Efficacy and Safety of Switching to the 2-Drug Regimen Dolutegravir/Lamivudine Versus Continuing a 3- or 4-Drug Regimen for Maintaining Virologic Suppression in Adults Living With Human Immunodeficiency Virus 1 (HIV-1): Week 48 Results From the Phase 3, Noninferiority SALSA Randomized Trial.

BACKGROUND: In TANGO, switching to dolutegravir/lamivudine (DTG/3TC) demonstrated long-term noninferior efficacy vs continuing tenofovir alafenamide-based regimens in treatment-experienced adults with HIV-1. The phase 3 SALSA study evaluated efficacy and safety of switching to DTG/3TC compared with continuing various 3-/4-drug current antiretroviral regimens (CARs). METHODS: Adults with HIV-1 RNA <50 copies/mL and no previous virologic failure were randomized (1:1, stratified by baseline third agent class) to switch to once-daily fixed-dose combination DTG/3TC or continue CAR (primary endpoint: proportion of participants with HIV-1 RNA ≥50 copies/mL at week 48; Snapshot, intention-to-treat-exposed population, 5% noninferiority margin). RESULTS: Overall, 493 adults (39% women; 39% aged ≥50 years; 19% African American/African heritage; 14% Asian) were randomized to switch to DTG/3TC (n = 246) or continue CAR (n = 247). At week 48, 1 (0.4%) participant in the DTG/3TC group and 3 (1.2%) in the CAR group had HIV-1 RNA ≥50 copies/mL (Snapshot), demonstrating noninferiority (adjusted difference, -0.8%; 95% CI, -2.4%, .8%). Zero participants met confirmed virologic withdrawal criteria; therefore, no resistance testing was performed. Drug-related adverse events were more frequent with DTG/3TC (20%) than CAR (6%) through week 48 but comparable post-week 24 (5% vs 2%, respectively). Proximal tubular renal function and bone turnover biomarkers improved with DTG/3TC. Both groups had generally minimal changes in lipids and inflammatory biomarkers. CONCLUSIONS: Switching to DTG/3TC was noninferior to continuing CAR for maintaining virologic suppression at week 48 with no observed resistance, supporting the efficacy, good safety, and high barrier to resistance of DTG/3TC. CLINICAL TRIALS REGISTRATION: www.clinicaltrials.gov, NCT04021290.

Dolutegravir plus lamivudine versus dolutegravir plus tenofovir disoproxil fumarate and emtricitabine in antiretroviral-naive adults with HIV-1 infection (GEMINI-1 and GEMINI-2): week 48 results from two multicentre, double-blind, randomised, non-inferiority, phase 3 trials.

BACKGROUND: Effective two-drug regimens could decrease long-term drug exposure and toxicity with HIV-1 antiretroviral therapy (ART). We therefore aimed to evaluate the efficacy and safety of a two-drug regimen compared with a three-drug regimen for the treatment of HIV-1 infection in ART-naive adults. METHODS: We conducted two identically designed, multicentre, double-blind, randomised, non-inferiority, phase 3 trials: GEMINI-1 and GEMINI-2. Both studies were done at 192 centres in 21 countries. We included participants (≥18 years) with HIV-1 infection and a screening HIV-1 RNA of 500 000 copies per mL or less, and who were naive to ART. We randomly assigned participants (1:1) to receive a once-daily two-drug regimen of dolutegravir (50 mg) plus lamivudine (300 mg) or a once-daily three-drug regimen of dolutegravir (50 mg) plus tenofovir disoproxil fumarate (300 mg) and emtricitabine (200 mg). Both drug regimens were administered orally. We masked participants and investigators to treatment assignment: dolutegravir was administered as single-entity tablets (similar to its commercial formulation, except with a different film colour), and lamivudine tablets and tenofovir disoproxil fumarate and emtricitabine tablets were over-encapsulated to visually match each other. Primary endpoint was the proportion of participants with HIV-1 RNA of less than 50 copies per mL at week 48 in the intention-to-treat-exposed population, using the Snapshot algorithm and a non-inferiority margin of -10%. Safety analyses were done on the safety population. GEMINI-1 and GEMINI-2 are registered with ClinicalTrials.gov, numbers NCT02831673 and NCT02831764, respectively. FINDINGS: Between July 18, 2016, and March 31, 2017, 1441 participants across both studies were randomly assigned to receive either the two-drug regimen (n=719) or three-drug regimen (n=722). At week 48 in the GEMINI-1 intention-to-treat-exposed population, 320 (90%) of 356 participants receiving the two-drug regimen and 332 (93%) of 358 receiving the three-drug regimen achieved plasma HIV-1 RNA of less than 50 copies per mL (adjusted treatment difference -2·6%, 95% CI -6·7 to 1·5); in GEMINI-2, 335 (93%) of 360 in the two-drug regimen and 337 (94%) of 359 in the three-drug regimen achieved HIV-1 RNA of less than 50 copies per mL (adjusted treatment difference -0·7%, 95% CI -4·3 to 2·9), showing non-inferiority at a -10% margin in both studies (pooled analysis: 655 [91%] of 716 in the two-drug regimen vs 669 [93%] of 717 in the three-drug regimen; adjusted treatment difference -1·7%, 95% CI -4·4 to 1·1). Numerically, more drug-related adverse events occurred with the three-drug regimen than with the two-drug regimen (169 [24%] of 717 vs 126 [18%] of 716); few participants discontinued because of adverse events (16 [2%] in the three-drug regimen and 15 [2%] in the two-drug regimen). Two deaths were reported in the two-drug regimen group of GEMINI-2, but neither was considered to be related to the study medication. INTERPRETATION: The non-inferior efficacy and similar tolerability profile of dolutegravir plus lamivudine to a guideline-recommended three-drug regimen at 48 weeks in ART-naive adults supports its use as initial therapy for patients with HIV-1 infection. FUNDING: ViiV Healthcare.

