HIV and Women

1. HIV and Women Prevention, fertility, contraception and pregnancy

2. Objectives To discuss the implications of the recent prevention trials on HIV transmission to women To discuss the alternatives for contraception for HIV-positive women To review means of safe conception for HIV concordant and serodiscordant couples To review the management of pregnancy in the setting of HIV

3. Prep trials to prevent transmission with oral agents in women FEM Prep trial of TDF/FTC: trial discontinued due to lack of efficacy VOICE study: oral TDF arm halted due to lack of efficacy; TDF/FTC arm continues Partners Prep study: both TDF and TDF/FTC decreased transmission in men and women (62�73% decrease) TDF2 trial in young adults in Botswana:63% reduction in transmission

4. Prep for prevention of transmission � topical treatments CAPRISA: 1% tenofovir gel, reduced transmission 39% overall, 54% in highly adherent women VOICE study: 1% tenofovir gel, study discontinued due to lack of efficacy FACTS study: 1% tenofovir gel in young women, ongoing Vaginal rings and gels with other agents

5. HPTN 052: HIV-1 transmission Early ART, suppressing replication, led to 96% reduction of sexual HIV-1 transmission in serodiscordant couples We screened 10, 838 infected people to enroll 1763 couples. Note that the couples were equally distributed in groups. 50% of the infected participants were men (WE NEED TO DELETE SOME DETAIL!!) We screened 10, 838 infected people to enroll 1763 couples. Note that the couples were equally distributed in groups. 50% of the infected participants were men (WE NEED TO DELETE SOME DETAIL!!)

6. Preconception Counseling

7. Preconception counseling Should begin at the first visit for any HIV-infected woman of child-bearing age Avoid undesired pregnancy (family planning) Avoid potential teratogens (e.g. efavirenz, ribavirin, tobacco, alcohol, drugs) Maximize physical and mental health before pregnancy Discuss reproduction options that are safe to partner Perform pelvic exam, pap smear, and sexually transmitted disease screening; treat abnormalities Encourage sexual partners to receive HIV testing, counseling, and care

8. Of the 490 HIV+ women, 416 had been pregnant (85%); 56% were UNINTENDED pregnancies Ontario fertility study

9. Birth control options

10. Female contraception in HIV-infection Hormonal contraception: differ mostly based on the progesterone component Combined contraception (combination estrogen and progesterone, including pills, injectables, rings, patches) Progestins only (injectable: depoprovera or DMPA most common, �mini pill�, progesterone-containing intrauterine devices [IUDs]) Non hormonal contraception Copper IUD Condom Diaphragm / cap Sterilization surgery

11. ARVs and oral contraceptives: Drug interactions

12. ACTG 5188: pharmacokinetics�of hormonal contraception when used with LPV/RTV 6-week PK study (oral and transdermal�contraception) looking at EE, Norelgestromin LPV levels in HIV-1 infected women on LPV/r containing regimens (arm A) compared with women on NRTI-only or no ARVs (arm B) Ethinylestradiol was lower (45% in the patch group) and norelgestromin concentrations higher (83% up in the patch group) Conclusion: there is a significant interaction with PI-containing ART regimens. However, due to the increase in progestin level the contraceptive efficacy of the patch is likely to be maintained.� In that case � use progestins only?

13. Hormonal effects on HIV progression Pregnancy: increasing levels of estrogen & progesterone (late plateau) � no substantial effect on disease progression Hormonal contraception (combined or progestin only) Based on animal studies, there is concern regarding adverse progestin effect on disease progression Earlier clinical data conflicting regarding HIV. Increased sexually transmitted infections Important in settings where ART is not available; there is a great need for safe and effective contraception

14. Safety and tolerability of DMPA No significant differences were seen between visits within each arm or in the group overall Women in the control arm were on no ARV therapy or on NRTI only. Women in all other arms were on two or more nucleoside agents along with the drug listedNo significant differences were seen between visits within each arm or in the group overall Women in the control arm were on no ARV therapy or on NRTI only. Women in all other arms were on two or more nucleoside agents along with the drug listed

15. ACTG A5093: DMPA-related toxicity (all mild to moderate)

16. Effect of DMPA on the pharmacokinatics of selected PI and NNRTI therapies Efficacy of DMPA did not appear to be altered DMPA was well-tolerated; side effects were similar to those reported in HIV-negative women Progesterone levels remained low (<1.5ng/mL), with no presumptive evidence of ovulation through week 12 Although NVP AUC levels were higher with DMPA, the increased levels do not appear to be clinically relevant DMPA appears to be safe and effective for HIV-infected women taking NFV, EFV, and NVP-based regimens

17. Hormonal contraception and risk of HIV acquisition among women in South Africa Analysis of women in the Carraguard Phase III efficacy trial: 270 of 5567 women (3.7/100wy) became infected 2.8/100wy oral contraceptive users 4.6/100wy DMPA 3.5/100wy Net-En (northisterone enanthate) 3.4/100wy in non-hormonal contraceptive group Adjusted and non-adjusted rates are not significantly different

18. Effects of injectable hormonal contraceptives on HIV seroconversion 2236 HIV-negative women in Durban, South Africa Those reporting using hormonal contraceptives were less likely to use condoms in their last sexual act Hormonal contraceptives increased risk of HIV infection � adjusted hazard ratio (HR)=1.72 (95% confidence interval [CI] 1.19�2.49; p=0.005)

19. Hormonal contraception and the risks of HIV transmission 3790 heterosexual�serodiscordant couples; in 1314 couples, the HIV seronegative partner was female Rates of HIV acquisition 6.61/100wy hormonal contraceptive group 3.78/100wy in those without Adjusted HR=1.98 (95% CI: 1.06�3.68; p=0.03) Issue � not the primary endpoint, date on contraceptives self report, confounders, absolute number of cases small

20. Contraceptive method and pregnancy incidence African women in HIV discordant partnerships: Significantly reduced pregnancy incidence in HIV+ and HIV- women who used injectable contraception (aHR=0.24; p=0.001) Oral contraceptives significantly reduced pregnancy risk only in HIV seropositive women (aHR=0.51; p=.004) Condoms marginally reduced pregnancy incidence No pregnancies among women with IUD

21. Increased risk of HIV transmission in pregnancy in African serodiscordant couples Partners in prevention study HIV incidence in women 7.35 per 100wy during pregnant period 3.01 per 100wy during non-pregnant period HR=2.34 (95% CI: 1.33�4.09) adjusted HR=1.71 (95% CI: 0.93�3.12)

22. General principles for pregnancy planning Take folic acid: 1�5 mg a day for 1�3 months before and during 1st trimester of pregnancy No smoking or drinking Maintain a balanced diet Terminate the use of recreational drugs 0.4 mg vs. 1mg??? PIC- foods high in folic acid0.4 mg vs. 1mg??? PIC- foods high in folic acid

23. Preconception counseling If pregnancy is planned while on ART: attain maximal virologic suppression prior to pregnancy If pregnancy is planned in women not on therapy: obtain resistance testing and make a decision on choice and timing of ART Prescribe folic acid or prenatal vitamins before conception for planned pregnancies Review diet and avoidance of alcohol, drugs and cigarettes Educate about ovulation and fertility (ovulation 101)

24. Case report: Mrs BK 32-year-old HIV-positive woman Immigrated from the UK to Canada for work advancement Diagnosed with HIV in 2005, clade A virus At diagnosis CD4 210/mm3 and VL 63,000 copies/ml Immediately started on efavirenz, abacavir and lamivudine

25. Case report: Mrs BK Considerable weight gain since diagnosis Increased from 70 to 107 kg, mostly centripetal

26. Case report: Mrs BK Non-smoker No alcohol or recreational drug use Immune to hepatitis B after vaccination Previous LSIL on PAP-, colposcopy normal; no therapy Partner HIV-negative; recently married Condoms for intercourse

