CROI 2017 Abstract e-Book

Abstract eBook

Poster and Themed Discussion Abstracts

Results: From 2014 to 2015, 74 women discontinued EFV/FTC/TDF postpartum (median CD4 571 cells/mm3, IQR 327), and had sample drawn for genotyping at median 5 weeks (IQR, 2) after EFV/FTC/TDF was stopped. Thirty-two (43%) women received a 1-week tail of FTC/TDF after stopping EFV, while 42 (57%) received no tail. Among 70 women with HIV-1 RNA at delivery, 58 (83%) had HIV-1 RNA<40cp/mL, while 45 (63%) of 71 women with HIV-1 RNA available 5 weeks post-EFV/FTC/TDF cessation had HIV-1 RNA<40cp/mL. Genotyping was attempted for all 74 women, and 35 (47%) were successfully sequenced; 4 (11%) of 35 had a major drug resistance mutation (K103N [n=2] and V106M [n=2]). None of the 4 women with drug resistance had received a FTC/TDF tail and 1 had received ARVs for PMTCT prior to this pregnancy. Conclusion: A high proportion of postpartumwomen remained virally suppressed at a median of 5 weeks from EFV/FTC/TDF cessation. Drug resistance mutations were detected in a small proportion of women after cessation of EFV/FTC/TDF. None of the women with drug resistance had received an FTC/TDF tail, which may help prevent selection of drug resistance when discontinuing EFV-based ART. 503 4’-MODIFIED NRTIS’ POTENT ANTI-HIV ACTIVITY STEMS FROM STRONG RT ACTIVE-SITE BINDING Kenji Maeda 1 , Yuki Takamatsu 2 , Debananda Das 2 , Satoru Kohgo 3 , Shinichiro Hattori 1 , Hironori Hayashi 1 , Kouki Matsuda 1 , Stefan G. Sarafianos 4 , Hiroaki Mitsuya 2 1 Natl Cntr for Global Hlth and Med Rsr Inst, Shinjuku, Tokyo, Japan 2 NIH, Bethesda, MD, USA, 3 Sojo Univ, Kumamoto, Japan, 4 Univ of Missouri, Columbia, MO, USA Background: 4’-Ethynyl-2-fluoro-2’-deoxyadenosine (EFdA or MK-8591), a novel nucleoside reverse transcriptase inhibitor (NRTIs) under clinical trials, is one of the most extremely potent and long-acting anti-HIV-1 agents (Grobler et al. CROI 2016: abstr# 98). EFdA and its derivatives, unlike other conventional NRTIs, possess a modified 4’-moiety while retaining the 3’-OH group in the ribose, and potently inhibit HIV-1 strains resistant to currently available NRTIs. Methods: We newly synthesized various 4’-modified NRTIs (4’-NRTIs) and tested their antiviral activity against a variety of NRTI-resistant HIV-1 strains. Anti-HIV-1 activity of EFdA and other 4’-NRTIs were examined using various cell-based assays including the MTT and p24 assays. Cytotoxicity of such NRTIs was also determined. Structural analyses were conducted using a recently defined crystal structure of EFdA-TP complexed with RT (Salie, Mitsuya, & Sarafianos. PNAS, 113:9274-9, 2016). Results: We found that EFdA and NRTIs with 4’-ethynyl- or 4’-cyano retain activity against HIV-1M184V and a multi-NRTI-resistant HIV-1 (HIV-1EFdAR), but not NRTIs with other moieties examined (e.g., 4’-methyl). Structural study revealed that EFdA and 4’-ethynyl/cyano-NRTIs (but not other 4’-modified NRTIs examined), had strong vdW interactions with RT’s residues such as F160, and the binding persisted even in the presence of the broadly resistance-endowing V184, thus potently exerting activity against drug-resistant HIV-1s. Conclusion: EFdA-derivatives with 4’-cyano- or 4’-ethynyl moiety exerted potent activity against HIV-1EFdAR, suggesting that EFdA and its derivatives with 4’-cyano- or 4’- ethynyl moiety should serve as promising candidates for further clinical development with potent activity against various multi-drug-resistant HIV-1 variants, high genetic barrier and QD- (or QW-) possible NRTIs. 504LB RISING TRANSMITTED RESISTANCE FORCES ABANDONMENT OF WHO-RECOMMENDED THERAPY IN ARUBA Laura Marije Hofstra 1 , Elena Sánchez Rivas 2 , Monique Nijhuis 1 , Eduan Wilkinson 3 , Karina Kelly 2 , Tania Mudrikova 1 , Rob Schuurman 1 , Tulio de Oliveira 3 , Jaclyn De Kort 2 , Annemarie Wensing 1 1 Univ Med Cntr Utrecht, Utrecht, Netherlands, 2 Dr. Horacio E. Oduber Hosp, Oranjestad, Aruba, 3 Univ of KwaZulu-Natal, Durban, South Africa Background: In Western countries emergence of HIV drug resistance has tremendously decreased and transmission of drug resistance has merely stabilized in recent years. However, in many endemic settings with limited resources rates of emerging and transmitted drug resistance are not regularly assessed. Methods: In Aruba, a highly endemic HIV area in the Caribbean, baseline resistance testing was randomly performed from 2010 on. We performed a survey including >50% of all newly diagnosed HIV-infected individuals in the country. Transmitted HIV drug resistance was determined using WHO-criteria. Transmission dynamics were investigated using phylogenetic analyses. In a subset, baseline samples were