Jeanna M. Piper

Tenofovir-Based Preexposure Prophylaxis for HIV Infection among African Women

BACKGROUND Reproductive-age women need effective interventions to prevent the acquisition of human immunodeficiency virus type 1 (HIV-1) infection. METHODS We conducted a randomized, placebo-controlled trial to assess daily treatment with oral tenofovir disoproxil fumarate (TDF), oral tenofovir-emtricitabine (TDF-FTC), or 1% tenofovir (TFV) vaginal gel as preexposure prophylaxis against HIV-1 infection in women in South Africa, Uganda, and Zimbabwe. HIV-1 testing was performed monthly, and plasma TFV levels were assessed quarterly. RESULTS Of 12,320 women who were screened, 5029 were enrolled in the study. The rate of retention in the study was 91% during 5509 person-years of follow-up. A total of 312 HIV-1 infections occurred; the incidence of HIV-1 infection was 5.7 per 100 person-years. In the modified intention-to-treat analysis, the effectiveness was -49.0% with TDF (hazard ratio for infection, 1.49; 95% confidence interval [CI], 0.97 to 2.29), -4.4% with TDF-FTC (hazard ratio, 1.04; 95% CI, 0.73 to 1.49), and 14.5% with TFV gel (hazard ratio, 0.85; 95% CI, 0.61 to 1.21). In a random sample, TFV was detected in 30%, 29%, and 25% of available plasma samples from participants randomly assigned to receive TDF, TDF-FTC, and TFV gel, respectively. Independent predictors of TFV detection included being married, being older than 25 years of age, and being multiparous. Detection of TFV in plasma was negatively associated with characteristics predictive of HIV-1 acquisition. Elevations of serum creatinine levels were seen more frequently among participants randomly assigned to receive oral TDF-FTC than among those assigned to receive oral placebo (1.3% vs. 0.2%, P=0.004). We observed no significant differences in the frequencies of other adverse events. CONCLUSIONS None of the drug regimens we evaluated reduced the rates of HIV-1 acquisition in an intention-to-treat analysis. Adherence to study drugs was low. (Funded by the National Institutes of Health; VOICE ClinicalTrials.gov number, NCT00705679.).

A Randomized, Controlled Trial of a Behavioral Intervention to Prevent Sexually Transmitted Disease among Minority Women

BACKGROUND African-American and Hispanic women are disproportionately affected by sexually transmitted diseases, including the acquired immunodeficiency syndrome (AIDS). In the effort to reduce infection rates, it is important to create and evaluate behavioral interventions that are specific to the target populations. METHODS We enrolled women with nonviral sexually transmitted diseases in a randomized trial of a sex- and culture-specific behavioral intervention. The intervention consisted of three small-group sessions of three to four hours each designed to help women recognize personal susceptibility, commit to changing their behavior, and acquire necessary skills. The control group received standard counseling about sexually transmitted diseases. The design of the intervention was based on the AIDS Risk Reduction Model and ethnographic data on the study populations. Participants in both groups underwent screening, counseling, and an interview before randomization and at the 6- and 12-month follow-up visits. The principal outcome variable was subsequent chlamydial or gonorrheal infection, which was evaluated on an intention-to-treat basis by logistic-regression analysis. RESULTS A total of 424 Mexican-Americans and 193 African-American women were enrolled; 313 were assigned to the intervention group and 304 to the control group. The rate of participation in the intervention was 90 percent. The rates of retention in the sample were 82 and 89 percent at the 6- and 12-month visits, respectively. Rates of subsequent infection were significantly lower in the intervention group than in the control group during the first 6 months (11.3 vs. 17.2 percent, P=0.05), during the second 6 months (9.1 vs. 17.7 percent, P=0.008), and over the entire 12-month study period (16.8 vs. 26.9 percent, P=0.004). CONCLUSIONS A risk-reduction intervention consisting of three small-group sessions significantly decreased the rates of chlamydial and gonorrheal infection among Mexican-American and African-American women at high risk for sexually transmitted disease.

Do growth-retarded premature infants have different rates of perinatal morbidity and mortality than appropriately grown premature infants?

Objective To determine if perinatal morbidity and mortality differ in growth-retarded, small for gestational age (SGA), premature infants and appropriate for gestational age (AGA) infants. Methods All consecutive, singleton, nondiabetic, preterm pregnancies delivered over a 15-year period were analyzed. Infants were categorized as SGA (at or below the tenth percentile) or AGA (11th to the 89th percentiles), then stratified by birth weight and gestational age categories. Perinatal morbidity and mortality were examined. Results We studied 4183 preterm deliveries, 1012 of them SGA and 3171 of them AGA. Overall, we found significantly higher rates of fetal and neonatal death in the SGA group. Stratification by gestational age revealed significantly higher rates of neonatal death for the SGA group compared with the AGA group in each gestational age category. Overall, comparison also revealed significantly higher rates of fetal heart rate abnormality in the SGA group but no difference in neonatal sepsis, birth trauma, cesarean delivery, hyaline membrance disease, or congenital anomalies. Conclusion Growth-retarded premature infants have a significantly higher risk of morbidity and mortality, both before and after delivery, than do appropriately grown infants.

