Phase Ib Study of Unesbulin (PTC596) Plus Dacarbazine for the Treatment of Locally Recurrent, Unresectable or Metastatic, Relapsed or Refractory Leiomyosarcoma.

PURPOSE: This multicenter, single-arm, open-label, phase Ib study was designed to determine the recommended phase II dose (RP2D) and to evaluate the safety and preliminary efficacy of unesbulin plus dacarbazine (DTIC) in patients with advanced leiomyosarcoma (LMS). PATIENTS AND METHODS: Adult subjects with locally advanced, unresectable or metastatic, relapsed or refractory LMS were treated with escalating doses of unesbulin orally twice per week in combination with DTIC 1,000 mg/m2 intravenously (IV) once every 21 days. The time-to-event continual reassessment method was used to determine the RP2D on the basis of dose-limiting toxicities (DLTs) assessed during the first two 21-day treatment cycles. All explored doses of unesbulin (200 mg up to 400 mg) were in combination with DTIC. An expansion cohort was enrolled to evaluate the safety and efficacy of unesbulin at the RP2D. RESULTS: Unesbulin 300 mg administered orally twice per week in combination with DTIC 1,000 mg/m2 IV once every 21 days was identified as the RP2D. On the basis of data from 27 subjects who were deemed DLT-evaluable, toxicity was higher in the unesbulin 400 mg group, with three of four subjects (75%) experiencing DLTs versus one of four subjects (25%) in the 200 mg group and three of 19 subjects (15.8%) in the 300 mg group. The most commonly reported DLTs and treatment-related grade 3 and 4 adverse events were thrombocytopenia and neutropenia. At the RP2D, seven subjects who were efficacy evaluable achieved partial response for an objective response rate of 24.1%. CONCLUSION: Unesbulin 300 mg twice per week plus DTIC 1,000 mg/m2 once every 21 days was identified as the RP2D, demonstrating a favorable benefit-risk profile in a heavily pretreated population of adults with advanced LMS.

Extended Prophylaxis With Nevirapine Does Not Affect Growth in HIV-Exposed Infants.

BACKGROUND: Effects of prolonged nevirapine prophylaxis exposure on growth among HIV-exposed uninfected (HEU) infants are unknown. This study examines the impact of extended nevirapine prophylaxis from 6 weeks to 6 months on the growth of HEU infants followed for 18 months and also identifies correlates of incident wasting, stunting, underweight, and low head circumference in the HPTN 046 trial. METHODS: Intention-to-treat analysis examined the effect of extended nevirapine exposure on: weight-for-age Z-score, length-for-age Z-score, weight-for-length Z-score, and head circumference-for-age Z-score. Multivariable linear mixed-effects and Cox proportional hazard models were used to compare growth outcomes between the study arms and identify correlates of incident adverse growth outcomes, respectively. RESULTS: Compared to placebo, extended prophylactic nevirapine given daily from 6 weeks to 6 months did not affect growth in HEU breastfeeding (BF) infants over time (treatment × time: P > 0.05). However, overall growth declined over time (time effect: P < 0.01) when compared with WHO general population norms. Male sex was associated with higher risk of all adverse growth outcomes (P < 0.05), whereas short BF duration was associated with wasting (P = 0.03). Maternal antiretroviral therapy exposure was protective against underweight (P = 0.02). Zimbabwe tended to have worse growth outcomes especially stunting, compared to South Africa, Uganda and Tanzania (P < 0.05). CONCLUSIONS: It is reassuring that prolonged exposure to nevirapine for prevention-of-mother-to-child HIV transmission does not restrict growth. However, targeted interventions are needed to improve growth outcomes among at-risk HEU infants (i.e., male sex, short BF duration, lack of maternal antiretroviral therapy exposure, and resident in Zimbabwe).

A Comparison of the Effects of a Powered and Manual Toothbrush on Gingivitis and Plaque: A Randomized Parallel Clinical Trial.

