Long-Acting Cabotegravir and Rilpivirine Dosed Every 2 Months in Adults With Human Immunodeficiency Virus 1 Type 1 Infection: 152-Week Results From ATLAS-2M, a Randomized, Open-Label, Phase 3b, Noninferiority Study.

BACKGROUND: Cabotegravir (CAB) + rilpivirine (RPV) dosed intramuscularly monthly or every 2 months is a complete, long-acting (LA) regimen for the maintenance of HIV-1 virologic suppression. Here, we report the antiretroviral therapy as long acting suppression (ATLAS)-2M study week 152 results. METHODS: ATLAS-2M is a phase 3b, randomized, multicenter study assessing the efficacy and safety of CAB+RPV LA every 8 weeks (Q8W) versus every 4 weeks (Q4W). Virologically suppressed (HIV-1 RNA <50 copies/mL) individuals were randomized to receive CAB+RPV LA Q8W or Q4W. Endpoints included the proportion of participants with plasma HIV-1 RNA ≥50 copies/mL and <50 copies/mL, incidence of confirmed virologic failure (CVF; 2 consecutive measurements ≥200 copies/mL), safety, and tolerability. RESULTS: A total of 1045 participants received CAB+RPV LA (Q8W, n = 522; Q4W, n = 523). CAB+RPV LA Q8W demonstrated noninferior efficacy versus Q4W dosing, with 2.7% (n = 14) and 1.0% (n = 5) of participants having HIV-1 RNA ≥50 copies/mL, respectively, with adjusted treatment difference being 1.7% (95% CI: 0.1-3.3%), meeting the 4% noninferiority threshold. At week 152, 87% of participants maintained HIV-1 RNA <50 copies/mL (Q8W, 87% [n = 456]; Q4W, 86% [n = 449]). Overall, 12 (2.3%) participants in the Q8W arm and 2 (0.4%) in the Q4W arm had CVF. Eight and 10 participants with CVF had treatment-emergent, resistance-associated mutations to RPV and integrase inhibitors, respectively. Safety profiles were comparable, with no new safety signals observed since week 48. CONCLUSIONS: These data demonstrate virologic suppression durability with CAB+RPV LA Q8W or Q4W for ∼3 years and confirm long-term efficacy, safety, and tolerability of CAB+RPV LA as a complete regimen to maintain HIV-1 virologic suppression.

Dynamics of two separate but linked HIV-1 CRF01_AE outbreaks among injection drug users in Stockholm, Sweden, and Helsinki, Finland.

Detailed phylogenetic analyses were performed to characterize an HIV-1 outbreak among injection drug users (IDUs) in Stockholm, Sweden, in 2006. This study investigated the source and dynamics of HIV-1 spread during the outbreak as well as associated demographic and clinical factors. Seventy Swedish IDUs diagnosed during 2004 to 2007 were studied. Demographic, clinical, and laboratory data were collected, and the V3 region of the HIV-1 envelope gene was sequenced to allow detailed phylogenetic analyses. The results showed that the Stockholm outbreak was caused by a CRF01_AE variant imported from Helsinki, Finland, around 2003, which was quiescent until the outbreak started in 2006. Local Swedish subtype B variants continued to spread at a lower rate. The number of new CRF01_AE cases over a rooted phylogenetic tree accurately reflected the transmission dynamics and showed a temporary increase, by a factor of 12, in HIV incidence during the outbreak. Virus levels were similar in CRF01_AE and subtype B infections, arguing against differences in contagiousness. Similarly, there were no major differences in other baseline characteristics. Instead, the outbreak in Stockholm (and Helsinki) was best explained by an introduction of HIV into a standing network of previously uninfected IDUs. The combination of phylogenetics and epidemiological data creates a powerful tool for investigating outbreaks of HIV and other infectious diseases that could improve surveillance and prevention.

Higher plasma drug levels in elderly people living with HIV treated with darunavir.

