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     

High Uptake of Exclusive Breastfeeding and Reduced Early Post-Natal HIV Transmission

Background

Empirical data showing the clear benefits of exclusive breastfeeding (EBF) for HIV prevention are needed to encourage implementation of lactation support programs for HIV-infected women in low resource settings among whom replacement feeding is unsafe. We conducted a prospective, observational study in Lusaka, Zambia, to test the hypothesis that EBF is associated with a lower risk of postnatal HIV transmission than non-EBF.

Methods and Results

As part of a randomized trial of early weaning, 958 HIV-infected women and their infants were recruited and all were encouraged to breastfeed exclusively to 4 months. Single-dose nevirapine was provided to prevent transmission. Regular samples were collected from infants to 24 months of age and tested by PCR. Detailed measurements of actual feeding behaviors were collected to examine, in an observational analysis, associations between feeding practices and postnatal HIV transmission. Uptake of EBF was high with 84% of women reporting only EBF cumulatively to 4 months. Post-natal HIV transmission before 4 months was significantly lower (p = 0.004) among EBF (0.040 95% CI: 0.024–0.055) than non-EBF infants (0.102 95% CI: 0.047–0.157); time-dependent Relative Hazard (RH) of transmission due to non-EBF = 3.48 (95% CI: 1.71–7.08). There were no significant differences in the severity of disease between EBF and non-EBF mothers and the association remained significant (RH = 2.68 95% CI: 1.28–5.62) after adjusting for maternal CD4 count, plasma viral load, syphilis screening results and low birth weight.

Conclusions

Non-EBF more than doubles the risk of early postnatal HIV transmission. Programs to support EBF should be expanded universally in low resource settings. EBF is an affordable, feasible, acceptable, safe and sustainable practice that also reduces HIV transmission providing HIV-infected women with a means to protect their children''s lives.

Trial Registration

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

Long-Term Biological and Behavioural Impact of an Adolescent Sexual Health Intervention in Tanzania: Follow-up Survey of the Community-Based MEMA kwa Vijana Trial

Background

The ability of specific behaviour-change interventions to reduce HIV infection in young people remains questionable. Since January 1999, an adolescent sexual and reproductive health (SRH) intervention has been implemented in ten randomly chosen intervention communities in rural Tanzania, within a community randomised trial (see below; {"type":"clinical-trial","attrs":{"text":"NCT00248469","term_id":"NCT00248469"}}NCT00248469). The intervention consisted of teacher-led, peer-assisted in-school education, youth-friendly health services, community activities, and youth condom promotion and distribution. Process evaluation in 1999–2002 showed high intervention quality and coverage. A 2001/2 intervention impact evaluation showed no impact on the primary outcomes of HIV seroincidence and herpes simplex virus type 2 (HSV-2) seroprevalence but found substantial improvements in SRH knowledge, reported attitudes, and some reported sexual behaviours. It was postulated that the impact on “upstream” knowledge, attitude, and reported behaviour outcomes seen at the 3-year follow-up would, in the longer term, lead to a reduction in HIV and HSV-2 infection rates and other biological outcomes. A further impact evaluation survey in 2007/8 (∼9 years post-intervention) tested this hypothesis.

Methods and Findings

This is a cross-sectional survey (June 2007 through July 2008) of 13,814 young people aged 15–30 y who had attended trial schools during the first phase of the MEMA kwa Vijana intervention trial (1999–2002). Prevalences of the primary outcomes HIV and HSV-2 were 1.8% and 25.9% in males and 4.0% and 41.4% in females, respectively. The intervention did not significantly reduce risk of HIV (males adjusted prevalence ratio [aPR] 0.91, 95%CI 0.50–1.65; females aPR 1.07, 95%CI 0.68–1.67) or HSV-2 (males aPR 0.94, 95%CI 0.77–1.15; females aPR 0.96, 95%CI 0.87–1.06). The intervention was associated with a reduction in the proportion of males reporting more than four sexual partners in their lifetime (aPR 0.87, 95%CI 0.78–0.97) and an increase in reported condom use at last sex with a non-regular partner among females (aPR 1.34, 95%CI 1.07–1.69). There was a clear and consistent beneficial impact on knowledge, but no significant impact on reported attitudes to sexual risk, reported pregnancies, or other reported sexual behaviours. The study population was likely to have been, on average, at lower risk of HIV and other sexually transmitted infections compared to other rural populations, as only youth who had reached year five of primary school were eligible.

