RESUMEN
Within-host HIV populations continually diversify during untreated infection, and this diversity persists within infected cell reservoirs during antiretroviral therapy (ART). Achieving a better understanding of on-ART proviral evolutionary dynamics, and a better appreciation of how the overall persisting pool of (largely genetically defective) proviruses differs from the much smaller replication-competent HIV reservoir, is critical to HIV cure efforts. We reconstructed within-host HIV evolutionary histories in blood from seven participants of the Women's Interagency HIV Study who experienced HIV seroconversion, and used these data to characterize the diversity, lineage origins, and ages of proviral env-gp120 sequences sampled longitudinally up to 12 years on ART. We also studied HIV sequences emerging from the reservoir in two participants. We observed that proviral clonality generally increased over time on ART, with clones frequently persisting long term. While on-ART proviral integration dates generally spanned the duration of untreated infection, HIV emerging in plasma was exclusively younger (i.e., dated to the years immediately pre-ART). The genetic and age distributions of distinct proviral sequences remained stable during ART in all but one participant, in whom there was evidence that younger proviruses had been preferentially eliminated after 12 years on ART. Analysis of the gag region in three participants corroborated our env-gp120-based observations, indicating that our observations are not influenced by the HIV region studied. Our results underscore the remarkable genetic stability of the distinct proviral sequences that persist in blood during ART. Our results also suggest that the replication-competent HIV reservoir is a genetically restricted, younger subset of this overall proviral pool.IMPORTANCECharacterizing the genetically diverse HIV sequences that persist in the reservoir despite antiretroviral therapy (ART) is critical to cure efforts. Our observations confirm that proviruses persisting in blood on ART, which are largely genetically defective, broadly reflect the extent of within-host HIV evolution pre-ART. Moreover, on-ART clonal expansion is not appreciably accompanied by the loss of distinct proviral lineages. In fact, on-ART proviral genetic composition remained stable in all but one participant, in whom, after 12 years on ART, proviruses dating to around near ART initiation had been preferentially eliminated. We also identified recombinant proviruses between parental sequence fragments of different ages. Though rare, such sequences suggest that reservoir cells can be superinfected with HIV from another infection era. Overall, our finding that the replication-competent reservoir in blood is a genetically restricted, younger subset of all persisting proviruses suggests that HIV cure strategies will need to eliminate a reservoir that differs in key respects from the overall proviral pool.
Asunto(s)
Infecciones por VIH , VIH-1 , Provirus , Niño , Femenino , Humanos , Linfocitos T CD4-Positivos , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , VIH-1/genética , Provirus/genética , Carga Viral , Integración ViralRESUMEN
The menopausal transition is a pivotal time of cardiovascular risk, but knowledge is limited in HIV. We studied longitudinal carotid artery intima-media thickness (CIMT) in the Women's Interagency HIV Study (2004-2019; 979 women/3247 person-visits; 72% with HIV). Among women with HIV only, those who transitioned had greater age-related CIMT progression compared to those remaining premenopausal (difference in slope = 1.64â µm/year, P = .002); and CIMT increased over time in the pretransition (3.47â µm/year, P = .002) and during the menopausal transition (9.41â µm/year, P < .0001), but not posttransition (2.9â µm/year, P = .19). In women with HIV, menopause may accelerate subclinical atherosclerosis as measured by CIMT.
Asunto(s)
Aterosclerosis , Infecciones por VIH , Humanos , Femenino , Grosor Intima-Media Carotídeo , Factores de Riesgo , Menopausia , Infecciones por VIH/complicacionesRESUMEN
Long COVID (LongC) is associated with a myriad of symptoms including cognitive impairment. We reported at the beginning of the COVID-19 pandemic that neuronal-enriched or L1CAM+ extracellular vesicles (nEVs) from people with LongC contained proteins associated with Alzheimer's disease (AD). Since that time, a subset of people with prior COVID infection continue to report neurological problems more than three months after infection. Blood markers to better characterize LongC are elusive. To further identify neuronal proteins associated with LongC, we maximized the number of nEVs isolated from plasma by developing a hybrid EV Microfluidic Affinity Purification (EV-MAP) technique. We isolated nEVs from people with LongC and neurological complaints, AD, and HIV infection with mild cognitive impairment. Using the OLINK platform that assesses 384 neurological proteins, we identified 11 significant proteins increased in LongC and 2 decreased (BST1, GGT1). Fourteen proteins were increased in AD and forty proteins associated with HIV cognitive impairment were elevated with one decreased (IVD). One common protein (BST1) was decreased in LongC and increased in HIV. Six proteins (MIF, ENO1, MESD, NUDT5, TNFSF14 and FYB1) were expressed in both LongC and AD and no proteins were common to HIV and AD. This study begins to identify differences and similarities in the neuronal response to LongC versus AD and HIV infection.