Safety and pharmacokinetics of intravenous zanamivir treatment in hospitalized adults with influenza: an open-label, multicenter, single-arm, phase II study.

BACKGROUND: Intravenous zanamivir is a neuraminidase inhibitor suitable for treatment of hospitalized patients with severe influenza. METHODS: Patients were treated with intravenous zanamivir 600 mg twice daily, adjusted for renal impairment, for up to 10 days. Primary outcomes included adverse events (AEs), and clinical/laboratory parameters. Pharmacokinetics, viral load, and disease course were also assessed. RESULTS: One hundred thirty patients received intravenous zanamivir (median, 5 days; range, 1-11) a median of 4.5 days (range, 1-7) after onset of influenza; 83% required intensive care. The most common influenza type/subtype was A/H1N1pdm09 (71%). AEs and serious AEs were reported in 85% and 34% of patients, respectively; serious AEs included bacterial pulmonary infections (8%), respiratory failure (7%), sepsis or septic shock (5%), and cardiogenic shock (5%). No drug-related trends in safety parameters were identified. Protocol-defined liver events were observed in 13% of patients. The 14- and 28-day all-cause mortality rates were 13% and 17%. No fatalities were considered zanamivir related. Pharmacokinetic data showed dose adjustments for renal impairment yielded similar zanamivir exposures. Ninety-three patients, positive at baseline for influenza by quantitative polymerase chain reaction, showed a median decrease in viral load of 1.42 log10 copies/mL after 2 days of treatment. CONCLUSIONS: Safety, pharmacokinetic and clinical outcome data support further investigation of intravenous zanamivir. CLINICAL TRIALS REGISTRATION: NCT01014988.

Dolutegravir + Lamivudine vs. Dolutegravir + Tenofovir Disoproxil Fumarate/Emtricitabine: Very-Low-Level HIV-1 Replication through 144 Weeks in the GEMINI-1 and GEMINI-2 Studies.

In GEMINI-1/-2, dolutegravir + lamivudine was non-inferior to dolutegravir + tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) in achieving viral suppression (viral load [VL] < 50 copies/mL) in treatment-naive adults. Abbott's RealTime HIV-1 assay provides quantitative VL (40-10,000,000 copies/mL) and qualitative target detected or target not detected (TND) for VL < 40 copies/mL. This post hoc analysis assessed very-low-level viremia and "blips" through Week 144. Proportions with VL < 40 copies/mL and TND are presented overall and by baseline VL and CD4+ cell count. "Blips" (single VL ≥ 50 to <200 copies/mL with adjacent values < 50 copies/mL) were assessed from Day 1 after VL suppression and from Weeks 48 through to 144. Proportions with TND increased through Week 48 and were similar between groups at all visits (Week 144: dolutegravir + lamivudine, 451/716 [63%]; dolutegravir + TDF/FTC, 465/717 [65%]). By observed analysis, TND rates were similar between groups across baseline subgroups. Through Week 144, proportions with ≥1 "blip" were generally comparable for dolutegravir + lamivudine vs. dolutegravir + TDF/FTC from Day 1 (15% vs. 20%) and from Week 48 (7% vs. 11%). Through 144 weeks, the proportions with TND or "blips" were similar between dolutegravir + lamivudine and the three-drug comparator, reinforcing the efficacy and durability of dolutegravir + lamivudine.

