Snapshot Algorithm Research Articles

900. Switching to DTG/3TC Fixed-Dose Combination (FDC) Is Non-inferior to Continuing a TAF-Based Regimen (TBR) in Maintaining Virologic Suppression Through 144 Weeks (TANGO Study)

BackgroundDTG/3TC is a complete 2-drug regimen (2DR) for the treatment of HIV-1 infection. Non-inferior virologic efficacy has been proven over 3 years in treatment-naive people living with HIV (PLWH) and 2 years in a stable switch setting. MethodsTANGO, a randomized, open-label, non-inferiority study, evaluates efficacy and safety of switching to DTG/3TC in PLWH who are virologically suppressed ( > 6 months, no prior virologic failure [VF], no major NRTI/INSTI resistance) vs remaining on a 3- or 4-drug TAF-based regimen (TBR), stratified by baseline 3rd agent class. Week 144 analyses assessed non-inferiority (NI) with a 4% NI margin for Snapshot virologic failure (VF) and 8% for virologic success (VS; FDA Snapshot algorithm, intention-to-treat–exposed [ITT-E] population).ResultsOf 741 randomized/exposed pts (DTG/3TC: 369; TBR: 372), most pts entered the study on EVG/c (66%). For Week 144 Snapshot VF, switching to DTG/3TC was non-inferior to continuing TBR in the ITT-E analysis: 0.3% vs 1.3%; adjusted difference (95% CI): −1.1% (−2.4%, 0.2%) and superior to TBR in the per-protocol analysis: 0% vs 1.1%; adjusted difference: −1.1% (−2.3, −0.0); P=0.044 (2-sided). Snapshot VS was high in both arms and demonstrated non-inferiority (Table). Zero pts on DTG/3TC and 3 (0.8%) on TBR met confirmed virologic withdrawal criteria with no resistance observed. Zero pts on DTG/3TC and 6 (1.6%) on TBR discontinued for lack of efficacy. Overall AE rates were similar between arms (Table). TC, LDL-C, and triglycerides improved with DTG/3TC, HDL-C improved with TBR, with no difference in TC/HDL-C ratio between arms. Changes in eGFR (cystatin C) and proximal tubular function marker were similar across arms. Adjusted mean change from BL in weight was 2.2 and 1.7 kg in the DTG/3TC and TBR arms, respectively, and proportion of pts with > 10% weight increase was similar across arms (13% and 12%, respectively).Table. Efficacy and Key Safety Results for the ITT-E and Safety Population ConclusionSwitching to the 2-drug regimen of DTG/3TC from a TAF-based 3- or 4-drug regimen resulted in high, non-inferior efficacy with zero confirmed virologic withdrawals and good tolerability over 3 years of treatment. DTG/3TC 2DR is a robust switch option with durable efficacy, good safety and tolerability, and a high barrier to resistance.Disclosures Olayemi Osiyemi, M.D, Gilead (Advisor or Review Panel member, Speaker’s Bureau)Merck (Advisor or Review Panel member)ViiV Healthcare (Advisor or Review Panel member, Speaker’s Bureau) Fiona Bisshop, MBBBS, Gilead (Grant/Research Support)ViiV Healthcare (Grant/Research Support) Stéphane De Wit, MD, Gilead (Grant/Research Support)Janssen (Grant/Research Support)Merck Sharpe & Dohme (Grant/Research Support)ViiV Healthcare (Grant/Research Support) Joaquín Portilla, MD, AbbVie (Other Financial or Material Support)Gilead (Grant/Research Support, Other Financial or Material Support)Janssen (Grant/Research Support, Other Financial or Material Support)Merck Sharpe & Dohme (Other Financial or Material Support)ViiV Healthcare (Grant/Research Support, Other Financial or Material Support) Jean-Pierre Routy, MD, FRCPC, ViiV Healthcare (Grant/Research Support) Mounir Ait-Khaled, PhD, ViiV Healthcare (Employee) Keith Pappa, PharmD, Glaxo Smith Kline (Shareholder)ViiV Healthcare (Employee) Ruolan Wang, Master of Science, ViiV Healthcare (Employee) Peter Leone, MD, viiv healthcare (Employee) Jonathan Wright, MSc, GlaxoSmithKline (Employee, Shareholder) Brian Wynne, MD, ViiV Healthcare (Employee, Shareholder, I have shares in GSK, the part owner of ViiV) Jean A. van Wyk, MB,ChB, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Michael Aboud, MBChB, MRCP, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Kimberly Smith, MD, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee)

877. North American Phase 3/3b Experience with Long-Acting Cabotegravir and Rilpivirine: Efficacy, Safety, and Virologic Outcomes

