Showing papers by "Adriana Weinberg published in 2015"

Influenza Vaccination of Pregnant Women and Protection of Their Infants

Abstract: Seasonal influenza vaccination for parturients is recommended because of their increased susceptibility to severe disease. The efficacy of inactivated influenza vaccine (IIV) in pregnant womenmay differ from that in healthy nonpregnant women or in men and could be more accentuated in parturients infected with HIV because of immunosuppression. This study comprised 2 blinded randomized controlled trials of trivalent IIV (IIV3) in parturients with and without HIV infection to evaluate safety, immunogenicity, and efficacy of IIV3 in these women and their infants to 24 weeks postpartum. The women were aged 18 to 38 years, with estimated gestations of 20 to 36 weeks. The primary objectives for women without HIV infection were to evaluate the efficacy of IIV3 vaccination during pregnancy in protecting their infants against influenza through 24 weeks postpartum and to compare seroconversion rates between IIV3 recipients and placebo recipients 1 month after vaccination. In women with HIV, another objective was to evaluate the immunogenicity of IIV3 along with determining vaccine efficacy inmothers and their infants until 24 weeks postpartum. All mothers and infants in the HIV-infected cohort and a nested group of 180 HIV-uninfected mother-infant dyads were enrolled in a safety and immunogenicity study. Intention-to-treat and per-protocol analyses were conducted. Among 2116 black African non–HIV-infected parturients, 1062 and 1054 received IIV3 and placebo, respectively; 1026 and 1023 live infants were born to IIV3 and placebo recipients, respectively. Of 194 HIV-infected parturients, 100 received IIV3 and 94 received placebo. Of the 376 participants in the immunogenicity subset, 142 IIV3 and 148 placebo recipients were included in the per-protocol analysis. Postvaccination geometric mean titers increased from baseline by a factor of 6 to 10 in IIV3 recipients and were significantly higher than titers in placebo recipients. A greater proportion of IIV3 recipients had seroprotective hemagglutination inhibition (HAI) titers after vaccination compared with placebo recipients. Newborns of IIV3 recipients had higher HAI geometric mean titers than newborns of placebo recipients and were more likely to have an uthorized reproduction of this article is prohibited. 4 Obstetrical and Gynecological Survey HAI titer of 1:40 or greater. The newborn-to-maternal ratios of HAI titers were 0.7 to 1.0 and were similar between study groups. In the HIV-infected women in the per-protocol immunogenicity arm, receipt of IIV3 resulted in increases in geometric mean titers of antibodies. A higher proportion of IIV3 recipients had seroprotective HAI titers after vaccination compared with placebo recipients. Newborns of IIV3 recipients had higher HAI geometric mean titers than did newborns of placebo recipients. The ratio of geometric mean HAI titers was 0.7 to 1.4. In the IIV3 group, titers for HAI were higher than those in the placebo group. Attack rates for influenza among the IIV3 recipients was lower as compared with the placebo recipients, 1.8% versus 3.6%, respectively, indicating a vaccine efficacy of 50.4% (95% confidence interval [CI], 14.5%–71.2%). Similarly, the attack rate was 1.9% for infants whose mothers were IIV3 recipients compared with 3.6% for those whose mothers received placebo; vaccine efficacy was 48.8% (95% CI, 11.6%–70.4%). Vaccine efficacy estimates in the per-protocol analysis were similar to the estimates in the intention-to-treat analysis. In the HIV-infected mothers, the attack rate was 7.0% in IIV3 recipients compared with 17.0% for placebo recipients, for an adjusted vaccine efficacy of 57.7% (95% CI, 0.2%–82.1%). The attack rates were 5.0% and 6.8% among infants of IIV3 and placebo recipients, respectively (efficacy, 26.7%; P = 0.60). Injection-site reactions were more frequent among IIV3 recipients in both cohorts, but no other significant differences in reactions were found. No significant between-group differences were found for rates of miscarriage, stillbirth, or premature birth or birth weight in the HIV-uninfected or -infected cohort. These results support the current World Health Organization recommendations for influenza vaccination during pregnancy, with a reduction in confirmed cases of influenza in both cohorts. Trivalent IIV was safe and immunogenic in HIV-uninfected and HIVinfected women. Because the study was conducted at a single center, the generalizability of the findingsmust be corroborated.