Three-year durable efficacy of dolutegravir plus lamivudine in antiretroviral therapy - naive adults with HIV-1 infection.

OBJECTIVE: To assess efficacy and safety of dolutegravir (DTG) + lamivudine (3TC) vs. DTG + tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) in treatment-naive adults with HIV-1 in the prespecified 144-week secondary analyses of GEMINI-1 and GEMINI-2. DESIGN: Identical, multicenter, phase III, randomized, non-inferiority studies (double-blind through 96 weeks). METHODS: Participants with HIV-1 RNA ≤500 000 copies/ml and no major viral resistance mutations to nucleoside reverse transcriptase inhibitors, nonnucleoside reverse transcriptase inhibitors, or protease inhibitors were randomized 1:1 to once-daily DTG + 3TC or DTG + TDF/FTC. RESULTS: At week 144, DTG + 3TC (N = 716) was noninferior to DTG + TDF/FTC (N = 717) in proportion of participants achieving HIV-1 RNA <50 copies/ml (Snapshot algorithm) in the pooled analysis (82% vs. 84%, respectively; adjusted treatment difference [95% confidence interval (CI)], -1.8% [-5.8, 2.1]), GEMINI-1 (-3.6% [-9.4, 2.1]), and GEMINI-2 (0.0% [-5.3, 5.3]). Twelve DTG + 3TC participants and nine DTG + TDF/FTC participants met protocol-defined confirmed virologic withdrawal (CVW) criteria; none developed treatment-emergent resistance. One DTG + 3TC participant who did not meet CVW criteria developed M184V at week 132 and R263R/K at week 144, conferring a 1.8-fold change in susceptibility to DTG; non-adherence to therapy was reported. Significantly fewer drug-related adverse events occurred with DTG + 3TC vs. DTG + TDF/FTC (20% vs. 27%; relative risk [95% CI], 0.76 [0.63-0.92]). Renal and bone biomarker changes favored DTG + 3TC. CONCLUSIONS: Three-year durable efficacy, long-term tolerability, and high barrier to resistance support first-line use of DTG + 3TC for HIV-1 treatment (see Supplemental Digital Content 1, http://links.lww.com/QAD/C297; video abstract).

Impact of treatment adherence on efficacy of dolutegravir plus lamivudine and dolutegravir plus tenofovir disoproxil fumarate/emtricitabine: pooled analysis of the GEMINI-1 and GEMINI-2 clinical studies.

Background: GEMINI-1 and GEMINI-2 (ClinicalTrials.gov, NCT02831673 and NCT02831764, respectively) are double-blind, multicenter, phase III studies that demonstrated the non-inferiority of once-daily dolutegravir + lamivudine to dolutegravir + tenofovir disoproxil fumarate/emtricitabine in achieving HIV-1 RNA <50 copies/mL at 48, 96, and 144 weeks in treatment-naive adults with HIV-1 infection.Objective: We present a post hoc analysis of the impact of treatment adherence on Week 48 virologic response.Methods: Adherence was estimated using pill counts and categorized as ≥90% vs <90%. Unadjusted treatment differences with exact 95% CIs were derived for the proportion of participants with HIV-1 RNA <50 copies/mL within each adherence category, using Snapshot algorithm and last available on-treatment viral load through Week 48.Results: In each treatment group, 5% of participants had <90% adherence (dolutegravir + lamivudine group, 35/716; dolutegravir + tenofovir disoproxil fumarate/emtricitabine group, 34/717). The proportion of participants with HIV-1 RNA <50 copies/mL (Snapshot) at Week 48 in the <90% adherence group was 69% in the dolutegravir + lamivudine group and 65% in the dolutegravir + tenofovir disoproxil fumarate/emtricitabine group (analysis by last on-treatment viral load: 91% and 85%, respectively). Corresponding proportions in the ≥90% adherence group were 93% and 96% (analysis by last on-treatment viral load: 97% and 99%, respectively).Conclusions: Decreased adherence resulted in lower Week 48 virologic efficacy outcomes that were comparable between treatment groups. These results indicate that the robust antiviral activity and regimen forgiveness of dolutegravir + lamivudine is similar to dolutegravir-containing 3-drug regimens (see graphical abstract).

