Kaposi sarcoma herpesvirus viral load in bronchoalveolar lavage as a diagnostic marker for pulmonary Kaposi sarcoma.

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. 0 copies/106 cell equivalent; P = 0.0047). A BAL KSHV viral load cutoff of 526 copies/106 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.

Immune cell phenotype and function patterns across the life course in individuals from rural Uganda.

Background: To determine the pattern of immune cell subsets across the life span in rural sub-Saharan Africa (SSA), and to set a reference standard for cell subsets amongst Africans, we characterised the major immune cell subsets in peripheral blood including T cells, B cells, monocytes, NK cells, neutrophils and eosinophils, in individuals aged 3 to 89 years from Uganda. Methods: Immune phenotypes were measured using both conventional flow cytometry in 72 individuals, and full spectrum flow cytometry in 80 individuals. Epstein-Barr virus (EBV) IFN-γ T cell responses were quantified in 332 individuals using an ELISpot assay. Full blood counts of all study participants were also obtained. Results: The percentages of central memory (TCM) and senescent CD4+ and CD8+ T cell subsets, effector memory (TEM) CD8+ T cells and neutrophils increased with increasing age. On the other hand, the percentages of naïve T (TN) and B (BN) cells, atypical B cells (BA), total lymphocytes, eosinophils and basophils decreased with increasing age. There was no change in CD4+ or CD8+ T effector memory RA (TEMRA) cells, exhausted T cells, NK cells and monocytes with age. Higher eosinophil and basophil percentages were observed in males compared to females. T cell function as measured by IFN-γ responses to EBV increased with increasing age, peaking at 31-55 years. Conclusion: The percentages of cell subsets differ between individuals from SSA compared to those elsewhere, perhaps reflecting a different antigenic milieu. These results serve as a reference for normal values in this population.

Plasmodium falciparum Malaria Is Associated With Increased Kaposi Sarcoma-Associated Herpesvirus (KSHV) Seropositivity and Higher KSHV Antibody Breadth and Magnitude: Results of a Case-Control Study From Rural Uganda.

BACKGROUND: Previously, we showed that children with asymptomatic Plasmodium falciparum (Pf) malaria infection had higher Kaposi sarcoma-associated herpesvirus (KSHV) viral load, increased risk of KSHV seropositivity, and higher KSHV antibody levels. We hypothesize that clinical malaria has an even larger association with KSHV seropositivity. In the current study, we investigated the association between clinical malaria and KSHV seropositivity and antibody levels. METHODS: Between December 2020 and March 2022, sick children (aged 5-10 years) presenting at a clinic in Uganda were enrolled in a case-control study. Pf was detected using malaria rapid diagnostic tests (RDTs) and subsequently with quantitative real-time polymerase chain reaction (qPCR). Children with malaria were categorized into 2 groups: RDT+/PfPCR+ and RDT-/PfPCR+. RESULTS: The seropositivity of KSHV was 60% (47/78) among Pf-uninfected children, 79% (61/77) among children who were RDT-/PfPCR+ (odds ratio [OR], 2.41 [95% confidence interval {CI}, 1.15-5.02]), and 95% (141/149) in children who were RDT+/PfPCR+ (OR, 10.52 [95% CI, 4.17-26.58]; Ptrend < .001). Furthermore, RDT+/PfPCR+ children followed by RDT-/PfPCR+ children had higher KSHV IgG and IgM antibody levels and reacted to more KSHV antigens compared to uninfected children. CONCLUSIONS: Clinical malaria is associated with both increased KSHV seropositivity and antibody magnitude, suggesting that Pf is affecting KSHV immunity.

Epstein-Barr virus (EBV) antibody changes over time in a general population cohort in rural Uganda, 1992-2008.