OBJECTIVES: To compare the effect of a powered and a manual toothbrush on gingivitis and plaque following two and four weeks of home use. METHODS: This was a randomized, parallel-design, single-blind clinical trial. Eligible participants were generally healthy non-smoking manual toothbrush users aged 18-65 years, with a plaque score of = 1.8 per Lobene and Soparkar Modified Plaque Index (MPI) following a 3-6 hour plaque accumulation period, and mild to moderate gingivitis defined as a Gingival Bleeding Index (GBI) = 1 on at least 20 sites. Subjects with advanced periodontal disease, xerostomia, excessive gingival recession, uncontrolled diabetes, and heavy deposits of calculus or rampant decay were excluded. Enrolled participants were randomly dispensed either a Philips Sonicare powered toothbrush used with the InterCare brush head (PTB) or an American Dental Association (ADA) reference manual toothbrush (MTB). Efficacy and safety variables were assessed at Baseline, and at two and four weeks following twice-daily product home use. The primary endpoint of the study was reduction of gingivitis per the Modified Gingival Index (MGI) after four weeks of home use. RESULTS: All 148 randomized subjects (74 per group) completed the study. A statistically significant difference in MGI reduction was observed between the two study groups (p < 0.001). The least square (LS) mean and standard error reduction from Baseline was 0.72 (0.04) for the PTB group compared to 0.09 (0.04) for the MTB group. Expressed as percent reduction from Baseline, the LS mean values were 35.77% (2.19%) and 4.22% (2.19%) for PTB and MTB, respectively. Statistically significant differences were also observed for MGI reduction at Week 2, as well as for MPI and GBI reduction at Weeks 2 and 4. CONCLUSIONS: The powered toothbrush was statistically significantly superior to a manual toothbrush in reducing gingival inflammation, gingival bleeding, and plaque following two and four weeks of home use.

A Randomized Parallel Study to Assess the Effect of Three Tongue Cleaning Modalities on Oral Malodor.

OBJECTIVES: The objective of this study was to compare the effects of three tongue hygiene regimens on oral malodor. METHODS: This was a single-center, randomized, parallel design study with three treatment groups. Subjects were randomly assigned to perform tongue hygiene with either the Philips Sonicare TongueCare+ BreathRx regimen (STC), Listerine Cool Mint antiseptic rinse (LCM), or tongue brushing with an ADA reference manual toothbrush (MTB). Tooth brushing was standardized for all subjects during the study period, and no other oral or breath hygiene measures were allowed. Eligible subjects met the following criteria: aged 18-70 years, in good general and oral health, non-smoker, with an organoleptic score between 2.7 and 4.5 following a 12-18 hour oral hygiene abstention period. Subjects who had oral appliances or who had periodontal disease or excessive recession were not eligible. The primary endpoint analysis was to evaluate oral malodor based on an organoleptic (OL) score. Additional surrogate measures for oral malodor included quantification of oral hydrogen sulfide (H2S) level and counts of oral bacteria in secondary analyses. At Day 1, all three malodor endpoints were assessed prior to product use, immediately after use, and four and eight hours after use. Subjects were then provided with instructions on product use at home. Subjects returned to the clinic on Day 8 and the assessments for malodor were repeated for each of the three endpoints, i.e., prior to in-clinic use of the products, immediately after use, and four and eight hours after use. RESULTS: One hundred sixty-eight (168) subjects were randomized to three groups, with 56 per treatment group. Of these, 165 completed all study visits. Randomized subjects were comparable for baseline characteristics (OL score, age, race, and ethnicity). Overall, oral malodor based on the organoleptic score decreased for all treatment groups at all timepoints. For the primary endpoint, reduction of OL score eight hours following a single product use, the STC regimen reduced malodor per OL score by 46.67% (SE = 2.28%), the LCM value was 22.83% (SE = 2.29%), and MTB was 26.19% (SE = 2.29%). The pair-wise comparisons between STC and each of the treatment groups were statistically significant (p-values < 0.0001). Statistically significant differences were also observed between STC and both LCM and MTB groups in pair-wise comparisons at Day 8 (p-values < 0.0001). CONCLUSIONS: Reductions in malodor were evident following a single use of each product, and also following a seven-day repeat use period. The STC regimen, however, was statistically significantly superior to both LCM and MTB at improving malodor eight hours following the first use. Statistically significant differences in OL scores were sustained between STC and LCM, and STC and MTB at each efficacy timepoint following the seven-day home use period.

Gingival Health and Plaque Regrowth Response Following a Four-Week Interdental Hygiene Intervention.