Pharmacokinetics and safety of extemporaneously compounded valacyclovir oral suspension in pediatric patients from 1 month through 11 years of age.

BACKGROUND: Valacyclovir provides enhanced acyclovir bioavailability in adults, but limited data are available in children. METHODS: Children 1 month through 5 years of age with or at risk for herpesvirus infection received a single 25 mg/kg dose of extemporaneously compounded valacyclovir oral suspension (n = 57), whereas children 1 through 11 years of age received 10 mg/kg valacyclovir oral suspension twice daily for 3-5 days (herpes simplex virus infection) (n = 28) or 20 mg/kg 3 times daily for 5 days (varicella-zoster virus infection) (n = 27). Blood samples for pharmacokinetic analysis were collected during the 6 h after the first dose. Safety was monitored throughout the studies. RESULTS: Dose proportionality in the maximum observed concentration (C(max)) of acyclovir and the area under the concentration-time curve from time zero extrapolated to infinity (AUC(0-infinity)) existed across the 10 to 20 mg/kg valacyclovir dose range. For children 2 through 5 years of age, an increase in dose from 20 to 25 mg/kg resulted in near doubling of the C(max) and AUC(0-infinity). Among infants 1 through 2 months of age receiving 25 mg/kg, the mean AUC(0-infinity) and C(max) were higher ( approximately 60% and 30%, respectively) than those among older infants and children receiving the same dose. Valacyclovir oral suspension was well tolerated. No clinically significant trends were noted in clinical chemical, hematologic, or urinalysis values from screening to follow-up. CONCLUSIONS: Among children 3 months through 11 years of age, the 20 mg/kg dose of this formulation of valacyclovir oral suspension produces favorable acyclovir blood concentrations and is well tolerated. A dosing recommendation cannot be made for infants <3 months of age because of decreased clearance in this age group. Trial registration. ClinicalTrials.gov identifier: NCT00297206 .

Durable Efficacy of Dolutegravir Plus Lamivudine in Antiretroviral Treatment-Naive Adults With HIV-1 Infection: 96-Week Results From the GEMINI-1 and GEMINI-2 Randomized Clinical Trials.

BACKGROUND: The 2-drug regimen dolutegravir + lamivudine was noninferior to dolutegravir + tenofovir disoproxil fumarate/emtricitabine in achieving HIV-1 RNA <50 copies/mL in treatment-naive adults in the 48-week primary analysis of the GEMINI trials. We present results from the prespecified 96-week secondary analyses. SETTING: One hundred eighty-seven centers in 21 countries. METHODS: GEMINI-1 and GEMINI-2 are identical, double-blind phase III studies. Participants with screening HIV-1 RNA ≤500,000 copies/mL were randomized 1:1 to once-daily dolutegravir + lamivudine or dolutegravir + tenofovir disoproxil fumarate/emtricitabine. RESULTS: At week 96, dolutegravir + lamivudine (N = 716) was noninferior to dolutegravir + tenofovir disoproxil fumarate/emtricitabine (N = 717) in achieving HIV-1 RNA <50 copies/mL (Snapshot algorithm; -10% noninferiority margin) in the pooled analysis (proportion of responders, 86.0% vs 89.5%, respectively; adjusted treatment difference [95% CI], -3.4% [-6.7 to 0.0007]), GEMINI-1 (-4.9% [-9.8 to 0.03]), and GEMINI-2 (-1.8% [-6.4 to 2.7]). Proportions of participants in the HIV-1 RNA ≥50 copies/mL Snapshot category were largely unchanged from week 48 to 96. Eleven participants taking dolutegravir + lamivudine and 7 taking dolutegravir + tenofovir disoproxil fumarate/emtricitabine met confirmed virologic withdrawal criteria through week 96; none had treatment-emergent resistance mutations. Dolutegravir + lamivudine had a lower rate of drug-related adverse events than dolutegravir + tenofovir disoproxil fumarate/emtricitabine (19.6% vs 25.0%; relative risk ratio, 0.78; 95% CI: 0.64 to 0.95). Renal and bone biomarker changes favored dolutegravir + lamivudine. CONCLUSIONS: Consistent with 48-week data, dolutegravir + lamivudine demonstrated long-term, noninferior efficacy vs dolutegravir + tenofovir disoproxil fumarate/emtricitabine without increased risk of treatment-emergent resistance, supporting its use in treatment-naive HIV-1-infected individuals.

Brief Report: Virologic Response by Baseline Viral Load With Dolutegravir Plus Lamivudine vs Dolutegravir Plus Tenofovir Disoproxil Fumarate/Emtricitabine: Pooled Analysis.

BACKGROUND: To investigate antiviral potency of the 2-drug regimen (2DR) dolutegravir plus lamivudine vs the 3-drug regimen (3DR) dolutegravir plus tenofovir disoproxil fumarate/emtricitabine, we performed a post-hoc analysis assessing antiviral response rates in the phase III GEMINI-1 and GEMINI-2 studies by baseline viral load (VL). SETTING: One hundred ninety-two centers in 21 countries. METHODS: Treatment-naive HIV-1-infected participants with screening VL ≤500,000 copies/mL were randomized 1:1 to once-daily dolutegravir plus lamivudine or dolutegravir plus tenofovir disoproxil fumarate/emtricitabine. Median change from baseline was determined for log10-transformed VL in the overall study population and the subpopulation with baseline VL >100,000 copies/mL. Proportion of participants achieving plasma VL <50 copies/mL (Snapshot algorithm) or <40 copies/mL (Abbott RealTime HIV-1 assay) and target not detected was assessed through week 48 by baseline VL. Time to viral suppression was determined (nonparametric Kaplan-Meier method). RESULTS: For 293 participants with baseline VL >100,000 copies/mL, median change from baseline at week 4 was -3.38 and -3.40 log10 copies/mL in the 2DR and 3DR groups, respectively; reduction was sustained throughout 48 weeks. Time to VL <50 copies/mL was longer in participants with baseline VL >100,000 copies/mL than the overall study population (57 [week 8] vs 29 days [week 4]) and similar between the 2DR and 3DR groups. Proportion of participants with VL <50 or <40 copies/mL and target not detected was similar between groups, irrespective of baseline VL, at all tested visits throughout 48 weeks. CONCLUSION: Dolutegravir plus lamivudine demonstrates high antiviral potency in treatment-naive HIV-1-infected individuals across baseline VL strata.

Implementation of the Electronic Columbia-Suicide Severity Rating Scale (eC-SSRS™) Across Four Phase IIIb Clinical Trials in HIV-infected Individuals (ARIA, STRIIVING, DAWNING and INSPIRING).

Objective: Increased rates of suicidal ideation/behavior have been reported in individuals with human immunodeficiency virus infection/acquired immunodeficiency syndrome. The electronic Columbia-Suicidality Severity Rating Scale (eC-SSRS™) is a validated tool for assessment of suicidal risk. The objective of this study was to assess the site perspectives on implementation of the eC-SSRS used in Phase IIIb studies of dolutegravir. Methods: We developed and validated the ViiV eC-SSRS Metrics and Perspectives Site Questionnaire (VEQ). Topics included ease of eC-SSRS administration, agreement with clinical assessment, unreported risk, and confidence in utility of the eC-SSRS. Results: Clinical data from two Phase IIIb studies were reviewed for correlation with the eC-SSRS results. The overall VEQ response rate was 83%. A total of 85% of respondents administered the eC-SSRS by phone, and 34% reported their patients would be unable to complete a web survey. First-time eC-SSRS users made up 64% of the responders; 85% of repeat administrators said implementation became easier over time. One-half said the eC-SSRS accurately predicted risk, and 14% said the eC-SSRS identified previously unreported risk. A total of 65% were somewhat/very confident their patients are being assessed accurately for suicide risk. Conclusion: Results of the eC-SSRS from ARIA and STRIIVING were consistent with the clinical data. The eC-SSRS identified previous unreported risk for suicidality and provided physicians opportunity for follow-up. Respondents felt the eC-SSRS helps them manage suicide risk, and they reported that its administration became easier with experience. Thus, the eC-SSRS is considered a useful tool in this setting.

Efficacy and safety of inhaled zanamivir in the prevention of influenza in community-dwelling, high-risk adult and adolescent subjects: a 28-day, multicenter, randomized, double-blind, placebo-controlled trial.

BACKGROUND: Influenza can cause significant morbidity and mortality in subjects at high risk for complications, including the elderly (age >or=65 years) and those with chronic respiratory, cardiovascular, or metabolic conditions. Effective prophylaxis can significantly reduce the disease burden in this population. Previous studies conducted primarily in non-high-risk subjects have reported the efficacy of inhaled zanamivir in preventing influenza. OBJECTIVE: This study investigated the efficacy and safety of zanamivir in preventing influenza in community-dwelling adult and adolescent subjects at high risk for complications of influenza. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled, parallel-group study in community-dwelling subjects aged >or=12 years who were at high risk for developing complications of influenza, were able to use the Diskhaler device (Glaxo Group Limited, Research Triangle Park, North Carolina), and were able to take the first dose of study medication within 5 days of laboratory-confirmed local influenza activity. Eligible subjects were randomized to receive inhaled zanamivir 10 mg or placebo once daily for 28 days. The primary end point was the proportion of randomized subjects who developed symptomatic influenza during prophylaxis, as confirmed by culture and/or serology. All adverse events (AEs) occurring after the first dose of study medication were recorded. RESULTS: The study enrolled 3363 subjects, of whom 58% were female and 93% were white; the mean age of participants was 60.4 years (range, 12-94 years), and 4% were adolescents. Significantly fewer zanamivir-treated subjects developed symptomatic, laboratory- confirmed influenza during prophylaxis compared with placebo recipients (4/1678 vs 23/1685, respectively), representing a relative risk (RR) of 0.17 (95% CI, 0.07-0.44; P < 0.001) and a protective efficacy of 83%. The incidence of complications was reduced in zanamivir-treated subjects compared with placebo recipients (1/1678 and 8/1685), representing an RR of 0.12 (95% CI, 0.02-0.73; P = 0.042) and a protective efficacy of 88%. The numbers of zanamivir recipients (151/1678 [9%]) and placebo recipients (169/1685 [ 10 % ] ) who developed symptomatic influenza-like illness regardless of laboratory confirmation did not differ significantly (RR = 0.86; 95% CI, 0.70-1.06), indicating that zanamivir was not effective in preventing influenza-like illness that was not caused by influenza infection. Similarly, there was no significant difference in the numbers of zanamivir and placebo recipients who developed laboratory-confirmed infection regardless of symptoms (39/1678 [2%] and 52/1685 [3%], respectively; RR = 0.76; 95% CI, 0.50-1.15). Of these, 64 subjects (35 and 29) were asymptomatic; seroconversion occurred in all but 1 subject, indicating that zanamivir prophylaxis did not prevent asymptomatic seroconversion. During prophylaxis, 51% of subjects in both treatment groups reported at least 1 AE. There were no major differences in the frequency or nature of AEs between groups. The most commonly reported AEs (>or=3% of subjects in each treatment group) were consistent with upper respiratory viral infection (headache: 17% zanamivir, 18% placebo; cough: 14% and 15%, respectively; throat and tonsil discomfort/pain: 13% and 14%). There were no differences between groups in the overall incidence of viral respiratory infections (5% in both groups) or ear, nose, and throat infections (2% in both groups). None of the analyzed isolates from confirmed cases of influenza exhibited reduced susceptibility to zanamivir or genotypic evidence of resistance. CONCLUSIONS: Zanamivir, administered once daily for 28 days, was efficacious in preventing infection with the predominant circulating strains in the 2000- 2001 influenza season in the Northern Hemisphere (influenza A/New Calendonia/20/99-1ike and influenza B/ Sichuan/379/99-like) in these high-risk community- dwelling subjects aged >or=12 years. Zanamivir was well tolerated, with a safety profile comparable to that of placebo. No emergence of resistant virus was detected.

Fixed-dose combination dolutegravir, abacavir, and lamivudine versus ritonavir-boosted atazanavir plus tenofovir disoproxil fumarate and emtricitabine in previously untreated women with HIV-1 infection (ARIA): week 48 results from a randomised, open-label, non-inferiority, phase 3b study.

