Long-Acting Cabotegravir and Rilpivirine after Oral Induction for HIV-1 Infection.

BACKGROUND: Long-acting injectable regimens may simplify therapy for patients with human immunodeficiency virus type 1 (HIV-1) infection. METHODS: We conducted a phase 3, randomized, open-label trial in which adults with HIV-1 infection who had not previously received antiretroviral therapy were given 20 weeks of daily oral induction therapy with dolutegravir-abacavir-lamivudine. Participants who had an HIV-1 RNA level of less than 50 copies per milliliter after 16 weeks were randomly assigned (1:1) to continue the current oral therapy or switch to oral cabotegravir plus rilpivirine for 1 month followed by monthly injections of long-acting cabotegravir plus rilpivirine. The primary end point was the percentage of participants who had an HIV-1 RNA level of 50 copies per milliliter or higher at week 48 (Food and Drug Administration snapshot algorithm). RESULTS: At week 48, an HIV-1 RNA level of 50 copies per milliliter or higher was found in 6 of 283 participants (2.1%) who received long-acting therapy and in 7 of 283 (2.5%) who received oral therapy (adjusted difference, -0.4 percentage points; 95% confidence interval [CI], -2.8 to 2.1), a result that met the criterion for noninferiority for the primary end point (margin, 6 percentage points). An HIV-1 RNA level of less than 50 copies per milliliter at week 48 was found in 93.6% who received long-acting therapy and in 93.3% who received oral therapy (adjusted difference, 0.4 percentage points; 95% CI, -3.7 to 4.5), a result that met the criterion for noninferiority for this end point (margin, -10 percentage points). Of the participants who received long-acting therapy, 86% reported injection-site reactions (median duration, 3 days; mild or moderate severity, 99% of cases); 4 participants withdrew from the trial for injection-related reasons. Grade 3 or higher adverse events and events that met liver-related stopping criteria occurred in 11% and 2%, respectively, who received long-acting therapy and in 4% and 1% who received oral therapy. Treatment satisfaction increased after participants switched to long-acting therapy; 91% preferred long-acting therapy at week 48. CONCLUSIONS: Therapy with long-acting cabotegravir plus rilpivirine was noninferior to oral therapy with dolutegravir-abacavir-lamivudine with regard to maintaining HIV-1 suppression. Injection-site reactions were common. (Funded by ViiV Healthcare and Janssen; FLAIR ClinicalTrials.gov number, NCT02938520.).

Hemophagocytic lymphohistiocytosis in HIV-associated lymphoproliferative disorders.

Compared to the general population the incidence of lymphoproliferative disorders (LPDs) is significantly elevated among people living with HIV (PLHIV). In high-income countries LPDs have become the most common HIV-associated cause of death among PLHIV. Lymphomas are one of the most frequent triggers of Hemophagocytic Lymphohistiocytosis (HLH), a life-threatening inflammatory syndrome that manifests as a sepsis-like syndrome thus obscuring the underlying condition and delaying its diagnosis and therapy. We performed this retrospective cohort study comprising all adult HIV-infected patients who started treatment for histologically proven LPDs between October 2013 and July 2019, to analyse risk factors, frequency and outcome of HLH among HIV-infected patients with LPDs. Of 75 patients, six (8%) presented with or developed HLH. Three patients had Hodgkin lymphoma and three had HHV-8 associated diseases. There was a significant correlation (p<0.01) between bone marrow involvement and the development of HLH. HLH was associated with lower overall survival (HR: 5.09; 95%CI: 1.53 - 16.91 p=0.008). In conclusion HLH appears to be more frequent in HIV-associated lymphomas than in HIV-negative lymphomas. The probability of developing HLH was particularly high in patients with Hodgkin lymphoma, lymphoma with bone marrow infiltration and HHV-8 associated lymphoma. Mortality was significantly increased in the presence of HLH.

Correction to: Clinical and economic effects of an antimicrobial stewardship intervention in a surgical intensive care unit.

The original version of this article unfortunately contained a mistake.

Clinical and economic effects of an antimicrobial stewardship intervention in a surgical intensive care unit.