Conclusions

SRH knowledge can be improved and retained long-term, but this intervention had only a limited effect on reported behaviour and no significant effect on HIV/STI prevalence. Youth interventions integrated within intensive, community-wide risk reduction programmes may be more successful and should be evaluated.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00248469","term_id":"NCT00248469"}}NCT00248469 Please see later in the article for the Editors'' Summary     

Impact of Community-Based Maternal Health Workers on Coverage of Essential Maternal Health Interventions among Internally Displaced Communities in Eastern Burma: The MOM Project

Background

Access to essential maternal and reproductive health care is poor throughout Burma, but is particularly lacking among internally displaced communities in the eastern border regions. In such settings, innovative strategies for accessing vulnerable populations and delivering basic public health interventions are urgently needed.

Methods

Four ethnic health organizations from the Shan, Mon, Karen, and Karenni regions collaborated on a pilot project between 2005 and 2008 to examine the feasibility of an innovative three-tiered network of community-based providers for delivery of maternal health interventions in the complex emergency setting of eastern Burma. Two-stage cluster-sampling surveys among ever-married women of reproductive age (15–45 y) conducted before and after program implementation enabled evaluation of changes in coverage of essential antenatal care interventions, attendance at birth by those trained to manage complications, postnatal care, and family planning services.

Results

Among 2,889 and 2,442 women of reproductive age in 2006 and 2008, respectively, population characteristics (age, marital status, ethnic distribution, literacy) were similar. Compared to baseline, women whose most recent pregnancy occurred during the implementation period were substantially more likely to receive antenatal care (71.8% versus 39.3%, prevalence rate ratio [PRR] = 1.83 [95% confidence interval (CI) 1.64–2.04]) and specific interventions such as urine testing (42.4% versus 15.7%, PRR = 2.69 [95% CI 2.69–3.54]), malaria screening (55.9% versus 21.9%, PRR = 2.88 [95% CI 2.15–3.85]), and deworming (58.2% versus 4.1%, PRR = 14.18 [95% CI 10.76–18.71]. Postnatal care visits within 7 d doubled. Use of modern methods to avoid pregnancy increased from 23.9% to 45.0% (PRR = 1.88 [95% CI 1.63–2.17]), and unmet need for contraception was reduced from 61.7% to 40.5%, a relative reduction of 35% (95% CI 28%–40%). Attendance at birth by those trained to deliver elements of emergency obstetric care increased almost 10-fold, from 5.1% to 48.7% (PRR = 9.55 [95% CI 7.21–12.64]).

Conclusions

Coverage of maternal health interventions and higher-level care at birth was substantially higher during the project period. The MOM Project''s focus on task-shifting, capacity building, and empowerment at the community level might serve as a model approach for similarly constrained settings. Please see later in the article for the Editors'' Summary     

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     

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     

Intermittent Preventive Treatment for Malaria in Papua New Guinean Infants Exposed to Plasmodium falciparum and P. vivax: A Randomized Controlled Trial

Background

Intermittent preventive treatment in infants (IPTi) has been shown in randomized trials to reduce malaria-related morbidity in African infants living in areas of high Plasmodium falciparum (Pf) transmission. It remains unclear whether IPTi is an appropriate prevention strategy in non-African settings or those co-endemic for P. vivax (Pv).

