Incidence of Antiphospholipid Syndrome: Is Estimation Currently Possible?

Antiphospholipid syndrome is a systemic autoimmune disorder characterized by vascular thrombosis and/or obstetric events in association with persistently elevated antiphospholipid antibodies. Antiphospholipid syndrome is typically considered a rare disease, but the true incidence is uncertain owing to the diverse antiphospholipid antibody-related clinical manifestations, inconsistent definitions of antiphospholipid antibody positivity, under-recognition of the disease, and limited population-based studies. Published estimates of the incidence of antiphospholipid syndrome range from approximately 2 to 80 per 100 000 person-years. A targeted literature review and applied methodology were performed to derive a best available estimate. Significant limitations of the published literature were observed, some of which have been previously reported. The incidence of antiphospholipid syndrome in the United States was estimated to be approximately 7.1 to 13.7 per 100 000 person-years in the general population. Although this estimate is likely more accurate than previously reported estimates, large, contemporary, population-based studies that reasonably adhere to the antiphospholipid syndrome classification criteria are needed to further refine estimates of the incidence of antiphospholipid syndrome.

Patient-Reported Outcomes in the Phase III BRIGHTE Trial of the HIV-1 Attachment Inhibitor Prodrug Fostemsavir in Heavily Treatment-Experienced Individuals.

INTRODUCTION: Heavily treatment-experienced (HTE) people living with HIV-1 (PLWH) have limited viable antiretroviral regimens available because of multidrug resistance and safety concerns. The first-in-class HIV-1 attachment inhibitor fostemsavir demonstrated efficacy and safety in HTE participants in the ongoing phase III BRIGHTE trial. OBJECTIVES: We describe patient-reported outcomes (PROs) through week 48. METHODS: Eligible participants for whom their current regimen was failing were assigned to the randomized cohort (RC; one to two fully active agents remaining) or the nonrandomized cohort (NRC; no fully active agents remaining). PRO assessments included the EQ-5D-3L, EQ-VAS, and Functional Assessment of HIV Infection (FAHI) instruments. RESULTS: Both cohorts achieved increases in EQ-5D-3L US- and UK-referenced utility score from baseline at week 24. Mean visual analog scale (VAS) scores in the RC and NRC increased from baseline by 8.7 (95% CI 6.2-11.2) and 5.6 points (95% CI 1.5-9.7) at week 24 and increased from baseline by 9.8 (95% CI 7.0-12.6) and 4.9 points (95% CI 0.6-9.2) at week 48, respectively. Mean increases in FAHI total score from baseline to weeks 24 and 48 in the RC were 6.9 (95% CI 4.2-9.7) and 5.8 (95% CI 2.7-9.0), respectively, whereas mean increases in physical and emotional well-being subscale scores were 2.7 (95% CI 1.9-3.6) and 2.4 (95% CI 1.3-3.4) and 3.2 (95% CI 2.2-4.2) and 2.6 (95% CI 1.6-3.7), respectively, with little to no change in other subscales. CONCLUSIONS: Improvements in major domains of the EQ-VAS and FAHI through week 48, combined with efficacy and safety results, support the use of fostemsavir for HTE PLWH. TRIAL REGISTRATION NUMBER AND DATE: NCT02362503; February 13, 2015.

Multi-level considerations for optimal implementation of long-acting injectable antiretroviral therapy to treat people living with HIV: perspectives of health care providers participating in phase 3 trials.

BACKGROUND: Long-acting injectable antiretroviral therapy (LA ART) has been shown to be non-inferior to daily oral ART, with high patient satisfaction and preference to oral standard of care in research to date, and has recently been approved for use in the United States and Europe. This study examined the perspectives of health care providers participating in LA ART clinical trials on potential barriers and solutions to LA ART roll-out into real world settings. METHODS: This analysis draws on two data sources: (1) open-ended questions embedded in a structured online survey of 329 health care providers participating in the ATLAS-2 M trial across 13 countries; and (2) in-depth interviews with 14 providers participating in FLAIR/ ATLAS/ATLAS-2 M trials in the United States and Spain. Both assessments explored provider views and clinic dynamics related to the introduction of LA ART and were analyzed using thematic content analysis. The Consolidated Framework for Implementation Research (CFIR) was drawn on as the conceptual framework underpinning development of a model depicting study findings. RESULTS: Barriers and proposed solutions to LA ART implementation were identified at the individual, clinic and health system levels. Provider perceptions of patient level barriers included challenges with adhering to frequent injection appointments and injection tolerability. Proposed solutions included patient education, having designated staff for clinic visit retention, and clinic flexibility with appointment scheduling. The main provider concern was identifying appropriate candidates for LA ART; proposed solutions focused on patient provider communication and decision making. Clinic level barriers included the need for additional skilled individuals to administer injections, shifts in workflow as demand increases and the logistics of cold-chain storage. Proposed solutions included staff hiring and training, strategic planning around workflow and logistics, and the possibility of offering injections in other settings, including the home. Health system level barriers included cost and approvals from national regulatory bodies. Potential solutions included governments subsidizing treatment, ensuring cost is competitive with oral ART, and offering co-pay assistance. CONCLUSIONS: Results suggest the importance of multi-level support systems to optimize patient-provider communication and treatment decision-making; clinic staffing, workflow, logistics protocols and infrastructure; and cost-related factors within a given health system.

