CROI 2015 Program and Abstracts

Abstract Listing

Poster Abstracts

Methods: We used verbal autopsy data collected in three community-based HIV cohorts from Tanzania (Kisesa), Malawi (Karonga) and South Africa (uMkhanyakude), which form part of the ALPHA network. Data on symptoms and circumstances were processed using the InSilicoVA algorithm, and cause of death distributions were classified by ART availability and HIV status of the deceased. The percentage of deaths assigned to HIV/AIDS using the algorithmwere compared to age-standardized HIV attributable mortality. HIV attributable mortality (PAF) was calculated by comparing the observed numbers of deaths in HIV positive individuals to the number expected if age-specific mortality rates were the same as those observed in the HIV negative group. Results: Following ART introduction, there were substantial declines in the percentage of deaths assigned to HIV/AIDS. The most dramatic declines were observed in Kisesa, where the percentage of deaths assigned to HIV/AIDS dropped from 43% in the pre-ART era to 26% once ART became widely available, compared to a decline from 36% to 32% in the PAF. Amongst HIV positive individuals in Kisesa the percentage of deaths assigned to TB increased with ART availability for both males (from 26.3% to 36.3%) and females (from 27.9% to 33.9%); neoplasms increased in females (from 4.3% to 10.1%) but not males where they remained at 8.0%. In uMkhanyakude there was a large increase in the percentage of HIV positive female deaths assigned to TB (from 24.8% to 36.5%) but no such trend was observed in males. There were no substantial changes in the percentage of deaths attributed to non-communicable diseases in uMkhanyakude. Conclusions: Increases in the percentage of deaths from neoplasms among the HIV positive are to be expected as deaths from classic HIV-related causes are suppressed by ART. The fact that TB continues to rise as a proportion of all assigned causes among the HIV-positive suggests better management of TB cases is needed at treatment start. 584 Facility-Level Factors AssociatedWith Mortality of Patients on ART: A Retrospective Cohort Study in Kenya, 2007-2012 Emily A. Dansereau 1 ; Allen Roberts 1 ; Herbert C. Duber 1 ; Gregoire Lurton 1 ; Brendan DeCenso 2 ;Thomas Odeny 1 ; Samuel Masters 3 ; Roy Burstein 1 ; Pamela Njuguna 1 ; Emmanuela Gakidou 1 1 University of Washington, Seattle, WA, US; 2 RTI International, Raleigh, NC, US; 3 University of North Carolina, Chapel Hill, NC, US Background: While the individual-level benefits of antiretroviral therapy (ART) are well established, much remains to be understood about the population-level impacts of ART scale-up in Kenya and other Sub-Saharan African countries. Most knowledge of mortality levels and determinants comes from relatively small or unrepresentative study sites that may not accurately reflect full national programs. In this study we analyze data from a large sample of Kenyan ART facilities, representing the general population receiving ART. Methods: We randomly extracted between 50 and 250 adult ART charts at a nationally-representative sample of Kenyan facilities. The charts were paired with a survey of facility resources and practices. A competing risk analysis was used to calculate crude cumulative mortality and loss to follow up (LTFU) after 6, 12 and 24 months on treatment. Adjusted mortality was also calculated for the same time points, which included a correction to account for death among LTFU patients. The correction was estimated at the facility-level, based on a meta-analysis of prior literature demonstrating the relationship between total percent LTFU and the percent of those that had died. Additional analyses examined cumulative mortality stratified by sex, and initial CD4. Regression analysis was done at the facility-level to assess predictors of adjusted mortality rates. Results: We extracted charts from 16,015 adult ART patients across 63 facilities. The crude cumulative mortality rate was 7%, 9% and 10% at 6, 12 and 24 months respectively. Cumulative LTFU for the same points was 22%, 27%, and 34%. After applying the LTFU correction, adjusted cumulative mortality was 14%, 17% and 18% at 6, 12 and 24 months. Public and rural facilities had significantly higher mortality rates, after controlling for the demographic and clinical composition of their patient populations. Other program characteristics, including nurse-led treatment, were not significant predictors. Conclusions: The adjusted mortality rates contribute important information about outcomes for a large, unbiased sample of Kenyan patients. Differences in mortality by location and ownership suggest the presence of inequities affecting rural and public clinics. The lack of significant differences across other dimensions indicates that comparable care may be possible with cost-saving changes such as task-shifting.

