Malaria Prevention with IPTp during Pregnancy Reduces Neonatal Mortality

Background

In the global context of a reduction of under-five mortality, neonatal mortality is an increasingly relevant component of this mortality. Malaria in pregnancy may affect neonatal survival, though no strong evidence exists to support this association.

Methods

In the context of a randomised, placebo-controlled trial of intermittent preventive treatment (IPTp) with sulphadoxine-pyrimethamine (SP) in 1030 Mozambican pregnant women, 997 newborns were followed up until 12 months of age. There were 500 live borns to women who received placebo and 497 to those who received SP.

Findings

There were 58 infant deaths; 60.4% occurred in children born to women who received placebo and 39.6% to women who received IPTp (p = 0.136). There were 25 neonatal deaths; 72% occurred in the placebo group and 28% in the IPTp group (p = 0.041). Of the 20 deaths that occurred in the first week of life, 75% were babies born to women in the placebo group and 25% to those in the IPTp group (p = 0.039). IPTp reduced neonatal mortality by 61.3% (95% CI 7.4%, 83.8%); p = 0.024].

Conclusions

Malaria prevention with SP in pregnancy can reduce neonatal mortality. Mechanisms associated with increased malaria infection at the end of pregnancy may explain the excess mortality in the malaria less protected group. Alternatively, SP may have reduced the risk of neonatal infections. These findings are of relevance to promote the implementation of IPTp with SP, and provide insights into the understanding of the pathophysiological mechanisms through which maternal malaria affects fetal and neonatal health.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00209781","term_id":"NCT00209781"}}NCT00209781     

A Randomized,Controlled, Trial of Short Cycle Intermittent Compared to Continuous Antiretroviral Therapy for the Treatment of HIV Infection in Uganda

Background

Short cycle treatment interruption could reduce toxicity and drug costs and contribute to further expansion of antiretroviral therapy (ART) programs.

Methods

A 72 week, non-inferiority trial enrolled one hundred forty six HIV positive persons receiving ART (CD4+ cell count ≥125 cells/mm³ and HIV RNA plasma levels <50 copies/ml) in one of three arms: continuous, 7 days on/7 days off and 5 days on/2 days off treatment. Primary endpoint was ART treatment failure determined by plasma HIV RNA level, CD4+ cell count decrease, death attributed to study participation, or opportunistic infection.

Results

Following enrollment of 32 participants, the 7 days on/7 days off arm was closed because of a failure rate of 31%. Six of 52 (11.5%) participants in the 5 days on/2 days off arm failed. Five had virologic failure and one participant had immunologic failure. Eleven of 51 (21.6%) participants in the continuous treatment arm failed. Nine had virologic failure with 1 death (lactic acidosis) and 1 clinical failure (extra-pulmonary TB). The upper 97.5% confidence boundary for the difference between the percent of non-failures in the 5 days on/2 days off arm (88.5% non-failure) compared to continuous treatment (78.4% non failure) was 4.8% which is well within the preset non-inferiority margin of 15%. No significant difference was found in time to failure in the 2 study arms (p = 0.39).

Conclusions

Short cycle 5 days on/2 days off intermittent ART was at least as effective as continuous therapy.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00339456","term_id":"NCT00339456"}}NCT00339456     

Effects of Genital Ulcer Disease and Herpes Simplex Virus Type 2 on the Efficacy of Male Circumcision for HIV Prevention: Analyses from the Rakai Trials

Background

Randomized trials show that male circumcision (MC) reduces the incidence of HIV and herpes simplex virus type 2 (HSV-2) infections, and symptomatic genital ulcer disease (GUD). We assessed the role of GUD and HSV-2 in the protection against HIV afforded by MC.