BackgroundCabotegravir (CAB) plus rilpivirine (RPV) is the first complete long-acting (LA) regimen recommended by treatment guidelines for the maintenance of HIV-1 virologic suppression. CAB+RPV LA dosed every 4 weeks (Q4W) or every 8 weeks (Q8W) demonstrated noninferior efficacy in multinational Phase 3/3b trials. This post hoc descriptive analysis summarizes efficacy, virologic outcomes, safety, and treatment preference for US and Canadian (CAN) participants through Week (W) 48. MethodsThis analysis focuses on data for US/CAN participants naive to CAB+RPV (n=376) from the larger pooled population of the ATLAS, FLAIR, and ATLAS-2M Phase 3/3b studies (N=1245). Endpoints included the proportion of participants with plasma HIV-1 RNA ≥ 50 and < 50 c/mL at W48 (FDA Snapshot algorithm), incidence of confirmed virologic failure (CVF; 2 consecutive HIV-1 RNA ≥ 200 c/mL), safety, and treatment preference through W48.Results376 US/CAN participants received CAB+RPV LA Q4W or Q8W. Median (range) age was 39y (20–74); 14.9% were female, 66.0% were White. At W48, 93.1% (350/376) maintained virologic suppression (HIV-1 RNA < 50 c/mL), 1.9% (7/376) had HIV-1 RNA ≥ 50 c/mL, and 0.8% (3/376) met the CVF criterion, consistent with the overall global pooled population (Table 1). Two of the three participants with CVF had ≥ 2 of the three baseline factors (archived RPV resistance-associated mutations [RAMs], HIV subtype A6/A1, body mass index [BMI] ≥ 30 kg/m2) previously associated with CVF. Among the US/CAN participants with a single baseline factor, none met CVF. Overall, archived RPV RAMs were observed in 3.2% (12/376), HIV subtype A6/A1 in 1.1% (4/376), and BMI ≥ 30 kg/m2 in 26.3% (99/376) of participants. Safety and injection site reaction findings were similar to the overall pooled population (Table 2). Most participants (120/134, 89.6%) preferred LA over oral dosing (7/134, 5.2%). Table 1. Snapshot outcomes following CAB+RPV LA Q4W and Q8W at Week 48 in participants naive to CAB+RPV from ATLAS, FLAIR, and ATLAS-2M (ITT-E population) Table 2. Safety summary through Week 48 following CAB+RPV LA Q4W and Q8W or comparator ART in participants naive to CAB+RPV from ATLAS, FLAIR, and ATLAS-2M ConclusionIn US/CAN Phase 3/3b trial participants, CAB+RPV LA was highly effective and well tolerated, with outcomes consistent with the overall pooled population. Baseline prevalence of archived RPV RAMs and subtype A6/A1 was low and aligned with regional prevalence/surveillance data. CAB+RPV LA provides a tolerable and effective injectable LA treatment option for virologically suppressed US/CAN individuals with HIV.Disclosures Babafemi O. Taiwo, MBBS, Gilead (Consultant)Merck (Consultant)ViiV Healthcare (Consultant) Darrell Tan, MD PhD, Abbvie (Grant/Research Support)Gilead (Grant/Research Support)GlaxoSmithKline (Scientific Research Study Investigator)ViiV Healthcare (Grant/Research Support) Parul Patel, PharmD, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Paula Teichner, PharmD, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Joseph Polli, PhD, FAAPS, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Louise Garside, PhD, GlaxoSmithKline (Employee) Ronald D’Amico, DO, MSc, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Christine L. Talarico, M.S., GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Rodica Van Solingen-Ristea, MD, Janssen Research and Development (Employee)ViiV Healthcare (Employee) Bryan Baugh, MD, Janssen, Johnson & Johnson (Employee, Shareholder) William Spreen, PharmD, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Michael Aboud, MBChB, MRCP, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Matthew Bosse, DO, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee)

Long-acting cabotegravir and rilpivirine for HIV-1 suppression: switch to 2-monthly dosing after 5 years of daily oral therapy.

Objectives:Long-acting formulations of cabotegravir (CAB) and rilpivirine (RPV) have demonstrated efficacy in Phase 3 studies. POLAR (NCT03639311) assessed antiviral activity and safety of CAB+RPV long-acting administered every 2 months (Q2M) in adults living with HIV-1 who previously received daily oral CAB+RPV in LATTE (NCT01641809).Design:A Phase 2b, multicenter, open-label, rollover study.Methods:LATTE participants with plasma HIV-1 RNA less than 50 copies/ml who completed at least 300 weeks on study were eligible. Participants elected to switch to either CAB+RPV long-acting Q2M or daily oral dolutegravir/RPV for maintenance of virologic suppression. The primary endpoint was the proportion of participants with HIV-1 RNA greater than or equal to 50 copies/ml at Month 12 (M12) per the Food and Drug Administration Snapshot algorithm. The incidence of confirmed virologic failure (CVF, two consecutive HIV-1 RNA measurements greater than or equal to 200 copies/ml), as well as safety, laboratory, and patient-reported outcomes (HIV Treatment Satisfaction and preference questionnaires) were also assessed.Results:Of 97 participants enrolled, 90 chose to receive CAB+RPV long-acting and seven chose dolutegravir/RPV. At M12, no participant had HIV-1 RNA greater than or equal to 50 copies/ml or met the CVF criterion in either treatment group. No new safety signals were identified. Total treatment satisfaction was high at Baseline and remained stable through M12 across both treatment groups. Overall, 88% (n = 77/88) of long-acting arm participants preferred CAB+RPV long-acting to oral CAB+RPV.Conclusion:CAB+RPV long-acting maintained virologic suppression in participants who had previously received daily oral CAB+RPV for at least 5 years in LATTE, with a favorable safety profile. Most participants preferred CAB+RPV long-acting to their prior oral CAB+RPV regimen at M12.

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.

BackgroundIn 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.MethodsAfter 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).ResultsAt 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.ConclusionsCabotegravir + rilpivirine LA exhibited long-term efficacy and tolerability, demonstrating its durability as maintenance therapy for HIV-1 infection.Clinical Trials Registration. NCT02120352.

Performance analysis of SBAS ephemeris corrections and integrity algorithms in China region

Satellite Based Augmentation Systems (SBASs) improve the positioning accuracy and integrity by broadcasting to the civil aviation community the corrections and integrity parameters. A snapshot algorithm based on the minimum variance estimation is investigated in this study to calculate the satellite clock and orbit corrections. A chi-square test is performed on the remaining errors in the corrected ephemeris to guarantee the integrity. User Differential Range Error (UDRE) and scaling matrix contained in Message Type 28 are derived using the covariance information based on the assumption that one of the reference stations failed. A software package is developed and applied in the real data collected at 26 stations. International GNSS (Global Navigation Satellite System) Service (IGS) precise clock and orbit products are taken as the references to assess the accuracy of corrections. For both Global Positioning System (GPS) and BeiDou Navigation Satellite System (BDS), the range accuracy of 0.10 m can be achieved with the employment of the derived corrections. No obvious performance difference between GPS and BDS is found. UDREs for all visible satellites are generated with the maximum index of 12 and minimum index of 3. The geometric range differences calculated with IGS precise products and broadcast ephemeris are employed to assess the integrity of UDRE. It is found that the UDRE is able to bound the residuals with 99.9% confidence which meet the requirement of aviation users. With ionospheric delay corrected by Global Ionosphere Map (GIM), the positioning accuracy of 0.98 m with GPS corrections and 0.80 m with multi-constellation augmentation can be achieved which indicates a significant improvement of GPS standalone results.