Methods and Findings

In this study, 1,121 Papua New Guinean infants were enrolled into a three-arm placebo-controlled randomized trial and assigned to sulfadoxine-pyrimethamine (SP) (25 mg/kg and 1.25 mg/kg) plus amodiaquine (AQ) (10 mg/kg, 3 d, n = 374), SP plus artesunate (AS) (4 mg/kg, 3 d, n = 374), or placebo (n = 373), given at 3, 6, 9 and 12 mo. Both participants and study teams were blinded to treatment allocation. The primary end point was protective efficacy (PE) against all episodes of clinical malaria from 3 to 15 mo of age. Analysis was by modified intention to treat. The PE (compared to placebo) against clinical malaria episodes (caused by all species) was 29% (95% CI, 10–43, p≤0.001) in children receiving SP-AQ and 12% (95% CI, −11 to 30, p = 0.12) in those receiving SP-AS. Efficacy was higher against Pf than Pv. In the SP-AQ group, Pf incidence was 35% (95% CI, 9–54, p = 0.012) and Pv incidence was 23% (95% CI, 0–41, p = 0.048) lower than in the placebo group. IPTi with SP-AS protected only against Pf episodes (PE = 31%, 95% CI, 4–51, p = 0.027), not against Pv episodes (PE = 6%, 95% CI, −24 to 26, p = 0.759). Number of observed adverse events/serious adverse events did not differ between treatment arms (p>0.55). None of the serious adverse events were thought to be treatment-related, and the vomiting rate was low in both treatment groups (1.4%–2.0%). No rebound in malaria morbidity was observed for 6 mo following the intervention.

Conclusions

IPTi using a long half-life drug combination is efficacious for the prevention of malaria and anemia in infants living in a region highly endemic for both Pf and Pv.

Trial registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00285662","term_id":"NCT00285662"}}NCT00285662 Please see later in the article for the Editors'' Summary     

Micronutrient Fortified Milk Improves Iron Status,Anemia and Growth among Children 1–4 Years: A Double Masked,Randomized, Controlled Trial

Background

Multiple micronutrient deficiencies are highly prevalent among preschool children and often lead to anemia and growth faltering. Given the limited success of supplementation and health education programs, fortification of foods could be a viable and sustainable option. We report results from a community based double-masked, randomized trial among children 1–4 years evaluating the effects of micronutrients (especially of zinc and iron) delivered through fortified milk on growth, anemia and iron status markers as part of a four group study design, running two studies simultaneously.

Methods and Findings

Enrolled children (n = 633) were randomly allocated to receive either micronutrients fortified milk (MN = 316) or control milk (Co = 317). Intervention of MN milk provided additional 7.8 mg zinc, 9.6 mg iron, 4.2 µg selenium, 0.27 mg copper, 156 µg vitamin A, 40.2 mg vitamin C, and 7.5 mg vitamin E per day (three serves) for one year. Anthropometry was recorded at baseline, mid- and end-study. Hematological parameters were estimated at baseline and end-study. Both groups were comparable at baseline. Compliance was over 85% and did not vary between groups. Compared to children consuming Co milk, children consuming MN milk showed significant improvement in weight gain (difference of mean: 0.21 kg/year; 95% confidence interval [CI] 0.12 to 0.31, p<0.001) and height gain (difference of mean: 0.51 cm/year; 95% CI 0.27 to 0.75, p<0.001). Mean hemoglobin (Hb) (difference of 13.6 g/L; 95% CI 11.1 to 16.0, p<0.001) and serum ferritin levels (difference of 7.9 µg/L; 95% CI 5.4 to 10.5, p<0.001) also improved. Children in MN group had 88% (odds ratio = 0.12, 95% CI 0.08 to 0.20, p<0.001) lower risk of iron deficiency anemia.

Conclusions/Significance

Milk provides an acceptable and effective vehicle for delivery of specific micronutrients, especially zinc and iron. Micronutrient bundle improved growth and iron status and reduced anemia in children 1–4 years old.

Trial Registration

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

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     

Bone mineral density in HIV-negative men participating in a tenofovir pre-exposure prophylaxis randomized clinical trial in San Francisco

Background

Pre-exposure prophylaxis (PrEP) trials are evaluating regimens containing tenofovir-disoproxil fumarate (TDF) for HIV prevention. We determined the baseline prevalence of low bone mineral density (BMD) and the effect of TDF on BMD in men who have sex with men (MSM) in a PrEP trial in San Francisco.

