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Summary Background In DISCOVER, a multinational, randomised controlled trial, emtricitabine and tenofovir alafenamide compared with emtricitabine and tenofovir disoproxil fumarate showed non-inferior efficacy for HIV prevention and improved bone mineral density and renal safety biomarkers at week 48. We report outcomes analysed after all participants had completed 96 weeks of follow-up. Methods This study is an ongoing, randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial done at 94 community, public health, and hospital-associated clinics located in Europe and North America. Adult cisgender men and transgender women who have sex with men, both with a high risk of acquiring HIV as determined by self-reported sexual behaviour or recent sexually transmitted infections, were randomly assigned (1:1) to receive either emtricitabine and tenofovir alafenamide (200/25 mg) tablets daily, with matched placebo tablets (emtricitabine and tenofovir alafenamide group), or emtricitabine and tenofovir disoproxil fumarate (200/300 mg) tablets daily, with matched placebo tablets (emtricitabine and tenofovir disoproxil fumarate group). The primary efficacy outcome was incident HIV infection. Incidence of HIV-1 infection per 100 person-years was assessed when the last participant had completed 96 weeks of follow-up. This trial is registered with ClinicalTrials.gov , number NCT02842086 . Findings Between Sept 13, 2016, and June 30, 2017, 5387 participants were randomly assigned to receive emtricitabine and tenofovir alafenamide (n=2694) or emtricitabine and tenofovir disoproxil fumarate (n=2693), contributing 10 081 person-years of follow-up. At 96 weeks of follow-up, there were eight HIV infections in participants who had received emtricitabine and tenofovir alafenamide (0·16 infections per 100 person-years [95% CI 0·07–0·31]) and 15 in participants who had received emtricitabine and tenofovir disoproxil fumarate (0·30 infections per 100 person-years [0·17–0·49]). Emtricitabine and tenofovir alafenamide maintained its non-inferiority to emtricitabine and tenofovir disoproxil fumarate for HIV prevention (IRR 0·54 [95% CI 0·23–1·26]). Approximately 78–82% of participants reported taking study medication more than 95% of the time across all study visits. Rates of sexually transmitted infections remained high and similar across groups (21 cases per 100 person-years for rectal gonorrhoea and 28 cases per 100 person-years for rectal chlamydia). Emtricitabine and tenofovir alafenamide continued to show superiority over emtricitabine and tenofovir disoproxil fumarate in all but one of the six prespecified bone mineral density and renal biomarkers. There was more weight gain among participants who had received emtricitabine and tenofovir alafenamide (median weight gain 1·7 kg vs 0·5 kg, p Interpretation Emtricitabine and tenofovir alafenamide is safe and effective for longer-term pre-exposure prophylaxis in cisgender men and transgender women who have sex with men. Funding Gilead Sciences.

Introduction Understanding differences in knowledge and behaviors among men who have sex with men (MSM), men who have sex with women (MSW), and women, is critical to tailor HIV treatment. We investigated these differences among an international sample of people living with HIV (PLHIV) in 25 countries. Methods Data came from the 2019 Positive Perspectives Study, an online convenience sample of PLHIV in 25 middleand high-income countries. Participants were categorized as MSM (n=1018), MSW (n=479), or women (n=696), based on self-classified gender and sexual orientation. Descriptive and multivariable analyses were performed (p

Objectives‘Undetectable equals Untransmittable’ (U=U) is an empowering message that may enable people living with HIV (PLHIV) to reach and maintain undetectability. We estimated the percentage of PLHIV who ever discussed U=U with their main HIV care provider, and measured associations with health-related outcomes. Secondarily, we evaluated whether the impact of the U=U message varied between those who heard it from their healthcare provider (HCP) vs from elsewhere.MethodsData were from the 25-country 2019 Positive Perspectives Survey of PLHIV on treatment (n=2389). PLHIV were classified as having discussed U=U with their HCP if they indicated that their HCP had ever told them about U=U. Those who had not discussed U=U with their HCP but were nonetheless aware that ‘My HIV medication prevents me from passing on HIV to others’ were classified as being made aware of U=U from non-HCP sources. Multivariable logistic regression was used to measure associations between exposure to U=U messages and health outcomes.ResultsOverall, 66.5% reported ever discussing U=U with their HCP, from 38.0% (South Korea) to 87.3% (Switzerland). Prevalence was lowest among heterosexual men (57.6%) and PLHIV in Asia (51.3%). Compared with those unaware of U=U, those reporting U=U discussions with their HCP had lower odds of suboptimal adherence (AOR=0.59, 95% CI 0.44 to 0.78) and higher odds of self-reported viral suppression (AOR=2.34, 95% CI 1.72 to 3.20), optimal sexual health (AOR=1.48, 95% CI 1.14 to 1.92) and reporting they ‘always shared’ their HIV status (AOR=2.99, 95% CI 1.42 to 6.28). While exposure to U=U information from non-HCP sources was beneficial too, the observed associations were attenuated relative to those seen with reported discussions with HCPs.ConclusionHCP discussion of U=U with PLHIV was associated with favourable health outcomes. However, missed opportunities exist since a third of PLHIV reported not having any U=U discussion with their HCP. U=U discussions with PLHIV should be considered as a standard of care in clinical guidelines.

Curing HIV infection will require the elimination of a reservoir of infected CD4(+) T cells that persists despite HIV-specific cytotoxic T cell (CTL) responses. Although viral latency is a critical factor in this persistence, recent evidence also suggests a role for intrinsic resistance of reservoir-harboring cells to CTL killing. This resistance may have contributed to negative outcomes of clinical trials, where pharmacologic latency reversal has thus far failed to drive reductions in HIV reservoirs. Through transcriptional profiling, we herein identified overexpression of the prosurvival factor B cell lymphoma 2 (BCL-2) as a distinguishing feature of CD4(+) T cells that survived CTL killing. We show that the inducible HIV reservoir was disproportionately present in BCL-2(hi) subsets in ex vivo CD4(+) T cells. Treatment with the BCL-2 antagonist ABT-199 was not sufficient to drive reductions in ex vivo viral reservoirs when tested either alone or with a latency-reversing agent (LRA). However, the triple combination of strong LRAs, HIV-specific T cells, and a BCL-2 antagonist uniquely enabled the depletion of ex vivo viral reservoirs. Our results provide rationale for novel therapeutic approaches targeting HIV cure and, more generally, suggest consideration of BCL-2 antagonism as a means of enhancing CTL immunotherapy in other settings, such as cancer.

