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Hiv and obgyn resident
- 1. Human immunodeficiency virus infection in Obstetrics and Gynaecology ผผผผผผผผผผผผผผผ ผผผผผผผผผผผผผผผ ผผผผผ หหหหหหหหหหหหหหหหหหหหหหหหหหหหหหหหหหหห หหหหหหหหหหหหหหหหห-หหหหหหหหหหห หหหหหหหหหหหหหหหหหหหหหหห หหหหหหหหหหหห
- 3. HIV attachment, binding and fusion http://chem3513-2007.pbworks.com/w/page/15648421/HIV%20Treatment
- 4. Uncoating, Reverse Transcription & Integration http://www.thebody.com/content/art14193.html 1 2 3 4
- 5. Latency, Protein Synthesis & Cleavage 5 6
- 6. Pathogenesis: Words to rememberPathogenesis: Words to remember Primary receptor for HIV Secondary receptor or co-receptors CD4 CXCR4 and CCR5 Dendritic cells Key role in transmission of HIV to draining lymph nodes where viral replication takes place. Sequence of HIV enzymes 1. Reverse transcriptase 2. Integrase 3. Protease
- 7. HIV evades the immune response during Primary HIV infection • Target on CD4 T cells and macrophages (both innate and adaptive immunity) • Latency (resting latently in infected cells) • Massive loss of HIV-1 specific CD4 T cells • Lack of CD4 impairs cytotoxic T cells. • Viral evolution (highly mutant) Chronic HIV infection
- 8. Test หหห หหหหหหหหหหหหหห (หหหหหหห Ab หหหหหหหหหหหหหหหห หหหหหหห Ag หหหหหหหหหหหห หหห A1 หหหหหหหหหหหห (หหหหหหหหห *ผผผผผผผผผผผผผผผผผ ผผผผผผผผผผผผผผผผผ National guideline: Thailand 2010
- 9. ผผผผผผผผผผผผผผผผผผผผผ ผผผผผผผผผผผผผผผผผผผผผผผ • หหหหหหหหหหหหหหหหหหหหหหหหหหห – Viral protein: หหหหหหหหหหหหหหหหห p24 Ag หหหหหหห หหหหหหหหหหหหหหหหหหหหหหหหหหหหหหหหหหหหหห หหหหหหหหหหหหหหหห หหหหหหหหห p24 Ag หหหหหหหห หหหหหหหหหหหหหหหหหหหหหหหหหหหหหหหหหหหหห หหห หหหหหหหหหหหหหหหหหหหหหหห antibody หหหหห หหหห 5 หหห – Nucleic acid Amplification Test (NAAT): หหหหหหหหหหห RNA หหหหหหหหหหหหหหหหหหหหหหหหหหหหหหหหห (positive or negative) • หหหหหหหหหหหหห antibody หหหหหหหหหหหหหหห หหหหหห – Enzyme-linked immunosorbent assay (ELISA): HIV antigen หหหหหหห หห solid phase หหหหหหหหหหหหหหหหหหหหหห antigen หหห antibody หหหหหหหหหหหหหหหหหหหหหหหหหหหหหห หหหหหหหหหหหหหหหหหหหหหห substrate หหหหหหหหห หหหหหหหหหหหหหหหหหหหหหหหหหหหหหห – Agglutination: HIV antigen หหหหหหหหหหหหหหหหหหหหหหห หหหหหหหหหหหหหหหหหหหหหหห หหหหหหหหหหห National guideline: Thailand 2010
- 11. หหหหหหหหหหหหหหหหหหหหหห หหหหหหหหหหหหห NRTIs, NtRTIs AZT = zidovudine, 3TC = lamivudine, TDF = tenofovir disoproxil fumarate, FTC = emtricitabine , ABC = abacavir, d4T = stavudine, ddI = didanosine, 3TC/FTC= Truvada® NNRTIs EFV = efavirens, NVP = nevirapine PIs LPV/r = lopinavir/ritonavir, ATV/r = atazanavir/ritonavir, DRV/r = darunavir/ritonavir, SQV/r = saquinavir/ritonavir National guideline: Thailand 2014 GPO vir Z-250: Nevirapine (NVP) 200 mg, Lamivudine (3TC) 150 mg, Zidovudine (AZT) 250 mg GPO vir S30:Nevirapine (NVP) 200 mg, Lamivudine (3TC) 150 mg, Stavudine (d4T) 30 mg
