AIDS-associated Kaposi's Sarcoma Research Articles

People living with HIV co-infected with the Kaposi Sarcoma-associated Herpes Virus have a distinct HIV Tat profile and higher rates of antiretroviral virologic failure, more evident among those with Kaposi's sarcoma.

Kaposi sarcoma (KS) is a neoplasm of vascular origin that promotes angiogenesis and the growth of endothelial cells triggered by the Kaposi Sarcoma-associated Herpes Virus (KSHV). When associated with HIV, KSHV becomes more aggressive and rapidly evolves. The HIV-1 TAT protein can be essential in developing AIDS-associated KS by promoting angiogenesis and increasing KSHV replication. Therefore, we evaluated the genetic profile of the first exon of tat gene among groups of people living with HIV (PLHIV) with (case group, n = 36) or without KS, this later with (positive control group, n = 46) and without KSHV infection (negative control group, n = 24); all individuals under antiretroviral therapy. The genetic diversity, the DN/DS ratio, and the genetic entropy of the first exon of tat were higher in the case group, followed by the positive control group, which was higher than the negative control group. The number of tat codons under positive selection was seven in the case group, six in the positive control group, and one in the negative control group. The prevalence of HIV viral loads below the detection limit was equal in the case and positive control groups, which were lower than in the negative control group. The mean CD4+ T cell counts were higher in the negative control group, followed by the positive control group, and followed by the case group. These results emphasize the negative influence of KSHV in antiretroviral treatment, as well as the HIV-specific TAT profile among PLHIV who developed KS.

Disseminated AIDS-associated Kaposi sarcoma without cutaneous involvement: a case report and review of literature.

Disseminated AIDS-associated Kaposi sarcoma (KS) without cutaneous lesions is rare and can present in varying ways. Diagnosis is even more challenging now when incidence of KS is on the decline. A high index of suspicion is required for early diagnosis and treatment. Therefore, the medical literature should be made aware of any manifestations of KS that can occur without the typical cutaneous lesions. A 23-year-old presented with worsening cervical lymphadenopathy, recurrent cough and bilateral leg swelling of a month duration. Examination revealed features of pericardial effusion, pulmonary fibrosis, necrotizing cervical lymphadenopathy and the presence of pityriasis rotunda at the periumbilical region. Patient was diagnosed human immunodeficiency virus (HIV) positive 6months before she presented and was placed on antiretroviral therapy. Histology confirmed AIDS-associated KS. However, patient died before commencement of chemotherapy. The clinical course of disseminated AIDS-associated KS without cutaneous lesions can be atypical and aggressive. It is important to include KS inthe differential diagnosis of cases with atypical or persistence/recurrence of clinical symptoms in spite of treatment especially in HIV patients.

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.

Guidelines for limited-stage human immunodeficiency virus-associated Kaposi sarcoma (AIDS/KS) recommend antiretroviral therapy (ART) as initial treatment. However, many such individuals show worsening KS and require additional chemotherapy. Methods to identify such patients are lacking. We studied whether serum levels of biomarkers associated with angiogenesis, systemic inflammation, and immune activation, which are elevated in HIV-infected individuals and implicated in the development of KS, could prospectively identify individuals with limited-stage AIDS-KS who would benefit from chemotherapy administered with ART. Serum specimens were obtained from participants in a randomized trial evaluating the value of adding oral etoposide chemotherapy to ART in treatment-naïve people with limited-stage AIDS-KS in resource-limited settings. Serum biomarkers of inflammation (C-reactive protein [CRP], interleukin [IL]-6, IL-8, IL-10, granulocyte colony stimulating factor, soluble tumor necrosis factor receptor-2), immune system activation (soluble IL-2 receptor alfa, C-X-C motif chemokine ligand 10/interferon gamma-induced protein 10, C-C motif ligand 2/monocyte chemoattractant protein 1), and angiogenesis (vascular endothelial growth factor, matrix metalloproteinase-2, -9, endoglin, hepatocyte growth factor) were measured at entry to determine whether baseline levels are associated with KS response. On-treatment changes in biomarker levels were determined to assess how etoposide modifies the effects of ART. Pretreatment CRP and IL-10 were higher in those whose KS progressed, and lowest in those who had good clinical responses. Pretreatment CRP, IL-6, and soluble tumor necrosis factor receptor-2 showed significant associations with KS progression at the week-48 primary endpoint. Immediate etoposide led to lower inflammation biomarker levels compared with ART alone. Early KS progression was associated with elevated pretreatment levels of inflammation-associated biomarkers and increasing levels post-treatment. Quantifying serum biomarkers, especially CRP, may help identify persons with AIDS-KS who would benefit from early introduction of chemotherapy in addition to ART.

