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To achieve compliance with the revised World Health Organization International Health Regulations (IHR 2005), countries must be able to rapidly prevent, detect, and respond to public health threats. Most nations, however, remain unprepared to manage and control complex health emergencies, whether due to natural disasters, emerging infectious disease outbreaks, or the inadvertent or intentional release of highly pathogenic organisms. The US Centers for Disease Control and Prevention (CDC) works with countries and partners to build and strengthen global health security preparedness so they can quickly respond to public health crises. This report highlights selected CDC global health protection platform accomplishments that help mitigate global health threats and build core, cross-cutting capacity to identify and contain disease outbreaks at their source. CDC contributions support country efforts to achieve IHR 2005 compliance, contribute to the international framework for countering infectious disease crises, and enhance health security for Americans and populations around the world. [ABSTRACT FROM AUTHOR]

The Joint External Evaluation (JEE), a consolidation of the World Health Organization (WHO) International Health Regulations 2005 (IHR 2005) Monitoring and Evaluation Framework and the Global Health Security Agenda country assessment tool, is an objective, voluntary, independent peer-to-peer multisectoral assessment of a country's health security preparedness and response capacity across 19 IHR technical areas. WHO approved the standardized JEE tool in February 2016. The JEE process is wholly transparent; countries request a JEE and are encouraged to make its findings public. Donors (e.g., member states, public and private partners, and other public health institutions) can support countries in addressing identified JEE gaps, and implementing country-led national action plans for health security. Through July 2017, 52 JEEs were completed, and 25 more countries were scheduled across WHO's 6 regions. JEEs facilitate progress toward IHR 2005 implementation, thereby building trust and mutual accountability among countries to detect and respond to public health threats. [ABSTRACT FROM AUTHOR]

Background: The combination of short-acting dihydroartemisinin and long-acting piperaquine (DP) is among the first-line therapies for the treatment of uncomplicated Plasmodium falciparum malaria. Population pharmacokinetic models of piperaquine (PQ) based on data from acute treatment of young children can be used to predict exposure profiles of piperaquine under different DP chemoprevention regimens. The purpose of our study was to make such predictions in young children. Methods: Based on a prior population pharmacokinetic model of PQ in young Ugandan children, we simulated capillary plasma concentration-time profiles (including their variability) of candidate chemoprevention regimens for a reference population of 1–2 year olds weighing at least 11 kg. Candidate regimens that were tested included monthly administration of standard therapeutic doses, bimonthly dosing, and weekly dosing (with and without a loading dose). Results: Once daily doses of 320 mg for three days (960 mg total) at the beginning of each month are predicted to achieve an average steady-state trough capillary piperaquine concentration of 35 ng/mL, with 60% achieving a level of 30 ng/mL or higher. In contrast, weekly dosing of 320 mg (i.e., 33% higher amount per month) is predicted to approximately double the average steady-state trough concentration, increase the percent of children predicted to achieve 30 ng/mL or higher (94%), while at the same time lowering peak concentrations. Exposure at steady-state, reached at approximately 3 months of multiple dosing, is expected to be approximately 2-fold higher than exposure following initial dosing, due to accumulation. A loading dose improves early exposure, thereby reducing the risk of breakthrough infections at the initiation of chemoprevention. Conclusions: Once weekly chemoprevention of DP predicts favourable exposures with respect to both trough and peak concentrations. These predictions need to be verified, as well as safety evaluated, in field-based clinical studies of young children. Simulations based on prior knowledge provide a systematic information-driven approach to evaluate candidate DP chemopreventive regimens for future trial designs. [ABSTRACT FROM AUTHOR]

The article focuses on global health and the global health strategy of the U.S. Centers for Disease Control and Prevention (CDC) as of July 2014. Topics discussed include the role of CDC in the U.S. President's Emergency Plan for AIDS Relief (PEPFAR), the CDC Option B+ approach to prevent mother-to-child transmission of Human Immunodeficiency Virus (HIV) in Malawi, and its collaboration with China's influenza scientists and public health authorities.

The article discusses a global health security (GHS) project conducted in Uganda in March to September 2013 by the U.S. Centers for Disease Control and Prevention (CDC), the World Health Organization (WHO), and the Uganda Ministry of Health (MoH). Topics addressed include the increased capacity of Ugandan laboratories' diagnostic and specimen referral networks, enhancing communications and information systems for outbreak response, and developing a public health emergency operations center.

After epidemic cholera emerged in Haiti in October 2010, the disease spread rapidly in a country devastated by an earthquake earlier that year, in a population with a high proportion of infant deaths, poor nutrition, and frequent infectious diseases such as HIV infection, tuberculosis, and malaria. Many nations, multinational agencies, and nongovernmental organizations rapidly mobilized to assist Haiti. The US government provided emergency response through the Office of Foreign Disaster Assistance of the US Agency for International Development and the Centers for Disease Control and Prevention. This report summarizes the participation by the Centers and its partners. The efforts needed to reduce the spread of the epidemic and prevent deaths highlight the need for safe drinking water and basic medical care in such difficult circumstances and the need for rebuilding water, sanitation, and public health systems to prevent future epidemics. [ABSTRACT FROM AUTHOR]

Background. We conducted a pharmacokinetic study of antimycobacterial drugs involving a cohort of patients with pulmonary tuberculosis (TB) in Gaborone, Botswana, to assess the prevalence of and risk factors for low drug concentrations in serum. Methods. Adults participated if they had a history of cough fl weeks, had abnormal chest radiograph findings, consented to testing for human immunodeficiency virus (HIV), had sputum cultures positive for Mycobacterium tuberculosis, and were receiving antituberculous therapy for >7 days. Observed maximum serum concentrations were compared with published normal ranges. Results. Of 91 patients enrolled, 89 (98%) were outpatients, and 59 (68%) of 87 patients tested had HIV infection. The following numbers of patients had low serum concentrations of the following drugs: isoniazid, 27 (30%) of 90; rifampin, 71(78%) of 91; ethambutol, 37 (41%) of 91; and pyrazinamide, 1 (1%) of 91. Low serum concentrations of both isoniazid and rifampin occurred in 23 (26%) of 90 patients. Low serum concentrations of rifampin were found in both HIV-infected and non-HIV-infected patients, and such patients were less likely to have >4 weeks of symptoms, more likely to have lymphadenopathy, and more likely to have low serum albumin levels (P < .05 for all). The associations with noncavitary pulmonary disease (P = .12) and HIV infection (P = .07) did not reach statistical significance. Delayed absorption was most common with ethambutol, followed by rifampin. Conclusions. These data, predominantly from HIV-infected patients with TB, suggest that low isoniazid, rifampin, and ethambutol concentrations are common in Botswana. In contrast, pyrazinamide usually is well absorbed. [ABSTRACT FROM AUTHOR]