"I feel empowered": women's perspectives on and experiences with long-acting injectable antiretroviral therapy in the USA and Spain.

Long-acting injectable antiretroviral therapy has been shown to be non-inferior to daily oral antiretroviral therapy in clinical trials and may soon become part of clinical care. While most trial participants to date have been men, approximately one quarter of ongoing Phase 3 trial participants are women offering an important opportunity to understand how long-acting antiretroviral therapy is perceived and experienced by women. We conducted in-depth interviews with 80 people living with HIV participating in Phase 2 and 3 clinical trials of long-acting antiretroviral therapy in the USA and Spain. Fifteen percent (12/80) of trial participants interviewed were women. Interviews were audio-recorded, transcribed and coded using content analysis, focused on gender-specific themes. Women shared many of the positive perceptions expressed by men but also had unique perspectives, including finding that long-acting antiretroviral therapy addressed the challenge of remembering pills amidst busy day-to-day realities including multiple roles and responsibilities, is less time consuming and creates less stress compared to oral antiretroviral therapy, and is emotionally freeing and empowering. The gendered nature of women's lives shaped why and how they were satisfied with long-acting antiretroviral therapy. Findings can inform interventions and support systems to facilitate uptake of and adherence to long-acting antiretroviral therapy in women.

Feasibility of Implementing Long-Acting Injectable Antiretroviral Therapy to Treat HIV: A Survey of Health Providers from the 13 Countries Participating in the ATLAS-2M Trial.

Long-acting (LA) injectable antiretroviral therapy (ART) was found noninferior to daily oral ART in Phase 3 trials with high patient satisfaction. Limited information on provider experiences with LA ART exists, which is critical to inform real-world implementation. An online survey of health providers from the 13 countries participating in the Phase 3b ATLAS-2M trial was conducted. A total of 293 providers responded to questions on LA ART feasibility. Multivariable regression was utilized to identify factors related to the feasibility of LA ART every month and every 2 months within routine care such as the characteristics, experiences, and attitudes of providers, and perceptions of patient benefits and barriers. A majority of providers indicated that it would be very feasible (62.8%) or somewhat feasible (32.1%) to administer monthly LA ART. Feasibility scores were higher for delivering LA ART every 2 months versus monthly (mean 28.3 vs. 26.9; p value <.001). African providers had higher odds of perceived overall feasibility of monthly LA ART [adjusted odds ratio (aOR) 2.9, 95% confidence interval (CI) 1.9-4.4] versus those from other regions, as did providers reporting a greater number of benefits for patients (aOR 1.1, 95% CI 1.0-1.1) versus those reporting less. Providers reporting a greater number of patient barriers to adhere to clinic appointments had lower odds of perceived feasibility of monthly LA ART (aOR 0.8, 95% CI 0.7-1.0) versus those reporting less. Findings highlight the need for further implementation research regarding barriers, facilitators, and strategies to optimize the introduction of LA ART outside of clinical trials.

Identifying appropriate candidates for long-acting antiretroviral therapy: findings from a survey of health care providers in the ATLAS-2M trial.