27. Case report: Mrs BK January 2009 CD4 468 (28%), VL <50/ml Decides she wants to become pregnant

28. How would you advise her? As her viral load is undetectable she is unlikely to transmit HIV, so can attempt pregnancy with husband without condoms Use the �turkey baster� approach to impregnation Give her husband PrEP with tenofovir/emtricitabine and attempt pregnancy Refer to a fertility clinic for consideration of intrauterine insemination

29. Prevention of horizontal transmission Different clinical scenarios: HIV+ woman with HIV- man (serodiscordant) or who is single or in same sex relationship HIV+ man and HIV- woman (serodiscordant) HIV+ man and HIV+ woman (seroconcordant) HIV+ man who is single, or in same sex relationship, or a couple seeking egg donation or a surrogate mother Different clinical scenarios have different risk of and require different strategies to prevent horizontal transmission Only going over first 3Only going over first 3

30. All scenarios Review all different options for insemination & continuum of risk including: Unprotected intercourse Unprotected intercourse with timed ovulation Home insemination (i.e. turkey baster method) Intrauterine insemination (IUI) (in fertility clinic) Sperm washing followed by IUI Other: in vitro fertilization, intra-cytoplasmic sperm injection, gestational carrier, adoption

31. HIV+ woman and HIV- man: Home insemination Inexpensive and simple Syringe or turkey baster sucks up semen and is inserted into the vagina Must be inserted deep enough to reach mouth of uterus Can be done on the day before and day of ovulation or every other day (from days 12�17 on a 28-day period cycle) Intrauterine insemination in fertility clinic

32. HIV+ man and HIV- woman: Sperm washing and intrauterine insemination Sperm Washing: process by which sperm is separated from seminal fluid by centrifugation Only seminal fluid carries HIV virus* Procedure takes out HIV-free sperm Intrauterine Insemination: Egg is fertilized inside woman�s body �washed sperm� drawn up into a catheter with a tube small enough to be inserted into the body Delivered directly into uterus through vagina Success rate: 10�20% An approximation of the pregnancy rates per cycle of superovulation/IUI performed for the correct indications are as follows: 20% for women under the age of 30.2. 15 % - 18% for women aged between 30 and 35.3. 10 - 15% for women aged 35 to 39.4. 5 - 10% for women over the age of 40. The success rates of superovulation with intrauterine insemination depend on a number of factors. Maternal age and the quality of the male partner sperm count are the most important. From http://www.victoriafertility.com/index.htmAn approximation of the pregnancy rates per cycle of superovulation/IUI performed for the correct indications are as follows: 20% for women under the age of 30.2. 15 % - 18% for women aged between 30 and 35.3. 10 - 15% for women aged 35 to 39.4. 5 - 10% for women over the age of 40. The success rates of superovulation with intrauterine insemination depend on a number of factors. Maternal age and the quality of the male partner sperm count are the most important. From http://www.victoriafertility.com/index.htm

33. HIV+ man and HIV- woman: Sperm washing and Intrauterine insemination Study involving 1036 serodiscordant couples (HIV+ male, HIV- female) wishing to procreate Results: No transmission of HIV to female partner observed after 3272 cycles with complete follow-up information Pregnancy resulted in 580 / 3315 cycles where outcome was known Clinical pregnancy rate = 17.5% (per cycle)

34. HIV+ man and HIV- woman: Unprotected Intercourse 62 HIV-serodiscordant couples, in which the man was positive in 40 cases Median VL was <500 at time of conception Results In all 40 cases, the HIV-seronegative partner remained uninfected One case of vertical transmission This was one of the studies that Vernazza et al cited in their statement for sexually non-infectious HIV+ individuals From this study, Barreiro et al. published a review and protocol for natural pregnancies among HIV+ individualsThis was one of the studies that Vernazza et al cited in their statement for sexually non-infectious HIV+ individuals From this study, Barreiro et al. published a review and protocol for natural pregnancies among HIV+ individuals

35. Correlation between plasma viral load versus semen viral load not perfect 5% of 145 HIV-infected men who enrolled in an ART program with plasma VL undetectable had detectable HIV-RNA in semen1 In 25 men who started ART rapidly suppressed virus in plasma and semen; but when monitored over time, 48% (12/25) had semen HIV shedding more than once and 16% (4/25) had semen VL > 5,000 copies/mL 2

36. Pre-exposure prophylaxis and timed intercourse for HIV discordant couples Male partner VL < 50/ml on cART No report of symptoms of current genital infection in either partner and no unprotected sex with other partners Luteinizing hormone (LH) peak to determine optimal time of conception (36hr after LH peak) PrEP with tenofovir, first dose at LH peak and second 24 hrs later 53 situations, no transmission Pregnancy rate 26% first attempt, 66% after five attempts

37. Both partners are HIV+ Superinfection: a condition in which a person with established HIV infection acquires a 2nd strain of the virus Review all different options for insemination and continuum of risk, including: Unprotected intercourse Unprotected intercourse with timed ovulation* Sperm washing with IUI (in fertility clinic)* Other: IVF, ICSI, sperm donor, adoption

38. Pregnancy issues in HIV

39. Pregnancy-related issues in HIV The following issues will be covered in this section of the slide deck. The following issues will be covered in this section of the slide deck.

40. Testing

41. Revised recommendations: Pregnant women � 1 of 2 Universal opt-out HIV screening in 1st trimester Include HIV in routine panel of prenatal screening tests Consent for prenatal care includes HIV testing Notification and option to decline Second test in 3rd trimester for pregnant women: Known to be at risk for HIV In jurisdictions with elevated HIV incidence In high HIV prevalence health care facilities These are the Recommendations for pregnant women: Universal, opt-out HIV screening for every pregnant woman during each pregnancy. Include HIV testing in the routine panel of prenatal screening tests Consent for prenatal care should include HIV testing Opt-out screening, after the patient is notified that testing will be done, and that she has the option to decline A second test during the 3rd trimester is recommended in certain circumstances, where there is an increased likelihood that a pregnant woman might become infected with HIV during pregnancy, after she has had a negative HIV test. A second test is recommended for women: - Known to be at high risk for HIV (e.g., injection drug users) - In jurisdictions with elevated HIV incidence: these are specified in the Recommendations, and will be revised periodically - In health care facilities in which prenatal screening identifies at least 1 HIV-infected pregnant woman per 1000 women screened These are the Recommendations for pregnant women: Universal, opt-out HIV screening for every pregnant woman during each pregnancy. Include HIV testing in the routine panel of prenatal screening tests Consent for prenatal care should include HIV testing Opt-out screening, after the patient is notified that testing will be done, and that she has the option to decline A second test during the 3rd trimester is recommended in certain circumstances, where there is an increased likelihood that a pregnant woman might become infected with HIV during pregnancy, after she has had a negative HIV test. A second test is recommended for women: - Known to be at high risk for HIV (e.g., injection drug users) - In jurisdictions with elevated HIV incidence: these are specified in the Recommendations, and will be revised periodically - In health care facilities in which prenatal screening identifies at least 1 HIV-infected pregnant woman per 1000 women screened

42. Revised recommendations: Pregnant women � 2 of 2 Opt-out rapid testing with option to decline for women with undocumented HIV status in L&D Initiate ARV prophylaxis on basis of rapid test result Rapid testing of newborn recommended if mother�s status unknown at delivery Initiate ARV prophylaxis within 12 hours of birth on basis of rapid test result (slide)(slide)