Methods/Findings

We evaluated 1) the prevalence of low BMD using Dual Energy X-ray Absorptiometry (DEXA) in a baseline cohort of 210 HIV-uninfected MSM who screened for a randomized clinical trial of daily TDF vs. placebo, and 2) the effects of TDF on BMD in a longitudinal cohort of 184 enrolled men. Half began study drug after a 9-month delay to evaluate changes in risk behavior associated with pill-use. At baseline, 20 participants (10%) had low BMD (Z score≤−2.0 at the L2–L4 spine, total hip, or femoral neck). Low BMD was associated with amphetamine (OR = 5.86, 95% CI 1.70–20.20) and inhalant (OR = 4.57, 95% CI 1.32–15.81) use; men taking multivitamins, calcium, or vitamin D were less likely to have low BMD at baseline (OR = 0.26, 95% CI 0.10–0.71). In the longitudinal analysis, there was a 1.1% net decrease in mean BMD in the TDF vs. the pre-treatment/placebo group at the femoral neck (95% CI 0.4–1.9%), 0.8% net decline at the total hip (95% CI 0.3–1.3%), and 0.7% at the L2–L4 spine (95% CI −0.1–1.5%). At 24 months, 13% vs. 6% of participants experienced >5% BMD loss at the femoral neck in the TDF vs. placebo groups (p = 0.13).

Conclusions

Ten percent of HIV-negative MSM had low BMD at baseline. TDF use resulted in a small but statistically significant decline in BMD at the total hip and femoral neck. Larger studies with longer follow-up are needed to determine the trajectory of BMD changes and any association with clinical fractures.

Trial Registration

ClinicalTrials.gov: {"type":"clinical-trial","attrs":{"text":"NCT00131677","term_id":"NCT00131677"}}NCT00131677     

Nevirapine- Versus Lopinavir/Ritonavir-Based Initial Therapy for HIV-1 Infection among Women in Africa: A Randomized Trial

Background

Nevirapine (NVP) is widely used in antiretroviral treatment (ART) of HIV-1 globally. The primary objective of the AA5208/OCTANE trial was to compare the efficacy of NVP-based versus lopinavir/ritonavir (LPV/r)-based initial ART.

Methods and Findings

In seven African countries (Botswana, Kenya, Malawi, South Africa, Uganda, Zambia, and Zimbabwe), 500 antiretroviral-naïve HIV-infected women with CD4<200 cells/mm³ were enrolled into a two-arm randomized trial to initiate open-label ART with tenofovir (TDF)/emtricitabine (FTC) once/day plus either NVP (n = 249) or LPV/r (n = 251) twice/day, and followed for ≥48 weeks. The primary endpoint was time from randomization to death or confirmed virologic failure ([VF]) (plasma HIV RNA<1 log₁₀ below baseline 12 weeks after treatment initiation, or ≥400 copies/ml at or after 24 weeks), with comparison between treatments based on hazard ratios (HRs) in intention-to-treat analysis. Equivalence of randomized treatments was defined as finding the 95% CI for HR for virological failure or death in the range 0.5 to 2.0. Baseline characteristics were (median): age = 34 years, CD4 = 121 cells/mm³, HIV RNA = 5.2 log₁₀copies/ml. Median follow-up = 118 weeks; 29 (6%) women were lost to follow-up. 42 women (37 VFs, five deaths; 17%) in the NVP and 50 (43 VFs, seven deaths; 20%) in the LPV/r arm reached the primary endpoint (HR 0.85, 95% CI 0.56–1.29). During initial assigned treatment, 14% and 16% of women receiving NVP and LPV/r experienced grade 3/4 signs/symptoms and 26% and 22% experienced grade 3/4 laboratory abnormalities. However, 35 (14%) women discontinued NVP because of adverse events, most in the first 8 weeks, versus none for LPV/r (p<0.001). VF, death, or permanent treatment discontinuation occurred in 80 (32%) of NVP and 54 (22%) of LPV/r arms (HR = 1.7, 95% CI 1.2–2.4), with the difference primarily due to more treatment discontinuation in the NVP arm. 13 (45%) of 29 women tested in the NVP versus six (15%) of 40 in the LPV/r arm had any drug resistance mutation at time of VF.