INTRODUCTION: Recent results from Phase 3 clinical trials with cabotegravir (CAB) and rilpivirine (RPV) long-acting (LA) have shown that a monthly regimen is non-inferior to daily oral antiretroviral therapy (ART). Additional insights are necessary to prepare for LA ART roll-out, including identifying the appropriate patients. METHODS: Within the ATLAS-2M trial, an online survey was administered to 329 health care providers (HCPs) in 13 countries. Multivariate logistic regression was conducted to identify factors associated with providers considering a greater proportion of patients as appropriate LA ART candidates. RESULTS: Forty-seven percent of HCPs believed that "some" patients (25-50%) would be appropriate while nearly one-quarter of HCPs (23%) felt that "many" patients (more than 50%) would be appropriate candidates for LA ART. Providers in the African region had a greater odds of identifying a greater proportion of their patients as appropriate candidates (AOR 8.97; p < 0.001) vs. other regions. Nurses/physician assistants and research staff/pharmacists had a higher odds of perceiving a greater proportion of their patients as appropriate candidates vs. physicians, respectively (AOR 3.42 p < 0.001; AOR 2.48; p = 0.19). Providers who had experience transitioning patients from LA to oral ART had a higher odds of reporting that more of their patients would be appropriate candidates (AOR 1.64; p = 0.008) vs. those without experience. CONCLUSION: A significant proportion of providers reported that many of their patients would be appropriate candidates for LA ART. To optimize roll-out after regulatory approval, it is important to support providers with tools to help identify patients who would most benefit from this option.

Examining adherence barriers among women with HIV to tailor outreach for long-acting injectable antiretroviral therapy.

BACKGROUND: Long-acting (LA) injectable antiretroviral therapy (ART) has been found non-inferior to daily oral ART in Phase 3 trials. LA ART may address key barriers to oral ART adherence and be preferable to daily pills for some people living with HIV. To date, women have been less represented than men in LA ART research. Using longitudinal data from the Women's Interagency HIV Study (WIHS) cohort of women living with HIV in the United States, we examined barriers and facilitators of daily oral ART adherence that may be related to or addressed by LA ART. METHODS: We conducted a secondary analysis of WIHS cohort data from 1998 to 2017 among participants seen for at least 4 visits since 1998 who reported using ART at least once (n = 2601). Two dichotomous outcomes, patient-reported daily oral ART adherence and viral suppression were fit using generalized linear models, examining the role of socio-demographic and structural factors. RESULTS: At study enrollment, the median age was 40.5 years, 63% of participants were African American and 22% were Latina. The majority (82%) reported taking ART more than 75% of the time and 53% were virally suppressed. In multivariate analysis, several sub-groups of women had lower odds of reported adherence and viral suppression: 1) younger women (adherence aOR: 0.71; viral suppression aOR: 0.63); 2) women who inject drugs (adherence aOR: 0.38; viral suppression aOR: 0.50) and those with moderate (adherence aOR: 0.59; viral suppression aOR: 0.74) and heavy alcohol consumption (adherence aOR: 0.51; viral suppression aOR: 0.69); 3) those with depressive symptoms (adherence aOR: 0.61; viral suppression aOR: 0.76); and 4) those with a history of going on and off ART (adherence aOR: 0.62, viral suppression aOR: 0.38) or changing regimens (adherence aOR: 0.83, viral suppression aOR: 0.56). CONCLUSIONS: Current injectable contraceptive users (vs. non-users) had greater odds of oral ART adherence (aOR: 1.87) and viral suppression (aOR: 1.28). Findings identify profiles of women who may benefit from and be interested in LA ART. Further research is warranted focused on the uptake and utility of LA ART for such key subpopulations of women at high need for innovative approaches to achieve sustained viral suppression.

"A dream come true": Perspectives on long-acting injectable antiretroviral therapy among female sex workers living with HIV from the Dominican Republic and Tanzania.

BACKGROUND: Long-acting injectable antiretroviral therapy (LA ART) was found to be non-inferior to daily oral ART in Phase 3 clinical trials. LA ART may offer an important alternative for people living with HIV with challenges adhering to daily oral ART or preferences for non-pill-based regimens. METHODS: Using a mixed methods approach integrating survey, in-depth interview and biological data from female sex workers (FSW) living with HIV in Tanzania (N = 208) and the Dominican Republic (DR) (N = 201), we assessed factors associated with the potential likelihood of LA ART use if it were available. We conducted multivariate logistic regression and thematic content analysis. RESULTS: Likelihood of LA ART use was high with 84.92% of FSW from the DR and 92.27% of FSW from Tanzania reporting they would be "likely" or "very likely" to use LA ART if available (p = 0.02). In Tanzania better HIV-related patient-provider communication (AOR 4.58; 95% CI 1.90-11.05) and quality of HIV clinical care (AOR 3.68; 95% CI 1.05-12.86) were positively associated with the high likelihood of LA ART use. In the DR, easier clinic access was associated with a higher likelihood of LA ART use (AOR 3.04; 95% CI 1.41-6.56), as was greater monthly income from sex work (AOR 2.37; 95% CI 1.27-4.41). In both settings, years on ART was significantly associated with a strong likelihood of LA ART use (TZ: AOR 1.16 per year; 95% CI 1.00-1.34/DR: AOR 1.07 per year; 95% CI 1.00-1.14). Qualitative findings underscored enthusiasm for LA ART and reinforced its potential to address sex work-specific barriers to daily oral ART adherence including work-related schedules and substance use. CONCLUSIONS: We found a high likelihood of LA ART use if available among FSW in two diverse settings and documented barriers to future uptake. Community-driven approaches which include tailored health education and improved patient-provider communication and quality of care, as well as strategies to facilitate appointment adherence are needed to optimize LA ART use among FSW.

