Visit Reason: Positive Pregnancy Test. HIV Treatment in the Childbearing Woman

Transcription

1 Visit Reason: Positive Pregnancy Test. HIV Treatment in the Childbearing Woman Thi-Thi Nguyen, PharmD, BCPS, AAHIVP Mountain Plains AIDS Education and Training Center Conference August 13th,

2 Objectives To discuss the rationale of HIV screening in the pregnant patient To identify the pharmacokinetic changes associated with pregnancy and antiretroviral agents choices in the pregnant patient To anticipate common pitfalls associated with the care of the HIV pregnant patient 2

3 HIV and Women 3

4 Quick Facts One in four people living with HIV infection in the United States are women 9,278 newly diagnosed in 2013 Only 32% have virus under control Heterosexual contact is the leading cause of HIV transmission HIV Among Women. Accesssed (May 27, 2015). HIV Surveillance in Women. Accessed (May 27, 2015) HIV Among Pregnant Women, Infants, and Children in the United States. Accessed (May 27, 2015). 4

5 Pregnancy in the United States 2008: 6,578,000 pregnancies pregnancies per 1,000 women aged 15 to 44 years old 4,248,000 live births 2006: 8,700 pregnancies in HIV women Ventura SJ et al. NSVR 2012; 60(7). HIV Among Pregnant Women, Infants, and Children in the United States. Accessed (May 27, 2015). 5

6 Why Screen for HIV? One Test. Two Lives. One Test. Two Lives. Accessed (May 27,2015). 6

7 Opportunities for Mother to Child HIV Transmission in Untreated HIV (5-10%) (20-30%) Breastfeeding (10-20%) Pre-mastication of food Aldrovandi GM et al. J Infect Dis (2010); 202: S366-S370. HIV Transmission from Mother to Child in the United States. From Epidemic to Near Elimination. Accessed (July 27, 2015). 7

8 Perinatal HIV Transmission Rate with Optimal Care Without optimal care, perinatal HIV transmission rate ranges from 15-40%. Providing optimal care will reduce perinatal HIV transmission to: 5% 8% 10% Less than 1% 8

9 Optimal care can reduce perinatal HIV transmission to less than 1% Cooper ER et al. JAIDS 2002; 29:

10 Prevention of HIV Transmission from Mother to Child Transmission (MTCT) Antepartum Intrapartum Postpartum Optimized HIV Antiretrovirals in Mother Antepartum HIV Antiretrovirals in Mother +/- IV Zidovudine Neonatal Postexposure Prophylaxis Breastfeeding 10

11 Prevention of HIV MTCT 11

12 Prevention of Mother to Child Transmission (MTCT) Antepartum Optimized HIV Antiretrovirals in Mother 12

13 Pharmacokinetics in Pregnancy 13

14 Pregnancy Associated Body Changes Absorption Metabolism Distribution Elimination 14

15 Absorption Delayed gastric emptying Prolonged small bowel transit time Nausea, vomiting Increase in gastric ph Costantine MM. Frontiers in Pharmacology 2014; 5:65.doi: /fphar Mirochnick M et al. Clin Pharmacokinet 2004; 43:

16 Metabolism Increase in CYP3A4 enzymes Decrease in drug concentration Responsible for metabolism of 50% of medications on the market Costantine MM. Frontiers in Pharmacology 2014; 5:65.doi: /fphar Anderson GD. Clin Pharmacokinet 2005; 44: Mirochnick M et al. Clin Pharmacokinet 2004; 43:

17 Distribution Increase in volume of distribution Decrease in albumin Increase in free fraction of the drugs Impact highly protein bound medications Anderson GD. Clin Pharmacokinet 2005; 44: Mirochnick M et al. Clin Pharmacokinet 2004; 43:

18 Elimination Increase in renal blood flow by 50% Increase in glomerular filtration rate by 50% Costantine MM. Frontiers in Pharmacology 2014; 5:65.doi: /fphar Anderson GD. Clin Pharmacokinet 2005; 44:

19 Pregnancy Associated Body Changes Which of the following pharmacokinetic characteristic change in pregnancy impacts antiretroviral therapy the most? Absorption Metabolism Distribution Elimination 19

