RESUMO
OBJECTIVE: Sexually transmitted infections (STIs) increase mucosal HIV infection risk and have the potential to reduce preexposure prophylaxis efficacy. Clinical trials of a broadly neutralizing antibody (bNAb) provided proof-of-concept that passive immunization against HIV can be efficacious in people. We sought to evaluate preclinically the protective efficacy of passive bNAb immunization against simian-human immunodeficiency virus (SHIV) infection in the context of concurrent vaginal STIs. DESIGN: Using a macaque model of combined ulcerative and nonulcerative vaginal STIs caused by Treponema pallidum , Chlamydia trachomatis , and Trichomonas vaginalis , we determined the protection that passively administered bNAb 10-1074 conferred against repeated vaginal SHIV challenges and compared correlates of protection to contemporaneous and historical controls without STIs. METHODS: Plasma viremia was monitored via RT-qPCR assay. Concentrations of 10-1074 were determined longitudinally in plasma samples via TZM-bl pseudovirus neutralization assay. RESULTS: Among macaques with vaginal STIs, a single subcutaneous injection of 10-1074 durably protected against vaginal SHIV acquisition, as compared with untreated controls. Interestingly, the median plasma concentration of 10-1074 at the time of SHIV breakthrough among macaques with STIs was significantly higher (10-fold) than that previously observed among 10-1074-treated macaques in the absence of STIs. CONCLUSION: Passive immunization with 10-1074 conferred significant protection against repeated vaginal SHIV challenges among macaques harboring vaginal STIs. However, our findings suggest that higher bNAb concentrations may be required for prophylaxis when STIs are present. Our findings potentially impact dose selection for the clinical development of bNAbs and highlight the importance of additional preclinical efficacy testing in STI models.
Assuntos
Infecções por HIV , HIV-1 , Infecções Sexualmente Transmissíveis , Síndrome de Imunodeficiência Adquirida dos Símios , Vírus da Imunodeficiência Símia , Animais , Feminino , Humanos , Anticorpos Amplamente Neutralizantes , Macaca , Infecções Sexualmente Transmissíveis/prevenção & controle , Anticorpos Anti-HIV , Anticorpos NeutralizantesRESUMO
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.
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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
PURPOSE OF REVIEW: We review macaque models for preexposure prophylaxis (PrEP) for HIV prevention and highlight their role in advancing currently approved and novel PrEP agents. RECENT FINDINGS: The development of the repeat low dose simian HIV (SHIV) challenge models represented a significant advancement in preclinical PrEP modeling that has allowed the investigation of PrEP under conditions that better mimic HIV exposures in humans. These models incorporate relevant drug pharmacology to inform drug correlates of PrEP protection. Models of rectal, vaginal, and penile infection are now available and have been found to predict clinical efficacy of all the currently approved PrEP strategies including daily oral PrEP with the combination of emtricitabine and tenofovir disoproxil fumarate or tenofovir alafenamide, and a long-acting formulation of the integrase inhibitor cabotegravir. These models are being used to test new PrEP modalities including the nucleoside reverse transcriptase-translocation inhibitor islatravir and long-acting capsid inhibitors. The SHIV models have also been supplemented by sexually transmitted infection co-infections with Chlamydia trachomatis, Treponema pallidum or Trichomonas vaginalis to assess the impact of inflammation on PrEP efficacy. SUMMARY: Clinical efficacy validated current PrEP macaque models supporting their continued use to advance novel PrEP agents to improve global PrEP coverage.