- 12. เเเเเเ CD4 เเเเเเเเเเเเเเเเเเเเเเเเเเเ National guideline: Thailand 2010 OI CD4 count Medication PCP ≤ 200 cells/mm3 Bactrim (Sulfomethoxazole/ Trimethoprim Toxoplasmosis ≤ 200 cells/mm3 Cryptococcosis ≤ 100 cells/mm3 Fluconazole Penicillosis/ Histoplasmosis ≤ 100 cells/mm3 MAC ≤ 100 cells/mm3 Azithromycin, Clarithromycin CMV ≤ 100 cells/mm3 Gangciclovir OI = opportunistic infection, PCP = Pneumocystis carinii pneumonia, MAC = Mycobacterium avium complex, CMV = cytomegalovirus
- 14. Food and Drug Administration (FDA) pregnancy category National guideline: Thailand 2010
- 20. National guideline: Thailand 2015
- 21. National guideline: Thailand 2015
- 22. How should screening for aneuploidy be undertaken? • HIV infection and/or HAART - biochemical markers – Second-trimester screening for Down syndrome: Elevated hCG, AFP1,2 was associated with high viral loads and low CD4 cell counts2 • Brossard et al (2008)3 - Case–control study of 312 HIV infected women – MOMs for PAPP-A and beta-hCG: lower in HIV-positive women (0.88 vs 1.05 and 0.84 vs 1.09, respectively; P<0.005) – No differences – Fetal NT, alpha fetoprotein (2nd trimester) – No impact on risk estimation of risk of Down syndrome 1 Yudin MH, et al. AJOG 2003; 189: 973–6 2 Gross S, et al. AJOG 2003; 188: 1052–6 3 Brossard P, et al. AIDS 2008; 22: 2013–7
- 23. How should screening for aneuploidy be undertaken? • Savvidou (2010): Case control study: 90 HIV-positive and 450 HIV-negative pregnant women, 1st trimester markers Savvidou et al. BJOG. 2010; 117: 1-5 Param eter HIV neg (n = 450) HIV pos (n = 90) P valu e HIV untreate d (n=49) HIV treated ( n=41) P value Delta NT 0.07 (-0.10 to 0.31) 0.05 (-0.14 to 0.25) 0.14 -0.05 (-0.22 to 0.17) 0.07 (-0.13 to 0.31) 0.16 Free beta hCG(M oM) 1.00 (0.68– 1.47) 0.93 (0.61– 1.45) 0.29 1.03 (0.76– 1.85) 0.74 (0.45– 1.32) 0.00 6 PAPP- A (Mo 1.00 (0.69– 0.94 (0.65– 0.89 1.05 (0.64– 0.89 (0.66– 0.41 No statistically significant differences in the levels of free beta-hCG, PAPP-A and fetal
- 24. How should screening for aneuploidy be undertaken? • Spencer (2010) – Case-control study • 1st trimester: 92 HIV-infected women VS 912 controls – No significant difference – Free Beta-hCG MoM level (0.978 vs. 0.981, p = 1.0) – PAPP-A MoM levels (1.190 vs. 1.102, p = 0.099) – Delta NT (0.1374 vs. 0.0445, p = 0.063) Spencer K. et al. Fetal Diagn Ther. 2010; 24: 1-4
- 25. How should screening for aneuploidy be undertaken? • Spencer (2010) – Case-control study • 2nd trimester: 52 HIV-infected women VS 378 controls – No significant difference: hCG (1.0575 vs. 0.9619, p = 0.18), AFP (0.9734 vs. 0.9350, p = 0.65) – UE3: significantly lower (0.970 vs. 1.110, p = 0.0005) – Further studies are required to evaluate UE3 levels and impact on screening in the second trimester Screening for aneuploidy can be offered to pregnant women who are HIV positive Spencer K. et al. Fetal Diagn Ther. 2010; 24: 1-4
- 26. How safe is invasive diagnostic testing? • Pre-HAART era - increased risk of HIV transmission (2-4 fold) • HAART era – limited data • Somigliana (2005) - multicenter case series: 63 HIV infected women underwent amniocentesis(89%), CVS or cordocentesis: 1st -2nd trimester – 2 of 60 viable infants (3.3%) were infected with HIV – No significant difference observed in women who did not undergo antenatal invasive techniques (1.7%, P = 0.30) – No transmissions occurred among 45 women on combination antiretroviral drug regimens Somigliana E, et al. AJOG 2005; 193: 437–42
