Presentation with late stage HIV disease at diagnosis of HIV infection in pregnancy

1. 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

2. 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

3. 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)

4. 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

5. 3605 women with first 3605 women: date of 1st positive HIV test available positive HIV test available 1266 diagnosed through 1266 diagnosed through 2339 received HIV 2339 received HIV antenatal HIV testing in antenatal HIV testing in diagnosis before pregnancy diagnosis before pregnancy index pregnancy index pregnancy 10 with no CD4 count 10 with no CD4 count available in pregnancy available in pregnancy 1256 women in study 1256 women in study population population Study population Eligibility criteria: • HIV diagnosis through antenatal testing Definition: • Women with baseline CD4 counts < 200 cells/mm3 were considered to have late-stage HIV diagnosis

6. 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 1985-89, 13% in 1990-94, 13% in 1995-99, 15% in 2000-04 and 19% in 2005-08 (p=0.024 for trend) • Median CD4 count at first measurement in pregnancy • Late-stage diagnosis: 140 cells/mm3 (IQR 90-147) • Other AN diagnosis: 460 cells/mm3 (IQR 333-650) • AIDS indicator diseases were identified during pregnancy in 11% (n=20) of women with delayed diagnosis

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

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

9. Type of antenatal ART Duration of antenatal ART Maternal treatment (1997-2008) • 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 11.6-20.7) and 13.0 weeks (IQR 11.6-20.7) for women with late-stage diagnosis and for other women respectively

10. 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 log10 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 log10 copies/ml • other women: 2.65 log10 copies/ml

11. Detectable HIV RNA in late pregnancy • Factors associated with having detectable VL in 3rd 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 3rd trimester detectable viral load than other women (AOR 1.81, 95%CI 0.98-3.33, 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)

12. Infant outcomes p=0.40 p<0.001 p<0.001 • 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 1.31-2.82) p<0.001)

13. 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 2005-2008); 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

14. 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 018865). 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.