[Show abstract][Hide abstract] ABSTRACT: Tuberculosis is a major cause of morbidity and mortality in women of childbearing age (15–44 years). Despite increased tuberculosis risk during pregnancy, optimal clinical treatment remains unclear: safety, tolerability, and pharmacokinetic data for many tuberculosis drugs are lacking, and trials of promising new tuberculosis drugs exclude pregnant women. To advance inclusion of pregnant and postpartum women in tuberculosis drug trials, the US National Institutes of Health convened an international expert panel.
Discussions generated consensus statements (>75% agreement among panelists) identifying high-priority research areas during pregnancy, including: (1) preventing progression of latent tuberculosis infection, especially in women coinfected with human immunodeficiency virus; (2) evaluating new agents/regimens for treatment of multidrug-resistant tuberculosis; and (3) evaluating safety, tolerability and pharmacokinetics of tuberculosis drugs already in use during pregnancy and postpartum. Incorporating pregnant women into clinical trials would extend evidence-based tuberculosis prevention and treatment standards to this special population.
Full-text · Article · Jan 2016 · Clinical Infectious Diseases
[Show abstract][Hide abstract] ABSTRACT: Tuberculosis is a major cause of morbidity and mortality in women of childbearing age (15–44 years). Despite increased tuberculosis
risk during pregnancy, optimal clinical treatment remains unclear: safety, tolerability, and pharmacokinetic data for many
tuberculosis drugs are lacking, and trials of promising new tuberculosis drugs exclude pregnant women. To advance inclusion
of pregnant and postpartum women in tuberculosis drug trials, the US National Institutes of Health convened an international
expert panel. Discussions generated consensus statements (>75% agreement among panelists) identifying high-priority research
areas during pregnancy, including: (1) preventing progression of latent tuberculosis infection, especially in women coinfected
with human immunodeficiency virus; (2) evaluating new agents/regimens for treatment of multidrug-resistant tuberculosis; and
(3) evaluating safety, tolerability and pharmacokinetics of tuberculosis drugs already in use during pregnancy and postpartum.
Incorporating pregnant women into clinical trials would extend evidence-based tuberculosis prevention and treatment standards
to this special population.
[Show abstract][Hide abstract] ABSTRACT: Objectives:
Depot medroxyprogesterone acetate (DMPA) was associated with increased HIV transmission and accelerated disease progression in untreated women. The potential underlying mechanisms include immune-modulation. We evaluated the effect of a single DMPA injection on cell-mediated immunity (CMI), T cell activation (Tact), regulation (Treg) and inflammation in HIV-infected women on cART.
Women with HIV plasma RNA ≤400 c/mL on stable cART received DMPA and had immunologic and MPA measurements at baseline, 4 weeks [peak MPA concentration (Cmax)] and 12 weeks [highest MPA area under the concentration curve (AUC)].
At baseline, among 24 women with median 32 years of age and 622 CD4+ cells/µL, ≥68% had HIV, VZV, PHA and CD3/CD28 CMI measured by lymphocyte proliferation and/or IFNγ/IL2 dual-color fluorospot. CMI did not significantly change after DMPA administration except for a 1.4-fold increase in IL2/IFNγ VZV fluorospot at week 12. Tact decreased after DMPA administration, reaching statistical significance at week 12 for CD4+CD25+%. Treg behaved heterogeneously with an increase in CD8+FOXP3+% at week 4 and a decrease in CD4+IL35+% at week 12. There was a decrease in TGFβ at week 12 and no other changes in plasma biomarkers. Correlation analyses showed that high MPA Cmax and/or AUC were significantly associated with increases of IFNγ HIV ELISPOT, CD4+IL35+% and CD4+TGFβ+% Treg and decreases of plasma IL10 from baseline to weeks 4 and/or 12.
A single dose of DMPA did not have immune-suppressive or pro-inflammatory effects in HIV-infected women on cART. Additional studies need to assess the effect of multiple doses.
No preview · Article · Sep 2015 · JAIDS Journal of Acquired Immune Deficiency Syndromes
[Show abstract][Hide abstract] 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 and circulating CD4(+)CD39(+)% and CD8(+)CD39(+)% Treg, with low CD8(+) cell numbers and CD19(+)FOXP3(+)% Breg, but not with CD4(+) cell numbers or HIV viral load. These data highlight the heterogeneity of T cell responses to vaccines in HIV-infected individuals on cART. Predictors of robust Th1 responses to IIV include CD8(+) cell numbers, T cell functionality, and circulating Breg and Treg.
