RESUMO
As of October 21, 2022, a total of 27,884 monkeypox cases (confirmed and probable) have been reported in the United States.§ Gay, bisexual, and other men who have sex with men have constituted a majority of cases, and persons with HIV infection and those from racial and ethnic minority groups have been disproportionately affected (1,2). During previous monkeypox outbreaks, severe manifestations of disease and poor outcomes have been reported among persons with HIV infection, particularly those with AIDS (3-5). This report summarizes findings from CDC clinical consultations provided for 57 patients aged ≥18 years who were hospitalized with severe manifestations of monkeypox¶ during August 10-October 10, 2022, and highlights three clinically representative cases. Overall, 47 (82%) patients had HIV infection, four (9%) of whom were receiving antiretroviral therapy (ART) before monkeypox diagnosis. Most patients were male (95%) and 68% were non-Hispanic Black (Black). Overall, 17 (30%) patients received intensive care unit (ICU)-level care, and 12 (21%) have died. As of this report, monkeypox was a cause of death or contributing factor in five of these deaths; six deaths remain under investigation to determine whether monkeypox was a causal or contributing factor; and in one death, monkeypox was not a cause or contributing factor.** Health care providers and public health professionals should be aware that severe morbidity and mortality associated with monkeypox have been observed during the current outbreak in the United States (6,7), particularly among highly immunocompromised persons. Providers should test all sexually active patients with suspected monkeypox for HIV at the time of monkeypox testing unless a patient is already known to have HIV infection. Providers should consider early commencement and extended duration of monkeypox-directed therapy in highly immunocompromised patients with suspected or laboratory-diagnosed monkeypox.§§ Engaging all persons with HIV in sustained care remains a critical public health priority.
Assuntos
Infecções por HIV , Mpox , Minorias Sexuais e de Gênero , Estados Unidos/epidemiologia , Humanos , Masculino , Adolescente , Adulto , Feminino , Infecções por HIV/diagnóstico , Homossexualidade Masculina , Etnicidade , Vigilância da População , Grupos Minoritários , Mpox/epidemiologiaRESUMO
Among men who have sex with men (MSM), those with a diagnosis of syphilis or other rectal sexually transmitted infections (STIs) are at a higher risk for human immunodeficiency virus acquisition, which is concerning given the large increase in recently reported syphilis cases in the United States. We have developed the first nonhuman primate model for rectally transmitted syphilis by exposing simian/human immunodeficiency virus-infected and naive rhesus macaques to Treponema pallidum in the rectum. All animals showed mucosal lesions, systemic dissemination, and seroconversion (treponemal antibodies). This model would be valuable for studying the manifestations of and interventions for T. pallidum infection, with and without human immunodeficiency virus coinfection.
Assuntos
Macaca mulatta , Síndrome de Imunodeficiência Adquirida dos Símios/complicações , Sífilis/transmissão , Animais , Linfócitos T CD4-Positivos , Coinfecção , Modelos Animais de Doenças , Feminino , Masculino , Peptídeos Cíclicos , Reto , Infecções Sexualmente Transmissíveis , Vírus da Imunodeficiência Símia , Treponema pallidum , ViremiaRESUMO
Background: Nondaily dosing of oral preexposure prophylaxis (PrEP) may provide equivalent coverage of sex events compared with daily dosing. Methods: At-risk men and transgender women who have sex with men were randomly assigned to 1 of 3 dosing regimens: 1 tablet daily, 1 tablet twice weekly with a postsex dose (time-driven), or 1 tablet before and after sex (event-driven), and were followed for coverage of sex events with pre- and postsex dosing measured by weekly self-report, drug concentrations, and electronic drug monitoring. Results: From July 2012 to May 2014, 357 participants were randomized. In Bangkok, the coverage of sex events was 85% for the daily arm compared with 84% for the time-driven arm (P = .79) and 74% for the event-driven arm (P = .02). In Harlem, coverage was 66%, 47% (P = .01), and 52% (P = .01) for these groups. In Bangkok, PrEP medication concentrations in blood were consistent with use of ≥2 tablets per week in >95% of visits when sex was reported in the prior week, while in Harlem, such medication concentrations occurred in 48.5% in the daily arm, 30.9% in the time-driven arm, and 16.7% in the event-driven arm (P < .0001). Creatinine elevations were more common in the daily arm (P = .050), although they were not dose limiting. Conclusions: Daily dosing recommendations increased coverage and protective drug concentrations in the Harlem cohort, while daily and nondaily regimens led to comparably favorable outcomes in Bangkok, where participants had higher levels of education and employment. Clinical Trials Registration: NCT01327651.