Patient-Reported Outcomes in ATLAS and FLAIR Participants on Long-Acting Regimens of Cabotegravir and Rilpivirine Over 48 Weeks.

The phase 3 ATLAS and FLAIR studies demonstrated that maintenance with Long-Acting (LA) intramuscular cabotegravir and rilpivirine is non-inferior in efficacy to current antiretroviral (CAR) oral therapy. Both studies utilized Patient-Reported Outcome instruments to measure treatment satisfaction (HIVTSQ) and acceptance (ACCEPT general domain), health status (SF-12), injection tolerability/acceptance (PIN), and treatment preference. In pooled analyses, LA-treated patients (n = 591) demonstrated greater mean improvements from baseline than the CAR group (n = 591) in treatment satisfaction (Week 44, + 3.9 vs. +0.5 HIVTSQs-points; p < 0.001) and acceptance (Week 48, +8.8 vs. +2.0 ACCEPT-points; p < 0.001). The acceptability of injection site reactions (PIN) significantly improved from week 5 (2.10 points) to week 48 (1.62 points; p < 0.001). In both studies, ≥ 97% of LA group participants with recorded data preferred LA treatment compared with prior oral therapy. These results further support the potential of a monthly injectable option for people living with HIV seeking an alternative to daily oral treatment.

Efficacy and Freedom: Patient Experiences with the Transition from Daily Oral to Long-Acting Injectable Antiretroviral Therapy to Treat HIV in the Context of Phase 3 Trials.

Long-acting injectable antiretroviral therapy (LA ART) may be an alternative for people living with HIV (PLHIV) with adherence challenges or who prefer not to take pills. Using in-depth interviews, this study sought to understand the experiences of PLHIV (n = 53) participating in Phase 3 LA ART trials in the United States and Spain. The most salient consideration when contemplating LA ART was its clinical efficacy; many participants reported wanting to ensure that it worked as well as daily oral ART, including with less frequent dosing (every 8 versus 4 weeks). While injection side effects were often reported, most participants felt that regimen benefits outweighed such drawbacks. Participants described the main benefit of LA ART as the "freedom" it afforded both logistically and psychosocially, including through reduced HIV stigma. Findings highlight the importance of patient-provider communication related to weighing potential benefits and side effects and the continued need to address HIV stigma.

"It made me more confident that I have it under control": Patient and provider perspectives on moving to a two-drug ART regimen in the United States and Spain.

BACKGROUND: Two-drug regimens (2DR) to treat HIV infection have the potential to reduce long-term toxicity and increase therapeutic options for people living with HIV (PLHIV). Prior phase III trials, SWORD-1 and SWORD-2, as well as GEMINI-1 and GEMINI-2, have demonstrated that a dolutegravir-based 2DR is as effective as three- or four-drug regimens among virologically suppressed patients. Limited information exists, however, on patient and provider experiences with 2DR to inform roll-out and integration into routine clinical care. METHODS: We conducted 39 in-depth interviews with PLHIV currently on 2DR in the context of routine care and 8 of their clinical care providers in the United States (U.S.) and Spain. Participants included 33 male and 6 female PLHIV and 8 providers. Interview topics explored perceptions of and experiences with 2DR compared to prior anti-retroviral regimens (ARVs), side effects, patient satisfaction, and clinical performance. Interviews were audio-recorded, transcribed and analyzed using thematic content analysis. RESULTS: Participants viewed 2DR as a significant and positive advance, in terms of its ability to effectively treat HIV with reduced toxicity and essentially no reported side effects. Patients noted the central role providers played in the decision to switch to a 2DR regimen and, among U.S. participants, the importance of insurance coverage making this preferred option feasible. Patients and providers agreed that a 2DR regimen would be appropriate for any PLHIV regardless of whether they were treatment naïve or had significant experience with ARVs. CONCLUSIONS: Participants' experiences with a 2DR regimen were positive with no participants, reporting side effects and all reporting continued viral suppression. Providers valued the reduced toxicity offered by 2DR and served as the primary gateway to a transition to 2DR for patients in both settings. This study provides a foundation for further research on the transition to 2DR regimens in other populations and contexts including low- and middle-income settings.