Methods and Findings

HIV-uninfected men were randomized to immediate (n = 2,756) or delayed MC (n = 2,775) in two randomized trials in Rakai, Uganda. GUD symptoms, HSV-2 status, and HIV acquisition were determined at enrollment and at 6, 12, and 24 mo of follow up. Ulcer etiology was assessed by PCR. We estimated the prevalence and prevalence risk ratios (PRRs) of GUD in circumcised versus uncircumcised men and assessed the effects of HSV-2 serostatus as a risk-modifying factor for GUD. We estimated the proportion of the effect of MC on HIV acquisition that was mediated by symptomatic GUD, and by HSV-2 infection. Circumcision significantly reduced symptomatic GUD in HSV-2-seronegative men (PRR = 0.51, 95% [confidence interval] CI 0.43–0.74), HSV-2-seropositive men (PRR = 0.66, 95% CI 0.51–0.69), and in HSV-2 seroconverters (PRR = 0.48, 95% CI 0.30–0.79). The proportion of acute ulcers due to HSV-2 detected by PCR was 48.0% in circumcised men and 39.3% in uncircumcised men (χ² p = 0.62). Circumcision reduced the risk of HIV acquisition in HSV-2 seronegative men (incidence rate ratio [IRR] = 0.34, 95% CI 0.15–0.81), and potentially in HSV-2 seroconverters (IRR = 0.56, 95% CI 0.19–1.57; not significant), but not in men with prevalent HSV-2 at enrollment (IRR = 0.89, 95% CI 0.49–1.60). The proportion of reduced HIV acquisition in circumcised men mediated by reductions in symptomatic GUD was 11.2% (95% CI 5.0–38.0), and the proportion mediated by reduced HSV-2 incidence was 8.6% (95% CI −1.2 to 77.1).

Conclusions

Circumcision reduced GUD irrespective of HSV-2 status, but this reduction played only a modest role in the protective effect of circumcision on HIV acquisition.

NIH Trial registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00425984","term_id":"NCT00425984"}}NCT00425984

Gates Foundation Trial registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00124878","term_id":"NCT00124878"}}NCT00124878 Please see later in the article for the Editors'' Summary     

Omega-3 Fatty Acid Deficiency in Infants before Birth Identified Using a Randomized Trial of Maternal DHA Supplementation in Pregnancy

Background

DHA is accumulated in the central nervous system (CNS) before birth and is involved in early developmental processes, such as neurite outgrowth and gene expression.

Objective

To determine whether fetal DHA insufficiency occurs and constrains CNS development in term gestation infants.

Design

A risk reduction model using a randomized prospective study of term gestation single birth healthy infants born to women (n = 270) given a placebo or 400 mg/day DHA from 16 wk gestation to delivery. Fetal DHA deficiency sufficient to constrain CNS development was assessed based on increased risk that infants in the placebo group would not achieve neurodevelopment scores in the top quartile of all infants in the study.

Results

Infants in the placebo group were at increased risk of lower language development assessed as words understood (OR 3.22, CL 1.49–6.94, P = 0.002) and produced (OR 2.61, CL 1.22–5.58, P = 0.01) at 14 mo, and words understood (OR 2.77, CL 1.23–6.28, P = 0.03) and sentences produced (OR 2.60, CL 1.15–5.89, P = 0.02) at 18 mo using the McArthur Communicative Developmental Inventory; receptive (OR 2.23, CL 1.08–4.60, P = 0.02) and expressive language (OR 1.89, CL 0.94–3.83, P = 0.05) at 18 mo using the Bayley Scales of Infant Development III; and visual acuity (OR 2.69, CL 1.10–6.54, P = 0.03) at 2 mo.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00620672","term_id":"NCT00620672"}}NCT00620672     

Options for the Delivery of Intermittent Preventive Treatment for Malaria to Children: A Community Randomised Trial

Background

Intermittent preventive treatment for malaria in children (IPTc) is a promising new intervention for the prevention of malaria but its delivery is a challenge. We have evaluated the coverage of IPTc that can be achieved by two different delivery systems in Ghana.

Methods

IPTc was delivered by volunteers in six villages (community-based arm) and by health workers at health centres or at Expanded Programme on Immunisation outreach clinics (facility based) in another six communities. The villages were selected randomly and drugs were administered in May, June, September and October 2006. The first dose of a three-dose regimen of amodiaquine plus sulphadoxine-pyrimethamine was administered under supervision to 3–59 month-old children (n = 964) in the 12 study villages; doses for days 2 and 3 were given to parents/guardians to administer at home.

Results

The proportion of children who received at least the first dose of 3 or more courses of IPTc was slightly higher in the community based arm (90.5% vs 86.6%; p = 0.059). Completion of the three dose regimen was high and similar with both delivery systems (91.6% and 91.7% respectively).

Conclusion

Seasonal IPTc delivered through community-based or facility-based systems can achieve a high coverage rate with the support and supervision of the district health management team. However, in order to maximise the impact of IPTc, both delivery systems may be needed in some settings.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00119132","term_id":"NCT00119132"}}NCT00119132     

Effectiveness of Cellulose Sulfate Vaginal Gel for the Prevention of HIV Infection: Results of a Phase III Trial in Nigeria

Background

This trial evaluated the safety and effectiveness of 6% cellulose sulfate vaginal gel in preventing male-to-female vaginal transmission of HIV, gonorrhea and chlamydial infection.