PURPOSE: To study the effects of an Antimicrobial Stewardship (AMS) programme designed as a once-weekly "Prospective Audit with Feedback and Intervention" in a surgical intensive care unit. METHODS: Retrospective, pre-/post-observational comparison of antimicrobial drug use, patient safety, and cost of care. RESULTS: During the 12-month AMS period the consumption of antimicrobials dropped by 18.3%. While the consumption of broad-spectrum antibiotics decreased by 17.4% the consumption of narrow spectrum penicillins increased by 89.9%, reaching 26.3% of the total antibiotic consumption. Treatment outcomes and rates of Clostridioides difficile infections before and during the programme were not significantly different. The reduction in antimicrobial costs of 46,393€ was offset by an expenditure of 8,047€, for both human resources and additional radiological procedures, resulting in a net saving of 38,346€. 92% of the antibiotic related savings were due to the reduced use of tigecycline and linezolid, and decreases in drug retail prices. CONCLUSIONS: AMS programmes can both reduce the consumption of antimicrobials and modify their spectrum in intensive care without negatively affecting treatment outcomes. The resulting cost savings are negligible. The incentive to implement such programmes cannot, therefore, be immediate institutional cost savings, but should be rather the long-term goal of reducing antibiotic resistance, and its consequences, in terms of long-term health care costs.

Immediate versus deferred antiretroviral therapy in HIV-infected patients presenting with acute AIDS-defining events (toxoplasmosis, Pneumocystis jirovecii-pneumonia): a prospective, randomized, open-label multicenter study (IDEAL-study).

BACKGROUND: To evaluate clinical outcomes after either immediate or deferred initiation of antiretroviral therapy in HIV-1-infected patients, presenting late with pneumocystis pneumonia (PCP) or toxoplasma encephalitis (TE). METHODS: Phase IV, multicenter, prospective, randomized open-label clinical trial. Patients were randomized into an immediate therapy arm (starting antiretroviral therapy (ART) within 7 days after initiation of OI treatment) versus a deferred arm (starting ART after completing the OI-therapy). All patients were followed for 24 weeks. The rates of clinical progression (death, new or relapsing opportunistic infections (OI) and other grade 4 clinical endpoints) were compared, using a combined primary endpoint. Secondary endpoints were hospitalization rates after completion of OI treatment, incidence of immune reconstitution inflammatory syndrome (IRIS), virologic and immunological outcome, adherence to proteinase-inhibitor based antiretroviral therapy (ART) protocol and quality of life. RESULTS: 61 patients (11 patients suffering TE, 50 with PCP) were enrolled. No differences between the two therapy groups in all examined primary and secondary endpoints could be identified: immunological and virologic outcome was similar in both groups, there was no significant difference in the incidence of IRIS (11 and 10 cases), furthermore 9 events (combined endpoint of death, new/relapsing OI and grade 4 events) occurred in each group. CONCLUSIONS: In summary, this study supports the notion that immediate initiation of ART with a ritonavir-boosted proteinase-inhibitor and two nucleoside reverse transcriptase inhibitors is safe and has no negative effects on incidence of disease progression or IRIS, nor on immunological and virologic outcomes or on quality of life.

Efficacy, safety and pharmacokinetics of simeprevir and TMC647055/ritonavir with or without ribavirin and JNJ-56914845 in HCV genotype 1 infection.

BACKGROUND: A Phase 2a, open-label study (NCT01724086) was conducted to assess the efficacy and safety of a once-daily, 2-direct-acting-antiviral-agent (2-DAA) combination of simeprevir + TMC647055/ritonavir ± ribavirin and of the 3-DAA combination of simeprevir + TMC647055/ritonavir + JNJ-56914845 in chronic hepatitis C virus genotype (GT)1-infected treatment-naïve and prior-relapse patients. METHODS: The study comprised four 12-week treatment panels: Panel 1 (n = 10; GT1a) and Panel 2-Arm 1 (n = 12; GT1b): simeprevir 75 mg once daily + TMC647055 450 mg once daily/ritonavir 30 mg once daily + ribavirin 1000-1200 mg/day; Panel 2-Arm 2 (n = 9; GT1b): simeprevir 75 mg + TMC647055 450 mg/ritonavir 30 mg without ribavirin; Panel 3: simeprevir 75 mg + TMC647055 600 mg/ritonavir 50 mg with (Arm 1: GT1a; n = 7) or without (Arm 2: GT1b; n = 8) ribavirin; Panel 4: simeprevir 75 mg + TMC647055 450 mg/ritonavir 30 mg + JNJ-56914845 30 mg once daily (Arm 1: n = 22; GT1a/GT1b) or 60 mg once daily (Arm 2: n = 22; GT1a/GT1b). Primary endpoint was sustained virologic response 12 weeks after end of treatment (12 weeks of combination treatment; SVR12). RESULTS: In Panel 1 and Panel 2-Arm 1, 5/10 and 6/12 (50%) GT1a/GT1b + ribavirin patients achieved SVR12, versus 3/9 (33%) GT1b without ribavirin patients in Panel 2-Arm 2. In Panel 3-Arm 1 and Panel 3-Arm 2, 6/7 (86%) GT1a + ribavirin and 4/8 (50%) GT1b without ribavirin patients, respectively, achieved SVR12. In Panel 4, 10/14 (71%) and 14/15 (93%) GT1a patients in Arms 1 and 2 achieved SVR12 compared with 8/8 and 7/7 (100%) GT1b patients in each arm, respectively. No deaths, serious adverse events (AEs), Grade 4 AEs or AEs leading to treatment discontinuation occurred. CONCLUSIONS: The 2- and 3-DAA combinations were well tolerated. High SVR rates of 93% and 100% in GT1a- and GT1b-infected patients, respectively, were achieved in this study by combining simeprevir with JNJ-56914845 60 mg and TMC647055/ritonavir. TRIAL REGISTRATION: NCT01724086 (date of registration: September 26, 2012).