OBJECTIVES: To compare the efficacy of three adjunct interproximal cleaning methods versus a manual toothbrush alone on gingivitis, and demonstrate that the Philips Sonicare AirflossPro™ interproximal (IP) cleaning device provides a similar reduction in gingivitis and plaque compared to string floss. METHODS: A randomized, single-blind, parallel-design study was conducted on generally healthy adults exhibiting mild to moderate gingivitis. Eligible subjects were non-smokers, aged 18-65 years, with ≥ 0.5 per the Rustogi Modified Navy Plaque Index (RMNPI) and a Gingival Bleeding Index (GBI) of ≥ 1 on at least 10 sites. Eligible subjects were randomly assigned to use one of four oral hygiene regimens: manual toothbrush (MTB) alone; MTB plus string floss (SF); MTB plus Philips Sonicare AirflossPro used with Cool Mint Listerine® Antiseptic (AFPL); and MTB plus Philips Sonicare AirflossPro used with BreathRx™ (AFPB). Subjects were followed over a 28-day home-use period, with follow-up visits for efficacy and safety conducted at Days 14 and 28. All subjects were instructed to use the MTB twice daily and perform interproximal cleaning once daily, if assigned. Study efficacy endpoints included the Modified Gingival Index (MGI), Rustogi Modified Navy Plaque Index, and the Gingival Bleeding Index. RESULTS: Of 290 randomized subjects, 287 were followed to Day 14 and 286 were followed to Day 28. For the primary endpoint at Day 14, significantly larger reductions in MGI were observed in each of the three IP cleaning groups compared to MTB alone (p < 0.001). The adjusted mean reductions and standard error estimates (SE) for MGI expressed as a percent reduction from Baseline at Day 14 were: 0.22% (0.55%) for MTB; 4.30% (0.44%) for SF; 4.55% (0.45%) for AFPL; and 4.20% (0.44%) for AFPB. A non-inferiority test comparing AirflossPro to SF showed AirflossPro to be non-inferior to SF (p < 0.001). CONCLUSIONS: The addition of interproximal cleaning to manual tooth brushing statistically significantly reduces gingivitis and plaque compared to manual tooth brushing alone. Among the adjunct interproximal cleaning regimens, AirflossPro provides a similar reduction in gingivitis and plaque to string floss. All study regimens were safe on oral tissues.

Ancillary benefits of antenatal ultrasound: an association between the introduction of a low-cost ultrasound program and an increase in the numbers of women receiving recommended antenatal treatments.

BACKGROUND: In June of 2010, an antenatal ultrasound program was introduced to perform basic screening examinations at a health care clinic in rural Uganda. The impact of the program on the existing antenatal care infrastructure including the proportion and number of women receiving recommended antenatal care at clinic visits was unknown. The aim of this study was to investigate the relationship between the advent of the ultrasound program and the proportion of women receiving recommended antenatal interventions at their clinic visits. Change in the absolute numbers of antenatal services provided was also assessed. METHODS: Records at the Nawanyago clinic were reviewed to determine the total numbers of women receiving specific interventions before and after the advent of the ultrasound program including HIV testing, intermittent preventive therapy for malaria, presumptive anti-parasitic treatment, and provision of iron and folate for anemia. The rate at which these interventions were provided (number of interventions per clinic visit) was also assessed. The differences in absolute numbers of antenatal interventions before and after the introduction of the ultrasound program were assessed using the Wilcoxon rank-sum test. Differences in intervention rate were assessed using negative binomial regression modeling. RESULTS: The mean monthly numbers of women receiving each of these interventions increased significantly with the greatest increase seen in numbers of women receiving anemia and deworming treatments at +113% and +102% respectively (p < 0.001). The intervention rate increased for anemia treatment, deworming treatment, and 2nd dose of intermittent preventive therapy for malaria. A slight decrease in intervention rate was observed for 1st dose of malaria treatment with a rate ratio of 0.88 (0.79 - 0.98, 95% CI). Intervention rate for HIV testing was not significantly changed. CONCLUSION: The introduction of a low-cost antenatal ultrasound program at a health care clinic in rural Uganda was associated with increases in the number of women receiving specific recommended antenatal care interventions. Effect on intervention rates was mixed but showed an overall increase. The use of ultrasound in this context may provide a benefit to the maternal and neonatal health of the community.

Efficacy and safety of an extended nevirapine regimen in infants of breastfeeding mothers with HIV-1 infection for prevention of HIV-1 transmission (HPTN 046): 18-month results of a randomized, double-blind, placebo-controlled trial.

