RESUMEN
HIV-1 infection greatly alters the NK cell phenotypic and functional repertoire. This is highlighted by the expansion of a rare population of FcRγ- NK cells exhibiting characteristics of traditional immunologic memory in people with HIV (PWH). Although current antiretroviral therapy (ART) effectively controls HIV-1 viremia and disease progression, its impact on HIV-1-associated NK cell abnormalities remains unclear. To address this, we performed a longitudinal analysis detailing conventional and memory-like NK cell characteristics in n = 60 PWH during the first 4 y of ART. Throughout this regimen, a skewed repertoire of cytokine unresponsive FcRγ- memory-like NK cells persisted and accompanied an overall increase in NK surface expression of CD57 and KLRG1, suggestive of progression toward immune senescence. These traits were linked to elevated serum inflammatory biomarkers and increasing Ab titers to human CMV, with human CMV viremia detected in approximately one-third of PWH at years 1-4 of ART. Interestingly, 40% of PWH displayed atypical NK cell subsets, representing intermediate stages of NK-poiesis based on single-cell multiomic trajectory analysis. Our findings indicate that NK cell irregularities persist in PWH despite long-term ART, underscoring the need to better understand the causative mechanisms that prevent full restoration of immune health in PWH.
Asunto(s)
Antígenos CD57 , Infecciones por VIH , VIH-1 , Células Asesinas Naturales , Humanos , Células Asesinas Naturales/inmunología , Infecciones por VIH/inmunología , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , VIH-1/inmunología , Masculino , Femenino , Antígenos CD57/inmunología , Adulto , Persona de Mediana Edad , Memoria Inmunológica/inmunología , Lectinas Tipo C/inmunología , Receptores Inmunológicos , Viremia/inmunología , Viremia/tratamiento farmacológico , Infecciones por Citomegalovirus/inmunología , Infecciones por Citomegalovirus/tratamiento farmacológico , Receptores de IgG/inmunología , Estudios Longitudinales , Antirretrovirales/uso terapéuticoRESUMEN
HIV post-treatment controllers (PTCs) are rare individuals who maintain low levels of viremia after stopping antiretroviral therapy (ART). Understanding the mechanisms of HIV post-treatment control will inform development of strategies aiming at achieving HIV functional cure. In this study, we evaluated 22 PTCs from 8 AIDS Clinical Trials Group (ACTG) analytical treatment interruption (ATI) studies who maintained viral loads ≤400 copies/mL for ≥24 wk. There were no significant differences in demographics or frequency of protective and susceptible human leukocyte antigen (HLA) alleles between PTCs and post-treatment noncontrollers (NCs, n = 37). Unlike NCs, PTCs demonstrated a stable HIV reservoir measured by cell-associated RNA (CA-RNA) and intact proviral DNA assay (IPDA) during analytical treatment interruption (ATI). Immunologically, PTCs demonstrated significantly lower CD4+ and CD8+ T cell activation, lower CD4+ T cell exhaustion, and more robust Gag-specific CD4+ T cell responses and natural killer (NK) cell responses. Sparse partial least squares discriminant analysis (sPLS-DA) identified a set of features enriched in PTCs, including a higher CD4+ T cell% and CD4+/CD8+ ratio, more functional NK cells, and a lower CD4+ T cell exhaustion level. These results provide insights into the key viral reservoir features and immunological profiles for HIV PTCs and have implications for future studies evaluating interventions to achieve an HIV functional cure.
