Presentation with late stage HIV disease at diagnosis of HIV infection in pregnancy Claire Thorne, Marie-Louise Newell for the European Collaborative Study MRC Centre of Epidemiology for Child Health, UCL Institute of Child Health, University College London Institute of Child Health

Background Late presentation and delayed diagnosis of HIV infection increases risk of HIV-related mortality Around 50-60% of pregnant HIV-infected women in Western Europe are unaware of their HIV status before their pregnancy and are diagnosed through antenatal testing Most women diagnosed antenatally are at relatively early stages of HIV disease, but some present with advanced HIV disease which poses considerable management challenges The size of the problem of late-stage diagnosis in pregnancy in Western Europe has not been quantified to date

Methods The European Collaborative Study on HIV-infected pregnant women and their children is a prospective birth cohort study, established in 1985 Women known to be HIV-infected before pregnancy and those diagnosed with HIV through antenatal or intrapartum testing are invited to participate; they and their children are followed according to standard protocol Data collected include maternal socio-demographics, mode of HIV acquisition, markers of HIV disease progression and antiretroviral treatment This analysis limited to the 25 centres from nine Western and Central European countries (Belgium, Denmark, Germany, Italy, the Netherlands, Poland, Spain, Sweden, UK) Analyses including logistic regression and linear mixed effects models were performed in SAS (v8.02)

Objectives To quantify the problem of presentation with late-stage HIV disease at diagnosis in pregnancy in Western European settings To describe the therapeutic management of women diagnosed with HIV infection during pregnancy and compare those with late-stage HIV diagnosis to other newly diagnosed women To evaluate the impact of late-stage diagnosis on pregnancy outcomes, including MTCT, prematurity, low birth weight

Study population Eligibility criteria: HIV diagnosis through antenatal testing Definition: Women with baseline CD4 counts < 200 cells/mm 3 were considered to have late-stage HIV diagnosis 3605 women with first positive HIV test available 1266 diagnosed through antenatal HIV testing in index pregnancy 2339 received HIV diagnosis before pregnancy 1256 women in study population 10 with no CD4 count available in pregnancy 3605 women: date of 1st positive HIV test available 1266 diagnosed through antenatal HIV testing in index pregnancy 2339 received HIV diagnosis before pregnancy 1256 women in study population 10 with no CD4 count available in pregnancy

Results Overall, 654 (53%) women were white, 499 (41%) were black (predominantly from sub-Saharan Africa) and 73 (6%) were of other ethnicities 15% (185/1256) of women had late-stage HIV disease at antenatal diagnosis This proportion has increased over time: 12% in , 13% in , 13% in , 15% in and 19% in (p=0.024 for trend) Median CD4 count at first measurement in pregnancy –Late-stage diagnosis: 140 cells/mm 3 (IQR ) –Other AN diagnosis: 460 cells/mm 3 (IQR ) AIDS indicator diseases were identified during pregnancy in 11% (n=20) of women with delayed diagnosis

Maternal characteristics p<0.001 p=0.15 p=0.008 p=0.6

Factors associated with late-stage diagnosis Logistic regression analysis including 613 women (delivering since 1996).

Maternal treatment ( ) 85% (94/110) of women with late-stage diagnosis received AN cART vs 67% (388/580) of other women (p<0.001) Median duration of cART was 16.9 weeks (IQR ) and 13.0 weeks (IQR ) for women with late-stage diagnosis and for other women respectively Type of antenatal ARTDuration of antenatal ART

Maternal HIV RNA levels Adjusting for time of measurement, type and duration of ART, late- stage diagnosis was associated with a significantly higher HIV RNA level over pregnancy (+0.29 log 10 copies/ml vs other women, p<0.001) (n=1670) Estimated mean HIV RNA levels in the third trimester / at delivery: –late-stage diagnosis: 2.94 log 10 copies/ml –other women: 2.65 log 10 copies/ml Median (IQR) [n] (log 10 copies/ml) 1 st trimester2 nd trimester3 rd trimester Late-stage diagnosis 4.82 ( ) [12] 3.62 ( ) [84] 2.13 ( ) [182] Other AN diagnosis 3.83 ( ) [62] 3.70 ( ) [334] 2.30 ( ) [926]

