1. Pregnancy, Protease Inhibitors and HIV.

2. Pregnancy and HIV most recent guidance? Protease Inhibitors ATV vs LPV? Newer regimens..

4. Townsend et al CROI 2013 poster 906

5. What we know? Excellent ART coverage Excellent PMTCT Preterm delivery concerns Drug or drug class? Timing of ART?

6. Lorenzi P, Spicher VM, Laubereau B et al. AIDS 1998; 12: F241–F247 Association between ART and PTD European Collaborative Study. J Acquir Immune Defic Syndr 2003;32: 380– 387. Association between ART and PTD Townsend CL, Cortina-Borja M et al AIDS 2007; 21: 1019–1026. 1.5-fold increased risk of PTD on ART - No association between PTD and PI- containing ART Townsend CL, Willey BA et al. AIDS 2009; 23: 519–524. Association between ART and PTD European Collaborative Study AIDS 2000; 14: 2913–2930. Association between ART and PTD - particularly marked in patients on PI’s European Collaborative Study. AIDS 2004; 18: 2337–2339. Association between ART and PTD - particularly marked in patients on PI’s Cotter AM, Garcia AG, Duthely ML et al J Infect Dis 2006; 193: 1195–1201. Association between ART and PTD - only if ART included a PI Schulte J, Dominguez K, Sukalac T et al Pediatrics 2007; 119: e900–e906. Association between ART and PTD - only if ART included a PI Tuomala RE, Shapiro DE, Mofenson LM et al. N Engl J Med 2002; 346: 1863–1870. No Association between ART and PTD Tuomala RE, Watts DH, Li D et al. J Acquir Immune Defic Syndr 2005;38:449–473. No Association between ART and PTD Kourtis AP, Schmid CH, Jamieson DJ, Lau J. AIDS 2007;21: 607–615 No Association between PTD and PI-containing ART Powis KM, Kitch D, Ogwu A et al. J Infect Dis 2011; 204: 506–514. Association between PI-based ART and PTD Kesho Bora Study Group, de Vincenzi I. Lancet Infect Dis 2011; 11: 171–180. No Association between ART and PTD

7. www.bhiva.org

8. As per HIV treatment guidelines for non pregnant individuals - based on VL, CD4 & genotype Conceive on ART remain on the same ART* Commencing ART for maternal health start ART ASAP All women should commence ART by 24W* No recommended dose adjustments. Therapeutic drug monitoring - only consider.

9. In clinical practice: ritonavir-boosted lopinavir ritonavir-boosted atazanavir Two most commonly used PIs in pregnancy in the UK are ritonavir-boosted lopinavir and ritonavir-boosted atazanavir Our Question? Atazanavir or lopinavir Atazanavir or lopinavir in pregnancy?

10. Lopinavir and atazanavir in pregnancy: preterm delivery rates, infant outcomes and virological efficacy. HIV Med. 2016 Jan;17(1):28-35. doi: 10.1111/hiv.12277. Epub 2015 Jul 22. Perry M, Taylor GP, Sabin CA, Conway K, Flanagan S, Dwyer E, Stevenson J, Mulka L, McKendry A, Williams E, Barbour A, Dermont S, Roedling S, Shah R, Anderson J, Rodgers M, Wood C, Sarner L, Hay P, Hawkins D, deRuiter A.

11. Outcomes Pre term delivery Infant outcomes transmission birth weight phototherapy requirement birth defects Tolerability and viral response clinical and virological aspects

12. Retrospective case note review 9 London HIV specialist care centres All pregnancies atazanavir or lopinavir commenced on atazanavir or lopinavir or atazanavir or lopinavir conceived on atazanavir or lopinavir delivered 1 st Sept 2007 - 30 th Aug 2012

13. Results n=493 pregnancies Median age 33 years Ethnicity 81% Black African. HIV acquisition 97% through heterosexual exposure 0.6% from injecting drug use Hepatitis co-infection Hep B – 4% Hep C – 1%

14. Atazanavir Lopinavir Total number of patients: 187 306

15. NRTI Backbone AtazanavirLopinavir % on standard dose 88% 92%

16. Numbers of patients AtazanavirLopinavirTotal Conceived on 9582177 Post conception 92224316 Total187306493

17. % of women who delivered <37W *8 percent (1 in 13) of general population UK live births are born preterm Atazanavir Lopinavir p-value Overall: 19 (13%) 40 (14%) ns Conceived on 11 (15%) 8 (12%)0.98 Post conception 16 (20%)24 (12%)0.12

18. Atazanavir Lopinavir Transmissions1 (0.7%)1 (0.4%) Overall MTCT rate: 0.5% % requiring phototherapy 2 (2%)2 (1%) Birth defects 3 (3%)2 (2%) (Conceived on) % <2500g birth weight 23 (15%) 40 (15%) Infant outcomes

19. Tolerability / toxicity Atazanavir Lopinavir Conceived on 2 (2%)5 (6%) Post conception5 (5%)24 (11%) 55% related to nausea & vomiting

20. Viral load decay ATV/r (despite the majority of women on ATV/r receiving the standard 300/100mg dose and co-prescribed tenofovir.) Atazanavir Lopinavir Gestation 20w 22w (at starting ART) % VL<=50 cps/ml 85% 81% 0.61 at delivery Median days VL <= 50 cps/ml 56days 43days 0.52

21. Conclusions Both regimens were successful in preventing MTCT ATV/rLPV/r No significant difference between ATV/r and LPV/r in preterm delivery rates infant outcomes tolerability and toxicity virological efficacy The PTD rates were comparable to those reported in previous studies and more favourable than others

22. Limitations Retrospective case note review Small case numbers Lacks power Limited scope for multivariable logistic regression analysis

23. Summary This is the first study comparing pregnancy outcomes between these two PIs. This study suggests both PI regimens at standard dosing are comparable in terms of virological efficacy, preterm delivery rates and infant outcomes.

24. Newer regimens? Darunavir

26. Newer regimens? Rilpivirine

28. Newer regimens? Integrase Inhibitors

29. Integrase inhibitors in late pregnancy and rapid HIV viral load reduction. Rahangdale L 1, Cates J 2, Potter J 3, Badell ML 4, Seidman D 5, Miller ES 6, Coleman JS 7, Lazenby GB 8, Levison J 9, Short WR 10, Yawetz S 11, Ciaranello A 12, Livingston E 13, Duthely L 3, Rimawi BH 14, Anderson JR 7, Stringer EM 15 ; HOPES (HIV OB Pregnancy Education Study) Group. CONCLUSION: ART that includes INSTIs appears to induce more rapid viral suppression than other ART regimens in pregnancy. Inclusion of an INSTI may play a role in optimal reduction of HIV RNA for HIV-infected pregnant women presenting late to care or failing initial therapy. Larger studies are urgently needed to assess the safety and effectiveness of this approach. Am J Obstet Gynecol. 2016 Mar;214(3):385.e1-7. doi: 10.1016/j.ajog.2015.12.052. Rahangdale LCates JPotter JBadell MLSeidman DMiller ESColeman JSLazenby GBLevison JShort WRYawetz SCiaranello ALivingston EDuthely LRimawi BH Anderson JRStringer EMHOPES (HIV OB Pregnancy Education Study) Group Am J Obstet Gynecol.

33. Questions?