Burden and spectrum of infectious disease in Germany 2009-2014: a multicentre study from Berlin's Municipal Hospitals.

PURPOSE: This study aimed at assessing the burden and spectrum of infectious diseases (ID) in a Metropolitan population in Germany. METHODS: A discharge database using ICD-10 codes enabled the identification of hospitalizations with infection-related diagnoses. All hospital admissions between 2009 and 2014 were analysed from 9 municipal hospitals serving approximately one-third of an urban population of 3.5 million people. RESULTS: We identified 114,168 admissions with a primary (first-listed) ID diagnosis and 220,483 admissions with any-listed ID diagnosis, accounting for 8.9 % [95 % confidence interval (CI) 8.9-9.0 %] and 17.2 % (95 % CI 17.1-17.3) of all 1,284,559 admissions, respectively. Annually, 439,837 bed-days (range 413,707-488,520) were occupied by patients with an ID diagnosis, utilizing 22.8 % of total bed capacity. The median length of stay for patients with primary ID diagnosis and secondary ID diagnosis was 6 days (IQR 3-11) and 10 days (IQR 5-19), respectively. The most common diagnosis across all age groups was "pneumonia" (22.8 and 16.2 % of ID admissions as primary and secondary diagnosis, respectively). In-hospital mortality was 6.8 % (95 % CI 6.6-6.9) and 8.9 % (95 % CI 8.7-9.1) for ID as primary and secondary diagnosis, respectively. CONCLUSION: Infectious diseases contribute significantly to the overall burden of disease in a health system caring for an urban German population. In view of the magnitude of ID's contribution, establishing more specialists in ID medicine and adjusting the reimbursements for managing infection-related admissions should be made a public health priority in Germany.

Cobicistat versus ritonavir as a pharmacoenhancer of atazanavir plus emtricitabine/tenofovir disoproxil fumarate in treatment-naive HIV type 1-infected patients: week 48 results.

BACKGROUND: Cobicistat (COBI) is a pharmacoenhancer with no antiretroviral activity in vitro. METHODS: An international, randomized, double-blind, double-dummy, active-controlled trial was conducted to evaluate the efficacy and safety of COBI versus ritonavir (RTV) as a pharmacoenhancer of atazanavir (ATV) in combination with emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF) in treatment-naive patients. The primary end point was a human immunodeficiency virus type 1 (HIV-1) RNA load of <50 copies/mL at week 48 by the Food and Drug Administration snapshot algorithm; the noninferiority margin was 12%. RESULTS: A total of 692 patients were randomly assigned to a treatment arm and received study drug (344 in the COBI group vs 348 in the RTV group). At week 48, virologic success was achieved in 85% of COBI recipients and 87% of RTV recipients (difference, -2.2% [95% confidence interval, -7.4% to 3.0%]); among patients with a baseline HIV-1 RNA load of >100 000 copies/mL, rates were similar (86% vs 86%). Similar percentages of patients in both groups had serious adverse events (10% of COBI recipients vs 7% of RTV recipients) and adverse events leading to discontinuation of treatment with the study drug (7% vs 7%). Median increases in the serum creatinine level were 0.13 and 0.09 mg/dL, respectively, for COBI and RTV recipients. CONCLUSIONS: COBI was noninferior to RTV in combination with ATV plus FTC/TDF at week 48. Both regimens achieved high rates of virologic success. Safety and tolerability profiles of the 2 regimens were comparable. Once-daily COBI is a safe and effective pharmacoenhancer of the protease inhibitor ATV.