Preview · Article · Aug 2015 · AIDS research and human retroviruses
[Show abstract][Hide abstract] ABSTRACT: Intended and unintended pregnancies occur frequently among human immunodeficiency virus (HIV)-infected women. We evaluated the occurrence of repeat pregnancy and characteristics associated with this outcome among HIV-infected women in Latin America and the Caribbean who were participating in the National Institute of Child Health and Human Development (NICHD) International Site Development Initiative (NISDI). Of the 1342 HIV-infected pregnant women enrolled in NISDI, 124 (9.2%) had one or more repeat pregnancies on study. Median time between the index delivery and date of conception of the subsequent pregnancy was 1.4 years (range 0.1-5.7). Younger age (odds ratio [OR] = 1.07, 95% confidence interval [CI]: 1.04-1.11 per one year decrease in age), hospitalization during the index pregnancy or up to six months post-partum [OR = 2.0, 95% CI: 1.2-3.4], and poor index pregnancy outcome (stillbirth or spontaneous/therapeutic abortion; OR = 3.4, 95% CI: 1.4-8.4) were associated with increased occurrence of repeat pregnancy in multivariable analysis. Among women with repeat pregnancies, the proportion receiving antiretroviral treatment (vs. prophylaxis) increased from 39.4% at the time of the index pregnancy to 81.8% at the time of the repeat pregnancy (p < 0.001). These results can help identify women most likely to benefit from reproductive counseling in order to assist with healthy pregnancy planning and prevention of unintended pregnancies.
[Show abstract][Hide abstract] ABSTRACT: Background:
Sexually transmitted infections (STIs) such as Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) can lead to adverse pregnancy and neonatal outcomes. The prevalence of STIs and its association with HIV mother-to-child transmission (MTCT) were evaluated in a substudy analysis from a randomized, multicenter clinical trial.
Urine samples from HIV-infected pregnant women collected at the time of labor and delivery were tested using polymerase chain reaction testing for the detection of CT and NG (Xpert CT/NG; Cepheid, Sunnyvale, CA). Infant HIV infection was determined by HIV DNA polymerase chain reaction at 3 months.
Of the 1373 urine specimens, 249 (18.1%) were positive for CT and 63 (4.6%) for NG; 35 (2.5%) had both CT and NG detected. Among 117 cases of HIV MTCT (8.5% transmission), the lowest transmission rate occurred among infants born to CT- and NG-uninfected mothers (8.1%) as compared with those infected with only CT (10.7%) and both CT and NG (14.3%; P = 0.04). Infants born to CT-infected mothers had almost a 1.5-fold increased risk for HIV acquisition (odds ratio, 1.47; 95% confidence interval, 0.9-2.3; P = 0.09).
This cohort of HIV-infected pregnant women is at high risk for infection with CT and NG. Analysis suggests that STIs may predispose to an increased HIV MTCT risk in this high-risk cohort of HIV-infected women.
[Show abstract][Hide abstract] ABSTRACT: Several observational studies have reported that HIV-1 acquisition seems to be higher in women who use depot medroxyprogesterone acetate (DMPA) than in those who do not use hormonal contraception. We aimed to assess whether two injectable progestin-only contraceptives, DMPA and norethisterone enanthate (NET-EN), confer different risks of HIV-1 acquisition.
We included data from South African women who used injectable contraception while participating in the VOICE study, a multisite, randomised, placebo-controlled trial that investigated the safety and efficacy of three formulations of tenofovir for prevention of HIV-1 infection in women between Sept 9, 2009, and Aug 13, 2012. Women were assessed monthly for contraceptive use and incident infection. We estimated the difference in incident HIV-1 infection between DMPA and NET-EN users by Cox proportional hazards regression analyses in this prospective cohort. The VOICE trial is registered with ClinicalTrials.gov, NCT00705679.
