sustained remission, (0copies/ml vs. 113copies/ml; p = 0.004) and (0copies/ml vs. 152copies/ml; p = 0.025) respectively. Plasma levels of IL-5, IL-6, and IP-10 are associated with recurrence of HIV-associated KS, while persistently detectable HIV viral loads increase the risk of KS recurrence.
| S-EPMC8253384 | biostudies-literature
Project description:Kaposi sarcoma (KS), a multifocal vascular neoplasm frequently observed in HIV-positive individuals, primarily affects the skin, mucous membranes, visceral organs, and lymph nodes. KS is associated primarily with Kaposi sarcoma-associated herpesvirus (KSHV) infection. In this case report, we present a rare occurrence of co-infection and co-localization of KSHV and Epstein-Barr virus (EBV) in KS arising from the conjunctiva, which, to our knowledge, has not been reported previously. Immunohistochemistry (IHC), DNA polymerase chain reaction (PCR), and EBV-encoded RNA in situ hybridization (EBER-ISH) were utilized to demonstrate the presence of KSHV and EBV infection in the ocular KS lesion. Nearly all KSHV-positive cells displayed co-infection with EBV. In addition, the KS lesion revealed co-localization of KSHV Latency-Associated Nuclear Antigen (LANA) and EBV Epstein Barr virus Nuclear Antigen-1 (EBNA1) by multi-colored immunofluorescence staining with different anti-EBNA1 antibodies, indicating the possibility of interactions between these two gamma herpesviruses within the same lesion. Additional study is needed to determine whether EBV co-infection in KS is a common or an opportunistic event that might contribute to KS development and progression.
| S-EPMC10623342 | biostudies-literature
Project description:Kaposi sarcoma (KS) is an incurable, human immunodeficiency virus (HIV)-associated malignancy. We reviewed 320 immunotherapy-treated patient records. Seventeen had HIV-associated malignancies, including nine men with KS. Median viral load was 20 copies/mL (range, undetectable to 549,704) and median CD4 count was 256 cells/?L (range, 10-603). Eight patients received nivolumab and one received pembrolizumab. Six patients (67%) achieved partial (N = 5) or complete remission (N = 1). No drug-related grade >2 toxicities occurred. In seven patients, CD4 counts increased (P = 0.09). Tissue and/or blood-derived circulating tumor DNA (ctDNA) was evaluated by next-generation sequencing. Four evaluable patients each showed anomalies in distinct genes: TP53, KRAS, TLL2, PTPN6 (tissue and/or ctDNA), and NF1 (ctDNA). Tumor mutational burden was low, and PD-L1 immunohistochemistry was negative (three and four assessable patients, respectively). Responders included patients with low CD4 counts, high HIV load, and/or visceral disease. In summary, checkpoint blockade demonstrated significant antitumor activity and low toxicity in patients with HIV-associated KS. Cancer Immunol Res; 6(10); 1129-35. ©2018 AACR.
| S-EPMC6248326 | biostudies-literature
Project description:PurposeEvaluate the effectiveness of compression while receiving chemotherapy compared with chemotherapy alone in the treatment of HIV-associated Kaposi sarcoma (KS) lymphedema.MethodsA randomized controlled trial was conducted in a single oncology clinic in western Kenya (NCT03404297). A computer-generated randomization schedule was used to allocate treatment arms. Randomized block design was used for stratification by lymphedema stage. Participants were HIV positive adults age ≥ 18 years on antiretroviral therapy with biopsy-proven KS associated with leg lymphedema and being initiated on chemotherapy. The intervention was 10 weeks of weekly clinic-based application of two-component paste compression bandages. The primary outcome was change in the Lower Extremity Lymphedema Index (LELI) score from week 0 to week 14. The secondary outcomes were change in the Lymphedema Quality of Life measure (LYMQOL) and change in the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 score from week 0 to week 14. Blinded outcome assessments were conducted.ResultsOf 30 participants randomly assigned, 25 eligible patients (chemotherapy [control], n = 13; compression plus chemotherapy [intervention], n = 12) returned at week 14. Change in LELI, LYMQOL, and EORTC QLQ-C30 scores between week 14 and week 0 did not significantly differ by arm. The mean (standard deviation) change in LELI score was -25.9 (34.6) for the control arm compared with -13.3 (29.5) for the intervention arm, P = .340. The difference (95% CI) in the change in LELI score was -12.6 (-39.3 to 14.1).ConclusionFuture studies evaluating a 14-week change in LELI for KS lymphedema should assume a standard deviation of approximately 30. Lessons learned from this pilot trial should inform the development of a larger, multicenter trial to evaluate the effectiveness of compression for KS lymphedema.