Background Black and Latina transgender women (BLTW) face significant HIV disparities with estimated HIV prevalence up to 50% and annual incidence rates as high as 2.8 per 100 person-years. However, few studies have evaluated the acceptability and uptake of high-impact HIV prevention interventions among BLTW. Setting Data collection took place in Baltimore, MD and Washington, DC from May 2015 to May 2017. Methods This mixed methods study included quantitative interviewer-administered surveys, key informant interviews, and focus group discussions. Rapid HIV testing followed each survey. Logistic regression models tested associations between legal gender affirmation (ie, desired name and gender marker on identity documents), transgender pride, history of exchange sex, HIV risk perception, and willingness to take pre-exposure prophylaxis (PrEP). Transcripts of qualitative data were coded to identify common themes related to engagement in HIV prevention. Results Among 201 BLTW, 56% tested HIV-positive and 87% had heard of PrEP. Only 18% who had heard of PrEP had ever taken it. Of the 72 self-reported HIV-negative or status-unknown BLTW who had never taken PrEP, 75% were willing to take it. In multivariable analyses, history of exchange sex was associated with willingness to take PrEP, whereas greater HIV knowledge and transgender pride were associated with lower likelihood of willingness to take PrEP. Concern about drug interactions with hormone therapy was the most frequently reported barrier to PrEP uptake. Conclusions Noting the disconnect between PrEP willingness and uptake among BLTW, HIV prevention programs could bridge this gap by responding to identified access barriers and incorporating community-derived strategies.

This book discusses the global prevalence as well as the geographic distribution of HIV-1 and HIV-2 infections and updates on recent shared global initiatives. The demographic trends in HIV in the United States, especially regarding gender, sexuality, race, ethnicity, age, injection-drug use, socioeconomic status, and recent initiatives are reviewed. Special attention is paid to HIV among communities of color, as well as women, children, and adolescences. The role of HIV in men who have sex with men and the transgender community is reviewed in detail. HIV Testing and Counselling lists and describes the various types of HIV testing available. The book also presents an overview of HIV counselling. HIV testing terminology and algorithms are presented to the reader along with descriptive figures. Laboratory markers for HIV are reviewed. The chapter describes who should be tested, as well as pre and post-test counselling elements. A section of the chapter is dedicated to special populations and environments (blood supply screening, prenatal screening, testing settings) Strategies to improve uptake of HIV testing are discussed.

To assess challenges with daily oral antiretroviral therapy (ART), we analyzed data for 2389 participants in the 2019 Positive Perspectives survey of people living with HIV in 25 countries. ART-related challenges reported included difficulty swallowing pills (33.1% [790/2389]); stress from daily dosing routine (33.3% [795/2389]); bad memories from daily intake of HIV medication (35.1%[839/2389]), and concern “that having to take pills every day means a greater chance of revealing my HIV status to others” (37.9% [906/2389]). Individuals who felt empowered by daily oral dosing [“taking my pill(s) every day reassures me that my HIV is being kept under control”] had 69% higher odds of optimal overall health (AOR 1.69, 95% CI 1.40–2.04). Conversely, odds of optimal overall health were lower among those who felt daily pill intake “limits my day-to-day life” (AOR 0.53, 95% CI 0.44–0.64). These findings show that there is need for increased flexibility of ART delivery to meet diverse patient needs. Electronic supplementary material The online version of this article (10.1007/s10461-020-03055-1) contains supplementary material, which is available to authorized users.

BackgroundThe impact of CD4+ T-cell count and highly active antiretroviral therapy (HAART) on the rate of surgical site infection (SSI) in patients with human immunodeficiency virus (HIV) undergoing total hip arthroplasty is still unclear. The goals of this study were to assess the rate of perioperative infection at a large tertiary care referral center and to identify risk factors in HIV+ patients undergoing total hip arthroplasty (THA).MethodsThis study was a prospective, observational study at a single medical center from 2000–2017. Patients who were HIV+ and underwent THA were followed from the preoperative assessment period, through surgery and for a 2-year follow-up period.ResultsSixteen of 144 HIV+ patients (11%) undergoing THA developed perioperative surgical site infections. Fourteen patients (10%) required revision THA within a range of 12 to 97 days after the initial surgery. The patients’ mean age was 49.6 ± 4.5 years, and the most common diagnosis prompting THA was osteonecrosis (96%). Patients who developed SSI had a lower waist-hip ratio (0.86 vs. 0.93,p= 0.047), lower high density lipoprotein cholesterol (45.8 vs. 52.5,p= 0.015) and were more likely to have post-traumatic arthritis (12.5% vs. 0%,p= 0.008). Logistic regression analysis demonstrated that current alcohol use and higher waist-hip ratio were significant protectors against infection (p< 0.05). No other demographic, medical, immunologic parameters, or specific HAART regimens were associated with perioperative infection.ConclusionsImmunologic status as measured by CD4+ cell count, HIV viral load, and medical therapy do not appear to influence the development of SSI in HIV+ patients undergoing THA. Metabolic factors and post-traumatic arthritis may influence the increased rate of infection in HIV+ patients following THA.

