Microbiome analysis of Brazilian women cervix reveals specific bacterial abundance correlation to RIG-like receptor gene expression.

The relationship among microbiome, immunity and cervical cancer has been targeted by several studies, yet many questions remain unanswered. We characterized herein the virome and bacteriome from cervical samples and correlated these findings with innate immunity gene expression in a Brazilian convenience sample of HPV-infected (HPV+) and uninfected (HPV-) women. For this purpose, innate immune gene expression data were correlated to metagenomic information. Correlation analysis showed that interferon (IFN) is able to differentially modulate pattern recognition receptors (PRRs) expression based on HPV status. Virome analysis indicated that HPV infection correlates to the presence of Anellovirus (AV) and seven complete HPV genomes were assembled. Bacteriome results unveiled that vaginal community state types (CST) distribution was independent of HPV or AV status, although bacterial phyla distribution differed between groups. Furthermore, TLR3 and IFNαR2 levels were higher in the Lactobacillus no iners-dominated mucosa and we detected correlations among RIG-like receptors (RLR) associated genes and abundance of specific anaerobic bacteria. Collectively, our data show an intriguing connection between HPV and AV infections that could foster cervical cancer development. Besides that, TLR3 and IFNαR2 seem to create a protective milieu in healthy cervical mucosa (L. no iners-dominated), and RLRs, known to recognize viral RNA, were correlated to anaerobic bacteria suggesting that they might be related to dysbiosis.

Evaluation of HIV-1 antiretroviral drug resistance profiles in the peripheral blood reservoir of successfully treated persons using massive sequencing and viral full genome characterization.

BACKGROUND: Antiretroviral therapy has revolutionized HIV treatment, increasing quality and life expectancy of people living with HIV (PLWH). However, the expansion of treatment has resulted in an increase in antiretroviral-resistant viruses, which can be an obstacle to maintenance of successful ART. OBJECTIVES: This study analysed the genetic composition of the HIV near full-length genome (NFLG) from archived proviruses of PLWH under successful ART, and determined the presence/frequency of drug resistance mutations (DRMs) and viral subtype. PATIENTS AND METHODS: Forty-six PLWH from Rio de Janeiro (RJ) and 40 from Rio Grande (RS) had proviral HIV NFLG PCR-amplified and ultradeep sequenced. The presence/frequency of DRMs were analysed in Geneious. Phylogenetic analyses were performed using PhyML and SimPlot. RESULTS: All samples included in the study were sequenced and 69 (80.2%) had the HIV NFLG determined. RJ and RS showed a predominance of HIV subtypes B (78.3%) and C (67.5%), respectively. Overall, 168 DRMs were found in 63 (73.3%) samples, and 105 (62.5%) of them were minority variants. Among DRMs, 41 (39.0%) minority variants and 33 (52.4%) variants with frequency above 20.0% in the viral population were able to confer some degree of resistance to at least one drug in use by respective patients, yet no one showed signs of therapeutic failure. CONCLUSIONS: Our study contributes to the understanding of the impact of DRMs on successful therapy and supports the sustainability of combinatorial ART, because all patients maintained their successful treatment despite the high prevalence of DRMs at low (62.5%) or high (37.5%) frequency.

Risk of adverse outcomes in offspring with RT-PCR confirmed prenatal Zika virus exposure: An individual participant data meta-analysis of 13 cohorts in the Zika Brazilian Cohorts Consortium.

Background: Knowledge regarding the risks associated with Zika virus (ZIKV) infections in pregnancy has relied on individual studies with relatively small sample sizes and variable risk estimates of adverse outcomes, or on surveillance or routinely collected data. Using data from the Zika Brazilian Cohorts Consortium, this study aims, to estimate the risk of adverse outcomes among offspring of women with RT-PCR-confirmed ZIKV infection during pregnancy and to explore heterogeneity between studies. Methods: We performed an individual participant data meta-analysis of the offspring of 1548 pregnant women from 13 studies, using one and two-stage meta-analyses to estimate the absolute risks. Findings: Of the 1548 ZIKV-exposed pregnancies, the risk of miscarriage was 0.9%, while the risk of stillbirth was 0.3%. Among the pregnancies with liveborn children, the risk of prematurity was 10,5%, the risk of low birth weight was 7.7, and the risk of small for gestational age (SGA) was 16.2%. For other abnormalities, the absolute risks were: 2.6% for microcephaly at birth or first evaluation, 4.0% for microcephaly at any time during follow-up, 7.9% for neuroimaging abnormalities, 18.7% for functional neurological abnormalities, 4.0% for ophthalmic abnormalities, 6.4% for auditory abnormalities, 0.6% for arthrogryposis, and 1.5% for dysphagia. This risk was similar in all sites studied and in different socioeconomic conditions, indicating that there are not likely to be other factors modifying this association. Interpretation: This study based on prospectively collected data generates the most robust evidence to date on the risks of congenital ZIKV infections over the early life course. Overall, approximately one-third of liveborn children with prenatal ZIKV exposure presented with at least one abnormality compatible with congenital infection, while the risk to present with at least two abnormalities in combination was less than 1.0%.