BACKGROUND: HPTN 046 compared the efficacy and safety of infant nevirapine (NVP) among HIV-exposed breastfed infants randomized at 6 weeks to 6 months to t NVP or placebo to prevent postnatal infection: we report final 18-month outcomes. METHODS: Randomized, placebo-controlled trial in 4 African countries. Infant diagnostic HIV testing was performed regularly from birth through 18 months. Kaplan-Meier analysis was used to assess 18-month cumulative infant HIV infection, HIV infection/or death, and mortality rates. RESULTS: Between 6 weeks and 6 months, postnatal HIV infection rates were significantly lower among infants receiving daily NVP from 6 weeks to 6 months 1.1% [95% confidence interval (CI): 0.2% to 1.8%], compared with placebo 2.4% (95% CI: 1.3% to 2.6%), P = 0.049, but not significantly lower thereafter. Eighteen-month postnatal infection rates were low: 2.2% (95% CI: 1.1% to 3.3%) versus 3.1% (95% CI: 1.9% to 4.4%), respectively, P = 0.28. Mortality and HIV infection/death did not differ between arms at any age. Infants of women receiving antiretroviral therapy (ART) for their own health had the lowest 18-month postnatal infection rates (0.5%, 95% CI: 0.0% to 1.1%). However, HIV infection/death rates at 18 months were not significantly different for infants of mothers on ART (3.7%, 95% CI: 1.9% to 5.5%), and infants of mothers with CD4 counts of ≥ 350 cells per cubic millimeter not receiving ART (4.8%, 95% CI: 2.7% to 6.8%; P = 0.46). There were no differences in adverse events between study arms. CONCLUSIONS: This trial demonstrated early but not late differences in postnatal HIV transmission among infants randomized at age 6 weeks to extended NVP or placebo, underscoring the importance of continued prophylaxis throughout breastfeeding.

Long-term follow-up of children in the HIVNET 012 perinatal HIV prevention trial: five-year growth and survival.

OBJECTIVES: To describe 5-year growth, survival, and long-term safety among children exposed to nevirapine or zidovudine in an African perinatal prevention trial, HIVNET 012. METHODS: All study children who were alive at the age 18 months were eligible for an extended follow-up study. Children whose families consented were enrolled and evaluated every 6 months from 24 to 60 months. At each visit, history, physical examination, and growth measures were taken. From these measurements, Z scores based on World Health Organization (WHO) standards were computed. Serious adverse event data were collected. Data from the initial and extended follow-up cohorts were included in the analysis. RESULTS: Five hundred twenty-eight study children were alive at the age 18 months, and 491 (426 HIV uninfected and 65 infected) were enrolled into the follow-up study. Both exposed but uninfected children and HIV-infected children were substantially below WHO growth standards for weight and height. Head circumference Z scores for uninfected children were comparable with WHO norms. Five-year survival rates were 93% for uninfected children versus 43% for infected children. Long-term safety and growth outcomes in the 2 study arms were similar. CONCLUSIONS: Both infected and uninfected children in the 5-year HIVNET 012 follow-up showed poor height and weight growth outcomes, underscoring the need for early nutritional interventions to improve long-term growth of all infants born to HIV-infected women in resource-limited settings. Similarly, the low 5-year survival among HIV-infected children support the importance of early initiation of antiretroviral therapy. Both peripartum nevirapine and zidovudine were safe.

Impact of maternal and infant antiretroviral drug regimens on drug resistance in HIV-infected breastfeeding infants.

BACKGROUND: The HIV Prevention Trials Network (HPTN) 046 trial evaluated the efficacy of extended infant nevirapine (NVP) administration for prevention of HIV transmission through breastfeeding. Infants received daily NVP up to 6 weeks of age. HIV-uninfected infants (the intent-to-treat group) received daily NVP or placebo up to 6 months of age. We analyzed emergence of NVP resistance in infants who acquired HIV infection despite prophylaxis. METHODS: HIV genotyping was performed using the ViroSeq HIV Genotyping System. Medians and proportions were used to summarize data. Two-sided Fisher exact tests were used to evaluate associations between categorical variables. RESULTS: NVP resistance was detected in 12 (92.3%) of 13 infants who were HIV-infected by 6 weeks and in 7 (28%) of 25 infants who were HIV-uninfected at 6 weeks and HIV-infected at 6 months of age (6/8 = 75% in the NVP arm, 1/17 = 5.9% in the placebo arm, P = 0.001). Among those 25 infants, 4 had mothers who initiated an antiretroviral treatment regimen by 6 months postpartum. In all 4 cases, the treatment regimen included a non-nucleoside reverse transcriptase inhibitor (NVP or efavirenz). NVP resistance was detected in all 4 of those infants by 6 months of age (4/4 = 100%). In contrast, only 3 (14.2%) of the remaining 21 HIV-infected infants whose mothers did not initiate antiretroviral treatment developed NVP resistance (P = 0.003). CONCLUSIONS: Extended NVP prophylaxis significantly increased the risk of NVP resistance in infants who acquired HIV infection after 6 weeks of age. Treatment of maternal HIV infection was also associated with emergence of NVP resistance in HIV-infected, breastfed infants.