Patient-reported tolerability and acceptability of cabotegravir + rilpivirine long-acting injections for the treatment of HIV-1 infection: 96-week results from the randomized LATTE-2 study.

Background: Long-acting (LA) injectable antiretroviral therapy (ART) is a novel modality currently under development as an alternative to daily oral ART.Objective: The LATTE-2 study (ClinicalTrials.gov identifier NCT02120352) showed that cabotegravir LA + rilpivirine LA maintained virologic suppression through 96 weeks and included further exploration of patient-reported treatment outcomes with an LA injectable form of treatment.Methods: Two-hundred and eighty-six virologically suppressed participants on oral cabotegravir + abacavir/lamivudine once-daily tablets (induction period) were randomized to cabotegravir LA + rilpivirine LA once every 4 weeks (n = 115), once every 8 weeks (n = 115), or the continuation of the oral tablet regimen (n = 56) during the maintenance period. Patient-reported outcome measures included the HIV Medications Questionnaire (HIVMQ) and the HIV Treatment Satisfaction Questionnaire status (HIVTSQ[s]) and change (HIVTSQ[c]) versions at prespecified study visits through Week 96 of the randomized maintenance period.Results: Most participants in the LA injectable groups reported injection-site-related adverse events; however, participants in the 4-week (median HIVTSQ[s] total score, 63.5; post hoc P = 0.02) and 8-week (65.0; post hoc P < 0.001) LA injectable groups were significantly more satisfied with treatment than participants in the oral maintenance group (60.0) at Week 96. This was consistent with results from the HIVTSQ[c] at Week 32, which revealed that participants in both LA groups were significantly more satisfied with therapy compared with patients receiving oral ART (both post hoc P < 0.001).Conclusion: Participants who received LA injectable therapy had high levels of treatment satisfaction and favorably viewed convenience and lifestyle-related aspects of the therapy.

Satisfaction and acceptability of cabotegravir long-acting injectable suspension for prevention of HIV: Patient perspectives from the ECLAIR trial.

BACKGROUND: Cabotegravir (GSK1265744) is an integrase strand transfer inhibitor in development as a long-acting (LA) intramuscular injectable suspension for HIV-1 pre-exposure prophylaxis (PrEP). OBJECTIVE: We report participant outcomes from the phase IIa ECLAIR study related to tolerability, acceptability, and satisfaction of cabotegravir LA. METHODS: The ECLAIR study (ClinicalTrials.gov identifier, NCT02076178) was a randomized, placebo-controlled study in healthy men not at high risk of acquiring HIV-1. Participants were randomized (5:1) to once-daily oral cabotegravir 30 mg or placebo tablets for 4 weeks, followed by gluteal intramuscular injections of cabotegravir LA 800 mg or saline placebo every 12 weeks. The primary objective was to evaluate the safety of cabotegravir LA over three injection cycles (to Week 41). Secondary objectives assessed the tolerability, satisfaction, and acceptability of cabotegravir LA. RESULTS: Among 115 participants who received injections in the cabotegravir (n = 94) and placebo (n = 21) groups, 93% (n = 87) and 95% (n = 20) completed the injection phase, respectively. Injection intolerability led to withdrawal in 4 participants (4%) receiving cabotegravir LA. The most frequently reported Grade ≥2 adverse event was injection-site pain. Most participants (74% [n = 67]) receiving consecutive injections favored cabotegravir LA vs oral cabotegravir. Most participants were satisfied with cabotegravir LA (75% [n = 64]), were willing to continue (79% [n = 68]), and would recommend (87% [n = 75]) the therapy. CONCLUSIONS: While Grade ≥2 injection-site pain was common, most participants reported overall satisfaction with and preference for cabotegravir LA, with few discontinuations due to injection intolerance. These findings support investigation of cabotegravir LA as an alternative to daily oral PrEP regimens.

A Review of Long-Term Toxicity of Antiretroviral Treatment Regimens and Implications for an Aging Population.

Human immunodeficiency virus (HIV) is a chronic infectious disease currently requiring lifelong antiretroviral therapy (ART). People living with HIV (PLWH) face an increased risk of comorbidities associated with aging, chronic HIV, and the toxicity arising from long-term ART. A literature review was conducted to identify the most recent evidence documenting toxicities associated with long-term ART, particularly among aging PLWH. In general, PLWH are at a greater risk of developing fractures, osteoporosis, renal and metabolic disorders, central nervous system disorders, cardiovascular disease, and liver disease. There remains limited evidence describing the economic burden of long-term ART. Overall, an aging HIV population treated with long-term ART presents a scenario in which the clinical, humanistic, and economic burden for healthcare systems will demand thoughtful policy solutions that preserve access to treatment. Newer treatment regimens with fewer drugs may mitigate some of the cumulative toxicity burden of long-term ART.Funding: ViiV Healthcare.