43. Why opt-out?Testing by strategy, USA, 1998�1999

44. Rapid HIV test: Understanding positive predictive values Test specificity 99.6% (correct 99.6% of the time) - testing 1000 patients, 4/1000 will have a false positive (wrong) result HIV prevalence = 10% True positive: 100 (10% of 1000). 4/100 will have a false positive result. Total positive tests: 104. Positive predictive value: 100/104 = 96% (96% of positives are true positive) HIV prevalence = 0.1% True positive: 1 (0.1% of 1000). 4/100 will have a false positive result. Positive predictive value: 1/5 = 20% (20% of positives are true positive)

45. Positive predictive value: Depends on specificity and varies with prevalence

46. Time of maternal HIV testing among infants with perinatally acquired HIV It is important for HIV-infected pregnant women to know their HIV infection status in order to make informed decisions about antiretroviral therapy to reduce perinatal transmission of HIV to their infants. The Public Health Service recommends that all pregnant women be offered HIV counseling and voluntary HIV tests. Among the 365 children born during 2006-2009 in the 40 states with confidential name-based HIV infection reporting since at least January 2006 who were perinatally infected with HIV, 39% were born to a mother who was tested before pregnancy, 27% were born to a mother who was tested during pregnancy, and 10% to a mother tested at the time of birth. An additional 14% of children with HIV infection were born to mothers tested after the child�s birth. The following 40 states have had laws or regulations requiring confidential name-based HIV infection reporting since at least January 2006: Alabama, Alaska, Arizona, Arkansas, Colorado, Connecticut, Florida, Georgia, Idaho, Illinois, Indiana, Iowa, Kansas, Kentucky, Louisiana, Maine, Michigan, Minnesota, Mississippi, Missouri, Nebraska, Nevada, New Hampshire, New Jersey, New Mexico, New York, North Carolina, North Dakota, Ohio, Oklahoma, Pennsylvania, South Carolina, South Dakota, Tennessee, Texas, Utah, Virginia, West Virginia, Wisconsin, and Wyoming. Data include persons with a diagnosis of HIV infection regardless of stage of disease at diagnosis. All displayed data have been estimated. Estimated numbers resulted from statistical adjustment that accounted for reporting delays, but not for incomplete reporting. It is important for HIV-infected pregnant women to know their HIV infection status in order to make informed decisions about antiretroviral therapy to reduce perinatal transmission of HIV to their infants. The Public Health Service recommends that all pregnant women be offered HIV counseling and voluntary HIV tests.

47. Mother-to- Child Transmission of HIV How can we prevent this?

48. Perinatal HIV transmission In 1994, before standard AZT use: 21% transmission In 1995, immediately after recommended standard AZT use: 11% transmission Today, risk can be <1�2% with: Routine prenatal care Effective ART Availability of scheduled cesarean section (C/S) if needed Formula feeding In Thailand, transmission rates are up to 24%, in the absence of maternal ARV use; in Africa in breastfeeding populations, the rate of transmission is up to 40%. The perinatal transmission rate in the United States was 21% in 1994 before ZDV recommendations in pregnancy. In 1995, the transmission rate was 11% after the adoption of the �076� ZDV regimen into practice . In a longitudinal epidemiologic US study since 1990, transmission was: 20% in women receiving no ARV treatment in pregnancy 10.4% in women on ZDV alone 3.8% in women receiving combination therapy without protease inhibitors 1.2% in women on combination therapy with protease inhibitors In Thailand, transmission rates are up to 24%, in the absence of maternal ARV use; in Africa in breastfeeding populations, the rate of transmission is up to 40%. The perinatal transmission rate in the United States was 21% in 1994 before ZDV recommendations in pregnancy. In 1995, the transmission rate was 11% after the adoption of the �076� ZDV regimen into practice . In a longitudinal epidemiologic US study since 1990, transmission was: 20% in women receiving no ARV treatment in pregnancy 10.4% in women on ZDV alone 3.8% in women receiving combination therapy without protease inhibitors 1.2% in women on combination therapy with protease inhibitors

49. Trends in reduction of MTCT: Results over time in the field US has experienced a greater than 80% decline in MTCT since PACTG 076, but for every 1 US child born infected, there are 3500�4000 children born infected in other parts of the world. However, improvements have been made: Thailand had slow start but now falls below 2% Africa <5%. Reference McIntyre J, et al 12th CROI 2005; #8US has experienced a greater than 80% decline in MTCT since PACTG 076, but for every 1 US child born infected, there are 3500�4000 children born infected in other parts of the world. However, improvements have been made: Thailand had slow start but now falls below 2% Africa <5%. Reference McIntyre J, et al 12th CROI 2005; #8

50. Mother to child transmission in the UK and Ireland � 2000�2006 (HAART era)

51. Factors associated with MTCT:

52. Timing of transmission

53. Selected clinical risk factors for MTCT Obstetrical Duration of rupture of membranes (ROM) Invasive labor procedures Concomitant STDs, especially ulcerative, also Bacterial vaginosis Chorioamnionitis Low birth weight HIV Disease Low CD4 Viral load at the time of delivery Lack of antivirals Other: other infections (hepatitis, CMV), Illicit drug use and cigarette smoking

54. HIV-RNA levels and ARV use are associated with perinatal transmission

55. Transmission according to last antenatal VL: PACTG 367 (1998�2002)

56. Residual transmission in France, 1997�2007 Case-control study in France: 19 cases (transmitters despite antenatal VL on ART <500); 60 controls (non-transmitters with same) Cases less likely to be on ART at conception (16% vs 45%) Viral load <500 copies/mL cases versus controls: 14 weeks: 0% vs 38.1% 28 weeks: 7.7% vs 62.1% 32 weeks: 21.4% vs 71.1% Multivariate analysis (VL, CD4+, timing of ART initiation): viral load only factor independently associated with MTCT Earlier and sustained control of viral load is associated with a decreasing �residual� risk of HIV MTCT

57. Case report: Mrs BK What would you recommend in terms of her ARV? She is currently on efavirenz and abacavir/3TC: Switch the efavirenz to lopinavir/r Switch the abacavir/3TC to AZT/3TC Leave her current ARV as her viral load is undetectable Switch the efavirenz to nevirapine Switch her to atripla

58. Case report: Mrs BK Efavirenz switched to LPV/r Continued on abacavir/3TC Initially considerable problems with gas and diarrhoea Manipulated diet and timing of tablets with improvement

59. Case report: Mrs BK May 2009: pregnant; EDC Jan 3, 2010 Referred to obstetrics, screening ultrasound, children�s hospital for counselling Increase in fatigue CD4 785 (34%), viral load <50/mL Added chronic suppressive therapy with acyclovir for genital HSV

60. Perinatal guidelines

61. Guidelines for ART in pregnancy: General principals ART to decrease transmission regardless of HIV parameters (VL, CD4) Combination therapy is standard of care both for treatment and pMTCT Longer duration of ART is better for pMTCT than shorter duration 3-part AZT should be included, unless there is significant toxicity or resistance; IV AZT for all Decisions regarding the use and choice of ARV drugs during pregnancy are complex. Several competing factors influencing risks and benefits must be weighed. Discussion regarding use of ARV in pregnancy should include: What is known and unknown about the effects of drugs on the fetus and newborn and lack of data on long-term effects Recommended treatment for the health of the woman The efficacy of ZDV for reducing perinatal HIV transmissionDecisions regarding the use and choice of ARV drugs during pregnancy are complex. Several competing factors influencing risks and benefits must be weighed. Discussion regarding use of ARV in pregnancy should include: What is known and unknown about the effects of drugs on the fetus and newborn and lack of data on long-term effects Recommended treatment for the health of the woman The efficacy of ZDV for reducing perinatal HIV transmission