3141 South African women using injectable contraception were included in the present analysis: 1788 (56·9%) solely used DMPA, 1097 (34·9%) solely used NET-EN, and 256 (8·2%) used both injectable types at different times during follow-up. During 2733·7 person-years of follow-up, 207 incident HIV-1 infections occurred (incidence 7·57 per 100 person-years, 95% CI 6·61-8·68). Risk of HIV-1 acquisition was higher among DMPA users (incidence 8·62 per 100 person-years, 95% CI 7·35-10·11) than among NET-EN users (5·67 per 100 person-years, 4·35-7·38; hazard ratio 1·53, 95% CI 1·12-2·08; p=0·007). This association persisted when adjusted for potential confounding variables (adjusted hazard ratio [aHR] 1·41, 95% CI 1·06-1·89; p=0·02). Among women seropositive for herpes simplex virus type 2 (HSV-2) at enrolment, the aHR was 2·02 (95% CI 1·26-3·24) compared with 1·09 (0·78-1·52) for HSV-2-seronegative women (pinteraction=0·07).
Although moderate associations in observational analyses should be interpreted with caution, these findings suggest that NET-EN might be an alternative injectable drug with a lower HIV risk than DMPA in high HIV-1 incidence settings where NET-EN is available.
National Institutes of Health, Mary Meyer Scholars Fund, and the Ruth Freeman Memorial Fund.
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] ABSTRACT: Importance
Most studies examining the association of prenatal antiretroviral (ARV) exposures with congenital anomalies (CAs) in children born to human immunodeficiency virus (HIV)–infected women have been reassuring, but some evidence suggests an increased risk with specific ARV agents.Objective
To evaluate the association of in utero ARV exposures with CAs in HIV-exposed uninfected children.Design, Setting, and Participants
Prospective cohort study design. The Pediatric HIV/AIDS Cohort Study’s Surveillance Monitoring of ART Toxicities (SMARTT) Study was performed at 22 US medical centers among 2580 HIV-exposed uninfected children enrolled in the SMARTT Study between March 23, 2007, and June 18, 2012.Exposures
First-trimester exposure to any ARV and to specific ARV medications.Main Outcomes and Measures
The primary end point was a CA based on physician review of infant physical examinations according to the Antiretroviral Pregnancy Registry modification of the Metropolitan Atlanta Congenital Defects Program. Rates of CAs were estimated overall and by birth year. Logistic regression models were used to evaluate the association of CAs with first-trimester ARV exposures, adjusting for demographic and maternal characteristics.Results
Congenital anomalies occurred in 175 of 2580 children, yielding a prevalence of 6.78% (95% CI, 5.85%-7.82%); 242 major CAs were confirmed, including 72 musculoskeletal and 55 cardiovascular CAs. The prevalence of CAs increased significantly among successive birth cohorts (3.8% for children born before 2002 and up to 8.3% for those born 2008-2010). In adjusted models, no association of first-trimester exposures with CAs was found for any ARV, for combination ARV regimens, or for any drug class. No individual ARV in the reverse transcriptase inhibitor drug classes was associated with an increased risk of CAs. Among protease inhibitors, higher odds of CAs were observed for atazanavir sulfate (adjusted odds ratio [aOR], 1.95; 95% CI, 1.24-3.05) and for ritonavir used as a booster (aOR, 1.56; 95% CI, 1.11-2.20). With first-trimester atazanavir exposure, risks were highest for skin (aOR, 5.23) and musculoskeletal (aOR, 2.55) CAs.Conclusions and Relevance
Few individual ARVs and no drug classes were associated with an increased risk of CAs in HIV-exposed infants after adjustment for calendar year and maternal characteristics. While the overall risk remained low, a relative increase was observed in successive years and with atazanavir exposure. Given the low absolute CA risk, the benefits of recommended ARV therapy use during pregnancy still outweigh such risks, although further studies are warranted.
[Show abstract][Hide abstract] ABSTRACT: : In resource-limited countries, interventions to prevent mother-to-child HIV transmission (PMTCT) have not yet realized their full potential health impact, illustrating the common gap between the scientific proof of an intervention's efficacy and effectiveness and its successful implementation at scale into routine health services. For PMTCT, this gap results, in part, from inadequate adaptation of PMTCT interventions to the realities of the implementation environment, including client and health care worker behaviors and preferences, health care policies and systems, and infrastructure and resource constraints. Elimination of mother-to-child HIV transmission can only be achieved through understanding of key implementation barriers and successful adaptation of scientifically proven interventions to the local environment. Central to such efforts is implementation science (IS), which aims to investigate and address major bottlenecks that impede effective implementation and to test new approaches to identifying, understanding, and overcoming barriers to the adoption, adaptation, integration, scale-up, and sustainability of evidence-based interventions. Advancing IS will require deliberate and strategic efforts to facilitate collaboration, communication, and relationship-building among researchers, implementers, and policy-makers. To speed the translation of effective PMTCT interventions into practice and advance IS more broadly, the US National Institutes of Health, in collaboration with the President's Emergency Plan for AIDS Relief launched the National Institutes of Health/President's Emergency Plan for AIDS Relief PMTCT IS Alliance, comprised of IS researchers, PMTCT program implementers, and policy-makers as an innovative platform for interaction and coordination.