Asunto(s)
Linfocitos T CD8-positivos , Infecciones por VIH , Humanos , Células Asesinas Naturales , Activación de Linfocitos , ARN , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , ViremiaRESUMEN
Causal indirect and direct effects provide an interpretable method for decomposing the total effect of an exposure on an outcome into the indirect effect through a mediator and the direct effect through all other pathways. A natural choice for a mediator in a randomized clinical trial is the treatment's targeted biomarker. However, when the mediator is a biomarker, values can be subject to an assay lower limit. The mediator is affected by the treatment and is a putative cause of the outcome, so the assay lower limit presents a compounded problem in mediation analysis. We propose two approaches to estimate indirect and direct effects with a mediator subject to an assay limit: (1) extrapolation and (2) numerical optimization and integration of the observed likelihood. Since these estimation methods solely rely on the so-called Mediation Formula, they apply to most approaches to causal mediation analysis: natural, separable, and organic indirect, and direct effects. A simulation study compares the two estimation approaches to imputing with half the assay limit. Using HIV interruption study data from the AIDS Clinical Trials Group described in Li et al 2016, AIDS; Lok and Bosch 2021, Epidemiology, we illustrate our methods by estimating the organic/pure indirect effect of a hypothetical HIV curative treatment on viral suppression mediated by two HIV persistence measures: cell-associated HIV-RNA and single-copy plasma HIV-RNA.
Asunto(s)
Biomarcadores , Causalidad , Simulación por Computador , Infecciones por VIH , Análisis de Mediación , Humanos , Infecciones por VIH/tratamiento farmacológico , Biomarcadores/sangre , Ensayos Clínicos Controlados Aleatorios como Asunto , Funciones de Verosimilitud , Modelos Estadísticos , Fármacos Anti-VIH/uso terapéuticoRESUMEN
Long-term consequences of human immunodeficiency virus (HIV) are likely the result of persistent inflammation and immune dysfunction of which cytomegalovirus (CMV) is a known contributor. We leveraged 2 AIDS Clinical Trials Group clinical trials exploring the effects of immune modulators (ruxolitinib and sirolimus) on inflammation in people with HIV on antiretroviral therapy to determine whether these interventions affected CMV shedding at various mucosal sites. Analyzing 635 mucosal samples collected, we found no significant difference in CMV levels across study arms or time points. Men had more CMV shedding than women. We did confirm an association between higher CMV DNA and immune markers associated with HIV persistence and HIV-associated mortality rates.
Asunto(s)
Infecciones por Citomegalovirus , Infecciones por VIH , Masculino , Humanos , Femenino , Citomegalovirus/genética , ADN Viral/genética , Infecciones por VIH/complicaciones , VIH/genética , Inflamación/complicaciones , Esparcimiento de VirusRESUMEN
Fourteen people with human immunodeficiency virus type 1 had longitudinal measurements of intact, defective, and total proviral DNA over the course of two decades of antiretroviral therapy. Three patterns of intact proviral DNA decay were revealed: (1) biphasic decline with markedly slower second-phase decline, (2) initial decline that transitions to a zero-slope plateau, and (3) initial decline followed by later increases in intact proviral DNA. Defective proviral DNA levels were essentially stable. Mechanisms of slowing or reversal of second-phase decay of intact proviral DNA may include the inability to clear cells with intact but transcriptionally silent proviruses and clonal expansion of cells with intact proviruses.
Asunto(s)
Infecciones por VIH , VIH-1 , Humanos , Provirus/genética , VIH-1/genética , ADN Viral/genética , Linfocitos T CD4-Positivos , Antirretrovirales/uso terapéuticoRESUMEN
BACKGROUND: Hospital readmission trends for persons with human immunodeficiency virus (PWH) in North America in the context of policy changes, improved antiretroviral therapy (ART), and aging are not well-known. We examined readmissions during 2005-2018 among adult PWH in NA-ACCORD. METHODS: Linear risk regression estimated calendar trends in 30-day readmissions, adjusted for demographics, CD4 count, AIDS history, virologic suppression (<400 copies/mL), and cohort. RESULTS: We examined 20 189 hospitalizations among 8823 PWH (73% cisgender men, 38% White, 38% Black). PWH hospitalized in 2018 versus 2005 had higher median age (54 vs 44 years), CD4 count (469 vs 274 cells/µL), and virologic suppression (83% vs 49%). Unadjusted 30-day readmissions decreased from 20.1% (95% confidence interval [CI], 17.9%-22.3%) in 2005 to 16.3% (95% CI, 14.1%-18.5%) in 2018. Absolute annual trends were -0.34% (95% CI, -.48% to -.19%) in unadjusted and -0.19% (95% CI, -.35% to -.02%) in adjusted analyses. By index hospitalization reason, there were significant adjusted decreases only for cardiovascular and psychiatric hospitalizations. Readmission reason was most frequently in the same diagnostic category as the index hospitalization. CONCLUSIONS: Readmissions decreased over 2005-2018 but remained higher than the general population's. Significant decreases after adjusting for CD4 count and virologic suppression suggest that factors alongside improved ART contributed to lower readmissions. Efforts are needed to further prevent readmissions in PWH.