| S-EPMC8769101 | biostudies-literature
Project description:PurposeKaposi sarcoma (KS), an endothelial cell tumor associated with KS herpesvirus (KSHV), remains among the most common malignancies occurring with HIV infection (HIV-KS). As an oral anti-inflammatory, antiangiogenic, and immunomodulatory agent, lenalidomide is potentially an attractive alternative to standard chemotherapy for KS.Experimental designThe primary objectives of this phase I/II trial were to determine the maximum tolerated dose (MTD) and response rates for lenalidomide in HIV-KS. Secondary objectives included correlating response with natural killer (NK) and T-cell subsets, plasma cytokines, viral copy number, and KSHV gene expression in biopsies. Four dose levels of oral lenalidomide taken 21 consecutive days of 28-day cycles were evaluated in adults with HIV-KS on antiretroviral therapy with controlled viremia.ResultsFifteen and 23 participants enrolled in phases I and II, respectively, 76% of whom had received prior KS therapy. The MTD was not reached, declaring 25 mg as the recommended phase II dose (RP2D). The most frequent adverse events were neutropenia, fatigue, leukopenia, and diarrhea. Of the 25 evaluable participants receiving RP2D, 60% responded. Correlative studies performed in a subset of participants demonstrated a significant increase in proportions of blood T cells with T-regulatory phenotype, and plasma cytokines trended toward a less inflammatory pattern. Clinical response was associated with loss of KSHV transcription.ConclusionsLenalidomide is active in HIV-KS. The most common adverse events were manageable. With 60% of participants receiving RP2D obtaining a partial response and <10% discontinuing due to adverse events, the response and tolerability to lenalidomide support its use in HIV-KS. See related commentary by Henry and Maki, p. 2485.
| S-EPMC9197984 | biostudies-literature
Project description:ObjectiveThere are four conditions caused by Kaposi sarcoma herpesvirus (KSHV): Kaposi sarcoma, KSHV-associated multicentric Castleman disease (MCD), primary effusion lymphoma (PEL), and KSHV inflammatory cytokine syndrome (KICS). These KSHV-associated disorders (KADs) often occur in people with HIV and can lead to multiorgan dysfunction requiring admission to the ICU. However, little is known about patient outcomes in this setting.MethodsA retrospective study of patients with KADs admitted to the ICU between 2010 and 2021 was conducted, examining KAD admission diagnoses, HIV characteristics, selected cytokine profiles, and ICU interventions. Primary outcomes were 60-day and median overall survival from ICU admission to death from any cause.ResultsForty-seven patients (all but one with HIV coinfection) were included. At ICU admission, 44 patients (94%) were on antiretroviral therapy with a median CD4 + count of 88 cells/μl and HIV viral load of 23 copies/ml. The most common presentation was respiratory failure alone (19%) or with hypotension (17%). Twenty-two (47%) patients had presumed KICS (with or without Kaposi sarcoma) at admission and an additional KAD was diagnosed in 36% of these patients. IL-6 levels did not vary across KAD subtype. Twenty (43%) patients received KAD-directed therapy in the ICU. Sixty-day survival was 70% and median overall survival was 9 months.ConclusionThe majority of patients with HIV and KADs admitted to the ICU had well controlled HIV. Additional KAD were diagnosed during ICU admission in a proportion of patients who presented with presumed KICS. Critical illness did not preclude a subset of patients from receiving KAD-directed therapy in the ICU.