Lower bone density and microarchitecture alterations in HIV-infected Brazilian men aged 50 years and older are associated with estradiol levels.

OBJECTIVE: Combination antiretroviral treatment (cART) allows for longer survival for people living with HIV and hence long-term complications of both disease and treatment are common. Our purpose was to evaluate bone alterations in men living with HIV (MLWH) and receiving cART and to identify associated factors that can be corrected or mitigated. PATIENTS AND DESIGN: Thirty MLWH and 36 healthy controls (≥50 years) were studied for areal bone mineral density (aBMD) and body composition (dual-energy X-ray absorptiometry), volumetric bone mineral density (vBMD) and bone microstructure (high-resolution peripheral quantitative computed tomography [HR-pQCT]), serum calcium, phosphate, parathyroid hormone, 25(OH)D, testosterone (T), estradiol (E2 ), glucose, creatinine, and albumin levels. RESULTS: The proportion of patients classified as osteoporosis (according to the lowest aBMD T-score) was higher among MLWH as compared to controls (17.9% vs. 5.9%, p = .011). The MLWH showed significant alterations in cortical and trabecular bone on HR-pQCT, which were not associated with the duration of HIV infection or cART. These differences in vBMD and bone microstructure seen in HR-pQCT persisted in the nonosteoporotic MLWH as compared to nonosteoporotic control subjects. Body mass index (BMI) and fat mass were lower in MLWH and positively associated with total vBMD, cortical bone area, and thickness. E2 and E2 /T ratios were lower in MLWH than in controls and significantly correlated with several cortical and trabecular bone parameters. Multivariate regression analysis entering simultaneously age, BMI, and E2 defined that E2 is an independent influence on bone parameters evaluated by HR-pQCT. CONCLUSION: MLWH have alterations in bone volumetric density and microstructure when compared with controls, irrespective of aBMD, which are associated with lower E2 and BMI.

Immunogenicity of Conjugated and Polysaccharide Pneumococcal Vaccines Administered During Pregnancy or Postpartum to Women With HIV.

BACKGROUND: Pneumococcal vaccination is recommended in people with HIV, prioritizing PCV. We compared the immunogenicity of PCV-10 and PPV-23 administered antepartum or postpartum. METHODS: This double-blind study randomized 346 pregnant women with HIV on antiretrovirals to PCV-10, PPV-23, or placebo at 14-34 weeks gestational age. Women who received placebo antepartum were randomized at 24 weeks postpartum to PCV-10 or PPV-23. Antibodies against 7 serotypes common to both vaccines and 1 serotype only in PPV-23 were measured by ELISA/chemiluminescence; B- and T-cell responses to serotype 1 by FLUOROSPOT; and plasma cytokines/chemokines by chemiluminescence. RESULTS: Antibody responses were higher after postpartum versus antepartum vaccination. PCV-10 generated lower antibody levels than PPV-23 against 4 and higher against 1 of 7 common serotypes. Additional factors associated with high postvaccination antibody concentrations were high prevaccination antibody concentrations and CD4+ cells; low CD8+ cells and plasma HIV RNA; and several plasma cytokines/chemokines. Serotype 1 B- and T-cell memory did not increase after vaccination. CONCLUSIONS: Antepartum immunization generated suboptimal antibody responses, suggesting that postpartum booster doses may be beneficial and warrant further studies. Considering that PCV-10 and PPV-23 had similar immunogenicity, but PPV-23 covered more serotypes, use of PPV-23 may be prioritized in women with HIV on antiretroviral therapy. CLINICAL TRAILS REGISTRATION: NCT02717494.

Seroprevalence of Listeria monocytogenes in HIV infected pregnant women from Brazil.