Asunto(s)
Infecciones por VIH , Readmisión del Paciente , Adulto , Masculino , Humanos , Estados Unidos/epidemiología , VIH , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/epidemiología , Estudios de Cohortes , Canadá/epidemiologíaRESUMEN
⢠Human immunodeficiency virus (HIV) drug resistance has implications for antiretroviral treatment strategies and for containing the HIV pandemic because the development of HIV drug resistance leads to the requirement for antiretroviral drugs that may be less effective, less well-tolerated, and more expensive than those used in first-line regimens. ⢠HIV drug resistance studies are designed to determine which HIV mutations are selected by antiretroviral drugs and, in turn, how these mutations affect antiretroviral drug susceptibility and response to future antiretroviral treatment regimens. ⢠Such studies collectively form a vital knowledge base essential for monitoring global HIV drug resistance trends, interpreting HIV genotypic tests, and updating HIV treatment guidelines. ⢠Although HIV drug resistance data are collected in many studies, such data are often not publicly shared, prompting the need to recommend best practices to encourage and standardize HIV drug resistance data sharing. ⢠In contrast to other viruses, sharing HIV sequences from phylogenetic studies of transmission dynamics requires additional precautions as HIV transmission is criminalized in many countries and regions. ⢠Our recommendations are designed to ensure that the data that contribute to HIV drug resistance knowledge will be available without undue hardship to those publishing HIV drug resistance studies and without risk to people living with HIV.
Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , VIH-1 , Humanos , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/epidemiología , Filogenia , VIH-1/genética , Farmacorresistencia Viral/genética , Antirretrovirales/uso terapéutico , Mutación , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/uso terapéuticoRESUMEN
INTRODUCTION: Cardiovascular disease (CVD) has become a leading cause of morbidity and mortality among people with HIV. Atorvastatin is known to reduce cardiovascular risk. We (1) compared atorvastatin concentrations between different boosted protease inhibitors (PIs) and with lipid outcomes and (2) compared pre-atorvastatin 25-OH vitamin D levels with atorvastatin concentrations and with lipid outcomes, in people with HIV with suppressed HIV-1 RNA and low-density lipoprotein cholesterol (LDL-C) <130 mg/dL. METHODS: A5275 was a randomized, double-blind, placebo-controlled crossover study of atorvastatin in virally suppressed people with HIV with fasting LDL-C <130 mg/dL. We analyzed results over the 20 weeks of active atorvastatin treatment. Atorvastatin was initiated at 10 mg daily and increased to 20 mg daily after 4 weeks if there were no findings of toxicity. Atorvastatin trough concentrations were measured at week 20. Participants took combination antiretroviral therapy (ART) that included a boosted PI throughout. RESULTS: Overall (n = 67), 70% of participants were male, and the median age was 51 years. There was no apparent association between atorvastatin trough concentrations and pre-atorvastatin vitamin D levels (r = 0.01, p = 0.9) or by boosted PI (p = 0.20). Median pre- to post-atorvastatin change was -39.0 mg/dL in fasting total cholesterol, -40.4 ng/mL in lipoprotein-associated phospholipase A2 (LP-PLA2), and -13.8 U/L in oxidized LDL, with all changes negatively correlated with atorvastatin trough concentrations (r = -0.19, -0.09, -0.21; p ≥ 0.096). CONCLUSIONS: No apparent associations between pre-atorvastatin vitamin D levels and outcomes were observed (all p > 0.70). In virologically suppressed people with HIV, higher atorvastatin concentrations were marginally associated with greater decreases in lipid outcomes.
