CROI 2018 Abstract eBook

Abstract eBook

Oral Abstracts

21 INTRON−CONTAINING HIV-1 RNA ACTIVATES TYPE I INTERFERON AND INFLAMMATORY CYTOKINES Sean McCauley , Kyusik Kim, Anetta Nowosielska, Ann Dauphin, William E. Diehl, Jeremy Luban University of Massachusetts, Worcester, MA, USA Background: HIV-1-infected people who take antiviral drugs that render viremia undetectable have ongoing inflammation of unknown etiology. The HIV-1 provirus, a permanent genetic element in long-lived cells of the immune system, is not eliminated by antiviral drugs. Most HIV-1 proviruses in infected people are replication defective but many are transcriptionally active. Therefore, a possible contributor to this chronic inflammation may be continual HIV-1 transcription in the absence of productive viral production. Methods: CD4+ T cells and monocytes were isolated from healthy blood donors. Dendritic cells and macrophages were generated through cytokine differentiation of monocytes. All viruses were defective to a single round of infection and produced through HEK293 transfection of 2 or 3 part viral plasmids. Results: We found that the HIV-1 provirus activated innate immune signaling in dendritic cells, macrophages, and CD4+ T cells. Immune activation required HIV-1 provirus transcription and expression of CRM1-dependent, Rev- dependent, RRE-containing, unspliced HIV-1 RNA. If rev was provided in trans, all HIV-1 coding sequences were dispensable except those cis-acting sequences required for replication or splicing. Conclusion: These results indicate that Rev-dependent, intron-containing, HIV-1 RNA is detected by the innate immune system, and that drugs which inhibit HIV-1 transcription or Rev-dependent, HIV-1 RNA metabolism, would add qualitative benefit to current antiviral drug regimens. Jean-Michel Molina 1 , Douglas Ward 2 , Indira Brar 3 , Anthony Mills 4 , Hans-Jurgen Stellbrink 5 , Luis López-Cortés 6 , Peter Ruane 7 , Daniel Podzamczer 8 , Cynthia Brinson 9 , Joseph M. Custodio 10 , Hui Liu 10 , Kristen Andreatta 10 , Hal Martin 10 , Andrew Cheng 10 , Erin Quirk 10 1 St. Louis Hospital, Paris, France, 2 Dupont Circle Physicians Group, Washington, DC, USA, 3 Henry Ford Hospital, Detroit, MI, USA, 4 Southern California Men’s Medical Group, Los Angeles, CA, USA, 5 ICH Study Center, Hamburg, Germany, 6 Hospital Universitario Virgen del Rocio, Sevilla, Spain, 7 Peter J Ruane, MD Inc, Los Angeles, CA, USA, 8 Hospital Universitario de Bellvitge, Barcelona, Spain, 9 Central Texas Clinical Research, Austin, TX, USA, 10 Gilead Sciences, Inc, Foster City, CA, USA Background: Bictegravir, a novel, unboosted INSTI with a high barrier to resistance and low potential for drug interactions, has been coformulated with the recommended NRTI backbone of emtricitabine and tenofovir alafenamide (B/F/TAF) as a fixed-dose combination (FDC). We report the primary Week (W) 48 efficacy and safety Phase 3 results of switching to B/F/TAF from dolutegravir plus abacavir/lamivudine (DTG+ABC/3TC) or FDC of DTG/ABC/3TC. Methods: HIV-infected adults virologically suppressed on DTG/ABC/3TC or DTG plus ABC/3TC (DTG/ABC/3TC group), with estimated glomerular filtration rate (eGFR) ≥50 mL/min were randomized 1:1 to switch to B/F/TAF (50/200/25 mg) once daily or continue current regimen as DTG/ABC/3TC through week 48 in a double-blinded fashion. Primary endpoint was proportion with HIV-1 RNA ≥50 copies/mL (c/mL) at W48 (FDA snapshot). Noninferiority was assessed through 95.002% confidence intervals (CI) using a margin of 4%. Secondary endpoints were proportion with HIV-1 RNA <50 copies/mL and safety (adverse events [AEs], laboratory results, bone mineral density [BMD], and renal biomarkers). Results: 563 participants were randomized and treated (B/F/TAF n=282, DTG/ ABC/3TC n=281): 11%women, 22% Black, median age 46 yrs (range 20-71). At W48, 1.1% switching to B/F/TAF and 0.4% continuing DTG/ABC/3TC had HIV-1 RNA ≥50 c/mL (difference 0.7%; 95%CI -1.0% to 2.8%, p=0.62), demonstrating noninferiority. At W48, proportion with HIV-1 RNA <50 c/mL was 93.6% on B/F/TAF and 95.0% on DTG/ABC/3TC. No participant developed resistance to any study drug. The most common AEs were upper respiratory tract infection (10% B/F/TAF, 10% DTG/ABC/3TC), diarrhea (9%, 5%), nasopharyngitis (7%, 8%) and headache (7%, 7%). Few participants (6 [2%], 2 [1%]) had AEs leading to premature study drug discontinuation. Mean BMD increased similarly in both groups. Percentage changes from baseline in renal biomarkers were similar between treatment groups (Table). Lipid parameters were similar between groups with the exception of a small decrease in triglycerides seen in the B/F/ TAF group. 22 SWITCH TO BICTEGRAVIR/F/TAF FROM DTG AND ABC/3TC