Methods

This Phase III, double-blind, randomized, placebo-controlled trial was conducted between November 2004 and March 2007 in Lagos and Port Harcourt, Nigeria. We enrolled 1644 HIV-antibody negative women at high risk of HIV acquisition. Study participants were randomized 1∶1 to cellulose sulfate or placebo and asked to use gel plus a condom for each act of vaginal intercourse over one year of follow-up. The participants were evaluated monthly for HIV, gonorrhea and chlamydial infection, and for adverse events.

Results

The trial was stopped prematurely after the data safety monitoring board of a parallel trial concluded that cellulose sulfate might be increasing the risk of HIV. In contrast, we observed fewer infections in the active arm (10) than on placebo (13), a difference that was nonetheless not statistically significant (HR = 0.8, 95% CI 0.3–1.8; p = 0.56). Rates of gonorrhea and chlamydial infection were lower in the CS group but the difference was likewise not statistically significant (HR = 0.8, 95% CI 0.5–1.1; p = 0.19 for the combined STI outcome). Rates of adverse events were similar across study arms. No serious adverse events related to cellulose sulfate use were reported.

Conclusions

Cellulose sulfate gel appeared to be safe in the evaluated study population but we found insufficient evidence that it prevented male-to-female vaginal transmission of HIV, gonorrhea or chlamydial infection. The early closure of the trial compromised the ability to draw definitive conclusions about the effectiveness of cellulose sulfate against HIV.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00120770","term_id":"NCT00120770"}}NCT00120770     

Routine Opt-Out HIV Testing Strategies in a Female Jail Setting: A Prospective Controlled Trial

Background

Ten million Americans enter jails annually. The objective was to evaluate new CDC guidelines for routine opt-out HIV testing and examine the optimal time to implement routine opt-out HIV testing among newly incarcerated jail detainees.

Methods

This prospective, controlled trial of routine opt-out HIV testing was conducted among 323 newly incarcerated female inmates in Connecticut''s only women''s jail. 323 sequential entrants to the women''s jail over a five week period in August and September 2007 were assigned to be offered routine opt-out HIV testing at one of three points after incarceration: immediate (same day, n = 108), early (next day, n = 108), or delayed (7 days, n = 107). The primary outcome was the proportion of women in each group consenting to testing.

Results

Routine opt-out HIV testing was significantly highest (73%) among the early testing group compared to 55% for immediate and 50% for 7 days post-entry groups. Other factors significantly (p = 0.01) associated with being HIV tested were younger age and low likelihood of early release from jail based on bond value or type of charge for which women were arrested.

Conclusions

In this correctional facility, routine opt-out HIV testing in a jail setting was feasible, with highest rates of testing if performed the day after incarceration. Lower testing rates were seen with immediate testing, where there is a high prevalence of inability or unwillingness to test, and with delayed testing, where attrition from jail increases with each passing day.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00624247","term_id":"NCT00624247"}}NCT00624247     

Reduction and Return of Infectious Trachoma in Severely Affected Communities in Ethiopia

Background

Antibiotics are a major tool in the WHO''s trachoma control program. Even a single mass distribution reduces the prevalence of the ocular chlamydia that causes trachoma. Unfortunately, infection returns after a single treatment, at least in severely affected areas. Here, we test whether additional scheduled treatments further reduce infection, and whether infection returns after distributions are discontinued.

Methods

Sixteen communities in Ethiopia were randomly selected. Ocular chlamydial infection in 1- to 5-year-old children was monitored over four biannual azithromycin distributions and for 24 months after the last treatment.

Findings

The average prevalence of infection in 1- to 5-year-old children was reduced from 63.5% pre-treatment to 11.5% six months after the first distribution (P<0.0001). It further decreased to 2.6% six months after the fourth and final treatment (P = 0.0004). In the next 18 months, infection returned to 25.2%, a significant increase from six months after the last treatment (P = 0.008), but still far lower than baseline (P<0.0001). Although the prevalence of infection in any particular village fluctuated, the mean prevalence of the 16 villages steadily decreased with each treatment and steadily returned after treatments were discontinued.