Asunto(s)
Anticolesterolemiantes , Infecciones por VIH , VIH-1 , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Masculino , Humanos , Persona de Mediana Edad , Femenino , Atorvastatina/farmacología , LDL-Colesterol , Vitamina D , Estudios Cruzados , Infecciones por VIH/tratamiento farmacológico , Método Doble Ciego , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Resultado del TratamientoRESUMEN
Many clinical studies evaluate the benefit of a treatment based on both survival and other continuous/ordinal clinical outcomes, such as quality of life scores. In these studies, when subjects die before the follow-up assessment, the clinical outcomes become undefined and are truncated by death. Treating outcomes as "missing" or "censored" due to death can be misleading for treatment effect evaluation. We show that if we use the median in the survivors or in the always-survivors as estimands to summarize clinical outcomes, we may conclude that a trade-off exists between the probability of survival and good clinical outcomes, even in settings where both the probability of survival and the probability of any good clinical outcome are better for one treatment. Therefore, we advocate not always treating death as a mechanism through which clinical outcomes are missing, but rather as part of the outcome measure. To account for the survival status, we describe the survival-incorporated median as an alternative summary measure for outcomes in the presence of death. The survival-incorporated median is the threshold such that 50% of the population is alive with an outcome above that threshold. Through conceptual examples and an application to a prostate cancer treatment study, we show that the survival-incorporated median provides a simple and useful summary measure to inform clinical practice.
Asunto(s)
Neoplasias de la Próstata , Calidad de Vida , Masculino , Humanos , Evaluación de Resultado en la Atención de Salud , Neoplasias de la Próstata/terapia , SobrevivientesRESUMEN
Clinical research to achieve antiretroviral therapy-free remission requires quantitative assays of the HIV-1 reservoir. Intact proviral DNA (IPD) measurement has greater throughput than the quantitative viral outgrowth assay (QVOA). In 25 individuals with well-documented long-term viral suppression, IPD levels and infectious units per million CD4+ T cells by QVOA strongly correlated (râ =â 0.59, Pâ =â .002), and IPD correlated with total cell-associated HIV-1 DNA and cell-associated HIV-1 RNA (râ =â 0.62 and râ =â 0.59, Pâ ≤â .002). IPD may provide an accessible marker of inducible replication-competent virus, total numbers of infected cells, and cellular expression of HIV-1 RNA.
Asunto(s)
Infecciones por VIH , Seropositividad para VIH , VIH-1 , Linfocitos T CD4-Positivos , Infecciones por VIH/tratamiento farmacológico , VIH-1/genética , Humanos , Provirus/genética , ARN , Carga Viral , Latencia del VirusRESUMEN
BACKGROUND: Development of human immunodeficiency virus (HIV) remission strategies requires precise information on time to HIV rebound after treatment interruption, but there is uncertainty regarding whether modern antiretroviral therapy (ART) regimens and timing of ART initiation may affect this outcome. METHODS: AIDS Clinical Trials Group (ACTG) A5345 enrolled individuals who initiated ART during chronic or early HIV infection and on suppressive ART for ≥2 years. Participants underwent carefully monitored antiretroviral interruption. ART was restarted upon 2 successive viral loads ≥1000 copies/mL. We compared participants of A5345 with participants of 6 historic ACTG treatment interruption studies. RESULTS: Thirty-three chronic-treated and 12 early-treated participants interrupted ART with evaluable time to viral rebound. Median time to viral rebound ≥1000 HIV RNA copies/mL was 22 days. Acute retroviral rebound syndrome was diagnosed in 9% of the chronic-treated and none of the early-treated individuals. All participants of the historic studies were on older protease inhibitor-based regimens, whereas 97% of A5345 participants were on integrase inhibitor-based ART. There were no differences in the timing of viral rebound comparing A5345 versus historic studies. In a combined analysis, a higher percentage of early-treated participants remained off ART at posttreatment interruption week 12 (chronic vs early: 2% vs 9%, Pâ =â .0496). One chronic-treated and one early-treated A5345 participant remained off ART for >24 weeks. All participants resuppressed after ART reinitiation. CONCLUSIONS: Early ART initiation, using either older or newer ART regimens, was associated with a significant delay in the time to HIV rebound after ART interruption, lowering the barrier for HIV remission.