20 Antiretroviral Agents Therapy (ART) in Pregnancy 20

21 ART in Pregnancy Risks vs benefits conversation ART selection Pregnancy associated body changes Co-morbidities Convenience Drug interactions Adverse events Resistance Experience from clinical studies 21

22 Risks vs Benefits of ART in Pregnancy 22

23 Risks of Initiation of ART Adverse drug reactions in the mother, fetus(es), infant(s) Drug interactions Limited long-term outcome data in pregnant patient population and infants with in utero drug exposure 23

24 Benefits of Initiation of ART Reduce perinatal transmission of HIV Reduce sexual transmission to discordant partner with sustained viral suppression Decrease risk of maternal disease progression Decrease risk of opportunistic infections 24

25 ART Selection in Pregnancy 25

26 General Principles Combination of ART (cart) is preferred Obtain HLA-B*5701 If HIV RNA level above copies/ml, obtain HIV genotype Initiation of cart before HIV genotype results are available Consider transplacental passage of ART Goal: undetectable HIV viral load 26

27 ART Options Preferred Alternative Insufficient data Not recommended 27

28 ART Options Preferred Regimens PI regimens: -Atazanavir/ritonavir + preferred two-nrti backbone **do not use in treatment experienced patients on tenofovir and H2-receptor antagonist -Darunavir/ritonavir + preferred two-nrti backbone NNRTI regimens -Efavirenz + preferred two-nrti backbone **preferably initiated after the first 8 weeks of pregnancy Integrase inhibitor regimen -Raltegravir+ preferred two-nrti backbone PI=protease inhibitor; NNRTI=non-nucleoside transcriptase inhibitor; NRTI=nucleoside reverse transcriptase inhibitor Preferred two-nrti backbone: Tenofovir/Lamivudine; Tenofovir/Emtricitabine; Abacavir/Lamivudine**requires HLA-B*5701 testing prior to initiation, not recommended to be used with atazanavir/ritonavir or efavirenz if HIV RNA>100,000 copies/ml; Zidovudine/Lamivudine ** twice daily regimen 28

29 ART Options Alternative Regimens PI regimens: -Lopinavir/ritonavir + preferred two-nrti backbone NNRTI regimens -Rilpivirine/Emtricitabine/Tenofovir -Rilpivirine + preferred two-nrti backbone **Do not use rilpivirine based regimens if pre-treatment HIV RNA>100,000 copies/ml or CD4<200 cells/mm^3 PI=protease inhibitor; NNRTI=non-nucleoside transcriptase inhibitor; NRTI=nucleoside reverse transcriptase inhibitor Preferred two-nrti backbone: Tenofovir/Lamivudine; Tenofovir/Emtricitabine; Abacavir/Lamivudine**requires HLA-B*5701 testing prior to initiation; Zidovudine/Lamivudine ** twice daily regimen 29

30 ART Options Insufficient data Dolutegravir Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Fosamprenavir Maraviroc Cobicistat 30

31 ART Options Not Recommended Inferior virologic efficacy: Abacavir/Lamivudine/Zidovudine; Nelfinavir Toxicity: Stavudine, Didanosine, Indinavir/ritonavir, Saquinavir/ritonavir, Ritonavir, Nevirapine Not recommended in ART-naïve patients: Etravirine, Enfuvirtide, Tipranavir/ritonavir 31

32 Pregnancy Associated Body Changes Absorption Metabolism Distribution Elimination 32

33 cart in Pregnancy at a Glance May have to delay cart with poorly controlled nausea/vomiting NRTI backbone due to high placental transfer PIs have low placental transfer PIs usually should be boosted Double-check PI dose and frequency Do not use ritonavir containing oral solution formulations (~40% alcohol content) 33

34 PI in Pregnancy Options Which of the following PIs require dosing changes during pregnancy? Atazanavir Darunavir Lopinavir/ritonavir All of the above 34