Antiviral effect, safety, and pharmacokinetics of five-day oral administration of Deleobuvir (BI 207127), an investigational hepatitis C virus RNA polymerase inhibitor, in patients with chronic hepatitis C.

Deleobuvir (BI 207127) is an investigational oral nonnucleoside inhibitor of hepatitis C virus (HCV) NS5B RNA polymerase. Antiviral activity, virology, pharmacokinetics, and safety were assessed in HCV genotype 1-infected patients receiving 5 days' deleobuvir monotherapy. In this double-blind phase 1b study, treatment-naive (TN; n = 15) and treatment-experienced (TE; n = 45) patients without cirrhosis received placebo or deleobuvir at 100, 200, 400, 800, or 1,200 mg every 8 h (q8h) for 5 days. Patients with cirrhosis (n = 13) received deleobuvir at 400 or 600 mg q8h for 5 days. Virologic analyses included NS5B genotyping and phenotyping of individual isolates. At day 5, patients without cirrhosis had dose-dependent median HCV RNA reductions of up to 3.8 log10 (with no placebo response); patients with cirrhosis had median HCV RNA reductions of approximately 3.0 log10. Three patients discontinued due to adverse events (AEs). The most common AEs were gastrointestinal, nervous system, and skin/cutaneous tissue disorders. Plasma exposure of deleobuvir was supraproportional at doses ≥ 400 mg q8h and approximately 2-fold higher in patients with cirrhosis than in patients without cirrhosis. No virologic breakthrough was observed. NS5B substitutions associated with deleobuvir resistance in vitro were detected in 9/59 patients; seven encoded P495 substitutions, including P495L, which conferred 120- to 310-fold-decreased sensitivity to deleobuvir. P495 variants did not persist in follow-up without selective drug pressure. Deleobuvir monotherapy was generally well tolerated and demonstrated dose-dependent antiviral activity against HCV genotype 1 over 5 days.

Improved outcome with rituximab in patients with HIV-associated multicentric Castleman disease.

Although HIV-associated multicentric Castleman disease (HIV-MCD) is not classified as an AIDS-defining illness, mortality is high and progression to lymphoma occurs frequently. At present, there is no widely accepted recommendation for the treatment of HIV-MCD. In this retrospective (1998-2010), multicentric analysis of 52 histologically proven cases, outcome was analyzed with respect to the use of different MCD therapies and potential prognostic factors. After a mean follow-up of 2.26 years, 19 of 52 patients died. Median estimated overall survival (OS) was 6.2 years. Potential risk factors, such as older age, previous AIDS, or lower CD4 T cells had no impact on OS. Treatment was heterogeneous, consisting of cytostatic and/or antiviral agents, rituximab, or combinations of these modalities. There were marked differences in the outcome when patients were grouped according to MCD treatment. Patients receiving rituximab-based regimens had higher complete remission rates than patients receiving chemotherapy only. The mean estimated OS in patients receiving rituximab alone or in combination with cytostatic agents was not reached, compared with 5.1 years (P = .03). Clinical outcome and overall survival of HIV-MCD have markedly improved with rituximab-based therapies, considering rituximab-based therapies (with or without cytostatic agents) to be among the preferred first-line options in patients with HIV-MCD.

Rapid and strong antiviral activity of the non-nucleosidic NS5B polymerase inhibitor BI 207127 in combination with peginterferon alfa 2a and ribavirin.