re-analyzed using next generation sequencing (NGS). Results: Baseline resistance was assessed in 104 newly diagnosed untreated individuals (54% of all newly diagnosed individuals in 2010-2015); 86%was men, 39%was foreign- born, and 22% had AIDS at diagnosis, which was in line with the overall HIV-infected population of 2010-2015. The prevalence of transmitted drug resistance was 33% (95% CI: 24-42%). Mutations associated with nucleoside reverse transcriptase inhibitors (NRTIs) or protease inhibitors were rare (both 2%; 95% CI: 0-5%). The prevalence of resistance to non-NRTIs (NNRTIs) reached 45% (95% CI: 27-64%) in 2015, all based on the prevalence of mutation K103N. NGS did not demonstrate additional minority K103N-variants in patients diagnosed with wild-type virus. In patients diagnosed with a K103N-variant, NGS showed persistence of K103N at high frequencies (range: 94.9-98.8%) despite long-term infection in some cases, underlining its potential to become widespread among therapy-naïve individuals. K103N-harboring strains were introduced into the therapy-naïve population via at least 6 independent transmissions which were epidemiologically linked to surrounding countries. Virological failure of the WHO-recommended first-line NNRTI- based regimen was higher in the presence of K103N. Conclusion: The prevalence of NNRTI-resistant HIV in Aruba has increased to alarming levels, compromising the WHO-recommended first-line regimen. Local and regional public health authorities have been informed and local guidelines have reinforced baseline resistance testing and have replaced the WHO recommended first-line regimen by an integrase inhibitor-based regimen. As adequate surveillance as advocated by the WHO is currently very limited, the Caribbean region could face an unidentified rise of NNRTI- resistant HIV. 505 LOW HIV-1 RESISTANCE IN SUBJECTS USING DARUNAVIR ONCE-DAILY REGIMENS ACROSS STUDIES Erkki Lathouwers 1 , Eric Y. Wong 2 , Donghan Luo 2 , Sareh Seyedkazemi 2 , Sandra De Meyer 1 , Kimberley Brown 2 1 Janssen Infectious Diseases BVBA, Beerse, Belgium, 2 Janssen Scientific Affairs, LLC, Titusville, NJ, USA Background: Across Phase 2/3 studies evaluating once-daily (QD) darunavir (DRV) regimens, treatment-naïve (TN) or treatment experienced (TE), including virologically suppressed, HIV-1–infected subjects were treated for 48-192 wk. We summarize treatment-emergent drug resistance-associated mutations (RAMs) for subjects receiving DRV QD dosing from 7 studies. Methods: Sponsored studies with available genotypes were assessed. TN studies: ARTEMIS (N=343; DRV+ritonavir [r]+emtricitabine [FTC]/tenofovir disoproxil fumarate [TDF]; 192 wk); GS-US-299-0102 (N=103 [DRV/cobicistat (c)/FTC/tenofovir alafenamide]; N=50 [DRV+c+FTC/TDF]; 48 wk). TE studies: ODIN (N=294; DRV+r+≥2 nucleos[t]ide reverse transcriptase inhibitors [NRTIs]; 48 wk); MONET (N=127 [DRV+r]; N=129 [DRV+r+2 NRTIs]; 144 wk); PROTEA (N=137 [DRV+r]; N=136 [DRV+r+2 NRTIs]; 96 wk). TN and TE studies: GS-US-216-0130 (295 TN, 18 TE; DRV+c+2 NRTIs; 48 wk); INROADS (42 TE, 12 TN; DRV+r+etravirine; 48 wk). Across studies, eligible TE subjects did not have DRV RAMs at screening. Criteria for post-baseline resistance testing and evaluation of treatment-emergent or presence of on-treatment RAMs (respective IAS-USA mutations) varied slightly across studies. Genotypic analyses were conducted at baseline except for switch studies enrolling virologically suppressed subjects (MONET, PROTEA). Results: Within the 7 studies, 2329 subjects were enrolled; 1687 (804 TN, 883 TE) subjects were treated with DRV QD and 193 (65 TN, 128 TE) subjects with protocol-defined virologic failure and post-baseline genotypes were analyzed. None of the TN subjects and 3 TE subjects displayed ≥1 primary protease inhibitor (PI) RAM ( Table ): 1 each from GS-US-216-0130 (I84I/V), MONET (monotherapy arm; L33F detected at Wk 12 with HIV-1 RNA of 63 copies/mL, but was resuppressed at subsequent visits until Wk 144), and ODIN (V32I+M46I+L76V+I84V). DRV phenotypic susceptibility was lost in only the ODIN subject, possibly related to previous lopinavir+r virologic failure. 7 TN and 5 TE subjects developed ≥1 NRTI RAM; 2 TE subjects from INROADS developed non-nucleoside reverse transcriptase inhibitor RAMs ( Table footnote). Conclusion: Among HIV-1–infected subjects treated with DRV QD regimens for 48-192 wk (N=1687), development of emergent resistance was rare. Overall, no TN subjects and 0.3% of TE subjects developed primary PI RAMs. Only 1 subject across studies lost DRV phenotypic susceptibility, confirming the high genetic barrier to DRV resistance development.

Poster and Themed Discussion Abstracts

CROI 2017 210