Profiling of Human Antibody Responses to Chlamydia trachomatis Urogenital Tract Infection Using Microplates Arrayed with 156 Chlamydial Fusion Proteins

ABSTRACT The available chlamydial genome sequences have made it possible to comprehensively analyze host responses to all chlamydial proteins, which is essential for further understanding of chlamydial pathogenesis and development of effective chlamydial vaccines. Microplates arrayed with 156 Chlamydia trachomatis fusion proteins were used to evaluate antibody responses in women urogenitally infected with C. trachomatis. Based on both the antibody recognition frequency and titer, seven chlamydial antigens encoded by open reading frames (ORFs) CT089, CT147, CT226, CT681, CT694, CT795, and CT858, respectively, were identified as relatively immunodominant; six of these are encoded by hypothetical ORFs. Antibody binding to these chlamydial fusion proteins was blocked by C. trachomatis-infected but not by normal HeLa cell lysates or irrelevant bacterial lysates. These results have revealed novel immune-reactive chlamydial antigens, not only indicating that the hypothetical ORF-encoded proteins are expressed during chlamydial infection in humans but also providing the proof of principle that the fusion protein-based approach can be used to profile human immune responses to chlamydial infection at the whole-genome scale.

Induction of labor in the nineties : Conquering the unfavorable cervix

Objective To determine the efficacy, safety, and duration of induced labor using an integrative approach (prostaglandin, amniotomy, oxytocin) and to depict these findings graphically. Methods Five hundred ninety-seven pregnancies requiring induction of labor between October 1993 and May 1995 were analyzed prospectively. Patients were categorized by Bishop score at entry and by parity for comparison of success of induction, maternal and fetal complications, and duration of labor. Results The women who had a Bishop score at entry of 3 or less had significantly higher rates of failed induction (9.4 versus 0.7%, P < .01) and of cesarean delivery (29 versus 15.4%, P < .01) than those with a Bishop score above 3. Compared with spontaneous labor, the rates of cesarean delivery in induced labor remained significantly elevated. Complications of induction were infrequent, regardless of Bishop score. The time from initiation of induction to achievement of active phase was significantly longer in women with lower Bishop scores. Conclusion Regardless of cervical status and parity, vaginal delivery can be anticipated in the majority of patients undergoing labor induction. The induction characteristics described may assist in the management of induced labor.

Human Antibody Responses to a Chlamydia-Secreted Protease Factor

ABSTRACT We have previously identified a chlamydia-secreted protein (designated chlamydial proteasome/protease-like activity factor, or CPAF) in the cytosol of chlamydia-infected cells. Although CPAF is known to degrade host transcription factors required for major histocompatibility complex antigen expression in cultured cells, it is not clear whether CPAF is produced and maintains similar functions in humans infected with chlamydial organisms. We now report that CPAF does not preexist in chlamydial organisms and that CPAF synthesis requires live organism replication in cultured cells. Mice inoculated with live, but not mice inoculated with dead, chlamydial organisms produced a strong antibody response to CPAF, correlating CPAF-specific antibody production with CPAF synthesis in animals. Sera from women diagnosed with Chlamydia trachomatis cervicitis displayed higher levels of antibodies to CPAF than to either chlamydial major outer membrane protein or heat shock protein 60, suggesting that CPAF is both produced and immunogenic during human chlamydial infection.

A Phase 1 Randomized, Double Blind, Placebo Controlled Rectal Safety and Acceptability Study of Tenofovir 1% Gel (MTN-007)

Objective Rectal microbicides are needed to reduce the risk of HIV acquisition associated with unprotected receptive anal intercourse. The MTN-007 study was designed to assess the safety (general and mucosal), adherence, and acceptability of a new reduced glycerin formulation of tenofovir 1% gel. Methods Participants were randomized 1∶1:1∶1 to receive the reduced glycerin formulation of tenofovir 1% gel, a hydroxyethyl cellulose placebo gel, a 2% nonoxynol-9 gel, or no treatment. Each gel was administered as a single dose followed by 7 daily doses. Mucosal safety evaluation included histology, fecal calprotectin, epithelial sloughing, cytokine expression (mRNA and protein), microarrays, flow cytometry of mucosal T cell phenotype, and rectal microflora. Acceptability and adherence were determined by computer-administered questionnaires and interactive telephone response, respectively. Results Sixty-five participants (45 men and 20 women) were recruited into the study. There were no significant differences between the numbers of ≥ Grade 2 adverse events across the arms of the study. Likelihood of future product use (acceptability) was 87% (reduced glycerin formulation of tenofovir 1% gel), 93% (hydroxyethyl cellulose placebo gel), and 63% (nonoxynol-9 gel). Fecal calprotectin, rectal microflora, and epithelial sloughing did not differ by treatment arms during the study. Suggestive evidence of differences was seen in histology, mucosal gene expression, protein expression, and T cell phenotype. These changes were mostly confined to comparisons between the nonoxynol-9 gel and other study arms. Conclusions The reduced glycerin formulation of tenofovir 1% gel was safe and well tolerated rectally and should be advanced to Phase 2 development. Trial Registration ClinicalTrials.gov NCT01232803.