BACKGROUND & AIMS: BI 207127 is a potent non-nucleoside hepatitis C virus (HCV) NS5B polymerase inhibitor in vitro. METHODS: In this double-blind, placebo-controlled study, 57 HCV genotype (GT)-1 patients (n=27 treatment-naïve [TN]; n=30 treatment-experienced [TE]) with compensated liver disease were randomised for 28-day treatment with 400, 600, or 800 mg BI 207127 three times daily (TID) or placebo (only TN) in combination with peginterferon alfa 2a and ribavirin (PegIFN/RBV). Plasma HCV RNA was measured by Roche COBAS TaqMan assay. RESULTS: HCV RNA decreased in a dose-dependent manner with little difference between 600 mg (TN 5.6 log(10), TE 4.2 log(10)) and 800 mg (TN 5.4 log(10), TE 4.5 log(10)). Rapid virological response (RVR; HCV RNA <15 IU/ml) at day 28 occurred in 11/19 TN and 4/30 TE patients treated with BI 207127. GT-1b patients had stronger reductions in HCV RNA than GT-1a (RVR: TN 64% vs. 43%; TE 33% vs. 5%). There were no breakthroughs (HCV RNA rebound >1 log(10) from nadir) in the TN groups, whereas 3/30 TE patients experienced breakthrough due to P495-mutations. Gastrointestinal adverse events (AEs) and rash were the major AEs and most frequent at higher doses. One and four patients discontinued due to AEs in the 600 and 800 mg groups, respectively. Overall, tolerability was good and better at 600 mg than 800 mg. CONCLUSIONS: BI 207127 in combination with PegIFN/RBV demonstrated strong antiviral activity with a favourable safety and tolerability profile. The best benefit/risk ratio was observed at 600 mg.

Efficacy of the protease inhibitor BI 201335, polymerase inhibitor BI 207127, and ribavirin in patients with chronic HCV infection.

BACKGROUND & AIMS: Therapeutic regimens are being developed for patients with hepatitis C virus (HCV) infection that do not include the combination of peginterferon alfa and ribavirin. We investigated the antiviral effect and safety of BI 201335 (an inhibitor of the NS3/4A protease) and BI 207127 (an inhibitor of the NS5B non-nucleoside polymerase) with ribavirin. METHODS: Thirty-two treatment-naïve patients with chronic HCV genotype 1 infection were randomly assigned to groups that were given 400 mg or 600 mg BI 207127 3 times daily plus 120 mg BI 201335 once daily and 1000 to 1200 mg/day ribavirin for 4 weeks. The primary efficacy end point was virologic response (HCV RNA level <25 IU/mL at week 4). Thirty-two patients received treatment; 31 completed all 4 weeks of assigned combination therapy. RESULTS: In the group given BI 207127 400 mg 3 times daily, the rates of virologic response were 47%, 67%, and 73% at days 15, 22, and 29; a higher rate of response was observed in patients with genotype-1b compared with genotype-1a infections. In the group given BI 207127 600 mg 3 times daily, the rates of virologic response were 82%, 100%, and 100%, respectively, and did not differ among genotypes. One patient in the group given 400 mg 3 times daily had virologic breakthrough (≥1 log(10) rebound in HCV RNA) at day 22. The most frequent adverse events were mild gastrointestinal disorders, rash, and photosensitivity. There were no severe or serious adverse events; no patients discontinued therapy prematurely. CONCLUSIONS: The combination of the protease inhibitor BI 201335, the polymerase inhibitor BI 207127, and ribavirin has rapid and strong activity against HCV genotype-1 and did not cause serious or severe adverse events.

Efficacy, Safety, and Durability of Long-Acting Cabotegravir and Rilpivirine in Adults With Human Immunodeficiency Virus Type 1 Infection: 5-Year Results From the LATTE-2 Study.

BACKGROUND: In the Long-Acting Antiretroviral Treatment Enabling Trial 2 (LATTE-2) phase 2b study, long-acting (LA) injectable cabotegravir + rilpivirine dosed every 8 weeks (Q8W) or every 4 weeks (Q4W) demonstrated comparable efficacy with daily oral antiretroviral therapy (ART) through 96 weeks in ART-naive adults with human immunodeficiency virus type 1 (HIV-1). Here we report efficacy, tolerability, and safety of cabotegravir + rilpivirine LA over approximately 5 years. METHODS: After 20 weeks of oral cabotegravir + abacavir/lamivudine, participants were randomized to cabotegravir + rilpivirine LA Q8W or Q4W or continue oral ART through the 96-week maintenance period. In the extension period through week 256, participants continued their current LA regimen (randomized Q8W/Q4W groups) or switched from oral ART to Q8W or Q4W LA therapy (extension-switch groups). Endpoints assessed included proportion of participants with HIV-1 RNA <50 copies/mL (Snapshot algorithm) and adverse events (AEs). RESULTS: At week 256, 186 of 230 (81%) participants in randomized Q8W/Q4W groups and 41 of 44 (93%) participants in extension-switch groups had HIV-1 RNA <50 copies/mL. No protocol-defined virologic failures occurred after week 48. Injection wsite reactions infrequently resulted in discontinuation (4 [2%] and 1 [2%] participants in randomized Q8W/Q4W and extension-switch groups, respectively). Three participants in randomized Q8W/Q4W groups experienced drug-related serious AEs, including 1 fatal serious AE (Q4W group); none occurred in extension-switch groups. Of 25 participants with AEs leading to withdrawal, 20 were in the randomized Q4W group; no AE leading to withdrawal occurred in >1 participant. CONCLUSIONS: Cabotegravir + rilpivirine LA exhibited long-term efficacy and tolerability, demonstrating its durability as maintenance therapy for HIV-1 infection.Clinical Trials Registration. NCT02120352.