35 PI Dosing in Pregnancy PI Standard Dosing -ATV 400 mg PO daily with food -ATV 300 mg+ RTV 100 mg PO daily with food if also on H2RA -ATV 400 mg+ RTV 100 mg PO daily with food if also on H2RA AND tenofovir -DRV 800 mg+ RTV 100 mg PO daily -DRV 600 mg+ RTV 100 mg PO BID -LPV 400mg/RTV 100 mg PO BID -LPV 800 mg/rtv 100 mg PO daily PI Dosing in Pregnancy -ATV 400 mg+ RTV 100 mg PO daily with food starting 2 nd trimester ** do not use if treatment-experienced patient on tenofovir and H2RA -DRV 600mg+ RTV 100 mg PO BID -LPV 600 mg/rtv 150 mg PO BID starting 2 nd trimester *Use tablets only ATV=atazanavir; RTV=ritonavir; DRV= darunavir; LPV=lopinavir; H2RA=H2 Receptor antagonist. 35

36 Monitoring HIV Standard Monitoring -Plasma HIV RNA at baseline, ART initiation or modification, 2-8 weeks after initiation or change, then every 4-8 weeks until HIV RNA undetectable -Once HIV RNA undetectable, obtain every 3-6 months -CD4 at entry of care, every 3-6 months before initiation of ART, ART initiation or modification, every 3-6 months -After 2 years of successful viral load suppression: if CD cells/mm^3, yearly if CD4 >500 cells/mm^3, optional HIV Monitoring in Pregnancy -Plasma HIV RNA at initial visit, 2-4 weeks after initiation or change in cart, monthly until HIV RNA undetectable -Once HIV RNA undetectable, obtain every 3 months and again at weeks of gestation -CD4 at initial visit, every 3 months -if on cart, obtain CD4 every 6 months provided successful viral load suppression and immune reconstitution

37 Prevention of Mother to Child Transmission (MTCT) Intrapartum Antepartum HIV Antiretrovirals in Mother +/- IV Zidovudine 37

38 Intrapartum Zidovudine In which of the following situations would you recommend the administration of IV Zidovudine during labor? Unknown HIV status in the mother HIV mother not on cart Unsuccessful HIV viral load suppression All of the above 38

39 Pitfalls and the Importance of Planning 39

40 Intrapartum Zidovudine Is HIV patient on cart? Yes No HIV viral load 1000 copies/ml? Zidovudine indicated? Yes No Yes Continue cart Zidovudine indicated? Continue cart Zidovudine indicated? No Yes 40

41 Intrapartum Zidovudine Continue cart PO Zidovudine replaced by IV Zidovudine Zidovudine timing: onset of active labor for vaginal delivery 3 hours before Caesarian section delivery Zidovudine dosing: 2 mg/kg IV loading dose x1, then 1mg/kg/hr until delivery Wong VV. J Obstetrics &Gynaecology 2011; 31: Briand N et al. CID 2013; 57: Cotter AM et al. Am J Obstet Gynecol 2012; 207: 482. e

42 Intrapartum-Zidovudine Related Pitfalls Where will birthing take place? Patient should bring own cart When is the due date? Is zidovudine available? Does the hospital have a protocol? 42

43 Intrapartum Method of Delivery Is HIV patient on cart? Yes HIV viral load 1000 copies/ml? No Caesarian section at 38 weeks Yes No Vaginal delivery Caesarian section at 39 weeks Caesarian section at 38 weeks Briand N et al. Am J Obstet Gynecol 2013; 209: 335. e

44 Prevention of Mother to Child Transmission (MTCT) Postpartum Neonatal Postexposure Prophylaxis Breastfeeding 44

45 Neonatal Postexposure Prophylaxis Zidovudine is a cornerstone of neonatal HIV postexposure prophylaxis. When should you consider adjunctive nevirapine? A. Unsuccessful HIV viral load suppression in the mother despite cart B. HIV Mother not on cart C. Answers a and b D. Successful HIV viral load suppression 45