Efficacy and safety of an extended nevirapine regimen in infant children of breastfeeding mothers with HIV-1 infection for prevention of postnatal HIV-1 transmission (HPTN 046): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Nevirapine given once-daily for the first 6, 14, or 28 weeks of life to infants exposed to HIV-1 via breastfeeding reduces transmission through this route compared with single-dose nevirapine at birth or neonatally. We aimed to assess incremental safety and efficacy of extension of such prophylaxis to 6 months. METHODS: In our phase 3, randomised, double-blind, placebo-controlled HPTN 046 trial, we assessed the incremental benefit of extension of once-daily infant nevirapine from age 6 weeks to 6 months. We enrolled breastfeeding infants born to mothers with HIV-1 in four African countries within 7 days of birth. Following receipt of nevirapine from birth to 6 weeks, infants without HIV infection were randomly allocated (by use of a computer-generated permuted block algorithm with random block sizes and stratified by site and maternal antiretroviral treatment status) to receive extended nevirapine prophylaxis or placebo until 6 months or until breastfeeding cessation, whichever came first. The primary efficacy endpoint was HIV-1 infection in infants at 6 months and safety endpoints were adverse reactions in both groups. We used Kaplan-Meier analyses to compare differences in the primary outcome between groups. This study is registered with ClinicalTrials.gov, number NCT00074412. FINDINGS: Between June 19, 2008, and March 12, 2010, we randomly allocated 1527 infants (762 nevirapine and 765 placebo); five of whom had HIV-1 infection at randomisation and were excluded from the primary analyses. In Kaplan-Meier analysis, 1·1% (95% CI 0·3-1·8) of infants who received extended nevirapine developed HIV-1 between 6 weeks and 6 months compared with 2·4% (1·3-3·6) of controls (difference 1·3%, 95% CI 0-2·6), equating to a 54% reduction in transmission (p=0·049). However, mortality (1·2% for nevirapine vs 1·1% for placebo; p=0·81) and combined HIV infection and mortality rates (2·3%vs 3·2%; p=0·27) did not differ between groups at 6 months. 125 (16%) of 758 infants given extended nevirapine and 116 (15%) of 761 controls had serious adverse events, but frequency of adverse events, serious adverse events, and deaths did not differ significantly between treatment groups. INTERPRETATION: Nevirapine prophylaxis can safely be used to provide protection from mother-to-child transmission of HIV-1 via breastfeeding for infants up to 6 months of age. FUNDING: US National Institutes of Health.

Analysis of HIV tropism in Ugandan infants.

HIV-infected infants may have CXCR4-using (X4-tropic) HIV, CCR5-using (R5-tropic) HIV, or a mixture of R5-tropic and X4-tropic HIV (dual/mixed, DM HIV). The level of infectivity for R5 virus (R5-RLU) varies among HIV infected infants. HIV tropism and R5-RLU were measured in samples from HIV-infected Ugandan infants using a commercial assay. DM HIV was detected in 7/72 (9.7%) infants at the time of HIV diagnosis (birth or 6-8 weeks of age, 4/15 (26.7%) with subtype D, 3/57 (5.3 %) with other subtypes, P=0.013). A transition from R5-tropic to DM HIV was observed in only two (6.7%) of 30 infants over 6-12 months. Six (85.7%) of seven infants with DM HIV died, compared to 21/67 (31.3%) infants with R5-tropic HIV (p=0.09). Higher R5-RLU at 6-8 weeks was not associated with decreased survival. Infants with in utero infection had a higher median R5-RLU than infants who were HIV-uninfected at birth (p=0.025).

Pregnancy does not affect HIV incidence test results obtained using the BED capture enzyme immunoassay or an antibody avidity assay.