62. Factors in choosing ART for pregnant women Indication for therapy (maternal HIV disease, pMTCT) Goals and consideration as in non-pregnant patients: potency, durability, preservation of future options, toxicity and tolerability, resistance, adherence Pregnancy specific issues: efficacy in pMTCT, maternal & fetal toxicity, teratogenicity, long-term toxicity, pK, transplacental transfer, timing of treatment initiation, hyperemesis and nausea of pregnancy Choice often made based on collective experience and consensus guidelines, rather than randomized trials

63. Placental transfer of antiviral drugs (antivirals as PrEP and fetal toxicity) PrEP of infant from transplacental passage of drug is an important component of prevention At least one NRTI with high placental transfer should be used: ZDV, 3TC, d4T, ABC, FTC, TDF All NNRTIs cross the placenta There is minimal placental transfer of PIs (LPV transferred better than others) Raltegravir likely crosses placenta

64. Safety of ART during pregnancy:Antiretroviral Pregnancy Registry A collaborative project managed by PharmaResearch Corporation on behalf of an advisory committee (OB/GYN, teratology, epidemiology & ID specialists, CDC, NIH) & sponsored by pharmaceutical companies Voluntary reporting Purpose: To assess safety of ARV drugs during pregnancy Telephone: (800) 258-4263 Fax: (800) 800-1052 available at http://www.apregistry.com

65. FDA pregnancy categories A Studies of pregnant women fail to demonstrate a risk to the fetus during the first trimester of pregnancy B Animal studies fail to demonstrate a risk to the fetus. Studies of pregnant women have not been done C Safety in human pregnancy has not been determined. Animal studies are either positive for fetal risk or have not been conducted D Evidence of human fetal risk. The benefits from the use of the drug in pregnancy may be acceptable despite its risks X Animal and /or human data indicate that the risk associated with the use of the drug in pregnancy clearly outweighs any possible benefit

66. Birth defects associated with first-trimester exposure to individual agents Manufacturers of antiretroviral agents maintain a registry of birth defects associated with antiretroviral therapy. As a group, the rate of birth defects in the first trimester are approximately equivalent to the background rate of birth defects. Didanosine (ddI) is a notable exception among nucleoside analogue reverse transcriptase inhibitors, and nelfinavir among the protease inhibitors. The 10 defects reported with 1st trimester exposure to EFV were (1) polydactyly,(2) hydronephrosis, (3) bilateral hip dislocation and umbilical hernia, (4) bilateral hip dislocation, (5) urinary obstruction, duplicated right collecting system with obstructed upper pole moiety, possibly associated with vesicoureteral reflux, (6) polydactyly, (7) long bones malformation, (8) sacral myelomeningocele and hydrocephalus, (9) shortening of right leg, (10) cutis aplasia (scalp) The Registry notes the high frequency of defects after 1st trimester exposure to didanosine compared with 2nd and 3rd trimester exposures. All defects were reviewed and no pattern was discovered. Data calculated from Table 5 APR CDC MACDP (Metropolitan Atlanta Congenital Defects Program) prevalence (1989-2003) 2.72/100 live births (95% CI 2.68, 2.76) Because MACDP does not publish CIs, these were calculated by the APR Antiviral Pregnancy Registry (APR) Overview International registry designed to: - Monitor prenatal drug exposure - Assess risk of major birth defects Relies on health care provider voluntary reporting of antiretroviral exposures during pregnancy, including Detailed information on antiretroviral exposure in pregnancy Demographic characteristics Other clinical information including indicators of maternal risk factors APR has IRB approval and requires informed consent Data reported from January 1989 through July 2010 676 first trimester exposures to LPV/r as of 31 July 2010 Manufacturers of antiretroviral agents maintain a registry of birth defects associated with antiretroviral therapy. As a group, the rate of birth defects in the first trimester are approximately equivalent to the background rate of birth defects. Didanosine (ddI) is a notable exception among nucleoside analogue reverse transcriptase inhibitors, and nelfinavir among the protease inhibitors. The 10 defects reported with 1st trimester exposure to EFV were (1) polydactyly,(2) hydronephrosis, (3) bilateral hip dislocation and umbilical hernia, (4) bilateral hip dislocation, (5) urinary obstruction, duplicated right collecting system with obstructed upper pole moiety, possibly associated with vesicoureteral reflux, (6) polydactyly, (7) long bones malformation, (8) sacral myelomeningocele and hydrocephalus, (9) shortening of right leg, (10) cutis aplasia (scalp) The Registry notes the high frequency of defects after 1st trimester exposure to didanosine compared with 2nd and 3rd trimester exposures. All defects were reviewed and no pattern was discovered. Data calculated from Table 5 APR CDC MACDP (Metropolitan Atlanta Congenital Defects Program) prevalence (1989-2003) 2.72/100 live births (95% CI 2.68, 2.76) Because MACDP does not publish CIs, these were calculated by the APR Antiviral Pregnancy Registry (APR) Overview International registry designed to: - Monitor prenatal drug exposure - Assess risk of major birth defects Relies on health care provider voluntary reporting of antiretroviral exposures during pregnancy, including Detailed information on antiretroviral exposure in pregnancy Demographic characteristics Other clinical information including indicators of maternal risk factors APR has IRB approval and requires informed consent Data reported from January 1989 through July 2010 676 first trimester exposures to LPV/r as of 31 July 2010

67. Safety of efavirenz in first-trimester observational cohorts Systemic review and meta-analysis of 16 studies found 9 prospective studies reporting on congenital abnormalities in infants exposed to ART in first trimester 1,132 live birth exposed to efavirenz containing regimens 7,163 live birth exposed non-efavirenz containing ART Across all studies, one neural tube defect was reported with efavirenz use No increased risk of overall birth defects was found when efavirenz was compared with other antiviral drugs Study VERY SMALL

68. Perinatal ARVs and congenital anomalies: P1025 Outcomes of infants enrolled in IMPAACT P1025 and born 2002�2007 61/1112 infants had congenital anomaly (5.49/100 live births [95% CI: 4.22�6.99)]) � higher than general population in 2008 (2.76/100 live births) and in WITS (3.6), APR (2.9) Efavirenz exposure in 1st trimester demonstrated odd ratio (OR) of 2.89 (95% CI: 1.15�7.25) for congenital anomaly Overall anomalies: 33 cardiac, 3 CNS, 3 chromosomal, 3 craniofacial, 3 eye, 5 GI, 7 GU, 15 musculoskeletal, 8 renalOverall anomalies: 33 cardiac, 3 CNS, 3 chromosomal, 3 craniofacial, 3 eye, 5 GI, 7 GU, 15 musculoskeletal, 8 renal

69. Perinatal ARVs and congenital anomalies: P1025 Overall anomalies: 33 cardiac, 3 CNS, 3 chromosomal, 3 craniofacial, 3 eye, 5 GI, 7 GU, 15 musculoskeletal, 8 renalOverall anomalies: 33 cardiac, 3 CNS, 3 chromosomal, 3 craniofacial, 3 eye, 5 GI, 7 GU, 15 musculoskeletal, 8 renal

70. Birth defects of ATZ in pregnancy From pregnancy registry N=698; 604 recorded outcomes N=368 first trimester; eight birth defects, prevalence 2.2% (0.9�4.2%) Second/ third trimester exposure (n=199); five defects, defect rate 2.5% No obvious pattern for defect

71. Safety of ATZ/r in pregnancy N=41 (n=20, 300/100mg; n=21 400/100mg) Grade 3�4 bilirubin in mother: 6/20; 13/21 All infants had normal bilirubin at birth through day 14 Then seven developed grade 3�4 bilirubin consistent with physiologic changes in normals Maternal bilirubin, cord ATZ levels poorly predictive of infant bilirubin

72. Safety of ART in pregnancy PIs Hyperglycemia Theoretical concern for kernicterus: IDV and ATV (indirect, protein binding) Controversial: premature birth, low birth weight � data may be biased by indication for PI therapy