Mathematical Model for Coinfection of HIV/AIDS and Kaposi’s Sarcoma with Treatment

HIV destroys T-cells in order to target the body's defence mechanism. Without treatment HIV infection advances in stages causing destruction and reduction in T-cells thus, rendering the body incapable of fighting other infections such as respiratory infections, sexually transmitted diseases and some cancers. Kaposi’s sarcoma is the cancer that allows a tumour to grow in an HIV patient and its presence in a patient is an indication that HIV has fully developed into AIDS in the patient. Research has indicated that AIDS-associated Kaposi Sarcoma was on the rise in sub-Saharan Africa until the introduction of Antiretroviral Therapy (ART). The Kenyan community has struggled in the past decade to combat the spread of HIV/AIDS and successes have been recorded in many areas. However, Kaposi Sarcoma, an opportunistic infection, has continued to rise steadily through the years. In this study, a simple model for the coinfection of HIV/AIDS and KS is developed and studied. The model solution is explored for positivity and boundedness while the DFE point is determined for stability where it was verified that the infection-free equilibrium <I>E</I>₀ is locally asymptotically stable when <img width="40" height="10" src="http://article.sciencepublishinggroup.com/journal/247/2471233/image001.png" />. The NGM is used to derive the basic reproduction number of the model. By providing treatment to the HIV and the co-infected population immune system is strengthened and thus progression rate to AIDS is reduced.

Evaluation of four chemotherapy regimens for treatment of advanced AIDS-associated Kaposi sarcoma in Kenya: a cost-effectiveness analysis

The most effective treatment for advanced AIDS-associated Kaposi sarcoma is paclitaxel or pegylated liposomal doxorubicin (PLD); neither is routinely used in sub-Saharan Africa due to limited availability and high cost. We examined the clinical impact, costs, and cost-effectiveness of paclitaxel or PLD in Kenya, compared with etoposide or bleomycin-vincristine. In this study, we use the Cost-Effectiveness of Preventing AIDS Complications (CEPAC)-International Model to project clinical outcomes and costs among people living with HIV and advanced Kaposi sarcoma on antiretroviral therapy. We compared four different treatment strategies: etoposide, bleomycin-vincristine, paclitaxel, or PLD. We derived cohort characteristics and costs from the Kenyan Academic Model for Providing Access to Healthcare network, and adverse events, efficacy, and mortality from clinical trials. We projected model outcomes over a lifetime and included life expectancy, per-person lifetime costs, and incremental cost-effectiveness ratios (ICERs). We conducted budget impact analysis for 5-year total costs and did deterministic and probabilistic sensitivity analyses to evaluate the effect of uncertainty in input parameters. We found that paclitaxel would be more effective than bleomycin-vincristine and would increase life expectancy by 4·2 years per person. PLD would further increase life expectancy by 0·6 years per person. Paclitaxel would be the most cost-effective strategy (ICER US$380 per year-of-life-saved compared with bleomycin-vincristine) and would remain cost-effective across a range of scenarios. PLD would be cost-effective compared with paclitaxel if its price were reduced to $100 per cycle (base case $180 per cycle). Implementing paclitaxel instead of bleomycin-vincristine would save approximately 6400 life-years and would increase the overall 5-year Kenyan health-care costs by $3·7 million; increased costs would be primarily related to ongoing HIV care given improved survival. Paclitaxel would substantially increase life expectancy and be cost-effective compared with bleomycin-vincristine for advanced AIDS-associated Kaposi sarcoma in Kenya and should be the standard of care. PLD would further improve survival and be cost-effective with a 44% price reduction. US National Institutes of Health and Massachusetts General Hospital. For the Swahili translation of the abstract see Supplementary Materials section.

STAT and Janus kinase targeting by human herpesvirus 8 interferon regulatory factor in the suppression of type-I interferon signaling

Human herpesvirus 8 (HHV-8), also known as Kaposi’s sarcoma (KS)-associated herpesvirus, is involved etiologically in AIDS-associated KS, primary effusion lymphoma (PEL), and multicentric Castleman’s disease, in which both viral latent and lytic functions are important. HHV-8 encodes four viral interferon regulatory factors (vIRFs) that are believed to contribute to viral latency (in PEL cells, at least) and/or to productive replication via suppression of cellular antiviral and stress signaling. Here, we identify vIRF-1 interactions with signal transducer and activator of transcription (STAT) factors 1 and 2, interferon (IFN)-stimulated gene factor 3 (ISGF3) cofactor IRF9, and associated signal transducing Janus kinases JAK1 and TYK2. In naturally infected PEL cells and in iSLK epithelial cells infected experimentally with genetically engineered HHV-8, vIRF-1 depletion or ablation, respectively, led to increased levels of active (phosphorylated) STAT1 and STAT2 in IFNβ-treated, and untreated, cells during lytic replication and to associated cellular-gene induction. In transfected 293T cells, used for mechanistic studies, suppression by vIRF-1 of IFNβ-induced phospho-STAT1 (pSTAT1) was found to be highly dependent on STAT2, indicating vIRF-1-mediated inhibition and/or dissociation of ISGF3-complexing, resulting in susceptibility of pSTAT1 to inactivating dephosphorylation. Indeed, coprecipitation experiments involving targeted precipitation of ISGF3 components identified suppression of mutual interactions by vIRF-1. In contrast, suppression of IFNβ-induced pSTAT2 was effected by regulation of STAT2 activation, likely via detected inhibition of TYK2 and its interactions with STAT2 and IFN type-I receptor (IFNAR). Our identified vIRF-1 interactions with IFN-signaling mediators STATs 1 and 2, co-interacting ISGF3 component IRF9, and STAT-activating TYK2 and the suppression of IFN signaling via ISGF3, TYK2-STAT2 and TYK2-IFNAR disruption and TYK2 inhibition represent novel mechanisms of vIRF function and HHV-8 evasion from host-cell defenses.

