RESUMO
To assess whether biomarkers of systemic inflammation are associated with HIV acquisition or with the timing of ART initiation ("immediate", at diagnosis, versus "deferred", at 24 weeks post-diagnosis) in men-who-have-sex-with-men (MSM) and transgender women, we conducted a retrospective study comparing inflammatory biomarkers in participants' specimens collected before infection and after ≥2 years of effective ART. We measured biomarkers in four longitudinally collected plasma, including two specimens collected from each participant before and two after HIV acquisition and confirmed ART-suppression. Biomarkers were quantified by enzyme-linked immuno-assay or Meso Scale Discovery. When evaluating systematic variation in these markers over time, we found that multiple biomarkers consistently varied across participants' two pre-infection or two post-ART-suppression specimens. Additionally, we compared changes in biomarkers after vs before HIV acquisition. Across 47 participants, the levels of C-reactive protein (CRP), monocyte chemo-attractant protein-1, tumor necrosis factor-α and interferon gamma-induced protein-10 significantly increased while leptin and lipopolysaccharide binding protein (LBP) significantly decreased following HIV infection. Randomization to deferred-ART initiation was associated with greater increases in CRP and no decrease in LBP. Acquisition of HIV appeared to induce systemic inflammation, with elevation of biomarkers previously associated with infections and cardiovascular disease. Initiation of ART during the early weeks of infection tempered the increase in pro-inflammatory biomarkers compared to delaying ART for ~24 weeks after HIV diagnosis. These findings provide insight into potential mediators by which immediate-ART initiation improves health outcomes, perhaps because immediate-ART limits the size of the HIV reservoir or limits immune dysregulation that in turn trigger systemic inflammation.
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Biomarcadores , Infecções por HIV , Humanos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Infecções por HIV/sangue , Masculino , Biomarcadores/sangue , Feminino , Adulto , Estudos Retrospectivos , Inflamação/sangue , Pessoa de Meia-Idade , Proteínas de Fase Aguda/metabolismo , Proteína C-Reativa/metabolismo , Proteína C-Reativa/análise , Fármacos Anti-HIV/uso terapêutico , Pessoas Transgênero , Proteínas de Transporte , Glicoproteínas de MembranaRESUMO
PURPOSE OF REVIEW: The relationship between antiretroviral therapy (ART) and cancer treatment outcomes among people living with HIV (PLWH) in low- and middle-income countries (LMICs) is complex and poorly understood for many cancers. We aimed to summarize existing evidence from LMICs regarding the benefit of ART on cancer treatment-related outcomes. RECENT FINDINGS: We included twelve observational studies that reported associations between ART status and cancer treatment outcomes among HIV-positive patients in LMICs. Most confirmed ART was associated with improved cancer treatment outcomes. Heterogeneity in cancers under study, outcome measurement, categorization of ART status, and reporting of HIV-related immune function made formal comparison between studies untenable. Where evaluated, ART generally has a positive effect on cancer outcomes in people with HIV in LMICs. However, there remains a substantial gap in the literature regarding the impact of ART on treatment outcomes for most cancer types. Future research should focus on the optimal timing and integration of ART and cancer treatment for PLWH with strategies applicable to constrained-resource settings.