Experiences with long acting injectable ART: A qualitative study among PLHIV participating in a Phase II study of cabotegravir + rilpivirine (LATTE-2) in the United States and Spain.

Challenges with adherence to daily oral antiretroviral therapy (ART) among people living with HIV (PLHIV) have stimulated development of injectable long-acting (LA) regimens. We conducted 39 in-depth interviews with participants and providers in a Phase IIb study (LATTE-2) evaluating an injectable LA regimen in the U.S. and Spain. Interviews exploring participant and provider attitudes and experiences with LA versus oral ART were audiotaped, transcribed and analyzed using thematic content analysis. Participants described the convenience of LA injections versus daily pills and emotional benefits such as minimized potential for HIV disclosure and eliminating the "daily reminder of living with HIV." Providers recognized benefits but cautioned that LA candidates still need to adhere to clinic visits for injections and raised questions around ongoing clinical management. LA was seen as preferable to daily oral ART among PLHIV. Further research is needed regarding appropriate candidates, including with women and "non-adherent" populations across settings.

Long-acting intramuscular cabotegravir and rilpivirine in adults with HIV-1 infection (LATTE-2): 96-week results of a randomised, open-label, phase 2b, non-inferiority trial.

BACKGROUND: Cabotegravir and rilpivirine are antiretroviral drugs in development as long-acting injectable formulations. The LATTE-2 study evaluated long-acting cabotegravir plus rilpivirine for maintenance of HIV-1 viral suppression through 96 weeks. METHODS: In this randomised, phase 2b, open-label study, treatment-naive adults infected with HIV-1 initially received oral cabotegravir 30 mg plus abacavir-lamivudine 600-300 mg once daily. The objective of this study was to select an intramuscular dosing regimen based on a comparison of the antiviral activity, tolerability, and safety of the two intramuscular dosing regimens relative to oral cabotegravir plus abacavir-lamivudine. After a 20-week induction period on oral cabotegravir plus abacavir-lamivudine, patients with viral suppression (plasma HIV-1 RNA <50 copies per mL) were randomly assigned (2:2:1) to intramuscular long-acting cabotegravir plus rilpivirine at 4-week intervals (long-acting cabotegravir 400 mg plus rilpivirine 600 mg; two 2 mL injections) or 8-week intervals (long-acting cabotegravir 600 mg plus rilpivirine 900 mg; two 3 mL injections) or continued oral cabotegravir plus abacavir-lamivudine. Randomisation was computer-generated with stratification by HIV-1 RNA (<50 copies per mL, yes or no) during the first 12 weeks of the induction period. The primary endpoints were the proportion of patients with viral suppression at week 32 (as defined by the US Food and Drug Administration snapshot algorithm), protocol-defined virological failures, and safety events through 96 weeks. All randomly assigned patients who received at least one dose of study drug during the maintenance period were included in the primary efficacy and safety analyses. The primary analysis used a Bayesian approach to evaluate the hypothesis that the proportion with viral suppression for each long-acting regimen is not worse than the oral regimen proportion by more than 10% (denoted comparable) according to a prespecified decision rule (ie, posterior probability for comparability >90%). Difference in proportions and associated 95% CIs were supportive to the primary analysis. The trial is registered at ClinicalTrials.gov, number NCT02120352. FINDINGS: Among 309 enrolled patients, 286 were randomly assigned to the maintenance period (115 to each of the 4-week and 8-week groups and 56 to the oral treatment group). This study is currently ongoing. At 32 weeks following randomisation, both long-acting regimens met primary criteria for comparability in viral suppression relative to the oral comparator group. Viral suppression was maintained at 32 weeks in 51 (91%) of 56 patients in the oral treatment group, 108 (94%) of 115 patients in the 4-week group (difference 2·8% [95% CI -5·8 to 11·5] vs oral treatment), and 109 (95%) of 115 patients in the 8-week group (difference 3·7% [-4·8 to 12·2] vs oral treatment). At week 96, viral suppression was maintained in 47 (84%) of 56 patients receiving oral treatment, 100 (87%) of 115 patients in the 4-week group, and 108 (94%) of 115 patients in the 8-week group. Three patients (1%) experienced protocol-defined virological failure (two in the 8-week group; one in the oral treatment group). Injection-site reactions were mild (3648 [84%] of 4360 injections) or moderate (673 [15%] of 4360 injections) in intensity and rarely resulted in discontinuation (two [<1%] of 230 patients); injection-site pain was reported most frequently. Serious adverse events during maintenance were reported in 22 (10%) of 230 patients in the intramuscular groups (4-week and 8-week groups) and seven (13%) of 56 patients in the oral treatment group; none were drug related. INTERPRETATION: The two-drug combination of all-injectable, long-acting cabotegravir plus rilpivirine every 4 weeks or every 8 weeks was as effective as daily three-drug oral therapy at maintaining HIV-1 viral suppression through 96 weeks and was well accepted and tolerated. FUNDING: ViiV Healthcare and Janssen R&D.