Conclusion: Switching to B/F/TAF was noninferior to continuing DTG/ABC/3TC with low rates of W48 virologic failure, high rates of maintained virologic suppression, and no resistance. B/F/TAF was well tolerated, with a similar bone and urine protein safety profile to DTG/ABC/3TC. - None

Oral Abstracts

23 IMPACT OF RALTEGRAVIR INTENSIFICATION OF FIRST-LINE ART ON IRIS IN THE REALITY TRIAL Diana Gibb 1 , Alexander J. Szubert 1 , Ennie Chidziva 2 , Abbas Lugemwa 3 , Shalton Mwaringa 4 , Abraham Siika 5 , Jane E. Mallewa 6 , Mutsa Bwakura-Dangarembizi 2 , Sheila Kabahenda 3 , Andrew Reid 2 , Keith Baleeta 3 , Sarah Walker 1 , Sarah Pett 1 1 MRC Clinical Trials Unit at UCL, London, UK, 2 University of Zimbabwe, Harare, Zimbabwe, 3 Joint Clinical Research Centre, Lubowa, Uganda, 4 KEMRI–Wellcome Trust Research Programme, Kilifi, Kenya, 5 Moi University, Eldoret, Kenya, 6 Malawi– Liverpool–Wellcome Trust Clinical Rsr Prog, Blantyre, Malawi Background: Among HIV-infected adults/children with CD4<100 cells/ ul initiating ART in sub-Saharan Africa, the REALITY trial (ISRCTN43622374) showed that 12-week raltegravir (RAL)-intensified quadruple therapy resulted in significantly faster VL declines through 24 weeks, but did not reduce overall mortality or WHO 3/4 events compared to standard triple-drug ART. Integrase inhibitors may replace NNRTIs in first-line ART; there is concern that more rapid VL declines may lead to higher rates of serious IRIS in severely immunocompromised individuals starting ART. Methods: ART-naïve HIV-infected adults/children ≥5y with CD4<100 cells/ul were randomized to initiate ART (2NRTI+NNRTI) with 12 weeks RAL (Std+RAL) or without (Std). Events, causes of death, and compatibility with IRIS were adjudicated by an endpoint review committee blind to randomization. Predictors of time to first fatal/non-fatal IRIS-compatible event were identified using backwards elimination treating death from other causes as a competing risk. Results: 1805 patients with median baseline CD4 37 cells/ul and VL 249770 c/ml (74.0%≥100,000c/ml) were randomized to Std+RAL (n=902) vs Std (n=903). Mean change in log 10 VL at week 4 was –3.4(SE 0.03) in Std+RAL vs -2.7(0.03) in Std (p<0.001; 42.8% vs 14.5%<50 c/ml respectively). In total 67(29.8%) of 225 deaths were adjudicated as IRIS-compatible, occurring a median 4.4(IQR2.6-9.4) weeks after ART initiation; a further 113 non-fatal IRIS-compatible events occurred after median 3.4(2.0-6.3) weeks on ART (figure). Fatal/non-fatal IRIS-compatible events occurred in 89(9.9%) Std+RAL vs 86(9.5%) Std patients (p=0.79). TB-IRIS occurred in 53(5.9%) vs 54(6.0%) respectively (p=1.00), cryptococcal-IRIS in 15(1.7%) vs 16(1.8%) (p=1.00), other IRIS events of known aetiology in 17(1.9%) vs 14(1.6%) (p=0.59) (Kaposi’s sarcoma (8 vs 4), viral hepatitis (1 vs 3), CNS event unknown pathogen (3 vs 1), CMV (2 vs 1), toxoplasmosis (1 vs 1), PCP (0 vs 2), lung event unknown pathogen (0 vs 2), and other (3 vs 0)), and IRIS events of unknown aetiology in 4(0.4%) vs 2(0.2%) respectively. Risks of non-fatal/fatal IRIS were independently higher in those with lower pre-ART CD4 (p<0.001), older individuals (p=0.004) and those with TB at ART initiation (p=0.01). Conclusion: Despite significantly more rapid declines in HIV VL, there was no evidence that 12 weeks’ RAL intensification impacted incidence or case-fatality of IRIS in severely immunocompromised individuals initiating ART.

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CROI 2018