OBJECTIVE: To describe the prevalence and factors associated with serologic response to Listeria monocytogenes in HIV infected and uninfected pregnant women in Brazil. METHODS: Cross-sectional study, pregnant women after 14 weeks of gestational age were enrolled. Positive serologic test for L. monocytogenes was defined as titers >1:80 (agglutination test). Comparisons were performed using logistic regression. RESULTS: A total of 213 women were enrolled, 73 (34%) were HIV infected. 55 women were seroreactive for L. monocytogenes, 27 (37%) HIV-infected and 28 (20%) HIV-uninfected (p < 0.01). Considering the diet record, white cheese consumption was associated with seroreactivity (p < 0.01). In the group of pregnant women living with HIV, the variables associated with L. monocytogenes positive serology were: lower CD4+ cells count at study entry OR=4.8 (95%CI=1.1-19.8) and having neonates admitted to the intensive care unit OR=5.9 (95%CI=1.01-34.9). CONCLUSION: Positive serology for Listeria monocytogenes was associated with HIV infection. Brazilian women should avoid white cheese during pregnancy.

Prevalence of Listeria monocytogenes fecal carriers in HIV-infected and -uninfected pregnant women from Brazil.

OBJECTIVE: The aim of this study is to describe the prevalence of Listeria spp. in feces of HIV-infected and -uninfected pregnant women in Brazil. METHODS: Cross-sectional study. Women on their second or third trimester of pregnancy were submitted to a clinical questionnaire and feces collection. The feces were inoculated on selective media and identification by biochemical tests combined with PCR. RESULTS: A total of 213 pregnant women were enrolled: 73 (34%) HIV-infected and 140 (66%) -non-infected. The prevalence of Listeria spp. and L. monocytogenes in feces of HIV-infected women were 8.2% and 2.7%. In the HIV-uninfected were 8.6% and 2.9% (p-values = 0.98 and 0.66, respectively). CONCLUSION: The prevalence of fecal carriers of Listeria spp. and L. monocytogenes was not associated with HIV infection during pregnancy.

Safety, immunogenicity, and transplacental antibody transport of conjugated and polysaccharide pneumococcal vaccines administered to pregnant women with HIV: a multicentre randomised controlled trial.

BACKGROUND: Pneumococcus remains an important cause of morbidity in pregnant women with HIV and their infants. We compared the safety and immunogenicity of PCV-10 and PPV-23 with placebo administered in pregnancy. METHODS: This double-blind, multicentre, randomised controlled trial was done at eight outpatient clinics in Brazil. Eligible participants were adult women with HIV who were pregnant at a gestational age between 14 weeks and less than 34 weeks and who were taking antiretroviral therapy at study entry. Participants were randomly assigned (1:1:1) to receive either PCV-10, PPV-23, or placebo. Participants and study teams were unaware of treatment allocation. Antibodies against seven vaccine serotypes in PCV-10 and PPV-23 were measured by ELISA. The primary outcomes were maternal and infant safety assessed by the frequency of adverse events of grade 3 or higher; maternal seroresponse (defined as ≥2-fold increase in antibodies from baseline to 28 days after immunisation) against five or more serotypes; and infant seroprotection (defined as anti-pneumococcus antibody concentration of ≥0·35 µg/mL) against five or more serotypes at 8 weeks of life. The study was powered to detect differences of 20% or higher in the primary immunological outcomes between treatment groups. This trial is registered with ClinicalTrials.gov, NCT02717494. FINDINGS: Between April 1, 2016, and Nov 30, 2017, we enrolled 347 pregnant women with HIV, of whom 116 were randomly assigned to the PCV-10 group, 115 to the PPV-23 group, and 116 to the placebo group. One participant in the PCV-10 group did not receive the vaccine and was excluded from subsequent analyses. The frequency of adverse events of grade 3 or higher during the first 4 weeks was similar in the vaccine and placebo groups (3% [90% CI 1-7] for the PCV-10 group, 2% [0-5] for the PPV-23 group, and 3% [1-8] for the placebo group). However, injection site and systemic grade 2 adverse reactions were reported more frequently during the first 4 weeks in the vaccine groups than in the placebo group (14% [9-20] for the PCV-10 group, 7% [4-12] for the PPV-23 group, and 3% [1-7] for the placebo group). The frequency of grade 3 or higher adverse effects was similar across maternal treatment groups (20% [14-27] for the PCV-10 group, 21% [14-28] for the PPV-23 group, and 20% [14-27] for the placebo group). Seroresponses against five or more serotypes were present in 74 (65%) of 114 women in the PCV-10 group, 72 (65%) of 110 women in the PPV-23 group, and none of the 113 women in the placebo group at 4 weeks post vaccination (p<0·0001 for PPV-23 group vs placebo and PCV-10 group vs placebo). Seroresponse differences of 20% or higher in vaccine compared with placebo recipients persisted up to 24 weeks post partum. At birth, 76 (67%) of 113 infants in the PCV-10 group, 62 (57%) of 109 infants in the PPV-23 group, and 19 (17%) of 115 infants in the placebo group had seroprotection against five or more serotypes (p<0·0001 for PPV-23 vs placebo and PCV-10 vs placebo). At 8 weeks, the outcome was met by 20 (19%) of 108 infants in the PCV-10 group, 24 (23%) of 104 infants in the PPV-23 group, and one (1%) of 109 infants in the placebo group (p<0·0001). Although a difference of 20% or higher compared with placebo was observed only in the infants who received PPV-23 at 8 weeks of life, the difference between the two vaccine groups was not appreciable. INTERPRETATION: PCV-10 and PPV-23 were equally safe and immunogenic in pregnant women with HIV and conferred similar levels of seroprotection to their infants. In areas in which childhood PCV administration decreased the circulation of PCV serotypes, PPV-23 administration to pregnant women with HIV might be more advantageous than PCV by virtue of including a broader range of serotypes. FUNDING: Eunice Kennedy Shriver National Institute of Child Health and Human Development. TRANSLATION: For the Portuguese translation of the abstract see Supplementary Materials section.

HPV Induces Changes in Innate Immune and Adhesion Molecule Markers in Cervical Mucosa With Potential Impact on HIV Infection.

While most HPV infections are asymptomatic and clear spontaneously, persistent infection with high-risk HPVs is associated with cervical cancer and with increased risk of HIV acquisition. Although several hypotheses have been proposed to explain this phenomenon, none has been confirmed. Our aim was to investigate the expression of host factors involved in the susceptibility to HIV infection among HPV-infected women. Cervical samples were collected to characterize the expression levels of HIV susceptibility markers in the mucosa of HPV-infected compared with HPV-uninfected women. No differences in the frequency of CCR5+, integrin α4ß7+, activated and memory CD4+ T-cell were detected between the groups. We additionally evaluated the expression levels of genes involved in innate immune responses and in cell adhesion. HPV infected patients expressed higher levels of TLR9 and lower levels of pattern recognition receptors that recognize RNA (TLR3, TLR7, and MDA5/IFIH1). We also detected an impaired IFN pathway, with an increased Type I IFN and a decreased IFNα2 receptor expression. HPV+ samples displayed reduced expression of genes for adherens and tight junctions. Taken together, these results suggest that although HPV infection does not result in the recruitment/activation of susceptible CD4+ T-cell in the female genital tract, it leads to changes in the innate antiviral immune responses and in cell adhesion that are likely to favor HIV infection.

Composite Analysis of the Virome and Bacteriome of HIV/HPV Co-Infected Women Reveals Proxies for Immunodeficiency.

The human cervical microbiome is complex, and its role in health and disease has just begun to be elucidated. In this study, 57 cervical swab samples from 19 HIV/HPV co-infected women were analyzed for both virome and bacteriome composition. Virome analysis focused on circular DNA viruses through rolling circle amplification followed by next-generation sequencing (NGS). Data were assigned to virus families and genera, and HPV types were identified. NGS data of bacterial 16S from a subset of 24 samples were assigned to operational taxonomic units and classified according to vaginal microbiome community state types (CSTs). Four viral families were found: Papillomaviridae, Anelloviridae, Genomoviridae, and Herpesviridae. Papillomavirus reads were more abundant in women with premalignant cervical lesions, which were also strongly associated with multiple (≥3) high-risk HPV infection. Anellovirus read abundance was negatively correlated with host CD4+ T-cell counts. The bacteriome revealed the presence of CST III and CST IV, and women with ≥1% frequency of genomovirus or herpesvirus reads displayed an increased risk of carrying CST IV. By characterizing the composition of the cervical circular DNA viruses and the bacteriome of HIV/HPV co-infected women, we identified putative interactions between these two microorganism communities and their associations with patients' clinical characteristics, notably immunodeficiency status.