Conclusion

In some of the most severely affected communities ever studied, we demonstrate that repeated mass oral azithromycin distributions progressively reduce ocular chlamydial infection in a community, as long as these distributions are given frequently enough and at a high enough coverage. However, infection returns into the communities after the last treatment. Sustainable changes or complete local elimination of infection will be necessary.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00221364","term_id":"NCT00221364"}}NCT00221364     

Prebiotic and Probiotic Fortified Milk in Prevention of Morbidities among Children: Community-Based,Randomized, Double-Blind,Controlled Trial

Background

Recent reviews suggest common infectious diseases continue to be a major cause of death among preschool children in developing countries. Identification of feasible strategies to combat this disease burden is an important public health need. We evaluated the efficacy of adding prebiotic oligosaccharide and probiotic Bifidobacterium lactis HN019 to milk, in preventing diarrhea, respiratory infections and severe illnesses, in children aged 1–4 years as part of a four group study design, running two studies simultaneously.

Methods and Findings

In a community based double-masked, randomized controlled trial, children 1–3 years of age, willing to participate, were randomly allocated to receive either control milk (Co; n = 312) or the same milk fortified with 2.4 g/day of prebiotic oligosaccharide and 1.9×10⁷ colony forming unit (c.f.u)/day of probiotic Bifidobacterium lactis HN019 (PP; n = 312). Children were followed up for 1 year providing data for 1–4 years. Biweekly household surveillance was conducted to gather information on compliance and morbidity. Both study groups were comparable at baseline; compliance to intervention was similar. Overall, there was no effect of prebiotic and probiotic on diarrhea (6% reduction, 95% Confidence Interval [CI]: −1 to 12%; p = 0.08). Incidence of dysentery episodes was reduced by 21% (95% CI: 0 to 38%; p = 0.05). Incidence of pneumonia was reduced by 24% (95% CI: 0 to 42%; p = 0.05) and severe acute lower respiratory infection (ALRI) by 35% (95% CI: 0 to 58%; p = 0.05). Compared to children in Co group, children in PP group had 16% (95% CI: 5 to 26%, p = 0.004) and 5% (95% CI: 0 to 10%; p = 0.05) reduction in days with severe illness and high fever respectively.

Conclusions/Significance

Milk can be a good medium for delivery of prebiotic and probiotic and resulted in significant reduction of dysentery, respiratory morbidity and febrile illness. Overall, impact of diarrhea was not significant. These findings need confirmation in other settings.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00255385","term_id":"NCT00255385"}}NCT00255385     

A Prospective Controlled Trial of Routine Opt-Out HIV Testing in a Men's Jail

Background

Approximately 10 million Americans enter jails annually. The Centers for Disease Control and Prevention now recommends routine opt-out HIV testing in these settings. The logistics for performing routine opt-out HIV testing within jails, however, remain controversial. The objective of this study was to evaluate the optimal time to routinely HIV test newly incarcerated jail detainees using an opt-out strategy.

Methods

This prospective, controlled trial of routine opt-out HIV testing was conducted among 298 newly incarcerated male inmates in an urban men''s jail in New Haven, Connecticut. 298 sequential entrants to the men''s jail over a three week period in March and April 2008 were assigned to be offered routine opt-out HIV testing at one of three points after incarceration: immediate (same day, n = 103), early (next day, n = 98), or delayed (7 days, n = 97). The primary outcome was the proportion of men in each group consenting to testing.

Results

Routine opt-out HIV testing was significantly higher for the early (53%: AOR = 2.6; 95% CI = 1.5 to 4.7) and immediate (45%: AOR = 2.3; 95% CI = 1.3 to 4.0) testing groups compared to the delayed (33%) testing group. The immediate and early testing groups, however, did not significantly differ (p = 0.67). In multivariate analyses, factors significantly associated with routine opt-out HIV testing were assignment to the ‘early’ testing group (p = 0.0003) and low (bond ≥$5,000, immigration or federal charges or pre-sentencing >30 days) likelihood of early release (p = 0.04). Two subjects received preliminary positive results and one of them was subsequently confirmed HIV seropositive.

Conclusions

In this men''s jail where attrition was high, routine opt-out HIV testing was not only feasible, but resulted in the highest rates of HIV testing when performed within 24 hours of incarceration.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00624247","term_id":"NCT00624247"}}NCT00624247     

Efficacy of Artesunate + Sulfamethoxypyrazine/Pyrimethamine versus Praziquantel in the Treatment of Schistosoma haematobium in Children

Background

This study was conducted to determine the efficacy of the antimalarial artemisinin-based combination therapy (ACT) artesunate +sulfamethoxypyrazine/pyrimethamine (As+SMP), administered in doses used for malaria, to treat Schistosoma haematobium in school aged children.