BACKGROUND: Epstein-Barr virus (EBV) infection is ubiquitous and in sub-Saharan Africa, occurs early in life. In a population-based rural African cohort, we leveraged historical samples from the General Population Cohort (GPC) in Uganda to examine the epidemiology of infection with EBV over time, in the era of HIV. METHODS: We used 9024 serum samples collected from the GPC in 1992, 2000, 2008, from 7576 participants across the age range (0-99 years of age) and tested for anti-EBV immunoglobulin G (IgG) antibodies to EAd, VCA, and EBNA-1 using a multiplex bead-based assay. The related gammaherpesvirus, Kaposi's sarcoma-associated herpesvirus (KSHV) seropositivity was also determined by detection of anti-KSHV IgG antibodies to K8.1 or ORF73 measured by recombinant protein enzyme-linked immunosorbent assay. Data on sex, age, and HIV serostatus were also collected. EBV seropositivity was modeled with age (excluding those under one year, who may have had maternal antibodies), sex, HIV serostatus, and KSHV serostatus using generalized linear mixed effects models to produce beta estimates. RESULTS: More than 93% of children were EBV seropositive by one year of age. EBV seropositivity was significantly associated with KSHV seropositivity. Anti-EBNA-1 antibody levels decreased with increasing age and were lower on average in people living with HIV. In general, anti-EAd antibody levels increased with age, were higher in males and KSHV seropositive persons, but decreased over calendar time. Anti-VCA antibody levels increased with age and with calendar time and were higher in KSHV seropositive persons but lower in males. CONCLUSIONS: This is the first study to identify factors associated with EBV antibodies across the entire life-course in rural sub-Saharan Africa. Consistent with other studies, EBV was near ubiquitous in the population by age one year. Patterns of antibodies show changes by age, sex and calendar time, but no association with HIV was evident, suggesting no relationship between EBV sero-epidemiology and the spread of HIV in the population over time in Uganda.

Prevalence, Incidence, and Predictors of Kaposi Sarcoma-associated Herpesvirus Infection Among Young Men Who Have Sex with Men in the Southern United States.

Kaposi Sarcoma (KS) continues to cause substantial morbidity and mortality in populations at risk in the southern US. Utilizing biospecimens from the Houston site of the Young Men's Affiliate Project, 351 men who have sex with men had blood tested for Kaposi Sarcoma-associated herpesvirus (KSHV) IgG. Measuring seroprevalence, seroconversion between timepoints, and demographic and clinical correlates, KSHV prevalence was 36.7% and incidence was 8.9 per 100 person-years, prevalence and incidence were higher among Black individuals, people living with HIV, and those with a history of syphilis. Further research on KSHV risk may improve health disparities in KS diagnosis and outcomes.

Effects of Maternal HIV Infection on Early Kaposi Sarcoma-Associated Herpesvirus Seroconversion in a Kenyan Mother-Infant Cohort.

BACKGROUND: We identified whether maternal human immunodeficiency virus (HIV) infection during pregnancy affects transplacental transfer of Kaposi sarcoma-associated herpesvirus (KSHV)-specific antibodies and subsequent infant infection. METHODS: We followed pregnant Kenyan women through delivery and their infants until age 2 years. Children were classified as HIV-exposed uninfected (HEU) or HIV-unexposed uninfected (HUU) based on maternal HIV status. Maternal venous and cord blood at delivery and child venous blood every 6 months were tested for antibodies to 20 KSHV antigens by multiplex bead-based immunoassay. Multiple comparisons were adjusted using false discovery rate (FDR). RESULTS: Maternal HIV infection was significantly associated with decreased transplacental transfer of antibodies against all KSHV antigens and lower cord blood levels for 8 antigens at FDR P < .10. Neither birth to 6-month antibody level changes nor 6-month levels differed in HEU and HUU, except for ORF50. By age 24 months, 74% of children KSHV seroconverted but HEU and HUU did not differ in time to seroconversion nor 2-year seropositivity after adjustment for child malaria infection. CONCLUSIONS: Maternal HIV infection reduced a child's initial KSHV antibody levels but did not affect age of infection. Regardless of HIV exposure in utero, KSHV seroconversion in Kenyan children occurred early; associated factors must be identified.

Comparison of Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus viral load in peripheral blood mononuclear cells and oral fluids of HIV-negative individuals aged 3-89 years from Uganda.

We previously found that age, sex and malaria were associated with KSHV in individuals from Uganda. In this study, we have evaluated these same factors in relation to EBV in the same specimens. Overall, 74% (oral fluids) and 46% (PBMCs) had detectable EBV. This was significantly higher than observed for KSHV (24% oral fluids and 11% PBMCs). Individuals with EBV in PBMCs were more likely to have KSHV in PBMCs (P = 0.011). The peak age for detection of EBV in oral fluids was 3-5 years while that of KSHV was 6-12 years. In PBMCs, there was a bimodal peak age for detection of EBV (at 3-5 years and 66 + years) while for KSHV there was a single peak at 3-5 years. Individuals with malaria had higher levels of EBV in PBMCs compared to malaria-negative individuals (P = 0.002). In summary, our results show that younger age and malaria are associated with higher levels of EBV and KSHV in PBMCs suggesting malaria impacts immunity to both gamma-herpesviruses.

High Seroprevalence of Kaposi Sarcoma-Associated Herpesvirus in Men Who Have Sex With Men With HIV in the Southern United States.

Background: Disparities in mortality in human immunodeficiency virus (HIV)-associated Kaposi sarcoma have been described, particularly in Black men in the southern United States. It is unclear if there are racial/ethnic differences in the seroprevalence of Kaposi sarcoma-associated herpesvirus (KSHV) that may be contributing. Methods: This is a cross-sectional study of men who have sex with men (MSM) and transgender women with HIV. Participants were recruited from an outpatient HIV clinic in Dallas, Texas, for a 1-time study visit and were excluded from analysis if they had any history of KSHV disease. Plasma was tested for antibodies to KSHV K8.1 or ORF73 antigens, and KSHV DNA was measured in oral fluids and blood by polymerase chain reaction. KSHV seroprevalence and viral shedding in blood and oral fluids were calculated. Additionally, independent risk factors for KSHV seropositivity were assessed by multivariable logistic regression analysis. Results: Two hundred five participants were included in our analysis. Overall, KSHV seroprevalence was high (68%) with no significant difference between racial/ethnic groups. Among seropositive participants, KSHV DNA was detected in 28.6% of oral fluids and 10.9% of peripheral blood specimens, respectively. The factors most strongly associated with KSHV seropositivity were oral-anal sex (odds ratio [OR], 3.02), oral-penile sex (OR, 4.63), and methamphetamine use (OR, 4.67). Conclusions: High local seroprevalence of KSHV is likely a key driver of the high burden of KSHV-associated diseases regionally, though it does not explain the observed disparities in KSHV-associated disease prevalence among racial/ethnic groups. Our findings support that KSHV is primarily transmitted via exchange of oral fluids.

Comparison of Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus viral load in peripheral blood mononuclear cells and oral fluids of HIV-negative individuals aged 3 to 89 years from Uganda.

We previously found that age, sex, and malaria were associated with KSHV viral load in individuals from Uganda. In this study, we have evaluated factors associated with presence of EBV DNA in blood and oral fluids among the same individuals, using the same biological samples. Overall, 74% of oral fluids samples and 46% of PBMCs had detectable EBV, compared to 24% and 11% for KSHV respectively Individuals with EBV in PBMCs were more likely to have KSHV in PBMCs (P=0.016). The peak age for detection of EBV in oral fluids was 3-5 years while that of KSHV was 6-12 years. In PBMCs, the peak age for detection of EBV was 66+ years and KSHV was 3-5 years. Individuals with malaria had higher levels of EBV in PBMCs compared to malaria-negative individuals (P=0.002). In summary, our results show that younger age and malaria are associated with higher levels of EBV and KSHV in PBMCs suggesting malaria impacts immunity to EBV and KSHV.

Immunization of Mice with Virus-Like Vesicles of Kaposi Sarcoma-Associated Herpesvirus Reveals a Role for Antibodies Targeting ORF4 in Activating Complement-Mediated Neutralization.

Infection by Kaposi sarcoma-associated herpesvirus (KSHV) can cause severe consequences, such as cancers and lymphoproliferative diseases. Whole inactivated viruses (WIV) with chemically destroyed genetic materials have been used as antigens in several licensed vaccines. During KSHV productive replication, virus-like vesicles (VLVs) that lack capsids and viral genomes are generated along with virions. Here, we investigated the immunogenicity of KSHV VLVs produced from a viral mutant that was defective in capsid formation and DNA packaging. Mice immunized with adjuvanted VLVs generated KSHV-specific T cell and antibody responses. Neutralization of KSHV infection by the VLV immune serum was low but was markedly enhanced in the presence of the complement system. Complement-enhanced neutralization and complement deposition on KSHV-infected cells was dependent on antibodies targeting viral open reading frame 4 (ORF4). However, limited complement-mediated enhancement was detected in the sera of a small cohort of KSHV-infected humans which contained few neutralizing antibodies. Therefore, vaccination that induces antibody effector functions can potentially improve infection-induced humoral immunity. Overall, our study highlights a potential benefit of engaging complement-mediated antibody functions in future KSHV vaccine development. IMPORTANCE KSHV is a virus that can lead to cancer after infection. A vaccine that prevents KSHV infection or transmission would be helpful in preventing the development of these cancers. We investigated KSHV VLV as an immunogen for vaccination. We determined that antibodies targeting the viral protein ORF4 induced by VLV immunization could engage the complement system and neutralize viral infection. However, ORF4-specific antibodies were seldom detected in the sera of KSHV-infected humans. Moreover, these human sera did not potently trigger complement-mediated neutralization, indicating an improvement that immunization can confer. Our study suggests a new antibody-mediated mechanism to control KSHV infection and underscores the benefit of activating the complement system in a future KSHV vaccine.

A novel approach for characterization of KSHV-associated multicentric Castleman disease from effusions.

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.

KSHV (HHV8) vaccine: promises and potential pitfalls for a new anti-cancer vaccine.

Seven viruses cause at least 15% of the total cancer burden. Viral cancers have been described as the "low-hanging fruit" that can be potentially prevented or treated by new vaccines that would alter the course of global human cancer. Kaposi sarcoma herpesvirus (KSHV or HHV8) is the sole cause of Kaposi sarcoma, which primarily afflicts resource-poor and socially marginalized populations. This review summarizes a recent NIH-sponsored workshop's findings on the epidemiology and biology of KSHV as an overlooked but potentially vaccine-preventable infection. The unique epidemiology of this virus provides opportunities to prevent its cancers if an effective, inexpensive, and well-tolerated vaccine can be developed and delivered.

Characteristics of patients admitted to the ICU with Kaposi sarcoma herpesvirus-associated diseases.

OBJECTIVE: There 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. METHODS: A 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. RESULTS: Forty-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. CONCLUSION: The 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.

Adaptive immune responses to Kaposi's sarcoma-associated herpesvirus.

Kaposi's sarcoma-associated herpesvirus (KSHV) is a gammaherpesvirus that causes Kaposi's sarcoma (KS), primary effusion lymphoma, multicentric Castleman's disease and KSHV-induced cytokine syndrome. KSHV established lifelong infection and has evolved numerous ways in which to evade adaptive immune responses. Most KSHV infections are asymptomatic but when disease occurs it does so in the context of immune suppression especially HIV infection. It is important therefore to study immune responses to KSHV in order to understand KSHV-related disease pathogenesis.

Systematic analysis of Kaposi's sarcoma (KS)-associated herpesvirus genomes from a KS case-control study in Cameroon: Evidence of dual infections but no association between viral sequence variation and KS risk.

In sub-Saharan Africa, Kaposi's sarcoma-associated herpesvirus (KSHV) is endemic, and Kaposi's sarcoma (KS) is a significant public health problem. Until recently, KSHV genotype analysis was performed using variable gene regions, representing a small fraction of the genome, and thus the contribution of sequence variation to viral transmission or pathogenesis are understudied. We performed near full-length KSHV genome sequence analysis on samples from 43 individuals selected from a large Cameroonian KS case-control study. KSHV genomes were obtained from 21 KS patients and 22 control participants. Phylogenetic analysis of the K1 region indicated the majority of sequences were A5 or B1 subtypes and all three K15 alleles were represented. Unique polymorphisms in the KSHV genome were observed including large gene deletions. We found evidence of multiple distinct KSHV genotypes in three individuals. Additionally, our analyses indicate that recombination is prevalent suggesting that multiple KSHV infections may not be uncommon overall. Most importantly, a detailed analysis of KSHV genomes from KS patients and control participants did not find a correlation between viral sequence variations and disease. Our study is the first to systematically compare near full-length KSHV genome sequences between KS cases and controls in the same endemic region to identify possible sequence variations associated with disease risk.

Oral Shedding of an Oncogenic Virus Alters the Oral Microbiome in HIV+ Patients.

Kaposi's Sarcoma (KS) caused by Kaposi's sarcoma-associated herpesvirus (KSHV) continues to be the most common AIDS-associated tumor. Involvement of the oral cavity represents one of the most common clinical manifestations of this tumor. Numerous types of cancer are associated with the alterations of in components of the microbiome. However, little is known about how KSHV coinfection affects the oral microbiome in HIV+ patients, especially in a "pre-cancer" niche. Using 16S rRNA pyrosequencing, we found that oral shedding of KSHV correlated with altered oral microbiome signatures in HIV+ patients, including a reduction in the microbiota diversity, changing the relative composition of specific phyla and species, and regulating microbial functions. Furthermore, we found that Streptococcus sp., one of the most increased species in the oral cavity of HIV+/KSHV+ patients, induced KSHV lytic reactivation in primary oral cells. Together, these data indicate that oral shedding of KSHV may manipulate the oral microbiome to promote viral pathogenesis and tumorigenesis especially in immunocompromised patients.

Environmental determinants of Kaposi's sarcoma-associated herpesvirus (KSHV) transmission in rural Uganda (ENDKU study): Contributions to research on KSHV infection and reactivation in African children; A longitudinal cohort study.

BACKGROUND: The Environmental Determinants of KSHV transmission in rural Uganda (ENDKU) study began enrollment in February 2020 with the purpose of defining the relationship between malaria, primarily caused by Plasmodium falciparum in sub-Saharan Africa, and KSHV susceptibility and reactivation. Uganda is an ideal study site, because both malaria and KSHV are endemic and widespread, even among young children. METHODS: ENDKU is a longitudinal cohort study of infants enrolled at six months of age and followed until three years of age. The main study, and one smaller sub-study, is nested within the General Population Cohort (GPC), a long-standing population cohort in rural Uganda. The ENDKU study was created to test the hypothesis that P. falciparum malaria increases an infant's susceptibility to KSHV infection. A sub-study to evaluate the effects of P. falciparum on KSHV reactivation involves an additional cohort of 5-10-year-old children with and without acute malaria who presented to the GPC study clinic. For each study, participants provided demographic and behavioral data through administered questionnaires and blood and saliva samples. RESULTS: Despite barriers presented by the COVID-19 pandemic, the study team was able to leverage the long-standing relationship of the UK Medical Research Council and the Uganda Virus Research Institute (MRC/UVRI) with the community, a strong commitment to research, and a multi-disciplinary team of experts to successfully implement the ENDKU study. CONCLUSION: The results of this multi-pronged approach will answer important questions about the etiology and transmission of KSHV in sub-Saharan Africa and the data and samples collected will be an important future resource for scientific research in the region.

HOPE in action: A prospective multicenter pilot study of liver transplantation from donors with HIV to recipients with HIV.

Liver transplantation (LT) from donors-with-HIV to recipients-with-HIV (HIV D+/R+) is permitted under the HOPE Act. There are only three international single-case reports of HIV D+/R+ LT, each with limited follow-up. We performed a prospective multicenter pilot study comparing HIV D+/R+ to donors-without-HIV to recipients-with-HIV (HIV D-/R+) LT. We quantified patient survival, graft survival, rejection, serious adverse events (SAEs), human immunodeficiency virus (HIV) breakthrough, infections, and malignancies, using Cox and negative binomial regression with inverse probability of treatment weighting. Between March 2016-July 2019, there were 45 LTs (8 simultaneous liver-kidney) at 9 centers: 24 HIV D+/R+, 21 HIV D-/R+ (10 D- were false-positive). The median follow-up time was 23 months. Median recipient CD4 was 287 cells/µL with 100% on antiretroviral therapy; 56% were hepatitis C virus (HCV)-seropositive, 13% HCV-viremic. Weighted 1-year survival was 83.3% versus 100.0% in D+ versus D- groups (p = .04). There were no differences in one-year graft survival (96.0% vs. 100.0%), rejection (10.8% vs. 18.2%), HIV breakthrough (8% vs. 10%), or SAEs (all p > .05). HIV D+/R+ had more opportunistic infections, infectious hospitalizations, and cancer. In this multicenter pilot study of HIV D+/R+ LT, patient and graft survival were better than historical cohorts, however, a potential increase in infections and cancer merits further investigation.

Safety, Activity, and Long-term Outcomes of Pomalidomide in the Treatment of Kaposi Sarcoma among Individuals with or without HIV Infection.

PURPOSE: Kaposi sarcoma (KS) is caused by Kaposi sarcoma herpesvirus (KSHV), also known as human herpesvirus 8 (HHV-8). KS, which develops most frequently among people with HIV, is generally treated with chemotherapy, but these drugs have acute and cumulative toxicities. We previously described initial results of a trial of pomalidomide, an oral immunomodulatory derivative of thalidomide, in patients with KS. Here, we present results on the full cohort and survival outcomes. PATIENTS AND METHODS: Participants with KS with or without HIV were treated with pomalidomide 5 mg once daily for 21 days per 28-day cycle with aspirin 81 mg daily for thromboprophylaxis. Participants with HIV received antiretroviral therapy. Response was defined by modified version of the AIDS Clinical Trial Group KS criteria. We evaluated tumor responses (including participants who had a second course), adverse events, progression-free survival (PFS), and long-term outcomes. RESULTS: Twenty-eight participants were enrolled. Eighteen (64%) were HIV positive and 21 (75%) had advanced (T1) disease. The overall response rate was 71%: 95% confidence interval (CI) 51%-87%. Twelve of 18 HIV-positive (67%; 95% CI, 41-87%) and 8 of 10 HIV-negative participants (80%; 95% CI, 44%-97%) had a response. Two of 4 participants who received a second course of pomalidomide had a partial response. The median PFS was 10.2 months (95% CI: 7.6-15.7 months). Grade 3 neutropenia was noted among 50% of participants. In the follow-up period, 3 participants with HIV had other KSHV-associated diseases. CONCLUSIONS: Pomalidomide is a safe and active chemotherapy-sparing agent for the treatment of KS among individuals with or without HIV.