Context: Meningococcal disease occurs worldwide, and serogroup B disease accounts for a large proportion of cases. Although persons younger than 4 years are at greatest risk for serogroup B meningococcal disease, vaccine efficacy has not been demonstrated in this age group.Objective: To evaluate serum bactericidal activity (SBA) against homologous vaccine type strains and a heterologous Chilean epidemic strain of Neisseria meningitidis as a potential correlate for vaccine efficacy.Design: Double-blind, randomized controlled trial conducted between March 14 and July 20, 1994. All blood samples were taken by December 1994.Setting: Santiago, Chile, where a clonal serogroup B meningococcal disease epidemic began in 1993.Participants: Infants younger than 1 year (n = 187), children aged 2 to 4 years (n = 183), and adults aged 17 to 30 years (n = 173).Intervention: Participants received 3 doses of outer-membrane protein (OMP) meningococcal vaccine developed in either Cuba or Norway or a control vaccine, with each dose given 2 months apart. Blood samples were obtained at baseline, prior to dose 3, and at 4 to 6 weeks after dose 3.Main Outcome Measure: Immune response, defined as a 4-fold or greater rise in SBA titer 4 to 6 weeks after dose 3 compared with prevaccination titer.Results: Children and adult recipients of either meningococcal vaccine were more likely than controls to develop an immune response to the heterologous epidemic strain. After 3 doses of vaccine, 31% to 35% of children responded to the vaccine vs 5% to placebo; 37% to 60% of adults responded to vaccine vs 4% to placebo (P<.05 vs control for all). Infants, however, did not respond. In contrast, against homologous vaccine type strains, the response rate was 67% or higher among children and adults and 90% or higher among infants (P<.001 vs control for all). Subsequent SBA against 7 isogenic homologous target strains identified class 1 OMP as the immunodominant antigen.Conclusions: These data suggest that neither serogroup B OMP meningococcal vaccine would confer protection during a heterologous epidemic. However, epidemic strain-specific vaccines homologous for class 1 OMP are promising candidates for the control of epidemic serogroup B meningococcal disease. [ABSTRACT FROM AUTHOR]

Evaluates the impact of prevention efforts against human listeriosis in the United States. Food-borne transmission as a major cause human listeriosis; Identification of cases in which Listeria monocytogenes was isolated from cultures or ordinarily sterile sites in an aggregate population of more than 19 million; Cases of perinatal and nonperinatal listeriosis.

Determines environmental risk factors for bacillary angiomatosis-bacillary peliosis (BAP) and confirm infection with Rochalimaea species. Case-control study of community and university hospitals and clinics; Data suggesting BAP is associated with traumatic exposure to cats and infection with Rochalimaea or a closely related organism.

The authors comment on the threat posed by infectious disease epidemics to several countries. Particular focus is given to the key elements of health security, as well as the revised International Health Regulations (IHR). Topics discussed include the economic impact of epidemic threats, keys to achieving rapid progress in health security, and Chinese efforts to improve detection of new threats. Also mentioned is the key lesson raised by previous health crises. INSET: Panel: Key global health security areas to prevent, detect,....

Examines the US Centers for Disease Control and Prevention's (CDC) national surveillance case definition for severe, unexplained adult respiratory distress syndrome (ARDS) due to Hantavirus pulmonary syndrome (HPS) using a toll-free telephone hotline number. Telephone inquiries; Identification of sporadic geographic distribution of HPS cases.

Focuses on a study that examined patients with cutaneous bacillary angiomatosis or bacillary splenitis without evidence of HIV infection. Characteristics of immunocompetent patients with bacillary angiomatosis and bacillary splenitis; Complications experienced by patients who lacked vascular lesions; Diagnosis of cutaneous bacillary angiomatosis in the patients.

The Joint External Evaluation (JEE), a consolidation of the World Health Organization (WHO) International Health Regulations 2005 (IHR 2005) Monitoring and Evaluation Framework and the Global Health Security Agenda country assessment tool, is an objective, voluntary, independent peer-to-peer multisectoral assessment of a country's health security preparedness and response capacity across 19 IHR technical areas. WHO approved the standardized JEE tool in February 2016. The JEE process is wholly transparent; countries request a JEE and are encouraged to make its findings public. Donors (e.g., member states, public and private partners, and other public health institutions) can support countries in addressing identified JEE gaps, and implementing country-led national action plans for health security. Through July 2017, 52 JEEs were completed, and 25 more countries were scheduled across WHO's 6 regions. JEEs facilitate progress toward IHR 2005 implementation, thereby building trust and mutual accountability among countries to detect and respond to public health threats. [ABSTRACT FROM AUTHOR]

To achieve compliance with the revised World Health Organization International Health Regulations (IHR 2005), countries must be able to rapidly prevent, detect, and respond to public health threats. Most nations, however, remain unprepared to manage and control complex health emergencies, whether due to natural disasters, emerging infectious disease outbreaks, or the inadvertent or intentional release of highly pathogenic organisms. The US Centers for Disease Control and Prevention (CDC) works with countries and partners to build and strengthen global health security preparedness so they can quickly respond to public health crises. This report highlights selected CDC global health protection platform accomplishments that help mitigate global health threats and build core, cross-cutting capacity to identify and contain disease outbreaks at their source. CDC contributions support country efforts to achieve IHR 2005 compliance, contribute to the international framework for countering infectious disease crises, and enhance health security for Americans and populations around the world. [ABSTRACT FROM AUTHOR]

The authors discuss the challenges and progress of public health in Haiti in January 2011, which was struck by a devastating earthquake a year before. They say that a devastating cholera epidemic and the piles of rubble remaining throughout the Haitian capital are stark reminders of the arising challenges in the absence of the institutions and infrastructure that people usually take for granted. They add that the Haitian Ministry of Public Health and Population (MSPP) has been effective in addressing the immediate public challenges.

An introduction is presented which discusses various reports within the issue on topics including the contributions of the U.S. Centers for Disease Control and Prevention (CDC) to improving global health security, the 2005 International Health Regulations (IHR), and public health issues.

The article focuses on the medical case of clinically differentiating between bacillary angiomatosis and Kaposi's sarcoma. Two figures are presented, one showing a bacillary angiomatosis lesion, the other Kaposi's sarcona lesion. An overview of the similarities in clinical appearances is discussed, in particular, the appearances of each condition with routine staining using hematoxylin and eosin. The article also discusses the clinical appearance of bacillary angiomatosis by using modified silver stains.

Background: From January through March 1993, there were 54 cases of meningococcal disease in Los Angeles County, California, of which 9 occurred among men incarcerated in the county's jail system, which was 40 percent above capacity at the time. Several of the 45 patients from the community had had contact with men recently released from a county jail. Methods: We interviewed patients from the community (n =42) and neighborhood controls matched with the patients for age, race, and ethnic group (n = 84) about potential exposures. We collected and cultured pharyngeal swabs for Neisseria meningitidis from men entering the central jail (n = 162), men leaving the central jail (n = 379), members of the jail staff (n = 121), and patients at a community health center (n = 214). Meningococcal isolates were identified by serogrouping and multilocus enzyme electrophoresis. Results: The presence of community-acquired meningococcal disease was strongly associated with exposure to a person who had been in or worked at one of the county jails (multivariate matched odds ratio, 18.5; 95 percent confidence interval, 3.8 to 90.8; P<0.001). Pharyngeal carriage of meningococcus was significantly more frequent among men released from jail (19 percent) or entering jail (17 percent) than among workers at the jails (3 percent) or community residents seen at the clinic (1 percent). Among men entering jail, those who had previously been incarcerated were more often carriers than those who had not (21 percent vs. 7 percent, P = 0.03). Of the isolates from nine community residents with serogroup C meningococcal disease, eight were the same strain as that isolated from the eight inmates with serogroup C disease. Conclusions: In this outbreak of meningococcal disease in Los Angeles County, nearly half of community residents with the disease had contact with persons who had been in a county jail. The high rates of carriage among recidivists and released inmates suggest that the men became meningococcal carriers while in jail. (N Engl J Med 1996;335:833-40.) [ABSTRACT FROM AUTHOR]

The article examines the distribution of the HIV-1 subtypes B and CRF01_AE in time and how it is affected by changes in injecting risk behavior and treatment among injecting drug users in Bangkok, Thailand. According to the authors, subtype B should remain prevalent in a small but considerable fraction of the population for a long time. They add changes in risk behavior and the introduction of treatment may alter the distribution of subtypes, but CRF01_AE should remain dominant.

