Integrase Inhibitors in Women and Pediatrics. Dr. Alberto Chaparro Sánchez

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1 Integrase Inhibitors in Women and Pediatrics Dr. Alberto Chaparro Sánchez

2 Disclosure Speaker Abbvie Speaker Bristol-Myers-Squibb

3 UNAIDS data 2018, recuperado de

4 Distribution of cases reported in Mexico Fuente SUIVE/DGE/SS. Sistema de vigilancia epidemiológica de VIH y sida, disponible en

5 Contraception Hormone metabolism by CYP P450 and uridine 5-diphosphate glucronosyltransferase isozymes Raltegravir.- Placebo controlled study EE / norgestimate, HIV negative patients, no significant difference in the pharmacokinetics of hormones Dolutegravir.- Placebo controlled study EE/norgestimate and DTG 50mg bid, no significant changes in AUC Elvitegravir/cobicistat.- Reduction of 6% Cmax and 25% in AUC of EE, with an increase of two folds the levels of norgestimate Clin Pharmacokinet2015 Jan;54(1):23-34 Annals of Pharmacotherapy 2015, Vol. 49(7)

6 Emergency Contraception Levonorgestrel.- Synthetic progestogen Ulipristal acetate.- Selective progesterone receptor modulator Comparative study of levonorgestrel with and without EFV in 21 HIV negative patients. 56% AUC (95 % CI 49 62) 41 % Cmax in the presence of EFV Duplicate the dose to 3g?? There are no studies referred to ulipristal acetate, is metabolized mainly by CYP3A4 potential interactions are inferred with PI/r, EFV, NVP, ETV. Do not increase the dose Raltegravir and Dolutegravir no expected interactions or requirement for posology change Clin Pharmacokinet2015 Jan;54(1):23-34

7 Pregnancy Modificate the indication of integrase inhibitors in pregnancy of alternatives under certain conditions preferred Pregnancy and: Late diagnosis Gastrointestinal intolerance and to other drugs Salvage therapy intensification of treatment Tuberculosis Accute infection prophylaxis in utero for the premature??

8 DHHS, Recommendations for the Use of Antiretroviral Drugs in Pregnant Women with HIV Infection and Interventions to Reduce Perinatal HIV Transmission in USA

9 Mexican Guidelines (CENSIDA)

10 Raltegravir During Pregnancy The status was modified in guidelines from "Recommended in special situations" to "Preferred scheme" with relevance in situations such as: Late diagnosis/high viral load Resistance to antiviral therapy Intolerance and to other drugs Report of supernumerary ribs in mice, without reports of congenital alterations in humans J Acquir Immune Defic Syndr Volume 72, Number 2, June 1, 2016

11 Raltegravir During Pregnancy RAL induces a rapid decline in HIV viral load Average weekly decrease in HIV viral load standard treatment 1.1 log in 4 to 8 weeks 1.7 to 2.2 Log with RAL vs RAL adequate diffusion in the cervix and cervicovaginal secretions, cervicovaginal fluid/plasma ratio 2.3 High and fast transplacental passage FDA category C Westing K. Rapid Decline in HIV Viral Load When Introducing Raltegravir-Containing Antiretroviral Treatment Late in Pregnancy. AIDS patient care and STDs 2012; 26 (12):

12 Enferm Infecc Microbiol Clin. 2014;32(9):

13 International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) 1026s Prospective, multicentric trial More than 90% of women with RAL reached VL <400cp/ml by the third trimester and at birth, 92% with undetectable HIV VL Non-HIV infection in children All infants were at least 36 weeks gestation at birth 7 neonates with congenital anomalies not related to RAL J Acquir Immune Defic Syndr 2014; 67 (4):

14 International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) 1026s Only 2 patients presented adverse events grade 2, one with vomiting and the other with transaminasemia transient; Grade 3 or 4 events in 4 women not related to the use of RAL Differences between the 2nd and 3rd trimester in relation to postpartum and AUC serum values No significant difference in oral clearance, average life and volume of distribution during pregnancy and postpartum. The median maternal serum levels of RAL at birth 0.140μg /ml, median umbilical cord μg/ml. Cord/stem ratio = 1.5 J Acquir Immune Defic Syndr 2014; 67 (4):

15 International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) 1026s Even with the differences in RAL [s] serum by trimester and postpartum in relation to non-pregnant women, no standard dose adjustment is required Serum levels in the newborn are 7 to 9 times higher than in the mother at 1-3 hours of birth RAL can be considered as a drug for pre-exposure prophylaxis (in utero) J Acquir Immune Defic Syndr 2014; 67 (4):