Dolutegravir or Darunavir in Combination with Zidovudine or Tenofovir to Treat HIV

BackgroundThe World Health Organization recommends dolutegravir with two nucleoside reverse-transcriptase inhibitors (NRTIs) for second-line treatment of human immunodeficiency virus type 1 (HIV-1) infection. Evidence is limited for the efficacy of this regimen when NRTIs are predicted to lack activity because of drug resistance, as well as for the recommended switch of an NRTI from tenofovir to zidovudine.MethodsIn a two-by-two factorial, open-label, noninferiority trial, we randomly assigned patients for whom first-line therapy was failing (HIV-1 viral load, ≥1000 copies per milliliter) to receive dolutegravir or ritonavir-boosted darunavir and to receive tenofovir or zidovudine; all patients received lamivudine. The primary outcome was a week 48 viral load of less than 400 copies per milliliter, assessed with the Food and Drug Administration snapshot algorithm (noninferiority margin for the between-group difference in the percentage of patients with the primary outcome, 12 percentage points).ResultsWe enrolled 464 patients at seven sub-Saharan African sites. A week 48 viral load of less than 400 copies per milliliter was observed in 90.2% of the patients in the dolutegravir group (212 of 235) and in 91.7% of those in the darunavir group (210 of 229) (difference, −1.5 percentage points; 95% confidence interval [CI], −6.7 to 3.7; P=0.58; indicating noninferiority of dolutegravir, without superiority) and in 92.3% of the patients in the tenofovir group (215 of 233) and in 89.6% of those in the zidovudine group (207 of 231) (difference, 2.7 percentage points; 95% CI, −2.6 to 7.9; P=0.32; indicating noninferiority of tenofovir, without superiority). In the subgroup of patients with no NRTIs that were predicted to have activity, a viral load of less than 400 copies per milliliter was observed in more than 90% of the patients in the dolutegravir group and the darunavir group. The incidence of adverse events did not differ substantially between the groups in either factorial comparison.ConclusionsDolutegravir in combination with NRTIs was effective in treating patients with HIV-1 infection, including those with extensive NRTI resistance in whom no NRTIs were predicted to have activity. Tenofovir was noninferior to zidovudine as second-line therapy. (Funded by Janssen; NADIA ClinicalTrials.gov number, NCT03988452.)

Rilpivirine plus cobicistat-boosted darunavir as alternative to standard three-drug therapy in HIV-infected, virologically suppressed subjects: Final results of the PROBE 2 trial.

Primary analysis at 24weeks showed that switching to rilpivirine plus darunavir/cobicistat was non-inferior to continuing a standard three-drug antiretroviral regimen in virologically suppressed people with HIV. We present efficacy and safety data from the 48-week analysis. PROBE 2 is a randomized, open-label trial. Adults who were on a three-drug therapy and had had <50 HIV-1 RNA copies/mL for at least 6months were randomly assigned (1:1) to 25mg rilpivirine plus 800/150 darunavir/cobicistat once daily (early switch group) or to continue their regimen for 24weeks before switching (late switch group). In the 48-week analysis, the efficacy endpoint was the proportion of participants with <50 copies/mL of HIV-RNA (US Food and Drug Administration snapshot algorithm). The trial is registered with ClinicalTrials.gov, number NCT04064632. 160 participants were recruited and randomized. At week 48, 70 (87.5%) in the early switch group and 76 (94.8%) in the late switch group maintained HIV-RNA <50 copies/mL. Virological failure (≥50 HIV-RNA copies/mL) was not seen in any patient of the early switch group and in 2 subjects in the late switch group none of which had treatment emergent resistance-associated mutation. Adverse events leading to treatment discontinuation occurred in 7 (8.7%) participants in the early switch group and in none in the late switch group. The combination of rilpivirine plus darunavir/cobicistat sustained virological suppression, was associated with a low frequency of virological failure, and had a favorable safety profile, which support its use as a nucleoside reverse transcriptase inhibitor-sparing and integrase inhibitor-sparing alternative to three-drug regimens.

Long-acting cabotegravir plus rilpivirine for treatment in adults with HIV-1 infection: 96-week results of the randomised, open-label, phase 3 FLAIR study