Kaposi Sarcoma of the Larynx: A Systematic Review.

Kaposi sarcoma (KS) of the larynx is a rare disease with few cases reported in the literature. This study aims to provide a comprehensive review of laryngeal KS, including patient characteristics, treatment, and clinical outcomes. PubMed, CINAHL, SCOPUS, and Cochrane Library. A systematic review of the published English literature was conducted. An electronic search and bibliographic examination of articles pertaining to laryngeal KS were performed. Demographic data, tumor site, treatment strategies, follow-up, and outcome were analyzed. A total 77 cases from 50 articles were included in the review. The mean age was 47.6 years (range, 8-81). There was an 8.6:1 male:female ratio. The most common presenting symptoms were dyspnea (n = 35) and hoarseness (n = 25). Laryngeal KS arose most frequently in the supraglottic region (n = 16). Chemotherapy alone (n = 27) was the most common treatment modality in patients with AIDS-associated KS, and surgical excision alone (n = 7) was most common in patients with other subtypes of KS (eg, classic, transplant associated). Average follow-up was 20.4 months (range, 0.75-120). Most patients with AIDS-associated KS died of other causes (n = 25), but most patients with other subtypes of KS were alive with no evidence of disease at follow-up (n = 13). This review contains the largest pool of laryngeal KS cases to date. Long-term outcomes were generally unfavorable, often due to advanced HIV disease at the time of diagnosis.

The Torque Teno Virus Titer in Saliva Reflects the Level of Circulating CD4+ T Lymphocytes and HIV in Individuals Undergoing Antiretroviral Maintenance Therapy.

IntroductionTorque teno virus (TTV) is a non-pathogenic virus present in body fluids. Its titer in the circulation increases in association with immune suppression, such as in HIV-infected individuals. We evaluated if the TTV titer in saliva from HIV-positive individuals undergoing antiretroviral therapy (ART) was related to the circulating CD4+ T lymphocyte concentration and the HIV titer.MethodsSaliva was collected from 276 asymptomatic individuals undergoing ART, and an additional 48 individuals positive for AIDS-associated Kaposi's Sarcoma (AIDS-KS). The salivary TTV titer was measured by gene amplification analysis. The circulating CD4+ T lymphocyte and HIV levels were obtained by chart review.ResultsTTV was detectable in saliva from 80% of the asymptomatic subjects and 87% of those with AIDS-KS. In the asymptomatic group the median log10 TTV titer/ml was 3.3 in 200 males vs. 2.4 in 76 females (p < 0.0001). TTV titer/ml was 3.7 when HIV was acquired by intravenous drug usage, 3.2 when by sexual acquisition and 2.4 when blood transfusion acquired. The salivary TTV titer was inversely correlated with the circulating CD4+ T lymphocyte level (p < 0.0001) and positively correlated with the circulating HIV concentration (p = 0.0005). The median salivary TTV titer and circulating HIV titer were higher, and the CD4+ count was lower, in individuals positive for AIDS-KS than in the asymptomatic subjects (p < 0.0001).ConclusionThe TTV titer in saliva is a potential biomarker for monitoring immune status in individuals undergoing ART.