16 IMPAACT P pharmacokinetics and exposure safety in utero / intrapartum to RAL Rapid transplacental passage - in 3h umbilical cord levels > at maternal plasma concentrations RAL metabolized by hepatic glucuronidation via UGT (Uridin-diphosphate-gluronosyl-transferase) Immaturity and little enzymatic activity cause low clearance Enterohepatic recirculation, intestinal B-glucuronidase releases the metabolites of RAL and is reabsorbed from meconium in high quantities combined with lack of intestinal motility and slow hepatic metabolism in preterm infants RAL and Bilirubin compete for UGT - Risk of bilirubin toxicity (Kernicterus) RAL and bilirubin compete for binding sites with albumin J Acquir Immune Defic Syndr 2014; 67 (3):

17 Pharmacokinetics in preterm infants exposed to RAL from mothers with HIV infection Inhibitory concentration - limit of efficacy in humans 15ng / ml Average life in adults 9 hours, in newborns 1 to 4 days (variable according to degree of maturity - approximately 7 days in preterm infants) 2 days old = 106ng / ml 1 month of age [ ] serum = 29ng / ml Antimicrobial Agents and Chemotherapy 2013; 57 (12):

18 - Elvitegravir, cobicistat both class B of the FDA - Reason [ ]'s maternal / cord for EVG = 1 (both 0.30mg / L) - Cobicistat under the limit of detection in umbilical cord - Similar AUC in 3rd trimester and postpartum - Cmin in 3rd trimester 60% than postpartum, below the suggested goal 0.13mg / dl AIDS Mar 13;30(5):807-8.

19 Lower AUC during pregnancy; in postpartum/antepartum similar to non-pregnant adults. Activity of UGT1A1 and CYP3A4 increased during pregnancy by progesterone levels, resulting in decreased concentrations of DTG. Elimination of DTG by the neonate up to more than 2 half lives compared to that observed in adults (elimination half-life = 35h) Congenital malformations reported pulmonary venous return, polycystic kidney, cystic fibrosis, congenital chin tremor, fibrolipoma of filum terminale, alterations of the sacrum. 4 children attended with hypoglycemia. CROI; February 22-25, 2016; Boston, Massachusetts, USA.

20 Category B - FDA First pharmacokinetic profile of DTG in pregnancy Significant fetal exposure at a dose of 50mg b.i.d. The effects of these exposure levels in utero are unknown Use with caution DTG 50mg b.i.d. In this case, careful monitoring of neonatal toxicity They require further studies to define the time schedule and assess the safety of DTG in pregnancy. AIDS 2016; 30 (8):

21 Description of the pharmacokinetics of DTG in a preterm infant after maternal Tx intensification in the last 2 weeks of pregnancy (TDF / FTC + ATV/r + DTG) DTG 50mg q. d. by the expected interaction of the ATV and DTG Enzymatic immaturity of prematurity increases the half-life of DTG estimated up to 4 times in relation to adults (46h to 68h) Antimicrobial Agents and Chemotherapy 2015; 59 (6):

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23 Integrase Inhibitors in children Children with HIV infection have more rapid disease and accelerated damage to the developing immune system, with high viral loads and less effective immune response

24 DHHS, Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

25 Mexican Guidelines (CENSIDA)

26 Raltegravir in children - First report of compassionate use in children with failure in conjunction with DRV / r + ETV - IMPAACT P Study 1277 fails to first scheme Advantage -Approved for children from 2-4 weeks and >2Kg -Children 8mg / Kg / dose bid, adolescents 400mg bid -Pediatric presentation (suspension and chewable tabs) Disadvantage -Dosage twice a day -There is no co-formulation Journal of the Pediatric Infectious Diseases Society, Vol. 4, No. 4, pp. e76 e83 J Clin Pharmacol July ; 55(7):

27 Journal of the Pediatric Infectious Diseases Society, Vol. 4, No. 4, pp. e76 e83 J Clin Pharmacol July ; 55(7):

28 Dolutegravir in children - Approved for children from 6 years old or >30Kg - IMPAACT P1093 Advantage -Coformulated -Pediatric presentation (small size) Disadvantages -Size of the very large coformulated tablet -Requires determination of HLA B5701 for coformulation Drugs (2015) 75: Pediatr Infect Dis J. 2015

29 Pediatr Infect Dis J. 2015

30 Elvitegravir/cobicistat in children and adolescents Authorized for use by the FDA in 2012 and EMA 2013 Preferred options in> 12 years and 25Kg Alternative option 6-12 years ADVANTAGES -Advantage -Coformulation -Dosage once a day -Option for scheme simplification DISADVANTAGES - Does not have a pediatric presentation - Pharmacological interactions - cobicistat - Evaluate stages of sexual maturity Drugs (2015) 75:

31 Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection A Phase 2/3, Open-Label Study of the Pharmacokinetics, Safety, and Antiviral Activity of the GS- 9883/Emtricitabine/Tenofovir Alafenamide (GS-9883/F/TAF) Fixed Dose Combination (FDC) in HIV-1 Infected Virologically Suppressed Adolescents and Children Estimated study completion date: July Recuperado el 29/08/2018 de

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