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Fármacos Anti-HIV , Infecções por HIV , Neoplasias , Fármacos Anti-HIV/uso terapêutico , Países em Desenvolvimento , Infecções por HIV/tratamento farmacológico , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/epidemiologia , Pobreza , Resultado do TratamentoRESUMO
BACKGROUND: Early antiretroviral therapy (ART) initiation (ie, within 3 months of infection) limits establishment of the HIV reservoir. However, the effect of early ART initiation on the long-term dynamics of the pool of infected cells remains unclear. METHODS: In this longitudinal analysis, we included cisgender men who have sex with men (MSM) and transgender women (aged 18-54 years) at high risk for HIV infection, enrolled in the ongoing longitudinal MERLIN study in Peru between Oct 28, 2014, and Nov 8, 2018. Participants were eligible if they had been infected with HIV less than 90 days before enrolment, and if they had cryopreserved peripheral blood mononuclear cell (PBMC) samples. Participants were stratified into three groups on the basis of whether they initiated ART at 30 days or less (acute group), at 31-90 days (early group), or more than 24 weeks (deferred group) after the estimated date of detectable infection. PBMC samples were collected before ART initiation and longitudinally for up to 4 years on ART. The main outcomes were to establish the size of the HIV reservoir before ART initiation and to assess the effect of the timing of ART initiation on the decay of the HIV reservoir over 4 years follow-up. We quantified viral load, and isolated CD4 cells to quantify total HIV DNA, integrated HIV DNA and 2-long terminal repeat circles. Longitudinal analysis of active and inducible HIV reservoirs were measured by quantifying the frequency of CD4 cells producing multiply-spliced HIV RNA ex vivo and after in-vitro stimulation with a tat/rev induced limiting dilution assay (TILDA). A mixed-effects model from the time of ART initiation was used to measure longitudinal decays in viral loads and each HIV reservoir measure in each of the three groups. FINDINGS: We included 56 participants in this analysis, all of whom were MSM: 15 were in the acute group, 19 were in the early group, and 22 were in the deferred group. Participants in all three groups had similar levels of all HIV reservoir markers before ART initiation. All participants, including those in the acute group, had a pool of transcriptionally silent HIV-infected cells before ART initiation, as indicated by a substantial increase in TILDA measures upon stimulation. Longitudinal analysis over 4 years of ART revealed a biphasic decay of all HIV persistence markers, with a rapid initial decline followed by a slower decay in all participants. During the first-phase decay, the half-lives of both total and integrated HIV DNA and TILDA measures were significantly shorter in the acute group than in the early and deferred groups. During the second-phase decay, HIV reservoir markers continued to decline only in participants in the acute group. INTERPRETATION: Participants who initiated ART within 30 days or less of HIV infection showed a steeper and more sustained decay in HIV reservoir measures, suggesting long-term benefit of acute ART initiation on reservoir clearance. FUNDING: The US National Institutes of Health and the Canadian Institutes for Health Research.
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Infecções por HIV , HIV-1 , Minorias Sexuais e de Gênero , Adolescente , Adulto , Antirretrovirais/uso terapêutico , Biomarcadores , Canadá , DNA Viral , Feminino , Infecções por HIV/tratamento farmacológico , HIV-1/genética , Homossexualidade Masculina , Humanos , Leucócitos Mononucleares , Masculino , Pessoa de Meia-Idade , Neurofibromina 2/uso terapêutico , Adulto JovemRESUMO
The long-term effects of CD19-targeted chimeric antigen receptor-modified T-cell immunotherapy (CD19-CARTx) for B-cell malignancies on humoral immunity are unclear. We examined antiviral humoral immunity in 39 adults with B-cell malignancies who achieved durable complete remission without additional therapy for >6 months after CD19-CARTx. Despite CD19+ B-cell aplasia in all patients, the incidence of viral infections occurring >90 days post-CD19-CARTx was low (0.91 infections per person-year). Because long-lived plasma cells are CD19- and should not be direct targets of CD19-targeted chimeric antigen receptor T cells, we tested the hypothesis that humoral immunity was preserved after CD19-CARTx based on linear mixed-effects models of changes in serum total immunoglobulin G (IgG) concentration, measles IgG concentration, and the number of viruses or viral epitopes to which serum IgG was directed (the "antivirome") using the novel VirScan assay. Samples were tested pre-CD19-CARTx and â¼1, 6, and 12 months post-CD19-CARTx. Although total IgG concentration was lower post-CD19-CARTx (mean change, -17.5%), measles IgG concentration was similar (mean change, 1.2%). Only 1 participant lost measles seroprotection post-CD19-CARTx but had undergone allogeneic hematopoietic cell transplantation before CD19-CARTx. The antivirome was also preserved, with mean absolute losses of 0.3 viruses and 6 viral epitopes detected between pre- and post-CD19-CARTx samples. Most participants gained IgG to ≥2 epitopes for ≥2 viruses, suggesting that humoral immunity to some viruses may be maintained or recover after successful CD19-CARTx. These findings may differ in children. Studies of immunoglobulin replacement and vaccination after CARTx are warranted.