Source attribution of community-acquired cases of Legionnaires' disease-results from the German LeTriWa study; Berlin, 2016-2019.

INTRODUCTION: Sources of infection of most cases of community-acquired Legionnaires' disease (CALD) are unknown. OBJECTIVE: Identification of sources of infection of CALD. SETTING: Berlin; December 2016-May 2019. PARTICIPANTS: Adult cases of CALD reported to district health authorities and consenting to the study; age and hospital matched controls. MAIN OUTCOME MEASURE: Percentage of cases of CALD with attributed source of infection. METHODS: Analysis of secondary patient samples for monoclonal antibody (MAb) type (and sequence type); questionnaire-based interviews, analysis of standard household water samples for Legionella concentration followed by MAb (and sequence) typing of Legionella pneumophila serogroup 1 (Lp1) isolates; among cases taking of additional water samples to identify the infectious source as appropriate; recruitment of control persons for comparison of exposure history and Legionella in standard household water samples. For each case an appraisal matrix was filled in to attribute any of three source types (external (non-residence) source, residential non-drinking water (RnDW) source (not directly from drinking water outlet), residential drinking water (RDW) as source) using three evidence types (microbiological results, cluster evidence, analytical-comparative evidence (using added information from controls)). RESULTS: Inclusion of 111 study cases and 202 controls. Median age of cases was 67 years (range 25-93 years), 74 (67%) were male. Among 65 patients with urine typable for MAb type we found a MAb 3/1-positive strain in all of them. Compared to controls being a case was not associated with a higher Legionella concentration in standard household water samples, however, the presence of a MAb 3/1-positive strain was significantly associated (odds ratio (OR) = 4.9, 95% confidence interval (CI) 1.7 to 11). Thus, a source was attributed by microbiological evidence if it contained a MAb 3/1-positive strain. A source was attributed by cluster evidence if at least two cases were exposed to the same source. Statistically significant general source types were attributed by calculating the population attributable risk (analytical-comparative evidence). We identified an external source in 16 (14%) cases, and RDW as source in 28 (25%). Wearing inadequately disinfected dentures was the only RnDW source significantly associated with cases (OR = 3.2, 95% CI 1.3 to 7.8) and led to an additional 8% of cases with source attribution, for a total of 48% of cases attributed. CONCLUSION: Using the appraisal matrix we attributed almost half of all cases of CALD to an infectious source, predominantly RDW. Risk for LD seems to be conferred primarily by the type of Legionella rather than the amount. Dentures as a new infectious source needs further, in particular, integrated microbiological, molecular and epidemiological confirmation.

Long-Acting Injectable Cabotegravir + Rilpivirine for HIV Maintenance Therapy: Week 48 Pooled Analysis of Phase 3 ATLAS and FLAIR Trials.