BACKGROUND: The proportion of elderly people living with HIV-1 (PLHIV) is rising. In older patients, comorbidities and concomitant medications are more frequent, increasing the risk of potential drug-drug interactions (PDDIs). Data on the pharmacokinetics of ART in individuals aged ≥ 65 years of age are scarce. We compared plasma drug levels of ART, PDDIs, and side-effects in PLHIV aged ≥ 65 years of age, with controls ≤ 49 years of age. METHODS: Patients ≥ 65 years of age and controls ≤ 49 years of age, all of whom were on stable treatment with atazanavir (ATV), darunavir (DRV), or efavirenz (EFV) were included cross-sectionally. Plasma drug levels of ART were analyzed, comorbidities, concomitant medication, adherence, and side-effects recorded, and PDDIs analyzed using drug interactions databases. RESULTS: Between 2013 and 2015, we included 100 individuals ≥ 65 years of age (study group) and 99 controls (≤ 49 years of age). Steady-state DRV concentrations were significantly higher in the study group than in the control group (p = 0.047). In the ATV group there was a trend towards a significant difference (p = 0.056). No significant differences were found in the EFV arm. The DRV arm had a higher frequency of reported side-effects than the ATV and EFV arms in the study group (36.7% vs. 0% and 23.8% respectively (p = 0.014), with significant differences between DRV vs. ATV, and EFV vs. ATV). CONCLUSIONS: Higher steady-state plasma levels of DRV and ATV (but not EFV) were found in PLHIV aged ≥ 65 years of age, compared to controls ≤ 49 years of age.

Long-acting cabotegravir and rilpivirine dosed every 2 months in adults with HIV-1 infection (ATLAS-2M), 96-week results: a randomised, multicentre, open-label, phase 3b, non-inferiority study.

BACKGROUND: Long-acting cabotegravir and rilpivirine administered monthly or every 2 months might address the challenges associated with daily oral antiretroviral therapy. The ATLAS-2M week 48 results showed non-inferiority of long-acting cabotegravir and rilpivirine administered every 8 weeks compared with that of every 4 weeks. In this study, we report the efficacy, safety, and tolerability results from the week 96 analysis. METHODS: ATLAS-2M is a randomised, multicentre, open-label, phase 3b, non-inferiority trial conducted in 13 countries, evaluating the safety and efficacy of maintenance treatment with intramuscular injections of long-acting cabotegravir and rilpivirine, administered every 8 weeks versus every 4 weeks, to people living with HIV-1. Virologically suppressed adults with HIV-1, either already receiving intramuscular long-acting cabotegravir and rilpivirine every 4 weeks (ie, ATLAS study rollover participants) or oral standard of care, were randomly assigned (1:1), in an unblinded fashion, to receive either intramuscular long-acting cabotegravir (600 mg) and rilpivirine (900 mg) every 8 weeks (ie, the every 8-week dosing group) or intramuscular long-acting cabotegravir (400 mg) and rilpivirine (600 mg) every 4 weeks (ie, the every 4-week dosing group). Randomisation was generated using the GlaxoSmithKline-validated randomisation software RANDALL NG (version 1.3.3). The primary endpoint at week 48 was the proportion of participants with plasma HIV-1 RNA measurements of 50 copies per mL or more (ie, the US Food and Drug Administration [FDA] Snapshot algorithm), which has been published previously. Here, we present the week 96 results: the proportion of participants with plasma HIV-1 RNA measurements of less than 50 copies per mL (FDA Snapshot algorithm), with a non-inferiority margin of -10%; the proportion of participants with plasma HIV-1 RNA measurements of 50 copies per mL or more (FDA Snapshot algorithm), with a non-inferiority margin of 4%; the proportion of participants with protocol-defined confirmed virological failure (ie, two consecutive plasma HIV-1 RNA measurements ≥200 copies per mL); safety; pharmacokinetics; and tolerability. This study is registered with ClinicalTrials.gov, number NCT03299049, and is currently ongoing. FINDINGS: Between Oct 27, 2017, and May 31, 2018, a total of 1149 participants were screened; of whom, 1049 (91%) were randomly assigned and 1045 (91%) initiated treatment (522 in the every 8-week dosing group and 523 in the every 4-week dosing group). The median age was 42 years (IQR 34-50). 280 (27%) of 1045 participants were assigned female at birth and 764 (73%) were white. At week 96 (FDA Snapshot algorithm), 11 (2%) of 522 participants in the every 8-week dosing group and six (1%) of 523 in the every 4-week dosing group had an HIV-1 RNA measurement of 50 copies per mL or more, with an adjusted treatment difference of 1·0 (95% CI -0·6 to 2·5), meeting the prespecified non-inferiority threshold of 4%; 475 (91%) of 522 participants in the every 8-week dosing group and 472 (90%) of 523 in the every 4-week dosing group maintained an HIV-1 RNA measurement of less than 50 copies per mL, with an adjusted treatment difference of 0·8 (95% CI -2·8 to 4·3), which met the prespecified non-inferiority threshold of -10%. One participant in the every 8-week dosing group met the confirmed virological failure criterion since the week 48 analysis at week 88, resulting in a total of nine participants in the every 8-week dosing group and two in the every 4-week dosing group having confirmed virological failure. No new safety signals were identified, and no treatment-related deaths occurred. Injection site reactions were the most common adverse event, occurring in 412 (79%) of 522 participants in the every 8-week dosing group and 400 (76%) of 523 in the every 4-week dosing group. Most injection site reactions were grade 1 or 2 (7453 [99%] of 7557 in both groups), with a median duration of 3 days (IQR 2-5). INTERPRETATION: Long-acting cabotegravir and rilpivirine dosed every 8 weeks had non-inferior efficacy compared with that of every 4 weeks through the 96-week analysis, with both regimens maintaining high levels of virological suppression. These results show the durable safety, efficacy, and acceptability of dosing long-acting cabotegravir and rilpivirine monthly and every 2 months as maintenance therapy for people living with HIV-1. FUNDING: ViiV Healthcare and Janssen Research & Development.

