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HIV Pharmacotherapy in Pregnancy
- 1. HIV Treatment andthe Pregnant HIV-1 Positive Woman Presented By: DeShawndre Bridley 6th Year Doctorate of Pharmacy Candidate Florida A&M University
- 2. Objectives Why are we particularly concerned with treatment of a pregnant HIV(+) woman? ) Have the Perinatal HIV guidelines changed? a Background (I don’t remember how to HIV is treated! Matter of fact, What is HIV?!) W What are some pharmacological principles of Antepartum HIV care? a What are some pharmacological principles of Intrapartum HIV care? c How can the guidelines be applied clinically?
- 3. Why are weparticularly concerned with treatment of a pregnant HIV(+) woman?
- 4. Factors to Considerin the Pregnant HIV Infected Woman 2. Antiretroviral treatment of the maternal HIV infection 3. Antiretroviral Chemoprophylaxis to reduce the risk of perinatal transmission of HIV
- 5. AIDS cases dueto the perinatal transmission of HIV infection, by year of diagnosis, 2001–2005, United States
- 6. Race/ethnicity of children(<13 years) with AIDS diagnosed during 2005 (includes all children with a diagnosis of AIDS, not just those who contracted HIV perinatally)
- 7. Have the PerinatalHIV guidelines changed?
- 8. Updated Perinatal Guidelines Updated as of Nov. 2, 2007 Available at http://AIDSinfo.nih.gov Updated/New Sections ◦ Lessons From Clinical Trials ◦ Antepartum management ◦ Intrapartum management ◦ Postpartum management ◦ Infant Management
- 9. Background (I don’tremember how to HIV is treated! Matter of fact, What is HIV?!)
- 10. Background What is HIV-1? ◦ Human Immunodeficiency Virus Type 1 is a human retrovirus that infects predominantly lymphocytes that bear the CD4 surface protein ◦ Over time immune dysfunction gives rise to AIDS (Acquired Immunodeficiency Syndrome) which is characterized by development of opportunistic infections, malignancies, and wasting ◦ The virus is transmitted sexually or parenterally, and perinatally
- 11. Background What is HAART? ◦ Highly Active Antiretroviral Therapy ◦ Consists of a minimum of three antiretroviral drugs Potent HAART regimen typically includes two NRTIs plus one or two Pis or an NNRTI
- 12. Background What isa NRTI? Nucleoside/Nucleotide analog reverse transcriptase inhibitor ◦ MOA: constrain HIV replication by incorporating into elongating strand DNA, causing chain termination ◦ Associated with Lactic Acidosis presumably related to mitochondrial toxicity Didanosine, Emtricitabine, Tenofovir Pregnancy category B
- 13. Background What isa NNRTI? Non-nucleoside reverse transcriptase inhibitor ◦ MOA: bind noncompetitively to reverse transcriptase ◦ Side effects include rash, increased ALT and AST, and Stevens-Johnson syndrome (more likely with nevirapine) ◦ CNS side effects are commonly experienced with efavirenz (sleepiness, vivid dreams, dizziness)
- 14. Background What isa PI Protease Inhibitor ◦ MOA: Blocks the action of viral protease required for protein processing late in the viral cycle ◦ Most common side effect is GI intolerance ◦ These agents are associated with glucose intolerance, increased cholesterol and triglycerides, and body fat redistribution ◦ Potent CYP 450 inhibitors Several Drug interactions Atazanavir, Saquinavir, Nelfinavir** Pregnancy Category B
- 15. Newer Agents Entry Inhibitors ◦ Enfuvirtide (Fuzeon) Pregnancy category B ◦ Maraviroc (Selzentry) Pregnancy category B Integrase Inhibitors ◦ Raltegravir (Isentress) Pregnancy category C
- 16. What are somepharmacological principles of Antepartum HIV care?