Introduction The worldview in relation to patient care has shifted from conquering diseases to improving overall wellbeing and quality of life. We examined treatment aspirations among people living with HIV (PLHIV). Methods In all, 2389 PLHIV were surveyed in the 25-country 2019 Positive Perspectives Study. Descriptive and multivariable analyses were used to explore attitudes towards treatment. Results Participants were from: Northern America (USA, Canada), 21.8% (520/2389); Europe, 46.8% (1119/2389); and other international regions, 31.4% (750/2389). Factors associated with some level of dissatisfaction with HIV medication among those otherwise fully satisfied with their HIV management included being on a multi-tablet regimen (AOR=2.76; 95% CI: 1.93–3.96), reporting polypharmacy (AOR=2.10; 95% CI: 1.45–3.03), and experiencing side effects from current HIV medication (AOR=2.12; 95% CI: 1.49–3.02). Of seven improvements to HIV medications assessed, the percentage ranking each attribute, as the first or second most important, was: ‘reduced long-term impact on my body’ (46.7%); ‘longer-lasting medicine so I don’t have to take it every day’ (43.1%); ‘fewer side effects’ (40.5%); ‘less HIV medicine each day but just as effective’ (25.4%); ‘less chance of affecting other medicines’ (21.6%); ‘no food restrictions/ requirements’ (14.0%); and ‘smaller pills’ (8.7%). Overall, 77.1% (1842/2389) believed ‘future advances in HIV treatment will improve my overall wellbeing’, 72.2% (1726/2389) were ‘open to taking an HIV treatment composed of fewer medicines’, while 54.7% (1306/2389) expressed openness towards longer-acting (non-daily) HIV medication. Compared to those not fully satisfied with either their HIV medication or management, those fully satisfied with both reported significantly higher prevalence of optimal treatment adherence (89.2% [372/417] vs 69.5% [763/1098]) and optimal overall health (70.3% [293/417] vs 47.8% [525/1098]) (all p

While geographic differences in HIV burden are well documented, less is known about regional differences in perceived treatment needs. To fill this gap, the 2019 Positive Perspectives study of people living with HIV (PLHIV) was conducted in 25 countries across Northern America, Latin America, the Asian region, Europe (EU/Schengen countries), Russia, Australia, and South Africa (n = 2389). Overall mean duration of HIV was 10.1 (SD = 9.6) years. The perception that HIV had a negative impact on day-to-day life was lowest among participants from South Africa (14.0%[25/179]) and highest among participants from the Asian region (55.2%[127/230]). Most of the regional gap in the perception that HIV had a negative impact on daily life was explained by regional differences in medication-related unmet needs, stigma, demographic factors, and comorbidities. The percentage who felt they understood their treatment was highest among participants from Australia (87.5%[105/120]) and lowest among those from Russia (62.0%[93/150]), the Asian region (62.2%[143/230]), and South Africa (62.6%[112/179]). Among participants from Northern America, Europe, and Latin America, the treatment goals with the largest absolute increase in perceived importance, from time of starting treatment to time of survey among those diagnosed for ≥1 year, were minimizing the long term impact of antiretroviral treatment and keeping the number of medicines in their antiretroviral regimen at a minimum. Tailored approaches to care of PLHIV are needed as different regions have different disease burden and treatment needs. Equitable approaches to HIV care are needed across and within regions to ensure that patients' unmet needs and preferences are addressed to improve their overall wellbeing and health-related quality of life.

Opening Paragraph (serves as abstract for submission) and BodyThe Intact Proviral DNA Assay (IPDA) was developed to address the critical need for a precise and scalable method for intact HIV reservoir quantification1. This duplexed droplet digital PCR (ddPCR) assay simultaneously targets the HIV Packaging Signal (Ψ) and the Rev Responsive Element (RRE) within Envelope (env) to distinguish genomically intact proviruses against a large background of defective ones2. The IPDA requires less time, resources, and biological material than the gold standard for replication-competent HIV reservoir measurement, the Quantitative Viral Outgrowth Assay (QVOA)3, and is being adopted in research and clinical studies4–7. In our cohort of HIV-1 subtype B-infected individuals from North America however, the IPDA yielded a 28% failure rate due to HIV polymorphism. We further demonstrate that within-host HIV diversity can lead the IPDA to underestimate intact HIV reservoir size, which could negatively impact clinical trial results interpretation. While the IPDA represents an important methodological advance, HIV diversity should be addressed before its widespread adoption.

Modern antiretroviral therapy (ART) has improved the lives of people living with HIV (PLHIV) but currently requires daily adherence. We assessed prevalence and correlates of suboptimal adherence, and measured associations with self-reported health outcomes. Data were from web-based surveys of confirmed HIV+ adults on antiretroviral treatment within 25 countries during 2019 (n = 2389). Suboptimal adherence was a report of ≥1 reason for missing ART ≥5 times within the past month. Multivariable logistic regression examined associations between suboptimal adherence and self-reported overall health and virologic suppression. Overall, 24.1% (575/2389) reported suboptimal adherence, from 10.0% (5/50) in Austria, to 62.0% (31/50) in China. The most common reasons for missing ART ≥5 times in the overall population were feeling depressed/overwhelmed (7.4%, 176/2389), trying to forget about HIV (7.0%, 168/2389), and work (6.1%, 145/2389). Correlates of suboptimal adherence included being heterosexual,50 years old, ≤high school, having gastrointestinal treatment side effects, and privacy concerns. Odds of suboptimal overall health were 1.41 (95%CI, 1.11-1.80), 2.10 (95%CI, 1.65-2.68), and 2.55 (95%CI, 2.00-3.25) among those who reported the maximum number of times missed ART for any reason within the past month as 1, 2-4, or ≥5 times respectively, vs not missing at all. Odds of virologic nonsuppression were 1.80 (95%CI, 1.33-2.45), and 2.24 (95%CI, 1.66-3.02) for 2-4, or ≥5 times of missed ART respectively, vs not missing at all; missing for only 1 time was not significantly associated with virologic nonsuppression. Novel ART strategies designed to improve adherence along with interventions to empower PLHIV and support self-medication may improve health outcomes and quality of life.