73. Preterm delivery rates by type of antiretroviral therapy

74. Effect of prenatal cARV exposure on live births Beckerman K, et al; Poster TULBPE018

75. TDF in pregnancy Recommended in special circumstances (HBV, resistance, ZDV intolerance) IMPAACT P1026s, tenofovir PKs: AUC lower. Troughs unchanged; significance not clear. No dose adjustments Theoretical safety concerns: bone mineralization, and renal function Animal studies: reversible bone abnormalities in some; dose, exposure, age, and species specific Case series of 76 women: well tolerated. In 20 TDF-exposed infants and 20 controls no differences in renal function, including cystatin C levels, through to 2 years of age Retrospective review of 16 pregnancy outcomes in 15 heavily ARV experienced women: normal growth and development in TDF-exposed infants

76. Mma Bana study, Botswana: Birth outcomes

77. In utero ARV exposure: Potentially concerning toxicities Congenital anomalies (EFV, other?) Prematurity/low birth weight (PI) Abnormal fetal bone mineralization and growth (TDF) Hematologic abnormalities (NRTI) Mitochondrial dysfunction (NRTI) Increased malignancy risk1�3? (NRTI, through mutagenesis, clastogenesis and telomere attrition) Cardiovascular abnormalities? (NRTI) Neurodevelopmental problems

78. When to start: Treating before or after organogenesis Treating Early Assess efficacy Assess tolerability Assess adherence Early and sustainable virologic control ? lower residual transmission Deferring to 2nd trimester Avoid fetal toxicity Delay treatment if undesired and not otherwise indicated Cost

79. Public Health Service Task Force ARVs in pregnant HIV-infected women

80. Drug PK in pregnancy: Physiologic changes affecting drug administration Cardiovascular: increased cardiac output, volume expansion, changes in regional blood flow ? dilution Gastrointestinal: delayed gastric emptying, increased gastric acidity, increased transit time ? absorption Renal: increased GFR 20�60% ? clearance Hepatic: enzyme activity changes: CYP34A and CYP2D6 increased, others decreased ? clearance

81. Case report: Mrs BK What do you recommend around the time of delivery? She should have a caesarean section You should increase her LPV/r dose You should monitor her viral load and if it increases then increase her LPV/r dose She should receive intravenous AZT during labour No changes, and allow a vaginal delivery

82. ARV PKs in pregnancy A: Controlled studies show no risk B: No evidence of risk in humans- ddI, TDF, ritonavir, nelfinavir, saquinavir, etravirine, maraviroc C: Risk cannot be ruled out- all other ARVs not listed above D: Positive evidence of risk- efavirenz, hydroxyurea X: Studies among animals or reports of adverse reactions have indicated that the risk associated with the use of the drug for pregnant women clearly outweighs any possible benefit. Contraindicated in pregnancy- ribavirin, thalidomide Treatment with efavirenz should be avoided during the first trimester because significant congenital central nervous system abnormalities were seen in cynomolgus monkeys born to mothers who received efavirenz during pregnancy at drug exposures similar to those representing human exposure. Severe central nervous system defects have been reported in four infants after first trimester exposure to efavirenz-containing regimens (three infants with meningomyelocele and one with a Dandy-Walker malformation). Based on these data, efavirenz has been classified as FDA Pregnancy Class D (positive evidence of human fetal risk) Food and Drug Administration Pregnancy Categories: A - Adequate and well-controlled studies of pregnant women fail to demonstrate a risk to the fetus during the first trimester of pregnancy (and no evidence exists of risk during later trimesters). B - Animal reproduction studies fail to demonstrate a risk to the fetus, and adequate but well-controlled studies of pregnant women have not been conducted. C - Safety in human pregnancy has not been determined; animal studies are either positive for fetal risk or have not been conducted, and the drug should not be used unless the potential benefit outweighs the potential risk to the fetus. D - Positive evidence of human fetal risk that is based on adverse reaction data from investigational or marketing experiences, but the potential benefits from the use of the drug among pregnant women might be acceptable despite its potential risks. X - Studies among animals or reports of adverse reactions have indicated that the risk associated with the use of the drug for pregnant women clearly outweighs any possible benefit. A: Controlled studies show no risk B: No evidence of risk in humans- ddI, TDF, ritonavir, nelfinavir, saquinavir, etravirine, maraviroc C: Risk cannot be ruled out- all other ARVs not listed above D: Positive evidence of risk- efavirenz, hydroxyurea X: Studies among animals or reports of adverse reactions have indicated that the risk associated with the use of the drug for pregnant women clearly outweighs any possible benefit. Contraindicated in pregnancy- ribavirin, thalidomide Treatment with efavirenz should be avoided during the first trimester because significant congenital central nervous system abnormalities were seen in cynomolgus monkeys born to mothers who received efavirenz during pregnancy at drug exposures similar to those representing human exposure. Severe central nervous system defects have been reported in four infants after first trimester exposure to efavirenz-containing regimens (three infants with meningomyelocele and one with a Dandy-Walker malformation). Based on these data, efavirenz has been classified as FDA Pregnancy Class D (positive evidence of human fetal risk) Food and Drug Administration Pregnancy Categories: A - Adequate and well-controlled studies of pregnant women fail to demonstrate a risk to the fetus during the first trimester of pregnancy (and no evidence exists of risk during later trimesters). B - Animal reproduction studies fail to demonstrate a risk to the fetus, and adequate but well-controlled studies of pregnant women have not been conducted. C - Safety in human pregnancy has not been determined; animal studies are either positive for fetal risk or have not been conducted, and the drug should not be used unless the potential benefit outweighs the potential risk to the fetus. D - Positive evidence of human fetal risk that is based on adverse reaction data from investigational or marketing experiences, but the potential benefits from the use of the drug among pregnant women might be acceptable despite its potential risks. X - Studies among animals or reports of adverse reactions have indicated that the risk associated with the use of the drug for pregnant women clearly outweighs any possible benefit.