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Anticorpos Antivirais/imunologia , Antígenos CD19/imunologia , Imunoterapia Adotiva , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Adulto , Idoso , Anticorpos Antivirais/sangue , Feminino , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Leucemia de Células B/imunologia , Leucemia de Células B/terapia , Depleção Linfocítica , Linfoma de Células B/imunologia , Linfoma de Células B/terapia , Masculino , Pessoa de Meia-Idade , Receptores de Antígenos de Linfócitos T/genética , Fatores de Tempo , Adulto JovemRESUMO
Further insight into humoral viral immunity after hematopoietic cell transplantation (HCT) could have potential impact on donor selection or monitoring of patients. Currently, estimation of humoral immune recovery is inferred from lymphocyte counts or immunoglobulin levels and does not address vulnerability to specific viral infections. We interrogated the viral antibody repertoire before and after HCT using a novel serosurvey (VirScan) that detects immunoglobulin G responses to 206 viruses. We performed VirScan on cryopreserved serum from pre-HCT and 30, 100, and 365 days after myeloablative HCT from 37 donor-recipient pairs. We applied ecologic metrics (α- and ß-diversity) and evaluated predictors of metrics and changes over time. Donor age and donor/recipient cytomegalovirus (CMV) serostatus and receipt systemic glucocorticoids were most strongly associated with VirScan metrics at day 100. Other clinical characteristics, including pre-HCT treatment and conditioning, did not affect antiviral repertoire metrics. The recipient repertoire was most similar (pairwise ß-diversity) to that of donor at day 100, but more similar to pre-HCT self by day 365. Gain or loss of epitopes to common viruses over the year post-HCT differed by donor and recipient pre-HCT serostatus, with highest gains in naive donors to seropositive recipients for several human herpesviruses and adenoviruses. We used VirScan to highlight contributions of donor and recipient to antiviral humoral immunity and evaluate longitudinal changes. This work builds a foundation to test whether such systematic profiling could serve as a biomarker of immune reconstitution, predict clinical events after HCT, or help refine selection of optimal donors.
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Anticorpos Antivirais/imunologia , Formação de Anticorpos/imunologia , Epitopos/imunologia , Transplante de Células-Tronco Hematopoéticas , Imunidade Humoral , Adulto , Anticorpos Antivirais/sangue , Formação de Anticorpos/genética , Citomegalovirus/imunologia , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/etiologia , Antígenos HLA/genética , Antígenos HLA/imunologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Período Pós-Operatório , Doadores de Tecidos , Transplantados , Transplante HomólogoRESUMO
PURPOSE: Health system constraints limit access to HIV and cancer treatment programs in sub-Saharan Africa. Limited access and continuity of care affect morbidity and mortality of patients with cancer and HIV. We assessed barriers in the care cascade of comorbid HIV and cancer. PATIENTS AND METHODS: Structured interviews were conducted with 100 adult patients with HIV infection and new diagnoses of cancer at the Uganda Cancer Institute. Participants completed follow-up questionnaires after 1 year to assess ongoing engagement with and barriers to care. RESULTS: The median time from new-onset cancer symptoms to initiation of cancer care at the Uganda Cancer Institute was 209 days (interquartile range, 113 to 384 days). Persons previously established in HIV care waited less overall to initiate cancer care ( P = .04). Patients established in HIV care experienced shorter times from initial symptoms to seeking of cancer care ( P = .02) and from seeking of care to cancer diagnosis ( P = .048). Barriers to receiving care for HIV and cancer included difficulty traveling to multiple clinics/hospitals (46%), conflicts between HIV and cancer appointments (23%), prohibitive costs (21%), and difficulty adhering to medications (15%). Reporting of any barriers to care was associated with premature discontinuation of cancer treatment ( P = .003). CONCLUSION: Patients with HIV-associated malignancies reported multiple barriers to receiving care for both conditions, although knowledge of HIV status and engagement in HIV care before presentation with malignancy reduced subsequent time to the start of cancer treatment. This study provides evidence to support creation and evaluation of integrated HIV and cancer care models.