Methodology/Principal Findings

The study was conducted in Djalakorodji, a peri-urban area of Bamako, Mali, using a double blind setup in which As+SMP was compared with praziquantel (PZQ). Urine samples were examined for Schistosoma haematobium on days −1, 0, 28 and 29. Detection of haematuria, and haematological and biochemical exams were conducted on day 0 and day 28. Clinical exams were performed on days 0, 1, 2, and 28. A total of 800 children were included in the trial. The cure rate obtained without viability testing was 43.9% in the As+SMP group versus 53% in the PZQ group (Chi² = 6.44, p = 0.011). Egg reduction rates were 95.6% with PZQ in comparison with 92.8% with As+SMP, p = 0.096. The proportion of participants who experienced adverse events related to the medication was 0.5% (2/400) in As+SMP treated children compared to 2.3% (9/399) in the PZQ group (p = 0.033). Abdominal pain and vomiting were the most frequent adverse events in both treatment arms. All adverse events were categorized as mild.

Conclusions/Significance

The study demonstrates that PZQ was more effective than As+SMP for treating Schistosoma haematobium. However, the safety and tolerability profile of As+SMP was similar to that seen with PZQ. Our findings suggest that further investigations seem justifiable to determine the dose/efficacy/safety pattern of As+SMP in the treatment of Schistosoma infections.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00510159","term_id":"NCT00510159"}}NCT00510159 http://clinicaltrials.gov/ct2/show/NCT00510159     

Health Extension Workers Improve Tuberculosis Case Detection and Treatment Success in Southern Ethiopia: A Community Randomized Trial

Background

One of the main strategies to control tuberculosis (TB) is to find and treat people with active disease. Unfortunately, the case detection rates remain low in many countries. Thus, we need interventions to find and treat sufficient number of patients to control TB. We investigated whether involving health extension workers (HEWs: trained community health workers) in TB control improved smear-positive case detection and treatment success rates in southern Ethiopia.

Methodology/Principal Finding

We carried out a community-randomized trial in southern Ethiopia from September 2006 to April 2008. Fifty-one kebeles (with a total population of 296, 811) were randomly allocated to intervention and control groups. We trained HEWs in the intervention kebeles on how to identify suspects, collect sputum, and provide directly observed treatment. The HEWs in the intervention kebeles advised people with productive cough of 2 weeks or more duration to attend the health posts. Two hundred and thirty smear-positive patients were identified from the intervention and 88 patients from the control kebeles. The mean case detection rate was higher in the intervention than in the control kebeles (122.2% vs 69.4%, p<0.001). In addition, more females patients were identified in the intervention kebeles (149.0 vs 91.6, p<0.001). The mean treatment success rate was higher in the intervention than in the control kebeles (89.3% vs 83.1%, p = 0.012) and more for females patients (89.8% vs 81.3%, p = 0.05).

Conclusions/Significance

The involvement of HEWs in sputum collection and treatment improved smear-positive case detection and treatment success rate, possibly because of an improved service access. This could be applied in settings with low health service coverage and a shortage of health workers.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00803322","term_id":"NCT00803322"}}NCT00803322     

High Risk of Severe Anaemia after Chlorproguanil-Dapsone+Artesunate Antimalarial Treatment in Patients with G6PD (A-) Deficiency

Background

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common inherited human enzyme defect. This deficiency provides some protection from clinical malaria, but it can also cause haemolysis after administration of drugs with oxidant properties.

Methods

The safety of chlorproguanil-dapsone+artesunate (CD+A) and amodiaquine+sulphadoxine-pyrimethamine (AQ+SP) for the treatment of uncomplicated P. falciparum malaria was evaluated according to G6PD deficiency in a secondary analysis of an open-label, randomized clinical trial [1]. 702 children, treated with CD+A or AQ+SP and followed for 28 days after treatment were genotyped for G6PD A- deficiency.

Findings

In the first 4 days following CD+A treatment, mean haematocrit declined on average 1.94% (95% CI 1.54 to 2.33) and 1.05% per day (95% CI 0.95 to 1.15) respectively in patients with G6PD deficiency and normal patients; a mean reduction of 1.3% per day was observed among patients who received AQ+SP regardless of G6PD status (95% CI 1.25 to 1.45). Patients with G6PD deficiency recipients of CD+A had significantly lower haematocrit than the other groups until day 7 (p = 0.04). In total, 10 patients had severe post-treatment haemolysis requiring blood transfusion. Patients with G6PD deficiency showed a higher risk of severe anaemia following treatment with CD+A (RR = 10.2; 95% CI 1.8 to 59.3) or AQ+SP (RR = 5.6; 95% CI 1.0 to 32.7).

Conclusions

CD+A showed a poor safety profile in individuals with G6PD deficiency most likely as a result of dapsone induced haemolysis. Screening for G6PD deficiency before drug administration of potentially pro-oxidants drugs, like dapsone-containing combinations, although seldom available, is necessary.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00461578","term_id":"NCT00461578"}}NCT00461578     

Differential Effects of Early Weaning for HIV-Free Survival of Children Born to HIV-Infected Mothers by Severity of Maternal Disease

Background

We previously reported no benefit of early weaning for HIV-free survival of children born to HIV-infected mothers in intent-to-treat analyses. Since early weaning was poorly accepted, we conducted a secondary analysis to investigate whether beneficial effects may have been hidden.

Methods

958 HIV-infected women in Lusaka, Zambia, were randomized to abrupt weaning at 4 months (intervention) or to continued breastfeeding (control). Children were followed to 24 months with regular HIV PCR tests and examinations to determine HIV infection or death. Detailed behavioral data were collected on when all breastfeeding ended. Most participants were recruited before antiretroviral treatment (ART) became available. We compared outcomes among mother-child pairs who weaned earlier or later than intended by study design adjusting for potential confounders.

Results

Of infants alive, uninfected and still breastfeeding at 4 months in the intervention group, 16.1% who weaned as instructed acquired HIV or died by 24 months compared to 16.0% who did not comply (p = 0.98). Children of women with less severe disease during pregnancy (not eligible for ART) had worse outcomes if their mothers weaned as instructed (RH = 2.60 95% CI: 1.06–6.36) compared to those who continued breastfeeding. Conversely, children of mothers with more severe disease (eligible for ART but did not receive it) who weaned early had better outcomes (p-value interaction = 0.002). In the control group, weaning before 15 months was associated with 3.94-fold (95% CI: 1.65–9.39) increase in HIV infection or death among infants of mothers with less severe disease.

Conclusion

Incomplete adherence did not mask a benefit of early weaning. On the contrary, for women with less severe disease, early weaning was harmful and continued breastfeeding resulted in better outcomes. For women with more advanced disease, ART should be given during pregnancy for maternal health and to reduce transmission, including through breastfeeding.

Trial Registration

Clinical trials.gov {"type":"clinical-trial","attrs":{"text":"NCT00310726","term_id":"NCT00310726"}}NCT00310726     

SMA CARNI-VAL Trial Part I: Double-Blind,Randomized, Placebo-Controlled Trial of L-Carnitine and Valproic Acid in Spinal Muscular Atrophy

Background

Valproic acid (VPA) has demonstrated potential as a therapeutic candidate for spinal muscular atrophy (SMA) in vitro and in vivo.

Methods

Two cohorts of subjects were enrolled in the SMA CARNIVAL TRIAL, a non-ambulatory group of “sitters” (cohort 1) and an ambulatory group of “walkers” (cohort 2). Here, we present results for cohort 1: a multicenter phase II randomized double-blind intention-to-treat protocol in non-ambulatory SMA subjects 2–8 years of age. Sixty-one subjects were randomized 1∶1 to placebo or treatment for the first six months; all received active treatment the subsequent six months. The primary outcome was change in the modified Hammersmith Functional Motor Scale (MHFMS) score following six months of treatment. Secondary outcomes included safety and adverse event data, and change in MHFMS score for twelve versus six months of active treatment, body composition, quantitative SMN mRNA levels, maximum ulnar CMAP amplitudes, myometry and PFT measures.

Results

At 6 months, there was no difference in change from the baseline MHFMS score between treatment and placebo groups (difference = 0.643, 95% CI = −1.22–2.51). Adverse events occurred in >80% of subjects and were more common in the treatment group. Excessive weight gain was the most frequent drug-related adverse event, and increased fat mass was negatively related to change in MHFMS values (p = 0.0409). Post-hoc analysis found that children ages two to three years that received 12 months treatment, when adjusted for baseline weight, had significantly improved MHFMS scores (p = 0.03) compared to those who received placebo the first six months. A linear regression analysis limited to the influence of age demonstrates young age as a significant factor in improved MHFMS scores (p = 0.007).

