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Introduction: In 2004, the US government began to utilize the Food and Drug Administration's (USFDA) tentative approval process (tFDA) as a basis to determine which HIV drugs are appropriate to be purchased and used in resource-constrained settings. This process permits products that are not approved for marketing in the US, including medicines with active patents or marketing restrictions in the US, to be purchased and distributed in resource-constrained settings. Although the tFDA was originally intended to support the United States' President's Emergency Plan for AIDS Relief (PEPFAR), the USFDA list has become a cornerstone of international HIV programmes that support procurement of ARVs, such as the World Health Organization and the Global Fund to Fight AIDS, Tuberculosis, and Malaria. Our objective in this article is to help the global HIV policy makers and implementers of HIV programmes better understand the benefits and limitations of the tFDA by providing an in-depth review of the relevant legal and regulatory processes. Discussion: USFDA's dedicated tFDA process for ARVs used by the PEPFAR programme has a wide impact globally; however, the implementation and the regulatory processes governing the programme have not been thoroughly described in the medical literature. This paper seeks to help stakeholders better understand the legal and regulatory aspects associated with review of ARVs under the tFDA by describing the following: (1) the tFDA and its importance to global ARV procurement; (2) the regulatory pathways for applications under tFDA for the PEPFAR programme, including modifications to applications, review timelines and costs; (3) the role of US patents, US marketing exclusivity rights, and the Medicines Patents Pool in tFDA; and (4) an overview of how applications for PEPFAR programme are processed through the USFDA. We also provide a case study of a new ARV, tenofovir alafenamide fumarate (TAF), not yet reviewed by USFDA for PEPFAR use. Conclusions: In this paper, we describe the importance and implementation of USFDA's tentative approval process to review ARVs for resource-constrained settings. We also highlight the impact of patents and exclusivities on review of HIV drugs under tFDA and illustrate the concepts using a new HIV drug as an example. [ABSTRACT FROM AUTHOR]

Introduction The extraordinary feat of proving the effectiveness of oral pre-exposure prophylaxis (PrEP) in clinical trials in different populations in a variety of settings may prove to have been easier than ensuring it is used well. Decision-makers must make difficult choices to realize the promise of antiretroviral prophylaxis for their countries. This paper outlines key economic, regulatory and distributive justice issues that must be addressed for effective and acceptable PrEP implementation. Discussion In considering the role that PrEP can play in combination prevention programmes, decision-makers must determine who can benefit most from PrEP, how PrEP can be provided safely and efficiently, and what kind of health system support will ensure successful implementation. To do this, they need contextualized information on disease burden by population, analyses of how PrEP services might best be delivered, and projections of the human resource and infrastructure requirements for each potential delivery model. There are cost considerations, varying cost-effectiveness results and regulatory challenges. The principles of ethics can inform thorny discussions about who should be prioritized for oral PrEP and how best to introduce it fairly. We describe the cost-effectiveness of PrEP in different populations at higher risk of HIV exposure, its price in low- and middle-income countries, and the current regulatory situation. We explore the principles of ethics that can inform resource allocation decision-making about PrEP anchored in distributive justice, at a time when universal access to antiretroviral treatment remains to be assured. We then highlight the role of advocacy in moving the PrEP agenda forward. Conclusions The time is ripe now for decisions about whether, how and for whom PrEP should be introduced into a country's HIV response. It has the potential to contribute significantly to high impact HIV prevention if it is tailored to those who can most benefit from it and if current regulatory and pricing barriers can be overcome. Advocacy at all levels can help inform decision-making and push the access agenda to avert HIV infections among those at highest risk of HIV exposure. The benefits will accrue beyond the individual level to slow HIV transmission at the population level. [ABSTRACT FROM AUTHOR]

The article discusses research which examined the role of pre-exposure prophylaxis (PrEP) in addressing the global HIV/AIDS epidemic. Topics discussed include the papers on the PrEP implementation, potential impact and efficiency, social science concerns and the study of modern PrEP implementation and cost-effectiveness analysis targeting PrEP and antiretroviral (ART).

Women continue to be at special risk for HIV acquisition due to a complex mix of biological, behavioural, structural, cultural and social factors, with unacceptable rates of new infection. Scientific advances over the past decade have highlighted the use of antiretroviral (ARV) drugs as pre-exposure prophylaxis (PrEP) to prevent HIV acquisition (sexually, parenterally and vertically) and ARV treatment (ART) for HIV-positive patients to prevent onward transmission (treatment as prevention - TasP). This paper reviews the evidence base for PrEP and TasP, describes new products in development and the need to translate research findings into programmes with impact at the population level. [ABSTRACT FROM AUTHOR]

The retinoid (10mM) increased viral reactivation mediated by IL-15 to a similar extent as HODHBt (100mM) but unlike HODHBt, specifically promoted cell death of latently infected cells compared to controls when combined with IL-15. This indicates that the retinoid is able to reactivate latent HIV through a mechanism mediated by IL-15 but not directly dependent on STAT5 phosphorylation. Among the clinically relevant latency reversing agents (LRA) under investigation, IL-15 or the IL-15 superagonist N-803 have been shown to reactivate latent HIV I ex vivo i and I in vivo i . [Extracted from the article]

ARV-based HIV prevention methods available in pill, gel or ring formulations (broadly referred to as microbicides) offer the possibility of protection against HIV for women who find it difficult because they cannot ask their partners to use condoms or even refuse sex. Partial efficacy of ARV-based medications has been demonstrated in a number of clinical trials around the world among various populations, building the evidence that ARV-based technologies will contribute to reducing the AIDS epidemic worldwide. Disappointing results, however, from two trials in sub-Saharan Africa, where poor adherence contributed to study closure due to futility, have raised questions about whether women at the centre of the epidemic are able to effectively use products that require routine use. Also, there are fears by some of risk compensation by decreased condom use because of the availability of microbicides when only partial efficacy has been demonstrated in microbicide trials to date. Of note, sub-analyses of biologic measures of adherence in trials where this was possible have shown a strong correlation between good adherence and efficacy, reinforcing the necessity of good adherence. Research conducted in conjunction with clinical trials and post-trials in advance of possible rollout of ARV-based products have examined social and cultural factors, gender-related and otherwise, influencing adherence and other aspects of women's use of products. These include HIV stigma, women's perception of risk, partner and community influences and the differing needs of women in various stages of life and in different circumstances. It is the purpose of this supplement to give voice to the needs of women who can benefit from woman-initiated methods by presenting research results and commentary to contribute to the global conversation about optimizing women's experience with ARV-based prevention. [ABSTRACT FROM AUTHOR]

Introduction: Successful population-level antiretroviral therapy (ART) adherence will be necessary to realize both the clinical and prevention benefits of antiretroviral scale-up and, ultimately, the end of AIDS. Although many people living with HIV are adhering well, others struggle and most are likely to experience challenges in adherence that may threaten virologic suppression at some point during lifelong therapy. Despite the importance of ART adherence, supportive interventions have generally not been implemented at scale. The objective of this review is to summarize the recommendations of clinical, research, and public health experts for scalable ART adherence interventions in resource-limited settings. Methods: In July 2015, the Bill and Melinda Gates Foundation convened a meeting to discuss the most promising ART adherence interventions for use at scale in resource-limited settings. This article summarizes that discussion with recent updates. It is not a systematic review, but rather provides practical considerations for programme implementation based on evidence from individual studies, systematic reviews, meta-analyses, and the World Health Organization Consolidated Guidelines for HIV, which include evidence from randomized controlled trials in low- and middle-income countries. Interventions are categorized broadly as education and counselling; information and communication technology-enhanced solutions; healthcare delivery restructuring; and economic incentives and social protection interventions. Each category is discussed, including descriptions of interventions, current evidence for effectiveness, and what appears promising for the near future. Approaches to intervention implementation and impact assessment are then described. Results and discussion: The evidence base is promising for currently available, effective, and scalable ART adherence interventions for resource-limited settings. Numerous interventions build on existing health care infrastructure and leverage available resources. Those most widely studied and implemented to date involve peer counselling, adherence clubs, and short message service (SMS). Many additional interventions could have an important impact on ART adherence with further development, including standardized counselling through multi-media technology, electronic dose monitoring, decentralized and differentiated models of care, and livelihood interventions. Optimal targeting and tailoring of interventions will require improved adherence measurement. Conclusions: The opportunity exists today to address and resolve many of the challenges to effective ART adherence, so that they do not limit the potential of ART to help bring about the end of AIDS. [ABSTRACT FROM AUTHOR]

Introduction: Specific environmental factors may play a role in the development of Pneumocystis pneumonia (PCP) in HIVpositive patients. The aim of this study was to estimate the PCP incidence and mortality in hospitalized HIV-positive patients in Spain during the combination antiretroviral therapy (cART) era (1997 to 2011), as well as to analyze the climatological factors and air pollution levels in relation to hospital admissions and deaths. Methods: We carried out a retrospective study. Data were collected from the National Hospital Discharge Database and the State Meteorological Agency of Spain. A case-crossover analysis was applied to identify environmental risk factors related to hospitalizations and deaths. For each patient, climatic factors and pollution levels were assigned based on readings from the nearest meteorological station to his or her postal code. Results: There were 13,139 new PCP diagnoses and 1754 deaths in hospitalized HIV-positive patients from 1997 to 2011. The PCP incidence (events per 1000 person-years) dropped from 11.6 in 1997 to 2000, to 5.4 in 2004 to 2011 (p<0.001). The mortality (events per 10,000 person-years) also decreased from 14.3 in 1997 to 2000, to 7.5 in 2004 to 2011 (p<0.001). Most hospital admissions and deaths occurred in the winter season and the fewest occurred in the summer, overlapping respectively with the lowest and highest temperatures of the year in Spain. Moreover, lower temperatures prior to PCP admission, as well as higher concentrations of NO2 and particulate matter up to 10 m in size (PM10) at the time of admission were associated with higher likelihoods of hospital admission due to PCP when two weeks, one month, 1.5 months or two months were used as controls (p<0.01). Furthermore, higher concentrations of ozone at one month (p=0.007), 1.5 months (p<0.001) and two months (p=0.006) prior to admission were associated with higher likelihoods of hospital admission with PCP. For PCP-related deaths, lower temperatures prior to admission and higher concentrations of atmospheric PM10 at the time of admission were related to higher likelihood of death when two weeks, one month and 1.5 months were used as controls (p<0.05). Conclusions: PCP was a significant health problem in the cART era (1997 to 2011), and PCP epidemiology was adversely influenced by colder climatological factors and higher ambient air pollution levels. [ABSTRACT FROM AUTHOR]

Introduction: Low bone mass is prevalent in HIV-positive patients. However, compared to Western countries, less is known about HIV-associated osteopenia in Asian populations. Methods: We performed a cross-sectional survey in Seoul National University Hospital from December 2011 to May 2012. We measured bone mineral density using central dual energy X-ray absorptiometry, with consent, in male HIV-positive patients, aged 40 years and older. Diagnosis of low bone mass was made using International Society for Clinical Densitometry Z-score criteria in the 40-49 years age group and World Health Organization T-score criteria in the >50-year age group. The data were compared with those of a community-based cohort in Korea. Results: Eighty-four HIV-positive male patients were included in this study. Median age was 49 (interquartile range [IQR], 45-56) years, and median body mass index (BMI) was 22.6 (IQR, 20.9-24.4). Viral suppression was achieved in 75 (89.3%) patients and median duration of antiretroviral therapy was 71 (IQR, 36-120) months. The overall prevalence of low bone mass was 16.7% in the 40-49 years age group and 54.8% in the>50 years age group. Our cohort had significantly lower bone mass at the femur neck and total hip than HIV-negative Koreans in the 40-49 years age group. Low bone mass was significantly associated with low BMI, and a high level of serum carboxy-terminal collagen crosslinks, but was not associated with antiretroviral regimen or duration of antiretroviral therapy. Conclusions: Low bone mass is prevalent in Korean HIV-positive males undergoing antiretroviral therapy, and may be associated with increased bone resorption. [ABSTRACT FROM AUTHOR]