BACKGROUND: Accurate incidence estimates are needed for surveillance of the HIV epidemic. HIV surveillance occurs at maternal-child health clinics, but it is not known if pregnancy affects HIV incidence testing. METHODS: We used the BED capture immunoassay (BED) and an antibody avidity assay to test longitudinal samples from 51 HIV-infected Ugandan women infected with subtype A, C, D and intersubtype recombinant HIV who were enrolled in the HIVNET 012 trial (37 baseline samples collected near the time of delivery and 135 follow-up samples collected 3, 4 or 5 years later). Nineteen of 51 women were also pregnant at the time of one or more of the follow-up visits. The BED assay was performed according to the manufacturer's instructions. The avidity assay was performed using a Genetic Systems HIV-1/HIV-2 + O EIA using 0.1M diethylamine as the chaotropic agent. RESULTS: During the HIVNET 012 follow-up study, there was no difference in normalized optical density values (OD-n) obtained with the BED assay or in the avidity test results (%) when women were pregnant (n = 20 results) compared to those obtained when women were not pregnant (n = 115; for BED: p = 0.9, generalized estimating equations model; for avidity: p = 0.7, Wilcoxon rank sum). In addition, BED and avidity results were almost exactly the same in longitudinal samples from the 18 women who were pregnant at only one study visit during the follow-up study (p = 0.6, paired t-test). CONCLUSIONS: These results from 51 Ugandan women suggest that any changes in the antibody response to HIV infection that occur during pregnancy are not sufficient to alter results obtained with the BED and avidity assays. Confirmation with larger studies and with other HIV subtypes is needed.

Analysis of HIV diversity using a high-resolution melting assay.

HIV viruses are usually genetically homogeneous shortly after infection, and become more heterogeneous over time. We developed a high-resolution melting (HRM) assay to analyze HIV diversity without sequencing. Plasma samples from the HIVNET 012 trial were obtained from nine Ugandan mother-infant pairs. DNA amplified from the HIV gag region was analyzed to determine the number of degrees over which the DNA melted (HRM score). HRM gag DNA was also cloned and sequenced (50 clones/mother; 20 clones/infant). The median HRM score for infants (4.3, range 4.2-5.3) was higher than that for control plasmids (3.4, range 3.2-3.8, p < 0.001) and lower than that for mothers (5.7, range 4.4-7.7, p = 0.005, exact Wilcoxon rank sum test). The intraclass correlation coefficient reflecting assay reproducibility was 94% (95% CI: 89-98%). HRM scores were also compared to sequenced-based measures of HIV diversity; higher HRM scores were associated with higher genetic diversity (p < 0.001), complexity (p = 0.009), and Shannon entropy (p = 0.022), but not with length variation (p = 0.111). The HRM assay provides a novel, rapid method for assessing HIV diversity without sequencing. This assay could be applied to any region of the HIV genome or to other genetic systems that exhibit DNA diversity.

A randomized, double-blind, placebo-controlled Phase II extended safety study of two Invisible Condom formulations in Cameroonian women.

BACKGROUND: Invisible Condom gel formulations being developed as microbicides to prevent the sexual transmission of HIV are advancing through the phases of clinical trials. The objectives of this study were to evaluate, after 8 weeks of vaginal application, the extended safety and acceptability of two Invisible Condom vaginal gel formulations: (i) the polymer alone and (ii) the polymer containing sodium lauryl sulfate (SLS) compared to placebo. STUDY DESIGN: This study is a randomized, doubled-blind, placebo-controlled Phase II extended safety study in healthy sexually active women from Yaoundé, Cameroon. Women were randomized into three gel arms: (i) placebo, (ii) polymer alone and (iii) polymer/SLS. Women applied gel intravaginally twice daily for 8 weeks. RESULTS: A total of 194 sexually active women applied placebo (n=41), polymer alone (n=76) and polymer/SLS (n=77). Invisible Condom gel formulations were well tolerated with no reported serious adverse events. The majority of reported adverse events were mild or moderate and mostly similar in all three arms, except for pelvic pain that was 10% higher in the polymer and polymer/SLS arms compared to placebo. Colposcopy showed neither genital ulceration nor mucosal lesions. Nugent score, H(2)O(2)-producing lactobacilli and vaginal pH were not affected by the study products. The gel formulations and applicator were generally acceptable and comfortable. CONCLUSION: This extended safety study showed that the Invisible Condom gel formulations and applicator were well tolerated and acceptable when applied intravaginally twice daily for 8 weeks. Thus, further phases of clinical development of Invisible Condom as a potential microbicide to prevent sexual transmission of HIV are warranted.

A randomized, double-blind, placebo-controlled safety and acceptability study of two Invisible Condom formulations in women from Cameroon.