Factors associated with the development of Congenital Zika Syndrome: a case-control study.

BACKGROUND: We aim to investigate possible maternal- and pregnancy-related factors associated with the development of Congenital Zika Syndrome (CZS) in children of mothers with probable gestational infection. METHODS: This case-control study, we recruited mother-infant pairs between May 2015 and October 2017 in a pediatric infectious disease clinic in Rio de Janeiro. Inclusion criteria required either that the mother reported Zika infection symptoms during pregnancy or that the infant presented with clinical or imaging features of the CZS. Exclusion criteria included detection of an alternative cause for the patient's presentation or negative polymerase chain reaction assays for Zika in all specimens tested within 12 days from the beginning of maternal symptoms. Infants with CZS (CDC definition) were selected as cases and infants without CZS, but with probable maternal Zika virus infection during pregnancy, were selected as controls. Maternal and pregnancy-related informations were collected and their relationship to the presence of congenital anomalies due to CZS was assessed by Fisher exact or Mann-Whitney test. RESULTS: Out of the 42 included neonates, 24 (57.1%) were diagnosed with CZS (cases). The mean maternal age at the birth was 21 years old. The early occurrence of maternal symptoms during pregnancy was the only variable associated with CZS (odds ratio = 0.87, 95% CI: 0.78-0.97). Case's mothers presented symptoms until the 25th week of gestational age (GA), while control's mothers presented until 36th weeks of GA. Income; illicit drug, alcohol, or tobacco use during pregnancy; other infections during pregnancy (including previous dengue infection) were not associated with CZS. CONCLUSIONS: Our study corroborates the hypothesis that Zika virus infection earlier in pregnancy is a risk factor to the occurrence of congenital anomalies in their fetuses.

Detection of sexually transmitted infections at a Brazilian gynecology center: high prevalence of co-infections / Detecção de infecções sexualmente transmissíveis em uma unidade ginecológica brasileira: alta prevalência de coinfecções

ABSTRACT Introduction: Sexually transmitted infections (STI) remain a major public health problem and surveillance is crucial for prevention and control strategies. Objective: Our aim was to assess the prevalence of STI in a reference center for gynecology in Rio de Janeiro, Brazil. Materials and methods: It is a cross-sectional study conducted between August 2016 and June 2017. Whole blood and cervical cells were collected from 62 women and tested for human papillomavirus (HPV), human immunodeficiency virus (HIV), syphilis, chlamydia, gonorrhea and herpes simples virus 1 and 2 (HSV-1/2). Cervical lesions were diagnosed by cytopathology and in some patients by colposcopy (79%). Other STI were evaluated during clinical examination. Results: Cervical lesions were detected by cytopathology examinations in 46.8% of patients; those with a history of four sexual partners were at higher risk of developing them. There was moderate agreement between the cytopathology e colposcopy results (Kappa = 0.69). The prevalence of HSV (96.7%), syphilis (6.4%) and HIV (3.2%) were higher than that described in the literature, while the prevalence of chlamydia (6.4%) and gonorrhea (1.6%) were similar. HPV was detected in 53.2% of women, 32.3% of which were infected by HPV 16. In the context of co-infections, 38 women (61.3%) presented more than one STI. Conclusion: Since most of the women analyzed were affected by more than one STI, our results suggest that routine screening for these infections at health centers would help in early detection, treatment and prevention of these infections. These measures would also impact on patients' cervical cancer control.