Asunto(s)
Infecciones por VIH , Antirretrovirales/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Humanos , Carga ViralRESUMEN
BACKGROUND: Biological sex and the estrogen receptor alpha (ESR1) modulate human immunodeficiency virus (HIV) activity. Few women have enrolled in clinical trials of latency reversal agents (LRAs); their effectiveness in women is unknown. We hypothesized that ESR1 antagonism would augment induction of HIV expression by the LRA vorinostat. METHODS: AIDS Clinical Trials Group A5366 enrolled 31 virologically suppressed, postmenopausal women on antiretroviral therapy. Participants were randomized 2:1 to receive tamoxifen (arm A, TAMOX/VOR) or observation (arm B, VOR) for 5 weeks followed by 2 doses of vorinostat. Primary end points were safety and the difference between arms in HIV RNA induction after vorinostat. Secondary analyses included histone 4 acetylation, HIV DNA, and plasma viremia by single copy assay (SCA). RESULTS: No significant adverse events were attributed to study treatments. Tamoxifen did not enhance vorinostat-induced HIV transcription (between-arm ratio, 0.8; 95% confidence interval [CI], .2-2.4). Vorinostat-induced HIV transcription was higher in participants with increases in H4Ac (fold increase, 2.78; 95% CI, 1.34-5.79) vs those 9 who did not (fold increase, 1.04; 95% CI, .25-4.29). HIV DNA and SCA plasma viremia did not substantially change. CONCLUSIONS: Tamoxifen did not augment vorinostat-induced HIV RNA expression in postmenopausal women. The modest latency reversal activity of vorinostat, postmenopausal status, and low level of HIV RNA expression near the limits of quantification limited assessment of the impact of tamoxifen. This study is the first HIV cure trial done exclusively in women and establishes both the feasibility and necessity of investigating novel HIV cure strategies in women living with HIV. CLINICAL TRIALS REGISTRATION: NCT03382834.
Asunto(s)
Síndrome de Inmunodeficiencia Adquirida , Infecciones por VIH , VIH-1 , Síndrome de Inmunodeficiencia Adquirida/tratamiento farmacológico , Linfocitos T CD4-Positivos , ADN/uso terapéutico , Receptor alfa de Estrógeno/metabolismo , Femenino , VIH-1/genética , Inhibidores de Histona Desacetilasas/metabolismo , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/uso terapéutico , Histonas/metabolismo , Histonas/uso terapéutico , Humanos , ARN/metabolismo , ARN/uso terapéutico , Tamoxifeno/efectos adversos , Tamoxifeno/metabolismo , Viremia/tratamiento farmacológico , Latencia del Virus , Vorinostat/metabolismo , Vorinostat/farmacología , Vorinostat/uso terapéuticoRESUMEN
BACKGROUND: Understanding advances in the care and treatment of adults with HIV as well as remaining gaps requires comparing differences in mortality between persons entering care for HIV and the general population. OBJECTIVE: To assess the extent to which mortality among persons entering HIV care in the United States is elevated over mortality among matched persons in the general U.S. population and trends in this difference over time. DESIGN: Observational cohort study. SETTING: Thirteen sites from the U.S. North American AIDS Cohort Collaboration on Research and Design. PARTICIPANTS: 82 766 adults entering HIV clinical care between 1999 and 2017 and a subset of the U.S. population matched on calendar time, age, sex, race/ethnicity, and county using U.S. mortality and population data compiled by the National Center for Health Statistics. MEASUREMENTS: Five-year all-cause mortality, estimated using the Kaplan-Meier estimator of the survival function. RESULTS: Overall 5-year mortality among persons entering HIV care was 10.6%, and mortality among the matched U.S. population was 2.9%, for a difference of 7.7 (95% CI, 7.4 to 7.9) percentage points. This difference decreased over time, from 11.1 percentage points among those entering care between 1999 and 2004 to 2.7 percentage points among those entering care between 2011 and 2017. LIMITATION: Matching on available covariates may have failed to account for differences in mortality that were due to sociodemographic factors rather than consequences of HIV infection and other modifiable factors. CONCLUSION: Mortality among persons entering HIV care decreased dramatically between 1999 and 2017, although those entering care remained at modestly higher risk for death in the years after starting care than comparable persons in the general U.S. population. PRIMARY FUNDING SOURCE: National Institutes of Health.