Conclusions

Initial ART with NVP+TDF/FTC demonstrated equivalent virologic efficacy but higher rates of treatment discontinuation and new drug resistance compared with LPV/r+TDF/FTC in antiretroviral-naïve women with CD4<200 cells/mm³.

Trial registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00089505","term_id":"NCT00089505"}}NCT00089505 Please see later in the article for the Editors'' Summary     

Effect of Peer Health Workers on AIDS Care in Rakai,Uganda: A Cluster-Randomized Trial

Background

Human resource limitations are a challenge to the delivery of antiretroviral therapy (ART) in low-resource settings. We conducted a cluster randomized trial to assess the effect of community-based peer health workers (PHW) on AIDS care of adults in Rakai, Uganda.

Methodology/Principal Findings

15 AIDS clinics were randomized 2∶1 to receive the PHW intervention (n = 10) or control (n = 5). PHW tasks included clinic and home-based provision of counseling, clinical, adherence to ART, and social support. Primary outcomes were adherence and cumulative risk of virologic failure (>400 copies/mL). Secondary outcomes were virologic failure at each 24 week time point up to 192 weeks of ART. Analysis was by intention to treat. From May 2006 to July 2008, 1336 patients were followed. 444 (33%) of these patients were already on ART at the start of the study. No significant differences were found in lack of adherence (<95% pill count adherence risk ratio [RR] 0.55, 95% confidence interval [CI] 0.23–1.35; <100% adherence RR 1.10, 95% CI 0.94–1.30), cumulative risk of virologic failure (RR 0.81, 95% CI 0.61–1.08) or in shorter-term virologic outcomes (24 week virologic failure RR 0.93, 95% CI 0.65–1.32; 48 week, RR 0.83, 95% CI 0.47–1.48; 72 week, RR 0.81, 95% CI 0.44–1.49). However, virologic failure rates ≥96 weeks into ART were significantly decreased in the intervention arm compared to the control arm (96 week failure RR 0.50, 95% CI 0.31–0.81; 120 week, RR 0.59, 95% CI 0.22–1.60; 144 week, RR 0.39, 95% CI 0.16–0.95; 168 week, RR 0.30, 95% CI 0.097–0.92; 192 week, RR 0.067, 95% CI 0.0065–0.71).

Conclusions/Significance

A PHW intervention was associated with decreased virologic failure rates occurring 96 weeks and longer into ART, but did not affect cumulative risk of virologic failure, adherence measures, or shorter-term virologic outcomes. PHWs may be an effective intervention to sustain long-term ART in low-resource settings.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00675389","term_id":"NCT00675389"}}NCT00675389     

Ten-Year Mortality and Cardiovascular Morbidity in the Finnish Diabetes Prevention Study—Secondary Analysis of the Randomized Trial

Background

The Finnish Diabetes Prevention Study (DPS) was a randomized controlled trial, which showed that it is possible to prevent type 2 diabetes by lifestyle changes. The aim of the present study was to examine whether the lifestyle intervention had an effect on the ten-year mortality and cardiovascular morbidity in the DPS participants originally randomized either into an intervention or control group. Furthermore, we compared these results with a population-based cohort comprising individuals of varying glucose tolerance states.