Detectable HIV RNA in late pregnancy Factors associated with having detectable VL in 3 rd trimester / at delivery were explored In univariable analysis, late-stage diagnosis was associated with a significantly increased likelihood of having detectable VL and antenatal cART with a decreased likelihood Adjusting for timing and type of ART, women with late-stage diagnosis were 81% more likely to have a 3 rd trimester detectable viral load than other women (AOR 1.81, 95%CI , p=0.06) (n=410) Most women starting cART had undetectable VL at their last measurement in pregnancy or at delivery –59% (34/58) in late-stage diagnosis group vs 67% (161/239) in other women (p=0.2)

Infant outcomes p<0.001 p=0.40 Women with late-stage diagnosis were twice as likely to deliver prematurely (<37 weeks) vs other women, adjusting for cART use (AOR 1.92 (95%CI ) p<0.001)

Conclusions In Western Europe, an increasing minority of HIV-infected pregnant women newly diagnosed through antenatal HIV testing already have advanced disease (one in five in ); black African women were at substantially greater risk of late- stage diagnosis during pregnancy than white women Women with late-stage diagnosis were more likely to start cART than other women, and to initiate this earlier, but they still had higher VL at delivery; they also had substantially worse pregnancy outcomes than women with better functioning immune systems It will be important to continue to monitor MTCT rates in this group and treatment outcomes in the women and infected children Barriers preventing timely access of women to HIV testing are important to address, for the health of the mother and her infant

Acknowledgements European Collaborative Study We would like to thank the women and their children who participated in the study. S Mahdavi, K England; Dr C Giaquinto, Dr O Rampon, Dr A Mazza and Prof A De Rossi; Prof I Grosch Wörner; Dr J Mok; Dr Ma I de José, Dra B Larrú Martínez, Dr J Ma Peña, Dr J Gonzalez Garcia, Dr JR Arribas Lopez and Dr MC Garcia Rodriguez; Prof F Asensi-Botet, Dr MC Otero, Dr D Pérez-Tamarit; Dr H J Scherpbier, M Kreyenbroek, Dr MH Godfried, Dr FJB Nellen and Dr K Boer; Dr L Navér, Dr AB Bohlin, Dr S Lindgren, Dr A Kaldma, Dr E Belfrage; Prof J Levy, Dr P Barlow, Dr Y Manigart, Dr M Hainaut and Dr T Goetghebuer; Prof B Brichard, J De Camps, N Thiry, G Deboone, H Waterloos; Prof C Viscoli; Prof A De Maria; Prof G Bentivoglio, Dr S Ferrero, Dr C Gotta; Prof A Mûr, Dr A Payà, Dr MA López-Vilchez, Dr R Carreras; Dr N H Valerius, Dr V Rosenfeldt; Dr O Coll, Dr A Suy, Dr J M Perez; Dr C Fortuny, Dr J Boguña; Dr V Savasi, Dr S Fiore, Dr M Crivelli; Dr A Viganò, Dr V Giacomet, Dr C Cerini, Dr C Raimondi and Prof G Zuccotti; S. Alberico, M. Tropea, C. Businelli; Dr G P Taylor, Dr EGH Lyall; Ms Z Penn; Drssa W. Buffolano, Dr R Tiseo, Prof P Martinelli, Drssa M Sansone, Dr G Maruotti, Dr A Agangi; Dr C Tibaldi, Dr S Marini, Dr G Masuelli, Prof C Benedetto; Dr T Niemieç, Prof M Marczynska, Dr S Dobosz, Dr J Popielska, Dr A Oldakowska; Dr R Malyuta, Dr I Semenenko, T Pilipenko. Funding: The ECS is a coordination action of the European Commission (PENTA/ECS ). Claire Thorne is supported by a Wellcome Trust Research Career Development Fellowship. GOSH/UCL: UK DoH NIHR Biomedical Research Centres funding scheme. The Centre for Paediatric Epidemiology and Biostatistics: UK Medical Research Council.