Antiretroviral Treatment Switching and Its Association With Economic Outcomes and Adverse Treatment Effects Among Commercially Insured and Medicaid-Enrolled Patients With HIV in the United States.

BACKGROUND: Antiretroviral therapy (ART) of HIV typically involves the use of 2 nucleoside reverse transcriptase inhibitors plus a third agent (eg, protease inhibitor). It has been shown that over the course of treatment, a proportion of patients switch their ART for various reasons (eg, tolerability, long-term toxicities). We hypothesize that there is a relationship between ART treatment switching and economic and clinical outcomes among HIV patients. OBJECTIVE: To determine whether switching ART regimens is associated with greater health care costs, resource use, and adverse treatment effects. METHODS: Administrative health care claims were used to identify commercially insured and Medicaid-enrolled patients in the United States who had ≥2 claims containing an HIV/AIDS diagnosis from 2006 to 2011 and received an ART prescription from 2007 to 2010. The final population included patients who were ≥18 years old on their index date (ie, date of first ART prescription) and had continuous health plan enrollment for ≥12 months before and after their index date. Treatment characteristics (eg, switching), adverse treatment effects, and health care resource utilization and costs, were evaluated during a 12-month follow-up period. Multivariable models assessed the relationship between ART switching and economic outcomes (ie, costs, number of health care encounters) and adverse treatment effects. RESULTS: A total of 14 590 commercially insured patients met all inclusion criteria and 12% had an ART switch; further, 5744 Medicaid-enrolled patients met all inclusion criteria, and 14% switched treatment. After adjusting for confounders, ART switching was associated with 64% and 36% (P < 0.0001) increases in hospitalizations, 36% and 25% (P < 0.0001) increases in nonpharmacy costs, and 15% and 18% (P < 0.0001) increases in pharmacy costs, among commercially insured and Medicaid-enrolled patients, respectively. ART switching increased the risk of adverse treatment effects, overall and for specific conditions of interest (eg, gastrointestinal intolerance). CONCLUSIONS: This study suggests that ART switching is associated with economic outcomes and certain adverse treatment effects. Efforts to put patients on an optimal ART regimen initially, therefore reducing the need for subsequent switching, may have a positive effect on patients specifically and the health care system in general.

Patient preferences for characteristics of antiretroviral therapies: results from five European countries.

INTRODUCTION: Patient preference to antiretroviral therapy (ART) characteristics should be a key consideration in treatment decisions. ART options exist for people living with HIV (PLWH), however concerns remain related to PLWH satisfaction with current ARTs. The current study examines patient preferences and the strength of preferences for treatment characteristics associated with ART. MATERIALS AND METHODS: Patients' preferences to ART were explored using a discrete choice experiment (DCE). Seven defined treatment characteristics (each with three categories) were identified from a literature review, input from experts, PLWH and physicians. A total of 1582 PLWH from France, Germany, Spain, Italy and the UK were recruited for the study. An adjusted odds ratio <1 signified lower odds of selecting a treatment with this characteristic category, compared to the reference category, independently of other characteristics. RESULTS: The patient preference analyses showed that participants preferred treatments with a rapid reduction in viral load (OR=0.78; 95% CI 0.74-0.81) and CD4 count (OR=0.86; 95% CI=0.82-0.89). Participants had a strong preference for avoiding diarrhoea (Odds ratio, OR=0.36 95% CI=0.33-0.38) and long term health problems (OR=0.30, 95% CI=0.28-0.32). Convenience related issues related to restrictions on taking drugs because of food or drug interactions were important to avoid (OR=0.80, 95% CI=0.76-0.83 and OR=0.72 95% CI=0.69-0.76 respectively). Participants also had a strong preference to avoid drugs which limited the effectiveness of future treatments (OR=0.70, 95% CI=0.67-0.73). CONCLUSIONS: Avoidance of diarrhoea and long-term complications were the most important drivers of patient choice. This study, from a large sample of European patients, demonstrates the importance to patients when different aspects of HIV treatment are considered simultaneously.