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Fármacos Anti-HIV , Infecções por HIV , Profilaxia Pré-Exposição , Animais , Fármacos Anti-HIV/uso terapêutico , Emtricitabina/uso terapêutico , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/prevenção & controle , Humanos , MacacaRESUMO
OBJECTIVE: We had previously shown that long-acting cabotegravir (CAB-LA) injections fully protected macaques from vaginal simian HIV (SHIV) infection. Here, we reassessed CAB-LA efficacy in the presence of depot medroxyprogesterone acetate and multiple sexually transmitted infections (STIs) that are known to increase HIV susceptibility in women. DESIGN: Two macaque models of increasing vaginal STI severity were used for efficacy assessment. METHODS: The first study (nâ=â11) used a double STI model that had repeated exposures to two vaginal STI, Chlamydia trachomatis and Trichomonas vaginalis. Six animals were CAB-LA treated and five were controls. The second study (nâ=â9) included a triple STI model with repeated exposures to C. trachomatis, T. vaginalis and syphilis, and the contraceptive, depot medroxyprogesterone acetate (DMPA). Six animals were CAB-LA treated and three were controls. All animals received up to 14 vaginal SHIV challenges. A survival analysis was performed to compare the number of SHIV challenges to infection in the drug-treated group compared with untreated controls over time. RESULTS: All six CAB-LA treated animals in both models, the double STI or the triple STI-DMPA model, remained protected after 14 SHIV vaginal challenges, while the untreated animals became SHIV-infected after a median of two challenges (log-rank Pâ<â0.001) or one challenge (log-rank Pâ=â0.002), respectively. Both models recapitulated human STI disease, with vaginal discharge, ulcers, and seroconversion. CONCLUSION: In these high and sustained susceptibility models spanning more than 3 months, CAB-LA maintained complete efficacy, demonstrating robustness of the CAB-LA dose used in clinical trials, and suggesting its insensitivity to multiple STIs and DMPA.
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Infecções por HIV , Infecções Sexualmente Transmissíveis , Síndrome de Imunodeficiência Adquirida dos Símios , Animais , Dicetopiperazinas , Feminino , Infecções por HIV/prevenção & controle , Humanos , Macaca , Acetato de Medroxiprogesterona , Piridonas , Infecções Sexualmente Transmissíveis/prevenção & controle , Síndrome de Imunodeficiência Adquirida dos Símios/prevenção & controleRESUMO
OBJECTIVE: The opioid epidemic has increased parentally acquired HIV infection. To inform the development of a long-acting prevention strategy, we evaluated the protective efficacy of broadly neutralizing antibodies (bNAbs) against intravenous simian-human immunodeficiency virus (SHIV) infection in macaques. DESIGN: Five cynomolgus macaques were injected once subcutaneously with 10-1074 and 3BNC117 (10âmg each kg-1) and were repeatedly challenged intravenously once weekly with SHIVAD8-EO (130 TCID50), until infection was confirmed via plasma viral load assay. Two control macaques, which received no antibody, were challenged identically. METHODS: Plasma viremia was monitored via RT-qPCR assay. bNAb concentrations were determined longitudinally in plasma samples via TZM-bl neutralization assays using virions pseudotyped with 10-1074-sensitive (X2088_c9) or 3BNC117-sensitive (Q769.d22) HIV envelope proteins. RESULTS: Passively immunized macaques were protected against a median of five weekly intravenous SHIV challenges, as compared to untreated controls, which were infected following a single challenge. Of the two bNAbs, 10-1074 exhibited relatively longer persistence in vivo. The median plasma level of 10-1074 at SHIV breakthrough was 1.1âµgâml-1 (range: 0.6-1.6âµgâml-1), whereas 3BNC117 was undetectable. Probit modeling estimated that 6.6âµgâml-1 of 10-1074 in plasma corresponded to a 99% reduction in per-challenge infection probability, as compared to controls. CONCLUSIONS: Significant protection against repeated intravenous SHIV challenges was observed following administration of 10-1074 and 3BNC117 and was due primarily to 10-1074. Our findings extend preclinical studies of bNAb-mediated protection against mucosal SHIV acquisition and support the possibility that intermittent subcutaneous injections of 10-1074 could serve as long-acting preexposure prophylaxis for persons who inject drugs.
