CROI 2020 Abstract eBook

Abstract eBook

Poster Abstracts

500 INVESTIGATION OF A POTENTIAL COMPOSITE ENDPOINT FOR IMMUNOLOGIC NONRESPONDER TRIALS

501 TREATMENT INTERRUPTION STRATEGIES FOR NNRTI-BASED ART: DOES THE NRTI MATTER? Alice K. Pau 1 , Jacqueline Neuhaus 2 , Edward M. Gardner 3 , Anna Maria Geretti 4 , Kimberly K. Scarsi 5 , John D. Baxter 6 , Nnakelu Eriobu 7 , Virginia L. Kan 8 , Vidar Ormaasen 9 , Sarah Pett 10 , H. Clifford Lane1, Andrew N. Phillips 10 , James Neaton 2 , for the INSIGHT SMART Study Group 1 NIAID, Bethesda, MD, USA, 2 University of Minnesota, Minneapolis, MN, USA, 3 Denver Health Medical Center, Denver, CO, USA, 4 University of Liverpool, Liverpool, UK, 5 University of Nebraska, Omaha, NE, USA, 6 Cooper University Hospital, Camden, NJ, USA, 7 Institute of Human Virology Nigeria, Abuja, Nigeria, 8 George Washington University, Washington, DC, USA, 9 Oslo University Hospital, Oslo, Norway, 10 University College London, London, UK Background: In the SMART trial, simultaneously stopping NRTIs and NNRTIs resulted in emergence of drug resistance mutations (DRMs) and lower HIV-RNA resuppression rates compared to either a PI-switch strategy or staggered discontinuation of the NNRTI before the NRTIs. This finding was proposed to be related to the longer half-life (T 1/2 ) of NNRTIs compared to NRTIs, resulting in short-term NNRTI monotherapy. We postulated that since TDF has a long intracellular T 1/2 (>60 hrs), stopping NNRTI-based ART containing TDF simultaneously may not result in lower resuppression rates or more resistance. Methods: A reanalysis of the SMART study was undertaken in participants who interrupted NNRTI-based ART and later restarted an NNRTI regimen. Participants were included who had HIV-RNA<400 c/mL at ART discontinuation and had an HIV-RNA level drawn 4-8 months after restart to assess resuppression. For individuals who had HIV RNA >1000 c/mL at 2 months after ART interruption and had standard HIV genotypic testing (TRUGENE), presence of NNRTI or NRTI DRMs was assessed. Results are given according to stopping approach, separately for TDF vs. non-TDF use. Results: Of the 513 participants who met the inclusion criteria, 319 (62.2%) received EFV, and 194 (37.8%) received NVP. Stopping was simultaneous in 100 (19.5%) participants, staggered in 302 (58.9%), and switched in 111 (21.6%). Overall, 124 (24.2%) received TDF and 389 (75.8%) received other NRTIs (AZT, D4T, or ddI); in both groups the most common second NRTI was 3TC or FTC. Irrespective of TDF use, resuppression was lowest with simultaneous stopping and highest with a switch strategy (Table). Among those who stopped simultaneously, there was no difference between TDF or non-TDF group for rate of resuppression (95% CI for difference: -26.3, 8.2; p=0.27) or percent with NNRTI DRM (95% CI for difference: -0.9, 34.3; p=0.20). Results were similar for those stopping EFV and NVP (data not shown). Conclusion: Despite TDF having a longer intracellular T 1/2 than other NRTIs, the resuppression rate after simultaneously stopping all ARVs in an NNRTI- regimen was not different for TDF versus non-TDF regimens, nor did TDF prevent emergence of DRMs. Though limited by small number of subjects on TDF, these data support the current recommendation that if stoppage of an NNRTI-based regimen is planned, ARVs should not be stopped simultaneously. This is particularly crucial when stopping NNRTI regimens during analytical ART interruption trials.

Virginia Sheikh 1 , Therri Usher 1 , Maximilian Rohde 1 , Thamban Valappil 1 , Sarah Connelly 1 , Richard Jefferys 2 , Kimberly Struble 1 , Adam Sherwat 1 , Wendy Carter 1 , Jeffrey S. Murray 1 1 FDA, Silver Spring, MD, USA, 2 Treatment Action Group, New York, NY, USA Background: Although most people with HIV (PWH) experience robust CD4 recovery after achieving virologic suppression on antiretroviral therapy (ART), immunologic non-responders (INR) have persistently low CD4 T cell counts. Studies suggest INRs have an increased risk of mortality and serious morbidity, but these events are uncommon in ART-treated PWH and may not be feasible trial endpoints. Patient advocates urged FDA to encourage drug development for INRs by providing guidance on acceptable endpoints for INR trials.Therefore, we investigated the feasibility of a composite endpoint designed to capture non-serious and serious adverse events associated with CD4 lymphopenia. Methods: Among Phase 3 clinical trial datasets submitted to the FDA (2005- 2016) in support of ART approval for ART-naïve adults, we identified datasets with 144 wks of HIV RNA, CD4, and safety data. We excluded subjects with virologic failure between Wks 24 and 144 and, based on the Week 96 CD4 value, categorized subjects as INR (CD4 <200 cells/µL), immunologic responders (IR, CD4 200 – 349 cells/µL) or optimal immunologic responders (OIR, CD4 ≥ 350 cells/µL). Using safety data between Wks 96 and 144 and descriptive statistics, we evaluated differences in our composite endpoint, which included 1993 CDC HIV Classification System events (Categories A, B and C [not limited by duration, response to tx, or recurrence]), non-AIDS related events included in the START study, HPV-related disease, skin and soft tissue infections, and neurocognitive events. Results: 79 (1.7%) participants met criteria for INR, 481 (10.3%) for IRs, and 4110 (88%) for OIRs. INRs were older (41.8 yrs) compared to IRs (39.6 yrs) and OIRs (36.7 yrs). INRs had lower baseline CD4 (64 c/µL) compared to IRs (152 c/µL) and OIRs (381 c/µL) and were more likely to have enrolled in a trial that started before 2010 (63% of IRs) than IRs (52.2%) and OIRs (20.2%). The composite endpoint occurred in 17 (21.5%) INRs, 92 (19.1%) IRs, and 709 OIRs (17.2%). Conclusion: INRs were uncommon among ART-naïve adults starting ART in the 2000s, and even more uncommon after 2010. Like previous studies, INRs were older with lower baseline CD4 counts. The proportion of INRs experiencing the composite endpoint was slightly higher compared to IRs and OIRs. Our results suggest our composite endpoint is not a feasible endpoint for clinical trials evaluating drugs to treat INRs.

Poster Abstracts

CROI 2020 178