Formulating the Future Research Agenda for Postexposure Prophylaxis for HIV: Methodological Challenges and Potential Approaches

Background. During a World Health Organization-convened Guideline Development Group meeting, recommendations for postexposure prophylaxis (PEP) for human immunodeficiency virus were made and research gaps identified. Methods. We used the PEP clinical management pathway and the Grading of Evidence, Assessment, Development and Evaluation (GRADE) system as a framework to formulate future research questions, describe the most feasible study design, and identify potential biases. Results. Three key study design formats were identified to address 12 research questions: (1) survey- and interview-driven research to identify barriers to access to PEP and related clinical care; (2) establishment of a global PEP registry to generate data to inform the choice of an optimal PEP drug regimen, record drug toxicities arising from specific PEP regimens, and track follow-up and linkage to care (including transition from PEP to preexposure prophylaxis); and (3) randomized controlled trials to determine the optimal adherence promotion strategies necessary for successful outcomes following PEP. Conclusions.  Positioning key clinical and programmatic research questions within the GRADE framework facilitates the formulation of an evidence-based research agenda and future revisions of guideline

Efficacy of HIV Postexposure Prophylaxis: Systematic Review and Meta-analysis of Nonhuman Primate Studies

Background. The efficacy of antiretrovirals as postexposure prophylaxis (PEP) to prevent viral acquisition was demonstrated in nonhuman primate models of human immunodeficiency virus (HIV) in the early 1990s. To complement the evidence base for efficacy of HIV PEP in humans, we systematically reviewed the published data on PEP efficacy across animal studies. Methods. PubMed, Web of Science, and Embase were searched from inception to 31 May 2014 for randomized and nonrandomized studies reporting seroconversions among uninfected animals exposed to HIV or simian immunodeficiency virus, irrespective of route of exposure. Seroconversion risk data were pooled using random-effects models, and associations explored through meta-regression. Results. Twenty-five studies (408 primates) were included for review. The risk of serconversion was 89% lower among animals exposed to PEP compared with those that did not receive PEP (odds ratio, 0.11 [95% confidence interval, .05-.23]). Heterogeneity was low (I2 = 0.0%). In meta-regression, a significant association was found between timing of PEP and seroconversion and the use of tenofovir compared with other drugs. Conclusions. This review provides further evidence of the protective benefit of PEP in preventing HIV acquisition, and the importance of initiating PEP as early as possible following virus exposur

Choice of Antiretroviral Drugs for Postexposure Prophylaxis for Adults and Adolescents: A Systematic Review

Background. The choice of preferred regimens for human immunodeficiency virus postexposure prophylaxis (PEP) has evolved over the last 2 decades as more data have become available regarding the safety and tolerability of newer antiretroviral drugs. We undertook a systematic review to assess the safety and efficacy of antiretroviral options for PEP to inform the World Health Organization guideline revision process. Methods. Four databases were searched up to 1 June 2014 for studies reporting outcomes associated with specific PEP regimens. Data on PEP completion and discontinuation due to adverse events was extracted and pooled estimates were obtained using random-effects meta-analyses. Results. Fifteen studies (1830 PEP initiations) provided evaluable information on 2-drug regimens (zidovudine [ZDV]- or tenofovir [TDF]-based regimens), and 10 studies (1755 initiations) provided evaluable information on the third drug, which was usually a protease inhibitor. The overall quality of the evidence was rated as very low. For the 2-drug regimen, PEP completion rates were 78.4% (95% confidence interval [CI], 66.1%-90.7%) for people receiving a TDF-based regimen and 58.8% (95% CI, 47.2%-70.4%) for a ZDV-based regimen; the rate of PEP discontinuation due to an adverse event was lower among people taking TDF-based PEP (0.3%; 95% CI, 0%-1.1%) vs a ZDV-based regimen (3.2%; 95% CI, 1.5%-4.9%). For the 3-drug comparison, PEP completion rates were highest for the TDF-based regimens (TDF+emtricitabine [FTC]+lopinavir/ritonavir [LPV/r], 71.1%; 95% CI, 43.6%-98.6%; TDF+FTC+raltegravir [RAL], 74.7%; 95% CI, 41.4%-100%; TDF+FTC+ boosted darunavir [DRV/r], 93.9%; 95% CI, 90.2%-97.7%) and lowest for ZDV+ lamivudine [3TC]+LPV/r (59.1%; 95% CI, 36.2%-82.0%). Discontinuations due to adverse drug reactions were lowest for TDF+FTC+RAL (1.9%; 95% CI, 0%-3.8%) and highest for ZDV+3TC+boosted atazanavir (21.2%; 95% CI, 13.5%-30.0%). Conclusions. The findings of this review provide evidence supporting the use of coformulated TDF and 3TC/FTC as preferred backbone drugs for PEP. Choice of third drug will depend on setting; for resource-limited settings, LPV/r is a reasonable choice, pending the improved availability of better-tolerated drugs with less potential for drug-drug interaction

