Efficacy and Safety of an Ad26.RSV.preF-RSV preF Protein Vaccine in Older Adults.

BACKGROUND: Respiratory syncytial virus (RSV) can cause serious lower respiratory tract disease in older adults, but no licensed RSV vaccine currently exists. An adenovirus serotype 26 RSV vector encoding a prefusion F (preF) protein (Ad26.RSV.preF) in combination with RSV preF protein was previously shown to elicit humoral and cellular immunogenicity. METHODS: We conducted a randomized, double-blind, placebo-controlled, phase 2b, proof-of-concept trial to evaluate the efficacy, immunogenicity, and safety of an Ad26.RSV.preF-RSV preF protein vaccine. Adults who were 65 years of age or older were randomly assigned in a 1:1 ratio to receive vaccine or placebo. The primary end point was the first occurrence of RSV-mediated lower respiratory tract disease that met one of three case definitions: three or more symptoms of lower respiratory tract infection (definition 1), two or more symptoms of lower respiratory tract infection (definition 2), and either two or more symptoms of lower respiratory tract infection or one or more symptoms of lower respiratory tract infection plus at least one systemic symptom (definition 3). RESULTS: Overall, 5782 participants were enrolled and received an injection. RSV-mediated lower respiratory tract disease meeting case definitions 1, 2, and 3 occurred in 6, 10, and 13 vaccine recipients and in 30, 40, and 43 placebo recipients, respectively. Vaccine efficacy was 80.0% (94.2% confidence interval [CI], 52.2 to 92.9), 75.0% (94.2% CI, 50.1 to 88.5), and 69.8% (94.2% CI, 43.7 to 84.7) for case definitions 1, 2, and 3, respectively. After vaccination, RSV A2 neutralizing antibody titers increased by a factor of 12.1 from baseline to day 15, a finding consistent with other immunogenicity measures. Percentages of participants with solicited local and systemic adverse events were higher in the vaccine group than in the placebo group (local, 37.9% vs. 8.4%; systemic, 41.4% vs. 16.4%); most adverse events were mild to moderate in severity. The frequency of serious adverse events was similar in the vaccine group and the placebo group (4.6% and 4.7%, respectively). CONCLUSIONS: In adults 65 years of age or older, Ad26.RSV.preF-RSV preF protein vaccine was immunogenic and prevented RSV-mediated lower respiratory tract disease. (Funded by Janssen Vaccines and Prevention; CYPRESS ClinicalTrials.gov number, NCT03982199.).

Prevention of Respiratory Syncytial Virus Infection in Healthy Adults by a Single Immunization of Ad26.RSV.preF in a Human Challenge Study.

BACKGROUND: Respiratory syncytial virus (RSV) is a significant cause of severe lower respiratory tract disease in children and older adults, but has no approved vaccine. This study assessed the potential of Ad26.RSV.preF to protect against RSV infection and disease in an RSV human challenge model. METHODS: In this double-blind, placebo-controlled study, healthy adults aged 18-50 years were randomized 1:1 to receive 1 × 1011 vp Ad26.RSV.preF or placebo intramuscularly. Twenty-eight days postimmunization, volunteers were challenged intranasally with RSV-A (Memphis 37b). Assessments included viral load (VL), RSV infections, clinical symptom score (CSS), safety, and immunogenicity. RESULTS: Postchallenge, VL, RSV infections, and disease severity were lower in Ad26.RSV.preF (n = 27) vs placebo (n = 26) recipients: median VL area under the curve (AUC) quantitative real-time polymerase chain reaction: 0.0 vs 236.0 (P = .012; predefined primary endpoint); median VL-AUC quantitative culture: 0.0 vs 109; RSV infections 11 (40.7%) vs 17 (65.4%); median RSV AUC-CSS 35 vs 167, respectively. From baseline to 28 days postimmunization, geometric mean fold increases in RSV A2 neutralizing antibody titers of 5.8 and 0.9 were observed in Ad26.RSV.preF and placebo, respectively. Ad26.RSV.preF was well tolerated. CONCLUSIONS: Ad26.RSV.preF demonstrated protection from RSV infection through immunization in a human challenge model, and therefore could potentially protect against natural RSV infection and disease. CLINICAL TRIALS REGISTRATION: NCT03334695; CR108398, 2017-003194-33 (EudraCT); VAC18193RSV2002.

Four Artemisinin-Based Treatments in African Pregnant Women with Malaria.