83. Lopinavir concentrations with 400/100mg BID dose (PACTG 1026S)

84. LPV/r PK studies: Tablets Brazil. PI: M. Oliveira. N=60 Pharmacokinetics of the Tablet Formulation of Lopinavir/r as Standard and Increased Dosage During Pregnancy in HIV-Infected Women Lopinavir/r (200/50 mg, 2 tablets every 12 hours) plus two nucleoside analogs, starting at any time between 14 and 30 weeks of gestation and maintained for at least 6 weeks after delivery. Lopinavir/r (200/50 mg, 2 tablets every 12 hours) plus two nucleoside analogs, starting at any time between 14 and 30 weeks of gestation, increase the lopinavir/r dosage (200/50 mg, 3 tablets every 12 hours) in the third trimester (from 25 weeks on), and return to standard dose(200/50 mg, 2 tablets every 12 hours) for at least 6 weeks after delivery. Estimated Study Completion Date: February 2010 Oliveira enrolled study: 60 (30 ea arm) planned 27 each arm adequate power Group 1 SD Bid Group 2 SD Bid to 24W EGA then 3 tab Bid to deliver Prospective, randomized PK of SD vs. HD Also evaluate transplacental passage of LPV/r maternal blood at delivery and in cord blood of the two drug dosages (SD & HD) during pregnancy 10 Endpoint: AUC for both LPV doses during T2 and T3 and 6 wk PP 20 Cmax and Cmin at same points Treatment for 6 wks PP No indication of outcomes collection It appears we only supported with drug Best: HD comparable exp to non-preg adult on SD. LPV exposure with increased dose inT3 still lower than that seen in these same women on SD at 2 wks PP VL<400 at delivery 23/26 subjects data were not available for 7 women Infant HIV neg 31; indeterminate 2 Kiser: 12 hr PK 20-24 wk (T1); 30-34wk (T2)\ Random levels drawn within 2 wk PK and dose adjusted if AUC and C12 below 25th (68.6 mcg*hr/mL) and 50th percentiles (4.5 mcg/mL) 8/10 required dose ? in T2; 2 in T3 LPV and RTV sig less protein bound during preg vs. PP. LPV and RTV 38-50% less protein bound during pregnancy vs. PP (p<0.04). LPV binding 17% ? in T3 vs.T2 (p=0.049). RTV binding similar in T2 and T3 Patterson 4 SS PK; 20-24 wk (PK1), 30 wk (PK2), 32 wks (PK3); 8 wks PP (PK4). Total and unbound LPV AUCs did not change significantly between PK1, PK2 and PK3, and all lower than PK4. Unbound AUC and C12h increased by ~22% from PK2 to PK3. No study-related AEs, viral rebounds or transmissions occurred All total Cmin concentrations >1000 ng/mL RTV not reported Brazil. PI: M. Oliveira. N=60 Pharmacokinetics of the Tablet Formulation of Lopinavir/r as Standard and Increased Dosage During Pregnancy in HIV-Infected Women Lopinavir/r (200/50 mg, 2 tablets every 12 hours) plus two nucleoside analogs, starting at any time between 14 and 30 weeks of gestation and maintained for at least 6 weeks after delivery. Lopinavir/r (200/50 mg, 2 tablets every 12 hours) plus two nucleoside analogs, starting at any time between 14 and 30 weeks of gestation, increase the lopinavir/r dosage (200/50 mg, 3 tablets every 12 hours) in the third trimester (from 25 weeks on), and return to standard dose(200/50 mg, 2 tablets every 12 hours) for at least 6 weeks after delivery. Estimated Study Completion Date: February 2010 Oliveira enrolled study: 60 (30 ea arm) planned 27 each arm adequate power Group 1 SD Bid Group 2 SD Bid to 24W EGA then 3 tab Bid to deliver Prospective, randomized PK of SD vs. HD Also evaluate transplacental passage of LPV/r maternal blood at delivery and in cord blood of the two drug dosages (SD & HD) during pregnancy 10 Endpoint: AUC for both LPV doses during T2 and T3 and 6 wk PP 20 Cmax and Cmin at same points Treatment for 6 wks PP No indication of outcomes collection It appears we only supported with drug Best: HD comparable exp to non-preg adult on SD. LPV exposure with increased dose inT3 still lower than that seen in these same women on SD at 2 wks PP VL<400 at delivery 23/26 subjects data were not available for 7 women Infant HIV neg 31; indeterminate 2 Kiser: 12 hr PK 20-24 wk (T1); 30-34wk (T2)\ Random levels drawn within 2 wk PK and dose adjusted if AUC and C12 below 25th (68.6 mcg*hr/mL) and 50th percentiles (4.5 mcg/mL) 8/10 required dose ? in T2; 2 in T3 LPV and RTV sig less protein bound during preg vs. PP. LPV and RTV 38-50% less protein bound during pregnancy vs. PP (p<0.04). LPV binding 17% ? in T3 vs.T2 (p=0.049). RTV binding similar in T2 and T3 Patterson 4 SS PK; 20-24 wk (PK1), 30 wk (PK2), 32 wks (PK3); 8 wks PP (PK4). Total and unbound LPV AUCs did not change significantly between PK1, PK2 and PK3, and all lower than PK4. Unbound AUC and C12h increased by ~22% from PK2 to PK3. No study-related AEs, viral rebounds or transmissions occurred All total Cmin concentrations >1000 ng/mL RTV not reported

85. Atazanavir in pregnancy IMPAACT (pACTG) 1026s: In 3rd trimester AUC below target in 33% w/o and 55% on TDF Trough concentration was below the target in 6% (1 of 18) A dose increase to 400 mg/100 mg may be necessary in pregnant women, especially if on TDF

86. PK of atazanavir in pregnancy N=17 Italian pregnant women on ATV+RTV with AZT+3TC Intensive 24 hour PK performed in T3 and 8-16 weeks post-partum ATV overall exposure at steady state during T3 similar to pre-partum 17/17 women VL<50 All infants HIV negative at 3 months

87. pACTG 1026s: Intense PK in 3rd trimester and 6�12 wks postpartum in women taking ATV/RTV 300/100 QD with (20) or without (18) TDF Median atazanavir C24 h significantly ? during 3rd trimester compared with postpartum both for women not receiving TDF (0.7 vs. 1.2 mcg/mL, P = 0.002) and those receiving TDF (0.5 vs. 0.8 mcg/mL, P = 0.0008) AUC below target in 33% of women not receiving TDF and 55% receiving TDF Ctrough below the target (0.15 mcg/mL) in 6% without TDF and 15% receiving TDF Author�s Conclusion: Dose ? of ATV/RTV to 400 mg/100 mg may be necessary in pregnant women to ensure ATV exposure equivalent to non-pregnant adults Atazanavir pharmacokinetics with and without tenofovir during pregnancy

88. Atazanavir pharmacokinetics with and without tenofovir during pregnancy

89. Case report: Mrs BK What do you recommend after delivery? Stop all ARV as her CD4 count is > 500 Switch the LPV/r back to efavirenz Continue the current regimen Allow her to breast feed as her viral load is undetectable and she is unlikely to transmit Do not recommend contraception as she will not likely get pregnant in the near future