Interventions to improve the rate or timing of initiation of antiretroviral therapy for HIV in sub-Saharan Africa: meta-analyses of effectiveness

Introduction: As global policy evolves toward initiating lifelong antiretroviral therapy (ART) regardless of CD4 count, initiating individuals newly diagnosed with HIV on ART as efficiently as possible will become increasingly important. To inform progress, we conducted a systematic review of pre-ART interventions aiming to increase ART initiation in sub-Saharan Africa. Methods: We searched PubMed, Embase and the ISI Web of Knowledge from 1 January 2008 to 1 March 2015, extended in PubMed to 25 May 2016, for English language publications pertaining to any country in sub-Saharan Africa and reporting on general adult populations. We included studies describing interventions aimed at increasing linkage to HIV care, retention in pre-ART or uptake of ART, which reported ART initiation as an outcome. We synthesized the evidence on causal intervention effects in meta-analysis of studies belonging to distinct intervention categories. Results and discussion We identified 22 studies, which evaluated 25 interventions and included data on 45,393 individual patients. Twelve of twenty-two studies were observational. Rapid/point-of-care (POC) CD4 count technology (seven interventions) (relative risk, RR: 1.26; 95% confidence interval, CI: 1.02–1.55), interventions within home-based testing (two interventions) (RR: 2.00; 95% CI: 1.36–2.92), improved clinic operations (three interventions) (RR: 1.36; 95% CI: 1.25–1.48) and a package of patient-directed services (three interventions) (RR: 1.54; 95% CI: 1.20–1.97) were all associated with increased ART initiation as was HIV/TB service integration (three interventions) (RR: 2.05; 95% CI: 0.59–7.09) but with high imprecision. Provider-initiated testing (three interventions) was associated with reduced ART initiation (RR: 0.91; 95% CI: 0.86–0.97). Counselling and support interventions (two interventions) (RR 1.08; 95% CI: 0.94–1.26) had no impact on ART initiation. Overall, the evidence was graded as low or moderate quality using the GRADE criteria. Conclusions: The literature on interventions to increase uptake of ART is limited and of mixed quality. POC CD4 count and improving clinic operations show promise. More implementation research and evaluation is needed to identify how best to offer treatment initiation in a manner that is both efficient for service providers and effective for patients without jeopardizing treatment outcomes

Facilitators and barriers in HIV linkage to care interventions: a qualitative evidence review

To synthesize qualitative evidence on linkage to care interventions for people living with HIV

The Role of ARV Associated Adverse Drug Reactions in Influencing Adherence Among HIV-Infected Individuals: A Systematic Review and Qualitative Meta-Synthesis

Poor adherence remains a major barrier to achieving the clinical and public health benefits of antiretroviral drugs (ARVs). A systematic review and qualitative meta-synthesis was conduct to evaluate how ARV adverse drug reactions may influence ARV adherence. Thirty-nine articles were identified, and 33 reported that ARV adverse drug reactions decreased adherence and six studies found no influence. Visually noticeable adverse drug reactions and psychological adverse reactions were reported as more likely to cause non-adherence compared to other adverse drug reactions. Six studies reported a range of adverse reactions associated with EFV-containing regimens contributing to decreased adherence. Informing HIV-infected individuals about ARV adverse drug reactions prior to initiation, counselling about coping mechanisms, and experiencing the effectiveness of ARVs on wellbeing may improve ARV adherence

Barriers and facilitators of interventions for improving antiretroviral therapy adherence: a systematic review of global qualitative evidence.