Kinetics of Hemagglutination-Inhibiting Antibodies Following Maternal Influenza Vaccination Among Mothers With and Those Without HIV Infection and Their Infants

Abstract: BACKGROUND We evaluated the immunogenicity of trivalent inactivated influenza vaccine (IIV3) in pregnant women with and those without human immunodeficiency virus (HIV) infection and the persistence of hemagglutination-inhibiting antibodies in mothers and infants. METHODS Antibodies were measured before vaccination, 1 month after vaccination, at delivery, and at postpartum week 24 in mothers and within 1 week of birth and at 8, 16, and 24 weeks of age in infants. RESULTS We enrolled 98 HIV-uninfected and 100 HIV-infected pregnant women, including 93% with a CD4(+) T-cell count of ≥ 200 cells/µL. Compared with HIV-uninfected women, HIV-infected women had lower seroconversion rates (ranging from 63%-92% vs 36%-40%), lower antibody titers through postpartum week 24, and overlapping antibody half-lives (ranging from 106-121 vs 87-153 days). Infant titers were lower than the maternal titers within 1 week of delivery, regardless of vaccine strain and HIV exposure status. Compared with HIV-unexposed infants, HIV-exposed infants had a similar transplacental influenza virus antibody transfer ratio, lower titers, and a lower frequency of titers ≥ 1:40 (ranging from 82%-95% vs 43%-79%) at birth and higher antibody half-lives (ranging from 43-45 vs 56-65 days). CONCLUSIONS Compared with HIV-uninfected pregnant women, HIV-infected pregnant women had lower antibody responses and persistence. Compared with HIV-unexposed infants, HIV-exposed infants had lower antibody levels at birth but similar antibody levels after 8 weeks of life. Early IIV3 administration during pregnancy did not decrease antibody titers among infants at birth.

Physical function impairment of older, HIV-infected adults is associated with cytomegalovirus immunoglobulin response.

Abstract: Cytomegalovirus (CMV) is associated with poor outcomes, including physical function impairment, in older HIV-uninfected adults. Whether CMV is associated with physical functional impairment in HIV-infected adults is unknown. The primary objective of this study was to determine the relationship between CMV-specific humoral and cell-mediated immune responses with functional impairment in well-controlled HIV infection. In a case-control study, low-function cases were matched by age, gender, and time from HIV diagnosis to high-function controls. Quantitative CMV IgG and %CMV-specific CD8+ and CD4+ T cells (interferon-γ expression following CMV pp65 stimulation) were used to estimate physical function. Among 30 low-function cases and 48 high-function matched controls, CMV IgG ranged from <10 to 8,830 EU/ml, including four controls with results <10 EU/ml. Each log10 increase in CMV IgG was associated with 5-fold greater odds of low function (p=0.01); these findings were robust to adjustment for concomi...

Determinants of vaccine immunogenicity in HIV-infected pregnant women: analysis of B and T cell responses to pandemic H1N1 monovalent vaccine.