- 17. Antepartum Care Initiating HAART therapy in a HIV positive pregnant woman with at or after 14 weeks gestation
- 18. Pharmacokinetic Changes inthe Pregnant woman Gastrointestinal transit time is decreased Decreased plasma protein concentrations Increased renal sodium reabsorption Changes in liver enzymatic metabolic pathways Body water and fat increase ◦ Increased cardiac output ◦ Increased ventilation ◦ Increased renal and liver blood flow
- 19. Protease Inhibitor Therapyand Hyperglycemia Hyperglycemia, new-onset diabetes mellitus, exacerbation of existing diabetes, and diabetic ketoacidosis have been reported Pregnancy itself is a risk factor for hyperglycemia Recommended to perform glucose tolerance testing between 24 to 28 weeks gestation
- 20. Considerations Nelfinavir (Viracept) should not be offered ◦ Pregnant patients already on nelfinavir should be switched to another agent ◦ 9/2007 Pfizer sent out a letter to providers regarding the presence of EMS (ethyl methane sulfonate) in it’s product Viracept Process related impurity EMS is mutagenic, carcinogenic, and teratogenic
- 21. Nevirapine(Viramune) and Hepatic/ RashToxicity Pregnancy category B NNRTI Single dose at the time of labor has been shown to decrease perinatal transmission of HIV Increases in ALT and AST levels associated with toxicity may be seen during the first 18 weeks of treatment Monitor transaminases at baseline, every two weeks for the first month, monthly through month 4, and every 1 to 3 months thereafter More common in women Risk varies with CD4 count CD4 count >250 cells/mcl Signs and Symptoms Fatigue, malaise, anorexia, nausea, jaundice, liver tenderness, hepatomegaly Can occur with or with elevated transaminases
- 22. Delavirdine (Rescriptor) NNRTI Pregnancy Category C Increased risk of ventricular septal defects in rodents NOT RECOMMENDED IN PREGNANCY
- 23. Efavirenz(Sustiva) NNRTI PregnancyCategory D NOT RECOMMENDED IN PREGNANCY
- 24. Mitochondrial Toxicity andNRTI drugs The relative potency of the nucleosides in inhibiting mitochondrial gamma DNA polymerase in vitro is highest for zalcitabine(ddC), followed by didanosine (ddl), stavudine (d4T), ZDV, 3TC, abacavir (ABC), and tenofovir Neuropathy, myopathy, cardiomyopathy, pancreatitis, hepatic steatosis, and lactic acidosis
- 25. Tenofovir Potential fetalbone defects Potential nephrotoxicity Use as a component of maternal combination regimens only after careful consideration of other alternatives
- 26. Zalcitabine (Hivid) Increasedrisk of hydrocephalus at high doses in rodents NOT RECOMMENDED IN PREGNANCY Removed from the market but still included in the updated guidelines
- 27. Special Considerations Antiretroviral Registry ◦ Any woman exposed to ART should be reported to www.APRegistry.com Resistance testing should be performed on all pregnant HIV (+) women who are treatment naïve Resistance testing should be performed in women who are treatment experienced but have not achieved optimal viral suppression
- 28. Special Considerations Combination Stavudine and didanosine ◦ Increased risk of steatosis and
- 29. What are some pharmacologicalprinciples of Intrapartum HIV care?
- 30. Lesson From ClinicalTrials: PACTG 076 (Pediatric AIDS Clinical Trials Group) Demonstrated that the administration of 3 part ZDV to the mother and her infant child could reduce perinatal transmission of HIV by 70% in 2004
- 31. What is 3part Zidovudine(ZDV) Oral ZDV initiated at 14 to 34 weeks gestation and continued throughout pregnancy ◦ 300mg PO BID or 200mg PO TID IV ZDV during labor Oral administration of ZDV to infant for 6 weeks after delivery
- 32. Considerations Studies haveshown that single dose Nevirapine alone or in combination with ZDV is effective in reducing the risk of perinatal HIV transmission d4T (stavudine) can be used during pregnancy but should be discontinued while ZDV is administered IV started at labor Antagonistic drug interaction
- 33. Special Considerations Cesarean Delivery is recommended for women with viral loads greater than 1000 copies/ml
- 34. How can theguidelines be applied clinically?
- 35. Clinical Scenario 1 HIV-1 infected woman who is antiretroviral naïve and has indications for antiretroviral therapy 1. Drug Resistance Testing 2. Initiate HAART Regimen 3. During Labor-ZDV intravenous continuous infusion; continue other agents orally 4. Scheduled cesarean delivery at 38 weeks if plasma HIV RNA >1000 copies/ml near time of delivery 5. Give infant ZDV for 6 weeks starting within 6-12 hours after birth
- 36. HAART Regimen Considerations Avoid EFV or other teratogenic drugs and combinations (d4T/ddl) in first trimester Avoid Nelfinavir until further notice Use ZDV if feasible NVP can be used as a component of HAART for women with CD4 count ≤250 cells/mm3, but should only be used as a component of therapy in women with CD4 counts >250 cells/ mm3 if the benefit clearly outweighs the risk due to an increased risk of severe hepatotoxicity.
- 37. Scenario 2 HIV infected woman in labor who has not received antiretroviral treatment prior to labor!!!!! 1. Give mother ZDV 2mg/kg IV over 1hr, followed by continuous infusion of 1mg/kg/hr during labor until delivery 2. Give infant ZDV for six weeks starting within 6 to 12 hours after birth Infant <35 weeks gestation: 1.5mg/kg/dose IV Infant >35 weeks gestation: 2mg/kg/dose PO q 12h advancing to q8h at two weeks of age if ≥ 30 weeks gestation at birth or at 4 weeks if of age if <30 weeks at birth
- 38. Scenario 2 Alternative 1. ZDV given as a continuous infusion during labor, PLUS a single dose of NVP 200mg PO at the start of labor 2. Give infant single dose NVP 2mg/kg PO at 2-3 days of birth if mother received single dose NVP at start of labor (give at birth if mother did not receive NVP at start of labor) and ZDV for 6 weeks starting within 6 to 12 hours after birth
- 39.
- 40. References Perinatal HIV Guidelines Working Group. Public Health Service Task Force Recommendations for Use of Antiretroviral Drugs in Pregnant HIV- Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States. November 2, 2007 1-96. Available at: http://aidsinfo.nih.gov/ContentFiles/PerinatalGL.pdf The Washington Manual of Medical Therapeutics 32nd Edition