A UNIQUE PRESENTATION OF PULMONARY KAPOSI SARCOMA IN A YOUNG PATIENT WITH CONCOMITANT CMV

TOPIC: Chest Infections TYPE: Medical Student/Resident Case Reports INTRODUCTION: Kaposi sarcoma (KS) is an AIDS-defining illness characterized by low-grade vascular tumors thought to be caused by HHV-8. Commonly described features include raised purplish skin nodules millimeters to centimeters in size on the face, groin, and lower extremities (1). Less discussed are the visceral manifestations and the co-infections which may contribute to the presentation. Our case demonstrates a young male with pulmonary KS confirmed by imaging and bronchoscopy with biopsy found to have co-infection with CMV. CASE PRESENTATION: A 29-year-old male with AIDS-related cutaneous Kaposi sarcoma (diagnosed 11/2020) presented with dyspnea, cough, hemoptysis, and lower extremity edema in 2/2021. On arrival, vitals were stable with SpO2 98% on room air. Admission labs revealed CD4 of 17, HIV viral load <30, WBC 7.4 with 1% atypical lymphocytes, AST/ALT 101/84, and negative testing for SARS-CoV-2 and influenza A/B. Chest X-ray on admission showed patchy bilateral airspace disease. CTA chest showed bilateral peribronchovascular flame-shaped ground glass opacities, bilateral pulmonary nodules, mediastinal and axillary lymphadenopathy, and moderate bilateral pleural effusions. Right thoracentesis was performed with removal of 900mL of serosanguinous fluid exudative by Light's criteria. Subsequent diagnostic bronchoscopy showed areas of thickened erythematous mucosa with predominance in the bilateral upper lobes. Bronchoalveolar lavage (BAL) revealed CMV level of 224 IU/mL without additional infectious agents. Transbronchial and endobronchial biopsy revealed neoplastic cells positive for CD31 and HHV-8, confirming pulmonary parenchymal and endobronchial KS. Patient continued with HAART and was started on liposomal doxorubicin. DISCUSSION: This case describes a young male with AIDS and cutaneous KS who presented with productive cough, dyspnea, and hemoptysis found to have pulmonary KS. An interesting aspect of this case is the possible contribution of CMV co-infection. In addition to BAL findings, imaging was consistent with aspects of both KS and CMV including flame shaped GGOs and pulmonary nodules, respectively (2,3). Also demonstrated were labs consistent with CMV, including atypical lymphocytes and moderately elevated AST/ALT (6). Interestingly, there are publications from as early as 1980 suggesting that CMV may contribute to the development of KS by working synergistically with HHV-8 (4,5). A 2009 study even went on to postulate that a particular CMV locus can activate the full KS-associated herpesvirus lytic replication cycle (7). CONCLUSIONS: Our case presents a patient with KS and CMV co-infection. CMV may directly or indirectly influence the presentation of respiratory illness in co-infected patients. Though some work has been done already, future studies should work to further elucidate the exact association between KS and CMV in AIDS patients. REFERENCE #1: Reference #1: Aboulafia D.M. The epidemiologic, pathologic, and clinical features of AIDS-associated pulmonary Kaposi's sarcoma. Chest. 2000;117(4):1128–1145.Reference #2: Restrepo C et al. Imaging manifestations of Kaposi sarcoma. Radiographics. 2006;99(4).Reference #3: McGuinness G et al. Cytomegalovirus pneumonitis: spectrum of parenchymal CT findings with pathologic correlation in 21 AIDS patients. Radiology. 1994;192(2). REFERENCE #2: Reference #4: Giraldo G, Beth E, Huang E. Kaposi's sarcoma and its relationship to cytomegalovirus (CMNV). III. CMV DNA and CMV early antigens in Kaposi's sarcoma. Int J Cancer. 1980;26(1).Reference #5: Goldman, J.M., Epstein M.A. Vaccine intervention against virus-induced tumors. Palgrave Macmillan, London;c1986. 93-103p.Reference #6: Goncalves C et al. Cytomegalovirus acute infection with pulmonary involvement in an immunocompetent patient. ID Cases. 2018;14. REFERENCE #3: Reference #7: Wells R, Stensland L, Vieira J. The human cytomegalovirus UL112-113 locus can activate the full kaposi's sarcoma-associated herpesvirus lytic replica ion cycle. Journal of Virology. Apr 2009;83(9) 4695-4699p. DISCLOSURES: No relevant relationships by Jacob Patrick, source=Web Response No relevant relationships by Yiseiry Perez-Melendez, source=Web Response

Pulmonary involvement in acquired immunodeficiency syndrome-associated Kaposi’s sarcoma: a descriptive analysis of thin-section manifestations in 29 patients

Acquired immunodeficiency syndrome-associated Kaposi's sarcoma (AIDS-KS) was the first malignant neoplasm to be described as being related to AIDS. The lungs are the most common visceral site of AIDS-KS. This study aimed to analyze the computed tomography (CT) manifestations of pulmonary involvement in AIDS-KS. Twenty-nine male patients were enrolled in this retrospective study. Imaging evaluation parameters included lesion distribution, the flame sign, interlobular septal thickening, peribronchovascular interstitium thickening, ground-glass opacity (GGO), dilated blood vessels in lesions, and pleural effusion. A peribronchovascular distribution was observed in all patients, predominantly in the lower lobes. Of the patients, 58.62% (17/29) exhibited the flame sign, 75.86% (22/29) had interlobular septal thickening, 72.41% (21/29) had peribronchovascular interstitium thickening, 82.76% (24/29) had GGO, and 34.48% (10/29) had pleural effusion. Enlarged lymph nodes with a short-axis diameter >1.0 cm were found in 41.38% (12/29) of the patients. Of the 12 patients who underwent contrast-enhanced CT (CECT), 90.91% (11/12) had dilated blood vessels, and nodules, consolidations, and lymph nodes were observed to be strongly enhanced. Intrapulmonary lesions decreased in size or number after appropriate treatment during follow-up. Common CT manifestations of pulmonary AIDS-KS include the flame sign, peribronchovascular distribution, peribronchovascular interstitium thickening, interlobular septa thickening, GGO, dilated blood vessel, and strong enhancement of nodules, consolidations, and lymph nodes. It is helpful to follow up the therapeutic effect of pulmonary AIDS-KS by chest CT.