Perinatal outcome and the type and number of maneuvers in shoulder dystocia

Objectives: To ascertain the type and order of maneuvers that should be used for the treatment of shoulder dystocia; and to attempt to quantify the severity of shoulder dystocia, and to determine its correlation with perinatal outcome. Methods: We reviewed all consecutive cases of shoulder dystocia from January 1986 to August 1994 in our institution to obtain the type, order and number of maneuvers used for delivery. Patients were stratified by the number of maneuvers required for delivery. Outcome parameters included cord pH, Apgar score, neonatal trauma (Erbs palsy and fracture), and maternal trauma. Results: The incidence of shoulder dystocia was 0.7% (39 280 total vaginal deliveries). Use of only two maneuvers, McRoberts and suprapubic pressure, resulted in resolution in 58% of cases. The addition of the Woods screw maneuver and/or delivery of the posterior arm was sufficient in all remaining cases. The rates of neonatal palsy and fracture, and maternal fourth‐degree laceration, increased with the number of maneuvers. Conclusions: The McRoberts maneuver and suprapubic pressure should be first‐line treatment for shoulder dystocia. More difficult and damaging maneuvers such as Woods screw and delivery of the posterior arm may be reserved for refractory cases. Additional maneuvers are rarely necessary for delivery. The number of maneuvers may serve as a measure of the severity of the shoulder dystocia.

Bacterial vaginosis and intraamniotic infection

OBJECTIVE We sought to determine the predictors of intraamniotic infection with use of the presence or absence of vaginal microbes and clinical variables. STUDY DESIGN Vaginal fluid was collected and analyzed on 936 of 2711 (35%) consecutive patients who were delivered over a 7-month period. Subjects were followed up prospectively for the development of intraamniotic infection. Intraamniotic infection was defined as an intrapartum fever > 37.8 degrees C plus at least two of the five following variables: maternal or fetal tachycardia, leukocytosis, tender uterus, or foul-smelling amniotic fluid. Bacterial vaginosis score and the presence or absence of aerobic vaginal organisms were independent microbial variables. Demographic, maternal, labor, and delivery characteristics were independent clinical variables. Stepwise logistic regression analysis was used to develop adjusted odds ratios for predicting intraamniotic infection (expressed as odds ratio [95% confidence interval]). Selection bias and microbiologic reliability were measured. RESULTS A bacterial vaginosis score of 7 to 10 (odds ratio 1.7, [95% confidence interval 1.0 to 3.9]), nulliparity (2.1 [1.3 to 3.4]), each hour of internal fetal electrode (1.2 [1.0-1.3]); and, each vaginal examination (1.7 [1.0-3.9]) were predictors of intraamniotic infection. Selected aerobic vaginal organisms such as group B streptococci or gram-negative rods were not predictive. Reanalysis with a bacterial vaginosis score > or = 4 revealed similar predictors of intraamniotic infection. Bacterial vaginosis had an adjusted odds ratio of 1.85 (1.16 to 2.9). Selected higher risk populations, vaginal examinations > or = 6 (n = 365), or rupture of membranes > or = 7 hours (n = 421) did not change the risk of a bacterial vaginosis score > or = 4 (adjusted odds ratio 1.87 and 1.98, respectively). CONCLUSION Abnormal vaginal flora combines with clinical variables to increase the risk of intraamniotic infection.

Prevention of gonorrhea and chlamydia through behavioral intervention: Results of a two-year controlled randomized trial in minority women

Background: Sexually transmitted disease (STD), including AIDS, disproportionately affects African-American and Hispanic women. Goal: To evaluate efficacy of standard and enhanced (addition of optional support groups) gender- and culture-specific, small-group behavioral interventions, compared to interactive STD counseling, in high risk minority women for two years. Methods: Women with a non-viral STD were treated and enrolled in a randomized trial. Follow-up screens and interviews occurred at 6 months, 1 year, 18 months (short interview, optional exam) and 2 years. The primary outcome was subsequent infection with chlamydia and/or gonorrhea. Secondary outcomes included risky sexual behaviors. We employed logistic regression based on intention-to-treat. Results: Data from 775 women were included; the retention rate was 91%. Adjusted infection rates were higher in the controls in Year 1 (26.8%), Year 2 (23.1%), and cumulatively (39.8%) than in the enhanced (15.4%, P = 0.004; 14.8%, P < 0.03; 23.7%, P < 0.001, respectively) and standard (15.7%, P = 0.006; 14.7%, P = 0.03; 26.2%, P < 0.008, respectively) intervention arms at these time points. Enhanced-intervention women who opted to attend support groups (attendees) had the lowest adjusted infection rates in Year 1 (12.0%) and cumulatively (21.8%). Intervention women in general, but particularly attendees, were significantly less likely than controls to have repeat infections. Multiple partners and unprotected sex with an untreated or incompletely treated partner helped explain group differences in infection. Conclusions: Risk-reduction interventions significantly decreased both single and multiple infective episodes with chlamydia and/or gonorrhea and risky sexual behaviors in the two-year study period. Support-group attendance appeared to contribute additional risk reduction in Year 1.