90. Caesarean section and HIV transmission 1. European Mode of Delivery Collaboration Lancet 1999;353:1035�1039; 2. Mandelbrot L et al. JAMA 1998;280:55�60. There was consensus among the Board members that it may not be necessary to utilise the triple approach (including caesarian section) to reduce the risk of transmission during pregnancy as this approach is based on old data. As shown in this slide. It was suggested that the mother�s well-being should be taken into account when deciding on the method of childbirth. In an ideal world, routine caesarian section in these patients may not now be necessary. However, members from Mexico and Germany reported that C section for PMTCT is still commonly practiced in their countries. In Germany, C section is recommended in the National Guidelines, whereas in Mexico it is commonly practiced, even though not recommended, mainly due to the high rates of diagnosis late in pregnancy, and because the results from viral load testing can take a long time. Sometimes arriving after delivery, which leaves insufficient time for effective HAART treatment. Reference 1. European Mode of Delivery Collaboration. Lancet 1999;353:1035-1039. Mandelbrot L et al. JAMA 1998;280:55-60 Lancet. 1999 Mar 27;353(9158):1035-9. Elective caesarean-section versus vaginal delivery in prevention of vertical HIV-1 transmission: a randomised clinical trial. European Mode of Delivery Collaboration. Collaborators (124) Parazzini F, Ricci E, Di Cintio E, Chiaffarino F, Chatenoud L, Pardi G, Parazzini F, Bortolus R, Cavalieri D'Oro L, Biraghi P, Bucceri A, Ravizza M, Grossi E, Muggiasca ML, Tibaldi C, Prati A, Iasci A, Aronica E, Ceccarelli E, Frigerio L, Borlone P, Stagnizza M, Agnoletto V, Togoni G, Lazzrin A, Massobrio M, Garzetti GG, Ciavattini A, Mosca S, Greco P, Vimercati A, Guerra B, Bianchi S, Bovicelli L, Prati E, Innocenti TA, Fiscella A, Bucceri A, Grossi E, Rossi G, Rancilio L, Ferraris G, Vignali M, Muggiasca ML, Semprini AE, Ravizza M, Castagna C, Della Torre M, Martinelli P, Sansone M, di Lenardo L, Russolo A, Rubino E, Lo Bue G, Maccabruni A, Arlandi L, Citernesi A, Villa P, Mancuso S, Pachi A, Scaravelli G, Tibaldi C, Benedetto C, Ziarati N, Gabiano C, Alberico S, Franchi M, Zanconato G, Fedele L, Newell ML, Bailey A, Peckham C, Darbyshire J, Sanchez E, Semprini AE, Leyes M, Ciria LM, Coll O, Fortuny C, Bogunya JM, Paya A, Mur A, Casellas M, Lain J, Anzen B, Lindgren S, Rudin C, Irion O, Bewley S, Kennedy J, Mandelbrot L, Bazin B, Aboulker JP, Crenn-Hebert C, Floch Tudal C, Bech A, Lobut R, Chemla JP, Milliez J, Courpotin C, Mandelbrot L, Firtion G, Benifla JL, Ottenwalter A, Vilmer E, Hocke C, Douard D, Berrebi A, Tricoire J, Pauly I, Le Lorier B, Bongain A, Monpoux F, Cravello L, Perrimond H, Newell ML, Darbyshire J, Peckham C, Coll O, Sanchez E, Mandelbrot L, Aboulker JP, Bazin B, Blanche S. Erratum in: Lancet 1999 May 15;353(9165):1714. Comment in: Abstract BACKGROUND: Results from observational studies suggest that caesarean-section delivery may reduce the risk of mother-to-child transmission of HIV-1 infection in comparison with vaginal delivery. We carried out a randomised clinical trial to address this issue and to assess the extent of postdelivery complications. METHODS: Eligible women were between 34 and 36 weeks of pregnancy, with a confirmed diagnosis of HIV-1 infection, and without an indication for caesarean-section delivery or a contraindication to this mode of delivery. Women were randomly assigned elective caesarean-section delivery at 38 weeks of pregnancy or vaginal delivery. An infant was classified as uninfected if he or she became negative for antibody to HIV-1 by age 18 months or was negative for virus by PCR or culture on at least two occasions, with no clinical, immunological, or viral evidence of infection. From 1993, to March, 1998, 436 women were randomised. FINDINGS: We present the results of an analysis updated to November, 1998, with data on the infection status of 370 infants. Three (1.8%) of 170 infants born to women assigned caesarean-section delivery were infected, compared with 21 (10.5%) of 200 born to women assigned vaginal delivery (p<0.001). Seven (3.4%) of 203 infants of women who actually gave birth by caesarean section were infected compared with 15 (10.2%) of 167 born vaginally (p=0.009). There were few postpartum complications and no serious adverse events in either group. INTERPRETATION: Our findings provide evidence that elective caesarean-section delivery significantly lowers the risk of mother-to-child transmission of HIV-1 infection without a significantly increased risk of complications for the mother. PMID: 10199349 JAMA. 1998 Jul 1;280(1):55-60. Perinatal HIV-1 transmission: interaction between zidovudine prophylaxis and mode of delivery in the French Perinatal Cohort. Mandelbrot L, Le Chenadec J, Berrebi A, Bongain A, B�nifla JL, Delfraissy JF, Blanche S, Mayaux MJ. Service de Gyn�cologie-Obst�trique I, H�pital Cochin-Port Royal and the Institut National de la Sant� et de la Recherche M�dicale U149, Paris, France. laurent.mandelbrot@cch.ap-hop-paris.fr Abstract CONTEXT: It is unclear whether elective cesarean delivery may have a protective effect against the transmission of human immunodeficiency virus 1 (HIV-1). OBJECTIVE: To investigate whether mode of delivery has an impact on perinatal HIV-1 transmission in the presence of zidovudine prophylaxis. DESIGN: A prospective cohort study. SETTING: The 85 perinatal centers in the French Perinatal Cohort, from 1985 to 1996. PATIENTS: A total of 2834 singleton children born to mothers with HIV-1 infection. MAIN OUTCOME MEASURE: Human immunodeficiency virus 1 infection of the infant. RESULTS: No zidovudine was used in 1917 pregnancies and zidovudine prophylaxis was used in 902 pregnancies. Cesarean deliveries were performed in 10.9% on an emergent basis and in 8.3% electively, prior to labor or membrane rupture. In 1917 mothers who did not receive zidovudine, of 1877 with information on mode of delivery, 17.2% transmitted HIV-1 to their child. Risk factors statistically significantly associated with transmission were maternal p24 antigenemia, cervicovaginal infections during pregnancy, amniotic fluid color, and rupture of membranes 4 hours or more before delivery. Mode of delivery was not related to transmission. In 902 mothers receiving zidovudine, transmission was 6.4% in 872 with information on mode of delivery, and elective cesarean delivery (n = 133) was associated with a lower transmission rate than emergent cesarean or vaginal delivery (0.8%, 11.4%, and 6.6%, respectively; P=.002). In a multivariate analysis of all mother-child pairs, including obstetrical risk factors, maternal p24 antigenemia, and zidovudine prophylaxis, interaction between mode of delivery and zidovudine prophylaxis was significant (P=.007). In the multivariate analysis of pregnancies with zidovudine prophylaxis, factors related to transmission rate were maternal p24 antigenemia, amniotic fluid color, and mode of delivery. Adjusted odds ratios (95% confidence intervals) were 1.6 (0.7-3.6) for emergent cesarean delivery and 0.2 (0.0-0.9) for elective cesarean delivery (P = .04) in comparison with vaginal delivery. CONCLUSIONS: We observed an interaction between zidovudine prophylaxis and elective cesarean delivery in decreasing transmission of HIV-1 from mother to child. This observation may have clinical implications for prevention. PMID: 9660364 There was consensus among the Board members that it may not be necessary to utilise the triple approach (including caesarian section) to reduce the risk of transmission during pregnancy as this approach is based on old data. As shown in this slide. It was suggested that the mother�s well-being should be taken into account when deciding on the method of childbirth. In an ideal world, routine caesarian section in these patients may not now be necessary. However, members from Mexico and Germany reported that C section for PMTCT is still commonly practiced in their countries. In Germany, C section is recommended in the National Guidelines, whereas in Mexico it is commonly practiced, even though not recommended, mainly due to the high rates of diagnosis late in pregnancy, and because the results from viral load testing can take a long time. Sometimes arriving after delivery, which leaves insufficient time for effective HAART treatment. Reference 1. European Mode of Delivery Collaboration. Lancet 1999;353:1035-1039. Mandelbrot L et al. JAMA 1998;280:55-60 Lancet. 1999 Mar 27;353(9158):1035-9. Elective caesarean-section versus vaginal delivery in prevention of vertical HIV-1 transmission: a randomised clinical trial. European Mode of Delivery Collaboration. Collaborators (124) Parazzini F, Ricci E, Di Cintio E, Chiaffarino F, Chatenoud L, Pardi G, Parazzini F, Bortolus R, Cavalieri D'Oro L, Biraghi P, Bucceri A, Ravizza M, Grossi E, Muggiasca ML, Tibaldi C, Prati A, Iasci A, Aronica E, Ceccarelli E, Frigerio L, Borlone P, Stagnizza M, Agnoletto V, Togoni G, Lazzrin A, Massobrio M, Garzetti GG, Ciavattini A, Mosca S, Greco P, Vimercati A, Guerra B, Bianchi S, Bovicelli L, Prati E, Innocenti TA, Fiscella A, Bucceri A, Grossi E, Rossi G, Rancilio L, Ferraris G, Vignali M, Muggiasca ML, Semprini AE, Ravizza M, Castagna C, Della Torre M, Martinelli P, Sansone M, di Lenardo L, Russolo A, Rubino E, Lo Bue G, Maccabruni A, Arlandi L, Citernesi A, Villa P, Mancuso S, Pachi A, Scaravelli G, Tibaldi C, Benedetto C, Ziarati N, Gabiano C, Alberico S, Franchi M, Zanconato G, Fedele L, Newell ML, Bailey A, Peckham C, Darbyshire J, Sanchez E, Semprini AE, Leyes M, Ciria LM, Coll O, Fortuny C, Bogunya JM, Paya A, Mur A, Casellas M, Lain J, Anzen B, Lindgren S, Rudin C, Irion O, Bewley S, Kennedy J, Mandelbrot L, Bazin B, Aboulker JP, Crenn-Hebert C, Floch Tudal C, Bech A, Lobut R, Chemla JP, Milliez J, Courpotin C, Mandelbrot L, Firtion G, Benifla JL, Ottenwalter A, Vilmer E, Hocke C, Douard D, Berrebi A, Tricoire J, Pauly I, Le Lorier B, Bongain A, Monpoux F, Cravello L, Perrimond H, Newell ML, Darbyshire J, Peckham C, Coll O, Sanchez E, Mandelbrot L, Aboulker JP, Bazin B, Blanche S. Erratum in: Lancet 1999 May 15;353(9165):1714. Comment in: Abstract BACKGROUND: Results from observational studies suggest that caesarean-section delivery may reduce the risk of mother-to-child transmission of HIV-1 infection in comparison with vaginal delivery. We carried out a randomised clinical trial to address this issue and to assess the extent of postdelivery complications. METHODS: Eligible women were between 34 and 36 weeks of pregnancy, with a confirmed diagnosis of HIV-1 infection, and without an indication for caesarean-section delivery or a contraindication to this mode of delivery. Women were randomly assigned elective caesarean-section delivery at 38 weeks of pregnancy or vaginal delivery. An infant was classified as uninfected if he or she became negative for antibody to HIV-1 by age 18 months or was negative for virus by PCR or culture on at least two occasions, with no clinical, immunological, or viral evidence of infection. From 1993, to March, 1998, 436 women were randomised. FINDINGS: We present the results of an analysis updated to November, 1998, with data on the infection status of 370 infants. Three (1.8%) of 170 infants born to women assigned caesarean-section delivery were infected, compared with 21 (10.5%) of 200 born to women assigned vaginal delivery (p<0.001). Seven (3.4%) of 203 infants of women who actually gave birth by caesarean section were infected compared with 15 (10.2%) of 167 born vaginally (p=0.009). There were few postpartum complications and no serious adverse events in either group. INTERPRETATION: Our findings provide evidence that elective caesarean-section delivery significantly lowers the risk of mother-to-child transmission of HIV-1 infection without a significantly increased risk of complications for the mother. PMID: 10199349 JAMA. 1998 Jul 1;280(1):55-60. Perinatal HIV-1 transmission: interaction between zidovudine prophylaxis and mode of delivery in the French Perinatal Cohort. Mandelbrot L, Le Chenadec J, Berrebi A, Bongain A, B�nifla JL, Delfraissy JF, Blanche S, Mayaux MJ. Service de Gyn�cologie-Obst�trique I, H�pital Cochin-Port Royal and the Institut National de la Sant� et de la Recherche M�dicale U149, Paris, France. laurent.mandelbrot@cch.ap-hop-paris.fr Abstract CONTEXT: It is unclear whether elective cesarean delivery may have a protective effect against the transmission of human immunodeficiency virus 1 (HIV-1). OBJECTIVE: To investigate whether mode of delivery has an impact on perinatal HIV-1 transmission in the presence of zidovudine prophylaxis. DESIGN: A prospective cohort study. SETTING: The 85 perinatal centers in the French Perinatal Cohort, from 1985 to 1996. PATIENTS: A total of 2834 singleton children born to mothers with HIV-1 infection. MAIN OUTCOME MEASURE: Human immunodeficiency virus 1 infection of the infant. RESULTS: No zidovudine was used in 1917 pregnancies and zidovudine prophylaxis was used in 902 pregnancies. Cesarean deliveries were performed in 10.9% on an emergent basis and in 8.3% electively, prior to labor or membrane rupture. In 1917 mothers who did not receive zidovudine, of 1877 with information on mode of delivery, 17.2% transmitted HIV-1 to their child. Risk factors statistically significantly associated with transmission were maternal p24 antigenemia, cervicovaginal infections during pregnancy, amniotic fluid color, and rupture of membranes 4 hours or more before delivery. Mode of delivery was not related to transmission. In 902 mothers receiving zidovudine, transmission was 6.4% in 872 with information on mode of delivery, and elective cesarean delivery (n = 133) was associated with a lower transmission rate than emergent cesarean or vaginal delivery (0.8%, 11.4%, and 6.6%, respectively; P=.002). In a multivariate analysis of all mother-child pairs, including obstetrical risk factors, maternal p24 antigenemia, and zidovudine prophylaxis, interaction between mode of delivery and zidovudine prophylaxis was significant (P=.007). In the multivariate analysis of pregnancies with zidovudine prophylaxis, factors related to transmission rate were maternal p24 antigenemia, amniotic fluid color, and mode of delivery. Adjusted odds ratios (95% confidence intervals) were 1.6 (0.7-3.6) for emergent cesarean delivery and 0.2 (0.0-0.9) for elective cesarean delivery (P = .04) in comparison with vaginal delivery. CONCLUSIONS: We observed an interaction between zidovudine prophylaxis and elective cesarean delivery in decreasing transmission of HIV-1 from mother to child. This observation may have clinical implications for prevention. PMID: 9660364