There is a need for more convenient, less frequent treatment to help address challenges associated with daily oral HIV treatment in people living with HIV, including stigma, pill burden, drug-food interactions, and adherence. The phase 3 ATLAS and FLAIR studies showed non-inferiority of long-acting cabotegravir and rilpivirine dosed every 4 weeks compared with standard oral therapy for the maintenance of virological suppression in adults with HIV-1 over 48 weeks. We present the 96-week findings. FLAIR is a randomised, phase 3, open-label, multicentre study done in 11 countries investigating whether switching to long-acting cabotegravir and rilpivirine is non-inferior to daily dolutegravir, abacavir, and lamivudine in virologically suppressed adults living with HIV-1. Antiretroviral therapy (ART)-naive participants received induction therapy with daily oral dolutegravir (50 mg), abacavir (600 mg), and lamivudine (300 mg) for 20 weeks. After 16 weeks, participants with less than 50 HIV-1 RNA copies per mL were randomly assigned (1:1) to continue the standard of care regimen (standard care group) or switch to receive daily oral cabotegravir 30 mg and rilpivirine 25 mg for at least 4 weeks followed by long-acting cabotegravir 400 mg and rilpivirine 600 mg, administered as two 2 mL intramuscular injections, every 4 weeks for at least 96 weeks (long-acting group). Randomisation was stratified by baseline (preinduction) HIV-1 RNA (<100 000 or ≥100 000 copies per mL) and sex at birth and used GlaxoSmithKline-verified randomisation software (RandAll NG, version 1.3.3) for treatment assignment. The primary endpoint was the proportion of participants with plasma HIV-1 RNA of 50 copies per mL or more assessed as per the US Food and Drug Administration (FDA) Snapshot algorithm at week 48, which has been reported previously. Here, we report the proportion of participants with 50 or more HIV-1 RNA copies per mL using the FDA Snapshot algorithm at week 96 (intention-to-treat population; non-inferiority margin 6%). The trial is registered with ClinicalTrials.gov, NCT02938520. Between Oct 27, 2016, and March 24, 2017, 809 participants were screened. 631 (78%) participants entered the induction phase and 566 (70%) were randomly assigned to either the standard care group (283 [50%] participants) or the long-acting group (283 [50%]). Median age was 34 years (IQR 29 to 43), 62 (11%) were 50 years or older, 127 (22%) were women (sex at birth), and 419 (74%) were white. At week 96, nine (3%) participants in each arm had 50 or more HIV-1 RNA copies per mL, with an adjusted difference of 0·0 (95% CI -2·9 to 2·9), consistent with non-inferiority established at week 48. Across both treatment groups, adverse events leading to withdrawal were infrequent (14 [5%] participants in the long-acting group and four [1%] in the standard care group). Injection site reactions were the most common adverse event, reported by 245 (88%) participants in the long-acting group; their frequency decreased over time. Median injection site reaction duration was 3 days (IQR 2 to 4), and 3082 (99%) of 3100 reactions were grade 1 or 2. No deaths occurred during the maintenance phase. The 96-week results reaffirm the 48-week results, showing long-acting cabotegravir and rilpivirine continued to be non-inferior compared with continuing a standard care regimen in adults with HIV-1 for the maintenance of viral suppression. These results support the durability of long-acting cabotegravir and rilpivirine, over an almost 2-year-long period, as a therapeutic option for virally suppressed adults with HIV-1. ViiV Healthcare and Janssen Research and Development.

AntiRetroviral Therapy In Second-line: investigating Tenofovir-lamivudine-dolutegravir (ARTIST): protocol for a randomised controlled trial.

Background: Dolutegravir has superior efficacy and tolerability than lopinavir-ritonavir in second-line antiretroviral therapy after failure of a first-line non-nucleoside reverse transcriptase inhibitors-based regimen, when dolutegravir is accompanied by at least one fully active nucleoside reverse transcriptase inhibitor (NRTI). Resistance testing to select NRTIs is not feasible in low- and middle-income countries due to cost and limited laboratory capacity. Evidence suggests that recycling tenofovir plus lamivudine or emtricitabine backbone with dolutegravir could provide an effective second-line option. This study aims to determine the virologic efficacy of tenofovir-lamivudine-dolutegravir (TLD) with and without a lead-in supplementary dose of dolutegravir (to counteract the inducing effect of efavirenz) in patients failing a first-line regimen of tenofovir-emtricitabine-efavirenz (TEE). Methods: We will perform a parallel group, randomised (1:1), double blind, placebo-controlled, Phase II trial, comparing TLD fixed dose combination daily with a lead-in supplementary 50 mg dolutegravir dose versus matching placebo taken 12 hours later for the first 14 days, in patients failing a first-line TEE regimen. The trial will be set in two primary care clinics in Khayelitsha; a large, peri-urban informal settlement in Cape Town, South Africa. We will enrol 130 participants, with follow-up to 48 weeks. The primary endpoint is proportion achieving viral load <50 copies/mL at week 24 using a modified intention-to-treat analysis and the U.S. Food and Drug Administration snapshot algorithm. Secondary endpoints include virologic suppression at weeks 12 and 48, time to suppression, emergence of dolutegravir and new NRTI resistance mutations, safety, and tolerability. Discussion: Impaired viral fitness due to NRTI resistance mutations and dolutegravir's high barrier to resistance provide rationale for switching patients from a failing TEE regimen to TLD; however, clinical evidence regarding virologic efficacy is lacking. This study provides estimates of such a strategy's early virologic efficacy with and without a supplementary dolutegravir dosing. Registration: ClinicalTrials.gov NCT03991013 (19/06/2019).

1024. Impact of Treatment Adherence on Efficacy of DTG/3TC and DTG + TDF/FTC: Pooled Analysis of the GEMINI 1 and 2 Clinical Trials

BackgroundGEMINI 1 & 2 are global double-blind, multi-center phase III non-inferiority studies evaluating efficacy and safety of dolutegravir (DTG) + lamivudine (3TC) once daily in treatment-naive HIV-1-infected adults with Screening HIV-1 RNA ≤ 500,000 c/mL (ClinicalTrials.gov: NCT02831673/NCT02831764). Participants were randomized 1:1 to treatment with DTG+3TC or DTG + tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC). The primary endpoint was the proportion of participants with plasma HIV-1 RNA < 50 c/mL at Week 48 (Snapshot algorithm). DTG+3TC was non-inferior to DTG+TDF/FTC at Weeks 48 and 96. Here we evaluate the impact of treatment adherence on Week 48 virologic response (VR) within the GEMINI trials as a post-hoc analysis.MethodsAdherence was estimated using pill counts data and categorized as follows: ≥ 90% vs < 90%. Week 48 VR was measured as % of participants with HIV-1 RNA < 50 c/mL by Food and Drug Administration Snapshot and by last on treatment viral load (VL) for the intention to treat–exposed population for which adherence could be derived. VR and differences between treatment arms within each adherence category were calculated along with exact unadjusted 95% confidence intervals.Results5% of participants had < 90% adherence in both treatment arms. Baseline VL and CD4+ cell counts were similar across adherence categories. VR was lower in the < 90% adherence group than the ≥ 90% group, but not different between the 2 treatment arms within the same adherence category: In the low adherence group, DTG+3TC VR was 69% compared to 65% in DTG+TDF/FTC arm by Snapshot and 91% and 85% respectively by last on treatment VL analysis (Table).Table. ConclusionIn the GEMINI studies, a lower Week 48 VR was observed in participants with < 90% adherence, but the impact of lower adherence on VR was similar in the DTG+3TC compared with DTG+TDF/FTC arms. One limitation of the analysis is the small number of participants in the lower adherence subgroup. However, the results add further information about the robustness of DTG+3TC compared to 3-drug DTG-containing regimens and may suggest similar regimen forgiveness.DisclosuresMounir Ait-Khaled, PhD, ViiV Healthcare (Employee, Shareholder) Choy Man, BSc, ViiV Healthcare (Employee, Shareholder) Jorg Sievers, DPhil, ViiV Healthcare (Employee) Richard Grove, MSc, GSK/ViiV (Employee, Shareholder) Brian Wynne, MD, ViiV Healthcare (Employee) Rimgaile Urbaityte, MSc, GlaxoSmithKline (Employee, Shareholder) Jean A. van Wyk, MB,ChB, ViiV Healthcare (Employee, Shareholder) Debbie Hagins, MD, Gilead Sciences Inc. (Consultant, Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member)Janssen (Grant/Research Support)Merck (Consultant, Grant/Research Support, Advisor or Review Panel member)Viiv Healthcare (Consultant, Grant/Research Support, Advisor or Review Panel member) Andrew Zolopa, MD, ViiV Healthcare (Employee)