Asunto(s)
Infecciones por VIH/mortalidad , Adulto , Causas de Muerte , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Vigilancia de la Población , Factores de Riesgo , Estados Unidos/epidemiologíaRESUMEN
BACKGROUND: Although adipose tissue has been proposed to harbor part of the human immunodeficiency virus 1 (HIV-1) reservoir, the influence of host characteristics, including sex and body mass index (BMI), on measures of HIV-1 persistence during antiretroviral therapy (ART) are incompletely understood. METHODS: We evaluated age, sex, BMI, waist circumference, years on ART, pre-ART HIV-1 RNA, pre-ART CD4+ T-cell count, and initial ART regimen with measures of HIV-1 persistence in blood (residual viremia, cellular HIV-1 DNA and RNA) in a cohort of 295 individuals with well-documented long-term virologic suppression (HIV-1 RNA <50 copies/mL) on ART (AIDS Clinical Trials Group study A5321). RESULTS: Men were more likely than women to have detectable plasma HIV-1 RNA by single-copy assay (52% vs 29%; P = .003), and the proportion of participants with detectable residual viremia increased in a stepwise fashion by BMI category (normal weight or underweight, 38%; overweight, 50%; and obese, 55%). ART regimen type was not associated with measures of HIV-1 persistence after controlling for ART duration. CONCLUSIONS: Sex and obesity are independently associated with residual viremia in people on long-term ART. Additional studies to confirm these relationships and to define the mechanisms by which sex and obesity affect HIV-1 persistence are needed to inform HIV-1 cure strategies.
Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , VIH-1 , Obesidad/complicaciones , Plasma/virología , Viremia/virología , Adulto , Antirretrovirales/uso terapéutico , Linfocitos T CD4-Positivos , Estudios Transversales , ADN Viral/sangre , Femenino , VIH-1/genética , Humanos , Masculino , Persona de Mediana Edad , ARN Viral/sangreRESUMEN
BACKGROUND: HIV-1 proviruses persist in people on antiretroviral therapy (ART) but most are defective and do not constitute a replication-competent reservoir. The decay of infected cells carrying intact compared with defective HIV-1 proviruses has not been well defined in people on ART. METHODS: We separately quantified intact and defective proviruses, residual plasma viremia, and markers of inflammation and activation in people on long-term ART. RESULTS: Among 40 participants tested longitudinally from a median of 7.1 years to 12 years after ART initiation, intact provirus levels declined significantly over time (median half-life, 7.1 years; 95% confidence interval [CI], 3.9-18), whereas defective provirus levels did not decrease. The median half-life of total HIV-1 DNA was 41.6 years (95% CI, 13.6-75). The proportion of all proviruses that were intact diminished over time on ART, from about 10% at the first on-ART time point to about 5% at the last. Intact provirus levels on ART correlated with total HIV-1 DNA and residual plasma viremia, but there was no evidence for associations between intact provirus levels and inflammation or immune activation. CONCLUSIONS: Cells containing intact, replication-competent proviruses are selectively lost during suppressive ART. Defining the mechanisms involved should inform strategies to accelerate HIV-1 reservoir depletion.
Asunto(s)
Fármacos Anti-VIH/farmacología , Infecciones por VIH/virología , VIH-1/genética , Provirus/efectos de los fármacos , Provirus/genética , Carga Viral , Adulto , Fármacos Anti-VIH/uso terapéutico , Terapia Antirretroviral Altamente Activa , Recuento de Linfocito CD4 , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/virología , ADN Viral , Femenino , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , VIH-1/inmunología , Humanos , Masculino , Persona de Mediana Edad , ARN Viral , Factores de TiempoRESUMEN
BACKGROUND: To assess the possible impact of antiretroviral therapy improvements, aging, and comorbidities, we examined trends in all-cause and cause-specific hospitalization rates among persons with HIV (PWH) from 2005 to 2015. METHODS: In 6 clinical cohorts, we followed PWH in care (≥1 outpatient CD4 count or HIV load [VL] every 12 months) and categorized ICD codes of primary discharge diagnoses using modified Clinical Classifications Software. Poisson regression estimated hospitalization rate ratios for calendar time trends, adjusted for demographics, HIV risk factor, and annually updated age, CD4, and VL. RESULTS: Among 28â 057 patients (125â 724 person-years), from 2005 to 2015, the median CD4 increased from 389 to 580 cells/µL and virologic suppression from 55% to 85% of patients. Unadjusted all-cause hospitalization rates decreased from 22.3 per 100 person-years in 2005 (95% confidence interval [CI], 20.6-24.1) to 13.0 in 2015 (95% CI, 12.2-14.0). Unadjusted rates decreased for almost all diagnostic categories. Adjusted rates decreased for all-cause, cardiovascular, and AIDS-defining conditions, increased for non-AIDS-defining infection, and were stable for most other categories. CONCLUSIONS: Among PWH with increasing CD4 counts and viral suppression, unadjusted hospitalization rates decreased for all-cause and most cause-specific hospitalizations, despite the potential effects of aging, comorbidities, and cumulative exposure to HIV and antiretrovirals.
Asunto(s)
Infecciones por VIH , Hospitalización/estadística & datos numéricos , Síndrome de Inmunodeficiencia Adquirida/tratamiento farmacológico , Síndrome de Inmunodeficiencia Adquirida/epidemiología , Envejecimiento , Fármacos Anti-VIH/uso terapéutico , Recuento de Linfocito CD4 , Canadá/epidemiología , Comorbilidad , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/epidemiología , Humanos , Factores de Riesgo , Estados Unidos/epidemiología , Carga ViralRESUMEN
BACKGROUND: Persons living with human immunodeficiency virus (HIV; PLWH) experience a high burden of cancer. It remains unknown which cancer types are reduced in PLWH with earlier initiation of antiretroviral therapy (ART). METHODS: We evaluated AIDS-free, ART-naive PLWH during 1996-2014 from 22 cohorts participating in the North American AIDS Cohort Collaboration on Research and Design. PLWH were followed from first observed CD4 of 350-500 cells/µL (baseline) until incident cancer, death, lost-to-follow-up, or December 2014. Outcomes included 6 cancer groups and 5 individual cancers that were confirmed by chart review or cancer registry linkage. We evaluated the effect of earlier (in the first 6 months after baseline) versus deferred ART initiation on cancer risk. Marginal structural models were used with inverse probability weighting to account for time-dependent confounding and informative right-censoring, with weights informed by subject's age, sex, cohort, baseline year, race/ethnicity, HIV transmission risk, smoking, viral hepatitis, CD4, and AIDS diagnoses. RESULTS: Protective results for earlier ART were found for any cancer (adjusted hazard ratio [HR] 0.57; 95% confidence interval [CI], .37-.86), AIDS-defining cancers (HR 0.23; 95% CI, .11-.49), any virus-related cancer (HR 0.30; 95% CI, .16-.54), Kaposi sarcoma (HR 0.25; 95% CI, .10-.61), and non-Hodgkin lymphoma (HR 0.22; 95% CI, .06-.73). By 15 years, there was also an observed reduced risk with earlier ART for virus-related NADCs (0.6% vs 2.3%; adjusted risk difference -1.6; 95% CI, -2.8, -.5). CONCLUSIONS: Earlier ART initiation has potential to reduce the burden of virus-related cancers in PLWH but not non-AIDS-defining cancers (NADCs) without known or suspected viral etiology.