Conclusions

This study demonstrated no benefit from six months treatment with VPA and L-carnitine in a young non-ambulatory cohort of subjects with SMA. Weight gain, age and treatment duration were significant confounding variables that should be considered in the design of future trials.

Trial Registry

Clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00227266","term_id":"NCT00227266"}}NCT00227266     

Genetic Variants of the α-Synuclein Gene SNCA Are Associated with Multiple System Atrophy

Background

Multiple system atrophy (MSA) is a progressive neurodegenerative disorder characterized by parkinsonism, cerebellar ataxia and autonomic dysfunction. Pathogenic mechanisms remain obscure but the neuropathological hallmark is the presence of α-synuclein-immunoreactive glial cytoplasmic inclusions. Genetic variants of the α-synuclein gene, SNCA, are thus strong candidates for genetic association with MSA. One follow-up to a genome-wide association of Parkinson''s disease has identified association of a SNP in SNCA with MSA.

Methodology/Findings

We evaluated 32 SNPs in the SNCA gene in a European population of 239 cases and 617 controls recruited as part of the Neuroprotection and Natural History in Parkinson Plus Syndromes (NNIPPS) study. We used 161 independently collected samples for replication. Two SNCA SNPs showed association with MSA: rs3822086 (P = 0.0044), and rs3775444 (P = 0.012), although only the first survived correction for multiple testing. In the MSA-C subgroup the association strengthened despite more than halving the number of cases: rs3822086 P = 0.0024, OR 2.153, (95% CI 1.3–3.6); rs3775444 P = 0.0017, OR 4.386 (95% CI 1.6–11.7). A 7-SNP haplotype incorporating three SNPs either side of rs3822086 strengthened the association with MSA-C further (best haplotype, P = 8.7×10⁻⁴). The association with rs3822086 was replicated in the independent samples (P = 0.035).

Conclusions/Significance

We report a genetic association between MSA and α-synuclein which has replicated in independent samples. The strongest association is with the cerebellar subtype of MSA.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00211224","term_id":"NCT00211224"}}NCT00211224. [{"type":"clinical-trial","attrs":{"text":"NCT00211224","term_id":"NCT00211224"}}NCT00211224]     

Asthma Is Inversely Associated with Helicobacter pylori Status in an Urban Population

Background

Microbial exposures have been suggested to confer protection from allergic disorders and reduced exposures to gastrointestinal microbiota have been proposed as an explanation for the increase in asthma prevalence. Since the general prevalence of Helicobacter pylori has been decreasing, we hypothesized that H. pylori serostatus would be inversely related to the presence of asthma.

Methods

Adults were recruited to participate in the New York University (NYU)/Bellevue Asthma Registry in New York City. Adult asthma cases (N = 318) and controls (N = 208) were identified and serum IgG antibodies to H. pylori whole cell antigens or the immunodominant CagA antigen were measured.

Results

As expected, the asthma cases and controls differed with respect to atopy and lung function. Seropositivity to H. pylori or CagA antigen was present in 47.1% of the total case and control study population. Asthma was inversely associated with CagA seropositivity (OR = 0.57, 95% CI = 0.36–0.89). Median age of onset of asthma (doctor''s diagnosis) was older (21 years) among individuals with CagA+ strains than among H. pylori- individuals (11 years) (p = 0.006).

Conclusion

These data are consistent with the hypothesis that colonization with CagA+ H. pylori strains is inversely associated with asthma and is associated with an older age of asthma onset in an urban population. The data suggest H. pylori as a marker for protection.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00212537","term_id":"NCT00212537"}}NCT00212537     

Characterization of Cytomegalovirus Disease in Solid Organ Transplant Recipients by Markers of Inflammation in Plasma

Background

While several studies have examined the general inflammatory responses in relation to cytomegalovirus infection, the identification of the various inflammatory mediators as well as their relative importance is far from clear.

Patients and Methods

Solid organ recipients enrolled in an international multicenter trial of cytomegalovirus disease treatment (the VICTOR study) were analyzed (n = 289) (ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00431353","term_id":"NCT00431353"}}NCT00431353). Plasma markers of inflammation and endothelial cell activation were assessed at baseline by enzyme immunoassays.

Results

The major findings were: (i) Plasma levels of the CXC-chemokine interferon-inducible protein-10 (P<0.001) and C-reactive protein (P = 0.046) were independently associated with the presence of cytomegalovirus DNAemia above lower level of quantification. (ii) High levels of CC-chemokine ligand 21 (P = 0.027) and pentraxin 3 (P = 0.033) were independently associated with tissue invasive cytomegalovirus disease as opposed to cytomegalovirus syndrome.