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Usuários de Drogas , Infecções por HIV , HIV-1 , Síndrome de Imunodeficiência Adquirida dos Símios , Vírus da Imunodeficiência Símia , Abuso de Substâncias por Via Intravenosa , Animais , Anticorpos Neutralizantes , Anticorpos Amplamente Neutralizantes , Anticorpos Anti-HIV , Infecções por HIV/prevenção & controle , Humanos , Macaca mulatta , Síndrome de Imunodeficiência Adquirida dos Símios/prevenção & controleRESUMO
Preexposure prophylaxis (PrEP) is an effective HIV prevention tool, although effectiveness is dependent upon adherence. It is important to characterize the impact of PrEP on HIV antibody responses in people who experience breakthrough infections to understand the potential impact on timely diagnosis and treatment. Longitudinal HIV-1-specific antibody responses were evaluated in 42 people who inject drugs (PWID) from the Bangkok Tenofovir Study (BTS) (placebo = 28; PrEP = 14) who acquired HIV while receiving PrEP. HIV-1 antibody levels and avidity to three envelope proteins (gp41, gp160, and gp120) were measured in the plasma using a customized Bio-Plex (Bio-Rad Laboratories, Hercules, CA) assay. A time-to-event analysis was performed for each biomarker to compare the distribution of times at which study subjects exceeded the recent/long-term assay threshold, comparing PrEP and placebo treatment groups. We fit mixed-effects models to identify longitudinal differences in antibody levels and avidity between groups. Overall, longitudinal antibody levels and avidity were notably lower in the PrEP breakthrough group compared to the placebo group. Time-to-event analyses demonstrated a difference in time to antibody reactivity between treatment groups for all Bio-Plex biomarkers. Longitudinal gp120 antibody levels within the PrEP breakthrough group were decreased compared to the placebo group. When accounting for PrEP adherence, both gp120 and gp160 antibody levels were lower in the PrEP breakthrough group compared to the placebo group. We demonstrate hindered envelope antibody maturation in PWID who became infected while receiving PrEP in the BTS, which has significant implications for HIV diagnosis. Delayed maturation of the antibody response to HIV may increase the time to detection for antibody-based tests. Clinical Trial Registration Number, NCT00119106.
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Fármacos Anti-HIV , Infecções por HIV , HIV-1 , Profilaxia Pré-Exposição , Fármacos Anti-HIV/uso terapêutico , Formação de Anticorpos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/prevenção & controle , Humanos , TailândiaRESUMO
Penile acquisition of HIV accounts for most infections among men globally. Nevertheless, candidate HIV interventions for men advance to clinical trials without preclinical efficacy data, due primarily to a paucity of relevant animal models of penile HIV infection. Using our recently developed macaque model, we show that a single subcutaneous administration of broadly neutralizing antibody (bNAb) 10-1074 conferred durable protection against repeated penile exposures to simian-human immunodeficiency virus (SHIVSF162P3). Macaques co-administered bNAbs 10-1074 and 3BNC117, or 3BNC117 alone, also exhibited significant protection against repeated vaginal SHIVAD8-EO exposures. Regression modeling estimated that individual plasma bNAb concentrations of 5 µg ml-1 correlated with ≥99.9% relative reduction in SHIV infection probability via penile (10-1074) or vaginal (10-1074 or 3BNC117) challenge routes. These results demonstrate that comparably large reductions in penile and vaginal SHIV infection risk among macaques were achieved at clinically relevant plasma bNAb concentrations and inform dose selection for the development of bNAbs as long-acting pre-exposure prophylaxis candidates for use by men and women.