Safety and efficacy of the mRNA BNT162b2 vaccine against SARS-CoV-2 in five groups of immunocompromised patients and healthy controls in a prospective open-label clinical trial.

BACKGROUND: Patients with immunocompromised disorders have mainly been excluded from clinical trials of vaccination against COVID-19. Thus, the aim of this prospective clinical trial was to investigate safety and efficacy of BNT162b2 mRNA vaccination in five selected groups of immunocompromised patients and healthy controls. METHODS: 539 study subjects (449 patients and 90 controls) were included. The patients had either primary (n=90), or secondary immunodeficiency disorders due to human immunodeficiency virus infection (n=90), allogeneic hematopoietic stem cell transplantation/CAR T cell therapy (n=90), solid organ transplantation (SOT) (n=89), or chronic lymphocytic leukemia (CLL) (n=90). The primary endpoint was seroconversion rate two weeks after the second dose. The secondary endpoints were safety and documented SARS-CoV-2 infection. FINDINGS: Adverse events were generally mild, but one case of fatal suspected unexpected serious adverse reaction occurred. 72.2% of the immunocompromised patients seroconverted compared to 100% of the controls (p=0.004). Lowest seroconversion rates were found in the SOT (43.4%) and CLL (63.3%) patient groups with observed negative impact of treatment with mycophenolate mofetil and ibrutinib, respectively. INTERPRETATION: The results showed that the mRNA BNT162b2 vaccine was safe in immunocompromised patients. Rate of seroconversion was substantially lower than in healthy controls, with a wide range of rates and antibody titres among predefined patient groups and subgroups. This clinical trial highlights the need for additional vaccine doses in certain immunocompromised patient groups to improve immunity. FUNDING: Knut and Alice Wallenberg Foundation, the Swedish Research Council, Nordstjernan AB, Region Stockholm, Karolinska Institutet, and organizations for PID/CLL-patients in Sweden.

Microbial translocation revisited: targeting the endotoxic potential of gut microbes in HIV-infected individuals.