Assuntos
Emtricitabina/uso terapêutico , Infecções por HIV/prevenção & controle , Adesão à Medicação , Profilaxia Pré-Exposição , Tenofovir/uso terapêutico , Pessoas Transgênero , Adolescente , Adulto , Fármacos Anti-HIV/uso terapêutico , Esquema de Medicação , Emtricitabina/administração & dosagem , Feminino , Infecções por HIV/tratamento farmacológico , Homossexualidade Masculina , Humanos , Masculino , Tenofovir/administração & dosagem , Adulto JovemRESUMO
Background: Recent studies have shown that some vaccines have beneficial effects that cannot be explained solely by the prevention of their respective targeted disease(s). Methods: We used the MarketScan US Commercial Claims Databases for 2005 to 2014 to assess the risk of hospital admission for nontargeted infectious (NTI) diseases in children aged 16 through 24 months according to the last vaccine type (live and/or inactivated). We included children continuously enrolled within a month of birth through 15 months who received at least 3 doses of diphtheria-tetanus-acellular pertussis vaccine by the end of 15 months of age. We used Cox regression to estimate hazard ratios (HRs), stratifying by birthdate to control for age, year, and seasonality and adjusting for sex, chronic diseases, prior hospitalizations, number of outpatient visits, region of residence, urban/rural area of domicile, prematurity, low birth weight, and mother's age. Results: 311663 children were included. In adjusted analyses, risk of hospitalization for NTI from ages 16 through 24 months was reduced for those who received live vaccine alone compared with inactivated alone or concurrent live and inactivated vaccines (HR, 0.50; 95% confidence interval [CI], 0.43, 0.57 and HR, 0.78; 95% CI, 0.67, 0.91, respectively) and for those who received live and inactivated vaccines concurrently compared with inactivated-only (HR, 0.64; 95% CI, 0.58, 0.70). Conclusions: We found lower risk of NTI disease hospitalizations from age 16 through 24 months among children whose last vaccine received was live compared with inactivated vaccine, as well as concurrent receipt compared with inactivated vaccine.
Assuntos
Doenças Transmissíveis/epidemiologia , Hospitalização/estatística & dados numéricos , Vacinação/estatística & dados numéricos , Adolescente , Adulto , Assistência Ambulatorial/estatística & dados numéricos , Pré-Escolar , Vacinas contra Difteria, Tétano e Coqueluche Acelular/administração & dosagem , Feminino , Humanos , Lactente , Masculino , Estudos Retrospectivos , Vacinas de Produtos Inativados/administração & dosagem , Adulto JovemRESUMO
BACKGROUND.: The OraQuick Advance Rapid HIV-1/2 Test is a point-of-care test capable of detecting human immunodeficiency virus (HIV)-specific antibodies in blood and oral fluid. To understand test performance and factors contributing to false-negative results in longitudinal studies, we examined results of participants enrolled in the Botswana TDF/FTC Oral HIV Prophylaxis Trial, the Bangkok Tenofovir Study, and the Bangkok MSM Cohort Study, 3 separate clinical studies of high-risk, HIV-negative persons conducted in Botswana and Thailand. METHODS.: In a retrospective observational analysis, we compared oral fluid OraQuick (OFOQ) results among participants becoming HIV infected to results obtained retrospectively using enzyme immunoassay and nucleic acid amplification tests on stored specimens. We categorized negative OFOQ results as true-negative or false-negative relative to nucleic acid amplification test and/or enzyme immunoassay, and determined the delay in OFOQ conversion relative to the estimated time of infection. We used log-binomial regression and generalized estimating equations to examine the association between false-negative results and participant, clinical, and testing-site factors. RESULTS.: Two-hundred thirty-three false-negative OFOQ results occurred in 80 of 287 seroconverting individuals. Estimated OFOQ conversion delay ranged from 14.5 to 547.5 (median, 98.5) days. Delayed OFOQ conversion was associated with clinical site and test operator (P < .05), preexposure prophylaxis (P = .01), low plasma viral load (P < .02), and time to kit expiration (P < .01). Participant age, sex, and HIV subtype were not associated with false-negative results. Long OFOQ conversion delay time was associated with antiretroviral exposure and low plasma viral load. CONCLUSIONS.: Failure of OFOQ to detect HIV-1 infection was frequent and multifactorial in origin. In longitudinal trials, negative oral fluid results should be confirmed via testing of blood samples.