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Vacinas contra a AIDS/administração & dosagem , Anticorpos Amplamente Neutralizantes/administração & dosagem , Anticorpos Anti-HIV/administração & dosagem , Síndrome de Imunodeficiência Adquirida dos Símios/prevenção & controle , Síndrome de Imunodeficiência Adquirida dos Símios/transmissão , Vírus da Imunodeficiência Símia/imunologia , Vacinas contra a AIDS/sangue , Animais , Anticorpos Amplamente Neutralizantes/sangue , Modelos Animais de Doenças , Feminino , Anticorpos Anti-HIV/sangue , Infecções por HIV/prevenção & controle , Infecções por HIV/transmissão , Meia-Vida , Imunização Passiva , Macaca mulatta , Masculino , Pênis/imunologia , Pênis/virologia , Profilaxia Pré-Exposição , Vagina/imunologia , Vagina/virologiaRESUMO
Natural-product derived lectins can function as potent viral inhibitors with minimal toxicity as shown in vitro and in small animal models. We here assessed the effect of rectal application of an anti-HIV lectin-based microbicide Q-Griffithsin (Q-GRFT) in rectal tissue samples from rhesus macaques. E-cadherin+ cells, CD4+ cells and total mucosal cells were assessed using in situ staining combined with a novel customized digital image analysis platform. Variations in cell numbers between baseline, placebo and Q-GRFT treated samples were analyzed using random intercept linear mixed effect models. The frequencies of rectal E-cadherin+ cells remained stable despite multiple tissue samplings and Q-GRFT gel (0.1%, 0.3% and 1%, respectively) treatment. Whereas single dose application of Q-GRFT did not affect the frequencies of rectal CD4+ cells, multi-dose Q-GRFT caused a small, but significant increase of the frequencies of intra-epithelial CD4+ cells (placebo: median 4%; 1% Q-GRFT: median 7%) and of the CD4+ lamina propria cells (placebo: median 30%; 0.1-1% Q-GRFT: median 36-39%). The resting time between sampling points were further associated with minor changes in the total and CD4+ rectal mucosal cell levels. The results add to general knowledge of in vivo evaluation of anti-HIV microbicide application concerning cellular effects in rectal mucosa.
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Fármacos Anti-HIV/farmacologia , Anti-Infecciosos Locais/farmacologia , Mucosa Intestinal/efeitos dos fármacos , Lectinas/farmacologia , Lectinas de Plantas/farmacologia , Reto/efeitos dos fármacos , Animais , Fármacos Anti-HIV/administração & dosagem , Antígenos CD4/metabolismo , Caderinas/metabolismo , Contagem de Células , Células Epiteliais/efeitos dos fármacos , Mucosa Intestinal/citologia , Mucosa Intestinal/imunologia , Lectinas/administração & dosagem , Macaca mulatta , Lectinas de Plantas/administração & dosagem , Proteínas Recombinantes , Reto/citologia , Reto/imunologia , Fatores de TempoRESUMO
OBJECTIVE: To estimate time of HIV infection in participants from the Bangkok Tenofovir Study (BTS) with daily oral tenofovir disoproxil fumarate (TDF) for preexposure prophylaxis (PrEP) and relate infection with adherence patterns. DESIGN: We used the diversity structure of the virus population at the first HIV RNA-positive sample to estimate the date of infection, and mapped these estimates to medication diaries obtained under daily directly observed therapy (DOT). METHODS: HIV genetic diversity was investigated in all 17 PrEP breakthrough infections and in 16 placebo recipients. We generated 10-25 HIV env sequences from each participant by single genome amplification, and calculated time since infection (and 95% confidence interval) using Poisson models of early virus evolution. Study medication diaries obtained under daily DOT were then used to compute the number of missed TDF doses at the approximate date of infection. RESULTS: Fifteen of the 17 PrEP breakthrough infections were successfully amplified. Of these, 13 were initiated by a single genetic variant and generated reliable estimates of time since infection (median = 47 [IQR = 35] days). Eleven of these 13 were under daily DOT at the estimated time of infection. Analysis of medication diaries in these 11 participants showed 100% adherence in five, 90-95% adherence in two, 55% adherence in one, and nonadherence in three. CONCLUSION: We estimated time of infection in participants from BTS and found several infections when high levels of adherence to TDF were reported. Our results suggest that the biological efficacy of daily TDF against parenteral HIV exposure is not 100%.