Examines the contents of the Photo Atlas for Microbicide Evaluation which describes the wide spectrum of epithelial appearances found during clinical examination and colposcopy in microbicide clinical trials. Documentation of genital findings; Rationale for the categorization of genital lesions into different lesion types; Standardization of colcoscopy.

As lymphatic filariasis (LF) programs move closer to established targets for validation elimination of LF as a public health problem, diagnostic tools capable of supporting the needs of the programs are critical for success. Known limitations of existing diagnostic tools make it challenging to have confidence that program endpoints have been achieved. In 2019, the World Health Organization (WHO) established a Diagnostic Technical Advisory Group (DTAG) for Neglected Tropical Diseases tasked with prioritizing diagnostic needs including defining use-cases and target product profiles (TPPs) for needed tools. Subsequently, disease-specific DTAG subgroups, including one focused on LF, were established to develop TPPs and use-case analyses to be used by product developers. Here, we describe the development of two priority TPPs for LF diagnostics needed for making decisions for stopping mass drug administration (MDA) of a triple drug regimen and surveillance. Utilizing the WHO core TPP development process as the framework, the LF subgroup convened to discuss and determine attributes required for each use case. TPPs considered the following parameters: product use, design, performance, product configuration and cost, and access and equity. Version 1.0 TPPs for two use cases were published by WHO on 12 March 2021 within the WHO Global Observatory on Health Research and Development. A common TPP characteristic that emerged in both use cases was the need to identify new biomarkers that would allow for greater precision in program delivery. As LF diagnostic tests are rarely used for individual clinical diagnosis, it became apparent that reliance on population-based surveys for decision making requires consideration of test performance in the context of such surveys. In low prevalence settings, the number of false positive test results may lead to unnecessary continuation or resumption of MDA, thus wasting valuable resources and time. Therefore, highly specific diagnostic tools are paramount when used to measure low thresholds. The TPP process brought to the forefront the importance of linking use case, program platform and diagnostic performance characteristics when defining required criteria for diagnostic tools. Author summary: High quality diagnostic tools are an essential component of lymphatic filariasis (LF) programs. Currently, diagnostic tools are used by national programs to establish baseline endemicity, monitor progress of program interventions, determine when interventions can be stopped, and surveillance. For years, LF programs have relied on diagnostic tools that have been central to informing key program decisions but were not necessarily designed to undertake the roles for which they are used. Known limitations of existing diagnostic tools make it challenging to have confidence that program endpoints have been achieved. Target product profiles (TPP) provide product requirements to guide developers and manufacturers in their efforts to design tools fit for purpose. However, development of diagnostic tools used in public health programs requires consideration of aspects beyond those considered when developing diagnostic tools used for clinical diagnosis. The TPP process for two LF use cases brought to the forefront the importance of linking use case, program platform and diagnostic performance characteristics when defining required criteria for diagnostic tools. [ABSTRACT FROM AUTHOR]

After tuberculosis and leprosy, Buruli-ulcer disease (caused by infection with Mycobacterium ulcerans) is the third most common mycobacterial disease in immunocompetent people. Countries in which the disease is endemic have been identified, predominantly in areas of tropical rain forest; the emergence of Buruli-ulcer disease in West African countries over the past decade has been dramatic. Current evidence suggests that the infection is transmitted through abraded skin or mild traumatic injuries after contact with contaminated water, soil, or vegetation; there is one unconfirmed preliminary report on possible transmission by insects. The clinical picture ranges from a painless nodule to large, undermined ulcerative lesions that heal spontaneously but slowly. Most patients are children. The disease is accompanied by remarkably few systemic symptoms, but occasionally secondary infections resulting in sepsis or tetanus cause severe systemic disease and death. Extensive scarring can lead to contractures of the limbs, blindness, and other adverse sequelae, which impose a substantial health and economic burden. Treatment is still primarily surgical, and includes excision, skin grafting, or both. Although BCG has a mild but significant protective effect, new vaccine developments directed at the toxins produced by M ulcerans are warranted. In West Africa, affected populations are underprivileged, and the economic burden imposed by Buruli-ulcer disease is daunting. Combined efforts to improve treatment, prevention, control, and research strategies (overseen by the WHO and funded by international relief agencies) are urgently needed. [ABSTRACT FROM AUTHOR]

The Global Health Security Agenda (GHSA), a partnership of nations, international organizations, and civil society, was launched in 2014 with a mission to build countries' capacities to respond to infectious disease threats and to foster global compliance with the International Health Regulations (IHR 2005). The US Centers for Disease Control and Prevention (CDC) assists partner nations to improve IHR 2005 capacities and achieve GHSA targets. To assess progress through these CDC-supported efforts, we analyzed country activity reports dating from April 2015 through March 2017. Our analysis shows that CDC helped 17 Phase I countries achieve 675 major GHSA accomplishments, particularly in the cross-cutting areas of public health surveillance, laboratory systems, workforce development, and emergency response management. CDC's engagement has been critical to these accomplishments, but sustained support is needed until countries attain IHR 2005 capacities, thereby fostering national and regional health protection and ensuring a world safer and more secure from global health threats. [ABSTRACT FROM AUTHOR]

Background: Sex workers in Uganda are at significant risk for HIV infection. We characterized the HIV epidemic among Kampala female sex workers (FSW).Methods: We used respondent-driven sampling to sample FSW aged 15+ years who reported having sold sex to men in the preceding 30 days; collected data through audio-computer assisted self-interviews, and tested blood, vaginal and rectal swabs for HIV, syphilis, neisseria gonorrhea, chlamydia trachomatis, and trichomonas vaginalis.Results: A total of 942 FSW were enrolled from June 2008 through April 2009. The overall estimated HIV prevalence was 33% (95% confidence intervals [CI] 30%-37%) and among FSW 25 years or older was 44%. HIV infection is associated with low levels of schooling, having no other work, never having tested for HIV, self-reported genital ulcers or sores, and testing positive for neisseria gonorrhea or any sexually transmitted infections (STI). Two thirds (65%) of commercial sex acts reportedly were protected by condoms; one in five (19%) FSW reported having had anal sex. Gender-based violence was frequent; 34% reported having been raped and 24% reported having been beaten by clients in the preceding 30 days.Conclusions: One in three FSW in Kampala is HIV-infected, suggesting a severe HIV epidemic in this population. Intensified interventions are warranted to increase condom use, HIV testing, STI screening, as well as antiretroviral treatment and pre-exposure prophylaxis along with measures to overcome gender-based violence. [ABSTRACT FROM AUTHOR]

Background: Intimate partner violence (IPV) is associated with higher HIV incidence, reduced condom use, and poor adherence to antiretroviral therapy and other medications. IPV may also affect adherence to pre-exposure prophylaxis (PrEP). Methods: We analyzed data from 1785 HIV-uninfected women enrolled in a clinical trial of PrEP among African HIV serodiscordant couples. Experience of verbal, physical, or economic IPV was assessed at monthly visits by face-to-face interviews. Low PrEP adherence was defined as clinic-based pill count coverage <80% or plasma tenofovir levels <40 ng/mL. The association between IPV and low adherence was analyzed using generalized estimating equations, adjusting for potential confounders. In-depth interview transcripts were examined to explain how IPV could impact adherence. Results: Sixteen percent of women reported IPV during a median of 34.8 months of follow-up (interquartile range 27.0-35.0). Overall, 7% of visits had pill count coverage <80%, and 32% had plasma tenofovir <40 ng/mL. Women reporting IPV in the past 3 months had increased risk of low adherence by pill count (adjusted risk ratio 1.49, 95% confidence interval: 1.17 to 1.89) and by plasma tenofovir (adjusted risk ratio 1.51, 95% confidence interval: 1.06 to 2.15). Verbal, economic, and physical IPV were all associated with low adherence. However, the impact of IPV diminished and was not statistically significant 3 months after the reported exposure. In qualitative interviews, women identified several ways in which IPV affected adherence, including stress and forgetting, leaving home without pills, and partners throwing pills away. Conclusions: Women who reported recent IPV in the Partners PrEP Study were at increased risk of low PrEP adherence. Strategies to mitigate PrEP nonadherence in the context of IPV should be evaluated. [ABSTRACT FROM AUTHOR]

Background: The pharmacokinetics and pharmacodynamics of lumefantrine, a component of the most widely used treatment for malaria, artemether-lumefantrine, has not been adequately characterized in young children.Methods: Capillary whole-blood lumefantrine concentration and treatment outcomes were determined in 105 Ugandan children, ages 6 months to 2 years, who were treated for 249 episodes of Plasmodium falciparum malaria with artemether-lumefantrine.Results: Population pharmacokinetics for lumefantrine used a 2-compartment open model with first-order absorption. Age had a significant positive correlation with bioavailability in a model that included allometric scaling. Children not receiving trimethoprim-sulfamethoxazole with capillary whole blood concentrations <200 ng/mL had a 3-fold higher hazard of 28-day recurrent parasitemia, compared with those with concentrations >200 ng/mL (P = .0007). However, for children receiving trimethoprim-sulfamethoxazole, the risk of recurrent parasitemia did not differ significantly on the basis of this threshold. Day 3 concentrations were a stronger predictor of 28-day recurrence than day 7 concentrations.Conclusions: We demonstrate that age, in addition to weight, is a determinant of lumefantrine exposure, and in the absence of trimethoprim-sulfamethoxazole, lumefantrine exposure is a determinant of recurrent parasitemia. Exposure levels in children aged 6 months to 2 years was generally lower than levels published for older children and adults. Further refinement of artemether-lumefantrine dosing to improve exposure in infants and very young children may be warranted. [ABSTRACT FROM AUTHOR]

Background: Plasmodium falciparum malaria remains a leading cause of childhood morbidity and mortality. There are important gaps in our understanding of the factors driving the development of antimalaria immunity as a function of age and exposure.Methods: We used data from a cohort of 93 children participating in a clinical trial in Tororo, Uganda, an area of very high exposure to P. falciparum We jointly quantified individual heterogeneity in the risk of infection and the development of immunity against infection and clinical disease.Results: Results showed significant heterogeneity in the hazard of infection and independent effects of age and cumulative number of infections on the risk of infection and disease. The risk of developing clinical malaria upon infection decreased on average by 6% (95% confidence interval [CI], 0%-12%) for each additional year of age and by 2% (95% CI, 1%-3%) for each additional prior infection. Children randomly assigned to receive dihydroartemisinin-piperaquine for treatment appeared to develop immunity more slowly than those receiving artemether-lumefantrine.Conclusions: Heterogeneity in P. falciparum exposure and immunity can be independently evaluated using detailed longitudinal studies. Improved understanding of the factors driving immunity will provide key information to anticipate the impact of malaria-control interventions and to understand the mechanisms of clinical immunity. [ABSTRACT FROM AUTHOR]

Objective: Tenofovir disoproxil fumarate (TDF) is associated with proximal tubular dysfunction (tubulopathy) when used in the treatment of human immunodeficiency virus (HIV) infection. We evaluated whether TDF causes tubulopathy when used as HIV preexposure prophylaxis (PrEP) and whether tubulopathy predicts clinically relevant decline (≥25%) in the estimated glomerular filtration rate (eGFR).Methods: A subgroup analysis of the Partners PrEP Study, a randomized, placebo-controlled trial of daily oral TDF, alone or with emtricitabine (FTC), in HIV-uninfected African men and women (Clinicaltrials.gov NCT00557245). Tubulopathy was assessed in concurrently obtained urine and serum samples at the 24-month or last on-treatment visit, predefined as ≥2 of the following: tubular proteinuria, euglycemic glycosuria, increased urinary phosphate, and uric acid excretion.Results: Of 1549 persons studied (776 receiving FTC-TDF, 773 receiving placebo), 64% were male, and the median age was 37 years. Over a median 24 months of study-drug exposure, the frequency of tubulopathy was 1.7% for FTC-TDF versus 1.3% for placebo (odds ratio, 1.30; 95% confidence interval, .52-3.33; P = .68); Tubulopathy occurred in 2 of 52 persons (3.8%) with versus 3 of 208 (1.4%) without ≥25% eGFR decline (adjusted odds ratio, 1.39; .10-14.0; P > .99).Conclusions: Daily oral FTC-TDF PrEP was not significantly associated with tubulopathy over the course of 24 months, nor did tubulopathy predict clinically relevant eGFR decline. [ABSTRACT FROM AUTHOR]

Background: Repeated exposure to Plasmodium falciparum is associated with perturbations in B cell sub-set homeostasis, including expansion atypical memory B cells. However, B cell perturbations immediately following acute malaria infection have been poorly characterized, especially with regard to their relationship with immunity to malaria. Methods: To better understand the kinetics of B cell sub-sets following malaria, the proportions of six B cell sub-sets were assessed at five time points following acute malaria in four to 5 years old children living in a high transmission region of Uganda. B cell sub-set kinetics were compared with measures of clinical immunity to malaria—lower parasite density at the time of malaria diagnosis and recent asymptomatic parasitaemia. Results: Atypical memory B cell and transitional B cell proportions increased following malaria. In contrast, plasmablast proportions were highest at the time of malaria diagnosis and rapidly declined following treatment. Increased proportions of atypical memory B cells were associated with greater immunity to malaria, whereas increased proportions of transitional B cells were associated with evidence of less immunity to malaria. Conclusions: These findings highlight the dynamic changes in multiple B cell sub-sets following acute, uncomplicated malaria, and how these sub-sets are associated with developing immunity to malaria. [ABSTRACT FROM AUTHOR]

FoxP3+ regulatory CD4 T cells (Tregs) help to maintain the delicate balance between pathogen-specific immunity and immune-mediated pathology. Prior studies suggest that Tregs are induced by P. falciparum both in vivo and in vitro; however, the factors influencing Treg homeostasis during acute and chronic infections, and their role in malaria immunopathogenesis, remain unclear. We assessed the frequency and phenotype of Tregs in well-characterized cohorts of children residing in a region of high malaria endemicity in Uganda. We found that both the frequency and absolute numbers of FoxP3+ Tregs in peripheral blood declined markedly with increasing prior malaria incidence. Longitudinal measurements confirmed that this decline occurred only among highly malaria-exposed children. The decline of Tregs from peripheral blood was accompanied by reduced in vitro induction of Tregs by parasite antigen and decreased expression of TNFR2 on Tregs among children who had intense prior exposure to malaria. While Treg frequencies were not associated with protection from malaria, there was a trend toward reduced risk of symptomatic malaria once infected with P. falciparum among children with lower Treg frequencies. These data demonstrate that chronic malaria exposure results in altered Treg homeostasis, which may impact the development of antimalarial immunity in naturally exposed populations. [ABSTRACT FROM AUTHOR]

The Ebola virus disease outbreak in West Africa was unprecedented in both its scale and impact. Out of this human calamity has come renewed attention to global health security—its definition, meaning, and the practical implications for programmes and policy. For example, how does a government begin to strengthen its core public health capacities, as demanded by the International Health Regulations? What counts as a global health security concern? In the context of the governance of global health, including WHO reform, it will be important to distil lessons learned from the Ebola outbreak. The Lancet invited a group of respected global health practitioners to reflect on these lessons, to explore the idea of global health security, and to offer suggestions for next steps. Their contributions describe some of the major threats to individual and collective human health, as well as the values and recommendations that should be considered to counteract such threats in the future. Many different perspectives are proposed. Their common goal is a more sustainable and resilient society for human health and wellbeing. [ABSTRACT FROM AUTHOR]

The article reports on U.S. government efforts in rapidly detecting and treating persons with Ebola virus disease as of March 2015. Topics discussed include the implementation of screening of travelers who are entering the U.S. from Guinea, Liberia, and Sierra Leone. Information is also presented on a tiered approach to U.S. hospital and health care facility preparedness.

The article reports on the World Health Organization (WHO)-recommended strategy on screening all individuals for Ebola virus disease (Ebola) when entering and exiting airports in West Africa (WA). Topics covered include implementation of the procedure in August 2014 by WA health ministries with global partners such as the U.S. Centers for Disease Control and Prevention (CDC). Also mentioned most Ebola affected WA countries including Guinea, Liberia and Sierra Leone.

Summary Background Antiretroviral pre-exposure prophylaxis (PrEP), with daily oral tenofovir disoproxil fumarate or tenofovir disoproxil fumarate in combination with emtricitabine, has been shown to be efficacious for HIV-1 prevention. Although the use of more than one antiretroviral agent is essential for effective HIV-1 treatment, more than one agent might not be required for effective prophylaxis. We assessed the efficacy of single-agent tenofovir disoproxil fumarate relative to combination emtricitabine plus tenofovir disoproxil fumarate as PrEP. Methods We did a randomised, double-blind, placebo-controlled three-group phase 3 trial of daily oral tenofovir disoproxil fumarate and emtricitabine plus tenofovir disoproxil fumarate PrEP in HIV-1 uninfected individuals in heterosexual HIV-1 serodiscordant couples from Kenya and Uganda. After an interim review, the trial's placebo group was discontinued and thereafter the active groups were continued, and participants initially randomly assigned to placebo were offered rerandomisation in a 1:1 ratio to tenofovir disoproxil fumarate or emtricitabine plus tenofovir disoproxil fumarate as PrEP. The primary endpoints were HIV-1 seroconversion and safety. This trial is registered with ClinicalTrials.gov , number NCT00557245 . Findings 4410 (99·6%) of 4427 couples received tenofovir disoproxil fumarate or emtricitabine plus tenofovir disoproxil fumarate and were followed up for HIV-1 acquisition. Of 52 incident HIV-1 infections, 31 occurred in individuals assigned tenofovir disoproxil fumarate (incidence 0·71 cases per 100 person-years) and 21 were in those assigned emtricitabine plus tenofovir disoproxil fumarate (0·48 cases per 100 person-years); HIV-1 incidence in the placebo group until discontinuation was two cases per 100 person-years. HIV-1 prevention efficacy with emtricitabine plus tenofovir disoproxil fumarate was not significantly different from that of tenofovir disoproxil fumarate alone (hazard ratio [HR] 0·67, 95% CI 0·39–1·17; p=0·16). Detection of tenofovir in plasma samples, compared with no detection and as measured in seroconverters and a subset of non-seroconverters, was associated with an 85% relative risk reduction in HIV-1 acquisition for the tenofovir disoproxil fumarate group (HR 0·15, 95% CI 0·06–0·37; p<0·0001) and 93% for the emtricitabine plus tenofovir disoproxil fumarate group (0·07, 0·02–0·23; p<0·0001). No significant differences were noted in the frequency of deaths, serious adverse events, or serum creatinine and phosphorus abnormalities between the two groups. Interpretation These results do not rule out the potential for a slight difference in HIV-1 protection with tenofovir disoproxil fumarate compared with emtricitabine plus tenofovir disoproxil fumarate, but show that once-daily oral tenofovir disoproxil fumarate or emtricitabine plus tenofovir disoproxil fumarate regimens both provide high protection against HIV-1 acquisition in heterosexual men and women. Funding Bill & Melinda Gates Foundation and US National Institutes of Health. [ABSTRACT FROM AUTHOR]

In October 2012, the Haitian Ministry of Health and the US CDC were notified of 25 recent dengue cases, confirmed by rapid diagnostic tests (RDTs), among non-governmental organization (NGO) workers. We conducted a serosurvey among NGO workers in Léogane and Port-au-Prince to determine the extent of and risk factors for dengue virus infection. Of the total 776 staff from targeted NGOs in Léogane and Port-au-Prince, 173 (22%; 52 expatriates and 121 Haitians) participated. Anti-dengue virus (DENV) IgM antibody was detected in 8 (15%) expatriates and 9 (7%) Haitians, and DENV non-structural protein 1 in one expatriate. Anti-DENV IgG antibody was detected in 162 (94%) participants (79% of expatriates; 100% of Haitians), and confirmed by microneutralization testing as DENV-specific in 17/34 (50%) expatriates and 42/42 (100%) Haitians. Of 254 pupae collected from 68 containers, 65% were Aedes aegypti; 27% were Ae. albopictus. Few NGO workers reported undertaking mosquito-avoidance action. Our findings underscore the risk of dengue in expatriate workers in Haiti and Haitians themselves. Author Summary: Dengue is the most common mosquito-borne viral disease in the world, and caused an estimated 390 million infections and 96 million cases in the tropics and subtropics in 2010. Over the last decade, the number of cases of dengue and the severity of dengue virus infections have increased in the Americas, including the Caribbean, yet little is still known about dengue in Haiti. Following an outbreak of dengue in mostly expatriate NGO workers, the investigators of this study took blood samples from expatriate and Haitian NGO workers living in two cities in Haiti and tested them for evidence of current, recent, and past dengue virus infection. They also investigated the amount and kinds of mosquitoes at homes and work sites. The study found recent infections among some Haitians and expatriates and widespread past infections among all Haitians and most expatriates. It also found that many people were not doing basic things to avoid mosquito bites, like applying mosquito repellent multiple times a day and wearing long sleeves or pants. These findings highlight the likely endemicity of dengue virus in Haiti, and the need to improve knowledge and awareness of dengue prevention among expatriates visiting Haiti and local Haitians. [ABSTRACT FROM AUTHOR]

In October 2012, the Haitian Ministry of Health and the US CDC were notified of 25 recent dengue cases, confirmed by rapid diagnostic tests (RDTs), among non-governmental organization (NGO) workers. We conducted a serosurvey among NGO workers in Léogane and Port-au-Prince to determine the extent of and risk factors for dengue virus infection. Of the total 776 staff from targeted NGOs in Léogane and Port-au-Prince, 173 (22%; 52 expatriates and 121 Haitians) participated. Anti-dengue virus (DENV) IgM antibody was detected in 8 (15%) expatriates and 9 (7%) Haitians, and DENV non-structural protein 1 in one expatriate. Anti-DENV IgG antibody was detected in 162 (94%) participants (79% of expatriates; 100% of Haitians), and confirmed by microneutralization testing as DENV-specific in 17/34 (50%) expatriates and 42/42 (100%) Haitians. Of 254 pupae collected from 68 containers, 65% were Aedes aegypti; 27% were Ae. albopictus. Few NGO workers reported undertaking mosquito-avoidance action. Our findings underscore the risk of dengue in expatriate workers in Haiti and Haitians themselves. [ABSTRACT FROM AUTHOR]

Objectives We conducted a nationwide survey to assess measles containing vaccine ( MCV) coverage among children aged 1-9 years in Haiti and identify factors associated with vaccination before and during the 2012 nationwide supplementary immunisation activities ( SIA). Methods Haiti was stratified into five geographic regions ( Metropolitan Port-au- Prince, North, Centre, South and West), 40 clusters were randomly selected in each region, and 35 households were selected per cluster. Results Among the 7000 visited households, 75.8% had at least one child aged 1-9 years; of these, 5279 (99.5%) households consented to participate in the survey. Of 9883 children enrolled, 91% received MCV before and/or during the SIA; 31% received MR for the first time during the SIA, and 50.7% received two doses of MCV (one before and one during the 2012 SIA). Among the 1685 unvaccinated children during the SIA, the primary reason of non-vaccination was caregivers not being aware of the SIA (31.0%). Children aged 1-4 years had significantly lower MR SIA coverage than those aged 5-9 years (79.5% vs. 84.8%) ( P < 0.0001). A higher proportion of children living in the West (12.3%) and Centre (11.2%) regions had never been vaccinated than in other regions (4.8-9.1%). Awareness, educational level of the mother and region were significantly associated with MR vaccination during and before the SIA ( P < 0.001). Conclusions The 2012 SIA successfully increased MR coverage; however, to maintain measles and rubella elimination, coverage needs to be further increased among children aged 1-4 years and in regions with lower coverage. [ABSTRACT FROM AUTHOR]

Artemether-lumefantrine and dihydroartemisinin-piperaquine were compared for the treatment of uncomplicated malaria in Ugandan children over a period of 4 years. Children randomized to dihydroartemisinin-piperaquine had a lower incidence of treatment for any episode of malaria, complicated malaria, and hospitalizations.Background. Artemisinin-based combination therapy (ACT) has become the standard of care for the treatment of uncomplicated Plasmodium falciparum malaria. Although several ACT regimens are approved, data guiding optimal choices of ACTs are limited. We compared short- and long-term outcomes in a cohort of young Ugandan children randomized to 2 leading ACTs.Methods. Overall, 312 children were randomized to artemether-lumefantrine or dihydroartemisinin-piperaquine (DP) at the time of the first episode of uncomplicated malaria (median age, 10.5 months). The same treatment was given for all subsequent episodes of uncomplicated malaria and children were followed until they reached 5 years of age. The cohort included a subgroup that was human immunodeficiency virus (HIV) infected (n = 44) or HIV exposed (n = 175) and prescribed trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis. Outcomes included time to recurrent malaria following individual treatments and the overall incidences of treatments for malaria, complicated malaria, and hospitalizations.Results. Among children not prescribed TMP-SMX prophylaxis, 4443 treatments for malaria were given over 790 person-years following randomization. Treatment with DP was associated with a lower hazard of recurrent malaria over the 84 days after treatment (hazard ratio, 0.66; 95% confidence interval [CI], .61–.70; P < .001). Children randomized to DP had a lower incidence of all treatments for malaria (incidence rate ratio [IRR], 0.85; 95% CI, .75–.96; P = .01), complicated malaria (IRR, 0.12; 95% CI, .04–.39; P < .001), and hospitalizations (IRR, 0.31; 95% CI, .13–.77; P = .01). Among children prescribed TMP-SMX prophylaxis, there were no significant differences in longitudinal outcomes.Conclusions. Compared to artemether-lumefantrine, the use of DP to treat uncomplicated malaria delayed the time to recurrent malaria and reduced the incidences of treatments for malaria, complicated malaria, and hospitalizations.Clinical Trials Registration. NCT00527800. [ABSTRACT FROM PUBLISHER]

Treatment of uncomplicated malaria with artemether-lumefantrine (AL) or dihydroartemisinin-piperaquine in HIV-infected children on antiretroviral therapy (ART) was safe and efficacious. However there was a high risk of recurrent parasitemia within 28 days following treatment with AL, varying with ART regimen.Background. Artemisinin-based combination therapies (ACTs) are highly efficacious and safe, but data from human immunodeficiency virus (HIV)–infected children concurrently receiving antiretroviral therapy (ART) and ACTs are limited.Methods. We evaluated 28-day outcomes following malaria treatment with artemether-lumefantrine (AL) or dihydroartemisinin-piperaquine (DP) in 2 cohorts of HIV-infected Ugandan children taking various ART regimens. In one cohort, children <6 years of age were randomized to lopinavir/ritonavir (LPV/r) or nonnucleoside reverse transcriptase inhibitor–based ART and treated with AL for uncomplicated malaria. In another cohort, children <12 months of age were started on nevirapine-based ART if they were eligible, and randomized to AL or DP for the treatment of their first and all subsequent uncomplicated malaria episodes.Results. There were 773 and 165 treatments for malaria with AL and DP, respectively. Initial response to therapy was excellent, with 99% clearance of parasites and <1% risk of repeat therapy within 3 days. Recurrent parasitemia within 28 days was common following AL treatment. The risk of recurrent parasitemia was significantly lower among children taking LPV/r-based ART compared with children taking nevirapine-based ART following AL treatment (15.3% vs 35.5%, P = .009), and those treated with DP compared with AL (8.6% vs 36.2%, P < .001). Both ACT regimens were safe and well tolerated.Conclusions. Treatment of uncomplicated malaria with AL or DP was efficacious and safe in HIV-infected children taking ART. However, there was a high risk of recurrent parasitemia following AL treatment, which was significantly lower in children taking LPV/r-based ART compared with nevirapine-based ART. [ABSTRACT FROM PUBLISHER]