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Infecções por HIV/tratamento farmacológico , Acessibilidade aos Serviços de Saúde/estatística & dados numéricos , Neoplasias/terapia , Adulto , Idoso , Infecções por HIV/complicações , Humanos , Adesão à Medicação/estatística & dados numéricos , Pessoa de Meia-Idade , Neoplasias/etiologia , Medição de Risco , Tempo para o Tratamento , Uganda , Adulto JovemAssuntos
Fármacos Anti-HIV/uso terapêutico , Antineoplásicos/uso terapêutico , Infecções por HIV/tratamento farmacológico , Neoplasias/tratamento farmacológico , Guias de Prática Clínica como Assunto , Medicina Baseada em Evidências/métodos , Medicina Baseada em Evidências/normas , HIV/efeitos dos fármacos , HIV/isolamento & purificação , Infecções por HIV/complicações , Infecções por HIV/imunologia , Infecções por HIV/virologia , Humanos , Oncologia/métodos , Oncologia/normas , Neoplasias/imunologia , Neoplasias/virologia , Estudos Observacionais como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de TempoRESUMO
This review highlights current interventional clinical trials for HIV-associated malignancies (HIVAMs), with emphasis on 4 mechanistic areas: immunomodulatory therapies and gene therapies, including immune checkpoint inhibitors; cytotoxic therapies; novel tumor-targeted and virally targeted therapies in both AIDS-defining and non-AIDS-defining cancers (NADC); and other screening or topical/ablative interventions. A search on ClinicalTrials.gov located 35 trials, including 12 immunomodulatory or gene therapy trials, 6 cytotoxic therapy trials, 10 trials of therapies with tumor or viral molecular targets, and 7 trials evaluating screening interventions or topical or ablative therapies. Study drugs, mechanisms, and outcomes of interest, including future directions, are discussed. Targeted therapies and immunotherapies address not only the tumor but underlying viral oncogens, including possible benefits on HIV-specific immunologic control. The resulting science from the trials listed in this review will provide important translational breakthroughs for people living with HIV (PLWH) and cancer. We highlight disease-specific challenges that could be addressed in future studies, including testing the safety and efficacy of cutting-edge immunotherapy and targeted treatments used in the general cancer population, and improving gaps in knowledge and practice for cancer screening and its treatment, especially in low-resource regions. Additional important considerations include identification of novel therapies for virally mediated tumors that disproportionally present in PLWH, how to treat persons with HIVAM and advanced immunosuppression, and how to comanage both diseases in antiretroviral therapy-naïve persons and those receiving care in settings where supportive therapies for hematologic toxicities and infections are limited. Current and future clinical trials should address needs of both resource-replete and -limited regions, as well as cancers that are uncommon in or respond differently to HIV-negative populations (eg, Kaposi sarcoma or anal cancer), in addition to an increased focus on NADCs not traditionally linked with HIV, such as lung or gastrointestinal tumors.