Conclusion

Our findings illustrate the complex interaction between cytomegalovirus and the immune system, involving a wide range of inflammatory mediators that could be associated to disease manifestations in cytomegalovirus related disease.     

Nevirapine Resistance and Breast-Milk HIV Transmission: Effects of Single and Extended-Dose Nevirapine Prophylaxis in Subtype C HIV-Infected Infants

Background

Daily nevirapine (NVP) prophylaxis to HIV-exposed infants significantly reduces breast-milk HIV transmission. We assessed NVP-resistance in Indian infants enrolled in the “six-week extended-dose nevirapine” (SWEN) trial who received single-dose NVP (SD-NVP) or SWEN for prevention of breast-milk HIV transmission but who also acquired subtype C HIV infection during the first year of life.

Methods/Findings

Standard population sequencing and cloning for viral subpopulations present at ≥5% frequency were used to determine HIV genotypes from 94% of the 79 infected Indian infants studied. Timing of infection was defined based on when an infant''s blood sample first tested positive for HIV DNA. SWEN-exposed infants diagnosed with HIV by six weeks of age had a significantly higher prevalence of NVP-resistance than those who received SD-NVP, by both standard population sequencing (92% of 12 vs. 38% of 29; p = 0.002) and low frequency clonal analysis (92% of 12 vs. 59% of 29; p = 0.06). Likelihood of infection with NVP-resistant HIV through breast-milk among infants infected after age six weeks was substantial, but prevalence of NVP-resistance did not differ among SWEN or SD-NVP exposed infants by standard population sequencing (15% of 13 vs. 15% of 20; p = 1.00) and clonal analysis (31% of 13 vs. 40% of 20; p = 0.72). Types of NVP-resistance mutations and patterns of persistence at one year of age were similar between the two groups. NVP-resistance mutations did differ by timing of HIV infection; the Y181C variant was predominant among infants diagnosed in the first six weeks of life, compared to Y188C/H during late breast-milk transmission.

Conclusions/Significance

Use of SWEN to prevent breast-milk HIV transmission carries a high likelihood of resistance if infection occurs in the first six weeks of life. Moreover, there was a continued risk of transmission of NVP-resistant HIV through breastfeeding during the first year of life, but did not differ between SD-NVP and SWEN groups. As with SD-NVP, the value of preventing HIV infection in a large number of infants should be considered alongside the high risk of resistance associated with extended NVP prophylaxis.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00061321","term_id":"NCT00061321"}}NCT00061321     

Sono-Electro-Magnetic Therapy for Treating Chronic Pelvic Pain Syndrome in Men: A Randomized,Placebo-Controlled,Double-Blind Trial

Objective

To assess the efficacy and safety of sono-electro-magnetic therapy compared to placebo in men with refractory CPPS.

Patients and Methods

In a randomized, placebo-controlled, double-blind single center trial, we assessed the effect of sono-electro-magnetic therapy in men with treatment refractory CPPS. Sixty male patients were randomly assigned to treatment with either sono-electro-magnetic (n = 30) or placebo therapy (n = 30) for 12 weeks. The primary outcome was a change in the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) from baseline to 12 weeks.

Results

The 12-week difference between sono-electro-magnetic and placebo therapy in changes of the NIH-CPSI total score was −3.1 points (95% CI −6.8 to 0.6, p = 0.11). In secondary comparisons of NIH-CPSI sub-scores, we found differences between groups most pronounced for the quality-of-life sub-score (difference at 12 weeks −1.6, 95% CI −2.8 to −0.4, p = 0.015). In stratified analyses, the benefit of sono-electro-magnetic therapy appeared more pronounced among patients who had a symptom duration of 12 months or less (difference in NIH-CPSI total score −8.3, 95% CI −14.5 to 2.6) than in patients with a longer symptom duration (−0.8, 95% CI −4.6 to 3.1; p for interaction = 0.023).

Conclusions

Sono-electro-magnetic therapy did not result in a significant improvement of symptoms in the overall cohort of treatment refractory CPPS patients compared to placebo treatment. Subgroup analysis indicates, however, that patients with a symptom-duration of 12 months or less may benefit from sono-electro-magnetic therapy, warranting larger randomized controlled trials in this subpopulation.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00688506","term_id":"NCT00688506"}}NCT00688506