- 27. • Mandelbrot (2009) - Multicenter French Perinatal HIV Cohort (1985 – 2006) - 142 amniocenteses / 9302 singleton pregnancies – MTCT in the amniocentesis group • mothers who received no antiretroviral agents – 3/12 (25.0%) • mothers receiving monotherapy or double-NRTI - 3/49 (6.1%) • mothers receiving HAART (0/81) VS 1.2% (30/2,528) when no amniocentesis was performed – Conclusion: Amniocentesis is not a major risk factor for MTCT in mothers treated with effective antiretroviral therapy How safe is invasive diagnostic testing? Mandelbrot L, et al. AJOG 2009;200:160.e1-160.e9
- 28. • For women known to be HIV positive – Taking HAART, viral load > 50 copies/ml - advisable to delay the amniocentesis until the maternal viral load < 50 copies/ml or undetectable – Not already taking HAART, administration of antiretrovirals to cover the procedure is advised – When performing amniocentesis, the placental route is absolutely contraindicated – CVS and cordocentesis - too risky to offer to HIV- infected women How safe is invasive diagnostic testing? RCOG, green top guidelines No 39. July 2010 Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women, USA 2010
- 29. When should ultrasound scanning be undertaken? • Antiretroviral drugs and congenital anomalies – No significant association – Townsend (2009)1 – UK national surveillance study, N=8,242 • Rate of reported major and minor congenital abnormality - 2.8% • No increased risk of abnormalities in infants exposed to efavirenz (2.4%) – NICHD International Site Development Initiative (NISDI) study(2010)2 • Overall prevalence of congenital anomaly - 6.2/100 live births • 1st trimester exposure - similar to 2nd or 3rd trimester exposure 1 Townsend C, et al. AIDS 2009, 23:519–524 2 Joao EC,et al. J Acquir Immune Defic Syndr 2010; 53: 176–85
- 30. What are the complications of HIV and adverse effects of HAART? - prior to antiretroviral use • Brocklehurst (1998) - meta-analysis; 31 prospective studies(1983 -1996) – Spontaneous abortion 4.05 (95% CI 2.75-5.96) – Stillbirth 3.91 (95% CI 2.65-5.77) – Perinatal mortality 1.79 (95% CI 1.14-2.81) – IUGR 1.70 (95% CI 1.43-2.02) – Low birthweight 2.09 (95% CI 1.86-2.35) – Preterm delivery 1.83 (95% CI 1.63-2.06) • More advanced disease and/or immunosuppression - higher rates of adverse outcomes Brocklehurst P, et al. BJOG. 1998;105:836-48
- 31. • Neonatal outcome of premature deliveries VS the increased risk of perinatal transmission • PPROM - GA > 34 weeks – The risk of chorioamnionitis and perinatal HIV transmission should be concerned – Delivery should be expedited • PPROM – GA < 34 weeks – Limited case series data regarding transmission risk in women taking HAART How should preterm PROM be managed?