Outcomes of AIDS-associated Kaposi sarcoma in Mozambique after treatment with pegylated liposomal doxorubicin

BackgroundKaposi’s sarcoma (KS) is a common HIV-associated malignancy frequently associated with poor outcomes. It is the most frequently diagnosed cancer in major cities of Mozambique. Antiretroviral therapy is the cornerstone of KS treatment, but many patients require cytotoxic chemotherapy. The traditional regimen in Mozambique includes conventional doxorubicin, bleomycin and vincristine, which is poorly tolerated. In 2016, pegylated liposomal doxorubicin was introduced at a specialized outpatient center in Maputo, Mozambique.MethodsWe performed a prospective, single-arm, open-label observational study to demonstrate the feasibility, safety, and outcomes of treatment with pegylated liposomal doxorubicin (PLD) in patients with AIDS-associated Kaposi sarcoma (KS) in a low-resource setting. Chemotherapy-naïve adults with AIDS-associated KS (T1 or T0 not responding to 6 months of antiretroviral therapy) were eligible if they were willing to follow up for 2 years. Patients with Karnofsky scores < 50 or contraindications to PLD were excluded. One hundred eighty-three patients were screened and 116 participants were enrolled. Patients received PLD on three-week cycles until meeting clinical stopping criteria. Follow-up visits monitored HIV status, KS disease, side effects of chemotherapy, mental health (PHQ-9) and quality of life (SF-12). Primary outcome measures included vital status and disease status at 6, 12, and 24 months after enrollment.ResultsAt 24 months, 23 participants (20%) had died and 15 (13%) were lost to follow-up. Baseline CD4 < 100 was associated with death (HR 2.7, 95%CI [1.2–6.2], p = 0.016), as was T1S1 disease compared to T1S0 disease (HR 2.7, 95%CI [1.1–6.4], p = 0.023). Ninety-two participants achieved complete or partial remission at any point (overall response rate 80%), including 15 (13%) who achieved complete remission. PLD was well-tolerated, and the most common AEs were neutropenia and anemia. Quality of life improved rapidly after beginning PLD.DiscussionPLD was safe, well-tolerated and effective as first-line treatment of KS in Mozambique. High mortality was likely due to advanced immunosuppression at presentation, underscoring the importance of earlier screening and referral for KS.

Evaluation of a Training Intervention to Improve Kaposi Sarcoma Care in Zimbabwe: A Prospective Community-Based Stepped-Wedge Cluster Randomised Trial

Background: Most Zimbabweans access medical care through tiered health systems, with decentralized HIV care and centralized oncology care. Local health centre staff are trained in ART administration but not in AIDS-associated Kaposi sarcoma (AIDS-KS) diagnosis or management. To improve AIDS-KS prognoses, interventions on screening, diagnosis, and treatment must be integrated into primary HIV care settings. We conducted a community-based randomized step-wedge cluster trial for a package of KS care training interventions. Methods: Interventions intended to improve KS detection and management included a standardized KS clinical evaluation tool, palliative care integration, standardized treatment, and improved consultative services. Interventions were evaluated at eight Zimbabwe primary HIV care sites by monitoring KS diagnoses and outcomes, including early diagnosis (T0 vs T1 tumor stage), patient retention, and mortality. Analyses controlled for within clinic correlations. Findings: 1102 suspected KS patients (96% HIV+) were enrolled: 47% newly diagnosed, 20% previously diagnosed, and 33% determined as not KS (incorrectly diagnosed). Diagnosis at T0 stage increased post-intervention, though not significant statistically (adjusted odds ratio (aOR)=1·48 (95% confidence interval (95%CI):0·66-3·79);p=0·37). New KS diagnosis rates increased 103% (95%CI:11%-273%);p=0·02) post-intervention, with parallel increased odds of incorrect diagnosis (aOR=2·08 (95%CI:0·33-3·24);p=0·001). Post-intervention, non-significant changes in 90-day return rates (adjusted hazard ratio (aHR)=0·69 (95%CI:0·38-1·45);p=0·21) and survival (aHR=1·36 (95%CI:0·85-2·20);p=0·20) were estimated. Interpretation: KS training interventions increased overall and incorrect KS diagnosis, but not early KS diagnosis, 90-day return rates, or survival at HIV primary care sites. Approaches to increase KS diagnosis accuracy in low-resource settings are needed. Trial Registration: Study design details are available at ClinicalTrials.gov NCT01764360. Funding: Funding was provided by the National Cancer Institute, National Institutes of Health: grant 1R01CA172050. Declaration of Interest: None to declare. Ethical Approval: The study was approved by the institutional review boards of Zimbabwe (Medical Research Council of Zimbabwe, MRCZ), University of Colorado Anschutz Medical Campus (COMIRB), and the Joint Parirenyatwa Hospital and University of Zimbabwe College of Health Sciences Research Ethics Committee (JREC).

