Accelerating investigation of new HIV drugs in pregnancy: advancing the research agenda from theory to action.

INTRODUCTION: Historical approaches to clinical development of novel therapeutics for treatment and prevention of HIV have led to unacceptable delays in the generation of data to support optimal antiretroviral drug use in pregnancy. Over the last 5 years, multiple stakeholders have voiced their concerns around the exclusion of pregnant women from drug trials, and some progress has been made to consolidate principles and forge consensus. Building on ongoing efforts, the World Health Organization (WHO) and the International Maternal Paediatric Adolescent AIDS Clinical Trials Network (IMPAACT) convened a technical consultation designed to move the discussion from theory to practice. DISCUSSION: Accelerating the inclusion of pregnant women in pre-licensure clinical trials, with a goal to have pharmacokinetics (PK) and preliminary safety data for all new HIV agents in pregnancy available at the time of drug approval, requires: (1) performing non-clinical developmental and reproductive toxicology studies early in drug development for all new HIV agents; (2) recognizing and acting on the central role of women of childbearing potential affected by HIV through the research being conducted and the dissemination of associated results; (3) enrolling pregnant women in studies to specifically determine pregnancy PK and preliminary safety, as soon as late non-clinical studies are completed with no negative signals, for all new HIV agents that have demonstrated preliminary evidence of safety and efficacy from phase 2 trials; (4) investigating adverse pregnancy and birth outcomes through dedicated pregnancy safety studies for all new priority HIV agents; and (5) expanding active surveillance of drug safety in pregnancy for rare events, such as birth defects. Strategic actions to pursue include developing tools and resources to support designing and implementing studies among pregnant and breastfeeding women, identifying and promoting modifications of the regulatory framework that are supportive of systematic ethical investigation of new drugs in pregnancy, coordinating surveillance efforts, mobilizing key stakeholders and promoting transparency and accountability for all involved. CONCLUSIONS: With more than 19 million women living with HIV worldwide, ensuring greater inclusion of pregnant women in research on novel therapeutics is a priority to support drug optimization and effective introduction of innovations for treatment and prevention of HIV.

Setting Global Research Priorities in Pediatric and Adolescent HIV Using the Child Health and Nutrition Research Initiative (CHNRI) Methodology.

BACKGROUND: WHO and the Collaborative Initiative for Paediatric HIV Education and Research (CIPHER) of the International AIDS Society (IAS) led a collaborative process to set global prioritized research agendas, aiming to focusing future research, funding, and stakeholder's efforts. This study describes the methodology used to establish the research agendas. METHODS: The Child Health and Nutrition Research Initiative methodology was adapted in parallel exercises on pediatric and adolescent HIV. After definition of scope by an expert working group, priority questions were collected from stakeholders through an online survey. Submitted questions were coded, analyzed, and collated. The same respondents were asked to score the collated lists through a second online survey. The top 10 ranked questions per thematic area (testing, treatment, and service delivery) were reviewed and priority themes developed with consideration of existing policy, systematic reviews, and planned, ongoing, and recently published research. RESULTS: A total of 375 respondents submitted 1735 priority research questions. The majority of respondents were from Africa; 55% self-identified as researchers. The final collated lists included 51 and 61 research questions for pediatric and adolescent HIV, respectively. The response rate for the second survey was 48%. The final research agendas include 5 priority research themes per area, discussed in 2 separate publications. CONCLUSIONS: To date, this is the largest example of the Child Health and Nutrition Research Initiative method in pediatric and adolescent HIV in terms of stakeholders reached, and the first to incorporate top thematic areas based on current evidence. Its impact on improving outcomes for these populations will require strong political and financial commitment.

A Global Research Agenda for Pediatric HIV.

BACKGROUND: Despite progress, 2016 still saw 160,000 new infections and 120,000 AIDS-related deaths among children. Evidence gaps on how to best diagnose, treat, and deliver services to children living with HIV remain. A global research prioritization exercise was undertaken by WHO and CIPHER to focus research efforts in the context of diminishing resources. METHODS: The Child Health and Nutrition Research Initiative methodology was adapted and used, as described by Irvine et al. Outcomes were reviewed by an expert group and 5 priority themes identified for testing, antiretroviral treatment, and service delivery, accounting for existing policies, published literature and ongoing research. RESULTS: A total of 749 questions were submitted by 269 individuals from 62 countries. For HIV testing, priority themes included strategies and interventions to improve access, uptake and linkage to care, including with novel diagnostic tools and entry points beyond antenatal care. For treatment, priorities included strategies to improve adherence, short- and long-term outcomes and management of coinfections, optimal drug formulations, and early ART. For service delivery, priorities included strategies or interventions to improve access, uptake and retention in care, including psychosocial and family support and approaches to HIV disclosure and reduction of stigma and discrimination. CONCLUSIONS: This is the largest Child Health and Nutrition Research Initiative exercise undertaken in HIV. The results provide guidance to focus future research in pediatric HIV for impact. Global commitment to support priority research, adequate investment, and strong leadership is urgently needed to improve the health and well-being of children living with and affected by HIV.