RESUMO Introdução: As infecções sexualmente transmissíveis (ISTs) ainda são um importante problema de saúde pública, e a vigilância é essencial para sua prevenção e seu controle. Objetivo: Avaliar a prevalência das ISTs em uma unidade de referência ginecológica no Rio de Janeiro, Brasil. Materiais e métodos: Trata-se de um estudo transversal realizado entre agosto de 2016 e junho de 2017. Foram coletados sangue total e células cervicais de 62 mulheres e realizados testes para detecção de papiloma vírus humano (HPV), vírus da imunodeficiência humana (HIV), sífilis, clamídia, gonorreia e vírus do herpes simples 1 e 2 (HSV-1/2). As lesões cervicais foram diagnosticadas por citopatologia, e em algumas pacientes, por colposcopia (79%). Outras ISTs foram avaliadas durante o exame clínico. Resultados: Foram encontradas lesões cervicais pelo exame citopatológico em 46,8% das pacientes; aquelas com história de quatro parceiros sexuais tiveram mais risco de desenvolvê-las. Houve concordância moderada entre os resultados da citopatologia e colposcopia (Kappa = 0,69). A prevalência de HSV (96,7%), sífilis (6,4%) e HIV (3,2%) foi maior que a descrita na literatura, enquanto a prevalência de clamídia (6,4%) e gonorreia (1,6%) foi similar. O HPV foi detectado em 53,2% das mulheres, sendo 32,3% delas infectadas pelo HPV 16. No contexto das coinfecções, 38 mulheres (61,3%) tinham mais de uma IST. Conclusão: Visto que a maioria das mulheres analisadas era acometida por mais de uma IST, nossos resultados sugerem que uma triagem rotineira dessas infecções nas unidades de saúde poderia auxiliar na detecção precoce, bem como no tratamento e na prevenção. Essas medidas também impactariam no controle do câncer cervical das pacientes.

Pregnancy outcomes in young mothers with perinatally and behaviorally acquired HIV infections in Rio de Janeiro.

BACKGROUND: Perinatally HIV-infected children are surviving into adulthood, and getting pregnant. There is a scarcity of information on health and pregnancy outcomes in these women. AIM: To evaluate characteristics related to HIV disease and pregnancy outcomes in perinatally infected women, and to compare these women with a group of youth with behaviorally acquired HIV-infection, at a reference hospital in Rio de Janeiro, Brazil. METHODS: A cohort study. Epidemiological, clinical, and laboratory data were compared between perinatally (PHIV) and behaviorally HIV-infected (BHIV) pregnant youth with the primary aim to study pregnancy outcomes in the PHIV group and compare with outcomes to BHIV group. RESULTS: Thirty-two pregnancies occurred in PHIV group, and 595 in BHIV group. A total of seven (22%) PHIV women and 64 (11%) BHIV women had a premature delivery (p=0.04), however, when adjusting for younger age at pregnancy, and antiretroviral therapy initiation in 1st trimester of pregnancy (OR=18.66, 95%CI=5.52-63.14), the difference was no longer significant. No cases of mother-to-child HIV transmission (MTCT) were observed in the PHIV group while there was a 2% MTCT rate in BHIV group. CONCLUSION: Pregnancy among PHIV was as safe as among BHIV. The differences between those groups were probably related to treatment and prolonged care in the first group.

Pregnancy outcomes in young mothers with perinatally and behaviorally acquired HIV infections in Rio de Janeiro

ABSTRACT Background: Perinatally HIV-infected children are surviving into adulthood, and getting pregnant. There is a scarcity of information on health and pregnancy outcomes in these women. Aim: To evaluate characteristics related to HIV disease and pregnancy outcomes in perinatally infected women, and to compare these women with a group of youth with behaviorally acquired HIV-infection, at a reference hospital in Rio de Janeiro, Brazil. Methods: A cohort study. Epidemiological, clinical, and laboratory data were compared between perinatally (PHIV) and behaviorally HIV-infected (BHIV) pregnant youth with the primary aim to study pregnancy outcomes in the PHIV group and compare with outcomes to BHIV group. Results: Thirty-two pregnancies occurred in PHIV group, and 595 in BHIV group. A total of seven (22%) PHIV women and 64 (11%) BHIV women had a premature delivery (p = 0.04), however, when adjusting for younger age at pregnancy, and antiretroviral therapy initiation in 1st trimester of pregnancy (OR = 18.66, 95%CI = 5.52-63.14), the difference was no longer significant. No cases of mother-to-child HIV transmission (MTCT) were observed in the PHIV group while there was a 2% MTCT rate in BHIV group. Conclusion: Pregnancy among PHIV was as safe as among BHIV. The differences between those groups were probably related to treatment and prolonged care in the first group.

Exposure to Latent Tuberculosis Treatment during Pregnancy. The PREVENT TB and the iAdhere Trials.