Methods and Findings

Middle-aged, overweight people with IGT (n = 522) were randomized into intensive intervention (including physical activity, weight reduction and dietary counseling), or control “mini-intervention” group. Median length of the intervention period was 4 years and the mean follow-up was 10.6 years. The population-based reference study cohort included 1881 individuals (1570 with normal glucose tolerance, 183 with IGT, 59 with screen-detected type 2 diabetes, 69 with previously known type 2 diabetes) with the mean follow-up of 13.8 years. Mortality and cardiovascular morbidity data were collected from the national Hospital Discharge Register and Causes of Death Register. Among the DPS participants who consented for register linkage (n = 505), total mortality (2.2 vs. 3.8 per 1000 person years, hazard ratio HR = 0.57, 95% CI 0.21–1.58) and cardiovascular morbidity (22.9 vs. 22.0 per 1000 person years, HR = 1.04, 95% CI 0.72–1.51) did not differ significantly between the intervention and control groups. Compared with the population-based cohort with impaired glucose tolerance, adjusted HRs were 0.21 (95% CI 0.09–0.52) and 0.39 (95% CI 0.20–0.79) for total mortality, and 0.89 (95% CI 0.62–1.27) and 0.87 (0.60–1.27) for cardiovascular morbidity in the intervention and control groups of the DPS, respectively. The risk of death in DPS combined cohort was markedly lower than in FINRISK IGT cohort (adjusted HR 0.30, 95% CI 0.17–0.54), but there was no significant difference in the risk of CVD (adjusted HR 0.88, 95% CI 0.64–1.21).

Conclusions

Lifestyle intervention among persons with IGT did not decrease cardiovascular morbidity during the first 10 years of follow-up. However, the statistical power may not be sufficient to detect small differences between the intervention and control groups. Low total mortality among participants of the DPS compared with individuals with IGT in the general population could be ascribed to a lower cardiovascular risk profile at baseline and regular follow-up.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00518167","term_id":"NCT00518167"}}NCT00518167     

Early Antiretroviral Therapy Reduces AIDS Progression/Death in Individuals with Acute Opportunistic Infections: A Multicenter Randomized Strategy Trial

Background

Optimal timing of ART initiation for individuals presenting with AIDS-related OIs has not been defined.

Methods and Findings

A5164 was a randomized strategy trial of “early ART” - given within 14 days of starting acute OI treatment versus “deferred ART” - given after acute OI treatment is completed. Randomization was stratified by presenting OI and entry CD4 count. The primary week 48 endpoint was 3-level ordered categorical variable: 1. Death/AIDS progression; 2. No progression with incomplete viral suppression (ie HIV viral load (VL) ≥50 copies/ml); 3. No progression with optimal viral suppression (ie HIV VL <50 copies/ml). Secondary endpoints included: AIDS progression/death; plasma HIV RNA and CD4 responses and safety parameters including IRIS.282 subjects were evaluable; 141 per arm. Entry OIs included Pneumocytis jirovecii pneumonia 63%, cryptococcal meningitis 12%, and bacterial infections 12%. The early and deferred arms started ART a median of 12 and 45 days after start of OI treatment, respectively.The difference in the primary endpoint did not reach statistical significance: AIDS progression/death was seen in 20 (14%) vs. 34 (24%); whereas no progression but with incomplete viral suppression was seen in 54 (38%) vs. 44 (31%); and no progression with optimal viral suppression in 67 (48%) vs 63 (45%) in the early vs. deferred arm, respectively (p = 0.22). However, the early ART arm had fewer AIDS progression/deaths (OR = 0.51; 95% CI = 0.27–0.94) and a longer time to AIDS progression/death (stratified HR = 0.53; 95% CI = 0.30–0.92). The early ART had shorter time to achieving a CD4 count above 50 cells/mL (p<0.001) and no increase in adverse events.

Conclusions

Early ART resulted in less AIDS progression/death with no increase in adverse events or loss of virologic response compared to deferred ART. These results support the early initiation of ART in patients presenting with acute AIDS-related OIs, absent major contraindications.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00055120","term_id":"NCT00055120"}}NCT00055120     

Effects of Point Mutations in Plasmodium falciparum Dihydrofolate Reductase and Dihydropterate Synthase Genes on Clinical Outcomes and In Vitro Susceptibility to Sulfadoxine and Pyrimethamine

Background

Sulfadoxine-pyrimethamine was a common first line drug therapy to treat uncomplicated falciparum malaria, but increasing therapeutic failures associated with the development of significant levels of resistance worldwide has prompted change to alternative treatment regimes in many national malaria control programs.