- 32. Duration of membranes rupture • Meta-analysis of 15 observational studies (4721 HIV- positive patients)* – 2% increase in the risk of transmission for each hour of rupture of membranes (AIDs) – Non-AIDs, 6% at 2 hours and 8% at 24 hours AIDs Non-AIDs Herpes Simplex and HIV infections and Preterm PROM. 2011; 54(2): 330-6
- 33. • PPROM – GA < 34 weeks – No clear guidelines for the management – Multidisciplinary team consultation – HIV physicians and pediatricians – Antenatal corticosteroids – Genital infection screening – Antibiotics for prolonged latency period – Evidence of chorioamnionitis and fetal distress - prompt delivery How should preterm PROM be managed? RCOG, green top guidelines No 39. July 2010 Panel on treatment of HIV-infected pregnant women and prevention of perinatal Transmission, NIH, USA, 2010
- 34. วววววววว • กกกกกกกกกกกกกกกกกกกกกกกก – กกกกกกกกก HAART – กกกกกกกกกกกกก 4 กกกกกกกกกกกกกกก – กกกกกกกกกกกกกกกกกกกกกกก – Viral load กกกกกกกกกกกก 36 กกกกกกก กกกกกกก 1000 copies/mm3 **กกกกกกกกกกกกกกกกกกกกกกกกกกกก 38 กกกกกกก กกกกกกกกก 600mg กกกกกกกกกก กกกกกกก SD-NVP 200mg กกกกกกกกก 4 กก. กกกกกกกกกกกกกกกก • กกกกกกกกกกกกกกกกกก – กกกกกกกกกกกกกกกกกกกกกกกกกกกก กกกกกกกกกกกกกกกกก National guideline: Thailand 2010
- 35. • กกกกกกกกกกกกกก กกกกกกกกกกกกกกกกก กกกก (HAART)กกกกกกกกกกกกกกก กกกกกกก กกกกกกกกกกกกกกกกกกกกกกกกกกกกกกกก – AZT Syrup – กกกกกกกกกกกกกกกกกกกกก 4 mg/kg กกก12 กกกกกกก, 4 กกกกกกก •กกกกกกกกกกกกกกกกกกกก กกกกกกกกกก กกกกกกกกกกกกกกกกกกกกกกกกกก กกกกกก กกกกกกกกก – AZT syrup กกกกกกกกกกกกกกกกกกกกก 4 mg/kg กกก 12 กกกกกกก, 6 กกกกกกก – 3TC syrup กกกกกกกกกกกกกกกกกกกกก 2 mg/kg กกก 12 กกกกกกก, 6 กกกกกกก – Nevirapine syrup 4 mg/kg กกกกกกกกกก กกก ววววววววววววววววววววว วววววววววววววว ววววววว ววววววววววววววววววววววววววววววววววววววววววววววว
- 36. ววววววววววววววววววววววววววววววว National guideline: Thailand 2010 Condom 100% Methods Categories HIV infection On HAART AIDs Pills 1 2 3 Patch 1 2 3 Nuva ring 1 2 3 Implant, injection 1 1 1 Intra-uterine device 2 2 3
- 38. Post-exposure prophylaxis (PEP) กกก V resistance กกกกกกกกกกกกกกกกกกกกกกกกกกกก National guideline, 2014
- 39. Pre-exposure prophylaxis (PrEP) กกกกกกกกกกกก Truvada® (FTC/TDF 200/300mg Per oral OD National guideline, 2014
Editor's Notes
- 0.1 microns in size (4 millionth of an inch!) Viral envelope=proteins gp120 and gp41 make up the “spikes” approx 72. Matrix, just below = p17 Core/capsid is “bullet” shaped (made of protein p24) Inside core: 3 enzymes Reverse Transcriptase Integrase Protease Two identical strands of RNA
- HIV approaches human T cell with CD4 receptor gp120 binds to CD4 receptor exposes V3 loop Binds to co-receptor CR5 or CXCR4 Gp120 dissociates from gp41 Gp41 inserts fusion peptide into cell membrane Fusion pore expands rapidly pushing gp41 aside Propels viral core into host cytoplasm
- Little known about this part Uncoats to release viral genome & accessory proteins RNA converted to DNA Reverse Transcriptase to make double Strand DNA by using nucleotides from cytoplasm Ready to hijack host cells machinery For reproduction of HIV Preintegration complex Viral RNA bridges nuclear membrane Integrase used to insert double stranded DNA Into host cell’s DNA
- Host cell latently infected Viral DNA is a provirus awaiting activation from immune cell Instruction to cell “machinery” to make HIV components 2 strands of RNA, transported out 1 strand translated into subunits of HIV Other strand, template for new HIV Protease separates (cleavage) subunits Subunits combine=new viron