Assuntos
Sorodiagnóstico da AIDS , Anticorpos Anti-HIV/análise , Infecções por HIV/diagnóstico , HIV-1/isolamento & purificação , Sistemas Automatizados de Assistência Junto ao Leito , Saliva/imunologia , Adulto , Botsuana/epidemiologia , Estudos Clínicos como Assunto , Reações Falso-Negativas , Feminino , Anticorpos Anti-HIV/sangue , Infecções por HIV/epidemiologia , Infecções por HIV/virologia , HIV-1/genética , HIV-1/imunologia , HIV-2/genética , HIV-2/imunologia , HIV-2/isolamento & purificação , Humanos , Técnicas Imunoenzimáticas , Masculino , Reação em Cadeia da Polimerase , Profilaxia Pré-Exposição , Kit de Reagentes para Diagnóstico , Análise de Regressão , Estudos Retrospectivos , Sensibilidade e Especificidade , Tailândia/epidemiologia , Carga ViralRESUMO
BACKGROUND: Sustained genital tract inflammation caused by sexually transmitted infections (STIs) is known to increase risk of vaginal human immunodeficiency virus (HIV) infections but, to our knowledge, there are no nonhuman primate studies that have evaluated its link to rectal HIV acquisition. METHODS: Rhesus macaques inoculated with Chlamydia trachomatis (CT) (serovars LGV-L2 and CT-E; n = 7) or saline (n = 7) received up to 20 rectal challenges twice a week of simian/HIV immunodeficiency virus (SHIVSF162p3). SHIV viremia was determined by real-time PCR and Chlamydia infection by APTIMA Combo 2 testing. The rectal cytokine-chemokine levels were evaluated by multiplex bead assays. RESULTS: Rectal Chlamydia infection was maintained throughout the study. We did not observe significant differences (P = 1.0) in frequency of SHIV acquisition between the STI and control arms. It took fewer SHIV challenges to infect the STI animals although the difference was not significant (P = 0.59). There were no significant differences in peak plasma viremia between STI and control arms (P = 0.63). The association of plasma viremia with rectal shedding was significantly different by arm (P = 0.038). CONCLUSIONS: In the first such study in a macaque model, we did not observe an increased risk of SHIV acquisition due to rectal Chlamydia coinfection. This macaque model can be further developed and expanded to better investigate the impact of different rectal STIs on HIV acquisition.
Assuntos
Infecções por Chlamydia/complicações , Coinfecção , Infecções por HIV/complicações , Linfogranuloma Venéreo/complicações , Infecções Sexualmente Transmissíveis/complicações , Síndrome de Imunodeficiência Adquirida dos Símios/complicações , Animais , Infecções por Chlamydia/microbiologia , Chlamydia trachomatis/fisiologia , Modelos Animais de Doenças , Infecções por HIV/virologia , Humanos , Linfogranuloma Venéreo/microbiologia , Macaca mulatta , Reto/microbiologia , Risco , Infecções Sexualmente Transmissíveis/microbiologia , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Vírus da Imunodeficiência Símia/fisiologiaRESUMO
BACKGROUND: Intravaginal rings (IVR) for HIV prevention will likely be used by women on depot medroxyprogesterone acetate (DMPA) hormonal contraception. We used pigtailed macaques to evaluate the effects of DMPA on tenofovir disoproxil fumarate (TDF) IVR pharmacokinetics and viral shedding. METHODS: Mucosal tenofovir (TFV) levels were compared in SHIVSF162p3 -negative DMPA-treated (n=4) and normally cycling (n=6) macaques receiving TDF IVRs. Plasma viremia and vaginal shedding were determined in groups of SHIVSF162p3 -positive DMPA-treated (n=6) and normally cycling (n=5) macaques. RESULTS: Similar median vaginal fluid TFV concentrations were observed in the DMPA-treated and cycling macaques over 4 weeks (1.2×105 and 1.1.×105 ng/mL, respectively). Median plasma viremia and vaginal shedding AUC of the DMPA-treated (2.73×107 and 8.15×104 copies/mL, respectively) and cycling macaques (3.98×107 and 1.47×103 copies/mL, respectively) were statistically similar. CONCLUSIONS: DMPA does not affect TDF IVR pharmacokinetics or SHIV shedding.