BACKGROUND: The objectives of this clinical trial were to evaluate the safety, tolerance and acceptability of two gel formulations of the Invisible Condom: (i) the polymer alone and (ii) the polymer-containing sodium lauryl sulfate (SLS) compared to placebo when applied intravaginally with our unique applicator in sexually abstinent and active woman volunteers. STUDY DESIGN: A randomized, doubled-blind, placebo-controlled study in healthy women from Yaoundé, Cameroon. Two hundred sixty women were randomized into three gel arms: (a) gel alone, (b) gel plus SLS and (c) placebo gel. Thirty-seven sexually abstinent women applied gel intravaginally once a day for 14 days, while 75, 74 and 74 sexually active women applied gel intravaginally once, twice or three times daily for 14 days, respectively. RESULTS: Retention rate was high at 85% and 221 women applied the two products and the placebo for a total of 6005 times. Nugent score, H(2)O(2)-producing lactobacilli and vaginal pH were stable throughout the study and were not affected by the study products. Colposcopy showed neither genital ulceration nor mucosal lesions. No study product-related serious adverse events were reported. The majority of reported adverse events were mild or moderate and largely similar in all 3 arms. Satisfaction questionnaire showed that the gel formulations and applicator were generally comfortable and acceptable. CONCLUSION: The Invisible Condom formulations and applicator were found to be comfortable, well tolerated and acceptable when applied intravaginally once, twice or thrice daily for 14 days. Thus, expanded safety evaluation is warranted.

Selected hematologic and biochemical measurements in African HIV-infected and uninfected pregnant women and their infants: the HIV Prevention Trials Network 024 protocol.

BACKGROUND: Reference values for hematological and biochemical assays in pregnant women and in newborn infants are based primarily on Caucasian populations. Normative data are limited for populations in sub-Saharan Africa, especially comparing women with and without HIV infection, and comparing infants with and without HIV infection or HIV exposure. METHODS: We determined HIV status and selected hematological and biochemical measurements in women at 20-24 weeks and at 36 weeks gestation, and in infants at birth and 4-6 weeks of age. All were recruited within a randomized clinical trial of antibiotics to prevent chorioamnionitis-associated mother-to-child transmission of HIV (HPTN024). We report nearly complete laboratory data on 2,292 HIV-infected and 367 HIV-uninfected pregnant African women who were representative of the public clinics from which the women were recruited. Nearly all the HIV-infected mothers received nevirapine prophylaxis at the time of labor, as did their infants after birth (always within 72 hours of birth, but typically within just a few hours at the four study sites in Malawi (2 sites), Tanzania, and Zambia. RESULTS: HIV-infected pregnant women had lower red blood cell counts, hemoglobin, hematocrit, and white blood cell counts than HIV-uninfected women. Platelet and monocyte counts were higher among HIV-infected women at both time points. At the 4-6-week visit, HIV-infected infants had lower hemoglobin, hematocrit and white blood cell counts than uninfected infants. Platelet counts were lower in HIV-infected infants than HIV-uninfected infants, both at birth and at 4-6 weeks of age. At 4-6 weeks, HIV-infected infants had higher alanine aminotransferase measures than uninfected infants. CONCLUSION: Normative data in pregnant African women and their newborn infants are needed to guide the large-scale HIV care and treatment programs being scaled up throughout the continent. These laboratory measures will help interpret clinical data and assist in patient monitoring in a sub-Saharan Africa context.

Predictors of early and late mother-to-child transmission of HIV in a breastfeeding population: HIV Network for Prevention Trials 012 experience, Kampala, Uganda.

OBJECTIVE: To determine the predictors for early versus later (breastfeeding) transmission of HIV-1. METHODS: Secondary data analysis was performed on HIV Network for Prevention Trials 012, a completed randomized clinical trial assessing the relative efficacy of nevirapine (NVP) versus zidovudine in reducing mother-to-child transmission (MTCT) of HIV-1. We used Cox regression analysis to assess risk factors for MTCT. The ViroSeq HIV genotyping and a sensitive point mutation assay were used to detect NVP resistance mutations. RESULTS: In this subset analyses, 122 of 610 infants were HIV infected, of whom 99 (81.1%) were infected early (first positive polymerase chain reaction < or =56 days). Incidence of MTCT after 56 days was low [0.7% per month (95% confidence interval, CI: 0.4 to 1.0)], but continued through 18 months. In multivariate analyses, early MTCT "factors" included NVP versus zidovudine (hazard ratio (HR) = 0.57, 95% CI: 0.38 to 0.86), pre-entry maternal viral load (VL, HR = 1.76, 95% CI: 1.28 to 2.41), and CD4 cell count (HR = 1.16, 95% CI: 1.05 to 1.28). Maternal VL (6-8 weeks) was associated with late MTCT (HR = 3.66, 95% CI: 1.78 to 7.50), whereas maternal NVP resistance (6-8 weeks) was not. CONCLUSIONS: Maternal VL was the best predictor of both early and late transmission. Maternal NVP resistance at 6-8 weeks did not predict late transmission.