BACKGROUND: Long-acting (LA) injectable regimens are a potential therapeutic option in people living with HIV-1. SETTING: ATLAS (NCT02951052) and FLAIR (NCT02938520) were 2 randomized, open-label, multicenter, multinational phase 3 studies. METHODS: Adult participants with virologic suppression (plasma HIV-1 RNA <50 copies/mL) were randomized (1:1) to continue with their current antiretroviral regimen (CAR) or switch to the long-acting (LA) regimen of cabotegravir (CAB) and rilpivirine (RPV). In the LA arm, participants initially received oral CAB + RPV once-daily for 4 weeks to assess individual safety and tolerability, before starting monthly injectable therapy. The primary endpoint of this combined analysis was antiviral efficacy at week 48 (FDA Snapshot algorithm: noninferiority margin of 4% for HIV-1 RNA ≥50 copies/mL). Safety, tolerability, and confirmed virologic failure (2 consecutive plasma HIV-1 RNA ≥200 copies/mL) were secondary endpoints. RESULTS: The pooled intention-to-treat exposed population included 591 participants in each arm [28% women (sex at birth), 19% aged ≥50 years]. Noninferiority criteria at week 48 were met for the primary (HIV-1 RNA ≥50 copies/mL) and key secondary (HIV-1 RNA <50 copies/mL) efficacy endpoints. Seven individuals in each arm (1.2%) developed confirmed virologic failure; 6/7 (LA) and 3/7 (CAR) had resistance-associated mutations. Most LA recipients (83%) experienced injection site reactions, which decreased in incidence over time. Injection site reactions led to the withdrawal of 6 (1%) participants. The serious adverse event rate was 4% in each arm. CONCLUSION: This combined analysis demonstrates monthly injections of CAB + RPV LA were noninferior to daily oral CAR for maintaining HIV-1 suppression.

Short-term randomized proof-of-principle trial of TMC278 in patients with HIV type-1 who have previously failed antiretroviral therapy.

BACKGROUND: In vitro, TMC278, an investigational next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI), has shown activity against wild-type and NNRTI-resistant HIV type-1 (HIV-1) and a higher genetic barrier to the development of resistance than efavirenz or nevirapine. This Phase II open-label trial evaluated the short-term (7-day) antiviral activity of TMC278 administered at three different doses replacing either the protease inhibitor (PI) or NNRTI of an ongoing failing treatment regimen in HIV-1-infected patients. METHODS: A total of 36 patients on failing antiretroviral therapy containing either an NNRTI or a PI (with evidence of > or =1 NNRTI resistance-associated mutation at screening for the PI group) and plasma viral load (VL)>1,000 copies/ml were randomized to one of three once-daily TMC278 doses (25 mg, 50 mg or 150 mg) for 7 days, while continuing NRTIs used at screening. The primary efficacy parameter was the change on day 8 in log(10) plasma VL from baseline. RESULTS: On day 8, median (min, max) changes from baseline in plasma VL were -0.87 (-2.3, 0.0), -0.95 (-1.8, 0.4) and -0.66 (-1.3, -0.2) log(10) copies/ml for the 25 mg, 50 mg and 150 mg once-daily TMC278 groups, respectively (P<0.001-<0.01). Overall, the median change from baseline was -1.19 log(10) copies/ml in the PI-substituted therapy group and -0.71 log(10) copies/ml in the NNRTI-substituted therapy group. TMC278 was generally safe and well tolerated with no apparent differences in safety among the three dose groups. CONCLUSIONS: Once-daily TMC278 showed significant antiviral activity against HIV-1 in treatment-experienced patients with NNRTI failure and/or resistance, and was generally safe and well tolerated.

Efficacy and safety of darunavir/ritonavir in treatment-experienced HIV type-1 patients in the POWER 1, 2 and 3 trials at week 96.

BACKGROUND: Long-term (96-week) efficacy and safety of the protease inhibitor (PI) darunavir coadministered with low-dose ritonavir (DRV/r) was evaluated in HIV type-1 (HIV-1)-infected patients with extensive prior treatment experience in the POWER 1, 2 and 3 trials. METHODS: Patients with HIV-1 RNA>or=1,000 copies/ml and >or=1 primary PI mutation were randomized to receive either DRV/r 600/100 mg twice daily plus an optimized background regimen (OBR), or an investigator-selected control PI (CPI) plus OBR (POWER 3 was a DRV/r 600/100 mg twice daily single-arm study). The proportion of patients with HIV-1 RNA<50 copies/ml at week 96 was assessed (intent-to-treat [ITT], time-to-loss of virological response algorithm). RESULTS: In total, 467 patients received DRV/r 600/100 mg twice daily; 124 patients received CPI(s). At week 96, 39% of DRV/r patients in POWER 1 and 2 (pooled analysis) versus 9% of CPI patients achieved HIV-1 RNA<50 copies/ml (ITT, time-to-loss of virological response algorithm; P<0.001). A similar proportion of DRV/r patients (42%) in POWER 3 achieved HIV-1 RNA<50 copies/ml at week 96. Mean absolute CD4(+) T-cell count increase for DRV/r at 96 weeks was 133 cells/mm(3) in POWER 1 and 2 and 103 cells/mm(3) in POWER 3. Grade 2-4 treatment-emergent adverse events at least possibly related to DRV/r (>or=2% incidence, excluding laboratory abnormalities) were diarrhoea (3%), vomiting (3%), nausea (2%) and headache (2%). CONCLUSIONS: Treatment with DRV/r 600/100 mg twice daily was well tolerated and led to sustained virological and immunological responses in treatment-experienced HIV-1-infected patients over 96 weeks.