BACKGROUND: Information regarding the safety and efficacy of artemisinin combination treatments for malaria in pregnant women is limited, particularly among women who live in sub-Saharan Africa. METHODS: We conducted a multicenter, randomized, open-label trial of treatments for malaria in pregnant women in four African countries. A total of 3428 pregnant women in the second or third trimester who had falciparum malaria (at any parasite density and regardless of symptoms) were treated with artemether-lumefantrine, amodiaquine-artesunate, mefloquine-artesunate, or dihydroartemisinin-piperaquine. The primary end points were the polymerase-chain-reaction (PCR)-adjusted cure rates (i.e., cure of the original infection; new infections during follow-up were not considered to be treatment failures) at day 63 and safety outcomes. RESULTS: The PCR-adjusted cure rates in the per-protocol analysis were 94.8% in the artemether-lumefantrine group, 98.5% in the amodiaquine-artesunate group, 99.2% in the dihydroartemisinin-piperaquine group, and 96.8% in the mefloquine-artesunate group; the PCR-adjusted cure rates in the intention-to-treat analysis were 94.2%, 96.9%, 98.0%, and 95.5%, respectively. There was no significant difference among the amodiaquine-artesunate group, dihydroartemisinin-piperaquine group, and the mefloquine-artesunate group. The cure rate in the artemether-lumefantrine group was significantly lower than that in the other three groups, although the absolute difference was within the 5-percentage-point margin for equivalence. The unadjusted cure rates, used as a measure of the post-treatment prophylactic effect, were significantly lower in the artemether-lumefantrine group (52.5%) than in groups that received amodiaquine-artesunate (82.3%), dihydroartemisinin-piperaquine (86.9%), or mefloquine-artesunate (73.8%). No significant difference in the rate of serious adverse events and in birth outcomes was found among the treatment groups. Drug-related adverse events such as asthenia, poor appetite, dizziness, nausea, and vomiting occurred significantly more frequently in the mefloquine-artesunate group (50.6%) and the amodiaquine-artesunate group (48.5%) than in the dihydroartemisinin-piperaquine group (20.6%) and the artemether-lumefantrine group (11.5%) (P<0.001 for comparison among the four groups). CONCLUSIONS: Artemether-lumefantrine was associated with the fewest adverse effects and with acceptable cure rates but provided the shortest post-treatment prophylaxis, whereas dihydroartemisinin-piperaquine had the best efficacy and an acceptable safety profile. (Funded by the European and Developing Countries Clinical Trials Partnership and others; ClinicalTrials.gov number, NCT00852423.).

Arsenic, antimony, and Leishmania: has arsenic contamination of drinking water in India led to treatment- resistant kala-azar?

BACKGROUND: In Bihar state, India, the cure rate of antimonial compounds (eg, sodium stibogluconate) in the treatment of visceral leishmaniasis (VL) has fallen from more than 85% to less than 50%. This reduction has been attributed to long-term, widespread misuse of antimonial drugs within the Indian private health-care system. We aimed to test the hypothesis that exposure to arsenic in drinking water in this region has resulted in antimony-resistant Leishmania parasites. METHODS: L donovani parasites were serially passaged in mice exposed to environmentally relevant concentrations of arsenic in drinking water. Arsenic concentrations in murine organs were quantified and the sensitivity of L donovani to sodium stibogluconate assessed at each passage. A retrospective field study on a cohort of antimony-treated patients with VL was performed in an arsenic-contaminated area of Bihar to assess risk of treatment failure and death in people exposed to arsenic. FINDINGS: Arsenic accumulation in organs of exposed mice was proportional to exposure level. After five passages, isolated parasites were refractory to sodium stibogluconate in in-vitro drug sensitivity assays. Treatment of arsenic exposed, infected mice with this drug confirmed that these parasites retained resistance in vivo. In the field work study, 110 patients with VL treated with sodium stibogluconate, failure rate was 59%. Patients using well water with high mean arsenic concentrations had a higher risk of treatment failure than patients using wells with arsenic levels of less than 10 µg/L (odds ratio 1·78, 95% CI 0·7-4·6, p=0·23). 21 patients died, 16 directly as a result of their disease. Mean arsenic concentrations of more than 10 µg/L increased the risk of all-cause and VL-related mortality (hazard ratio 3·27, 95% CI 1·4-8·1, and 2·65, 0·96-7·65, respectively). INTERPRETATION: These data suggest that arsenic contamination might have contributed to the development of antimonial resistance in Leishmania parasites in Bihar. Our epidemiological study was underpowered and retrospective in nature, so firm conclusions cannot be made. Further research into the associations between arsenic exposure and antimonial treatment failure and death in the leishmaniases is warranted. FUNDING: Wellcome Trust.

Design and analysis considerations in the Ebola_Tx trial evaluating convalescent plasma in the treatment of Ebola virus disease in Guinea during the 2014-2015 outbreak.

The Ebola virus disease outbreak in 2014-2015 led to a huge caseload with a high case fatality rate. No specific treatments were available beyond supportive care for conditions such as dehydration and shock. Evaluation of treatment with convalescent plasma from Ebola survivors was identified as a priority. We evaluated this intervention in an emergency setting, where randomization was unacceptable. The original trial design was an open-label study comparing patients receiving convalescent plasma and supportive care to patients receiving supportive care alone. The comparison group comprised patients recruited at the start of the trial before convalescent plasma became available, as well as patients presenting during the trial for whom there was insufficient blood group-compatible plasma or no staffing capacity to provide additional transfusions. However, during the trial, convalescent plasma was available to treat all new patients. The design was changed to use a comparator group comprising patients previously treated at the same Ebola treatment center prior to the start of the trial. In the analysis, it was planned to adjust for any differences in prognostic variables between intervention and comparison groups, specifically baseline polymerase chain reaction cycle threshold and age. In addition, adjustment was planned for other potential confounders, identified in the analysis, such as patient presenting symptoms and time to treatment seeking. Because plasma treatment started up to 3 days after diagnosis and we could not define a similar time-point for the comparator group, patients who died before the third day after confirmation of diagnosis were excluded from both intervention and comparison groups in a per-protocol analysis. Some patients received additional experimental treatments soon after plasma treatment, and these were excluded. We also analyzed mortality including all patients from the time of confirmed diagnosis, irrespective of whether those in the trial series actually received plasma, as an intention-to-treat analysis. Per-protocol and intention-to-treat approaches gave similar conclusions. An important caveat in the interpretation of the findings is that it is unlikely that all potential sources of confounding, such as any variation in supportive care over time, were eliminated. Protocols and electronic data capture systems have now been extensively field-tested for emergency evaluation of treatment with convalescent plasma. Ongoing studies seek to quantify the level of neutralizing antibodies in different plasma donations to determine whether this influences the response and survival of treated patients.

Lower Levels of Antiretroviral Therapy Enrollment Among Men with HIV Compared with Women - 12 Countries, 2002-2013.

Equitable access to antiretroviral therapy (ART) for men and women with human immunodeficiency virus (HIV) infection is a principle endorsed by most countries and funding bodies, including the U.S. President's Emergency Plan for AIDS (acquired immunodeficiency syndrome) Relief (PEPFAR) (1). To evaluate gender equity in ART access among adults (defined for this report as persons aged ≥15 years), 765,087 adult ART patient medical records from 12 countries in five geographic regions* were analyzed to estimate the ratio of women to men among new ART enrollees for each calendar year during 2002-2013. This annual ratio was compared with estimates from the Joint United Nations Programme on HIV/AIDS (UNAIDS)(†) of the ratio of HIV-infected adult women to men in the general population. In all 10 African countries and Haiti, the most recent estimates of the ratio of adult women to men among new ART enrollees significantly exceeded the UNAIDS estimates for the female-to-male ratio among HIV-infected adults by 23%-83%. In six African countries and Haiti, the ratio of women to men among new adult ART enrollees increased more sharply over time than the estimated UNAIDS female-to-male ratio among adults with HIV in the general population. Increased ART coverage among men is needed to decrease their morbidity and mortality and to reduce HIV incidence among their sexual partners. Reaching more men with HIV testing and linkage-to-care services and adoption of test-and-treat ART eligibility guidelines (i.e., regular testing of adults, and offering treatment to all infected persons with ART, regardless of CD4 cell test results) could reduce gender inequity in ART coverage.

A general framework for comparative Bayesian meta-analysis of diagnostic studies.

BACKGROUND: Selecting the most effective diagnostic method is essential for patient management and public health interventions. This requires evidence of the relative performance of alternative tests or diagnostic algorithms. Consequently, there is a need for diagnostic test accuracy meta-analyses allowing the comparison of the accuracy of two or more competing tests. The meta-analyses are however complicated by the paucity of studies that directly compare the performance of diagnostic tests. A second complication is that the diagnostic accuracy of the tests is usually determined through the comparison of the index test results with those of a reference standard. These reference standards are presumed to be perfect, i.e. allowing the classification of diseased and non-diseased subjects without error. In practice, this assumption is however rarely valid and most reference standards show false positive or false negative results. When an imperfect reference standard is used, the estimated accuracy of the tests of interest may be biased, as well as the comparisons between these tests. METHODS: We propose a model that allows for the comparison of the accuracy of two diagnostic tests using direct (head-to-head) comparisons as well as indirect comparisons through a third test. In addition, the model allows and corrects for imperfect reference tests. The model is inspired by mixed-treatment comparison meta-analyses that have been developed for the meta-analysis of randomized controlled trials. As the model is estimated using Bayesian methods, it can incorporate prior knowledge on the diagnostic accuracy of the reference tests used. RESULTS: We show the bias that can result from using inappropriate methods in the meta-analysis of diagnostic tests and how our method provides more correct estimates of the difference in diagnostic accuracy between two tests. As an illustration, we apply this model to a dataset on visceral leishmaniasis diagnostic tests, comparing the accuracy of the RK39 dipstick with that of the direct agglutination test. CONCLUSIONS: Our proposed meta-analytic model can improve the comparison of the diagnostic accuracy of competing tests in a systematic review. This is however only true if the studies and especially information on the reference tests used are sufficiently detailed. More specifically, the type and exact procedures used as reference tests are needed, including any cut-offs used and the number of subjects excluded from full reference test assessment. If this information is lacking, it may be better to limit the meta-analysis to direct comparisons.

The significance of Lactobacillus crispatus and L. vaginalis for vaginal health and the negative effect of recent sex: a cross-sectional descriptive study across groups of African women.

BACKGROUND: Women in sub-Saharan Africa are vulnerable to acquiring HIV infection and reproductive tract infections. Bacterial vaginosis (BV), a disruption of the vaginal microbiota, has been shown to be strongly associated with HIV infection. Risk factors related to potentially protective or harmful microbiota species are not known. METHODS: We present cross-sectional quantitative polymerase chain reaction data of the Lactobacillus genus, five Lactobacillus species, and three BV-related bacteria (Gardnerella vaginalis, Atopobium vaginae, and Prevotella bivia) together with Escherichia coli and Candida albicans in 426 African women across different groups at risk for HIV. We selected a reference group of adult HIV-negative women at average risk for HIV acquisition and compared species variations in subgroups of adolescents, HIV-negative pregnant women, women engaging in traditional vaginal practices, sex workers and a group of HIV-positive women on combination antiretroviral therapy. We explored the associations between presence and quantity of the bacteria with BV by Nugent score, in relation to several factors of known or theoretical importance. RESULTS: The presence of species across Kenyan, South African and Rwandan women was remarkably similar and few differences were seen between the two groups of reference women in Kenya and South Africa. The Rwandan sex workers and HIV-positive women had the highest G. vaginalis presence (p = 0.006). Pregnant women had a higher Lactobacillus genus mean log (7.01 genome equivalents (geq)/ml) compared to the reference women (6.08 geq/ml). L. vaginalis (43%) was second to L. iners (81.9%) highly present in women with a normal Nugent score. Recent sexual exposure negatively affected the presence of L. crispatus (<0.001), L. vaginalis (p = 0.001), and Lactobacillus genus (p < 0.001). Having more than one sexual partner in the last three months was associated with an increased prevalence of G. vaginalis (p = 0.044) and L. iners (p = 0.001). CONCLUSIONS: Although the composition of species across the studied African countries was similar, the presence of protective species i.e. L. crispatus and L. vaginalis in women with a normal Nugent score appeared lower compared to non-African studies. Furthermore, Lactobacillus species were negatively affected by sexual behavioural. Strategies to support protective Lactobacillus species are urgently needed. TRIAL REGISTRATION: The study is registered at the Trial Registration at the National Health Research Ethics Council South Africa with the number DOH2709103223.

Correlates of the molecular vaginal microbiota composition of African women.

BACKGROUND: Sociodemographic, behavioral and clinical correlates of the vaginal microbiome (VMB) as characterized by molecular methods have not been adequately studied. VMB dominated by bacteria other than lactobacilli may cause inflammation, which may facilitate HIV acquisition and other adverse reproductive health outcomes. METHODS: We characterized the VMB of women in Kenya, Rwanda, South Africa and Tanzania (KRST) using a 16S rDNA phylogenetic microarray. Cytokines were quantified in cervicovaginal lavages. Potential sociodemographic, behavioral, and clinical correlates were also evaluated. RESULTS: Three hundred thirteen samples from 230 women were available for analysis. Five VMB clusters were identified: one cluster each dominated by Lactobacillus crispatus (KRST-I) and L. iners (KRST-II), and three clusters not dominated by a single species but containing multiple (facultative) anaerobes (KRST-III/IV/V). Women in clusters KRST-I and II had lower mean concentrations of interleukin (IL)-1α (p < 0.001) and Granulocyte Colony Stimulating Factor (G-CSF) (p = 0.01), but higher concentrations of interferon-γ-induced protein (IP-10) (p < 0.01) than women in clusters KRST-III/IV/V. A lower proportion of women in cluster KRST-I tested positive for bacterial sexually transmitted infections (STIs; ptrend = 0.07) and urinary tract infection (UTI; p = 0.06), and a higher proportion of women in clusters KRST-I and II had vaginal candidiasis (ptrend = 0.09), but these associations did not reach statistical significance. Women who reported unusual vaginal discharge were more likely to belong to clusters KRST-III/IV/V (p = 0.05). CONCLUSION: Vaginal dysbiosis in African women was significantly associated with vaginal inflammation; the associations with increased prevalence of STIs and UTI, and decreased prevalence of vaginal candidiasis, should be confirmed in larger studies.