Asunto(s)
Enfermedad de Alzheimer , COVID-19 , Vesículas Extracelulares , Infecciones por VIH , Humanos , Síndrome Post Agudo de COVID-19 , Microfluídica , PandemiasRESUMEN
Menopause may impact the earlier onset of aging-related comorbidities among women with versus without human immunodeficiency virus (HIV). We found that menopausal status, age, and HIV were independently associated with higher comorbidity burden, and that HIV impacted burden most in the pre-/perimenopausal phases.
Asunto(s)
Infecciones por VIH , VIH , Femenino , Humanos , Infecciones por VIH/complicaciones , Infecciones por VIH/epidemiología , Menopausia , Envejecimiento , ComorbilidadRESUMEN
BACKGROUND: People with human immunodeficiency virus (HIV) have been reported to have increased risk of clinical and subclinical cardiovascular disease. Existing studies have focused on men and often have been uncontrolled or lacked adequate HIV-negative comparators. METHODS: We performed echocardiography in the Women's Interagency HIV Study to investigate associations of HIV and HIV-specific factors with cardiac phenotypes, including left ventricular systolic dysfunction (LVSD), isolated LV diastolic dysfunction (LVDD), left atrial enlargement (LAE), LV hypertrophy (LVH), and increased tricuspid regurgitation velocity (TRV). RESULTS: Of 1654 participants (age 51 ± 9 years), 70% had HIV. Sixty-three (5.4%) women with HIV (WWH) had LVSD; 71 (6.5%) had isolated LVDD. Compared with women without HIV (WWOH), WWH had a near-significantly increased risk of LVSD (adjusted relative risk = 1.69; 95% confidence interval = 1.00 to 2.86; P = .051). No significant association was noted for HIV seropositivity with other phenotypes, but there was a risk gradient for decreasing CD4+ count among WWH that approached or reached significance for isolated LVDD, LAE, and LVH. WWH with CD4+ count <200 cells/mm3 had significantly higher prevalence of LAE, LVH, and high TRV than WWOH. There were no consistent associations for viral suppression or antiretroviral drug exposure. CONCLUSIONS: This study suggests that WWH have a higher risk of LVSD compared with sociodemographically similar WWOH, but their risk for isolated LVDD, LAE, LVH, and high TRV is increased only with reduced CD4+ count. Although these findings warrant replication, they support the importance of cardiovascular risk-factor and HIV-disease control for heart disease prevention in this population.
Asunto(s)
Infecciones por VIH , Disfunción Ventricular Izquierda , Masculino , Humanos , Femenino , Estados Unidos/epidemiología , Adulto , Persona de Mediana Edad , VIH , Factores de Riesgo , Disfunción Ventricular Izquierda/diagnóstico por imagen , Disfunción Ventricular Izquierda/epidemiología , Disfunción Ventricular Izquierda/complicaciones , Ecocardiografía , Hipertrofia Ventricular Izquierda/diagnóstico por imagen , Hipertrofia Ventricular Izquierda/epidemiología , Hipertrofia Ventricular Izquierda/etiología , Infecciones por VIH/complicaciones , Infecciones por VIH/epidemiologíaRESUMEN
There is an unmet need for a point-of-care test that is accurate, affordable, and simple to diagnose bacterial vaginosis, the most common cause of vaginal symptoms among women. Bacterial vaginosis leaves patients with undesirable vaginal discharge, malodor, and discomfort. Currently, the diagnosis of bacterial vaginosis is inaccurate and complex, leading to high rates of misdiagnosis. Inaccurate diagnoses are unsafe as bacterial vaginosis increases the risks of acquiring sexually transmitted infections as well as the likelihood of miscarriages. To date, the most commonly identified bacteria associated with bacterial vaginosis is Gardnerella vaginalis. We developed a method for the expression, purification, and detection of vaginolysin, the most well-characterized virulence factor of G. vaginalis. Elevated levels of G. vaginalis have been shown to lead to a toxic vaginal environment, facilitating bacterial vaginosis. We have developed an enzyme-linked immunosorbent assay for the detection of vaginolysin, which was translated to a lateral flow assay for use in a rapid, straightforward, cost-effective paper-based diagnostic test for vaginolysin that does not require the use of instrumentation. In conjunction, we have employed a commercially available smartphone microscopy kit to visualize clue cells without the need for equipment or electricity. The combination of these methodologies allows for an accurate and easy approach to diagnose bacterial vaginosis with minimal resources for use in any setting.