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Infecções por HIV/complicações , HIV/patogenicidade , Imunoterapia/métodos , Neoplasias/terapia , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Ensaios Clínicos como Assunto , Terapia Genética/métodos , HIV/imunologia , Infecções por HIV/imunologia , Infecções por HIV/terapia , Infecções por HIV/virologia , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Terapia de Alvo Molecular/métodos , Neoplasias/imunologia , Neoplasias/mortalidade , Neoplasias/virologia , Proteínas Oncogênicas Virais/antagonistas & inibidores , Proteínas Oncogênicas Virais/imunologia , Fatores de Risco , Análise de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND: Human herpesvirus-8 (HHV-8), the etiologic agent of Kaposi sarcoma (KS), establishes lifelong latent infection with periodic lytic replication ("shedding") at mucosal sites, especially the oropharynx. Patterns of HHV-8 shedding are not well understood, and require elucidation to better predict risk of HHV-8 related malignancies in those infected. We sought to characterize patterns of HHV-8 oropharyngeal shedding among diverse cohorts that enrolled HHV-8 seropositive persons. METHODS: We quantified HHV-8 oral shedding using PCR among HHV-8 seropositive persons who collected at least 14 days of oral swabs in 22 studies on 3 continents. We excluded persons taking antivirals during sampling or any prior use of antiretrovirals in those who were HIV-infected. RESULTS: 248 participants were enrolled from the US, Peru, Cameroon, Uganda, and Kenya; 61 % were men, 58 % were HIV seropositive, and 16 % had KS. Overall, 3,123 of 10,557 samples (29.6 %) had HHV-8 detected. Quantity of virus shed was highly correlated with shedding rate, (ρ = 0.72, p < 0.0001). HHV-8 was detected in ≥1 sample in 55 % of participants with a median of 7 % of days in the US and Kenya, 0 % in Uganda and Peru, and 18 % in Cameroon. Median episode duration was three days, and episodes with high median quantity lasted longer (42 vs 3 days, p < 0.0001). In persons with multiple observations over time, 66 % of shedding rate variance was attributable to differences between individuals. CONCLUSIONS: In HHV-8 infected individuals from diverse settings, oral mucosal shedding rate, quantity, and duration were correlated; individual shedding was highly variable. Studies are needed to determine factors accounting for between-person variation and the relationship of HHV-8 shedding to development of associated diseases.
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Vascular endothelial growth factor (VEGF) plays an important role in Kaposi's sarcoma (KS). We administered PTC299, a post-transcriptional inhibitor of pathogenic VEGF, to persons with HIV-related KS. Seventeen participants received 3 different doses of PTC299. Adverse events typically observed with VEGF inhibition were absent. Three participants had partial tumor responses and 11 had stable disease. There were no differences in exposure to PTC299 by antiretroviral regimen. Serum VEGF, but not KS-associated herpesvirus DNA, decreased on treatment. Given redundancies in the VEGF feedback loop, future trials should consider combining PTC299 with agents that inhibit different pathways implicated in KS and KS-associated herpesvirus proliferation.
Assuntos
Infecções Oportunistas Relacionadas com a AIDS/tratamento farmacológico , Inibidores Enzimáticos/uso terapêutico , Imidazóis/uso terapêutico , Sarcoma de Kaposi/tratamento farmacológico , Tiazóis/uso terapêutico , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Adulto , DNA Viral/sangue , Inibidores Enzimáticos/efeitos adversos , Herpesvirus Humano 8/genética , Humanos , Imidazóis/efeitos adversos , Interleucina-6/sangue , Masculino , Pessoa de Meia-Idade , Tiazóis/efeitos adversos , Fator A de Crescimento do Endotélio Vascular/sangueRESUMO
We report on a human immunodeficiency virus-infected man undergoing urgent anorectal surgery, with multi-centimeter fungating masses discovered inside the anus. Initial pathology was inconclusive. After the patient developed a disseminated rash postoperatively determined to be secondary syphilis, the anorectal pathology was reviewed and Treponema pallidum DNA was amplified by polymerase chain reaction from the mass.
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INTRODUCTION: Infection and malignancy often have common characteristics which render the differential diagnosis for a prolonged fever difficult. Imaging and tissue biopsy are crucial in making a correct diagnosis, though differentiating between chronic osteomyelitis and malignancy is not always straightforward as they possess many overlapping features. CASE PRESENTATION: A 52-year-old Caucasian man was treated with antibiotics for his diabetic foot infection after a superficial culture showed Staphylococcus aureus. He had persistent fevers for several weeks and later developed acute onset of back pain which was treated with several courses of antibiotics. Radiographic and pathological findings were atypical, and a diagnosis of Hodgkin's lymphoma was made 12 weeks later. CONCLUSION: Clinicians should maintain a suspicion for Hodgkin's lymphoma or other occult malignancy when features of presumed osteomyelitis are atypical. Chronic vertebral osteomyelitis in particular often lacks features common to acute infectious disease processes, and the chronic lymphocytic infiltrates seen on histopathology have very similar features to Hodgkin's lymphoma, highlighting a similar inflammatory microenvironment sustained by both processes.