Annual direct medical cost of active systemic lupus erythematosus in five European countries.

OBJECTIVES: To evaluate the annual direct medical cost of managing adult systemic lupus erythematosus (SLE) patients with active autoantibody positive disease in Europe. METHODS: A 2-year, retrospective, multicentre, observational study was conducted in five countries (France, Germany, Italy, Spain and the UK). Data included patients' characteristics, disease activity and severity, flare assessments and health resource use (eg, laboratory tests, medications, specialist visits and hospitalisations). Costs were assessed from the public payers' perspective. Cost predictors were estimated by multivariate regression models. RESULTS: Thirty-one centres enrolled 427 consecutive eligible patients stratified equally by disease severity. At baseline, mean (SD) age was 44.5 (13.8) years, 90.5% were women and mean (SD) SLE duration was 10.7 (8.0) years. The SELENA-SLEDAI (11.2 vs 5.3) and SLICC/ACR index (1.0 vs 0.7) scores were higher in severe patients. Over the study period, patients experienced on average 1.02 (0.71) flares/year. The mean annual direct medical cost was higher in severe compared to non-severe patients (€4748 vs €2650, p<0.001). Medication costs were €2518 in severe versus €1251 in non-severe patients (p<0.001). Medications represented 53% and 47% of the total cost for severe and non-severe patients, respectively, primarily due to immunosuppressants and biologics. Flares, especially severe flares, were identified as the major cost predictor, with each flare increasing the annual total cost by about €1002 (p<0.001). CONCLUSIONS: The annual direct medical cost of SLE patients in Europe is related to disease severity and flares. Medical treatments were the main cost drivers. Severe flares and major organ involvement were identified as important cost predictors.

Evaluation of the national Cleanyourhands campaign to reduce Staphylococcus aureus bacteraemia and Clostridium difficile infection in hospitals in England and Wales by improved hand hygiene: four year, prospective, ecological, interrupted time series study.

OBJECTIVE: To evaluate the impact of the Cleanyourhands campaign on rates of hospital procurement of alcohol hand rub and soap, report trends in selected healthcare associated infections, and investigate the association between infections and procurement. DESIGN: Prospective, ecological, interrupted time series study from 1 July 2004 to 30 June 2008. SETTING: 187 acute trusts in England and Wales. INTERVENTION: Installation of bedside alcohol hand rub, materials promoting hand hygiene and institutional engagement, regular hand hygiene audits, rolled out nationally from 1 December 2004. MAIN OUTCOME MEASURES: Quarterly (that is, every three months) rates for each trust of hospital procurement of alcohol hand rub and liquid soap; Staphylococcus aureus bacteraemia (meticillin resistant (MRSA) and meticillin sensitive (MSSA)) and Clostridium difficile infection for each trust. Associations between procurement and infection rates assessed by mixed effect Poisson regression model (which also accounted for effect of bed occupancy, hospital type, and timing of other national interventions targeting these infections). RESULTS: Combined procurement of soap and alcohol hand rub tripled from 21.8 to 59.8 mL per patient bed day; procurement rose in association with each phase of the campaign. Rates fell for MRSA bacteraemia (1.88 to 0.91 cases per 10,000 bed days) and C difficile infection (16.75 to 9.49 cases). MSSA bacteraemia rates did not fall. Increased procurement of soap was independently associated with reduced C difficile infection throughout the study (adjusted incidence rate ratio for 1 mL increase per patient bed day 0.993, 95% confidence interval 0.990 to 0.996; P < 0.0001). Increased procurement of alcohol hand rub was independently associated with reduced MRSA bacteraemia, but only in the last four quarters of the study (0.990, 0.985 to 0.995; P < 0.0001). Publication of the Health Act 2006 was strongly associated with reduced MRSA bacteraemia (0.86, 0.75 to 0.98; P = 0.02) and C difficile infection (0.75, 0.67 to 0.84; P < 0.0001). Trust visits by Department of Health improvement teams were also associated with reduced MRSA bacteraemia (0.91, 0.83 to 0.99; P=0.03) and C difficile infection (0.80, 0.71 to 0.90; P=0.01), for at least two quarters after each visit. CONCLUSIONS: The Cleanyourhands campaign was associated with sustained increases in hospital procurement of alcohol rub and soap, which the results suggest has an important role in reducing rates of some healthcare associated infections. National interventions for infection control undertaken in the context of a high profile political drive can reduce selected healthcare associated infections.