The ring plus project: safety and acceptability of vaginal rings that protect women from unintended pregnancy.

BACKGROUND: Research is ongoing to develop multipurpose vaginal rings to be used continuously for contraception and to prevent Human Immunodeficiency Virus (HIV) infection. Contraceptive vaginal rings (CVRs) are available in a number of countries and are most of the time used intermittently i.e. three weeks out of a 4-week cycle. Efficacy trials with a dapivirine-containing vaginal ring for HIV prevention are ongoing and plans to develop multi-purpose vaginal rings for prevention of both HIV and pregnancy have been elaborated. In contrast with the CVRs, multi-purpose vaginal rings will have to be used continuously. Women who continuously use a CVR will no longer have menses. Furthermore, some safety aspects of CVR use have never been studied in-depth in the past, such as the impact of the vaginal ring on the vaginal microbiota, biofilm formation and induction of inflammation. We studied acceptability and these novel aspects of safety in Rwandan women. Although significant progress has been made over the past decade, Rwanda still has a high unmet need for contraception (with 47% unplanned births) and a generalized HIV epidemic, and CVRs are not yet available. METHODS: We will conduct an open label, single centre, randomized controlled trial. A total of 120 HIV-negative women will be randomized to intermittent CVR use (to allow menstruation) or continuous CVR use. Women will be followed for a maximum of 14 weeks. In parallel, we will conduct a qualitative study using in-depth interview and focus group discussion methodology. DISCUSSION: In addition to evaluating the safety and acceptability of intermittent and continuous CVR use in Rwandan women, we hope that our findings will inform the development of future multipurpose vaginal rings, will prepare Rwandan study populations for future clinical trials of multipurpose vaginal rings, and will pave the way for introduction of CVRs on African markets. TRIAL REGISTRATION: Clinicaltrials.gov NCT01796613 . Registered 14 February 2013.

Safe and efficacious artemisinin-based combination treatments for African pregnant women with malaria: a multicentre randomized control trial.

BACKGROUND: Asymptomatic and symptomatic malaria during pregnancy has consequences for both mother and her offspring. Unfortunately, there is insufficient information on the safety and efficacy of most antimalarials in pregnancy. Indeed, clinical trials assessing antimalarial treatments systematically exclude pregnancy for fear of teratogenicity and embryotoxicity. The little available information originates from South East Asia while in sub-Saharan Africa such information is still limited and needs to be provided. DESIGN: A Phase 3, non-inferiority, multicentre, randomized, open-label clinical trial on safety and efficacy of 4 ACT when administered during pregnancy was carried out in 4 African countries: Burkina Faso, Ghana, Malawi and Zambia. This is a four arm trial using a balanced incomplete block design. Pregnant women diagnosed with malaria are randomised to receive either amodiaquine-artesunate (AQ-AS), dihydroartemisinin-piperaquine (DHA-PQ), artemether-lumefantrine (AL), or mefloquine-artesunate (MQAS). They are actively followed up until day 63 post-treatment and then monthly until 4-6 weeks post-delivery. The offspring is visited at the time of the first birthday. The primary endpoint is treatment failure (PCR adjusted) at day 63 and safety profiles. Secondary endpoints included PCR unadjusted treatment failure up to day 63, gametocyte carriage, Hb changes, placenta malaria, mean birth weight and low birth weight. The primary statistical analysis will use the combined data from all 4 centres, with adjustment for any centre effects, using an additive model for the response rates. This will allow the assessment of all 6 possible pair-wise treatment comparisons using all available data. DISCUSSION: The strength of this trial is the involvement of several African countries, increasing the generalisability of the results. In addition, it assesses most ACTs currently available, determining their relative '-value-' compared to others. The balanced incomplete block design was chosen because using all 4-arms in each site would have increased complexity in terms of implementation. Excluding HIV-positive pregnant women on antiretroviral drugs may be seen as a limitation because of the possible interactions between antiretroviral and antimalarial treatments. Nevertheless, the results of this trial will provide the evidence base for the formulation of malaria treatment policy for pregnant women in sub-Saharan Africa.

Retention and risk factors for attrition among adults in antiretroviral treatment programmes in Tanzania, Uganda and Zambia.

OBJECTIVES: We assessed retention and predictors of attrition (recorded death or loss to follow-up) in antiretroviral treatment (ART) clinics in Tanzania, Uganda and Zambia. METHODS: We conducted a retrospective cohort study among adults (≥18 years) starting ART during 2003-2010. We purposefully selected six health facilities per country and randomly selected 250 patients from each facility. Patients who visited clinics at least once during the 90 days before data abstraction were defined as retained. Data on individual and programme level risk factors for attrition were obtained through chart review and clinic manager interviews. Kaplan-Meier curves for retention across sites were created. Predictors of attrition were assessed using a multivariable Cox-proportional hazards model, adjusted for site-level clustering. RESULTS: From 17 facilities, 4147 patients were included. Retention ranged from 52.0% to 96.2% at 1 year to 25.8%-90.4% at 4 years. Multivariable analysis of ART initiation characteristics found the following independent risk factors for attrition: younger age [adjusted hazard ratio (aHR) and 95% confidence interval (95%CI) = 1.30 (1.14-1.47)], WHO stage 4 ([aHR (95% CI): 1.56 (1.29-1.88)], >10% bodyweight loss [aHR (95%CI) = 1.17 (1.00-1.38)], poor functional status [ambulatory aHR (95%CI) = 1.29 (1.09-1.54); bedridden aHR1.54 (1.15-2.07)], and increasing years of clinic operation prior to ART initiation in government facilities [aHR (95%CI) = 1.17 (1.10-1.23)]. Patients with higher CD4 cell count were less likely to experience attrition [aHR (95%CI) = 0.88 (0.78-1.00)] for every log (tenfold) increase. Sites offering community ART dispensing [aHR (95%CI) = 0.55 (0.30-1.01) for women; 0.40 (0.21-0.75) for men] had significantly less attrition. CONCLUSIONS: Patient retention to an individual programme worsened over time especially among males, younger persons and those with poor clinical indicators. Community ART drug dispensing programmes could improve retention.

Antiretroviral therapy enrollment characteristics and outcomes among HIV-infected adolescents and young adults compared with older adults--seven African countries, 2004-2013.

Although scale-up of antiretroviral therapy (ART) since 2005 has contributed to declines of about 30% in the global annual number of human immunodeficiency (HIV)-related deaths and declines in global HIV incidence, estimated annual HIV-related deaths among adolescents have increased by about 50% and estimated adolescent HIV incidence has been relatively stable. In 2012, an estimated 2,500 (40%) of all 6,300 daily new HIV infections occurred among persons aged 15-24 years. Difficulty enrolling adolescents and young adults in ART and high rates of loss to follow-up (LTFU) after ART initiation might be contributing to mortality and HIV incidence in this age group, but data are limited. To evaluate age-related ART retention challenges, data from retrospective cohort studies conducted in seven African countries among 16,421 patients, aged ≥15 years at enrollment, who initiated ART during 2004-2012 were analyzed. ART enrollment and outcome data were compared among three groups defined by age at enrollment: adolescents and young adults (aged 15-24 years), middle-aged adults (aged 25-49 years), and older adults (aged ≥50 years). Enrollees aged 15-24 years were predominantly female (81%-92%), commonly pregnant (3%-32% of females), unmarried (54%-73%), and, in four countries with employment data, unemployed (53%-86%). In comparison, older adults were more likely to be male (p<0.001), employed (p<0.001), and married, (p<0.05 in five countries). Compared with older adults, adolescents and young adults had higher LTFU rates in all seven countries, reaching statistical significance in three countries in crude and multivariable analyses. Evidence-based interventions to reduce LTFU for adolescent and young adult ART enrollees could help reduce mortality and HIV incidence in this age group.

Rapid tests for the diagnosis of visceral leishmaniasis in patients with suspected disease.

BACKGROUND: The diagnosis of visceral leishmaniasis (VL) in patients with fever and a large spleen relies on showing Leishmania parasites in tissue samples and on serological tests. Parasitological techniques are invasive, require sophisticated laboratories, consume time, or lack accuracy. Recently, rapid diagnostic tests that are easy to perform have become available. OBJECTIVES: To determine the diagnostic accuracy of rapid tests for diagnosing VL in patients with suspected disease presenting at health services in endemic areas. SEARCH METHODS: We searched MEDLINE, EMBASE, LILACS, CIDG SR, CENTRAL, SCI-expanded, Medion, Arif, CCT, and the WHO trials register on 3 December 2013, without applying language or date limits. SELECTION CRITERIA: This review includes original, phase III, diagnostic accuracy studies of rapid tests in patients clinically suspected to have VL. As reference standards, we accepted: (1) direct smear or culture of spleen aspirate; (2) composite reference standard based on one or more of the following: parasitology, serology, or response to treatment; and (3) latent class analysis. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed quality of included studies using the QUADAS-2 tool. Discrepancies were resolved by a third author. We carried out a meta-analysis to estimate sensitivity and specificity of rapid tests, using a bivariate normal model with a complementary log-log link function. We analysed each index test separately. As possible sources of heterogeneity, we explored: geographical area, commercial brand of index test, type of reference standard, disease prevalence, study size, and risk of bias (QUADAS-2). We also undertook a sensitivity analysis to assess the influence of imperfect reference standards. MAIN RESULTS: Twenty-four studies containing information about five index tests (rK39 immunochromatographic test (ICT), KAtex latex agglutination test in urine, FAST agglutination test, rK26 ICT, and rKE16 ICT) recruiting 4271 participants (2605 with VL) were included. We carried out a meta-analysis for the rK39 ICT (including 18 studies; 3622 participants) and the latex agglutination test (six studies; 1374 participants). The results showed considerable heterogeneity. For the rK39 ICT, the overall sensitivity was 91.9% (95% confidence interval (95% CI) 84.8 to 96.5) and the specificity 92.4% (95% CI 85.6 to 96.8). The sensitivity was lower in East Africa (85.3%; 95% CI 74.5 to 93.2) than in the Indian subcontinent (97.0%; 95% CI 90.0 to 99.5). For the latex agglutination test, overall sensitivity was 63.6% (95% CI 40.9 to 85.6) and specificity 92.9% (95% CI 76.7 to 99.2). AUTHORS' CONCLUSIONS: The rK39 ICT shows high sensitivity and specificity for the diagnosis of visceral leishmaniasis in patients with febrile splenomegaly and no previous history of the disease, but the sensitivity is notably lower in east Africa than in the Indian subcontinent. Other rapid tests lack accuracy, validation, or both.

Could prophylactic antivirals reduce dengue incidence in a high-prevalence endemic area?

Prophylactic drugs against dengue are currently under development. In this study, we explored how such prophylactic approaches might affect dengue cases in four communes of Nha Trang City, Vietnam. A community level dengue transmission survey indicated high levels of previous exposure to dengue (89.7%; 95% CI: 87.2,92.0). We fitted a spatially explicit model to an observed outbreak and simulated likely effectiveness of Case-Area Targeted Interventions (CATI) and One-Time Mass Distribution (OTMD) of drug and vector control strategies. Increasing radius and effectiveness and decreasing delay of CATI was most effective, with drugs being more effective in averting dengue cases than vector control. Using an OTMD approach early in the outbreak required the least number of treatments to avert a case, suggesting that OTMD strategies should be considered as pre-emptive rather than reactive strategies. These findings show that pre-emptive interventions can substantially reduce the burden of dengue outbreaks in endemic settings.

Stage determination in sleeping sickness: comparison of two cell counting and two parasite detection techniques.

OBJECTIVES: Diagnosis of the neurological stage of human African trypanosomiasis is performed by examination of cerebrospinal fluid (CSF) for the presence of trypanosomes and numbers of white blood cells (WBC). Both CSF parameters are also used to assess treatment outcome during follow-up. In view of the importance of CSF examination, and the practical problems encountered with it, we compared the sensitivity of two trypanosome concentration techniques and the repeatability of two cell counting methods, as well as occurrence of systematic differences between them. METHODS: Patients were recruited at Dipumba hospital, in Mbuji-Mayi in the Democratic Republic of the Congo. In 94 CSF samples, trypanosome detection was performed with modified single centrifugation (MSC) and double centrifugation (DC). On 189 CSF samples with ≤30 cells/µl, cell counting was performed in duplicate in a Fuchs-Rosenthal counting chamber and in a disposable Uriglass counting chamber. RESULTS: Modified single centrifugation detected trypanosomes in significantly (P < 0.0001) more patients (85) than DC (46). Cell counts did not differ systematically in the two methods. Variability in the differences between duplicate cell counts was significantly higher (P = 0.002) in Uriglass (SD of differences 2.03) than in Fuchs-Rosenthal (SD of differences 1.62). CONCLUSIONS: For analysis of CSF in the context of sleeping sickness stage determination and follow-up after treatment, we strongly recommend the MSC for parasite detection and the application of disposable counting chambers. When the first cell count is ≤20 cells/µl, we recommend repeating the counting procedure on the same CSF specimen and taking the average of both countings.

Challenges of non-commercial multicentre North-South collaborative clinical trials.

The last decade has witnessed a substantial increase of multi-centre, public health-oriented clinical trials in poor countries. However, non-commercial research groups have less staff and financial resources than traditional commercial sponsors, so the trial teams have to be creative to comply with Good Clinical Practices (GCP) requirements. According to the recent experience of a large multicentre trial on antimalarials, major challenges result from the complexity of multiple ethical review, the costs of in-depth monitoring at several sites, setting up an adequate Good Clinical Laboratory Practices (GCLP) framework, lack of insurers in host countries, and lack of adequate non-commercial data management software. Public research funding agencies need to consider these challenges in their funding policies. They also could support common spaces where North-South collaborative research groups may share critical information, such as on research insurance and open-source, GCP-compliant software. WHO should update its GCP guidelines, which date back to 1995, to incorporate the perspectives and needs of non-commercial clinical research.

Clinical signs and symptoms cannot reliably predict Plasmodium falciparum malaria infection in pregnant women living in an area of high seasonal transmission.

BACKGROUND: Malaria in pregnancy is a major public health problem in endemic countries. Though the signs and symptoms of malaria among pregnant women have been already described, clinical presentation may vary according to intensity of transmission and local perceptions. Therefore, determining common signs and symptoms among pregnant women with a malaria infection may be extremely useful to identify those in need of further investigation by rapid diagnostic test or microscopy. METHODS: Six hundred pregnant women attending the maternity clinic of Nanoro District Hospital, Burkina Faso were recruited, 200 with suspected clinical malaria and 400 as controls. Cases were matched with controls by gestational age and parity. Signs and symptoms were collected and a blood sample taken for rapid diagnostic test, microscopy and haemoglobin measurement. A multivariate model was used to assess the predictive value of signs and symptoms for malaria infection. RESULTS: The overall prevalence of malaria was 42.6% (256/600) while anaemia was found in 60.8% (365/600) of the women. Nearly half (49%) of the cases and 39.5% of the controls had a malaria infection (p = 0.03). The most common signs and symptoms among the cases were fever (36%,72/200), history of fever (29%,58/200) and headache (52%,104/200). The positive predictive value for fever was 53% (95% CI:41-64), history of fever 58% (95% CI:37-63) and headache 51% (95% CI:41-61). CONCLUSION: Signs and symptoms suggestive of malaria are frequent among pregnant women living in areas of intense transmission. Common malaria symptoms are not strong predictors of infection. For a better management of malaria in pregnancy, active screening to detect and treat malaria infection early should be performed on all pregnant women attending a health facility.

A global comparative evaluation of commercial immunochromatographic rapid diagnostic tests for visceral leishmaniasis.

BACKGROUND: Poor access to diagnosis stymies control of visceral leishmaniasis (VL). Antibody-detecting rapid diagnostic tests (RDTs) can be performed in peripheral health settings. However, there are many brands available and published reports of variable accuracy. METHODS: Commercial VL RDTs containing bound rK39 or rKE16 antigen were evaluated using archived human sera from confirmed VL cases (n = 750) and endemic non-VL controls (n = 754) in the Indian subcontinent (ISC), Brazil, and East Africa to assess sensitivity and specificity with 95% confidence intervals. A subset of RDTs were also evaluated after 60 days' heat incubation (37°C, 45°C). Interlot and interobserver variability was assessed. RESULTS: All test brands performed well against ISC panels (sensitivity range, 92.8%-100%; specificity range, 96%-100%); however, sensitivity was lower against Brazil and East African panels (61.5%-91% and 36.8%-87.2%, respectively). Specificity was consistently > 95% in Brazil and ranged between 90.8% and 98% in East Africa. Performance of some products was adversely affected by high temperatures. Agreement between lots and readers was good to excellent (κ > 0.73-0.99). CONCLUSIONS: Diagnostic accuracy of VL RDTs varies between the major endemic regions. Many tests performed well and showed good heat stability in the ISC; however, reduced sensitivity against Brazilian and East African panels suggests that in these regions, used alone, several RDTs are inadequate for excluding a VL diagnosis. More research is needed to assess ease of use and to compare performance using whole blood instead of serum and in patients coinfected with human immunodeficiency virus.

Visceral leishmaniasis in rural bihar, India.

To identify factors associated with incidence of visceral leishmaniasis (VL), we surveyed 13,416 households in Bihar State, India. VL was associated with socioeconomic status, type of housing, and belonging to the Musahar caste. Annual coverage of indoor residual insecticide spraying was 12%. Increasing such spraying can greatly contribute to VL control.