Switching to Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide in Adults With HIV and M184V/I Mutation.

Background:The ability of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) to maintain virologic suppression in participants with M184V and/or M184I resistance mutations from historical genotypic reports when switching from a tenofovir disoproxil fumarate–based or abacavir (ABC)-based regimen was investigated.Setting:Phase IIIb, 48-week, open-label, single-arm, multicenter, clinical trial (NCT02616029).Methods:Virologically suppressed adults with HIV and documented M184V/I on historical genotypic records switched to E/C/F/TAF from a tenofovir disoproxil fumarate–based or ABC-based regimen. The primary end point was HIV-1 RNA of <50 copies per milliliter at week 12 using pure virologic response (PVR). Secondary end points included HIV-1 RNA of <50 copies per milliliter at weeks 24/48 (PVR) and at weeks 12, 24, and 48 (Food and Drug Administration snapshot algorithm), and change in CD4+ count at weeks 12, 24, and 48.Results:M184V alone was reported in 82.8% of 64 participants; 9.4% and 7.8% had M184I and M184V/I, respectively, and 43.8% had archived M184V/I (baseline DNA). All (62/62 with available data, 100%, 95% confidence interval 94.2% to 100%) participants maintained PVR at weeks 12, 24, and 48. By Food and Drug Administration snapshot algorithm, one participant had HIV-1 RNA of ≥50 copies per milliliter (week 12); confirmatory HIV-1 RNA was <50 copies per milliliter. No significant changes were observed in CD4+ cell count. Drug-related adverse events (AEs) were reported by 10 (15.6%) participants. Six (9.4%) and 5 (7.8%) participants had grade 3–4 AEs or serious AEs, respectively (none drug related).Conclusions:The presence of the resistance mutations M184V/I did not jeopardize the efficacy of switching to E/C/F/TAF in virologically suppressed adults. High rates of virologic suppression were maintained throughout 48 weeks of therapy and treatment was well tolerated.

Efficacy and safety of dolutegravir plus emtricitabine versus standard ART for the maintenance of HIV-1 suppression: 48-week results of the factorial, randomized, non-inferiority SIMPL'HIV trial.

Dolutegravir (DTG)-based dual therapy is becoming a new paradigm for both the initiation and maintenance of HIV treatment. The SIMPL'HIV study investigated the outcomes of virologically suppressed patients on standard combination antiretroviral therapy (cART) switching to DTG + emtricitabine (FTC). We present the 48-week efficacy and safety data on DTG + FTC versus cART. SIMPL'HIV was a multicenter, open-label, non-inferiority randomized trial with a factorial design among treatment-experienced people with HIV in Switzerland. Participants were enrolled between 12 May 2017 and 30 May 2018. Patients virologically suppressed for at least 24 weeks on standard cART were randomized 1:1 to switching to DTG + FTC or to continuing cART, and 1:1 to simplified patient-centered monitoring versus standard monitoring. The primary endpoint was the proportion of patients virologically suppressed with <100 copies/ml through 48 weeks. The secondary endpoints included virological suppression at 48 weeks according to the US Food and Drug Administration (FDA) snapshot analysis. Non-inferiority of DTG + FTC versus cART for viral suppression was assessed using a stratified Mantel-Haenszel risk difference, with non-inferiority declared if the lower bound of the 95% confidence interval was greater than -12%. Adverse events were monitored to assess safety. Quality of life was evaluated using the PROQOL-HIV questionnaire. Ninety-three participants were randomized to DTG + FTC, and 94 individuals to cART. Median nadir CD4 count was 246 cells/mm3; median age was 48 years; 17% of participants were female. DTG + FTC was non-inferior to cART. The proportion of patients with viral suppression (<100 copies/ml) through 48 weeks was 93.5% in the DTG + FTC arm and 94.7% in the cART arm in the intention-to-treat population (risk difference -1.2%; 95% CI -7.8% to 5.6%). Per-protocol analysis showed similar results, with viral suppression in 96.5% of patients in both arms (risk difference 0.0%; 95% CI -5.6% to 5.5%). There was no relevant interaction between the type of treatment and monitoring (interaction ratio 0.98; 95% CI 0.85 to 1.13; p = 0.81). Using the FDA snapshot algorithm, 84/93 (90.3%) participants in the DTG + FTC arm had an HIV-1 RNA viral load of <50 copies/ml compared to 86/94 (91.5%) participants on standard cART (risk difference -1.1%; 95% CI -9.3% to 7.1%; p = 0.791). The overall proportion of patients with adverse events and discontinuations did not differ by randomization arm. The proportion of patients with serious adverse events was higher in the cART arm (16%) compared to the DTG + FTC arm (6.5%) (p = 0.041), but none was considered to be related to the study medication. Quality of life improved more between baseline and week 48 in the DTG + FTC compared to the cART arm (adjusted difference +2.6; 95% CI +0.4 to +4.7). The study's main limitations included a rather small proportion of women included, the open label design, and its short duration. In this study, DTG + FTC as maintenance therapy was non-inferior to cART in terms of efficacy, with a similar safety profile and a greater improvement in quality of life, thus expanding the offer of 2-drug simplification options among virologically suppressed individuals. ClinicalTrials.gov NCT03160105.