A novel mathematical model of AIDS-associated Kaposi's sarcoma: Analysis and optimal control

Kaposi's sarcoma (KS) has been the most common HHV-8 virus-induced neoplasm associated with HIV-1 infection. Although the standard KS therapy has not changed in 20 years, not all cases of KS will respond to the same therapy. The goal of current AIDS-KS treatment modalities is to reconstitute the immune system and suppress HIV-1 replication, but newer treatment modalities are on horizon. There are very few mathematical models that have included HIV-1 viral load (VL) measures, despite VL being a key determinant of treatment outcome. Here we introduce a mathematical model that consolidates the effect of both HIV-1 and HHV-8 VL on KS tumor progression by incorporating low or high VLs into the proliferation terms of the immune cell populations. Regulation of HIV-1/HHV-8 VL and viral reservoir cells is crucial for restoring a patient to an asymptomatic stage. Therefore, an optimal control strategy given by a combined antiretroviral therapy (cART) is derived. The results indicate that the drug treatment strategies are capable of removing the viral reservoirs faster and consequently, the HIV-1 and KS tumor burden is reduced. The predictions of the mathematical model have the potential to offer more effective therapeutic interventions based on viral and virus-infected cell load and support new studies addressing the superiority of VL over CD4+ T-cell count in HIV-1 pathogenesis.

Admitted AIDS-associated Kaposi sarcoma patients: Indications for admission and predictors of mortality.

Kaposi sarcoma (KS) is an AIDS-defining angioproliferative malignancy associated with high morbidity and mortality. Most KS patients in regions with high incidence such as sub-Saharan Africa present late with advanced stage disease. Admitted KS patients have high mortality rates. Factors associated with mortality of admitted KS patients are poorly defined.We conducted a retrospective file review to ascertain reasons for admission and identify factors associated with mortality of admitted HIV-associated (epidemic) KS patients in Zambia. Baseline study variables were collected, and patients were retrospectively followed from admission to time of discharge or death.Mortality rate for admitted epidemic KS patients was high at 20%. The most common reasons for admission included advanced KS disease, severe anemia, respiratory tract infections, and sepsis. The majority (48%) of admitted patients had advanced clinical stage with visceral involvement on admission. Clinical predictors of mortality on univariate analysis included visceral KS [odds ratio (OR) = 13.74; 95% confidence interval (95% CI) = 1.68–113; P = 0.02), fever (OR = 26; 95% CI = 4.85–139; P = .001), and sepsis (OR = 35.56; 95% CI = 6.05–209; P = .001). Baseline hemoglobin levels (5.6 vs 8.2 g/dL; P = .001) and baseline platelet counts (63 x 10^9/L vs 205 x 10^9/L; P = .01) were significantly lower in mortalities vs discharges. Baseline white cell counts were higher in mortalities vs discharges (13.78 x 10^9/L vs 5.58 x 10^9/L; P = .01), and HIV-1 viral loads at the time of admission were higher in mortalities vs discharges (47,607 vs 40 copies/μL; P = .02). However, only sepsis (or signs and symptoms of sepsis) were independently associated with mortality after controlling for confounders.In conclusion, common reasons for admission of epidemic KS patients include advanced disease, severe anemia, respiratory tract infections, and signs and symptoms of sepsis. Signs and symptoms of sepsis are independent predictors of mortality in these patients.

Sarcoma de Kaposi lingual. Rara variante en paciente VIH positivo. A propósito de un caso.

Kaposi's sarcoma is a vascular lesion of intermediate-grade malignant potential affecting skin, mucosa, lymph nodes, and viscera. Four clinical variants have been recognized: classic, African Kaposi sarcoma, immunosuppression-associated Kaposi sarcoma and AIDS-associated Kaposi sarcoma. Human herpes virus type 8 is implicated as the etiological agent in all of them. We present a 39-year-old man with a history of pulmonary tuberculosis under treatment, and two months of evolution HIV / AIDS, with a lympangiomatous Kaposi sarcoma in an atypical location. Keywords: Kaposi's sarcoma; HIV; HHV-8; vascular neoplasia; lymphangioma-like Kaposi sarcoma.