Purpose: Washington, DC, has the highest prevalence of transgender persons in the United States at 2.8%. Transgender persons in DC have lower income, less stable housing, and more HIV infection than nontrans persons. Data are scarce regarding primary care quality among trans persons. We provide a detailed analysis of transgender patients at Whitman-Walker Health, an HIV- and LGBT-focused community health center. Methods: We performed a retrospective electronic medical record review of transgender patients ≥18 years of age from 2008 to 2016, evaluating demographic factors, HIV status, gender-affirming care, and primary care quality indicators. Results: Of 20,097 patients, 1822 (9.0%) self-identify as transgender (62.9% trans female and 37.2% trans male), and 18,275 were nontransgender. Transgender patients are more likely to be young, white, HIV negative, and reside outside Washington, DC, than nontrans patients. Transgender patients are more likely to engage in primary care and have a similar likelihood of mammogram and colonoscopy screening than nontrans patients. Trans males are more likely to be privately insured, have lower rates of HIV testing than nontrans patients, and have higher rates of cervical Pap smears than cis females. Trans females have a high prevalence of HIV infection (26.6%). Conclusion: This is the largest single-center U.S. transgender cohort to date. Over a quarter of trans females are HIV positive, consistent with a national prevalence of 27.7%. Transgender and nontrans patients do not receive statistically different quality of primary care. Trans patients' high engagement in primary care may result from providing hormone therapy and primary care within a single provider visit.

The spectrum of inclusion, diversity, access, and equity among the Infectious Diseases (ID) workforce is ever-growing, ever-evolving, and continuously benefiting from the contributions made by the unique differences among our workforce which make us stronger, smarter, and better prepared to respond to whatever emerging ID challenge we will encounter next.

Persons living with human immunodeficiency virus (HIV) and others receiving antiretrovirals are at risk for medication errors during hospitalization and at transitions of care. These errors may result in adverse effects or viral resistance, limiting future treatment options. A range of interventions is described in the literature to decrease the occurrence or duration of medication errors, including review of electronic health records, clinical checklists at care transitions, and daily review of medication lists. To reduce the risk of medication-related errors, antiretroviral stewardship programs (ARVSPs) are needed to enhance patient safety. This call to action, endorsed by the Infectious Diseases Society of America, the HIV Medicine Association, and the American Academy of HIV Medicine, is modeled upon the success of antimicrobial stewardship programs now mandated by the Joint Commission. Herein, we propose definitions of ARVSPs, suggest resources for ARVSP leadership, and provide a summary of published, successful strategies for ARVSP that healthcare facilities may use to develop locally appropriate programs., Persons receiving antiretrovirals are at risk for medication-related errors in the inpatient setting. This joint policy paper endorses antiretroviral stewardship and antiretroviral stewardship programs, designed to improve patient safety

BACKGROUND: HIV infection is associated with increased susceptibility to common pathogens which may trigger chronic antigenic stimulation and hyperactivation of B-cells, events known to precede the development of AIDS-associated non-Hodgkin lymphoma (AIDS-NHL). METHODS: To explore whether cumulative exposure to infectious agents contributes to AIDS-NHL risk, we tested sera from 199 AIDS-NHL patients (pre-NHL, average lead-time 3.9 years) and 199 matched HIV-infected controls from the Multicenter AIDS Cohort Study (MACS), for anti-IgG responses to 18 pathogens using multiplex serology. Odds ratios and 95% confidence intervals were estimated using conditional logistic regression models. RESULTS: We found no association between cumulative exposure to infectious agents and AIDS-NHL risk (OR 1.01, 95% CI 0.91–1.12). However, seropositivity for trichodysplasia spinulosa polyomavirus (TSPyV), defined as presence of antibodies to TSPyV capsid protein VP1, was significantly associated with a 1.6-fold increase in AIDS-NHL risk (OR 1.62, 95% CI 1.02–2.57). High Epstein-Barr virus (EBV) anti-VCA p18 antibody levels closer to the time of AIDS-NHL diagnosis (

The article Physical, Emotional, and Psychosocial Challenges Associated with Daily Dosing of HIV Medications and Their Impact on Indicators of Quality of Life: Findings from the Positive Perspectives Study, written by Patricia de los Rios · Chinyere Okoli · Erika Castellanos · Brent Allan · Benjamin Young · Garry Brough · Marvelous Muchenje · Anton Eremin · Giulio Maria Corbelli · Marta McBritton · W. David Hardy· Nicolas Van de Velde was originally published electronically on the publisher’s internet portal on 17th December 2020 without open access. With the author(s)’ decision to opt for Open Choice the copyright of the article changed on 16th February 2021 to © The Author’s 2021 and the article is forthwith distributed under a Creative Commons Attribution.

Curing HIV infection will require the elimination of a reservoir of infected CD4+ T-cells that persists despite HIV-specific CTL responses. While viral latency is a critical factor in this persistence, recent evidence also suggests a role for intrinsic resistance of reservoir-harboring cells to CTL killing. We explored the hypothesis that this resistance is mediated by BCL-2 family proteins, which can antagonize CTL-induced apoptosis. We show that the reactivatable HIV reservoir is disproportionately present in BCL-2hi CD4+ T-cells, which are relatively resistant to CTL. BCL-2/BCL-XL antagonists were sufficient for inducing the elimination of HIV-infected cells from a primary-cell model of latency, but did not drive reductions in ex vivo viral reservoirs when tested either alone or with a latency reversing agent (LRA). The triple combination of LRAs, HIV-specific T-cells, and a BCL-2 antagonist uniquely enabled depletions in ex vivo viral reservoirs, providing rationale for novel therapeutic approaches targeting HIV cure.

Background As people with HIV are living longer, focusing quality improvement (QI) initiatives on health maintenance and comprehensive patient-centered care is essential. This QI study evaluated chart-document performance in selected HIV care practices across the United States. Methods Participants were randomly selected from 11 Ryan White-funded HIV clinics in community (n = 7), hospital (n = 3), and academic (n = 1) settings. At baseline, 200 consecutive charts (~20 per clinic) were reviewed for documentation of guideline-directed practices. Clinic teams participated in audit-feedback interventions to develop improvement plans. Three months later, consecutive charts were reviewed according to baseline methods. Chi-square tests were conducted to analyze pre- and post-intervention differences. Results Significant improvements were seen in sexually transmitted infection (STI) screening, and patient counseling on sexual risk, pre-exposure prophylaxis (PrEP), and antiretroviral therapy (ART). Documentation of several health maintenance measures improved significantly. Conclusion Audit-feedback of QI measures improved performance. This approach can inform future QI initiatives. Table: HIV Patient Characteristics and Percentages of Charts Documented for Quality Measures Baseline (n = 200) Post-Intervention (n = 120) P-value Demographic characteristicsa Median years of age 51 40 50 years 7 5 0.299 Creatinine clearance 15 58

A 35-year-old man was admitted to hospital 2 weeks after rough oral sex with Streptococcus pyogenes bacteremia, toxic shock syndrome and extensive necr otizing fasciitis of the abdominal and pelvic walls requiring debridement. His partner was diagnosed with strep throat shortly after their sexual encounter.

CME Educational Objectives 1. Understand the impact of the diagnostic entities that comprise HIV-associated neurocognitive disorder (HAND) on cognitive function and on associated activities of daily living and to understand how to differentiate these entities. 2. Understand the current clinical issues related to the changes in the incidence and prevalence of HAND, as well as the changes in its risk factors and actual clinical manifestations. 3. Understand the advantages and disadvantages of the methods currently available to screen for the diagnostic entities that comprise HAND. More than 34 million people worldwide are currently estimated to live with HIV infection. (Note: Although there are two types of HIV, only one is endemic in the United States — HIV type 1 [HIV-1], which is denoted throughout simply as “HIV.”) Nearly 7,000 people worldwide are newly infected with HIV on a daily basis, which is about 300 people per hour. 1 In the United States, there have been dramatic declines in the annual number of new HIV infections, from a peak of about 130,000 in the mid-1980s to a low of approximately 50,000 in the early 1990s. The rate of new infections increased in the late 1990s, followed by a leveling-off pattern since 2000 to about 55,000 new cases per year. The United States incidence figure had been previously estimated at 40,000 per year until a revision for those who were unknown to be seropositive was included. 2 This figure has remained stable for more than a decade despite the ongoing attempts of the Centers for Disease Control and Prevention (CDC) to reduce it.

Summary Background Dolutegravir (S/GSK1349572) is a once-daily HIV integrase inhibitor with potent antiviral activity and a favourable safety profile. We compared dolutegravir with HIV integrase inhibitor raltegravir, as initial treatment for adults with HIV-1. Methods SPRING-2 is a 96 week, phase 3, randomised, double-blind, active-controlled, non-inferiority study that began on Oct 19, 2010, at 100 sites in Canada, USA, Australia, and Europe. Treatment-naive adults (aged ≥18 years) with HIV-1 infection and HIV-1 RNA concentrations of 1000 copies per mL or greater were randomly assigned (1:1) via a computer-generated randomisation sequence to receive either dolutegravir (50 mg once daily) or raltegravir (400 mg twice daily). Study drugs were given with coformulated tenofovir/emtricitabine or abacavir/lamivudine. Randomisation was stratified by screening HIV-1 RNA (≤100 000 copies per mL or >100 000 copies per mL) and nucleoside reverse transcriptase inhibitor backbone. Investigators were not masked to HIV-1 RNA results before randomisation. The primary endpoint was the proportion of participants with HIV-1 RNA less than 50 copies per mL at 48 weeks, with a 10% non-inferiority margin. Main secondary endpoints were changes from baseline in CD4 cell counts, incidence and severity of adverse events, changes in laboratory parameters, and genotypic or phenotypic evidence of resistance. Our primary analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01227824. Findings 411 patients were randomly allocated to receive dolutegravir and 411 to receive raltegravir and received at least one dose of study drug. At 48 weeks, 361 (88%) patients in the dolutegravir group achieved an HIV-1 RNA value of less than 50 copies per mL compared with 351 (85%) in the raltegravir group (adjusted difference 2·5%; 95% CI −2·2 to 7·1). Adverse events were similar between treatment groups. The most common events were nausea (59 [14%] patients in the dolutegravir group vs 53 [13%] in the raltegravir group), headache (51 [12%] vs 48 [12%]), nasopharyngitis (46 [11%] vs 48 [12%]), and diarrhoea (47 [11%] in each group). Few patients had drug-related serious adverse events (three [ vs five [1%]), and few had adverse events leading to discontinuation (ten [2%] vs seven [2%] in each group). CD4 cell counts increased from baseline to week 48 in both treatment groups by a median of 230 cells per μL. Rates of graded laboratory toxic effects were similar. We noted no evidence of treatment-emergent resistance in patients with virological failure on dolutegravir, whereas of the patients with virologic failure who received raltegravir, one (6%) had integrase treatment-emergent resistance and four (21%) had nucleoside reverse transcriptase inhibitors treatment-emergent resistance. Interpretation The non-inferior efficacy and similar safety profile of dolutegravir compared with raltegravir means that if approved, combination treatment with once-daily dolutegravir and fixed-dose nucleoside reverse transcriptase inhibitors would be an effective new option for treatment of HIV-1 in treatment-naive patients. Funding ViiV Healthcare.

Few orthotopic heart transplantations have been performed in patients infected with the human immunodeficiency virus since the first such case was reported in 2001. Since that time, advances in highly active antiretroviral therapy have resulted in potent and durable suppression of the causative human immunodeficiency virus—accompanied by robust immune reconstitution, reversal of previous immunodeficiency, a marked decrease in opportunistic and other infections, and near-normal long-term survival. Although human immunodeficiency virus infection is not an absolute contraindication, few centers in the United States and Canada have performed heart transplantations in this patient population; these patients have been de facto excluded from this procedure in North America. Re-evaluation of the reasons for excluding these patients from cardiac transplantation is warranted in light of such significant advances in antiretroviral therapy. This case report documents successful orthotopic heart transplantation in 2 patients infected with human immunodeficiency virus, and we describe their antiretroviral therapy and immunosuppressive management challenges. Both patients were doing well without sequelae 43 and 38 months after transplantation.

Heart disease is a major contributor to morbidity and mortality in persons infected with human immunodeficiency virus (HIV), and both HIV and highly active antiretroviral therapy (HAART) may be associated with abnormalities in cardiac function and metabolism [(1)][1]. Ectopic fat deposition in

Antibiotic resistance is increasing resulting in a decreasing number of fully active antimicrobial agents available to treat infections with multi-drug resistant (MDR) bacteria. Herbal medicines may offer alternative treatment options. A direct inoculation method simulating the standard disc diffusion assay was developed to determine in vitro antimicrobial activity of sixty herbal extracts against MDR-Acinetobacter baumannii (A. baumannii). Eighteen herbal extracts inhibited MDR-A. baumannii on agar plates, although the magnitude and quality of bacterial inhibition differed considerably among the antibacterial herbal extracts. Next, minimal inhibitory concentration (MIC) of these antibacterial herbal extracts was calculated using a broth microdilution assay. For most herbal extracts, the larger the zone of inhibition on agar plates, the lower the MIC. In general, hetero-resistance on agar plates correlated with higher MIC. The skip well phenomenon was seen with two herbal extracts. In conclusion, 30% of the screened herbal extracts demonstrated in vitro antibacterial activity against MDR-A. baumannii using similar rigorous testing methods as those commonly employed for assessing antimicrobial activity of synthetic antibacterial agents. Characterization of a specific compound conferring this antibacterial activity of the herbal extracts may help to identify novel antimicrobial agents active against highly resistant bacteria.

BackgroundThe aim of the current study was to examine whether the use of highly active antiretroviral therapy (HAART) in patients with HIV is associated with changes in pericardial fat and myocardial lipid content measured by cardiovascular magnetic resonance (CMR).MethodsIn this prospective case-control study, we compared 27 HIV seropositive (+) male subjects receiving HAART to 22 control male subjects without HIV matched for age, ethnicity and body mass index. All participants underwent CMR imaging for determination of pericardial fat [as volume at the level of the origin of the left main coronary artery (LM) and at the right ventricular free wall] and magnetic resonance spectroscopy (MRS) for evaluation of intramyocardial lipid content (% of fat to water in a single voxel at the interventricular septum). All measurements were made by two experienced readers blinded to the clinical history of the study participants. Two-sample t-test, Spearman's correlation coefficient or Pearson's correlation coefficient and multivariable logistic regression were used for statistical analysis.ResultsPericardial fat volume at the level of LM origin was higher in HIV (+) subjects (33.4cm(3) vs. 27.4cm(3), p = 0.03). On multivariable analysis adjusted for age, Framingham risk score (FRS) and waist/hip ratio, pericardial fat remained significantly associated to HIV-status (OR 1.09, p = 0.047). For both HIV (+) and HIV (-) subjects, pericardial fat volume showed strong correlation with intramyocardial lipid content (r = 0.58, p 5years), who demonstrate HAART-related lipo-accumulation and prolonged HIV duration of infection. Further investigation is warranted to determine whether increased pericardial fat is associated with higher cardiovascular risk leading to premature cardiovascular events in this patient population.

Background: The oral formulation of ganciclovir is approved at a dose of 3.0 g/day for maintenance treatment of cytomegalovirus (CMV) retinitis following an initial induction course of intravenous (IV) anti-CMV therapy. Median time to progression of CMV retinitis is 12–20 days shorter with oral compared to IV ganciclovir maintenance, likely due to the limited oral bioavailability of ganciclovir. Objectives: We hypothesized that higher systemic drug exposures associated with increased doses of oral ganciclovir would be associated with increased efficacy. Study design: Maintenance treatment of CMV retinitis with higher than standard doses of oral ganciclovir (>3.0 g/day) was studied in 281 AIDS patients with previously treated, stable retinitis randomized to 3.0, 4.5 or 6.0 g/day oral, or 5 m/kg/day IV ganciclovir. Graders unaware of treatment assignments determined retinitis progression using fundus photographs. Vision, other ophthalmic measures and safety were assessed open-label. Results: Median days to photographic progression were 41, 50, 57 and 70, respectively ( P =0.052; 3.0 g vs. IV). Hazard ratios for progression relative to IV were 1.66, 1.28 and 1.19 ( P =0.016 for 3.0 g). NONMEM-modeled estimates of average serum ganciclovir concentration area under the curve (AUC 0–24 ) correlated best with time to progression ( P =0.0019). Six grams per day oral ganciclovir was most similar in efficacy to IV, although broad confidence intervals prevented a conclusive comparison. Patients receiving oral ganciclovir had a lower frequency of sepsis and IV catheter events. Conclusions: This study suggests that the efficacy of ganciclovir for the maintenance treatment of CMV retinitis improves with increasing total drug exposure (measured as average serum concentration AUC 0–24 ). All four regimens of ganciclovir were reasonably well tolerated, with safety profiles similar to what has been reported in prior work.

Early in the HIV/AIDS epidemic, the deleterious consequences of HIV-1 infection in the central and peripheral nervous system were described. They were considered to be due to severe immunosuppression, and encephalitis was considered predominantly attributable to concomitant cytomegalovirus (CMV) infection. Antiretroviral agents (ARVs) was further noted that patients with HIV-1-associated neurocognitive disorders would initially improve but later progress despite the continued use of zidovudine (ZDV). In December 1995, the highly active antiretroviral therapy (HAART) era began when the protease inhibitors (PIs) were introduced into practice with the FDA approval of saquinavir. A number of changes have occurred across the spectrum of HIV-1-associated neurocognitive disorders since the introduction of HAART. The incidence of HIV-1-associated dementia (HAD) is widely reported to have decreased following the introduction of HAART; however, the incidence of HIV-1 encephalopathy (as defined neuropathologically) appears to have increased, although interestingly, both the neuropathological and the clinical aspects of the syndrome seem to be less severe than those observed in the pre-HAART era. In addition to the above-mentioned changes in clinical manifestations of HIV-1-associated neurocognitive disorders, their underlying pathophysiology has also evolved. Aside from the original focus on virologic (pathogen), inflammatory/immunologic (host response), and comorbid infection factors, there are now three additional categories of pathogenic factors that demand attention. These are the vascular, medication toxicity, and genetic factors. Molecular investigations of multidrug resistance (MDR) resulted in the isolation and characterization of genes coding for several associated proteins, including P-glycoprotein and the MDR-associated protein MRP1.

Treatment of HIV infection is rapidly changing from a hit-or-miss hodgepodge of unknowns, in which nearly anything beneficial was acceptable, to a true science based on reproducible principles. With this growth in complexity, HIV therapy has become a valid field of medicine. The potency of available agents, their success in suppressing the destructive nature of HIV infection, and the increasingly rapid pace of technology development in this area require that HIV-seropositive patients be treated by physicians specializing in the field. The growing but finite number of antiretroviral therapeutic agents demands that a thoughtful, strategic, long-term approach be formulated. The evolving science of antiretroviral resistance testing offers great promise for better shaping this approach, which is still less than straightforward. Potential interactions, some good and some bad, between mutations within HIV genes will profoundly affect therapy and are still to be defined. Declaring that a regimen has failed and choosing a new one to replace it is a complex task, particularly when all the factors involved are considered (e.g., rising viral load, declining CD4 count, patient adherence, patient preferences, drug interactions, adverse effects). Care of HIV-positive patients has always been an art, and now at last it is becoming a science.

Background: Present combination antiretroviral therapy (cART) alone does not cure HIV infection and requires lifelong drug treatment. The potential role of HIV therapeutic vaccines as part of an HIV cure is under consideration. Our aim was to assess the efficacy, safety, and immunogenicity of Vacc-4x, a peptide-based HIV-1 therapeutic vaccine targeting conserved domains on p24Gag, in adults infected with HIV-1. Methods: Between July, 2008, and June, 2010, we did a multinational double-blind, randomised, phase 2 study comparing Vacc-4x with placebo. Participants were adults infected with HIV-1 who were aged 18-55 years and virologically suppressed on cART (viral load

Background: Maraviroc is unique among approved antiretroviral drugs in targeting the host-cell chemokine coreceptor type-5 receptor. With its novel mechanism of action, we sought to describe the 5-year safety profile of maraviroc. Methods: Two large phase 3 studies of maraviroc enrolled HIV-infected treatment-experienced patients and followed them up for 5 or more years. Survival and selected clinical end points were identified and assessed. Results: A total of 938 enrolled patients received maraviroc-containing regimens. Rates of death and selected clinical events (eg, hepatic failure, malignancy, and myocardial infarction) were low during follow-up. Conclusions: Maraviroc was generally safe in treatment-experienced participants for >5 years.

Antiretroviral medications can be taken by HIV-negative persons to prevent HIV infection, also known as pre-exposure prophylaxis (PrEP). PrEP was first shown to be effective during the iPrEX study. We conducted a survey involving HIV healthcare providers to document their attitudes and prescribing practices about PrEP in response to this study. An online survey was completed by 189 members and credentialees of the American Academy of HIV Medicine between April 2011 and September 2011. Ninety percent of respondents were familiar with the results of the iPrEx study, and most (78%) were familiar with CDC's interim guidance regarding the use of PrEP in MSM. Only 19% of respondents had prescribed PrEP. The majority of PrEP prescribers were compliant with CDC interim guidance; however, only 61% screened for hepatitis B. Of PrEP prescribers, 78% prescribed to MSM, 31% to MSW, and 28% to WSM. Greatest concerns about prescribing PrEP included development of antiretroviral resistance (32%), potential increase in high-risk behavior, (22%) and poor medication adherence (21%). Fifty-eight percent stated that HIV serodiscordance within a relationship most influenced their decision to prescribe PrEP to the HIV-seronegative partner. This study demonstrates that, despite awareness of the efficacy of PrEP, its use is limited. Survey participants used PrEP most commonly in MSM; however, a significant percentage also prescribed PrEP to women. The best candidate for PrEP is felt to be individuals in an HIV-serodiscordant relationship. Limitations to our study included a low response rate, changes in the evidence base, and the novelty of PrEP.

Background The clinical benefits of zidovudine remain unproved in patients with asymptomatic human immunodeficiency virus (HIV) infection when CD4 cell counts exceed 500 per cubic millimeter. We compared zidovudine therapy given immediately with deferred therapy in such subjects. Methods Beginning in 1987, subjects with asymptomatic HIV infection and 500 or more CD4 cells per cubic millimeter were randomly assigned to receive placebo or zidovudine (either 500 or 1500 mg per day, starting immediately). In 1989, the study was modified so that open-label treatment with 500 mg of zidovudine per day (deferred therapy) was offered when CD4 cell counts fell below 500 per cubic millimeter. The study end points included overall survival, survival free of the acquired immunodeficiency syndrome (AIDS), toxic effects, and changes in CD4 cell counts. Results There were 1637 subjects who could be evaluated: 547 in the deferred-therapy group, 549 in the group receiving 500 mg of zidovudine immediately, and 541 in the 15...

The myeloid-specific transcription factor, CCAAT/enhancer-binding protein ε (C/EBPε) is a critical mediator of myelopoiesis. Mutation of this gene is responsible for neutrophil-specific granule deficiency in humans, a condition that confers susceptibility to Staphylococcus aureus infection. We found that C/EBPε-deficient mice are severely affected by infection with S. aureus, and C/EBPε deficiency in neutrophils contributes to the infectious phenotype. Conversely, exposure to the epigenetic modulator nicotinamide (vitamin B3) increased expression of C/EBPε in WT myeloid cells. Further, nicotinamide increased the activity of C/EBPε and select downstream antimicrobial targets, particularly in neutrophils. In a systemic murine infection model as well as in murine and human peripheral blood, nicotinamide enhanced killing of S. aureus by up to 1,000 fold but had no effect when administered to either C/EBPε-deficient mice or mice depleted of neutrophils. Nicotinamide was efficacious in both prophylactic and therapeutic settings. Our findings suggest that C/EBPε is an important target to boost killing of bacteria by the innate immune system.

m l t p a d u r n o n c IN JUNE 1981, the first clinical cases were reported that would become known as the beginning of the acquired mmunodeficiency syndrome (AIDS) epidemic.1 Over the past 30 years, significant progress has been made in treating patients infected with the human immunodeficiency virus-1 (HIV)—the cause of AIDS. Although the initial impact and devastation of HIV/AIDS is now less than it was during the first 15 years of the epidemic, the HIV pandemic is far from over.2 In fact, the US Centers for Disease Control and Prevention (CDC) report that there are more persons living with HIV/AIDS now than at any time since the epidemic began. Both the prevalence and incidence of HIV infection show no signs of abating; an estimated 1.2 million people live with HIV infection in the United States, and 56,000 new HIV infections develop annually.3 Worldwide, more than 33 million persons are living with HIV/ AIDS, with sub-Saharan Africa being the most heavily impacted region of the world.4 The development and widely adopted initiation of highly active antiretroviral therapy (HAART) beginning in the mid1990s has significantly altered the high mortality and morbidity associated with HIV infection.5 However, new challenges inluding medication intolerance, medication adherence, both hort-term and long-term adverse effects of medications, viral esistance to medications secondary to the rapid development f mutations, and the inability to fund and implement an rganized distribution method of drug therapy for all patients nfected with HIV worldwide continue to pose obstacles in anaging the HIV pandemic.6 Currently, the identification of ersons infected with HIV and the rapid initiation of HAART “test and treat” programs) have become a significant part of ational and international strategies for the prevention of new ases of HIV infection.7,8 The 21st century is experiencing the emergence of the “HIV baby boomer generation”—those persons who have survived the initial infection period, have initiated HAART with well-suppressed HIV replication and at least partially reconstituted immune systems, and are now living to previously unexpected ages. The estimated median survival of asymptomatic persons infected with HIV without hepatitis C and subsequently receiving HAART after diagnosis is approximately 53 years for persons diagnosed at the age of 25.9 In addition, the CDC predicts that by 2015, 50% of all HIV-infected adults will be over the age of 50 years.10 Therefore, as the number of HIV patients continues to rise nd subsequently grow older because of the efficacy of AART, patients with HIV/AIDS likely will present for urgical procedures at an increasing rate.

Antibiotic resistance is increasing resulting in a decreasing number of fully active antimicrobial agents available to treat infections with multi-drug resistant (MDR) bacteria. Herbal medicines may offer alternative treatment options. A direct inoculation method simulating the standard disc diffusion assay was developed to determine in vitro antimicrobial activity of sixty herbal extracts against MDR-Acinetobacter baumannii (A. baumannii). Eighteen herbal extracts inhibited MDR-A. baumannii on agar plates, although the magnitude and quality of bacterial inhibition differed considerably among the antibacterial herbal extracts. Next, minimal inhibitory concentration (MIC) of these antibacterial herbal extracts was calculated using a broth microdilution assay. For most herbal extracts, the larger the zone of inhibition on agar plates, the lower the MIC. In general, hetero-resistance on agar plates correlated with higher MIC. The skip well phenomenon was seen with two herbal extracts. In conclusion, 30% of the screened herbal extracts demonstrated in vitro antibacterial activity against MDR-A. baumannii using similar rigorous testing methods as those commonly employed for assessing antimicrobial activity of synthetic antibacterial agents. Characterization of a specific compound conferring this antibacterial activity of the herbal extracts may help to identify novel antimicrobial agents active against highly resistant bacteria.

Highly active antiretroviral therapy in coinfected patients is complicated by a potentially increased risk for hepatotoxicity. Therefore, treatment strategies are urgently needed.In HIV/hepatitis B virus coinfected patients with an indication for therapy for both HIV and hepatitis B, tenofovir plus lamivudine or emtricitabine containing highly active antiretroviral therapy regimens are the favored first-line treatment as they include medications which are dually active. Although highly active antiretroviral therapy has no direct effect on hepatitis C replication, the associated immune restoration appears to slow down the progression of liver fibrosis. In patients with HIV and tuberculosis coinfection without any prior highly active antiretroviral therapy, delay of initiation of antiviral therapy for 4-8 weeks after initiation of tuberculosis treatment allows for a better discrimination of causes of adverse events and paradoxical reactions.With the introduction of new medications for treatment of hepatitis B virus, therapeutic options for HIV/hepatitis B virus coinfected patients have improved considerably. Initiation of highly active antiretroviral therapy may be a promising option for slowing down further progression of hepatitis C-associated liver disease. Simultaneous treatment of tuberculosis and HIV infection remains a therapeutic challenge requiring specific knowledge of drug-drug interactions as well as management strategies for possible immune reconstitution syndromes.

Zidovudine (AZT) is a potent inhibitor of the replication of the human immunodeficiency virus (HIV), and it has been shown to improve survival in advanced HIV disease. We conducted a randomized, double-blind trial in adults with asymptomatic HIV infection who had CD4+ cell counts of fewer than 500 per cubic millimeter on entry into the study. The subjects (92 percent male) were randomly assigned to one of three treatment groups: placebo (428 subjects); zidovudine, 500 mg per day (453); or zidovudine, 1500 mg per day (457). After a mean follow-up of 55 weeks (range, 19 to 107), 33 of the subjects assigned to placebo had the acquired immunodeficiency syndrome (AIDS), as compared with 11 of those assigned to receive 500 mg of zidovudine (P = 0.002; relative risk, 2.8; 95 percent confidence interval, 1.4 to 5.6) and 14 of those assigned to receive 1500 mg of zidovudine (P = 0.05; relative risk, 1.9; 95 percent confidence interval, 1.0 to 3.5). In the three treatment groups, the rates of progression (per 100 person-years) to either AIDS or advanced AIDS-related complex were 7.6, 3.6, and 4.3, respectively. As compared with those assigned to placebo, the subjects in the zidovudine groups had significant increases in the number of CD4+ cells and significant declines in p24 antigen levels. In the 1500-mg zidovudine group, severe hematologic toxicity (anemia or neutropenia) was more frequent than in the other groups (P less than 0.0001). In the 500-mg zidovudine group, nausea was the only toxicity that was significantly more frequent (in 3.3 percent) than in the placebo group (P = 0.001). We conclude that zidovudine is safe and effective in persons with asymptomatic HIV infection and fewer than 500 CD4+ cells per cubic millimeter. Additional study will be required to determine whether such treatment will ultimately improve survival for persons infected with HIV.