Asunto(s)
Vaginosis Bacteriana , Femenino , Gardnerella vaginalis/metabolismo , Humanos , Pruebas en el Punto de Atención , Teléfono Inteligente , Vagina/microbiología , Vaginosis Bacteriana/diagnóstico , Vaginosis Bacteriana/microbiologíaRESUMEN
OBJECTIVE: Syphilis rates among women in the USA more than doubled between 2014 and 2018. We sought to identify correlates of syphilis among women enrolled in the Women's Interagency HIV Study (WIHS) to inform targeted interventions. METHODS: The retrospective cross-sectional analysis of secondary data included women with HIV or at-risk of HIV who enrolled in the multisite US WIHS cohort between 1994 and 2015. Syphilis screening was performed at baseline. Infection was defined serologically by a positive rapid plasma reagin test with confirmatory treponemal antibodies. Sociodemographic and behavioural characteristics stratified by baseline syphilis status were compared for women enrolled during early (1994-2002) and recent (2011-2015) years. Multivariable binomial modelling with backward selection (p>0.2 for removal) was used to model correlates of syphilis. RESULTS: The study included 3692 women in the early cohort and 1182 women in the recent cohort. Syphilis prevalence at enrolment was 7.5% and 3.7% in each cohort, respectively (p<0.01). In adjusted models for the early cohort, factors associated with syphilis included age, black race, low income, hepatitis C seropositivity, drug use, HIV infection and >100 lifetime sex partners (all p<0.05). In the recent cohort, age (adjusted prevalence OR (aPOR) 0.2, 95% CI 0.1 to 0.6 for 30-39 years; aPOR 0.5, 95% CI 0.2 to 1.0 for 40-49 years vs ≥50 years), hepatitis C seropositivity (aPOR 2.1, 95% CI 1.0 to 4.1) and problem alcohol use (aPOR 2.2, 95% CI 1.1 to 4.4) were associated with infection. CONCLUSIONS: Syphilis screening is critical for women with HIV and at-risk of HIV. Targeted prevention efforts should focus on women with hepatitis C and problem alcohol use.
Asunto(s)
Infecciones por VIH/epidemiología , Serodiagnóstico de la Sífilis/estadística & datos numéricos , Sífilis/epidemiología , Sífilis/inmunología , Adolescente , Adulto , Estudios Transversales , Femenino , Humanos , Persona de Mediana Edad , Embarazo , Complicaciones Infecciosas del Embarazo/epidemiología , Estudios Retrospectivos , Factores de Riesgo , Estudios Seroepidemiológicos , Sífilis/etiología , Estados Unidos , Adulto JovenRESUMEN
Long-acting injectable (LAI) modalities have been developed for ART and PrEP. Women face unique barriers to LAI use yet little research has examined women's perceptions of potential LAI HIV therapy candidates. We conducted 89 in-depth interviews at six Women's Interagency HIV Study (WIHS) sites with women living with HIV (n = 59) and HIV-negative women (n = 30) from 2017 to 2018. Interviews were recorded, transcribed, and analyzed using thematic content analysis. Participants identified specific sub-populations who could most benefit from LAI over daily pills: (1) young people; (2) women with childcare responsibilities; (3) people with adherence-related psychological distress; (4) individuals with multiple sex partners; and (5) people facing structural insecurities such as homelessness. Women are underserved by current HIV care options and their perspectives are imperative to ensure a successful scale-up of LAI PrEP and LAI ART that prioritizes equitable access and benefit for all individuals.
Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , Profilaxis Pre-Exposición , Adolescente , Fármacos Anti-VIH/uso terapéutico , Ciudades , Femenino , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/prevención & control , Infecciones por VIH/psicología , Humanos , Aceptación de la Atención de Salud , Estados Unidos/epidemiologíaRESUMEN
BACKGROUND: The prevalence and burden of age-related non-AIDS comorbidities (NACMs) are poorly characterized among women living with HIV (WLWH). METHODS: Virologically suppressed WLWH and HIV-seronegative participants followed in the Women's Interagency HIV Study (WIHS) through at least 2009 (when >80% of WLWH used antiretroviral therapy) were included, with outcomes measured through 31 March 2018. Covariates, NACM number, and prevalence were summarized at most recent WIHS visit. We used linear regression models to determine NACM burden by HIV serostatus and age. RESULTS: Among 3232 women (2309 WLWH, 923 HIV-seronegative) with median observation of 15.3 years, median age and body mass index (BMI) were 50 years and 30 kg/m2, respectively; 65% were black; 70% ever used cigarettes. WLWH had a higher mean NACM number than HIV-seronegative women (3.6 vs 3.0, Pâ <â .0001) and higher prevalence of psychiatric illness, dyslipidemia, non-AIDS cancer, kidney, liver, and bone disease (all Pâ <â .01). Prevalent hypertension, diabetes, and cardiovascular and lung disease did not differ by HIV serostatus. Estimated NACM burden was higher among WLWH versus HIV-seronegative women in those aged 40-49 (Pâ <â .0001) and ≥60 years (Pâ =â .0009) (HIV × age interaction, Pâ =â .0978). In adjusted analyses, NACM burden was associated with HIV, age, race, income, BMI, alcohol abstinence, cigarette, and crack/cocaine use; in WLWH, additional HIV-specific indices were not associated, aside from recent abacavir use. CONCLUSIONS: Overall, NACM burden was high in the cohort, but higher in WLWH and in certain age groups. Non-HIV traditional risk factors were significantly associated with NACM burden in WLWH and should be prioritized in clinical guidelines for screening and intervention to mitigate comorbidity burden in this high-risk population.
Asunto(s)
Infecciones por VIH , Adulto , Estudios de Cohortes , Comorbilidad , Femenino , Infecciones por VIH/complicaciones , Infecciones por VIH/epidemiología , Humanos , Persona de Mediana Edad , Prevalencia , Factores de Riesgo , Estados Unidos/epidemiologíaRESUMEN
BACKGROUND: Human immunodeficiency virus (HIV) infection may accelerate development of aging-related non-AIDS comorbidities (NACMs). The incidence of NACMs is poorly characterized among women living with HIV (WLWH). METHODS: WLWH and HIV-seronegative participants followed in the Women's Interagency HIV Study (WIHS) through 2009 (when >80% of WLWH used antiretroviral therapy) or onward were included, with outcomes measured through 31 March 2018. Sociodemographics, clinical covariates, and prevalent NACM were determined at enrollment. We used Poisson regression models to determine incident NACM burden (number of NACMs accrued through most recent WIHS visit out of 10 total NACMs assessed) by HIV serostatus and age. RESULTS: There were 3129 participants (2239 WLWH, 890 HIV seronegative) with 36 589 person-years of follow-up. At enrollment, median age was 37 years, 65% were black, and 47% currently smoked. In fully adjusted analyses, WLWH had a higher incident NACM rate compared with HIV-seronegative women (incidence rate ratio, 1.36 [95% confidence interval (CI), 1.02-1.81]). Incident NACM burden was higher among WLWH vs HIV-seronegative women in most age strata (HIV × age interaction: Pâ =â .0438), and women <25 years old had the greatest incidence rate ratio by HIV serostatus at 1.48 (95% CI, 1.19-1.84) compared with those in older age groups. Incident NACM burden was associated with traditional comorbidity risk factors but not HIV-specific indices. CONCLUSIONS: Incident NACM burden was higher among WLWH than HIV-seronegative women. This difference was most dramatic among women aged <25 years, a group for whom routine comorbidity screening is not prioritized. Established non-HIV comorbidity risk factors were significantly associated with incident NACM burden. More data are needed to inform best practices for NACM screening, prevention, and management among WLWH, particularly young women.
Asunto(s)
Síndrome de Inmunodeficiencia Adquirida , Infecciones por VIH , Adulto , Anciano , Comorbilidad , Femenino , VIH , Infecciones por VIH/complicaciones , Infecciones por VIH/epidemiología , Humanos , Factores de Riesgo , Estados Unidos/epidemiologíaRESUMEN
BACKGROUND: Current US cervical cancer screening guidelines recommend screening cessation at the age of 65 years provided women have adequate previous screening and no history of precancer. Women living with HIV are at higher risk of cervical cancer than women living without HIV. Furthermore, limited data exists to quantify the risk of cervical cancer among women who otherwise would qualify for screening cessation. OBJECTIVE: This study aimed to determine whether guidelines recommending women to discontinue cervical cancer screening at the age of 65 years are appropriate for women living with HIV. STUDY DESIGN: Semiannual Papanicolaou testing was performed as part of surveillance visits in the Women's Interagency HIV Study. Launched in October 1994, the Women's Interagency HIV Study is a federally funded US multisite cohort study that has enrolled 3678 women living with HIV and 1304 women living without HIV; we included data throughout September 2019 onward. Conventional Papanicolaou tests were collected at scheduled 6-month visits and read centrally according to the 1991 Bethesda System criteria. Results were analyzed among women at least 65 years of age. The primary endpoint was high-grade cytology, including high-grade squamous intraepithelial lesions; atypical glandular cells; atypical squamous cells, cannot exclude high-grade lesions; and malignant cytology. Wilcoxon rank-sum tests were used to compare the continuous variables, and Chi-square tests or the Fisher exact tests were used to compare the categorical variables. The Kaplan-Meier method was used to calculate the cumulative incidence. Poisson regression was used to compare 2 incidence rates. RESULTS: Of 169 eligible women (121 women living with HIV and 48 women living without HIV) who contributed 678.4 person-years of observation after reaching the age of 65 years, 2.2% had high-grade cytologic abnormalities. However, no cancer was found. Furthermore, 20 women had previous precancer results, and 74 women had abnormal Papanicolaou test results in the previous decade. Among 50 women (38 women living with HIV and 12 women living without HIV) with a previous hysterectomy and no history of cervical precancer, the cumulative incidence rates of high-grade squamous intraepithelial lesions were 0.6 (95% confidence interval, 0.0-3.2) per 100 person-years for women living with HIV and 0.0 (95% confidence interval, 0.0-8.1) per 100 person-years for women living without HIV (P=.61). Only 48 women (27 women living with HIV and 21 women living without HIV) had cervices and met the current guidelines to discontinue screening; their risk of experiencing high-grade squamous intraepithelial lesions was 2.2 (95% confidence interval, 0.6-5.5) per 100 person-years overall and did not vary by HIV status (2.3 [95% confidence interval, 0.5-6.8] per 100 person-years for women living with HIV and 1.8 [95% confidence interval, 0.0-9.8] per 100 person-years for women living without HIV; P=.81). CONCLUSION: Most women living with HIV do not meet the criteria for cervical cancer screening cessation and will need to continue screening over the age of 65 years; however, women who meet the criteria for screening cessation have risks of high-grade squamous lesions similar to women living without HIV and may choose to discontinue.
Asunto(s)
Células Escamosas Atípicas del Cuello del Útero/patología , Carcinoma de Células Escamosas/epidemiología , Infecciones por VIH/epidemiología , Lesiones Intraepiteliales Escamosas de Cuello Uterino/epidemiología , Neoplasias del Cuello Uterino/epidemiología , Anciano , Carcinoma de Células Escamosas/patología , Estudios de Casos y Controles , Comorbilidad , Detección Precoz del Cáncer , Femenino , Humanos , Prueba de Papanicolaou , Guías de Práctica Clínica como Asunto , Lesiones Intraepiteliales Escamosas de Cuello Uterino/patología , Neoplasias del Cuello Uterino/patología , Frotis VaginalRESUMEN
As the use of Integrase inhibitor (INSTI)-class antiretroviral medications becomes more common to maintain long-term viral suppression, early reports suggest the potential for CNS side-effects when starting or switching to an INSTI-based regimen. In a population already at higher risk for developing mood and anxiety disorders, these drugs may have significant effects on PTSD scale symptom scores, particularly in women with HIV (WWH). A total of 551 participants were included after completing ≥ 1 WIHS study visits before and after starting/switching to an INSTI-based ART regimen. Of these, 14% were ART naïve, the remainder switched from primarily a protease inhibitor (PI) or non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen. Using multivariable linear mixed effects models, we compared PTSD Civilian Checklist subscale scores before and after a "start/switch" to dolutegravir (DTG), raltegravir (RAL), or elvitegravir (EVG). Start/switch to EVG improved re-experiencing subscale symptoms (P's < 0.05). Switching to EVG improved symptoms of avoidance (P = 0.01). Starting RAL improved arousal subscale symptoms (P = 0.03); however, switching to RAL worsened re-experiencing subscale symptoms (P < 0.005). Starting DTG worsened avoidance subscale symptoms (P = 0.03), whereas switching to DTG did not change subscale or overall PTSD symptoms (P's > 0.08). In WWH, an EVG-based ART regimen is associated with improved PTSD symptoms, in both treatment naïve patients and those switching from other ART. While a RAL-based regimen was associated with better PTSD symptoms than in treatment naïve patients, switching onto a RAL-based regimen was associated with worse PTSD symptoms. DTG-based regimens either did not affect, or worsened symptoms, in both naïve and switch patients. Further studies are needed to determine mechanisms underlying differential effects of EVG, RAL and DTG on stress symptoms in WWH.
Asunto(s)
Infecciones por VIH , Inhibidores de Integrasa VIH , Trastornos por Estrés Postraumático , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/efectos adversos , Antirretrovirales/administración & dosificación , Antirretrovirales/efectos adversos , Femenino , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/psicología , Inhibidores de Integrasa VIH/administración & dosificación , Inhibidores de Integrasa VIH/efectos adversos , Inhibidores de la Proteasa del VIH/administración & dosificación , Inhibidores de la Proteasa del VIH/efectos adversos , Humanos , Raltegravir Potásico/administración & dosificación , Raltegravir Potásico/efectos adversos , Inhibidores de la Transcriptasa Inversa/administración & dosificación , Inhibidores de la Transcriptasa Inversa/efectos adversos , Trastornos por Estrés Postraumático/tratamiento farmacológico , Trastornos por Estrés Postraumático/epidemiologíaRESUMEN
Infection by human papillomavirus (HPV) type 16, the most oncogenic HPV type, was found to be the least affected by HIV-status and CD4 count of any of the approximately 13 oncogenic HPV types. This relative independence from host immune status has been interpreted as evidence that HPV16 may have an innate ability to avoid the effects of immunosurveillance. However, the impact of immune status on other individual HPV types has not been carefully assessed. We studied type-specific HPV infection in a cohort of 2,470 HIV-positive (HIV[+]) and 895 HIV-negative (HIV[-]) women. Semi-annually collected cervicovaginal lavages were tested for >40 HPV types. HPV type-specific prevalence ratios (PRs), incidence and clearance hazard ratios (HRs), were calculated by contrasting HPV types detected in HIV[+] women with CD4 < 200 to HIV[-] women. HPV71 and HPV16 prevalence had the weakest associations with HIV-status/CD4 count of any HPV, according to PRs. No correlations between PRs and HPV phylogeny or oncogenicity were observed. Instead, higher HPV type-specific prevalence in HIV[-] women correlated with lower PRs (ρ = -0.59; p = 0.0001). An alternative (quadratic model) statistical approach (PHIV+ = a*PHIV- + b*PHIV- 2 ; R2 = 0.894) found similar associations (p = 0.0005). In summary, the most prevalent HPV types in HIV[-] women were the types most independent from host immune status. These results suggest that common HPV types in HIV[-] women may have a greater ability to avoid immune surveillance than other types, which may help explain why they are common.
Asunto(s)
Seropositividad para VIH/inmunología , Evasión Inmune , Papillomaviridae/inmunología , Infecciones por Papillomavirus/epidemiología , Neoplasias del Cuello Uterino/prevención & control , Adulto , Recuento de Linfocito CD4 , Cuello del Útero/patología , Cuello del Útero/virología , ADN Viral/genética , ADN Viral/aislamiento & purificación , Femenino , Seropositividad para VIH/sangre , Seropositividad para VIH/diagnóstico , Humanos , Prueba de Papanicolaou/estadística & datos numéricos , Papillomaviridae/genética , Papillomaviridae/aislamiento & purificación , Infecciones por Papillomavirus/inmunología , Infecciones por Papillomavirus/patología , Infecciones por Papillomavirus/virología , Filogenia , Prevalencia , Estudios Prospectivos , Neoplasias del Cuello Uterino/inmunología , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/virología , Adulto JovenRESUMEN
The altered immune states of aging and HIV infection may affect intracellular metabolism of tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC); increased cellular senescence decreases FTC-triphosphate (FTCtp) concentrations. The effects of age and inflammation on the ratio of intracellular metabolites (IMs; tenofovir diphosphate [TFVdp] and FTCtp) to their endogenous nucleotides (ENs; dATP and dCTP), a potential treatment efficacy marker, were assessed among participants of the Women's Interagency HIV Study (WIHS), who ranged from 25 to 75 years. Samples from women receiving TDF-FTC with viral loads of <200 copies/ml were dichotomized by age at collection into two groups (≤45 years and ≥60 years). IM/EN concentrations were measured in peripheral blood mononuclear cell (PBMC) pellets; interleukin-6 (IL-6) and sCD163 were measured in plasma; senescent CD8+ T cells were measured in viable PBMCs. The TFVdp:dATP and FTCtp:dCTP ratios had statistically significantly different distributions in older and younger women (log-rank test, P = 0.0023 and P = 0.032, respectively); in general, IM and EN concentrations were higher in the older women. After adjusting for potential confounders, these findings were not significant. In women aged ≤45 years, TFVdp was negatively associated with IL-6 and sCD163, while FTCtp was positively associated with sCD163 and IL-6 in women aged ≥60 years. Body mass index (BMI) was positively associated with IL-6 in both age groups and negatively associated with TFVdp in women aged ≤45 years. After adjustment, age remained significant for sCD163, while black race, BMI, and renal function remained significant for several IMs and ENs, suggesting that factors associated with aging, but not age itself, govern intracellular TDF-FTC pharmacology.
Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , Adulto , Anciano , Fármacos Anti-VIH/uso terapéutico , Linfocitos T CD8-positivos , Emtricitabina/uso terapéutico , Femenino , Infecciones por VIH/tratamiento farmacológico , Humanos , Leucocitos Mononucleares , Persona de Mediana Edad , Tenofovir/uso terapéuticoRESUMEN
IL-7 therapy has been evaluated in patients who do not regain normal CD4 T cell counts after virologically successful antiretroviral therapy. IL-7 increases total circulating CD4 and CD8 T cell counts; however, its effect on HIV-specific CD8 T cells has not been fully examined. TRAF1, a prosurvival signaling adaptor required for 4-1BB-mediated costimulation, is lost from chronically stimulated virus-specific CD8 T cells with progression of HIV infection in humans and during chronic lymphocytic choriomeningitis infection in mice. Previous results showed that IL-7 can restore TRAF1 expression in virus-specific CD8 T cells in mice, rendering them sensitive to anti-4-1BB agonist therapy. In this article, we show that IL-7 therapy in humans increases the number of circulating HIV-specific CD8 T cells. For a subset of patients, we also observed an increased frequency of TRAF1+ HIV-specific CD8 T cells 10 wk after completion of IL-7 treatment. IL-7 treatment increased levels of phospho-ribosomal protein S6 in HIV-specific CD8 T cells, suggesting increased activation of the metabolic checkpoint kinase mTORC1. Thus, IL-7 therapy in antiretroviral therapy-treated patients induces sustained changes in the number and phenotype of HIV-specific T cells.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Infecciones por VIH/inmunología , Infecciones por VIH/metabolismo , VIH-1/inmunología , Proteína S6 Ribosómica/metabolismo , Factor 1 Asociado a Receptor de TNF/metabolismo , Terapia Antirretroviral Altamente Activa , Recuento de Linfocito CD4 , Citocinas/biosíntesis , Expresión Génica , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , Receptor 2 Celular del Virus de la Hepatitis A/metabolismo , Humanos , Interleucina-7/farmacología , Interleucina-7/uso terapéutico , Recuento de Linfocitos , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Receptor de Muerte Celular Programada 1/metabolismo , Unión Proteica , Proteínas Recombinantes/farmacología , Proteínas Recombinantes/uso terapéutico , Proteína S6 Ribosómica/genética , Factor 1 Asociado a Receptor de TNF/genética , Carga ViralRESUMEN
AIDS Clinical Trial Group study A5202 (ClinicalTrials.gov identifier NCT00118898) was a phase 3b, randomized, partially blinded equivalence study of open-label atazanavir/ritonavir or efavirenz, plus either placebo-controlled tenofovir disoproxil fumarate/emtricitabine or abacavir/lamivudine, in treatment-naive adults living with HIV-1, evaluating efficacy, safety, and tolerability. We report an analysis of the contribution of participant characteristics to the disposition of tenofovir plasma concentrations. Tenofovir concentration data from a total of 817 individuals (88% of the total number of eligible patients randomly assigned to receive treatment in the TDF-containing arms of A5202) were available for analysis. Pharmacokinetic analysis was performed using nonlinear mixed-effects modeling. One- and two-compartment models with first-order absorption and first-order elimination were evaluated. An exponential error model was used for examination of interindividual variability (IIV), and a proportional and mixed-error model was assessed for residual variability. The final structural model contained two compartments with first-order absorption and elimination. IIV was estimated for apparent clearance (CL/F) and the first-order absorption rate constant (ka ), and a proportional residual variability model was selected. The final mean parameter estimates were as follows: ka = 2.87 h-1, CL/F = 37.2 liters/h, apparent volumes of the central and peripheral compartments = 127 and 646 liters, respectively, and apparent intercompartmental clearance = 107 liters/h. In addition to race/ethnicity, creatinine clearance and assignment to atazanavir/ritonavir or efavirenz were significantly associated with CL/F (P < 0.001). In conclusion, race/ethnicity is associated with tenofovir oral CL in HIV-1 positive, treatment-naive adults. This covariate relationship raises questions about the possibility of differences in efficacy and risk of adverse events in different patient populations and suggests that examining preexposure prophylaxis regimens and tenofovir exposure in different race/ethnicity groups be considered.
Asunto(s)
Fármacos Anti-VIH/sangre , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/etnología , Inhibidores de la Proteasa del VIH/uso terapéutico , VIH-1 , Tenofovir/sangre , Adulto , Alquinos , Fármacos Anti-VIH/farmacocinética , Fármacos Anti-VIH/uso terapéutico , Benzoxazinas/sangre , Benzoxazinas/uso terapéutico , Ciclopropanos , Didesoxinucleósidos/sangre , Didesoxinucleósidos/uso terapéutico , Combinación de Medicamentos , Emtricitabina/sangre , Emtricitabina/uso terapéutico , Femenino , Inhibidores de la Proteasa del VIH/farmacocinética , Humanos , Lamivudine/sangre , Lamivudine/uso terapéutico , Masculino , Persona de Mediana Edad , Modelos Biológicos , Ritonavir/farmacocinética , Ritonavir/uso terapéutico , Tenofovir/farmacocinética , Tenofovir/uso terapéuticoRESUMEN
A nested case-cohort study was performed in participants of a clinical trial of first-line human immunodeficiency virus treatments to investigate plasma biomarkers of inflammation and microbial translocation for their association with immune reconstitution inflammatory syndrome (IRIS). Fifty-one of 1452 participants with baseline CD4 count <350 cells/µL developed IRIS. Plasma from 51 IRIS cases, including 6 stratified by preenrollment CD4 count ≤200 cells/µL, were analyzed and compared to 94 non-IRIS controls. At baseline, CXCL10, lipopolysaccharide, soluble CD14, 16S ribosomal DNA, and interferon-α2 were associated with greater risk of IRIS. Systemic inflammation through persistent monocyte activation and microbial translocation appear to be important in IRIS pathogenesis.
Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Biomarcadores/sangre , Citocinas/sangre , Infecciones por VIH/tratamiento farmacológico , Síndrome Inflamatorio de Reconstitución Inmune/sangre , Síndrome Inflamatorio de Reconstitución Inmune/inmunología , Translocación Genética/inmunología , Estudios de Cohortes , HumanosRESUMEN
BACKGROUND: Efavirenz is currently suggested as an alternative to recommended antiretroviral (ARV) regimens by the Department of Health and Human Services for the treatment of HIV-1 in ARV-naive patients. A mid-dosing interval therapeutic range between 1000 and 4000 ng/mL for efavirenz has been proposed in the literature, with patients more likely to experience virologic failure below this range and adverse effects above. The current study reports an analysis of virologic outcome between those above, below, or within the reported efavirenz therapeutic range (1000-4000 ng/mL) and within subgroups. METHODS: This analysis examined efavirenz plasma concentrations obtained from participants enrolled in AIDS Clinical Trials Group Study A5202. This investigation divided subjects into those who experienced virologic failure and those who did not. These subjects were further separated to investigate those who had "high," "within," or "low" plasma concentrations, based on the therapeutic range. The association between virologic failure and plasma concentration was statistically examined in addition to the variables: race/ethnicity, sex, assigned nucleos(t)ide reverse transcriptase inhibitor backbone, age at study entry, history of intravenous drug use, weight, and screening HIV-1 RNA stratification level. RESULTS: In univariate analyses, a statistically significant difference was found when comparing the efavirenz concentration groups, (22 failures among the "low" concentration group [19%], 65 failures among the "within" concentration group [12%], and 11 failures among the "high" concentration group [9%]) when evaluating virologic failure as an outcome (P = 0.04). In addition, the proportion of participants with virologic failure differed across race/ethnicity groups (P = 0.03) with black non-Hispanic participants observed to have the highest rate (17%). Efavirenz concentration group, race/ethnicity, age, weight, and the interaction between efavirenz concentration group and weight were found to be significantly associated with virologic failure in multivariable logistic regression analysis. CONCLUSIONS: The proposed efavirenz therapeutic range, combined with the impact of a patient's weight, is associated with virologic failure in HIV-infected ARV-naive individuals in the United States. Additional analysis is recommended to determine the most appropriate concentration value that defines the lower limit of the efavirenz therapeutic range.
Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Benzoxazinas/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , VIH-1 , Adulto , Alquinos , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/sangre , Benzoxazinas/administración & dosificación , Benzoxazinas/sangre , Ciclopropanos , Femenino , Humanos , Masculino , Persona de Mediana Edad , ARN Viral , Insuficiencia del Tratamiento , Carga ViralRESUMEN
This study aimed to describe demographic and psychological characteristics among HIV-infected young women, and to identify knowledge, attitudes, and behaviors associated with conception, with the goal of informing interventions or programmatic decisions regarding preconception counseling methods for young women living with HIV. Behaviorally and perinatally HIV-infected young women (n = 34) were conveniently sampled in Miami, Florida. Participants were asked to complete measures of reproductive knowledge, attitudes toward conception, and risk behaviors, as well as measures of depression and cognitive functioning. Perinatally and behaviorally HIV-infected young women were very similar in important areas of health preconception practices such as conception-related health literacy and conception-related communication with providers. Behaviorally infected women, however, were somewhat more likely to have been pregnant in the past, and had greater knowledge of healthy contraception practices and family planning. Despite the difference among groups, both the perinatally and behaviorally acquired women demonstrated having adequate overall knowledge. Depression was higher and consistent with moderate depression among the behaviorally HIV-infected women in comparison to perinatally infected women. This study found that that despite adequate reproductive knowledge, most young HIV-infected women were not using contraception. Given the consequences of presentation of advanced HIV during pregnancy, the need for both treatment adherence and preconception counseling is essential. Results suggest that interventions or programmatic decisions regarding preconception counseling methods for young women living with HIV are necessary and potentially transferrable between populations.
Asunto(s)
Consejo , Infecciones por VIH/psicología , Conocimientos, Actitudes y Práctica en Salud , Complicaciones Infecciosas del Embarazo/psicología , Atención Prenatal , Adolescente , Servicios de Salud del Adolescente , Adulto , Servicios de Planificación Familiar , Femenino , Florida , Humanos , Recién Nacido , Embarazo , Asunción de Riesgos , Adulto JovenRESUMEN
BACKGROUND: Intravaginal practices (IVP) (cleansing or introducing products inside the vagina for hygiene, health or to please sexual partners) are common among women with HIV. IVP increase the risk of developing bacterial Vaginosis (BV), the most common genital infection associated with transmission of sexually transmitted infections and HIV. This study tested a pilot intervention to reduce IVP and BV in HIV infected women in Zambia. METHODS: One hundred twenty-eight HIV infected women engaging in IVP were randomized to two conditions: enhanced standard of care (n = 70) and experimental (n = 58) from May 1, 2013 to February 28, 2014. All participants received a brief educational counseling session on discontinuation of IVP, and those with BV, were provided with medical treatment for BV. Women in the experimental condition received an additional group-based, culturally tailored intervention. Participants completed questionnaires assessing sexual risk factors and IVP and were assessed for BV using Nugent criteria at baseline, 6 months and 12 months. RESULTS: At 12-month, the proportion of self-reported use of IVPs decreased in the experimental condition: soap (28% vs. 47%); cloth or a rag (19% vs. 38%); and traditional medicines (22% vs. 42%) (all p < 0.05)) compared with the enhanced standard of care condition. The prevalence of BV at 6 and 12 months did not differ by study condition but averaging over study condition, prevalence of BV decreased from 64.2% at baseline to 15.6% at 6 months (p < 0.01) and to 23.6% at 12 months (p = 0.15). Using an enhanced standard of care approach and an enhanced standard of care + a group intervention, IVP and BV decreased over time, but the experimental condition had greater reduction in self-reported use of IVP. CONCLUSIONS: Future studies should address interventions in communities with high burden of IVP, BV and HIV. Interventions that could be administered during routine medical care and decrease IVP and BV are needed, and should be considered part of women's health programs. TRIAL REGISTRATION NUMBER: NCT03134924 (retrospectively registered 21st April 2017).