Introduction: Shifting HIV treatment tasks from physicians to nurses and midwives is essential to scaling-up HIV services in sub-Saharan Africa. Updating nursing and midwifery regulations to include task shifting and pre-service education reform can help facilitate reaching new HIV targets. Donor-supported initiatives to update nursing and midwifery regulations are increasing. However, there are gaps in our knowledge of current practice and education regulations and a lack of information to target and implement regulation strengthening efforts. We conducted a survey of national nursing and midwifery councils to describe current nursing and midwifery regulations in 13 African countries. Methods: A 30-item survey was administered to a convenience sample of 13 national nursing and midwifery regulatory body leaders in attendance at the PEPFAR-supported African Health Profession Regulatory Collaborative meeting in Nairobi, Kenya on 28 February, 2011. The survey contained questions on task shifting and regulations such as registration, licensure, scope of practice, pre-service education accreditation, continuing professional development and use of international guidelines. Survey data were analyzed to present country-level, comparative and regional findings. Results: Task shifting to nurses and midwives was reported in 11 of the 13 countries. Eight countries updated their scope of practice within the last five years; only one reported their regulations to reflect task shifting. Countries vary with regard to licensure, pre-service accreditation and continuing professional development regulations in place. There was no consistency in terms of what standards were used to design national practice and education regulations. Discussion: Many opportunities exist to assist countries to modernise regulations to incorporate important advancements from task shifting and pre-service reform. Appropriate, revised regulations can help sustain successful health workforce strategies and contribute to further scale-up HIV services and other global health priorities. Conclusions: This study provides fundamental information from which to articulate goals and to measure the impact of regulation strengthening efforts [ABSTRACT FROM AUTHOR]

Introduction: Papulopruritic eruption (PPE) occurs in people living with HIV in India. Understanding the risk factors associated with this disease may help decrease the prevalence of PPE. Methods: This study was a case-control study performed at the Government Hospital of Thoracic Medicine, a tertiary care hospital in Chennai, India. Cases included HIV-positive, antiretroviral (ARV) therapy-naïve adults experiencing a pruritic skin eruption for longer than one month, with evidence of multiple papular or nodular lesions and biopsy consistent with arthropod bite. Controls included HIV-positive, ARV-naïve patients without active skin rash. Main outcome measures were CD4 cell count, histology, and environmental exposures. We performed statistical analysis using Epi Info version 3.5.1 and SPSS version 11.0 (SPSS Inc., Chicago, IL). Categorical variables such as gender, urban versus rural residence, occupation, treatment history, CD4 count, use of insect repellents, and environmental exposures were evaluated using the x2 test (or the Fisher exact test when an expected value for a category was less than 5). The t-test was used to evaluate differences in age and the duration since HIV diagnosis. The Mann-Whitney test was used to compare non-normally distributed values such as CD4 cell count. A p-value that was less than 0.05 was considered to be statistically significant. Results: Forty-one cases and 149 control subjects were included. Subjects with PPE had significantly lower CD4 cell counts compared to controls (225.5 cells/μL vs. 425 cells/μL; p=0.0001). Sixty-six percent of cases had a CD4 cell count less than 350 cells/μL. PPE cases were less likely to use mosquito repellent techniques (odds ratio 2.81, CI=1.45-5.45). Discussion: PPE may be an altered and exaggerated immune response to arthropod bites in HIV-positive patients. CD4 cell count is significantly lower in patients with PPE, and therefore it may be considered a qualifying clinical finding for ARV initiation in resource-poor settings. Protective measures against mosquito bites appeared to be important in preventing PPE in subjects at risk. [ABSTRACT FROM AUTHOR]

Until now, we have all been desperately trying to run behind the HIV/AIDS epidemic and catch up with it, but despite all our eff orts, the epidemic remains well ahead of us. In 2010, the antiretroviral treatment (ART) gap was about 60%, AIDS-related deaths were almost two million a year, and on top of these fi gures, for every one person started on ART, there were two new HIV infections. What is needed to change this situation is to think ahead of the epidemic in terms of the programmatic tasks we will be faced with and try to act boldly in trying to implement those tasks. From a programmatic perspective, we: a) highlight what needs to fundamentally change in our thinking and overall approach to the epidemic; and b) outline a number of key task areas for implementation and related operational research. [ABSTRACT FROM AUTHOR]