THURSDAY, FEBRUARY 26, 2015 Session P-L1 Poster Session

Poster Hall

Poster Abstracts

2:30 pm– 4:00 pm HIV Drug Resistance: Mechanisms and Mutations 585 Structural Basis of Inhibition and Resistance Mechanism to EFdA, a Highly Potent NRTI Zhe Li 1 ; Karen Kirby 1 ; Bruno Marchand 1 ; Michailidis Eleftherios 1 ; Eiichi Kodama 2 ; Hiroaki Mitsuya 3 ; Michael Parniak 4 ; Stefan Sarafianos 1 1 University of Missouri, Columbia, MO, US; 2 Tohoku University, Sendai, Japan; 3 National Institutes of Health, Division of AIDS, Bethesda, MD, US; 4 University of Pittsburgh, Pittsburgh, PA, US

Background: Unlike any current clinical nucleoside reverse transcriptase inhibitors (NRTIs), 4’-ethynyl-2-fluoro-2’-deoxyadenosine (EFdA) retains a 3’-OH. EFdA has exceptional potency in vivo and in vitro , highly efficient against drug-resistant strains and has outstanding specificity index. EFdA can act as an immediate or as a delayed chain terminator, by affecting translocation of RT after its incorporation in the nascent DNA chain. It can also be efficiently misincorporated by RT, leading to mismatches that are hard to extend and also protected from excision. The M184V mutation causes mild resistance to EFdA (7.5 fold). To unravel the structural basis of EFdA’s extraordinary activity, unique set of inhibition mechanisms and excellent resistance profile, we solved crystal structures of RT (wild-type and M184V) in complex with DNA and EFdA-triphosphate (TP) or with DNA that has EFdA incorporated in it. Methods: Dideoxy-terminated DNA containing a thioalkyl tethered guanosine was covalently cross-linked to RT, mixed with EFdA-TP and crystallized to obtain RT/DNA dd /EFdA-TP complexes. RT-terminated with EFdA at the primer terminus (RT/DNA EFdA ) was also crystallized. Crystals were dehydrated, flash-cooled in liquid N 2 , and diffraction data were collected at Advanced Light Source. Results: The ternary complex structure of wild-type RT/DNA dd /EFdA-TP was solved at 2.4 Å resolution. This structure reveals the atomic interactions of EFdA-TP that make it a tight binder at the pre-translocation site, thus preventing RT translocation and explaining the inhibition mechanism as a translocation-defective RT inhibitor. Comparison of the 2.9 Å RT M184V /DNA dd /EFdA-TP structure with control structures RT M184V /DNA dd /dA-TP or RT M184V /DNA dd /4’-Ethyl-dA-TP (2.9 Å and 3.2 Å) explain how this mutation affects molecular interactions with EFdA and influences its potency, enhancing our understanding of why resistance to EFdA is difficult to develop. A 2.8 Å structure of an RT/DNA complex with an EFdA-MP incorporated at the 3’ primer end and further extended by a mismatched second EFdA-MP (RT/DNA EFdA-MP – EFdA-MP )also provides insights into the structural details of EFdA in the translocation process as well as mismatched incorporation. Conclusions: The 4’-ethynyl group of EFdA-TP or EFdA-MP-terminated DNA can bind tightly at a polymerase active site hydrophobic pocket, suppressing translocation and inhibiting further DNA synthesis. The M184V mutation mildly decreases EFdA-TP binding through interactions with the 4’E.

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CROI 2015