| S-EPMC9617765 | biostudies-literature
Project description:Intra-host tumor virus variants may influence the pathogenesis and treatment responses of some virally-associated cancers. However, the intra-host variability of Kaposi sarcoma-associated herpesvirus (KSHV), the etiologic agent of Kaposi sarcoma (KS), has to date been explored with sequencing technologies that possibly introduce more errors than that which occurs in the viral population, and these studies have only studied variable regions. Here, full-length KSHV genomes in tumors and/or oral swabs from 9 Ugandan adults with HIV-associated KS were characterized. Furthermore, we used deep, short-read sequencing using duplex unique molecular identifiers (dUMI)-random double-stranded oligonucleotides that barcode individual DNA molecules before library amplification. This allowed suppression of PCR and sequencing errors to ~10-9/base as well as afforded accurate determination of KSHV genome numbers sequenced in each sample. KSHV genomes were assembled de novo, and rearrangements observed were confirmed by PCR and Sanger sequencing. 131-kb KSHV genome sequences, excluding major repeat regions, were successfully obtained from 23 clinical specimens, averaging 2.3x104 reads/base. Strikingly, KSHV genomes were virtually identical within individuals at the point mutational level. The intra-host heterogeneity that was observed was confined to tumor-associated KSHV mutations and genome rearrangements, all impacting protein-coding sequences. Although it is unclear whether these changes were important to tumorigenesis or occurred as a result of genomic instability in tumors, similar changes were observed across individuals. These included inactivation of the K8.1 gene in tumors of 3 individuals and retention of a region around the first major internal repeat (IR1) in all instances of genomic deletions and rearrangements. Notably, the same breakpoint junctions were found in distinct tumors within single individuals, suggesting metastatic spread of rearranged KSHV genomes. These findings define KSHV intra-host heterogeneity in vivo with greater precision than has been possible in the past and suggest the possibility that aberrant KSHV genomes may contribute to aspects of KS tumorigenesis. Furthermore, study of KSHV with use of dUMI provides a proof of concept for utilizing this technique for detailed study of other virus populations in vivo.
| S-EPMC7845968 | biostudies-literature
Project description:BACKGROUND:HIV-associated Kaposi sarcoma (KS) is commonly staged using the AIDS Clinical Trials Group criteria, which classify 3 variables- tumor extent (T), immune status (I), and systemic symptoms (S)-into good risk (0) and poor risk (1). Although validated in the United States and Europe, these criteria have not been systematically evaluated in sub-Saharan Africa, where the burden of KS is greatest. METHODS:We reviewed medical charts of adult patients with HIV-associated KS seen at the Uganda Cancer Institute from 1992 to 2007. Vital status at 2 years after KS diagnosis was determined from the medical chart, or by contacting the patient or next of kin. Survival estimates used Kaplan-Meier methods. Predictors were evaluated for 2 periods: 0-4 months and 4-24 months after diagnosis. RESULTS:At 2 years after diagnosis, 167 (41%) patients were alive, 156 (39%) had died, and 81 (20%) were lost to follow-up. The Kaplan-Meier estimate of 2-year survival was 57%. S1 was associated with death in months 0-4 [hazard ratio: 6.4, 95% confidence interval: 1.9-21.1], whereas T1 was associated with death in months 4-24 [hazard ratio: 4.0, 95% confidence interval: 1.4 to 11.5]. Immune status was not associated with survival. CONCLUSIONS:Systemic symptoms were strongly associated with death in the early period after KS diagnosis, whereas tumor status was most predictive of death in the 4- to 24-month period. These findings suggest that different processes may influence outcomes in early and late periods following KS diagnosis. Further studies are needed to confirm these observations and to identify better predictors of KS survival in sub-Saharan Africa.
| S-EPMC5340582 | biostudies-literature
Project description:BackgroundProtease inhibitors (PIs) may inhibit Kaposi sarcoma (KS) carcinogenesis. However, PI-based antiretroviral therapy (ART) is rarely a first-line choice in people living with HIV (PLWH) because of cost and toxicities. This is the first systematic review to assess KS incidence stratified by ART type.MethodsWe searched PubMed to identify original, full research reports of KS incidence in ART-treated adult PLWH, stratified by ART class, published between 1996 and 2017. For overlapping cohorts, we included only the most recent study and supplemented data with earlier relevant analyses. We described study design, sociodemographic characteristics, statistical adjustment factors, and KS incidence.ResultsWe identified 3 unique retrospective cohort studies, and supplemented one of the studies with results from 6 previous subgroup reports, which included 242,309 PLWH and 3570 incident KS cases. Overall, KS crude incidence decreased by a factor of 10 between untreated and ART-treated PLWH; CD4-adjusted KS incidence decreased by ∼50%, with either non-nucleoside reverse transcriptase inhibitor- or PI-based ART. A single study measured a cumulative dose-/time-dependent effect of ART, which reported a relative risk reduction in only the cohort receiving boosted PI-based ART. Other studies defined ART categories by first-line therapy only.ConclusionsThe risk of incident KS was significantly reduced, regardless of ART class even after adjusting for CD4 count. The quality of evidence (ie, most studies categorizing users by first-line ART) does not permit KS risk reduction comparisons across ART types. Given the limited number and retrospective nature of these studies, prospective data are indicated.
| S-EPMC9415696 | biostudies-literature