OBJECTIVE: Translocation of microbial products such as lipopolysaccharides (LPS) from the gut may contribute to chronic inflammation in HIV-infected individuals. Recent studies indicate that differences in degree of acylation of gut-bacterial-derived LPS may explain variable immune effects, with hexa-acylated rather than penta-acylated LPS having proinflammatory capacity. We investigated whether the degree of acylation of gut-derived LPS associates with systemic inflammation, and the potential effect of probiotic intervention. METHODS: Gut microbiota profiles from a probiotics intervention were investigated and validated in a cohort of HIV-infected individuals commencing antiretroviral therapy. The PiCRUSt software was used to predict overall functional capacity of the microbiota and in-house bioinformatics to distinguish between bacteria producing hexa-acylated and penta-acylated LPS. RESULTS AND CONCLUSION: HIV-infected individuals with the highest ratio of proinflammatory hexa-acylated LPS to noninflammatory penta-acylated LPS-producing bacteria exhibited increased levels of systemic inflammation (neopterin, P < 0.001) and tryptophan catabolism (kynurenine/tryptophan ratio, P = 0.01), indicating a link between proinflammatory LPS, tryptophan catabolism and inflammation. After probiotics for 8 weeks, there was a decrease in Gram-negative bacteria (P = 0.01), related primarily to a reduction in bacteria producing penta-acylated LPS (P = 0.01), but not hexa-acylated LPS. The reduction in Gram-negative bacteria correlated positively with decreased plasma LPS (r = 0.72), mainly related to a reduction in bacteria producing noninflammatory penta-acylated LPS (r = 0.58). Notably, gut bacteria producing hexa-acylated LPS were outnumbered by penta-acylated LPS with a factor of 25 in HIV-infected individuals. Further studies are warranted to determine whether microbes producing hexa-acylated LPS might be a more relevant trigger of systemic inflammation compared with plasma LPS captured by the existing limulus assay.

Staphylococcus aureus bacteraemia and endocarditis - epidemiology and outcome: a review.

PURPOSE: To review the epidemiology of Staphylococcus aureus bacteraemia (SAB) and endocarditis (SAE), and discuss the short- and long-term outcome. Materials and methods: A literature review of the epidemiology of SAB and SAE. RESULTS: The reported incidence of SAB in Western countries is 16-41/100,000 person-years. Increasing incidence has been observed in many regions, in Iceland by 27% during 1995-2008. The increase is believed to depend on changes in population risk factors and possibly better and more frequent utilization of diagnostic procedures. S. aureus is now the leading causes of infective endocarditis (IE) in many regions of the world. It accounts for 15-40% of all IE cases, and the majority of cases in people who inject drugs (PWID). Recently, the incidence of SAE in PWID in Stockholm, Sweden, was found to be 2.5/1000 person-years, with an in-hospital mortality of 2.5% in PWID as compared to 15% in non-drug users. The 30-day mortality associated with SAB amounts to 15-25% among adults in Western countries, but is lower in children (0-9%). Mortality associated with SAE is high (generally 20-30% in-hospital mortality), and symptomatic cerebral embolizations are common (12-35%). The 1-year mortality reported after SAB and SAE is 19-62% and reflects deaths from underlying diseases and complications caused by the infection. In a subset of SAE cases, valvular heart surgery is needed (15-45%), but active intravenous drug use seems to be a reason to refrain from surgery. Despite its importance, there are insufficient data on the optimal management of SAB and SAE, especially on the required duration of antibiotic therapy. Conclusions: The epidemiology of SAB and SAE has been changing in the past decades. They still carry a substantial morbidity and mortality. Intensified studies on treatment are warranted for improving patient outcome.

Patient Self-Reported Adherence to Ritonavir-Boosted Darunavir Combined With Either Raltegravir or Tenofovir Disoproxil Fumarate/Emtricitabine in the NEAT001/ANRS143 Trial.