46 Neonatal Postexposure Prophylaxis with Zidovudine Gestational Age (weeks) Zidovudine Dosing (Initiate within 6-12 hours of delivery) <30 2mg/kg/dose POx1 (or 1.5 mg/kg/dose IV), then q12h through 4 weeks; then 3 mg/kg/dose PO (or 2.3 mg/kg/dose IV) q12h thereafter. 30 to <35 2mg/kg/dose POx1 (or 1.5 mg/kg/dose IV), then q12h through 2 weeks; then 3 mg/kg/dose PO (or 2.3 mg/kg/dose IV) q12h thereafter. >=35 4 mg/kg/dose (or 3mg/kg/dose IV) PO BID Duration Birth through 4-6 weeks Birth through 4-6 weeks Birth through 4-6 weeks 46

47 PACTG % of infants born to HIV infected mothers will become infected In utero Labor and delivery Breast-feeding To assess the safety and efficacy of zidovudine in the prevention of maternal to infant HIV transmission Connor EM et al. NEJM 1994; 331:

48 PACTG 076 Randomized, double-blind, placebocontrolled, multicenter study Key exclusion criteria: antepartum ART Zidovudine protocol vs. placebo Antepartum: 100 mg PO five times daily Intrapartum: 2 mg/kg IV x1 over 1 h, then 1 mg/kg/h until delivery Newborn: 8-12 h after birth: 2mg/kg PO q6hx 6 weeks Connor EM et al. NEJM 1994; 331:

49 PACTG 076 Results Connor EM et al. NEJM 1994; 331:

50 Ferguson et al Irish 10 year observational cohort from 01/01/1999 to 12/31/2008 of infants born from HIV mothers on cart To assess efficacy of abbreviated neonatal postexposure prophylaxis with zidovudine (4 weeks) Infants could also be on combination of nevirapine; nevirapine + lamivudine Ferguson W et al. Pediatr Infect Dis J 2011; 30:

51 Ferguson et al Efficacy Overall vertical transmission rate ~1% If mother on cart for at least 4 weeks, vertical transmission rate of 0.4% Ferguson W et al. Pediatr Infect Dis J 2011; 30:

52 PACTG 076 Results Connor EM et al. NEJM 1994; 331:

53 NICHD HPTN 040/PACTG 1043 Multi-center, randomized study of infants born from HIV mothers not on ART Population: infants 32 weeks of gestational age, born in the last 48h, >=1.5kg Nielsen-Saines K et al. NEJM 2012; 366:

54 NICHD HPTN 040/PACTG 1043 Zidovudine >2 kg: 12 mg PO BID x 6 weeks 2 kg: 8 mg PO BID x 6 weeks Zidovudine + Nevirapine >2 kg: Zidovudine 12 mg PO BID x 6 weeks Nevirapine 12 mg PO x 3 doses (0-48h; 48h after 1 st dose; 96h after 2 nd dose) 2 kg: Zidovudine 8 mg PO BID x 6 weeks Nevirapine 8 mg PO x 3 doses (0-48h; 48h after 1 st dose; 96h after 2 nd dose) Zidovudine + Lamivudine + Nelfinavir >3 kg: Zidovudine 12 mg PO BID x 6 weeks Lamivudine 6 mg PO BID x 2 weeks/nelfinavir 200 mg PO BID x 2 weeks >2 kg: Zidovudine 12 mg PO BID x 6 weeks Lamivudine 6 mg PO BID x 2 weeks/nelfinavir 150 mg PO BID x 2 weeks 2 kg: Zidovudine 8 mg PO BID x 6 weeks Lamivudine 4 mg PO BID x 2 weeks/nelfinavir 100 mg PO BID x 2weeks Nielsen-Saines K et al. NEJM 2012; 366:

55 NICHD HPTN 040/PACTG 1043 Treatment group Infected no./total no. at 3 months (%) Adjusted Odds Ratio (95% CI) P Value Zidovudine 24/529 (4.5) 1 n/a Zidovudine+ Nevirapine 11/534 (2.1) 0.39 ( ) 0.01 Zidovudine+ Nelfinavir+ Lamivudine 12/528 (2.3) 0.50 ( ) 0.05 Adjusted odds ratio for maternal viral load, and illegal substance use during pregnancy Nielsen-Saines K et al. NEJM 2012; 366:

56 Neonatal Postexposure Prophylaxis with Zidovudine Gestational Age (weeks) Zidovudine Dosing (Initiate within 6-12 hours of delivery) <30 2mg/kg/dose POx1 (or 1.5 mg/kg/dose IV), then q12h through 4 weeks; then 3 mg/kg/dose PO (or 2.3 mg/kg/dose IV) q12h thereafter. 30 to <35 2mg/kg/dose POx1 (or 1.5 mg/kg/dose IV), then q12h through 2 weeks; then 3 mg/kg/dose PO (or 2.3 mg/kg/dose IV) q12h thereafter. >=35 4 mg/kg/dose (or 3mg/kg/dose IV) PO BID Duration Birth through 4-6 weeks Birth through 4-6 weeks Birth through 4-6 weeks 56

57 Adjunct Neonatal Postexposure Prophylaxis with Nevirapine Birth Weight (kg) Nevirapine Dosing (Initiate within 48h of birth) Indicated in HIV-exposed infants of women on no antepartum cart and of women on antepartum cart with unsuccessful viral load suppression first dose: 0-48h: 8 mg/dose PO x1 -second dose: 48h after the 1 st dose: 8 mg PO x1 -third dose: 96h after the 2 nd dose: 8 mg PO x1 >2 -first dose: 0-48h: 12 mg/dose PO x1 -second dose: 48h after the 1 st dose: 12 mg PO x1 -third dose: 96h after the 2 nd dose: 12 mg PO x1 57

58 Neonatal Postexposure Prophylaxis Summary Is HIV mother on cart? Yes No HIV viral load 1000 copies/ml? Yes No Zidovudine x 6 weeks, Nevirapine in first 8 days of life Zidovudine x 4 weeks Zidovudine x 6 weeks, Nevirapine in first 8 days of life 58

59 Breastfeeding Optimal nutrition Reduction in infant morbidity and mortality Diarrheal, lower respiratory tract infections Protection from common childhood infections Promotes child spacing Bulterys M et al. Clin Perinatol 2010; 37:

60 HIV Transmission via Breastfeeding Breast milk contains HIV RNA- cell-free virus HIV DNA- cell-associated virus, which replicates in macrophages of ductal and alveolar mammary epithelial cells Viral load highest just after birth cart does NOT suppress HIV DNA in breast milk Bulterys M et al. Clin Perinatol 2010; 37: Slater M et al. Pediatr Drugs 2010; 12:

61 HIV Transmission via Breastfeeding HIV transmission risk increases with Longer duration of breastfeeding % per month during the first year 0.3% per month during the second year Mixed feeding Mastitis Higher viral load Lower CD4 count in mother Maternal malnutrition Bulterys M et al. Clin Perinatol 2010; 37: Slater M et al. Pediatr Drugs 2010; 12:

62 Breastfeeding is not recommended when acceptable, feasible, affordable, sustainable, and safe replacement feeding is available. Slater M et al. Pediatr Drugs 2010; 12: 1-9. Bulterys M et al. Clin Perinatol 2010; 37:

63 Neonatal HIV Diagnosis HIV antibody NOT reliable for patients <=18 months old HIV DNA PCR and HIV RNA PCR preferred due to passive transmission of maternal HIV antibody Obtain HIV DNA PCR and HIV RNA PCR 0-21 days, 1-2 months, and 4-6 months 63

64 Neonatal HIV Diagnosis Definitive HIV diagnosis rule out if 1 month and 4 months negative Initiation of Pneumocystis jirovecii pneumonia (PCP) prophylaxis at age 4-6 weeks until HIV excluded Trimethoprim 5-10 mg/kg/day with sulfamethoxazole mg/kg PO daily

65 Wrap Up 65

66 Optimal care can reduce perinatal HIV transmission to less than 1% Cooper ER et al. JAIDS 2002; 29:

67 Prevention of Mother to Child Transmission (MTCT) Antepartum Intrapartum Postpartum Optimized HIV Antiretrovirals in Mother Antepartum HIV Antiretrovirals in Mother +/- IV Zidovudine Neonatal Postexposure Prophylaxis Breastfeeding One Test. Two Lives. One Test. Two Lives. Accessed (May 27,2015). 67