Background. Artemisinin-based combination therapies, including artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DP), are recommended to treat uncomplicated falciparum malaria. Sensitivities to components of AL and DP are impacted by polymorphisms in pfmdr1 and pfcrt. We monitored changes in prevalences of polymorphisms in Tororo, Uganda, from 2008 to 2012.Methods. Polymorphic loci in pfmdr1 and pfcrt were characterized in samples from 312 children randomized to AL or DP for each episode of uncomplicated malaria (50 samples per arm for each 3-month interval) utilizing a fluorescent microsphere assay. Treatment outcomes and impacts of prior therapies were also characterized.Results. Prevalence increased significantly over time for pfmdr1 N86 (AL: odds ratio [OR], 2.08 [95% confidence interval {CI}, 1.83–2.38]; DP: 1.41 [95% CI, 1.25–1.57]), pfmdr1 D1246 (AL: 1.46 [95% CI, 1.29–1.64]; DP: 1.36 [95% CI, 1.23–1.50]), and pfcrt K76 (AL: 3.37 [95% CI, 1.85–6.16]; DP: 5.84 [95% CI, 1.94–17.53], and decreased for pfmdr1 Y184 (AL: 0.78 [95% CI, .70–.86]; DP: 0.84 [95% CI, .76–1.50]); changes were consistently greater in the AL arm. Recent AL treatment selected for pfmdr1 N86, D1246, and 184F in subsequent episodes; DP selected for the opposite alleles.Conclusions. Genotypes with decreased sensitivity to AL components increased over time. This increase was greater in children receiving AL, suggesting that the choice of treatment regimen can profoundly influence parasite genetics and drug sensitivity.Clinical Trials Registration. NCT00527800. [ABSTRACT FROM PUBLISHER]

Background: Malaria remains a major public health problem, and its control has been hampered by drug resistance. For a number of drugs, Plasmodium falciparum single nucleotide polymorphisms (SNPs) are associated with altered drug sensitivity and can be used as markers of drug resistance. Several techniques have been studied to assess resistance markers. The most widely used methodology is restriction fragment length polymorphism (RFLP) analysis. The ligase detection reaction fluorescent microsphere (LDR-FM) assay was recently shown to provide high throughput assessment of P. falciparum SNPs associated with drug resistance. The aim of this study was to validate the reliability and accuracy of the LDR-FM assay in a field setting. Methods: For 223 samples from a clinical trial in Tororo, Uganda in which P. falciparum was identified by blood smear, DNA was extracted from dried blood spots, genes of interest were amplified by PCR, amplicons were analysed by both RFLP and LDR-FM assays, and results were compared. Results: SNP prevalence (wild type/mixed/mutant) with RFLP analysis was 8/5/87% for pfcrt K76T, 34/37/29% for pfmdr1 N86Y, 64/17/19% for pfmdr1 Y184F, and 42/21/37% for pfmdr1 D1246Y. These prevalences with the LDR-FM assay were 7/5/88%, 31/24/45%, 62/20/18%, and 48/19/33% for the four SNPs, respectively. Combining mixed and mutant outcomes for analysis, agreement between the assays was 97% (K = 0.77) for pfcrt K76T, 79% (K = 0.55) for pfmdr1 N86Y, 83% (K = 0.65) for pfmdr1 Y184F, and 91% (K = 0.82) for pfmdr1 D1246Y, with most disagreements due to discrepant readings of mixed genotypes. Conclusion: The LDR-FM assay provides a high throughput, relatively inexpensive and accurate assay for the surveillance of P. falciparum SNPs associated with drug resistance in resource-limited countries. [ABSTRACT FROM AUTHOR]

Background Artemisinin-based combination therapy (ACT) is widely recommended as first-line therapy for uncomplicated Plasmodium falciparum malaria worldwide. Artemisinin resistance has now been reported in Southeast Asia with a clinical phenotype manifested by slow parasite clearance. Although there are no reliable reports of artemisinin resistance in Africa, there is a need to better understand the dynamics of parasite clearance in African children treated with ACT in order to better detect the emergence of artemisinin resistance. Methods Data from a cohort of Ugandan children four to five years old, enrolled in a longitudinal, randomized, clinical trial comparing two leading ACT, artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DP), were analysed. For all episodes of uncomplicated P. falciparum malaria over a 14-month period, daily blood smears were performed for three days following the initiation of therapy. Associations between pre-treatment variables of interest and persistent parasitaemia were estimated using multivariate, generalized, estimating equations with adjustment for repeated measures in the same patient. Results A total of 202 children were included, resulting in 416 episodes of malaria treated with AL and 354 episodes treated with DP. The prevalence of parasitaemia on days 1, 2, and 3 following initiation of therapy was 67.6, 5.6 and 0% in those treated with AL, and 52.2, 5.7 and 0.3% in those treated with DP. Independent risk factors for persistent parasitaemia on day 1 included treatment with AL vs DP (RR = 1.34, 95% CI 1.20-1.50, p < 0.001), having a temperature ⩾38.0°C vs < 37.0°C (RR = 1.19, 95% CI 1.05-1.35, p = 0.007) and having a parasite density >20,000/μL vs <4,000/ μL (RR = 3.37, 95% CI 2.44-4.49, p < 0.001). Independent risk factors for having persistent parasitaemia on day 2 included elevated temperature, higher parasite density, and being HIV infected. Conclusions Among Ugandan children, parasite clearance following treatment with AL or DP was excellent with only one of 752 patients tested having a positive blood slide three days after initiation of therapy. The type of ACT given, pre-treatment temperature, pre-treatment parasite density and HIV status were associated with differences in persistent parasitaemia, one or two days following therapy. [ABSTRACT FROM AUTHOR]

Although evidence suggests that T cells are critical for immunity to malaria, reliable T cell correlates of exposure to and protection from malaria among children living in endemic areas are lacking. We used multiparameter flow cytometry to perform a detailed functional characterization of malaria-specific T cells in 78 four-year-old children enrolled in a longitudinal cohort study in Tororo, Uganda, a highly malaria-endemic region. More than 1800 episodes of malaria were observed in this cohort, with no cases of severe malaria. We quantified production of IFNγ, TNFα, and IL-10 (alone or in combination) by malaria-specific T cells, and analyzed the relationship of this response to past and future malaria incidence. CD4+ T cell responses were measurable in nearly all children, with the majority of children having CD4+ T cells producing both IFNγ and IL-10 in response to malaria-infected red blood cells. Frequencies of IFNγ/IL10 co-producing CD4+ T cells, which express the Th1 transcription factor T-bet, were significantly higher in children with ≥2 prior episodes/year compared to children with <2 episodes/year (P<0.001) and inversely correlated with duration since malaria (Rho = −0.39, P<0.001). Notably, frequencies of IFNγ/IL10 co-producing cells were not associated with protection from future malaria after controlling for prior malaria incidence. In contrast, children with <2 prior episodes/year were significantly more likely to exhibit antigen-specific production of TNFα without IL-10 (P = 0.003). While TNFα-producing CD4+ T cells were not independently associated with future protection, the absence of cells producing this inflammatory cytokine was associated with the phenotype of asymptomatic infection. Together these data indicate that the functional phenotype of the malaria-specific T cell response is heavily influenced by malaria exposure intensity, with IFNγ/IL10 co-producing CD4+ T cells dominating this response among highly exposed children. These CD4+ T cells may play important modulatory roles in the development of antimalarial immunity. [ABSTRACT FROM AUTHOR]