BACKGROUND: The NEAT001/ANRS143 trial demonstrated noninferiority of ritonavir-boosted darunavir combined with either raltegravir (RAL + DRV/r) or tenofovir disoproxil fumarate/emtricitabine (TDF/FTC + DRV/r) in HIV-positive, antiretroviral-naive adults. In post hoc analyses, however, RAL + DRV/r showed inferiority in patients with baseline CD4 <200/mm and HIV-1 RNA ≥100,000 copies per milliliter. This preplanned ancillary study was conducted to assess whether differences in adherence might explain efficacy results. SETTING: Phase III, open-label, randomized, multicenter study in 15 European countries (ClinicalTrials.gov, NCT01066962). METHODS: Seven hundred seventy-four participants self-reported adherence (modified AIDS Clinical Trials Group questionnaire) over 96 weeks [383 RAL + DRV/r (twice daily; 5 pills/day), 391 TDF/FTC + DRV/r (once daily; 4 pills/day)]. Primary endpoint was ≥95% versus <95% adherence to prescribed doses recorded (1) over the last 4 days or (2) on the visual analogue scale over the last 30 days. RESULTS: Characteristics, except age, were similar between arms; 9% had CD4 <200 cells/mm and HIV-1 RNA ≥100,000 copies per milliliter. Adherence ≥95% in the last 4 days (P = 0.029) or at the visual analogue scale (P = 0.0072) was higher with TDF/FTC + DRV/r than with RAL + DRV/r. Adherence ≥95% over the last 4 days was associated with lower probability of virological failure (P = 0.015). Adherence in patients with baseline CD4 <200 cells/mm and HIV-1 RNA ≥100,000 copies per milliliter was similar to the rest of the population, and not significantly associated with efficacy measures, with no significant differences between arms. CONCLUSION: Adherence was high and slightly better in the TDF/FTC + DRV/r than in the RAL + DRV/r arm. No convincing evidence was found that higher failure rate in the RAL + DRV/r arm in the subgroup with worse baseline viroimmunological status is caused by adherence differences.

Switching from tenofovir disoproxil fumarate to tenofovir alafenamide coformulated with rilpivirine and emtricitabine in virally suppressed adults with HIV-1 infection: a randomised, double-blind, multicentre, phase 3b, non-inferiority study.

BACKGROUND: Tenofovir alafenamide, a tenofovir prodrug, results in 90% lower tenofovir plasma concentrations than does tenofovir disproxil fumarate, thereby minimising bone and renal risks. We investigated the efficacy, safety, and tolerability of switching to a single-tablet regimen containing rilpivirine, emtricitabine, and tenofovir alafenamide compared with remaining on rilpivirine, emtricitabine, and tenofovir disoproxil fumarate. METHODS: In this randomised, double-blind, multicentre, placebo-controlled, non-inferiority trial, HIV-1-infected adults were screened and enrolled at 119 hospitals in 11 countries in North America and Europe. Participants were virally suppressed (HIV-1 RNA <50 copies per mL) on rilpivirine, emtricitabine, and tenofovir disoproxil fumarate for at least 6 months before enrolment and had creatinine clearance of at least 50 mL/min. Participants were randomly assigned (1:1) to receive a single-tablet regimen of either rilpivirine (25 mg), emtricitabine (200 mg), and tenofovir alafenamide (25 mg) or to remain on a single-tablet regimen of rilpivirine (25 mg), emtricitabine (200 mg), and tenofovir disoproxil fumarate (300 mg), with matching placebo, once daily for 96 weeks. Investigators, participants, study staff, and those assessing outcomes were masked to treatment group. All participants who received one dose of study drug and were on the tenofovir disoproxil fumarate regimen before screening were included in primary efficacy analyses. The primary endpoint was the proportion of participants with less than 50 copies per mL of plasma HIV-1 RNA at week 48 (by the US Food and Drug Administration snapshot algorithm), with a prespecified non-inferiority margin of 8%. This study was registered with ClinicalTrials.gov, number NCT01815736. FINDINGS: Between Jan 26, 2015, and Aug 25, 2015, 630 participants were randomised (316 to the tenofovir alafenamide group and 314 to the tenofovir disoproxil fumarate group). At week 48, 296 (94%) of 316 participants on tenofovir alafenamide and 294 (94%) of 313 on tenofovir disoproxil fumarate had maintained less than 50 copies per mL HIV-1 RNA (difference -0·3%, 95·001% CI -4·2 to 3·7), showing non-inferiority of tenofovir alafenamide to tenofovir disoproxil fumarate. Numbers of adverse events were similar between groups. 20 (6%) of 316 participants had study-drug related adverse events in the tenofovir alafenamide group compared with 37 (12%) of 314 in the tenofovir disoproxil fumarate group; none of these were serious. INTERPRETATION: Switching to rilpivirine, emtricitabine, and tenofovir alafenamide was non-inferior to continuing rilpivirine, emtricitabine, tenofovir disoproxil fumarate in maintaining viral suppression and was well tolerated at 48 weeks. These findings support guidelines recommending tenofovir alafenamide-based regimens, including coformulation with rilpivirine and emtricitabine, as initial and ongoing treatment for HIV-1 infection. FUNDING: Gilead Sciences.