Switching to Bictegravir, Emtricitabine, and Tenofovir Alafenamide in Virologically Suppressed Adults With Human Immunodeficiency Virus.

BackgroundBictegravir (B)/emtricitabine (F)/tenofovir alafenamide (TAF) is guideline-recommended treatment for human immunodeficiency virus type 1 (HIV-1). We evaluated whether people receiving dolutegravir (DTG) plus F/TAF or F/TDF (tenofovir disoproxil fumarate) with viral suppression can switch to B/F/TAF without compromising safety or efficacy, regardless of preexisting nucleoside reverse transcriptase inhibitor (NRTI) resistance.MethodsIn this multicenter, randomized, double-blinded, active-controlled, noninferiority trial, we enrolled adults who were virologically suppressed for ≥6 months before screening (with documented/suspected NRTI resistance) or ≥3 months before screening (with no documented/suspected NRTI resistance) on DTG plus either F/TDF or F/TAF. We randomly assigned (1:1) participants to switch to B/F/TAF or DTG + F/TAF once daily for 48 weeks, each with matching placebo. The primary endpoint was proportion of participants with plasma HIV-1 RNA ≥50 copies/mL at week 48 (snapshot algorithm); the prespecified noninferiority margin was 4%.ResultsFive hundred sixty-seven adults were randomized; 565 were treated (284 B/F/TAF, 281 DTG + F/TAF). At week 48, B/F/TAF was noninferior to DTG + F/TAF, as 0.4% (1/284) vs 1.1% (3/281) had HIV-1 RNA ≥50 copies/mL (difference, −0.7% [95.001% confidence interval {CI}, −2.8% to 1.0%]). There were no significant differences in efficacy among participants with suspected or confirmed prior NRTI resistance (n = 138). No participant had treatment-emergent drug resistance. Median weight change from baseline at week 48 was +1.3 kg (B/F/TAF) vs +1.1 kg (DTG + F/TAF) (P = .46). Weight change differed by baseline NRTIs (+2.2 kg [F/TDF] and +0.6 kg [F/TAF], P < .001), with no differences between B/F/TAF and DTG + F/TAF.ConclusionsThe single-tablet regimen B/F/TAF is a safe, effective option for people virologically suppressed on DTG plus either F/TDF or F/TAF, including in individuals with preexisting resistance to NRTIs.Clinical Trials RegistrationNCT03110380.

Fixed-dose combination bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir-containing regimens for initial treatment of HIV-1 infection: week 144 results from two randomised, double-blind, multicentre, phase 3, non-inferiority trials

In the primary week-48 analyses of two phase 3 studies, coformulated bictegravir, emtricitabine, and tenofovir alafenamide was non-inferior to a dolutegravir-containing regimen in treatment-naive people with HIV. We report week-144 efficacy and safety results from these studies. We did two double-blind, active-controlled studies (now in open-label extension phase). Study 1 randomly assigned (1:1) HLA-B*5701-negative adults without hepatitis B virus co-infection to receive coformulated bictegravir 50 mg, emtricitabine 200 mg, and tenofovir alafenamide 25 mg, or coformulated dolutegravir 50 mg, abacavir 600 mg, and lamivudine 300 mg once daily. Study 2 randomly assigned (1:1) adults to bictegravir, emtricitabine, and tenofovir alafenamide, or dolutegravir 50 mg given with coformulated emtricitabine 200 mg and tenofovir alafenamide 25 mg. We previously reported non-inferiority at the primary endpoint. Here, we report the week-144 secondary outcome of proportion of participants with plasma HIV-1 RNA less than 50 copies per mL at week 144, by US Food and Drug Administration Snapshot algorithm, analysed in the same manner. These studies were registered with ClinicalTrials.gov, NCT02607930 and NCT02607956. 629 participants were randomly assigned and treated in study 1 (314 to bictegravir, emtricitabine, and tenofovir alafenamide, and 315 to dolutegravir, abacavir, and lamivudine) and 645 in study 2 (327 to bictegravir, emtricitabine, and tenofovir alafenamide, 325 to dolutegravir, emtricitabine, tenofovir alafenamide). At week 144, bictegravir, emtricitabine, and tenofovir alafenamide was non-inferior to both dolutegravir-containing regimens for efficacy. In study 1, 256 (82%) of 314 participants had plasma HIV-1 RNA less than 50 copies per mL in the bictegravir, emtricitabine, and tenofovir alafenamide group and 265 (84%) of 315 in the dolutegravir, abacavir, and lamivudine group (difference -2·6%, 95% CI -8·5 to 3·4). In study 2, 262 (82%) of 320 participants had plasma HIV-1 RNA less than 50 copies per mL in the bictegravir, emtricitabine, and tenofovir alafenamide group and 273 (84%) of 325 in the dolutegravir, emtricitabine, and tenofovir alafenamide group (difference -1·9%, -7·8 to 3·9). In both studies, no participant had treatment-emergent resistance to study drugs up to week 144. All treatment regimens were well tolerated with additional exposure. Adverse events that led to study drug discontinuation were reported for no participants in the bictegravir, emtricitabine, and tenofovir alafenamide group versus five (2%) of 315 in the dolutegravir, abacavir, and lamivudine group (study 1), and six (2%) of 320 in the bictegravir, emtricitabine, and tenofovir alafenamide versus six (2%) of 325 in the dolutegravir, emtricitabine, and tenofovir alafenamide group (study 2). In study 1, statistically significant differences were observed in median changes from baseline in fasting total cholesterol (14 mg/dL vs 10 mg/dL; p=0·034), direct LDL (21 mg/dL vs 14 mg/dL; p=0·004), and total cholesterol to HDL ratio (-0·1 vs -0·3; p=0·007) at week 144; no differences were observed between groups in study 2. Weight gain was seen across all treatment groups in both studies, with no differences in median changes from baseline in weight at week 144 for either study. These long-term data support the use of bictegravir, emtricitabine, and tenofovir alafenamide as a safe, well tolerated, and durable treatment for people with HIV, with no emergent resistance. Gilead Sciences.