Abstract: Influenza infections have high frequency and morbidity in HIV-infected pregnant women, underscoring the importance of vaccine-conferred protection. To identify the factors that determine vaccine immunogenicity in this group, we characterized the relationship of B- and T-cell responses to pandemic H1N1 (pH1N1) vaccine with HIV-associated immunologic and virologic characteristics. pH1N1 and seasonal-H1N1 (sH1N1) antibodies were measured in 119 HIV-infected pregnant women after two double-strength pH1N1 vaccine doses. pH1N1-IgG and IgA B-cell FluoroSpot, pH1N1- and sH1N1-interferon γ (IFNγ) and granzyme B (GrB) T-cell FluoroSpot, and flow cytometric characterization of B- and T-cell subsets were performed in 57 subjects. pH1N1-antibodies increased after vaccination, but less than previously described in healthy adults. pH1N1-IgG memory B cells (Bmem) increased, IFNγ-effector T-cells (Teff) decreased, and IgA Bmem and GrB Teff did not change. pH1N1-antibodies and Teff were significantly correlated with each other and with sH1N1-HAI and Teff, respectively, before and after vaccination. pH1N1-antibody responses to the vaccine significantly increased with high proportions of CD4+, low CD8+ and low CD8+HLADR+CD38+ activated (Tact) cells. pH1N1-IgG Bmem responses increased with high proportions of CD19+CD27+CD21- activated B cells (Bact), high CD8+CD39+ regulatory T cells (Treg), and low CD19+CD27-CD21- exhausted B cells (Bexhaust). IFNγ-Teff responses increased with low HIV plasma RNA, CD8+HLADR+CD38+ Tact, CD4+FoxP3+ Treg and CD19+IL10+ Breg. In conclusion, pre-existing antibody and Teff responses to sH1N1 were associated with increased responses to pH1N1 vaccination in HIV-infected pregnant women suggesting an important role for heterosubtypic immunologic memory. High CD4+% T cells were associated with increased, whereas high HIV replication, Tact and Bexhaust were associated with decreased vaccine immunogenicity. High Treg increased antibody responses but decreased Teff responses to the vaccine. The proportions of immature and transitional B cells did not affect the responses to vaccine. Increased Bact were associated with high Bmem responses to the vaccine.

Depot Medroxyprogesterone Acetate in Combination with a Twice-Daily Lopinavir-Ritonavir-Based Regimen in HIV-Infected Women Showed Effective Contraception and a Lack of Clinically Significant Interactions, with Good Safety and Tolerability: Results of the ACTG 5283 Study

Abstract: We conducted an open-label, steady-state pharmacokinetic (PK) study of drug-drug interactions between depot medroxyprogesterone acetate (DMPA) and twice-daily lopinavir (LPV) plus low-dose ritonavir (RTV) (LPV/r) among 24 HIV-infected women and compared the results to those for HIV-infected women receiving DMPA while on no antiretroviral therapy or on nucleosides only (n = 14 subjects from the control arm of AIDS Clinical Trials Group [ACTG] study 5093). The objectives of the study were to address the effect of LPV/r on DMPA and to address the effect of DMPA on LPV/r therapy. PK parameters were estimated using noncompartmental analysis with between-group comparisons of medroxyprogesterone acetate (MPA) PKs and within-subject comparisons of LPV and RTV PKs before and 4 weeks after DMPA dosing. Plasma progesterone concentrations were measured every 2 weeks after DMPA dosing through week 12. Although the MPA area under the concentration-time curve and maximum concentration of drug in plasma were statistically significantly increased in the study women on LPV/r compared to those in the historical controls, these increases were not considered clinically significant. There were no changes in LPV or RTV exposure after DMPA. DMPA was well tolerated, and suppression of ovulation was maintained. (This study has been registered at ClinicalTrials.gov under registration no. NCT01296152.).

Serious adverse events are uncommon with combination neonatal antiretroviral prophylaxis: a retrospective case review.