Intrapartum antibiotic exposure and early neonatal, morbidity, and mortality in Africa.

BACKGROUND: Infants born to women who receive intrapartum antibiotics may have higher rates of infectious morbidity and mortality than unexposed infants. OBJECTIVE: Our goal was to determine the association of maternal intrapartum antibiotics and early neonatal morbidity and mortality. METHODS: We performed secondary analysis of data from a multisite randomized, placebo-controlled clinical trial of antibiotics to prevent chorioamnionitis-associated mother-to-child transmission of HIV-1 and preterm birth in sub-Saharan Africa. Early neonatal morbidity and mortality were analyzed. In an intention-to-treat (ITT) analysis, infants born to women randomly assigned to antibiotics or placebo were compared. In addition, non-ITT analysis was performed because some women received nonstudy antibiotics for various clinical indications. RESULTS: Overall, 2659 pregnant women were randomly assigned. Of these, 2466 HIV-1-infected and HIV-1-uninfected women delivered 2413 live born and 84 stillborn infants. In the ITT analysis, there were no significant associations between exposure to antibiotics and early neonatal outcomes. Non-ITT analyses showed more illness at birth (11.2% vs 8.6%, P = .03) and more admissions to the special care infant unit (12.6% vs 9.8%, P = .04) among infants exposed to maternal intrapartum antibiotics than among unexposed infants. Additional analyses revealed greater early neonatal morbidity and mortality among infants of mothers who received nonstudy antibiotics than of mothers who received study antibiotics. CONCLUSIONS: There is no association between intrapartum exposure to antibiotics and early neonatal morbidity or mortality. The associations observed in non-ITT analyses are most likely the result of women with peripartum illnesses being more likely to receive nonstudy antibiotics.

In utero HIV infection is associated with an increased risk of nevirapine resistance in ugandan infants who were exposed to perinatal single dose nevirapine.

Use of single dose nevirapine (sdNVP) to prevent HIV mother-to-child transmission is associated with the emergence of NVP resistance in many infants who are HIV infected despite prophylaxis. We combined results from four clinical trials to analyze predictors of NVP resistance in sdNVP-exposed Ugandan infants. Samples were tested with the ViroSeq HIV Genotyping System and a sensitive point mutation assay (LigAmp, for detection of K103N, Y181C, and G190A). NVP resistance was detected at 6-8 weeks in 36 (45.0%) of 80 infants using ViroSeq and 33 (45.8%) of 72 infants using LigAmp. NVP resistance was more frequent among infants who were infected in utero than among infants who were diagnosed with HIV infection after birth by 6-8 weeks of age. Detection of NVP resistance at 6-8 weeks was not associated with HIV subtype (A vs. D), pre-NVP maternal viral load or CD4 cell count, infant viral load at 6-8 weeks, or infant sex. NVP resistance was still detected in some infants 6-12 months after sdNVP exposure. In this study, in utero HIV infection was the only factor associated with detection of NVP resistance in infants 6-8 weeks after sdNVP exposure.

Primary HIV-1 infection among infants in sub-Saharan Africa: HPTN 024.

OBJECTIVES: Our objectives were to assess clinical signs and diagnoses associated with primary HIV-1 infection among infants. METHODS: We analyzed data from a clinical trial (HIV Prevention Trials Network Protocol 024) in sub-Saharan Africa. Study visits were conducted at birth, at 4-6 weeks, and at 3, 6, 9, and 12 months. The study population comprised live born, singleton, first-born infants of HIV-1-infected women with negative HIV-1 RNA assays who were still breastfeeding at 4-6 weeks. RESULTS: Of 1317 HIV-1-exposed infants, 84 became HIV-1 infected after 4-6 weeks and 1233 remained uninfected. There were 102 primary and 5650 nonprimary infection visits. The most common signs were cough and diarrhea, and the most common diagnoses were malaria and pneumonia. Primary infection was associated with significantly increased odds of diarrhea [odds ratio (OR) = 2.4], pneumonia (OR = 3.5), otitis media (OR = 3.1), and oral thrush (OR = 2.9). For the clinical signs and diagnoses evaluated, sensitivity was low (1%-16.7%) and specificity was high (88.2%-99%). Positive predictive values ranged from 0.1%-1.4%. Negative predictive values ranged from 28.0%-51.1%. CONCLUSIONS: Certain clinical signs and diagnoses, although more common during primary HIV-1 infection, had low sensitivity and high specificity. Efforts to expand access to laboratory assays for the diagnosis of primary HIV-1 infection among infants of HIV-1-infected women should be emphasized.