Full-text · Article · Nov 2014 · JAIDS Journal of Acquired Immune Deficiency Syndromes
[Show abstract][Hide abstract] ABSTRACT: Objective: To estimate the effects of infection by HIV on the type-specific cumulative detection of cervicovaginal infection by human papillomavirus (HPV). Design: Retrospective assessment of prospectively collected data in a multicenter US cohort. Methods: HIV-seropositive and at-risk seronegative participants in the Women's Interagency HIV Study were followed semiannually for up to 11 years. HPV typing was determined from cervicovaginal lavage specimens by PCR; types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68 were considered carcinogenic. Results: Among the 3438 women enrolled (2543 HIV-seropositive, 895 seronegative), the cumulative detection of any HPV infection rose among HIV-seropositive women from 53% at baseline to 92% at 8 years, and among seronegative women from 22 to 66% (P< 0.0001 for HIV-seropositive vs. seronegative women). The 8-year cumulative detection of carcinogenic and noncarcinogenic HPV was 67 and 89% among HIV-seropositive, and 36 and 56% among seronegative women (P = 0.001 for both carcinogenic and noncarcinogenic HPV). The 8-year cumulative detection of HPV16 and HPV18 was 15.2 and 15.0% in HIV-seropositive, and 6.7 and 6.1% in HIV-seronegative women (P< 0.0001 for both). In multivariable regression analyses, lower CD4(+) cell count, age under 30 years, and smoking, but not number of lifetime sexual partners, were significant correlates of cumulative HPV detection. Conclusion: More than 90% of the HIV-seropositive women have HPV detected during a long follow-up. The rates are lower among at-risk HIV-seronegative women, though most also develop HPV infections. (c) 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
No preview · Article · Sep 2014 · AIDS (London, England)
[Show abstract][Hide abstract] ABSTRACT: Objective:
We evaluated the pharmacokinetics (PK) of raltegravir in HIV-infected women during pregnancy and postpartum.
International Maternal Pediatric Adolescent AIDS Clinical Trials 1026s is an ongoing prospective study of antiretroviral PK during pregnancy (NCT00042289). Women receiving 400 mg raltegravir twice daily in combination antiretroviral therapy had intensive steady-state 12-hour PK profiles performed during pregnancy and at 6- to 12-week postpartum. Targets were trough concentration above 0.035 μg/mL, the estimated 10th percentile in nonpregnant historical controls.
Median raltegravir area under the curve was 6.6 μg·h/mL for second trimester (n = 16), 5.4 μg·h/mL for third trimester (n = 41), and 11.6 μg·h/mL postpartum (n = 38) (P = 0.03 postpartum vs second trimester, P = 0.001 pp vs third trimester). Trough concentrations were above the target in 69%, 80%, and 79% of second trimester, third trimester, and postpartum subjects, respectively, with wide variability (<0.010-0.917 μg/mL), and no significant difference between third trimester and postpartum trough concentrations was detected. The median ratio of cord blood/maternal raltegravir concentrations was 1.5. HIV RNA levels were <400 copies per milliliter in 92% of women at delivery. Adverse events included elevated liver transaminases in 1 woman and vomiting in 1. All infants with known status are HIV uninfected.
Median raltegravir area under the curve was reduced by approximately 50% during pregnancy; trough concentrations were frequently below target both during late pregnancy and postpartum. Raltegravir readily crossed the placenta. High rates of viral suppression at delivery and the lack of a clear relationship between raltegravir concentration and virologic effect in nonpregnant adults suggest that despite the decreased exposure during pregnancy, a higher dose is not necessary.
No preview · Article · Aug 2014 · JAIDS Journal of Acquired Immune Deficiency Syndromes