Assuntos
Fármacos Anti-HIV/farmacocinética , Anticoncepcionais Femininos/farmacologia , Infecções por HIV/virologia , Acetato de Medroxiprogesterona/farmacologia , Tenofovir/farmacocinética , Administração Intravaginal , Animais , Anticoncepcionais Femininos/administração & dosagem , Dispositivos Anticoncepcionais Femininos , Feminino , HIV/fisiologia , Macaca nemestrina , Acetato de Medroxiprogesterona/administração & dosagem , Viremia/sangue , Eliminação de Partículas Virais/efeitos dos fármacosRESUMO
BACKGROUND: Rectal STI coinfection models enhance the understanding of rectal HIV transmission risk factors. MATERIALS AND METHODS: Rhesus macaques (n=9) were exposed to one of three rectal Chlamydia trachomatis (CT) challenges: C. trachomatis L2 (CT-L2 ); C. trachomatis serovar E (CT-E), followed by CT-L2 ; or CT-E, treatment/clearance, then CT-L2 . Infections were monitored by PCR. Weekly blood and rectal secretion/lavage samples were collected for cytokine analyzes and/or epithelial sloughing, occult, and overt blood determinations. RESULTS: Chlamydial infections were successfully established in each animal, with varying degrees of persistence. Mucosal IL-1beta was upregulated in animals consecutively infected with CT-E then CT-L2 (P=.05). Epithelial sloughing was also significantly increased post-infection in this group (P=.0003). CONCLUSIONS: This study demonstrates successful rectal infection of rhesus macaques with CT-E and CT-L2 and describes measures of assessing rectal inflammation and pathology. Different infection strategies yield varying inflammatory and pathologic outcomes, providing well-described models for future SIV/SHIV susceptibility studies.
Assuntos
Infecções por Chlamydia/complicações , Chlamydia trachomatis/fisiologia , Modelos Animais de Doenças , Infecções por HIV/complicações , Macaca mulatta , Infecções Sexualmente Transmissíveis/complicações , Animais , Infecções por Chlamydia/sangue , Infecções por Chlamydia/patologia , Coinfecção , Feminino , Infecções por HIV/sangue , Infecções por HIV/virologia , Reto , Sorogrupo , Infecções Sexualmente Transmissíveis/sangue , Infecções Sexualmente Transmissíveis/microbiologia , Infecções Sexualmente Transmissíveis/virologia , Vírus da Imunodeficiência Símia/fisiologiaRESUMO
Genital inflammation associated with sexually transmitted infections increases susceptibility to human immunodeficiency virus (HIV), but it is unclear whether the increased risk can reduce the efficacy of pre-exposure prophylaxis (PrEP). We investigated whether coinfection of macaques with Chlamydia trachomatis and Trichomonas vaginalis decreases the prophylactic efficacy of oral emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF). Macaques were exposed to simian/human immunodeficiency virus (SHIV) vaginally each week for up to 16 weeks and received placebo or FTC/TDF pericoitally. All animals in the placebo group were infected with SHIV, while 4 of 6 PrEP recipients remained uninfected (P= .03). Oral FTC/TDF maintains efficacy in a macaque model of sexually transmitted coinfection, although the infection of 2 macaques signals a modest loss of PrEP activity.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por Chlamydia/complicações , Combinação Emtricitabina e Fumarato de Tenofovir Desoproxila/uso terapêutico , Infecções por HIV/prevenção & controle , Síndrome de Imunodeficiência Adquirida dos Símios/prevenção & controle , Vaginite por Trichomonas/complicações , Animais , Chlamydia trachomatis/isolamento & purificação , Coinfecção , Modelos Animais de Doenças , Feminino , Humanos , Macaca mulatta , Profilaxia Pré-Exposição , Vagina/microbiologia , Vagina/virologiaRESUMO
For human immunodeficiency virus (HIV) prevention, microbicides or drugs delivered as quick-dissolving films may be more acceptable to women than gels because of their compact size, minimal waste, lack of an applicator, and easier storage and transport. This has the potential to improve adherence to promising products for preexposure prophylaxis. Vaginal films containing IQP-0528, a nonnucleoside reverse transcriptase inhibitor, were evaluated for their pharmacokinetics in pigtailed macaques. Polymeric films (22 by 44 by 0.1 mm; providing 75% of a human dose) containing IQP-0528 (1.5%, wt/wt) with and without poly(lactic-co-glycolic acid) (PLGA) nanoparticle encapsulation were inserted vaginally into pigtailed macaques in a crossover study design (n = 6). With unencapsulated drug, the median (range) vaginal fluid concentrations of IQP-0528 were 160.97 (2.73 to 2,104), 181.79 (1.86 to 15,800), and 484.50 (8.26 to 4,045) µg/ml at 1, 4, and 24 h after film application, respectively. Median vaginal tissue IQP-0528 concentrations at 24 h were 3.10 (0.03 to 222.58) µg/g. The values were similar at locations proximal, medial, and distal to the cervix. The IQP-0528 nanoparticle-formulated films delivered IQP-0528 in vaginal tissue and secretions at levels similar to those obtained with the unencapsulated formulation. A single application of either formulation did not disturb the vaginal microflora or the pH (7.24 ± 0.84 [mean ± standard deviation]). The high mucosal IQP-0528 levels delivered by both vaginal film formulations were between 1 and 5 log higher than the in vitro 90% inhibitory concentration (IC90) of 0.146 µg/ml. The excellent coverage and high mucosal levels of IQP-0528, well above the IC90, suggest that the films may be protective and warrant further evaluation in a vaginal repeated low dose simian-human immunodeficiency virus (SHIV) transmission study in macaques and clinically in women.