Methodology and Finding

We conducted an in vivo therapeutic efficacy trial of sulfadoxine-pyrimethamine at two locations in the Peruvian Amazon enrolling 99 patients of which, 86 patients completed the protocol specified 28 day follow up. Our objective was to correlate the presence of polymorphisms in P. falciparum dihydrofolate reductase and dihydropteroate synthase to in vitro parasite susceptibility to sulfadoxine and pyrimethamine and to in vivo treatment outcomes. Inhibitory concentration 50 values of isolates increased with numbers of mutations (single [108N], sextuplet [BR/51I/108N/164L and 437G/581G]) and septuplet (BR/51I/108N/164L and 437G/540E/581G) with geometric means of 76 nM (35–166 nM), 582 nM (49-6890- nM) and 4909 (3575–6741 nM) nM for sulfadoxine and 33 nM (22–51 nM), 81 nM (19–345 nM), and 215 nM (176–262 nM) for pyrimethamine. A single mutation present in the isolate obtained at the time of enrollment from either dihydrofolate reductase (164L) or dihydropteroate synthase (540E) predicted treatment failure as well as any other single gene alone or in combination. Patients with the dihydrofolate reductase 164L mutation were 3.6 times as likely to be treatment failures [failures 85.4% (164L) vs 23.7% (I164); relative risk = 3.61; 95% CI: 2.14 – 6.64] while patients with the dihydropteroate synthase 540E were 2.6 times as likely to fail treatment (96.7% (540E) vs 37.5% (K540); relative risk = 2.58; 95% CI: 1.88 – 3.73). Patients with both dihydrofolate reductase 164L and dihydropteroate synthase 540E mutations were 4.1 times as likely to be treatment failures [96.7% vs 23.7%; RR = 4.08; 95% CI: 2.45 – 7.46] compared to patients having both wild forms (I164 and K540).

Conclusions

In this part of the Amazon basin, it may be possible to predict treatment failure with sulfadoxine-pyrimethamine equally well by determination of either of the single mutations dihydrofolate reductase 164L or dihydropteroate synthase 540E.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00951106","term_id":"NCT00951106"}}NCT00951106 {"type":"clinical-trial","attrs":{"text":"NCT00951106","term_id":"NCT00951106"}}NCT00951106     

An Online Randomized Controlled Trial Evaluating HIV Prevention Digital Media Interventions for Men Who Have Sex with Men

Background

As HIV infection continues unabated, there is a need for effective interventions targeting at-risk men who have sex with men (MSM). Engaging MSM online where they meet sexual partners is critical for HIV prevention efforts.

Methods

A randomized controlled trial (RCT) conducted online among U.S. MSM recruited from several gay sexual networking websites assessed the impact of 2 HIV prevention videos and an HIV prevention webpage compared to a control condition for the study outcomes HIV testing, serostatus disclosure, and unprotected anal intercourse (UAI) at 60-day follow-up. Video conditions were pooled due to reduced power from low retention (53%, n = 1,631). No participant incentives were provided.

Principal Findings

Follow-up was completed by 1,631 (53%) of 3,092 eligible men. In the 60 days after the intervention, men in the pooled video condition were significantly more likely than men in the control to report full serostatus disclosure (‘asked and told’) with their last sexual partner (OR 1.32, 95% CI 1.01–1.74). Comparing baseline to follow-up, HIV-negative men in the pooled video (OR 0.70, 95% CI 0.54–0.91) and webpage condition (OR 0.43, 95% CI 0.25–0.72) significantly reduced UAI at follow-up. HIV-positive men in the pooled video condition significantly reduced UAI (OR 0.38, 95% CI 0.20–0.67) and serodiscordant UAI (OR 0.53, 95% CI 0.28–0.96) at follow-up.

Conclusions/Significance

Findings from this online RCT of MSM recruited from sexual networking websites suggest that a low cost, brief digital media intervention designed to engage critical thinking can increase HIV disclosure to sexual partners and decrease sexual risk. Effective, brief HIV prevention interventions featuring digital media that are made widely available may serve as a complementary part of an overall behavioral and biomedical strategy for reducing sexual risk by addressing the specific needs and circumstances of the target population, and by changing individual knowledge, motivations, and community norms.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00649701","term_id":"NCT00649701"}}NCT00649701     

Uptake of Genital Mucosal Sampling in HVTN 097, a Phase 1b HIV Vaccine Trial in South Africa

Because sexual transmission of HIV occurs across mucosal membranes, understanding the immune responses of the genital mucosa to vaccines may contribute knowledge to finding an effective candidate HIV vaccine. We describe the uptake of rectal secretion, cervical secretion and seminal mucosal secretion sampling amongst volunteers in a Phase 1b HIV vaccine trial. Age at screening, gender, study site and the designation of the person conducting the informed consent procedure were collected for volunteers who screened for the HVTN 097 study. A total of 211 volunteers (54% female) were screened at three sites in South Africa: Soweto (n = 70, 33%), Cape Town (n = 68, 32%) and Klerksdorp (n = 73, 35%). Overall uptake of optional mucosal sampling amongst trial volunteers was 71% (n = 149). Compared to Cape Town, volunteers from Soweto and Klerksdorp were less likely to consent to sampling (Soweto OR 0.08 CI: 0.03–0.25 p<0.001 and Klerksdorp OR 0.13 CI: 0.04–0.41 p = 0.001). In contrast, volunteers over 25 years of age were 2.39 times more likely to consent than younger volunteers (CI: 1.13–5.08, p = 0.02). Further studies are required to better understand the cultural, demographic and sociobehavioral factors which influence willingness to participate in mucosal sampling in HIV prevention studies.

Trial Registration

ClinicalTrials.gov: {"type":"clinical-trial","attrs":{"text":"NCT02109354","term_id":"NCT02109354"}}NCT02109354     

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     

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     

Effectiveness of a Pre-treatment Snack on the Uptake of Mass Treatment for Schistosomiasis in Uganda: A Cluster Randomized Trial

Background

School-based mass treatment with praziquantel is the cornerstone for schistosomiasis control in school-aged children. However, uptake of treatment among school-age children in Uganda is low in some areas. The objective of the study was to examine the effectiveness of a pre-treatment snack on uptake of mass treatment.

Methods and Findings

In a cluster randomized trial carried out in Jinja district, Uganda, 12 primary schools were randomized into two groups; one received education messages for schistosomiasis prevention for two months prior to mass treatment, while the other, in addition to the education messages, received a pre-treatment snack shortly before mass treatment. Four weeks after mass treatment, uptake of praziquantel was assessed among a random sample of 595 children in the snack schools and 689 children in the non-snack schools as the primary outcome. The occurrence of side effects and the prevalence and mean intensity of Schistosoma mansoni infection were determined as the secondary outcomes. Uptake of praziquantel was higher in the snack schools, 93.9% (95% CI 91.7%–95.7%), compared to that in the non-snack schools, 78.7% (95% CI 75.4%–81.7%) (p = 0.002). The occurrence of side effects was lower in the snack schools, 34.4% (95% CI 31.5%–39.8%), compared to that in the non-snack schools, 46.9% (95% CI 42.2%–50.7%) (p = 0.041). Prevalence and mean intensity of S. mansoni infection was lower in the snack schools, 1.3% (95% CI 0.6%–2.6%) and 38.3 eggs per gram of stool (epg) (95% CI 21.8–67.2), compared to that in the non-snack schools, 14.1% (95% CI 11.6%–16.9%) (p = 0.001) and 78.4 epg (95% CI 60.6–101.5) (p = 0.001), respectively.

Conclusions

Our results suggest that provision of a pre-treatment snack combined with education messages achieves a higher uptake compared to the education messages alone. The use a pre-treatment snack was associated with reduced side effects as well as decreased prevalence and intensity of S. mansoni infection.

Trial registration

www.ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01869465","term_id":"NCT01869465"}}NCT01869465 Please see later in the article for the Editors'' Summary