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

BackgroundLong-acting injectable regimens may simplify therapy for patients with human immunodeficiency virus type 1 (HIV-1) infection.MethodsWe 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).ResultsAt 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.ConclusionsTherapy 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.)

Rilpivirine plus cobicistat-boosted darunavir as a two-drug switch regimen in HIV-infected, virologically suppressed subjects on steady standard three-drug therapy: a randomized, controlled, non-inferiority trial (PROBE 2).

We explored the combination of rilpivirine plus cobicistat-boosted darunavir [a two-drug regimen (2DR)] when switching from standard triple combined ART. In this randomized, open-label, non-inferiority trial, participants had an HIV-RNA <50 copies/mL on a stable (>6 months) three-drug regimen. The primary endpoint was proportion with HIV-RNA <50 copies/mL at Week 24 (snapshot algorithm), with a -12% non-inferiority margin. ClinicalTrials.gov: NCT04064632. One hundred and sixty patients were allocated (1:1) to 2DR or to continue current ART (CAR). At Week 24, 72 (90.0%) of participants with 2DR and 75 (93.8%) with CAR maintained HIV-RNA <50 copies/mL [difference -3.75% (95% CI = -11.63 to 5.63)], confirming non-inferiority. Non-inferiority was confirmed considering an HIV-RNA >50 copies/mL (0% for 2DR; 3.7% for CAR; 95% CI = -0.4 to 7.9). Four patients reported adverse events not leading to treatment discontinuation (one patient in the 2DR group and three patients in the CAR group); eight subjects discontinued therapy in the 2DR group and three in the CAR group. With 2DR, lipid serum concentrations increased, but differences were statistically significant only for tenofovir disoproxil fumarate-containing CAR and in 2DR patients receiving a pre-switch regimen including tenofovir disoproxil fumarate. Median bone stiffness decreased in the CAR group from 86.1 g/cm2 (IQR = 74-98) to 83.2 g/cm2 (IQR = 74-97) and increased in the 2DR group from 84.9 g/cm2 (IQR = 74-103) to 85.5 g/cm2 (IQR = 74-101). The reduction within the CAR group was significant (P = 0.043). Once-daily rilpivirine plus cobicistat-boosted darunavir is an effective 2DR that combines a high virological efficacy with a potential to avoid major NRTI toxicities.

Switching from tenofovir disoproxil fumarate to tenofovir alafenamide in virologically suppressed patients with chronic hepatitis B: a randomised, double-blind, phase 3, multicentre non-inferiority study

Treatment with tenofovir disoproxil fumarate has been associated with renal toxicity or reductions in bone mineral density, or both, in some patients with chronic hepatitis B virus (HBV) infection. Tenofovir alafenamide is a tenofovir prodrug with high intrahepatic concentrations of active drug and reduced systemic tenofovir exposures compared with tenofovir disoproxil fumarate. In patients with chronic HBV, tenofovir alafenamide has shown efficacy non-inferior to that of tenofovir disoproxil fumarate with improved renal and bone safety. With this non-inferiority study, we aimed to evaluate the efficacy and safety of tenofovir alafenamide in patients with HBV infection switching from tenofovir disoproxil fumarate who are virally suppressed. Patients with chronic HBV infection who had been receiving tenofovir disoproxil fumarate for 48 weeks or more and who had HBV DNA less than the lower limit of quantification (LLOQ) for at least 12 weeks were recruited to this randomised, multicentre, double-blind, phase 3 non-inferiority study. Patients were randomly assigned in a 1:1 ratio to receive tenofovir alafenamide 25 mg once a day or to continue tenofovir disoproxil fumarate 300 mg once a day. The primary efficacy endpoint was loss of virological control, defined as the proportion of patients who received at least one dose of study drug who had HBV DNA of at least 20 IU/mL at week 48 by the modified US Food and Drug Administration (FDA) snapshot algorithm. Key safety endpoints were changes in hip and spine bone mineral density, estimated creatinine clearance by Cockcroft-Gault, and markers of bone turnover and renal tubular function. The study was powered for non-inferiority in efficacy of tenofovir alafenamide versus tenofovir disoproxil fumarate with a 4% margin. Investigators and patients were unaware of treatment allocation and on-treatment results. This trial is ongoing and is registered with ClinicalTrials.gov, number NCT02979613. Participants in this study were enrolled between Dec 29, 2016, and Oct 20, 2017. 541 patients were screened and 490 patients were randomly assigned to switch to tenofovir alafenamide or to stay on tenofovir disoproxil fumarate. Two patients assigned to receive tenofovir alafenamide did not receive treatment; thus the full analysis set for efficacy and safety analyses consisted of 243 patients in the tenofovir alafenamide group and 245 in the tenofovir disoproxil fumarate group. At week 48, one patient from each treatment group (both <1%) had HBV DNA of at least 20 IU/mL (difference in proportion 0·0%, 95% CI -1·9 to 2·0), thereby showing non-inferior efficacy of tenofovir alafenamide to tenofovir disoproxil fumarate. Patients who received tenofovir alafenamide had significantly increased bone mineral density at hip (mean change 0·66% [SD 2·08] vs -0·51% [SD 1·91]; difference in least square means 1·17% [95% CI 0·80 to 1·54; p<0·0001]) and at spine (mean change 1·74% [3·46] vs -0·11% [3·13]; difference in least square means 1·85% [1·24 to 2·46; p<0·0001]), creatinine clearance by Cockcroft-Gault relative to tenofovir disoproxil fumarate (median change 0·94 mL/min [IQR -4·47 to 6·24] vs -2·74 mL/min [-7·89 to 1·88]; p <0·0001), and improved markers of bone turnover and tubular function at week 48. The most common treatment-emergent adverse events were upper respiratory tract infection (18 [7%] of 243 patients in the tenofovir alafenamide group and 16 [7%] of 245 patients in the tenofovir disoproxil fumarate group) and nasopharyngitis (13 [5%] of 243 patients in the tenofovir alafenamide group and 12 [5%] of 245 patients in the tenofovir disoproxil fumarate group). The incidence of grade 3 and above adverse events and serious adverse events was low and similar between groups. No viral resistance was observed in patients who qualified for viral sequencing. These findings suggest that tenofovir alafenamide can be substituted for tenofovir disoproxil fumarate in patients with HBV infection for improved safety without a loss of efficacy. Gilead Sciences.