RATIONALE: Data are limited regarding the safety of 12-dose once-weekly isoniazid (H, 900 mg) plus rifapentine (P, 900 mg) (3HP) for latent infection treatment during pregnancy. OBJECTIVES: To assess safety and pregnancy outcomes among pregnant women who were inadvertently exposed to study medications in two latent tuberculosis infection trials (PREVENT TB or iAdhere) evaluating 3HP and 9 months of daily isoniazid (H, 300 mg) (9H). METHODS: Data from reproductive-age (15-51 yr) women who received one or more study dose of 3HP or 9H in either trial were analyzed. Drug exposure during pregnancy occurred if the estimated date of conception was on or before the last dose date. RESULTS: Of 126 pregnancies (125 participants) that occurred during treatment or follow-up, 87 were exposed to study drugs. Among these, fetal loss was reported for 4/31 (13%) and 8/56 (14%), 3HP and 9H, respectively (difference, 13% - 14% = -1%; 95% confidence interval = -17% to +18%) and congenital anomalies in 0/20 and 2/41 (5%) live births, 3HP and 9H, respectively (difference, 0% - 5% = -5%; 95% confidence interval = -18% to +16%). All fetal losses occurred in pregnancies of less than 20 weeks. Of the total 126 pregnancies, fetal loss was reported in 8/54 (15%) and 9/72 (13%), 3HP and 9H, respectively; and congenital anomalies in 1/37 (3%) and 2/56 (4%) live births, 3HP and 9H, respectively. The overall proportion of fetal loss (17/126 [13%]) and anomalies (3/93 [3%]) were similar to those estimated for the United States, 17% and 3%, respectively. CONCLUSIONS: Among reported pregnancies in these two latent tuberculosis infection trials, there was no unexpected fetal loss or congenital anomalies. These data offer some preliminary reassurance to clinicians and patients in circumstances when these drugs and regimens are the best option in pregnancy or in women of child-bearing potential. This work used the identifying trial registration numbers NCT00023452 and NCT01582711, corresponding to the primary clinical trials PREVENT TB and iAdhere (Tuberculosis Trials Consortium Study 26 and 33).

Analysis of the cervical microbiome and potential biomarkers from postpartum HIV-positive women displaying cervical intraepithelial lesions.

The cervical microbiota composition and diversity of HIV-positive women in the postpartum period is unknown. Using a high-throughput bacterial 16S rRNA gene sequencing, we identified four community state types (CSTs). CST III (Lactobacillusdominant) and CST IV (IV-A, IV-B.1, IV-B.2; high-diversity) were found in 41% and 59% of samples, respectively. We did not find association of any CST to postpartum period (six or twelve months), HPV infection or cytology (normal or lesion). However, five bacterial genera were associated with cervical lesions (Gardnerella, Aerococcus, Schlegelella, Moryella and Bifidobacterium), with significant odds ratio (OR) of 40 (2.28-706) for the presence of Moryella and 3.5 (1.36-8.9) for Schlegelella. Longitudinal analysis of samples at postpartum that regressed (lesion to normal), progressed (normal to lesion) and maintained the cytology (lesion or normal) evidenced Gardnerella with a significantly higher abundance in regressing lesions. In the current study, we report the first data on the cervical microbiota of HIV-positive women in the postpartum period. Consistent with previous studies of HIV-negative cohorts, HIV-positive women present a stable cervical microbiota of high-diversity in the postpartum period. Our results highlight that specific microbiota species may serve as sensors for changes in the cervical microenvironment associated with cervical lesions.

Safety and immune response after two-dose meningococcal C conjugate immunization in HIV-infected children and adolescents in Rio de Janeiro, Brazil.

We aimed to evaluate immunogenicity and adverse events (AEs) after a booster dose of Meningococcal C conjugated (MCC) vaccine in HIV-infected children and adolescents, who had a previous low seroconversion rate after priming with MCC, at a reference HIV-care center in Rio de Janeiro. METHODS: 2-18 years old HIV-infected subjects with CD4+ T-lymphocyte cell (CD4) ≥15%, without active infection or antibiotic use, were enrolled to receive 2 doses of conjugated meningococcal C oligosaccharide-CRM197 12-18 months apart. All patients were evaluated before and 1-2 months after immunization for seroprotection [defined as human serum bactericidal activity (hSBA) titer ≥1:4]. AEs were assessed at 20 min, 3 and 7 days after each dose. Factors independently associated with seroprotection were studied. RESULTS: 156 subjects were enrolled and 137 received a booster MCC dose. 55% were female, and median age was 12 years. Eight-nine percent were receiving combined antiretroviral therapy (cART) at the booster visit (median duration of 7.7 years), 59.9% had undetectable viral load (VL) at baseline, and 56.2% at the booster visit. Seroprotection was achieved in 78.8% (108/137) subjects, with a significantly higher GMT than after the priming dose (p < 0.01). Mild AEs were experienced after a second MCC dose (38%). In logistic regression, undetectable viral load at entry [odds ratio (OR) = 7.1, 95% confidence interval (95%CI): 2.14-23.37], and probably higher CD4 percent at the booster immunization visit (OR): 1.1, 95%CI: 1.01-1.17 were associated with seroprotection after a booster dose of MCC. CONCLUSION: A booster dose of MCC was safe and induced high seroprotection rate even 12-18 months after priming. MCC should be administered after maximum virologic suppression has been achieved. These results support the recommendation of 2-dose of MCC for primary immunization in HIV-infected children and adolescents with restored immune function.