Assuntos
Infecções por HIV/prevenção & controle , HIV-1/genética , Adesão à Medicação , Profilaxia Pré-Exposição/métodos , Administração Oral , Animais , Fármacos Anti-HIV/administração & dosagem , Método Duplo-Cego , Feminino , Variação Genética , Humanos , Macaca , Masculino , Tenofovir/administração & dosagemRESUMO
BACKGROUND: Three consecutive prospective studies were conducted among people who inject drugs (PWID) from May 1995 through June 2012 in Bangkok, Thailand. We examined data from these studies to evaluate HIV incidence and explore trends in risk behaviours. METHODS: We used data from a 1995-1998 cohort study, a 1999-2004 HIV vaccine trial, and a 2005-2012 HIV pre-exposure prophylaxis (PrEP) study to examine per-quarter trends in HIV incidence, using a restricted cubic spline function for time in a Poisson regression. We also examined temporal trends in HIV-associated risk behaviours. FINDINGS: HIV incidence declined from 5.7 per 100 person-years during the cohort study, to 2.7 per 100 person-years in the vaccine trial, to 0.7 per 100 person-years among PrEP study placebo recipients. Incidence peaked at 12.1 per 100 person-years in 1996 and declined to < 1 per 100 person-years during 2005-2012. Reports of injecting drugs and sharing needles also declined from the cohort study to the PrEP study (pâ¯<â¯0.0001). Heroin was the most common drug injected during the cohort study and the vaccine trial, but stimulants (e.g., methamphetamine) and sedatives (e.g., midazolam) were injected more often during the PrEP study. INTERPRETATION: HIV incidence among PWID declined during 2005-2012. Several factors likely contributed to the decline, including decreases in the frequency of injecting and sharing, improved access to HIV testing and antiretroviral therapy, and the use of PrEP. Expanding access to effective HIV prevention tools can hasten control of the HIV epidemic among PWID. FUNDING: The Bangkok Metropolitan Administration and U.S. Centers for Disease Control and Prevention, Division of HIV/AIDS Prevention.
RESUMO
Background: Approximately 1% of adults in Thailand are infected with hepatitis C virus (HCV). New direct-acting antiviral agents achieve sustained virologic responses in >95% of HCV-infected patients and are becoming available in countries around the world. To prepare for new HCV treatment options in Thailand, this study characterized HCV infections among people who inject drugs (PWID) in Bangkok. Methods: The Bangkok Tenofovir Study (BTS) was a pre-exposure prophylaxis trial conducted among PWID, 2005-2013. Blood specimens were randomly selected from PWID screened for the BTS, to test for anti-HCV antibody and HCV RNA. The HVR1 region was amplified by polymerase chain reaction, using multiplex primer sets with unique identifier sequences; amplification products were pooled in sets of 25; and consensus sequencing was performed to characterize individual HCV genotypes. Results: The median age of 3679 participants tested for anti-HCV antibody was 31 years, 3016 (82.0%) were male and 447 (12.2%) were HIV infected. The prevalence of anti-HCV antibody was 44.3%. The adjusted odds of testing positive for anti-HCV antibody were higher in men (adjusted odds ratio [aOR] 3.2, 95% confidence interval [CI] 2.4-4.3), those aged 40 years or older (aOR 2.7, 95% CI 2.1-3.5), those who had more than a primary school education (aOR 1.7, 95% CI 1.4-2.1), and those who tested HIV positive (aOR 5.2, 95% CI 3.7-7.4). HCV RNA was detected in 644 (81.3%) of the 792 anti-HCV antibody-positive specimens, yielding an HCV RNA-positive prevalence of 36.0% (95% CI 33.8-38.2). Among a random sample of 249 of the 644 specimens, 218 could be characterized, and the most common HCV subtypes were 1a (30.3%), 1b (12.8%), 3a (35.8%), 3b (6.9%) and 6n (8.7%). Conclusion: The prevalence of anti-HCV antibody among PWID was 44.3% and more than one third (36.0%) were HCV RNA positive. Genotypes 1, 3 and 6 accounted for all typable infections. As the government of Thailand considers introduction of direct-acting antiviral medications for people with hepatitis C, it will be important to ensure that the medications target these subtypes.