HIV and lymphoma: from oncological futility to treatment

Cancer and HIV have been inextricably linked since the first report in 1982 of biopsy-confirmed Kaposi's sarcoma among previously healthy homosexual men living in Los Angeles and Orange counties, California, USA. 1 Centers for Disease ControlA cluster of Kaposi's sarcoma and pneumocystis carinii pneumonia among homosexual male residents of Los Angeles and Orange counties, California. MMWR Morb Mortal Wkly Rep. 1982; 31: 305-307 PubMed Google Scholar The cases established concerns for what later would be defined as AIDS. The report speculated: “One hypothesis consistent with the observations reported here is that infectious agents are being sexually transmitted among homosexually active males. Infectious agents not yet identified may cause the acquired cellular immunodeficiency that appears to underlie KS [Kaposi's sarcoma] and/or PCP [Pneumocystis carcinii pneumonia] among homosexual males.” The discovery of HIV proved it to be the aetiological agent. Given the known association between immunodeficiency and cancer and oncogenic virus and cancer, the discovery of human herpesvirus 8 (also known as Kaposi's sarcoma-associated herpesvirus) completed the puzzle on the mysterious outbreak of Kaposi's sarcoma. 2 Chang Y Cesarman E Pessin MS et al. Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma. Science. 1994; 266: 1865-1869 Crossref PubMed Scopus (4973) Google Scholar Epidemiology of haematological malignancies in people living with HIVPeople living with HIV or AIDS are at increased risk of Hodgkin and non-Hodgkin lymphoma compared with HIV-negative individuals. Data on the risk of multiple myeloma or leukaemia are inconsistent and of low quality but the risk does not seem to be increased. Specific haematological malignancies occur in different contexts of age, CD4 cell count, HIV control, viral co-infections, or chronic inflammation, and the expansion of combination antiretroviral therapy has led to varied demographic and epidemiological shifts among people with HIV. Full-Text PDF CAR T-cell therapy for cancer and HIV through novel approaches to HIV-associated haematological malignanciesPeople living with HIV are a global population with increased cancer risk but their access to modern immunotherapies for cancer treatment has been limited by socioeconomic factors and inadequate research to support safety and efficacy in this population. These immunotherapies include immune checkpoint inhibitors and advances in cellular immunotherapy, particularly chimeric antigen receptor (CAR) T-cell therapy. Despite the field of cancer immunotherapy rapidly expanding with ongoing clinical trials, people with HIV are often excluded from such trials. Full-Text PDF Haemopoietic cell transplantation in patients living with HIVHaemopoietic cell transplantation is established as a standard treatment approach for people living with HIV who have haematological malignancies with poor prognosis. Studies with autologous and allogeneic haemopoietic cell transplantation suggest that HIV status does not adversely affect outcomes, provided that there is adequate infection prophylaxis. Attention to possible drug–drug interactions is important. Allogeneic haemopoietic cell transplantation substantially reduces the long-term HIV reservoir when complete donor chimerism is established. Full-Text PDF Treatment management of haematological malignancies in people living with HIVAlthough the incidence of HIV-associated lymphomas decreased after the introduction of effective combination antiretroviral therapy, they became the most common AIDS-related cancer in high-income countries. Moreover, as people living with HIV live longer, a wide range of non-AIDS-related cancer has emerged, including other haematological malignancies. Nonetheless, combination antiretroviral therapy has offered people with HIV the opportunity to receive the same therapies as those provided to the general population, and intensive curative therapies have become the standard. Full-Text PDF

Early Progression and Immune Reconstitution Inflammatory Syndrome During Treatment of Mild-To-Moderate Kaposi Sarcoma in Sub-Saharan Africa and South America: Incidence, Long-Term Outcomes, and Effects of Early Chemotherapy.

Early progression of AIDS-associated Kaposi sarcoma (KS-PD) and immune reconstitution inflammatory syndrome (KS-IRIS) sometimes occur after the initiation of antiretroviral therapy (ART). Early KS-PD and KS-IRIS were assessed in the A5264/AMC-067 trial in which participants with mild-to-moderate AIDS-KS were randomized to initiate ART with either immediate or as-needed oral etoposide. Early KS-PD was defined as tumor progression within 12 weeks of ART initiation. When investigators had concern that early KS-PD was KS-IRIS, additional evaluations were performed. Suspected KS-IRIS was defined as early KS-PD accompanied by a CD4 count increase of ≥50 cells per cubic millimeter or plasma HIV-1 RNA decrease of ≥0.5 log10 copies/mL. Clinical outcome was a composite end point categorized as failure, stable, and response at 48 and 96 weeks compared with baseline. Fifty of 190 participants had early KS-PD (27%): 28 had KS-IRIS and 22 were not evaluated for KS-IRIS. Early KS-PD and KS-IRIS incidences with immediate etoposide versus ART alone were 16% versus 39%, and 7% versus 21%, respectively. Week 48 clinical outcome was 45% failure, 18% stable, and 37% response for no early KS-PD; 82% failure, 2% stable, and 16% response for early KS-PD; and 88% failure, 0% stable, and 12% response for KS-IRIS. Cumulative incidence of KS tumor response by week 96 was 64% for no early KS-PD, 22% with early KS-PD, and 18% with KS-IRIS. Early KS-PD, including suspected KS-IRIS, was common after starting ART for AIDS-KS and was associated with worse long-term clinical outcomes. Starting ART concurrently with etoposide reduced the incidence of both early KS-PD and KS-IRIS compared with ART alone.