Identification of novel human papillomavirus lineages and sublineages in HIV/HPV-coinfected pregnant women by next-generation sequencing.

Infection by human papillomavirus (HPV) is a necessary condition for development of cervical cancer, and has also been associated with malignancies of other body anatomical sites. Specific HPV types have been associated with premalignant lesions and invasive carcinoma, but mounting evidence suggests that within-type lineages and sublineages also display distinct biological characteristics associated with persistent infections and evolution to cervical cancer. In the present study, we have assessed HPV multiple infection and variation from a cohort of highly susceptible, HIV(+) pregnant women using next-generation sequencing and an in-house pipeline for HPV full-length genome assembly. Seventy-two consensus sequences representing complete or near-complete (>97%) HPV genomes were assembled, spanning 28 different types. Genetic distance and phylogenetic analyses allowed us to propose the classification of novel HPV lineages and sublineages across nine HPV types, including two high-risk types. HPV diversity may be a hallmark of immunosuppressed patients upon HIV infection and AIDS progression.

Bonafide, type-specific human papillomavirus persistence among HIV-positive pregnant women: predictive value for cytological abnormalities, a longitudinal cohort study.

This study investigated the rate of human papillomavirus (HPV) persistence, associated risk factors, and predictors of cytological alteration outcomes in a cohort of human immunodeficiency virus-infected pregnant women over an 18-month period. HPV was typed through L1 gene sequencing in cervical smears collected during gestation and at 12 months after delivery. Outcomes were defined as nonpersistence (clearance of the HPV in the 2nd sample), re-infection (detection of different types of HPV in the 2 samples), and type-specific HPV persistence (the same HPV type found in both samples). An unfavourable cytological outcome was considered when the second exam showed progression to squamous intraepithelial lesion or high squamous intraepithelial lesion. Ninety patients were studied. HPV DNA persistence occurred in 50% of the cases composed of type-specific persistence (30%) or re-infection (20%). A low CD4+T-cell count at entry was a risk factor for type-specific, re-infection, or HPV DNA persistence. The odds ratio (OR) was almost three times higher in the type-specific group when compared with the re-infection group (OR = 2.8; 95% confidence interval: 0.43-22.79). Our findings show that bonafide (type-specific) HPV persistence is a stronger predictor for the development of cytological abnormalities, highlighting the need for HPV typing as opposed to HPV DNA testing in the clinical setting.

Bonafide, type-specific human papillomavirus persistence among HIV-positive pregnant women: predictive value for cytological abnormalities, a longitudinal cohort study

This study investigated the rate of human papillomavirus (HPV) persistence, associated risk factors, and predictors of cytological alteration outcomes in a cohort of human immunodeficiency virus-infected pregnant women over an 18-month period. HPV was typed through L1 gene sequencing in cervical smears collected during gestation and at 12 months after delivery. Outcomes were defined as nonpersistence (clearance of the HPV in the 2nd sample), re-infection (detection of different types of HPV in the 2 samples), and type-specific HPV persistence (the same HPV type found in both samples). An unfavourable cytological outcome was considered when the second exam showed progression to squamous intraepithelial lesion or high squamous intraepithelial lesion. Ninety patients were studied. HPV DNA persistence occurred in 50% of the cases composed of type-specific persistence (30%) or re-infection (20%). A low CD4+T-cell count at entry was a risk factor for type-specific, re-infection, or HPV DNA persistence. The odds ratio (OR) was almost three times higher in the type-specific group when compared with the re-infection group (OR = 2.8; 95% confidence interval: 0.43-22.79). Our findings show that bonafide (type-specific) HPV persistence is a stronger predictor for the development of cytological abnormalities, highlighting the need for HPV typing as opposed to HPV DNA testing in the clinical setting.