Low mortality but increasing incidence of Staphylococcus aureus endocarditis in people who inject drugs: Experience from a Swedish referral hospital.

Staphylococcus aureus is a leading cause of infective endocarditis in people who inject drugs (PWID). The management of S aureus endocarditis (SAE) in PWID can be problematic. The objective of this retrospective observational study was to assess the epidemiology, clinical characteristics, and mortality of S aureus endocarditis (SAE) in PWID in Stockholm, Sweden.The Department of Infectious Diseases at the Karolinska University Hospital serves as a regional referral center for drug users with severe infections. Patients with active intravenous drug use treated for SAE at the department between January 2004 and December 2013 were retrospectively identified. Clinical and microbiological data were obtained from medical records and the diagnosis verified according to the modified Duke criteria.In total, 120 SAE episodes related to intravenous drug use were identified. Its incidence in Stockholm was 0.76/100,000 adult person-years for the entire period, increasing from 0.52/100,000 person-years in 2004 to 2008 to 0.99 in 2009 to 2013 (P = 0.02). The SAE incidence among PWID specifically was 249 (range 153-649) /100,000 person-years. Forty-two (35%) episodes were left-sided, and multiple valves were involved in 26 (22%). Cardiac valve surgery was performed in 10 (8%) episodes, all left-sided. The in-hospital and 1-year mortality rates were 2.5% (3 deaths) and 8.0% (9 deaths), respectively.We noted a high and increasing incidence over time of SAE related to intravenous drug use in Stockholm. The increased incidence partly reflects a rising number of PWID during the study period. The low mortality noted, despite a substantial proportion with left-sided endocarditis, probably in part reflects the quality of care obtained at a large and specialized referral center for drug users with severe infections.

Reduced Levels of D-dimer and Changes in Gut Microbiota Composition After Probiotic Intervention in HIV-Infected Individuals on Stable ART.

BACKGROUND: Microbial translocation and chronic inflammation may contribute to non-AIDS morbidity in patients with HIV. This study assessed the impact of probiotic intervention on microbial translocation and inflammation in patients on antiretroviral therapy with viral suppression and subnormal CD4 count. METHODS: Thirty-two patients receiving antiretroviral therapy (CD4 <500 cells/µL) were randomized in a double-blind fashion to multistrain daily probiotics (n = 15), placebo (n = 9), or controls (n = 8) for 8 weeks. Soluble inflammation markers, D-dimer, lipopolysaccharide (LPS), sCD14, T-cell activation, tryptophan metabolites, and gut microbiota composition were analyzed at baseline and end of study. Nonparametric statistics were applied. RESULTS: Twenty-four participants completed the study and were included in as-treated analyses. In patients receiving probiotics, there was a significant reduction in D-dimer levels (median change 33%, P = 0.03) and a tendency to reduced levels of C-reactive protein (CRP) (P = 0.05) and interleukin (IL)-6 (P = 0.06). The changes in CRP and IL-6 were highly correlated (r = 0.95, P < 0.01), whereas changes in D-dimer did not correlate with changes in CRP or IL-6. Increases in Bifidobacteria (P = 0.04) and Lactobacilli (P = 0.06) were observed in the probiotic group, whereas the relative abundance of Bacteroides decreased (P ≤ 0.01). No significant changes were seen in markers of microbial translocation or T-cell activation. However, the expansion of Bifidobacteria correlated negatively with differences in LPS (r = -0.77, P = 0.01), whereas the reduction in Bacteroides correlated positively with changes in LPS during the study period (r = 0.72, P = 0.02). CONCLUSIONS: Probiotic intervention seemed to reduce markers of coagulation and inflammation without overt changes in microbial translocation. These findings warrant further studies in larger cohorts with long-term follow-up.