Assuntos
Hepatite C/diagnóstico , Adolescente , Adulto , Antivirais/uso terapêutico , Distribuição de Qui-Quadrado , Feminino , Hepacivirus/efeitos dos fármacos , Hepacivirus/patogenicidade , Hepatite C/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Abuso de Substâncias por Via Intravenosa , Inquéritos e Questionários , Tenofovir/uso terapêutico , Tailândia/epidemiologiaRESUMO
PROBLEM: In women, the use of progestin-based contraception may increase the risk of vaginal HIV acquisition. We previously showed in macaques that there is a significantly higher simian-human immunodeficiency virus (SHIV) acquisition rate in the luteal phase of the menstrual cycle, which presents a naturally high-progesterone state, and this may be attributable to altered expression of innate immune factors. We hypothesized that progestin-based contraception, especially depot medroxyprogesterone acetate (DMPA), would, in a similar way, affect mucosal immune factors that influence HIV acquisition risk. METHOD OF STUDY: We used a pig-tailed macaque model to evaluate the effects of two progestin-based contraceptives, DMPA, and levonorgestrel (LNG)/ethinyl estradiol (EE)-based combined oral contraceptives (COCs), on innate mucosal factors. We compared the vaginal epithelial thickness data from previous studies and used cytokine profiling and microarray analysis to evaluate contraception-induced molecular changes in the vagina. RESULTS: The administration of DMPA caused a reduction in the thickness of the vaginal epithelium relative to that of the follicular or luteal phase. DMPA also induced a significant increase in vaginal levels of the anti-inflammatory cytokine IL-10. Both DMPA- and LNG-based contraception induced a signature of gene expression similar to that of the luteal phase, only more exacerbated, including widespread downregulation of antiviral genes. CONCLUSION: The use of progestin-based contraception might engender a milieu that poses an increased risk of HIV acquisition as compared to both the luteal and follicular phases of the menstrual cycle.
Assuntos
Anticoncepção/efeitos adversos , Anticoncepcionais Femininos/efeitos adversos , Etinilestradiol/efeitos adversos , Infecções por HIV/transmissão , Levanogestrel/efeitos adversos , Acetato de Medroxiprogesterona/efeitos adversos , Progestinas/efeitos adversos , Vagina/efeitos dos fármacos , Animais , Anticoncepção/métodos , Anticoncepcionais Femininos/farmacologia , Etinilestradiol/farmacologia , Feminino , Infecções por HIV/patologia , Interleucina-10/metabolismo , Levanogestrel/farmacologia , Macaca nemestrina , Acetato de Medroxiprogesterona/farmacologia , Mucosa/metabolismo , Progestinas/farmacologia , Fatores de RiscoRESUMO
Topical microbicides are being explored as an HIV prevention method for individuals who practice receptive anal intercourse. In vivo studies of these microbicides are critical to confirm safety. Here, we evaluated the impact of a rectal microbicide containing the antiviral lectin, Griffithsin (GRFT), on the rectal mucosal proteome and microbiome. Using a randomized, crossover placebo-controlled design, six rhesus macaques received applications of hydroxyethylcellulose (HEC)- or carbopol-formulated 0.1% GRFT gels. Rectal mucosal samples were then evaluated by label-free tandem MS/MS and 16 S rRNA gene amplicon sequencing, for proteomics and microbiome analyses, respectively. Compared to placebo, GRFT gels were not associated with any significant changes to protein levels at any time point (FDR < 5%), but increased abundances of two common and beneficial microbial taxa after 24 hours were observed in HEC-GRFT gel (p < 2E-09). Compared to baseline, both placebo formulations were associated with alterations to proteins involved in proteolysis, activation of the immune response and inflammation after 2 hours (p < 0.0001), and increases in beneficial Faecalibacterium spp. after 24 hours in HEC placebo gel (p = 4.21E-15). This study supports the safety profile of 0.1% GRFT gel as an anti-HIV microbicide and demonstrates that current placebo formulations may associate with changes to rectal proteome and microbiota.