Treatment of advanced AIDS-associated Kaposi sarcoma in resource-limited settings: a three-arm, open-label, randomised, non-inferiority trial

Optimal treatment regimens for AIDS-associated Kaposi sarcoma, a frequent contributor to morbidity and mortality among people with HIV, have not been systematically evaluated in low-income and middle-income countries, where the disease is most common. In this study, we aimed to investigate optimal treatment strategies for advanced stage disease in areas of high prevalence and limited resources. In this open-label, non-inferiority trial, we enrolled people with HIV and advanced stage AIDS-associated Kaposi sarcoma attending 11 AIDS Clinical Trials Group sites in Brazil, Kenya, Malawi, South Africa, Uganda, and Zimbabwe. Eligible participants were randomly assigned (1:1:1) with a centralised computer system to receive either intravenous bleomycin and vincristine or oral etoposide (the investigational arms), or intravenous paclitaxel (the control arm), together with antiretroviral therapy (ART; combined efavirenz, tenofovir disoproxil fumarate, and emtricitabine). The primary outcome was progression-free survival (PFS) at week 48, using a 15% non-inferiority margin to compare the investigational groups against the active control group. Safety was assessed in all eligible treated study participants. The study was registered with ClinicalTrials.gov, NCT01435018. 334 participants were enrolled between Oct 1, 2013, and March 8, 2018, when the study was closed early due to inferiority of the bleomycin and vincristine plus ART arm, as per the recommendations of the Data and Safety Monitoring Board (DSMB). The etoposide plus ART arm also closed due to inferiority in March, 2016, following a DSMB recommendation. Week-48 PFS rates were higher in the paclitaxel plus ART arm than in both investigational arms. The absolute differences in PFS were -30% (95% CI -52 to -8) for the comparison of paclitaxel plus ART (week 48 PFS 50%, 32 to 67; n=59) and etoposide plus ART (20%, 6 to 33; n=59), and -20% (-33% to -7%) for the comparison of paclitaxel plus ART (64%, 55 to 73; n=138) and bleomycin and vincristine plus ART (44%, 35 to 53; n=132). Both CIs overlapped the non-inferiority margin. The most common adverse events, in 329 eligible participants who began treatment, were neutropenia (48 [15%]), low serum albumin (33 [10%]), weight loss (29 [9%]), and anaemia (28 [9%]), occurring at similar frequency across treatment arms. Non-inferiority of either investigational intervention was not shown, with paclitaxel plus ART showing superiority to both oral etoposide plus ART and bleomycin and vincristine plus ART, supporting its use in treating advanced AIDS-associated Kaposi sarcoma in resource-limited settings. US National Institute of Allergy and Infectious Diseases and National Cancer Institute, National Institutes of Health.

Identification of AIDS-Associated Kaposi Sarcoma: A Functional Genomics Approach.

BackgroundKaposi sarcoma-associated herpes virus (KSHV) is one of the most common causal agents of Kaposi Sarcoma (KS) in individuals with HIV-infections. The virus has gained attention over the past few decades due to its remarkable pathogenic mechanisms. A group of genes, ORF71, ORF72, and ORF73, are expressed as polycistronic mRNAs and the functions of ORF71 and ORF72 in KSHV are already reported in the literature. However, the function of ORF73 has remained a mystery. The aim of this study is to conduct comprehensive exploratory experiments to clarify the role of ORF73 in KSHV pathology and discover markers of AIDS-associated KSHV-induced KS by bioinformatic approaches.Methods and ResultsWe searched for homologues of ORF-73 and attempted to predict protein-protein interactions (PPI) based on GeneCards and UniProtKB, utilizing Position-Specific Iterated BLAST (PSI-BLAST). We applied Gene Ontology (GO) and KEGG pathway analyses to identify highly conserved regions between ORF-73 and p53to help us identify potential markers with predominant hits and interactions in the KEGG pathway associated with host apoptosis and cell arrest. The protein p53 is selected because it is an important tumor suppressor antigen. To identify the potential roles of the candidate markers at the molecular level, we used PSIPRED keeping the conserved domains as the major parameters to predict secondary structures. We based the FUGE interpretation consolidations of the sequence-structure comparisons on distance homology, where the score for the amino acids matching the insertion/deletion (indels) detected were based on structures compared to the FUGE database of structural profiles. We also calculated the compatibility scores of sequence alignments accordingly. Based on the PSI-BLAST homologues, we checked the disordered structures predicted using PSI-Pred and DISO-Pred for developing a hidden Markov model (HMM). We further applied these HMMs models based on the alignment of constructed 3D models between the known structure and the HMM of our sequence. Moreover, stable homology and structurally conserved domains confirmed that ORF-73 maybe an important prognostic marker for AIDS-associated KS.ConclusionCollectively, similar variants of ORF-73 markers involved in the immune response may interact with targeted host proteins as predicted by our computational analysis. This work also suggests the existence of potential conformational changes that need to be further explored to help elucidate the role of immune signaling during KS towards the development of therapeutic applications.

Two Rare Variants of Kaposi Sarcoma: Case Report

bstract- We reported two cases of immunocompetent patients with a rare form of AIDS-associated Kaposi sarcoma (KS), without visceral involvement, presenting with an unusual clinical and histopathological picture called telangiectatic and lymphangioma-like KS, respectively. Dermatologists and pathologists need to be aware of this uncommon described variant to avoid the potential for misdiagnosis.