BACKGROUND: Dolutegravir is a once-daily integrase strand transfer inhibitor with no need for pharmacokinetic boosting that is approved for the treatment of HIV-1 infection. Because women are often under-represented in HIV clinical trials, we addressed the safety and efficacy of dolutegravir in women with HIV-1. METHODS: The ARIA study is a randomised, open-label, multicentre, active-controlled, parallel-group, non-inferiority phase 3b study done in 86 hospital and university infectious disease clinics, local health clinics, and private infectious disease clinics in 12 countries and one US territory, in North America, South America, Europe, Africa, and Asia. Eligible participants were women aged 18 years or older who had HIV-1 RNA viral loads of 500 copies per mL or greater, had received 10 days or less of previous antiretroviral therapy, and had tested negative for the HLA-B*5701 allele. Pregnant women were excluded. Eligible women were randomly assigned (1:1) to receive either a single-tablet regimen of dolutegravir plus abacavir and lamivudine once a day (dolutegravir group) or a three-tablet combination of ritonavir-boosted atazanavir plus coformulated tenofovir disoproxil fumarate and emtricitabine once a day (atazanavir group). Random treatment group assignment was stratified by plasma HIV-1 RNA viral loads and CD4 cell count at baseline. The primary endpoint was the proportion of participants with HIV-1 RNA viral loads of less than 50 copies per mL at week 48 in all participants who received at least one dose of study medication (intention-to-treat exposed population). We used a non-inferiority margin of -12%. Investigators monitored adverse events to assess safety. This study is registered with ClinicalTrials.gov, number NCT01910402. FINDINGS: Between Aug 22, 2013, and Sept 22, 2015, of 705 women assessed, 499 were randomly assigned to either the dolutegravir group (n=250) or the atazanavir group (n=249); two participants from each group were randomised to treatment but did not receive study medication. At week 48, 203 (82%) of 248 participants in the dolutegravir group compared with 176 (71%) of 247 in the atazanavir group had HIV-1 RNA viral loads of less than 50 copies per mL (mean difference 10·5%, 95% CI 3·1-17·8, p=0·005). One participant in the atazanavir group had nucleoside reverse transcriptase inhibitor-associated resistance that led to reduced emtricitabine susceptibility. Adverse events were similar between the dolutegravir and atazanavir groups; the most common were nausea (46 [19%] of 248 in the dolutegravir group vs 49 [20%] of 247 in the atazanavir group) and headache (28 [11%] vs 32 [13%]). Fewer participants in the dolutegravir group than the atazanavir group reported drug-related adverse events (83 [33%] vs 121 [49%]) or adverse events that led to discontinuation (ten [4%] vs 17 [7%]). One death was reported in each treatment group, but neither was considered related to the study medications. INTERPRETATION: The non-inferior efficacy and similar safety profile of the dolutegravir combined regimen compared with the atazanavir regimen support the use of dolutegravir for HIV-1 infection in treatment-naive women. FUNDING: ViiV Healthcare.

Phenotypic and genotypic analysis of influenza viruses isolated from adult subjects during a phase II study of intravenous zanamivir in hospitalised subjects.

Intravenous zanamivir (IVZ) is a neuraminidase (NA) inhibitor (NAI) under investigation for the treatment of subjects hospitalised with influenza. The study included 130 symptomatic, hospitalised adults with influenza. Subjects received IVZ for 5-10 days. Viruses were cultured and analysed for susceptibility to zanamivir. Mean IC50s (n = 50) (±SD) for influenza A/H1N1pdm09, A/H3N2 and influenza B were 0.20 ± 0.06, 0.26 ± 0.07 and 1.61 ± 0.35 nM, respectively, and are comparable to data observed for sensitive isolates. A total of 185 NA and 180 haemagglutinin (HA) sequences were obtained from 123 subjects; the majority did not contain resistance substitutions. Four influenza A/H1N1pdm09 viruses from four subjects harboured NA resistance substitutions: three, Y155H, D199G and S247N, were present at Day 1 before IVZ exposure and the fourth, E119D/E, was detected at Post Treatment +5 Days but was not present at 5 other timepoints. Five subjects harboured virus with treatment-emergent NA substitutions not associated with resistance; N63D, V83A, W190C, M269K (A/H1N1pdm09) and R210K (A/H3N2). Viruses from fifteen subjects harboured HA resistance substitutions, (A/H1N1pdm09) one emerged during treatment: S162N (Day 5). Five viruses harboured treatment-emergent HA substitutions (A/H1N1pdm09) not associated with resistance: E81K, V108L, S164D, D168N and S185N. 10/92 subjects with A/H1N1pdm09 harboured a D222 HA substitution, which has been associated with increased virulence. The emergent substitutions are not associated with resistance but may have arisen due to selection pressure during IVZ treatment or by chance. In this study, there was evidence for resistance selection in a post treatment sample but the resistant variant did not persist in later visit samples.