Long-term efficacy and safety of atazanavir/ritonavir treatment in a real-life cohort of treatment-experienced patients with HIV type 1 infection.

Atazanavir-based regimens have established efficacy and safety in both antiretroviral (ARV)-naive and -experienced patients. However, data evaluating effectiveness beyond 2 years is sparse. Therefore, we assessed the long-term outcomes of ritonavir-boosted atazanavir (ATV/r)-containing regimens in ARV-experienced patients in a clinical setting in a noncomparative, retrospective, observational study collecting data from three European HIV databases on ARV-experienced adults with HIV-1 infection starting an ATV/r-based regimen. Data were extracted every 6 months (maximum follow-up 5 years). Primary outcome was the proportion of patients remaining on ATV/r by baseline HIV-1 RNA (<500 or ≥500 copies/ml). Secondary outcomes included time to virologic failure, reasons for discontinuation, and long-term safety profile. The duration of treatment and time to virologic failure were analyzed using the Kaplan-Meier method. Data were analyzed for 1,294 ARV-experienced patients (male 74%; mean ART exposure 5.7 years). After 3 years, 56% (95% CI: 52%, 60%) of patients with baseline HIV-1 RNA <500 copies/ml and 53% (95% CI: 49%, 58%) of those with HIV-1 RNA ≥500 copies/ml remained on ATV/r. After 3 years, 75% (95% CI: 69%, 80%) of patients with baseline HIV-1 RNA <50 copies/ml remained suppressed and 51% (95% CI: 47%, 55%) of those with baseline HIV-1 RNA ≥50 copies/ml achieved and maintained virologic suppression. Although adverse events (AEs) were the main known reason for discontinuation, no unexpected AEs were observed. In a real-life setting ATV/r-based regimens demonstrated sustained virologic suppression in ARV-experienced patients. After long-term therapy the majority of patients remained on treatment and no unexpected AEs were observed.

Long-term gender-based outcomes for atazanavir/ritonavir (ATV/r)- containing regimens in treatment-experienced patients with HIV.

Clinical data on antiretroviral effectiveness in women are limited, especially long-term data, because women are usually underrepresented in clinical trials. This sub-analysis of a large European non-comparative, retrospective, observational cohort study evaluated gender differences in long-term outcomes in antiretroviral-experienced adult patients with HIV-1 infection switched to an ATV/r-based regimen between October 2004 and March 2007. Data were extracted from 3 European HIV databases every 6 months (maximum follow-up 5 years). Time to virological failure (VF), defined as two consecutive HIV-1 RNA≥50 c/mL or one HIV-1 RNA≥50 c/mL followed by treatment discontinuation (TD), and time to TD were analyzed using the Kaplan-Meier method. Associations of gender with VF and TD were analyzed using multivariate Cox proportional models. Safety and tolerability were evaluated. In total, 1294 patients (336 women, 958 men) were analyzed. No gender differences in time to VF were observed; at 3 years, the probability of not having VF was 0.59 (95%CI: 0.52, 0.65) and 0.63 (95%CI: 0.59, 0.67) for women and men, respectively. In multivariate analyses, women had a higher risk of TD than men (hazard ratio [HR], 1.54; 95%CI: 1.28, 1.85) but no increased risk of VF (HR, 1.06; 95%CI: 0.85, 1.33). Safety and tolerability were comparable between genders. In a clinical setting, long-term efficacy and safety outcomes of ATV/r-based regimens were similar by gender. Women had a higher risk of TD but no increased risk of VF. ATV/r is an effective and well-tolerated therapeutic option for treatment-experienced men and women with HIV-1 infection.

In-hospital and long-term mortality in infective endocarditis in injecting drug users compared to non-drug users: a retrospective study of 192 episodes.