Assuntos
Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/farmacocinética , Pirimidinonas/efeitos adversos , Pirimidinonas/farmacocinética , Vagina/virologia , Administração Intravaginal , Animais , Fármacos Anti-HIV/administração & dosagem , Feminino , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , HIV-1/patogenicidade , Ácido Láctico/química , Macaca nemestrina , Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Pirimidinonas/administração & dosagem , Pirimidinonas/química , Vagina/efeitos dos fármacosRESUMO
Topical preexposure prophylaxis interrupts HIV transmission at the site of mucosal exposure. Intermittently dosed vaginal gels containing the HIV-1 reverse transcriptase inhibitor tenofovir protected pigtailed macaques depending on the timing of viral challenge relative to gel application. However, modest or no protection was observed in clinical trials. Intravaginal rings (IVRs) may improve efficacy by providing long-term sustained drug delivery leading to constant mucosal antiretroviral concentrations and enhancing adherence. Although a few IVRs have entered the clinical pipeline, 100% efficacy in a repeated macaque vaginal challenge model has not been achieved. Here we describe a reservoir IVR technology that delivers the tenofovir prodrug tenofovir disoproxil fumarate (TDF) continuously over 28 d. With four monthly ring changes in this repeated challenge model, TDF IVRs generated reproducible and protective drug levels. All TDF IVR-treated macaques (n = 6) remained seronegative and simian-HIV RNA negative after 16 weekly vaginal exposures to 50 tissue culture infectious dose SHIV162p3. In contrast, 11/12 control macaques became infected, with a median of four exposures assuming an eclipse of 7 d from infection to virus RNA detection. Protection was associated with tenofovir levels in vaginal fluid [mean 1.8 × 10(5) ng/mL (range 1.1 × 10(4) to 6.6 × 10(5) ng/mL)] and ex vivo antiviral activity of cervicovaginal lavage samples. These observations support further advancement of TDF IVRs as well as the concept that extended duration drug delivery devices delivering topical antiretrovirals could be effective tools in preventing the sexual transmission of HIV in humans.
Assuntos
Adenina/análogos & derivados , Sistemas de Liberação de Medicamentos/métodos , HIV/efeitos dos fármacos , Infecções por Lentivirus/prevenção & controle , Organofosfonatos/farmacologia , Vírus da Imunodeficiência Símia/efeitos dos fármacos , Adenina/administração & dosagem , Adenina/farmacologia , Administração Intravaginal , Animais , Preparações de Ação Retardada , Feminino , Macaca mulatta , Organofosfonatos/administração & dosagem , TenofovirRESUMO
We evaluated the in vivo pharmacokinetics and used a complementary ex vivo coculture assay to determine the pharmacodynamics of IQB3002 gel containing 1% IQP-0528, a nonnucleoside reverse transcriptase inhibitor (NNRTI), in rhesus macaques (RM). The gel (1.5 ml) was applied vaginally to 6 simian-human immunodeficiency (SHIV)-positive female RM. Blood, vaginal fluids, and rectal fluids were collected at 0, 1, 2, and 4 h. RM were euthanized at 4 h, and vaginal, cervical, rectal, and regional lymph node tissues were harvested. Anti-human immunodeficiency virus (HIV) activity was evaluated ex vivo by coculturing fresh or frozen vaginal tissues with activated human peripheral blood mononuclear cells (PBMCs) and measuring the p24 levels for 10 days after an HIV-1Ba-L challenge. The median levels of IQP-0528, determined using liquid chromatography-tandem mass spectroscopy (LC-MS/MS) methods, were between 10(4) and 10(5) ng/g in vaginal and cervical tissue, between 10(3) and 10(4) ng/g in rectal tissues, and between 10(5) and 10(7) ng/ml in vaginal fluids over the 4-h period. The vaginal tissues protected the cocultured PBMCs from HIV-1 infection ex vivo, with a viral inhibition range of 81 to 100% in fresh and frozen tissues that were proximal, medial, and distal relative to the cervix. No viral inhibition was detected in untreated baseline tissues. Collectively, the median drug levels observed were 5 to 7 logs higher than the in vitro 50% effective concentration (EC50) range (0.21 ng/ml to 1.29 ng/ml), suggesting that 1.5 ml of the gel delivers IQP-0528 throughout the RM vaginal compartment at levels that are highly inhibitory to HIV-1. Importantly, antiviral activity was observed in both fresh and frozen vaginal tissues, broadening the scope of the ex vivo coculture model for future NNRTI efficacy studies.