Efficacy and Safety of Switching to Dolutegravir/Lamivudine Fixed-Dose 2-Drug Regimen vs Continuing a Tenofovir Alafenamide-Based 3- or 4-Drug Regimen for Maintenance of Virologic Suppression in Adults Living With Human Immunodeficiency Virus Type 1: Phase 3, Randomized, Noninferiority TANGO Study.

BackgroundThe 2-drug regimen dolutegravir (DTG) + lamivudine (3TC) is indicated for treatment-naive adults with human immunodeficiency virus type 1 (HIV-1). We present efficacy and safety of switching to DTG/3TC in virologically suppressed individuals.MethodsTANGO is an open-label, multicenter, phase 3 study that randomized adults (1:1, stratified by baseline third agent class) with HIV-1 RNA <50 copies/mL to switch to once-daily fixed-dose DTG/3TC or remain on a tenofovir alafenamide (TAF)–based regimen. The primary end point was proportion of participants with HIV-1 RNA ≥50 copies/mL at week 48 (US Food and Drug Administration Snapshot algorithm) in the intention-to-treat–exposed population (4% noninferiority margin).Results743 adults were enrolled; 741 received ≥1 dose of study drug (DTG/3TC, N = 369; TAF-based regimen, N = 372). At week 48, proportion of participants with HIV-1 RNA ≥50 copies/mL receiving DTG/3TC was 0.3% (1/369) vs 0.5% (2/372) with a TAF-based regimen (adjusted treatment difference [95% confidence interval], −0.3 [−1.2 to .7]), meeting noninferiority criteria. No participants receiving DTG/3TC and 1 receiving a TAF-based regimen met confirmed virologic withdrawal criteria, with no emergent resistance at failure. Drug-related grade ≥2 adverse events and withdrawals due to adverse events occurred in 17 (4.6%) and 13 (3.5%) participants with DTG/3TC and 3 (0.8%) and 2 (0.5%) with a TAF-based regimen, respectively.ConclusionsDTG/3TC was noninferior in maintaining virologic suppression vs a TAF-based regimen at week 48, with no virologic failure or emergent resistance reported with DTG/3TC, supporting it as a simplification strategy for virologically suppressed people with HIV-1.Clinical Trials RegistrationNCT03446573.

A cooperative partial snapshot algorithm for checkpoint‐rollback recovery of large‐scale and dynamic distributed systems and experimental evaluations

SummaryA distributed system consisting of a huge number of computational entities is prone to faults because faults in a few nodes cause the entire system to fail. Consequently, fault tolerance of distributed systems is a critical issue. Checkpoint‐rollback recovery is a universal and representative technique for fault tolerance; it periodically records the entire system state (configuration) to non‐volatile storage, and the system restores itself using the recorded configuration when the system fails. To record a configuration of a distributed system, a specific algorithm known as a snapshot algorithm is required. However, many snapshot algorithms require coordination among all nodes in the system; thus, frequent executions of snapshot algorithms require unacceptable communication cost, especially if the systems are large. As a sophisticated snapshot algorithm, a partial snapshot algorithm has been introduced that takes a partial snapshot (instead of a global snapshot). However, if two or more partial snapshot algorithms are concurrently executed, and their snapshot domains overlap, they should coordinate, so that the partial snapshots (taken by the algorithms) are consistent. In this paper, we propose a new efficient partial snapshot algorithm with the aim of reducing communication for the coordination. In a simulation, we show that the proposed algorithm drastically outperforms the existing partial snapshot algorithm, in terms of message and time complexity.

Virological response and retention in care according to time of starting ART in Italy: data from the Icona Foundation Study cohort.

To describe: (i) factors associated with rapid and delayed ART initiation; (ii) rates of 12 week virological response; and (iii) virologically controlled retention in care by 1 year from ART initiation according to timing of start in a real-life setting. All individuals in the Icona cohort diagnosed with HIV in 2016-17 who initiated ART were grouped according to the time between HIV diagnosis and ART initiation: Group 1, ≤7 days; Group 2, 8-14 days; Group 3, 15-30 days; Group 4, 31-120 days; and Group 5, >120 days. Multivariable logistic regression models were used to identify factors associated with: (i) the probability of rapid (Group 1) and very delayed (Group 5) ART initiation; (ii) the 12 week virological response (by a modified snapshot algorithm); and (iii) the probability of retention in care at 1 year (on ART with HIV-RNA <50 copies/mL). A total of 1247 individuals were included [82 (6.6%) in Group 1, 115 (9.2%) in Group 2, 267 (21.4%) in Group 3, 641 (51.4%) in Group 4 and 142 (11.4%) in Group 5]. Main predictors of rapid ART start (Group 1) were low CD4 cell count and high HIV-RNA at first contact with the infectious diseases centre. There was no association between probability of virological response and timing of ART initiation. Overall, 90% of individuals remained on ART after 1 year, 91% with undetectable HIV-RNA. Participants of Italian nationality, those with higher CD4 cell count and lower HIV-RNA at ART initiation were more likely to be retained in care after 1 year. In our high-income observational setting, we did not observe differences in the 1 year rate of virological response and retention in care according to timing of ART initiation.