In a retrospective study, in-hospital and long-term mortality for patients with infective endocarditis (IE) was analysed. The study was conducted at a department of infectious diseases in Stockholm, Sweden. Mortality was compared between injecting drug users (IDUs) and patients without drug abuse (non-IDUs). 192 episodes of IE from 1995 to 2000 were analysed, 60 in IDUs and 135 in non-IDUs, median follow-up 4.4 y. Episodes were classified using the Duke criteria: 145 definite and 47 possible. Of 53 definite episodes in IDUs, 55% were right-sided IE and 43% left-sided IE (including combined left- and right-sided). Surgical treatment was used in 34/145 definite episodes, all being left-sided IE. The in-hospital mortality was 14/145 (9.6%). There was no difference in in-hospital mortality between patient groups with left-sided IE. The IDU patients with left-sided IE had a higher long-term mortality with the increased mortality rate explained by late deaths in the surgically treated IDUs. Treatment results for IDUs with right-sided IE were good with no in-hospital mortality, no relapses and no increase in long-term mortality. This difference in prognosis between left-sided and right-sided IE in IDUs makes high quality echocardiography important to identify patients with left-sided IE and worse prognosis.

Swedish guidelines for diagnosis and treatment of infective endocarditis.

Swedish guidelines for diagnosis and treatment of infective endocarditis (IE) by consensus of experts are based on clinical experience and reports from the literature. Recommendations are evidence based. For diagnosis 3 blood cultures should be drawn; chest X-ray, electrocardiogram, and echocardiography preferably transoesophageal should be carried out. Blood cultures should be kept for 5 d and precede intravenous antibiotic therapy. In patients with native valves and suspicion of staphylococcal aetiology, cloxacillin and gentamicin should be given as empirical treatment. If non-staphylococcal etiology is most probable, penicillin G and gentamicin treatment should be started. In patients with prosthetic valves treatment with vancomycin, gentamicin and rifampicin is recommended. Patients with blood culture negative IE are recommended penicillin G (changed to cefuroxime in treatment failure) and gentamicin for native valve IE and vancomycin, gentamicin and rifampicin for prosthetic valve IE, respectively. Isolates of viridans group streptococci and enterococci should be subtyped and MIC should be determined for penicillin G and aminoglycosides. Antibiotic treatment should be chosen according to sensitivity pattern given 2-6 weeks intravenously. Cardiac valve surgery should be considered early, especially in patients with left-sided IE and/or prosthetic heart valves. Absolute indications for surgery are severe heart failure, paravalvular abscess, lack of response to antibiotic therapy, unstable prosthesis and multiple embolies. Follow-up echocardiography should be performed on clinical indications.

Candida albicans tricuspid valve endocarditis in an intravenous drug addict: successful treatment with fluconazole.

An addicted, intravenous drug user was treated for Candida albicans tricuspid valve endocarditis with high dose fluconazole for 8 months, without relapse after 30 months.

Tricuspid valve endocarditis caused by a new species of actinomyces: Actinomyces funkei.

We present a case of tricuspid valve endocarditis in a 40-y-old woman with a history of heroin abuse. Blood cultures yielded a Gram-positive rod, preliminarily identified as "Actinomyces turicensis-like", but subsequently formally described as Actinomyces funkei sp. nov. The patient was cured by prolonged treatment with 10 weeks of i.v. antibiotics followed by oral antibiotic treatment for 12 weeks.

Streptococcus viridans septicaemia: a comparison study in patients admitted to the departments of infectious diseases and haematology in a university hospital.

Infective endocarditis caused by viridans streptococci is a well-described disease. Streptococcus viridans is also an important etiologic agent causing septicaemia in neutropenic patients with haematological diseases. In this study we retrospectively reviewed charts from 111 patients with 121 episodes of viridans streptococci septicaemia during the period 1992-97 for clinical data, presence of endocarditis, subtype and outcome. Forty-seven episodes of S. viridans septicaemia were documented in 45 non-neutropenic patients treated at the Department of Infectious Diseases (Group A). Thirty of these episodes were defined as definite and 9 as possible infective endocarditis, using Duke's critera. Seventy-four episodes of S. viridans septicaemia were identified in 66 patients treated at the Department of Haematology (Group B), only 1 of which fulfilled the criteria for possible infective endocarditis. S. sanguis was the most common subtype (18/47; 38%) in Group A and S. mitis was the major subtype (51/74; 69%) in Group B.