Background. Although dihydroartemisinin-piperaquine (DP) is used primarily in children, pharmacokinetic/pharmacodynamic (PK/PD) data on DP use in young children are lacking.Methods. We conducted a prospective PK/PD study of piperaquine in 107 young children in Uganda. Samples were collected up to 28 days after 218 episodes of malaria treatment, which occurred during follow-up periods of up to 5 months. Malaria follow-up was conducted actively to day 28 and passively to day 63.Results. The median capillary piperaquine concentration on day 7 after treatment was 41.9 ng/mL. Low piperaquine concentrations were associated with an increased risk of recurrent malaria for up to 42 days, primarily in those receiving trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis. In children not receiving TMP-SMX, low piperaquine concentrations were only modestly associated with an increased risk of recurrent malaria. However, for children receiving TMP-SMX, associations were strong and evident for all sampling days, with PQ concentrations of ≤27.3 ng/mL on day 7 associated with a greatly increased risk of recurrent malaria. Notably, of 132 cases of recurrent malaria, 119 had detectable piperaquine concentrations at the time of presentation with recurrent malaria.Conclusions. These piperaquine PK/PD data represent the first in children <2 years of age. Piperaquine exposure on day 7 correlated with an increased risk of recurrent malaria after DP treatment in children receiving TMP-SMX prophylaxis. Interestingly, despite strong associations, infants remained at risk for malaria, even if they had residual levels of piperaquine. [ABSTRACT FROM AUTHOR]

Background: Antiretroviral preexposure prophylaxis is a promising approach for preventing human immunodeficiency virus type 1 (HIV-1) infection in heterosexual populations. Methods: We conducted a randomized trial of oral antiretroviral therapy for use as preexposure prophylaxis among HIV-1-serodiscordant heterosexual couples from Kenya and Uganda. The HIV-1-seronegative partner in each couple was randomly assigned to one of three study regimens — once-daily tenofovir (TDF), combination tenofovir-emtricitabine (TDF-FTC), or matching placebo — and followed monthly for up to 36 months. At enrollment, the HIV-1-seropositive partners were not eligible for antiretroviral therapy, according to national guidelines. All couples received standard HIV-1 treatment and prevention services. Results: We enrolled 4758 couples, of whom 4747 were followed: 1584 randomly assigned to TDF, 1579 to TDF-FTC, and 1584 to placebo. For 62% of the couples followed, the HIV-1-seronegative partner was male. Among HIV-1-seropositive participants, the median CD4 count was 495 cells per cubic millimeter (interquartile range, 375 to 662). A total of 82 HIV-1 infections occurred in seronegative participants during the study, 17 in the TDF group (incidence, 0.65 per 100 person-years), 13 in the TDF-FTC group (incidence, 0.50 per 100 person-years), and 52 in the placebo group (incidence, 1.99 per 100 person-years), indicating a relative reduction of 67% in the incidence of HIV-1 with TDF (95% confidence interval [CI], 44 to 81; P<0.001) and of 75% with TDF-FTC (95% CI, 55 to 87; P<0.001). Protective effects of TDF-FTC and TDF alone against HIV-1 were not significantly different (P=0.23), and both study medications significantly reduced the HIV-1 incidence among both men and women. The rate of serious adverse events was similar across the study groups. Eight participants receiving active treatment were found to have been infected with HIV-1 at baseline, and among these eight, antiretroviral resistance developed in two during the study. Conclusions: Oral TDF and TDF-FTC both protect against HIV-1 infection in heterosexual men and women. (Funded by the Bill and Melinda Gates Foundation; Partners PrEP ClinicalTrials.gov number, NCT00557245.) [ABSTRACT FROM AUTHOR]

Objective We report experience of HIVQUAL-T implementation in Thailand. Design Program evaluation. Setting Twelve government hospital clinics. Participants People living with HIV/AIDS (PLHAs) aged ≥15 years with two or more visits to the hospitals during 2002–08. Intervention HIVQUAL-T is a process for HIV care performance measurement (PM) and quality improvement (QI). The program includes PM using a sample of eligible cases and establishment of a locally led QI infrastructure and process. PM indicators are based on Thai national HIV care guidelines. QI projects address needs identified through PM; regional workshops facilitate peer learning. Annual benchmarking with repeat measurement is used to monitor progress. Main Outcome Measure Percentages of eligible cases receiving various HIV services. Results Across 12 participating hospitals, HIV care caseloads were 4855 in 2002 and 13 887 in 2008. On average, 10–15% of cases were included in the PM sample. Percentages of eligible cases receiving CD4 testing in 2002 and 2008, respectively, were 24 and 99% (P< 0.001); for ARV treatment, 100 and 90% (P= 0.74); for Pneumocystis jiroveci pneumonia prophylaxis, 94 and 93% (P= 0.95); for Papanicolau smear, 0 and 67% (P< 0.001); for syphilis screening, 0 and 94% (P< 0.001); and for tuberculosis screening, 24 and 99% (P< 0.01). PM results contributed to local QI projects and national policy changes. Conclusions Hospitals participating in HIVQUAL-T significantly increased their performance in several fundamental areas of HIV care linked to health outcomes for PLHA. This model of PM-QI has improved clinical care and implementation of HIV guidelines in hospital-based clinics in Thailand. [ABSTRACT FROM PUBLISHER]

We measured virologic suppression among 34 nevirapine (NVP)-exposed HIV-infected children with median age of 8.6 months (range: 3.2–19.9) initiating NVP-based antiretroviral therapy (ART) in rural Uganda. In Kaplan–Meier analysis, the cumulative probability of virologic suppression, defined as having two consecutive HIV-1 RNA <400 copies ml−1 by 18 months was 56%. In multivariate Cox proportional hazard modeling, the following pre-ART measurements were independently associated with an increased probability of viral suppression: increasing age [hazard ratio (HR) =1.28 per 1 month increase in age, p = 0.002], lower viral load (HR = 3.54 for HIV RNA > 7 50 000 copies ml−1, p = 0.03) and high CD4% (HR = 6.0 for CD4% > 25, p = 0.003). These results lend additional support to the 2010 World Health Organization recommendations that protease inhibitors be used to treat NVP-exposed children, but that NVP-based ART should be initiated before the decline of CD4% to optimize outcomes in NVP-exposed children when protease inhibitors are not available. [ABSTRACT FROM PUBLISHER]