Assuntos
Piperidinas/administração & dosagem , Piperidinas/farmacocinética , Pirimidinonas/farmacocinética , Inibidores da Transcriptase Reversa/farmacocinética , Administração Intravaginal , Animais , Técnicas de Cocultura , Criopreservação , Feminino , Infecções por HIV/prevenção & controle , HIV-1/efeitos dos fármacos , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/virologia , Macaca mulatta , Pirimidinonas/administração & dosagem , Inibidores da Transcriptase Reversa/administração & dosagem , Síndrome de Imunodeficiência Adquirida dos Símios/tratamento farmacológicoRESUMO
BACKGROUND: HIV acquisition in the female genital tract remains incompletely understood. Quantitative data on biological HIV risk factors, the influence of reproductive hormones, and infection risk are lacking. We evaluated vaginal epithelial thickness during the menstrual cycle in pigtail macaques (Macaca nemestrina). This model previously revealed increased susceptibility to vaginal infection during and after progesterone-dominated periods in the menstrual cycle. METHODS: Nucleated and nonnucleated (superficial) epithelial layers were quantitated throughout the menstrual cycle of 16 macaques. We examined the relationship with previously estimated vaginal SHIVSF162P3 acquisition time points in the cycle of 43 different animals repeatedly exposed to low virus doses. RESULTS: In the luteal phase (days 17 to cycle end), the mean vaginal epithelium thinned to 66% of mean follicular thickness (days 1-16; P = 0.007, Mann-Whitney test). Analyzing 4-day segments, the epithelium was thickest on days 9 to 12 and thinned to 31% thereof on days 29 to 32, with reductions of nucleated and nonnucleated layers to 36% and 15% of their previous thickness, respectively. The proportion of animals with estimated SHIV acquisition in each cycle segment correlated with nonnucleated layer thinning (Pearson r = 0.7, P < 0.05, linear regression analysis), but not nucleated layer thinning (Pearson r = 0.6, P = 0.15). CONCLUSIONS: These data provide a detailed picture of dynamic cycle-related changes in the vaginal epithelium of pigtail macaques. Substantial thinning occurred in the superficial, nonnucleated layer, which maintains the vaginal microbiome. The findings support vaginal tissue architecture as susceptibility factor for infection and contribute to our understanding of innate resistance to SHIV infection.
Assuntos
Ciclo Menstrual , Síndrome de Imunodeficiência Adquirida dos Símios/transmissão , Vírus da Imunodeficiência Símia/isolamento & purificação , Vagina/patologia , Vagina/virologia , Animais , Modelos Animais de Doenças , Suscetibilidade a Doenças , Epitélio/patologia , Epitélio/virologia , Feminino , Macaca nemestrina , Masculino , Síndrome de Imunodeficiência Adquirida dos Símios/patologiaRESUMO
There are few nonhuman primate models of enhanced HIV susceptibility. Such models can improve comprehension of HIV acquisition risk factors and provide rigorous testing platforms for preclinical prevention strategies. This paper reviews past, current, and proposed research on macaque HIV acquisition risk models and identifies areas where modeling is significantly lacking. We compare different experimental approaches and provide practical considerations for designing macaque susceptibility studies. Modifiable (mucosal and systemic coinfections, hormonal contraception, and rectal lubricants) and non-modifiable (hormonal fluctuations) risk factors are highlighted. Risk acquisition models via vaginal, rectal, and penile challenge routes are discussed. There is no consensus on the best statistical model for evaluating increased susceptibility, and additional research is required. The use of enhanced susceptibility macaque models would benefit multiple facets of the HIV research field, including basic acquisition and pathogenesis studies as well as the vaccine and other biomedical preventions pipeline.