Switch from a ZDV/3TC-based regimen to a completely once daily (QD) regimen of emtricitabine/tenofovir DF fixed dose combination plus a third QD agent (SONETT).

OBJECTIVES: To assess the efficacy and safety of a treatment switch from a twice-daily (BID) regimen containing zidovudine (ZDV) and lamivudine (3TC) plus a third agent to a once daily (QD) regimen containing the fixed-dose combination of tenofovir DF/emtri?citabine (TDF/FTC, Truvada) plus a divergent third QD agent in HIV-1 infected patients. METHODS: Prospective, 48-week, non-randomised, single-group, open-label, study. Fifty-one patients on stable ZDV/3TC-containing HAART, with HIV-1 RNA <50 copies/ml and CD4+ T-cell count >50 cells/microl, were switched to TDF/FTC plus a third agent. Plasma HIV-1 RNA, CD4+ and CD8+ T-cell counts were assessed at baseline and weeks 4, 12, 24, 36 and 48 post-switch. RESULTS: During the 48-week study, 10 patients discontinued prematurely, including three due to adverse events (AEs). At week 48, plasma HIV-1 RNA was <50 copies/ml in 40 patients (78.4%). No patient experienced virological failure (defined as HIV-1 RNA > or =50 copies/ml at two consecutive post-baseline measurements) during the study. Immunologic control was maintained, with no significant changes in CD4+ or CD8+ T-cell counts. A statistically significant improvement from baseline in haemoglobin level was observed at week 48 (median change 0.8 g/dl; p<0.001). There was also a statistically significant decrease in total cholesterol concentration at week 48 (-26.0 mg/dl; p = 0.001) in a subset of patients (n = 22) entering the study with elevated total cholesterol. Treatment was well tolerated and no treatment-related grade 3 or 4 AEs were seen. - CONCLUSIONS: Results from this study support switching from a ZDV/3TC-containing HAART regimen to a completely QD regimen of TDF/FTC plus a third agent. Virologic and immunologic control are maintained, with apparent benefits in haemoglobin.

Indication for treatment and severity of disease in treatment-naive patients with chronic hepatitis B virus infection.

BACKGROUND AND AIMS: The prevalence of chronic hepatitis B virus (HBV) infection in Europe is poorly defined. Data on the proportion of patients eligible for therapy are lacking but are crucial to meet WHO elimination goals. The aims of our study were to provide an estimate of the need for antiviral treatment and to assess the prevalence of advanced liver disease in treatment-naive, chronic HBV-infected patients. PATIENTS AND METHODS: We performed a retrospective, cross-sectional analysis of all treatment-naive HBV-infected patients. Baseline clinical assessments included sociodemographic data, hepatitis B-specific analyses, and liver stiffness measurement (LSM). RESULTS: Between 2010 and 2017, 465 patients with chronic HBV infection were referred, with 301 (64.7%) being eligible for our analysis. Overall, 40% were female, and the mean age was 39.3±13.1 years. Moreover, 61% of patients were born outside Europe, predominantly in the Asia-Pacific region. The median HBV viral load was 1630 IU/ml (interquartile range: 240-35 000 IU/ml), 145 (48.2%) patients had an HBV viral load above 2000 IU/ml, and 14.3% were HBeAg positive.Median LSM was 5.2 kPa (interquartile range: 4.2-6.6 kPa). LSM indicating clinically significant fibrosis (≥F2) was found in 96/271 (35.0%) patients, including 20/271 (7.4%) patients with suspected advanced fibrosis/cirrhosis. Overall, 26% of patients met EASL 2017 treatment criteria. CONCLUSION: In HBV-infected patients referred to one of the largest ID clinics in Berlin, only 26% met EASL treatment criteria and 7% had suspected cirrhosis at presentation. Only in 4% of all patients, a treatment indication could not be determined by a noninvasive approach.