Asunto(s)
Síndrome de Inmunodeficiencia Adquirida , Infecciones por VIH , Neoplasias , Sarcoma de Kaposi , Recuento de Linfocito CD4 , VIH , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/epidemiología , Humanos , Neoplasias/epidemiologíaRESUMEN
Mediation analysis, which started in the mid-1980s, is used extensively by applied researchers. Indirect and direct effects are the part of a treatment effect that is mediated by a covariate and the part that is not. Subsequent work on natural indirect and direct effects provides a formal causal interpretation, based on cross-worlds counterfactuals: outcomes under treatment with the mediator set to its value without treatment. Organic indirect and direct effects avoid cross-worlds counterfactuals, using so-called organic interventions on the mediator while keeping the initial treatment fixed at treatment. Organic indirect and direct effects apply also to settings where the mediator cannot be set. In linear models where the outcome model does not have treatment-mediator interaction, both organic and natural indirect and direct effects lead to the same estimators as in the original formulation of mediation analysis. Here, we generalize organic interventions on the mediator to include interventions combined with the initial treatment fixed at no treatment. We show that the product method holds in linear models for organic indirect and direct effects relative to no treatment even if there is treatment-mediator interaction. Moreover, we find a product method for binary mediators. Furthermore, we argue that the organic indirect effect relative to no treatment is very relevant for drug development. We illustrate the benefits of our approach by estimating the organic indirect effect of curative HIV treatments mediated by two HIV persistence measures, using data on interruption of antiretroviral therapy without curative HIV treatments combined with an estimated or hypothesized effect of the curative HIV treatments on these mediators. See video abstract at http://links.lww.com/EDE/B796.
Asunto(s)
Análisis de Mediación , Modelos Estadísticos , Causalidad , Humanos , Resultado del TratamientoRESUMEN
PURPOSE OF REVIEW: Analytical treatment interruption (ATI) remains an essential component in clinical studies investigating novel agents or combination treatment strategies aiming to induce HIV treatment-free remission or long-term viral control. We provide an overview on key study design aspects of ATI trials from the perspective of statisticians. RECENT FINDINGS: ATI trial designs have evolved towards shorter treatment interruption phases and more frequent viral load monitoring aiming to reduce prolonged viremia risks. Criteria for ART resumption have evolved as well. Common outcome measures in modern ATI trials include time to viral rebound, viral control, and viral set point. Design of the ATI component in HIV clinical trials is driven by the scientific question and the mechanism of action of the intervention being investigated.
Asunto(s)
Infecciones por VIH , Antirretrovirales/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Humanos , Carga Viral , Viremia , Privación de TratamientoRESUMEN
AIDS Clinical Trials Group study A5308 found reduced T-cell activation and exhaustion in human immunodeficiency virus (HIV) controllers start antiretroviral therapy (ART). We further assessed HIV-specific T-cell responses and post-ART viral loads. Before ART, the 31% of participants with persistently undetectable viremia had more robust HIV-specific T-cell responses. During ART, significant decreases were observed in a broad range of T-cell responses. Eight controllers in A5308 and the Study of the Consequences of the Protease Inhibitor Era (SCOPE) cohort showed no viremia above the level of quantification in the first 12 weeks after ART discontinuation. ART significantly reduced HIV-specific T-cell responses in HIV controllers but did not adversely affect controller status after ART discontinuation.