Assuntos
Modelos Animais de Doenças , Suscetibilidade a Doenças , Infecções por HIV/imunologia , Macaca , Animais , Modelos EstatísticosRESUMO
OBJECTIVES: We examined the causes of hospitalization and death of people who inject drugs participating in the Bangkok Tenofovir Study, an HIV preexposure prophylaxis trial. METHODS: The Bangkok Tenofovir Study was a randomized, double-blind, placebo-controlled trial conducted during 2005 to 2012 among 2413 people who inject drugs. We reviewed medical records to define the causes of hospitalization and death, examined participant characteristics and risk behaviors to determine predictors of death, and compared the participant mortality rate with the rate of the general population of Bangkok, Thailand. RESULTS: Participants were followed an average of 4 years; 107 died: 22 (20.6%) from overdose, 13 (12.2%) from traffic accidents, and 12 (11.2%) from sepsis. In multivariable analysis, older age (40-59 years; P = .001), injecting drugs (P = .03), and injecting midazolam (P < .001) were associated with death. The standardized mortality ratio was 2.9. CONCLUSIONS: People who injected drugs were nearly 3 times as likely to die as were those in the general population of Bangkok and injecting midazolam was independently associated with death. Drug overdose and traffic accidents were the most common causes of death, and their prevention should be public health priorities.
Assuntos
Abuso de Substâncias por Via Intravenosa/mortalidade , Acidentes de Trânsito/mortalidade , Adenina/administração & dosagem , Adenina/análogos & derivados , Adulto , Fármacos Anti-HIV/administração & dosagem , Causas de Morte , Método Duplo-Cego , Overdose de Drogas/mortalidade , Feminino , Infecções por HIV/prevenção & controle , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Uso Comum de Agulhas e Seringas , Organofosfonatos/administração & dosagem , Profilaxia Pré-Exposição , Assunção de Riscos , Inquéritos e Questionários , Tenofovir , Tailândia/epidemiologiaRESUMO
Varying susceptibility during menstrual cycling could be a factor for S(H)IV infection risk in female rhesus macaques. We retrospectively determined vaginal SIV infection time points relative to the menstrual cycle in a group of rhesus macaques (n=11) enrolled in an HIV transmission trial. Eight of nine rhesus macaques became infected around menstruation time.
Assuntos
Macaca mulatta , Ciclo Menstrual , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Vírus da Imunodeficiência Símia/fisiologia , Vagina/virologia , Animais , Feminino , Estudos RetrospectivosRESUMO
BACKGROUND: Injectable hormonal contraception may increase women's risk of HIV acquisition and can affect biological risk factors in animal models of HIV. We established, for the first time, a model to investigate whether combined oral contraceptives (COC) alter SHIV susceptibility in macaques. METHODS: Seven pigtail macaques were administered a monophasic levonorgestrel (LNG)/ethinyl estradiol (EE) COC at 33% or 66% of the human dose for 60 days. Menstrual cycling, vaginal epithelial thickness, and other SHIV susceptibility factors were monitored for a mean of 18 weeks. RESULTS: Mean vaginal epithelial thicknesses were 290.8 µm at baseline and 186.2 µm during COC (P = 0.0141, Mann-Whitney U-test). Vaginal pH decreased from 8.5 during treatment to 6.5 post-treatment (0.0176 two-tailed t-test). Measured microflora was unchanged. CONCLUSIONS: COC caused thinning of the vaginal epithelium and vaginal pH changes, which may increase SHIV susceptibility. 0.033 mg LNG + .0066 mg EE appeared effective in suppressing ovulation.
Assuntos
Anticoncepcionais Orais Combinados/farmacologia , Suscetibilidade a Doenças/induzido quimicamente , Etinilestradiol/farmacologia , Infecções por HIV/fisiopatologia , Levanogestrel/farmacologia , Mucosa/efeitos dos fármacos , Síndrome de Imunodeficiência Adquirida dos Símios/fisiopatologia , Animais , Anticoncepcionais Orais Combinados/efeitos adversos , Modelos Animais de Doenças , Suscetibilidade a Doenças/fisiopatologia , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Etinilestradiol/efeitos adversos , Feminino , Levanogestrel/efeitos adversos , Macaca nemestrina , Ciclo Menstrual/efeitos dos fármacos , Vírus da Imunodeficiência Símia/efeitos dos fármacos , Vagina/efeitos dos fármacosRESUMO
BACKGROUND: Depot-medroxyprogesterone acetate (DMPA) has been associated in some studies with increased HIV susceptibility in women. We used a pigtail macaque model to document the effects of repeated DMPA treatments and their potential contribution to increased SHIV susceptibility. METHODS: Nine pigtails were administered 2.5, 1.5, or 0.5 mg/kg DMPA in study weeks one and four. Menstrual cycling, vaginal epithelial thickness, and other SHIV susceptibility factors were monitored for a mean of 24 study weeks. RESULTS: All DMPA treatments suppressed menstrual cycling and increased vaginal pH. The vaginal epithelium thinned naturally during baseline menstrual cycles (from mean of 351 to 161 µm in late-luteal phase). Following DMPA, the non-nucleated layer was temporarily absent. Two weeks post-second DMPA injection, mean epithelial thickness was 53, 45, and 167 µm for the descending doses, respectively. CONCLUSIONS: All animals showed temporal vaginal epithelial thinning with loss of the non-nucleated layer, and vaginal pH changes post-DMPA injections.
Assuntos
Anticoncepcionais Femininos/administração & dosagem , Macaca nemestrina , Acetato de Medroxiprogesterona/administração & dosagem , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Vírus da Imunodeficiência Símia/fisiologia , Vagina/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Suscetibilidade a Doenças/virologia , Relação Dose-Resposta a Droga , Feminino , Humanos , Concentração de Íons de Hidrogênio , Ciclo Menstrual/efeitos dos fármacos , Mucosa/efeitos dos fármacos , Progesterona/metabolismo , Vagina/anatomia & histologiaRESUMO
BACKGROUND: Sexually transmitted infections (STIs) are associated with an increased risk of human immunodeficiency virus (HIV) infection, but their biological effect on HIV susceptibility is not fully understood. METHODS: Female pig-tailed macaques inoculated with Chlamydia trachomatis and Trichomonas vaginalis (n = 9) or medium (controls; n = 7) were repeatedly challenged intravaginally with SHIVSF162p3. Virus levels were evaluated by real-time polymerase chain reaction, plasma and genital cytokine levels by Luminex assays, and STI clinical signs by colposcopy. RESULTS: Simian/HIV (SHIV) susceptibility was enhanced in STI-positive macaques (P = .04, by the log-rank test; relative risk, 2.5 [95% confidence interval, 1.1-5.6]). All STI-positive macaques were SHIV infected, whereas 3 controls (43%) remained uninfected. Moreover, relative to STI-negative animals, SHIV infections occurred earlier in the menstrual cycle in STI-positive macaques (P = .01, by the Wilcoxon test). Levels of inflammatory cytokines (interferon γ, interleukin 6, and granulocyte colony-stimulating factor [G-CSF]) were higher in STI-positive macaques during STI inoculation and SHIV exposure periods (P ≤ .05, by the Wilcoxon test). CONCLUSIONS: C. trachomatis and T. vaginalis infection increase the susceptibility to SHIV, likely because of prolonged genital tract inflammation. These novel data demonstrate a biological link between these nonulcerative STIs and the risk of SHIV infection, supporting epidemiological associations of HIV and STIs. This study establishes a macaque model for studies of high-risk HIV transmission and prevention.
Assuntos
Infecções por Chlamydia/complicações , Chlamydia trachomatis , Coinfecção/imunologia , Vírus da Imunodeficiência Símia/fisiologia , Vaginite por Trichomonas/complicações , Trichomonas vaginalis , Animais , Colo do Útero/microbiologia , Colo do Útero/parasitologia , Colo do Útero/patologia , Colposcopia , Feminino , Macaca nemestrina , Fatores de Risco , Infecções Sexualmente Transmissíveis/complicações , Síndrome de Imunodeficiência Adquirida dos Símios/transmissão , Síndrome de Imunodeficiência Adquirida dos Símios/virologiaRESUMO
BACKGROUND: Tenofovir disoproxil fumarate (tenofovir) has been associated with renal dysfunction in people infected with human immunodeficiency virus (HIV) receiving combination antiretroviral therapy. We reviewed data from an HIV preexposure prophylaxis trial to determine if tenofovir use was associated with changes in renal function in an HIV-uninfected population. METHODS: During the trial, 2413 HIV-uninfected people who inject drugs were randomized to receive tenofovir or placebo. We assessed the renal function of trial participants with the Cockcroft-Gault, Modification of Diet in Renal Disease (MDRD), and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations using t tests for cross-sectional analysis and linear regression for longitudinal analysis. RESULTS: Creatinine clearance and glomerular filtration rate (GFR) results were lower at 24, 36, 48, and 60 months in the tenofovir group compared with the placebo group. Results declined more in the tenofovir group than in the placebo group during follow-up using the Cockcroft-Gault (P < .001) and CKD-EPI (P = .007) equations, but not MDRD (P = .12). Creatinine clearance measured when study drug was stopped was lower in the tenofovir group than the placebo group (P < .001), but the difference resolved when tested a median of 20 months later (P = .12). CONCLUSIONS: We found small but significant decreases in cross-sectional measures of creatinine clearance and GFR in the tenofovir group compared with the placebo group and modest differences in downward trends in longitudinal analysis using the Cockcroft-Gault and CKD-EPI equations. These results suggest that with baseline assessments of renal function and routine monitoring of creatinine clearance during follow-up, tenofovir can be used safely for HIV preexposure prophylaxis. Clinical Trials Registration. NCT00119106.