A Global Research Agenda for Adolescents Living With HIV.

BACKGROUND: Despite growing interest in undertaking research in adolescent HIV, the current pace of interventional research in particular remains very low compared with the needs of adolescents living with HIV (ALHIV). More robust evidence is needed to inform innovative and targeted interventions that bridge research gaps, inform policy, and improve outcomes for adolescents. A global research prioritization exercise was undertaken by WHO and CIPHER to focus efforts on priority research in the context of diminishing resources. METHODS: The Child Health and Nutrition Research Initiative (CHNRI) methodology was adapted and used. Outcomes were reviewed by an expert group and 5 priority themes identified for testing, treatment, and service delivery, accounting for existing policies, published literature, and ongoing research. RESULTS: A total of 986 research questions were submitted by 323 individuals from 67 countries. For HIV testing, priority themes included strategies and interventions to improve access, uptake, and linkage to care, and self-testing, particularly for key populations. For treatment, priorities included strategies to monitor and improve adherence, novel drug delivery systems, preventions and management of coinfections, optimal drug sequencing, and short- and long-term outcomes. For service delivery, priorities included service delivery models across the cascade, strategies to improve retention in care and sexual and reproductive health, support for pregnant ALHIV, and the provision of psychosocial support. CONCLUSIONS: This prioritized research agenda assists in focusing future research in ALHIV and will help to fill critical knowledge gaps. Key stakeholders, donors, program managers, and researchers should all support these priority questions and themes to collaboratively drive the adolescent HIV research agenda forward.

Protocol for a retrospective, controlled cohort study of the impact of a change in Nature journals' editorial policy for life sciences research on the completeness of reporting study design and execution.

In recent years there has been increasing concern about the rigor of laboratory research. Here we present the protocol for a study comparing the completeness of reporting of in vivo and in vitro research carried in Nature Publication Group journals before and after the introduction of a change in editorial policy (the introduction of a set of guidelines for reporting); and in similar research published in other journals in the same periods.

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 (I(2) = 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 exposure.

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 interactions.

Starter packs versus full prescription of antiretroviral drugs for postexposure prophylaxis: a systematic review.

BACKGROUND: The provision of starter packs for human immunodeficiency virus postexposure prophylaxis (PEP) is practiced in many settings to facilitate rapid initiation by nonexperts and encourage adherence. However, the impact of starter packs on PEP completion rates has not been systematically assessed. We systematically reviewed the evidence on outcomes associated with starter packs for PEP compared to full prescriptions. METHODS: Four databases and 2 conference abstract sites were searched up to December 2013; this search was updated in 1 database in June 2014. PEP completion rates, stratified by prescribing practice, were pooled using random-effects meta-analysis. RESULTS: Fifty-four studies provided data on 11 714 PEP initiations. Thirty-seven studies, including 3 randomized controlled trials (RCTs) and 34 observational cohorts, provided information on starter packs (although none of the RCTs specifically assessed starter packs), and 17 studies, including 2 RCTs and 15 observational cohorts, provided information on full prescriptions. Overall, outcomes were better when participants were offered a full 28-day course of PEP at initial presentation to healthcare, with fewer refusals (11.4% [95% confidence interval {CI}, 5.3%-17.5%] vs 22% [95% CI, 16.7%-28.1%]) and higher completion rates (70% [95% CI, 56.7%-77.3%] vs 53.2% [95% CI, 44.4%-62.2%]). More than a quarter (28% [95% CI, 21.4%-34.5%]) of individuals provided with a PEP starter pack failed to return for their subsequent appointment and therefore defaulted prior to receiving a full course of PEP. The quality of the evidence overall was rated as very low. CONCLUSIONS: The findings of this review suggest that starter packs do not improve adherence to PEP and may result in lower adherence and completion rates.

End Users' Views and Preferences on Prescribing and Taking Postexposure Prophylaxis for Prevention of HIV: Methods to Support World Health Organization Guideline Development.

The 2014 World Health Organization guidelines for human immunodeficiency virus postexposure prophylaxis (PEP) are the first to combine recommendations for all populations and exposures. To inform the development of these guidelines, we gathered views of end users on key aspects of PEP provision. A mixed-methods approach was used to gather views from the populations for whom the guideline will be of relevance. Data gathered from an online survey, focus group discussions, and previously collected data from in-depth interviews with key populations were used to inform the development of recommendations, in particular where there is a paucity of evidence to assess the benefits and harms of an intervention. This was a successful method to gather end users' views and preferences; however, limitations exist in the generalizability and reliability of the evidence. Future guideline development processes should consider methods to include the views of end users to guide the decision-making process.

