CROI 2016 Abstract eBook

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Oral Abstracts

33 Breast Milk and In Utero HIV-1 Transmission Select for Unique Envelope Signatures Thomas A.Wilkinson 1 ; Kyle J. Nakamura 1 ; Laura M. Heath 2 ; Katherine Semrau 3 ; Chipepo Kankasa 4 ; Nicholas E. Webb 5 ; Benhur Lee 5 ; Louise Kuhn 6 ; James I. Mullins 2 ; Grace M. Aldrovandi 1 1 Children’s Hosp of Los Angeles, Los Angeles, CA, USA; 2 Univ of Washington, Seattle, WA, USA; 3 Boston Univ Sch of PH, Boston, MA, USA; 4 Univ Teaching Hosp, Lusaka, Zambia; 5 Univ of California Los Angeles, Los Angeles, CA, USA; 6 Columbia Univ, New York, NY, USA Background: Despite improved prevention of mother-to-child transmission (MTCT) of human immunodeficiency virus-type 1 (HIV-1) in developing countries, 240,000 children acquired the virus in 2013. HIV-1 MTCT can occur by three distinct routes: in utero (transplacental passage), intrapartum, and postpartum through breastfeeding. Disease progression can vary dramatically among these transmission modes, with infants infected in utero showing the shortest survival times. Methods: Twenty-two maternal-infant transmission pairs were selected from the Zambia Exclusive Breastfeeding Study (ZEBS). Viral transmission route ( in utero or through breastfeeding) was determined by the timing of the first HIV-1 polymerase chain reaction (PCR)-positive test in the infant. Full-length gp160 sequences were cloned from either reverse-transcribed plasma RNA or from cellular DNA. Neutralization assays were performed using TZM‑bl cells and pseudotyped virus bearing envelope sequences frommaternal or infant isolates. Affinofile cells were used to assess CD4 surface density requirements for a given isolate to gain viral entry. Inhibitor slope values were determined by fitting the median effect model to experimental dose response curves. Results: Analysis of 647 viral envelopes from 22 maternal-infant pairs revealed unique genotypic and phenotypic signatures that depend upon transmission route. Relative to maternal strains, intrauterine HIV transmission selects infant isolates that are more resistant to soluble CD4 (sCD4) neutralization (p < 0.001), have shorter V1 loops with fewer potential N-glycosylation sites (PNGs) (p ≤ 0.017), and have fewer V5 PNGs (p = 0.017). Breast milk transmission selects infant isolates with fewer gp41 PNGs than their maternal counterparts (p = 0.017) and that are more sensitive to the glycan-dependent broadly neutralizing antibodies PG9 and PG16 (p ≤ 0.014). In addition, median effect analysis suggests that HIV-1 envelope trimers engage target CD4 receptors with negative cooperativity. Finally, experiments with Affinofile cells indicate that compared to maternal viral strains, virus from infants require increased levels of surface CD4 receptor for productive infection. Conclusions: These data provide the first evidence for transmission route-specific selection of HIV‑1 variants, and suggest a role for envelope-CD4 avidity in viral entry. These findings potentially inform therapeutic strategies or vaccine designs that can be tailored over the course of HIV-1 exposure. 34 Impact of Option B+ on ART Uptake and Retention in Swaziland: A Stepped-Wedge Trial Elaine J. Abrams 1 ; Nontokozo Langwenya 2 ; Averie Gachuhi 3 ; Allison Zerbe 3 ;Thabo Hlophe 4 ; Simangele Mthethwa-Hleta 5 ; Harriet Nuwagaba-Biribonwoha 4 ; Ruben Sahabo 4 ;Velephi Okello 5 ; Landon Myer 2 1 ICAP, Columbia Univ Mailman Sch of PH, New York, NY, USA; 2 Univ of Cape Town, Cape Town, South Africa; 3 ICAP at Columbia Univ, New York, NY, USA; 4 ICAP at Columbia Univ, Mbabane, Swaziland; 5 Ministry of Hlth, Mbabane, Swaziland Background: Retaining HIV-infected pregnant and postpartumwomen in care is critical to prevent mother-to-child HIV transmission (PMTCT) and promote maternal health. New PMTCT approaches call for lifelong antiretroviral therapy (ART) for all HIV+ pregnant women (Option B+), a departure from strategies that used CD4 count to determine ART eligibility (Option A). Yet there are few implementation data on the impact of Option B+ on maternal retention in antenatal and postnatal care. Methods: Using a stepped-wedge design the ‘Sitkulwane Lesiphephile–Safe Generations’ study compared maternal retention under Option A (based on <350 cells/µL) versus Option B+ in 10 primary care facilities across Swaziland. Pregnant HIV+ women not on ART making a first antenatal visit formed monthly facility-level cohorts that were followed through 6 months postpartum using routine health records. In analysis, the month of transition from A to B+ was excluded. Retention was defined as engagement in care within 56 days of delivery during the antenatal period and during a 3-month window before 6 months postpartum. Generalized estimating equations with a probit link were used to generate adjusted risk ratios (aRR) comparing outcomes under Options A versus B+ after accounting for age, CD4, gestation at 1 st antenatal visit, and known HIV status. Results: 2315 women were included: 45% (n=1043) under B+ and 55% (n=1272) under A. Patient characteristics were similar under B+ and A: mean age, 26 years; median gestational age at first antenatal visit, 20 weeks; median CD4, 404 cells/µL; CD4 <350, 33%. After transitioning to B+, the proportion of women receiving ART antenatally was higher (93%) vs A (30%; p<0.001). The proportion of women with CD4 <350 initiating ART antenatally also increased under B+ (94% vs 63%; p<0.001). Among all HIV+ women, 61% attended at least one visit prior to delivery: 68% under B+ vs 54% under A (aRR, 1.30; p<0.001). Overall, postpartum retention was low (37%). In the analysis of all HIV+ women, postpartum retention was significantly higher under B+ (50%) vs A (26%) (aRR, 1.54; p<0.001). However, when the analysis was restricted to women on ART, postnatal retention was somewhat lower under B+ vs A (53% vs 65%; aRR, 0.73; p<0.001). Conclusions: Implementation of Option B+ greatly increased ART initiation antenatally and improved ART coverage among women with advanced HIV disease in Swaziland, but postpartum retention remains an important challenge requiring urgent intervention. 35LB National HIV Transmission in 4-12Week Olds in Malawi’s PMTCT Option B+ Program BethTippett Barr 1 ; Erik Schouten 2 ; Joep van Oosterhout 3 ; Sundeep K. Gupta 4 ; Happy Phiri 2 ; DeusThindwa 2 ; Christopher Blair 2 ; Andreas Jahn 5 ; Monique von Lettow 6 ; for the NEMAPP Consortium 1 CDC, Harare, Zimbabwe; 2 Management Sciences for Hlth, Lilongwe, Malawi; 3 Dignitas Intl, Zomba, Malawi; 4 CDC, Lilongwe, Malawi; 5 Ministry of Hlth, Lilongwe, Malawi; 6 Dignitas International, Lilongwe, Malawi Background: Option B+ was conceptualized and implemented in Malawi in 2011. Recognizing that additional data would be needed to validate program results documented by the Ministry of Health, and to provide further detail on variation in transmission by ART coverage and timing, a two year cohort study called the National Evaluation of Malawi’s PMTCT Program (NEMAPP) was implemented in November 2014. A primary objective of NEMAPP is to measure mother-to-child-transmission (MTCT) in the era of Option B+. Methods: NEMAPP is ongoing at 54 randomly selected health facilities in 10 districts. A stratified cluster sampling design was used to identify a nationally representative sample of 4-12 week old infants. Mothers were consecutively consented and screened for HIV while attending an under-5 clinic, and all identified HIV-exposed infants underwent HIV-1 DNA testing. This paper presents unweighted results of early infant transmission at the time of enrollment into NEMAPP. Results: Amongst 1,851 HIV-positive mothers of 4-12 week old infants, 98.2% reported knowing their HIV status in pregnancy. Overall MTCT was 3.9%. Among those on ART in pregnancy (coverage 93.5%) MTCT was 2.8%. Of the 6.5% of women who either never start ART, or chose to stop ART at any time during or immediately after pregnancy, MTCT was 20%. MTCT varied by timing of ART initiation: from 1.4% in the 46.5% of women on ART prior to pregnancy, to 21.3% in the 5.8% of women who had never started ART. Conclusions: Overall, vertical transmission of HIV is very low under Option B+. In women who are entering pregnancy already on ART, transmission is now on a similar scale to that observed in developed nations. Any ART coverage, even when started postpartum or taken temporarily, as in the case of defaulters, results in significant reduction in transmission.

Oral Abstracts

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CROI 2016