INTRODUCTION: Qualitative research on antiretroviral therapy (ART) adherence interventions can provide a deeper understanding of intervention facilitators and barriers. This systematic review aims to synthesize qualitative evidence of interventions for improving ART adherence and to inform patient-centred policymaking. METHODS: We searched 19 databases to identify studies presenting primary qualitative data on the experiences, attitudes and acceptability of interventions to improve ART adherence among PLHIV and treatment providers. We used thematic synthesis to synthesize qualitative evidence and the CERQual (Confidence in the Evidence from Reviews of Qualitative Research) approach to assess the confidence of review findings. RESULTS: Of 2982 references identified, a total of 31 studies from 17 countries were included. Twelve studies were conducted in high-income countries, 13 in middle-income countries and six in low-income countries. Study populations focused on adults living with HIV (21 studies, n=1025), children living with HIV (two studies, n=46), adolescents living with HIV (four studies, n=70) and pregnant women living with HIV (one study, n=79). Twenty-three studies examined PLHIV perspectives and 13 studies examined healthcare provider perspectives. We identified six themes related to types of interventions, including task shifting, education, mobile phone text messaging, directly observed therapy, medical professional outreach and complex interventions. We also identified five cross-cutting themes, including strengthening social relationships, ensuring confidentiality, empowerment of PLHIV, compensation and integrating religious beliefs into interventions. Our qualitative evidence suggests that strengthening PLHIV social relationships, PLHIV empowerment and developing culturally appropriate interventions may facilitate adherence interventions. Our study indicates that potential barriers are inadequate training and compensation for lay health workers and inadvertent disclosure of serostatus by participating in the intervention. CONCLUSIONS: Our study evaluated adherence interventions based on qualitative data from PLHIV and health providers. The study underlines the importance of incorporating social and cultural factors into the design and implementation of interventions. Further qualitative research is needed to evaluate ART adherence interventions

Changes in pulmonary tuberculosis prevalence: Evidence from the 2010 population survey in a populous province of China

Background: This paper reports findings from the prevalence survey conducted in Shandong China in 2010, a province with a population of 94 million. This study aimed to estimate TB prevalence of the province in 2010 in comparison with the 2000 survey; and to compare yields of TB cases from different case finding approaches. Methods: A population based, cross-sectional survey was conducted using multi-stage random cluster sampling. 54,279 adults participated in the survey with a response rate of 96%. Doctors interviewed and classified participants as suspected TB cases if they presented with persistent cough, abnormal chest X-ray (CXRAY), or both. Three sputum specimens of all suspected cases were collected and sent for smear microscopy and culture. Results: Adjusted prevalence rate of bacteriologically confirmed cases was 34 per 100,000 for adults in Shandong in 2010. Compared to the 2000 survey, TB prevalence has declined by 80%. 53% of bacteriologically confirmed cases did not present persistent cough. The yield of bacteriologically confirmed cases was 47% by symptom screening and 95% by CXRAY. Over 50% of TB cases were among over 65's. Conclusions: The prevalence rate of bacteriologically confirmed cases was significantly reduced compared with 2000. The survey raised challenges to identify TB cases without clear symptoms

Florence Adler Swims Forever: A Novel

It’s the summer of 1934 and Florence Adler has returned home to Atlantic City from college, intent on swimming the English Channel by summer’s end. When she drowns, while out on a training swim, she leaves behind seven family members and friends who must navigate her loss over the course of the summer—and beyond. There is Florence’s older sister, Fannie, who is pregnant again after recently losing a baby. She’s on bed rest at Atlantic City Hospital while her seven-year-old daughter, Gussie, and her husband, Isaac, make do without her. There are Fannie and Florence’s parents, Esther and Joseph, who have built Adler’s Bakery from the ground up and who thought, until now, that they had realized the American dream. Anna is a young woman, almost exactly Florence’s age, who Joseph recently helped emigrate from Nazi Germany. And there’s Stuart who is a lifeguard with the Atlantic City Beach Patrol and heir to a Boardwalk hotel that doesn’t serve Jewish guests. In the aftermath of the tragedy, Esther decides that the family must keep the news of Florence’s death a secret—at least until Fannie has delivered a healthy baby. This decision and its resulting tensions, becomes the backdrop against which other family secrets are slowly revealed. The novel examines the secrets we keep for the benefit of others and whether we have the right to decide what people get to know about their own lives. This thesis is comprised of the first six chapters of the novel

Evaluation of how active acoustic measurement can create a more intelligent process

I många processindustrier är det viktigt att kunna mäta processvätskors egenskaper på ett bra sätt. Detta går att göra på olika vis. Företaget Acosense AB producerar och säljer ett instrument för att analysera processvätskors egenskaper. Denna metod är en onlineanalys som baseras på aktiv akustisk spektroskopi. Onlineanalysen fungerar på så sätt att en ljudsignal med olika frekvenser skickas genom ett rör där processvätskan strömmar genom. På andra sidan röret sitter en sensor som registrerar ljudsignalen. Beroende på processvätskans egenskaper påverkas ljudsignalen olika mycket och på olika sätt. Det som mäts är hur ljudsignalen förändras. Vid Stora Enso Skutskär produceras pappers- och fluffmassa och anläggningen är en av de industrier som använder tekniken. Genom att i realtid mäta vissa egenskaper hos processvätskorna kan produktionen av massa effektiviseras. Examensarbetet går ut på att ta reda på hur bra tekniken fungerar för att analysera variablerna TOC(totalt organiskt kol), otvättad massakoncentration, tvättad massakoncentration och kappatal. Även en utvärdering av vilken nytta Stora Enso Skutskär kan ha av onlineanalysen görs. För att undersöka tekniken tas massaprover vid kokare 2 hos Stora Enso Skutskär. Proverna analyseras med avseende på de nämnda variablerna. Provresultaten kopplas sedan samman med akustiska spektrum som den akustiska mätutrustningen genererar. Tanken är att utvärdera om det går att analysera variablerna TOC, otvättad massakoncentration, tvättad massakoncentration och kappa med hjälp av akustiska spektrum och statistiska modelleringsmetoder. Denna sammankoppling görs med multivariat analys genom att skapa PCA- och PLS-modeller i programvaran SIMCA. Prover och akustiska spektrum som anses vara på något sätt fel eller icke representativt för massaprocessen eller den akustiska mätutrustningen utesluts för att inte påverka modellerna på ett negativt sätt. PLS-modellerna som tas fram för TOC, otvättad massakoncentration och tvättad massakoncentration har enligt SIMCA dåliga predikteringsförmågor. Även vid test med observationer som inte påverkar modellerna blir resultaten inte korrekta. Det få antalet observationer som modellerna bygger på tros vara en stor orsak till att modellernas predikteringsförmågor inte blir bra. Vid skapandet av PLS-modellen för kappa används betydligt fler observationer. Denna modells predikteringsförmåga blir bättre. För att kunna göra modellerna bättre föreslås att fler prover tas så att modellerna kan byggas upp av fler observationer. Genom att använda en fungerande akustisk onlineanalys går det troligen att effektivisera produktionen på fler än bara ett ställe vid Stora Enso Skutskär.In many process industries, it is important to be able to measure the properties of process fluids in a good way. This can be done in different ways. The company Acosense AB produces and sells an instrument that is able to analyze the properties of process fluids. This method is an online analysis based on active acoustic spectroscopy. The online analysis functions by sending an audio signal with different frequencies through a pipe where the process fluid flows through. At the other side of the pipe a sensor is located that registers the audio signal. Depending on the properties of the process fluids the audio signal is affected to a certain degree and in different ways. What is measured is how the audio signal changes. Stora Enso Skutskär where paper and fluff pulp is produced is one of the industries that use the technology. By measuring certain characteristics of the process fluid in real time the production of pulp can get more effective. The purpose of the thesis is to find out how well the technology is working to analyze the variables TOC (total organic carbon), unwashed pulp concentration, washed pulp concentration and kappa number. An evaluation of what benefits Stora Enso Skutskär may get from using the online analysis is also made. To investigate the technology pulp samples are taken at boiler 2 at Stora Enso Skutskär. The samples are analyzed with regard to the mentioned variables. The test results are then linked together to the acoustic spectrum that the acoustic measurement equipment generates. The idea is that it should possible to predict the variables TOC, unwashed pulp concentration, washed pulp concentration and kappa number by using only the acoustic spectrum and statistical modeling methods. This connection is made with multivariate analysis by creating PCA and PLS models in the software SIMCA. Samples and acoustic spectrum that are considered to stand out to much or are non-representative of the pulping process or of the acoustic measurement equipment are excluded so they don’t affect the models in a negative way. The PLS models are developed for TOC, unwashed pulp concentration and washed pulp concentration has, according to SIMCA poor ability to predict. When testing with the observations that do not affect the models, the results are still poor. The reason for the poor ability to predict is believed to be the low number of observations which the models are based on. When creating the PLS model for the kappa number a significantly higher number of observations are used. This models ability to predict is better.I In order to make better models it is suggested that more samples are taken so that the models can be based on more observations. By using a functional acoustic online analysis the production can probably get more efficient in more than one location at Stora Enso Skutskär