Drug repurposing: a systematic approach to evaluate candidate oral neuroprotective interventions for secondary progressive multiple sclerosis.

OBJECTIVE: To develop and implement an evidence based framework to select, from drugs already licenced, candidate oral neuroprotective drugs to be tested in secondary progressive multiple sclerosis. DESIGN: Systematic review of clinical studies of oral putative neuroprotective therapies in MS and four other neurodegenerative diseases with shared pathological features, followed by systematic review and meta-analyses of the in vivo experimental data for those interventions. We presented summary data to an international multi-disciplinary committee, which assessed each drug in turn using pre-specified criteria including consideration of mechanism of action. RESULTS: We identified a short list of fifty-two candidate interventions. After review of all clinical and pre-clinical evidence we identified ibudilast, riluzole, amiloride, pirfenidone, fluoxetine, oxcarbazepine, and the polyunsaturated fatty-acid class (Linoleic Acid, Lipoic acid; Omega-3 fatty acid, Max EPA oil) as lead candidates for clinical evaluation. CONCLUSIONS: We demonstrate a standardised and systematic approach to candidate identification for drug rescue and repurposing trials that can be applied widely to neurodegenerative disorders.

Adherence to HIV postexposure prophylaxis: a systematic review and meta-analysis.

INTRODUCTION: We evaluated variations in completion rates for HIV postexposure prophylaxis (PEP) according to the exposure type (occupational, nonoccupational, and sexual assault), patient, and programme characteristics. METHODS: Four major databases were searched together with conference abstract databases from inception to 1 December 2013, updated in PubMed on 1 June 2014. Randomized and nonrandomized studies reporting completion rates for PEP were included regardless of exposure type, age, or geographical location and data pooled using random-effects meta-analysis. RESULTS: Ninety-seven studies, reporting outcomes on 21 462 PEP initiations, were reviewed. Nonoccupational exposure to HIV was the main reason for PEP in 34 studies (n = 11 840), occupational exposure in 22 studies (n = 3058), sexual assault in 26 studies (n = 3093), and the remainder of studies (15 studies, n = 3471) reported outcomes for mixed exposures. Overall, 56.6% [95% confidence (CI) 50.9-62.2%; τ(2) 0.25] of people considered eligible for PEP completed the full standard 28-day course. Compared with the overall estimate of PEP completion, rates were highest for studies reporting PEP for nonoccupational exposures (65.6%, 95% CI 55.6-75.6%) and lowest for sexual assault (40.2%, 95% CI 31.2-49.2%); higher rates of PEP completion were also reported for MSM (67.2%, 95% CI 59.5-74.9%). Completion rates appeared to be lower for adolescents (36.6%, 95% CI 4.0-69.2%) compared with adults (59.1%, 95% CI 53.9-64.2%) or children (64.0%, 95% CI 41.2-86.8%). CONCLUSION: Adherence to a full 28-day course of antiretroviral drugs prescribed for PEP is poor. Efforts should be made to simplify guidelines for prescribers and support adherence for people taking PEP, with particular attention needed for adolescents and victims of sexual assault.

Efficacy of antidepressants in animal models of ischemic stroke: a systematic review and meta-analysis.

BACKGROUND AND PURPOSE: Poststroke depression is a prevalent complication of stroke with unclear pathogenesis. The benefits of antidepressants in this context and their effects on stroke recovery other than effects on mood are not clearly defined, with some studies suggesting efficacy in improving functional outcome in both depressed and nondepressed stroke patients. We have analyzed the preclinical animal data on antidepressant treatment in focal cerebral ischemia, modeled±depression, to help inform clinical trial design. METHODS: We performed a systematic review and meta-analysis of data from experiments testing the efficacy of antidepressants versus no treatment to reduce infarct volume or improve neurobehavioral or neurogenesis outcomes in animal models of stroke. We used random-effects metaregression to test the impact of study quality and design characteristics and used trim and fill to assess publication bias. RESULTS: We identified 44 publications describing the effects of 22 antidepressant drugs. The median quality checklist score was 5 of a possible 10 (interquartile range, 4-7). Overall, antidepressants reduced infarct volume by 27.3% (95% confidence interval, 20.7%-33.8%) and improved neurobehavioral outcomes by 53.7% (46.4%-61.1%). There was little evidence for an effect of selective serotonin reuptake inhibitors on infarct volume. For neurobehavioral outcomes there was evidence of publication bias. Selective serotonin reuptake inhibitors were the most frequently studied antidepressant subtype and improved neurobehavioral outcome by 51.8% (38.6%-64.9%) and increased neurogenesis by 2.2 SD (1.3-3.0). CONCLUSIONS: In line with current clinical data and despite some limitations, antidepressant treatments seem to improve infarct volume and neurobehavioral outcome in animal models of ischemic stroke.