Abstract: Six weeks of zidovudine (ZDV) is recommended for postnatal prophylaxis of HIV-exposed infants, but combination antiretrovirals are indicated if HIV transmission risk is increased We investigated the frequency and severity of adverse events (AE) in infants receiving multiple drug prophylaxis compared to ZDV alone In this retrospective review of 148 HIV-exposed uninfected infants born between 1997–2009, we determined clinical and laboratory AE that occurred between days of life 8–42 Thirty-six infants received combination prophylaxis; among those, a three-drug regimen containing ZDV, lamivudine, and nevirapine was most common (53%) Rates of laboratory AE grade ≥1 were as follows for the combination prophylaxis and ZDV alone groups, respectively: neutropenia 55% and 39%; anemia 50% and 39%; thrombocytopenia 0 and 3%; elevated aspartate aminotransferase 3% and 3%; elevated alanine aminotransferase 0 and 1%; hyperbilirubinemia 19% and 42% Anemia occurred more frequently in infants who received three-drug prophylaxis compared to infants who received ZDV alone (63% vs 39%, p = 004); all anemia AE were grade 1 or 2 in the three-drug prophylaxis group Overall, 75% of infants on combination prophylaxis and 66% of infants on ZDV alone developed grade ≥1 AE (p = 032), and 17% of infants in either group developed grade ≥3 AE Stavudine was substituted for ZDV in 23 infants due to anemia or neutropenia After this antiretroviral change, 50% of evaluable infants demonstrated improvement in AE grade, and 25% had no change In conclusion, low grade anemia, neutropenia, and hyperbilirubinemia occurred frequently regardless of the prophylactic regimen, but serious AE were uncommon Although most AE were typical of ZDV toxicity, the combination of ZDV with lamivudine and nevirapine resulted in an increased frequency of low-grade anemia Further studies are needed to identify prophylactic regimens with less toxicity for infants born to HIV-infected mothers

Characterization of Functional Antibody and Memory B-Cell Responses to pH1N1 Monovalent Vaccine in HIV-Infected Children and Youth

Abstract: Objectives We investigated immune determinants of antibody responses and B-cell memory to pH1N1 vaccine in HIV-infected children. Methods Ninety subjects 4 to <25 years of age received two double doses of pH1N1 vaccine. Serum and cells were frozen at baseline, after each vaccination, and at 28 weeks post-immunization. Hemagglutination inhibition (HAI) titers, avidity indices (AI), B-cell subsets, and pH1N1 IgG and IgA antigen secreting cells (ASC) were measured at baseline and after each vaccination. Neutralizing antibodies and pH1N1-specific Th1, Th2 and Tfh cytokines were measured at baseline and post-dose 1. Results At entry, 26 (29%) subjects had pH1N1 protective HAI titers (≥1:40). pH1N1-specific HAI, neutralizing titers, AI, IgG ASC, IL-2 and IL-4 increased in response to vaccination (p<0.05), but IgA ASC, IL-5, IL-13, IL-21, IFNγ and B-cell subsets did not change. Subjects with baseline HAI ≥1:40 had significantly greater increases in IgG ASC and AI after immunization compared with those with HAI <1:40. Neutralizing titers and AI after vaccination increased with older age. High pH1N1 HAI responses were associated with increased IgG ASC, IFNγ, IL-2, microneutralizion titers, and AI. Microneutralization titers after vaccination increased with high IgG ASC and IL-2 responses. IgG ASC also increased with high IFNγ responses. CD4% and viral load did not predict the immune responses post-vaccination, but the B-cell distribution did. Notably, vaccine immunogenicity increased with high CD19+CD21+CD27+% resting memory, high CD19+CD10+CD27+% immature activated, low CD19+CD21-CD27-CD20-% tissue-like, low CD19+CD21-CD27-CD20-% transitional and low CD19+CD38+HLADR+% activated B-cell subsets. Conclusions HIV-infected children on HAART mount a broad B-cell memory response to pH1N1 vaccine, which was higher for subjects with baseline HAI≥1:40 and increased with age, presumably due to prior exposure to pH1N1 or to other influenza vaccination/infection. The response to the vaccine was dependent on B-cell subset distribution, but not on CD4 counts or viral load. Trial Registration ClinicalTrials.gov NCT00992836

Screening and Monitoring for Infectious Complications When Immunosuppressive Agents Are Studied in the Treatment of Autoimmune Disorders

Abstract: Significant progress has been made in the development, investigation, and clinical application of immunosuppressive agents to treat a variety of autoimmune disorders. The expansion of clinical applications of these new agents requires the performance of large multicenter clinical trials. These large clinical trials are particularly important as one considers these agents for the treatment of type 1 diabetes, which although autoimmune in its pathogenesis, is not classically treated as an autoimmune disorder. Although these agents hold promise for amelioration or cure of this disease, they have the potential to facilitate infectious complications. There are limited data regarding the prospective assessment of infectious risks with these agents in trials of this nature. Pediatric subjects may be at greater risk due to the higher likelihood of primary infection. A subgroup of experts associated with TrialNet (a National Institutes of Health [NIH]-funded Type 1 diabetes mellitus research network) with expertise in infectious diseases, immunology, and diagnostics developed an approach for screening and monitoring of immunosuppression-associated infections for prospective use in clinical trials. The goals of these recommendations are to provide a structured approach to monitor for infections, to identify specific laboratory testing and surveillance methods, and to consider therapies for treatment of these potential complications. Prospective evaluations of these infectious risks allow for greater scientific rigor in the evaluation of risk, which must be balanced with the potential benefits of these therapies. Our experience supports an important role for investigators with expertise in infections in immunocompromised individuals in protocol development of immunosuppressive trials in type 1diabetes and potentially other autoimmune diseases.

Effect of Cytomegalovirus Co-Infection on Normalization of Selected T-Cell Subsets in Children with Perinatally Acquired HIV Infection Treated with Combination Antiretroviral Therapy

Abstract: Background We examined the effect of cytomegalovirus (CMV) co-infection and viremia on reconstitution of selected CD4+ and CD8+ T-cell subsets in perinatally HIV-infected (PHIV+) children 1-year old who participated in a partially randomized, open-label, 96-week combination antiretroviral therapy (cART)-algorithm study.

Heterogeneity of T Cell Responses to Pandemic pH1N1 Monovalent Vaccine in HIV-Infected Pregnant Women

Abstract: We investigated the Th1 protective and regulatory T and B cell (Treg and Breg) responses to pH1N1 monovalent influenza vaccine (IIV1) in HIV-infected pregnant women on combination antiretroviral therapy (cART). Peripheral blood mononuclear cells (PBMCs) from 52 study participants were cryopreserved before and after vaccination and analyzed by flow cytometry. pH1N1-specific Th1, Treg, and Breg responses were measured in PBMCs after in vitro stimulation with pH1N1 and control antigen. The cohort analysis did not detect changes in pH1N1-Th1, Treg, or Breg subsets postvaccination. However, individual analyses distinguished subjects who mounted vigorous Th1 responses postvaccination from others who did not. Postvaccination, high pH1N1-Th1 correlated with high pH1N1-Treg and Breg responses, suggesting that low influenza effector responses did not result from excessive vaccine-induced immune regulation. High postvaccination pH1N1-Th1 responses correlated with baseline high PHA- and pH1N1-IFN-γ ELISpot a...

Intrahepatic cholestasis of pregnancy and serum bile acids in HIV infected pregnant women.

Abstract: Objectives: Intra-hepatic cholestasis of pregnancy (ICP) is uncommon, but has severe effects on pregnancy outcomes. ICP is characterized by elevated serum bile acids and liver enzymes and preferentially affects women with liver disorders. We compared bile acids and pregnancy outcomes of HIV-infected pregnant women, who commonly have elevated live enzymes, with uninfected controls. Methods: Twenty-four HIV-infected, including 2 co-infected with hepatitis C virus (HCV), and 25 uninfected women were tested during early and late pregnancy and postpartum. Results: After exclusion of the HCV-infected women, serum bile acids were similar in HIV-infected and uninfected participants. -glutamyl transpeptidase was elevated in HIV-infected compared with uninfected women during pregnancy and postpartum. Bilirubin and aspartate transaminase were higher in uninfected compared with HIV-infected women in early pregnancy, but subsequently similar. Bile acids in late pregnancy correlated with bile acids in the baby at birth. An HIV- and HCV-co-infected pregnant woman with active hepatitis developed ICP complicated by fetal distress. Another co-infected participant without active hepatitis had an uneventful pregnancy and delivery. Conclusion: In the absence of HCV co-infection, bile acid metabolism appeared to be similar in HIV-infected and uninfected pregnant women. Both HIV-infected and uninfected pregnant women had mild liver enzyme elevations.