Assuntos
Fármacos Anti-HIV/administração & dosagem , Anti-Infecciosos Locais/administração & dosagem , Infecções por HIV/tratamento farmacológico , Microbiota/genética , Mucosa/efeitos dos fármacos , Lectinas de Plantas/administração & dosagem , Proteoma/análise , Reto/efeitos dos fármacos , Animais , Fármacos Anti-HIV/farmacologia , Géis , Infecções por HIV/metabolismo , Infecções por HIV/microbiologia , HIV-1/efeitos dos fármacos , Humanos , Macaca mulatta , Microbiota/efeitos dos fármacos , Mucosa/metabolismo , Mucosa/microbiologia , Proteoma/efeitos dos fármacos , Reto/metabolismo , Reto/microbiologiaRESUMO
This study evaluated effects of differing gel volumes on pharmacokinetics (PK). IQB4012, a gel containing the non-nucleoside reverse transcriptase inhibitor IQP-0528 and tenofovir (TFV), was applied to the pigtailed macaque vagina and rectum. Vaginal gel volumes (1% loading of both drugs) were 0.5 or 1.5 ml; following wash-out, 1 or 4 ml of gel were then applied rectally. Blood, vaginal, and rectal fluids were collected at 0, 2, 4, and 24 h. Vaginal and rectal tissue biopsies were collected at 4 and 24 h. There were no statistically significant differences in concentrations for either drug between gel volumes within compartments at matched time points. After vaginal gel application, median IQP-0528 concentrations were ~ 104-105 ng/g, 105-106 ng/ml, and 103-105 ng/ml in vaginal tissues, vaginal fluids, and rectal fluids, respectively (over 24 h). Median vaginal TFV concentrations were 1-2 logs lower than IQP-0528 levels at matched time points. After rectal gel application, median IQP-0528 and TFV concentrations in rectal fluids were ~ 103-105 ng/ml and ~ 102-103 ng/ml, respectively. Concentrations of both drugs sampled in rectal tissues were low (~ 101-103 ng/g). For 1 ml gel, half of sampled rectal tissues had undetectable concentrations of either drug, and over half of sampled rectal fluids had undetectable TFV concentrations. These results indicate differences in drug delivery between the vaginal and rectal compartments, and that smaller vaginal gel volumes may not significantly compromise microbicide PK and prophylactic potential. However, effects of rectal gel volume on PK for both drugs were less definitive.
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Fármacos Anti-HIV/farmacocinética , Pirimidinonas/farmacocinética , Tenofovir/farmacocinética , Administração Retal , Animais , Fármacos Anti-HIV/administração & dosagem , Feminino , Macaca , Pirimidinonas/administração & dosagem , Tenofovir/administração & dosagem , Cremes, Espumas e Géis VaginaisRESUMO
Penile acquisition of HIV infection contributes substantially to the global epidemic. Our goal was to establish a preclinical macaque model of penile HIV infection for evaluating the efficacy of new HIV prevention modalities. Rhesus macaques were challenged once or twice weekly with consistent doses of SHIVsf162P3 (a chimeric simian-human immunodeficiency virus containing HIV env) ranging from 4-600 TCID50 (50% tissue culture infective dose), via two penile routes, until systemic SHIV infection was confirmed. One route exposed the inner foreskin, glans and urethral os to virus following deposition into the prepuce (foreskin) pouch. The second route introduced the virus non-traumatically into the distal urethra only. Single-route challenges resulted in dose-dependent rates of SHIV acquisition informing selection of optimal SHIV dosing. Concurrent SHIV challenges via the prepuce pouch (200 TCID50) and urethra (16 TCID50) resulted in infection of 100% (10/10) animals following a median of 2.5 virus exposures (range, 1-12). We describe the first rhesus macaque repeat-exposure SHIV challenge model of penile HIV acquisition. Utilization of the model should further our understanding of penile HIV infection and facilitate the development of new HIV prevention strategies for men.
Assuntos
Infecções por HIV/prevenção & controle , Síndrome de Imunodeficiência Adquirida dos Símios/diagnóstico , Vírus da Imunodeficiência Símia/patogenicidade , Animais , Modelos Animais de Doenças , Prepúcio do Pênis/virologia , Humanos , Macaca mulatta , Masculino , RNA Viral/análise , Síndrome de Imunodeficiência Adquirida dos Símios/patologia , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Vírus da Imunodeficiência Símia/genética , Uretra/virologia , Carga ViralRESUMO
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 JovemAssuntos
Doenças Transmissíveis , Criança , Hospitalização , Humanos , Estados Unidos , Vacinas AtenuadasRESUMO
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: 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.