68 Pitfalls to Avoid CYP3A4 enzyme affected by pregnancy-double check protease inhibitor dosing, frequency, and ensure boosting Continue cart even during labor! Care coordination in zidovudine timing Neonatal postexposure prophylaxis determined by HIV viral load suppression in mother No breastfeeding allowed after birth HIV antibody testing not reliable for diagnosis in patients <=18 months old 68

69 Review To discuss the rationale of HIV screening in the pregnant patient To identify the pharmacokinetic changes associated with pregnancy and antiretroviral agents choices in the pregnant patient To anticipate common pitfalls associated with the care of the HIV pregnant patient 69

70 Questions? 70

71 References Anderson GD. Pregnancy-induced changes in pharmacokinetics a mechanistic-based approach. Clin Pharmacokinet (2005); 44: Aldrovandi GM and L Kuhn. What infants and breasts can teach us about natural protection from HIV infection. J Infect Dis (2010); 202: S366-S370. Briand N, C Jasseron, J Sibiude et al. Cesarean section for HIV-infected women in the combination antiretroviral therapies era, Am J Obstet Gynecol (2013); 209: 335.e1-12. Briand N, J Warszawski, L Mandelbrot et al. Is intrapartum intravenous zidovudine for prevention of mother-to-child HIV-1 transmission still useful in the combination antiretroviral therapy era? CID (2013); 57: Bulterys M, S Ellington, and AP Kourtis. HIV-1 and breastfeeding: biology of transmission and advances in prevention. Clin Perinatol (2010); 37: Connor EM, RS Sperling, R Gelber et al. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. NEJM (1994); 331: Cooper ER, M Charurat, L Mofenson et al. Combination antiretroviral strategies for the treatment of pregnant HIV-1-infected women and prevention of perinatal HIV-1 transmission. JAIDS(2002); 29:

72 References Costantine MM. Physiologic and pharmacokinetic changes in pregnancy. Front Pharmacol (2014); 5:65.doi: /fphar Cotter AM, KF Brookfield, LM Duthely et al. Duration of membrane rupture and risk of perinatal transmission of HIV-1 in the era of combination antiretroviral therapy. Am J Obstet Gynecol (2012); 207: 482.e1-5. Ferguson W, M Goode, A Walsh et al. Evaluation of 4 weeks neonatal antiretroviral prophylaxis as a component of a prevention of mother-to-child transmission program in a resource-rich setting. Pediatr Infect Dis J (2011); 30: HIV Among Women. Available at Accessed (May 27,2015). HIV Among Pregnant Women, Infants, and Children in the United States. Available at Accessed (May 27, 2015). HIV Surveillance in Women. PPT Format. Available at Accessed (May 27, 2015). 72

73 References HIV Transmission from Mother to Child in the United States. From Epidemic to Near Elimination. Available at nichd.nih.gov. Accessed (July 27, 2015). Mirochnick M and E Capparelli. Pharmacokinetics of antiretrovirals in pregnant women. Clin Pharmacokinet (2004); 43: Nielsen-Saines K, H Watts, VG Veloso et al. Three postpartum antiretroviral regimens to prevent intrapartum HIV infection. NEJM (2012); 366: One Test. Two Lives. Picture available at Accessed (May 27, 2015). Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1 infected adults and adolescents. Department of Health and Human Services. Available at Accessed (June 23, 2015). Table 3. Panel on Opportunistic Infections in HIV-Exposed and HIV-Infected Children. Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Exposed and HIV-Infected Children. Department of Health and Human Services. Available at Accessed (August 3, 2015). 73

74 References Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission. Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States. Available at Accessed (April 14, 2015) Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission. Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States. Available at Accessed (August 6, 2015) Slater M, EM Stringer, and JSA Stringer. Breastfeeding in HIV-positive women what can be recommended? Pediatr Drugs (2010); 12: 1-9. Ventura SJ, Curtin SC, Abma JC et al. Estimated pregnancy rates and rates of pregnancy outcomes for the United States, National vital statistics reports; vol 60 no 7. Hyattsville, MD: National Center for Health Statistics Wong VV. Is peripartum zidovudine absolutely necessary for patients with a viral load less than 1,000 copies/ml? J Obstetrics&Gynaecology (2011); 31: