A prospective study of clinical outcomes of HIV-associated and HIV-negative Kaposi sarcoma in Uganda

Abstract

Objective:Improved understanding of the effect of HIV infection on Kaposi sarcoma (KS) presentation and outcomes will guide development of more effective KS staging and therapeutic approaches. We enrolled a prospective cohort of epidemic (HIV-positive; HIV+KS) and endemic (HIV-negative; HIV−KS) KS patients in Uganda to identify factors associated with survival and response.Methods:Adults with newly diagnosed KS presenting for care at the Uganda Cancer Institute (UCI) in Kampala, Uganda, between October 2012 and December 2019 were evaluated. Participants received chemotherapy per standard guidelines and were followed over 1 year to assess overall survival (OS) and treatment response.Results:Two hundred participants were enrolled; 166 (83%) had HIV+KS, and 176 (88%) were poor-risk tumor (T1) stage. One-year OS was 64% (95% confidence interval [CI] 57–71%), with the hazard of death nearly threefold higher for HIV+KS (hazard ratio [HR] = 2.93; P = 0.023). Among HIV+KS, abnormal chest X-ray (HR = 2.81; P = 0.007), lower CD4+ T-cell count (HR = 0.68 per 100 cells/μl; P = 0.027), higher HIV viral load (HR = 2.22 per log10 copies/ml; P = 0.026), and higher plasma Kaposi sarcoma-associated herpesvirus (KSHV) copy number (HR = 1.79 per log10 copies/ml; P = 0.028) were associated with increased mortality. Among HIV−KS, factors associated with mortality included Karnofsky score <70 (HR = 9.17; P = 0.045), abnormal chest X-ray (HR = 8.41; P = 0.025), and higher plasma KSHV copy number (HR = 6.21 per log10 copies/ml; P < 0.001).Conclusions:Although survival rates were better for HIV−KS than HIV+KS, the high mortality rate seen in both groups underscores the urgent need to identify new staging and therapeutic approaches. Factors associated with mortality, including high plasma KSHV, may serve as important targets of therapy.

The signature of a T-cell response to KSHV persists across space and time in individuals with epidemic and endemic KS from Uganda

“…We used a multi-omic approach to study the T-cells infiltrating Kaposi sarcoma tumors from HIV-seropositive and HIV-seronegative adults presenting to the Uganda Cancer Institute (Phipps et al, 2023). We compiled a total of 363 T-cell receptor β chain ( TRB ) repertoires from KS tumor biopsies and biopsies of uninvolved axillary skin from 106 HIV + and 38 HIV − adults at study entry.…”

“…Adults 18 years or older with histologically confirmed Kaposi sarcoma who were naïve to ART and had received no prior chemotherapy were enrolled between October 2012 and May 2021 on a prospective cohort study (termed “HIPPOS”) at the Uganda Cancer Institute (UCI) in Kampala, Uganda, as previously described (Phipps et al, 2023). Participants completed an enrollment visit and up to 10 follow-up visits over ∼1 year.…”

“…For comparison we also analyzed AIRR-Seq data from tumor biopsies from 49 children and adolescents with Burkitt lymphoma (BL) from Uganda and Ghana (Lombardo et al, 2017). The 106 individuals with epidemic KS had significantly higher plasma KSHV titers (mean of 36,091 copies/μL vs 8,428 copies/μL) and significantly lower CD4 + T-cell counts (mean of 226 cells/mL vs 808 cells/mL) than the 38 individuals with endemic KS at study entry (Supplementary Figure 2A; 2B) (Phipps et al, 2023). We used the generalized entropy measure, Rényi entropy, calculated at different values of the parameter α (alpha), to assess the diversity of the TCR repertoires at the time of study enrollment across the different groups.…”

Predictive Value of Serum Biomarkers for Response of Limited-Stage AIDS-Associated Kaposi Sarcoma to Antiretroviral Therapy With or Without Concomitant Chemotherapy in Resource-Limited Settings

“…In addition, the increase in serum CRP levels in acute-phase responses can be as great as 10,000-fold, 27,29 a much greater relative increase than is observed in serum levels of inflammation-associated cytokines, which rarely increase by more than 100-fold. Although KSHV activity is likely the proximal cause of the elevated levels of both inflammatory cytokines and CRP, and elevated KSHV viral loads have been associated with prognosis in patients with KS, 30,31 most clinical laboratories can quantify CRP, whereas quantification of KSHV and cytokine levels is not widely available in settings where the burden of KS is highest and access to chemotherapy is limited. Thus, quantification of CRP before treatment initiation may be useful in identifying patients, particularly those in resourcelimited settings, who may benefit from the early addition of chemotherapy to ART.…”

Evaluation of human herpesvirus‐8 viremia and antibody positivity in patients with HIV infection with human herpesvirus‐8‐related diseases

“…HHV-8 viremia, as observed in MCD and KICS, is involved in systemic inflammation and reportedly associated with mortality in patients with KS. 4,5 In this study, we aimed to investigate the presence of plasma HHV-8-DNA and anti-HHV-8 antibodies in patients infected with HIV, explore their correlation with plasma IL-6 levels and various clinical manifestations, and identify factors associated with elevated plasma HHV-8-DNA levels. Understanding these relationships is essential for elucidating the role of HHV-8 in these diseases and improving patient care.…”