91. MTCT in the UK and Ireland2000�2006 (HAART era) Among 2117 infants born to women on HAART, with VL < 50, only three (0.1%) were infected, two with evidence of in-utero transmission Longer duration of HAART was associated with reduced transmission after adjusting for VL, mode of delivery and sex (adjusted odds ratio 0.90, or 10% reduction, per week of HAART (P=0.007) Among women on HAART, there was no difference in MTCT rates between elective CS (0.7%, 17/2286) and planned vaginal delivery (0.7%, 4/559); adjusted for sex and viral load

92. Case report: Mrs BK Would you recommend a C-section if she also had HCV? Yes No Depends on her HCV viral load

93. Can I breast feed? Complete avoidance of breastfeeding is efficacious in pMTCT of HIV Formula milk also has disadvantages Discrimination/stigma of not breastfeeding in some communities If breastfeeding is initiated, three interventions to be considered Continuing ART for the mother following delivery Chronic ART prophylaxis for the infant (nevirapine alone, or nevirapine with zidovudine) Limiting breastfeeding to the first few months of life The concerns HIV transmission (HIV-DNA in milk of women with undetectable VL) ART passed through milk to child with unknown long-term effects

94. Mma Bana study A Randomized Trial Comparing Highly Active Antiretroviral Therapy Regimens for Virologic Efficacy and the Prevention of Mother-to-Child HIV Transmission among Breastfeeding Women in Botswana Primary outcomes: Maternal HIV-1 RNA < 400 copies/mL at delivery & throughout breastfeeding at 1, 3, 6M (or weaning) MTCT rates by infant HIV DNA PCR at birth and 1, 3, 6 months

95. Mma Bana study 730 women enrolled: 560 randomized (PI vs NRTI); 170 observational (Obs) HIV-1 RNA suppression did not differ by randomization arm at birth (93% PI vs 96% NRTI; p=0.18), or throughout breastfeeding (93% PI vs 92% NRTI; p=0.98) and Obs 95% MTCT rates were low: <1% in PI (one in utero transmission) vs 2% NRTI (three in utero and two breastfeeding); p=0.53 and <1% Obs (one in utero) Infant 6-month mortality was 3% PI; 2% NRTI and Obs 4%

96. Mma Bana study

97. BAN study (Breastfeeding, Antiretroviral and Nutrition): 28-week results

98. BAN study: Results By Week 2 after delivery, infants in each three study groups had similar estimated risk of infection: 5.4% control group, 5.5% maternal-regimen group, & 4.4% infant-regimen group (p=0.35) Estimated risk of HIV-1 transmission by 28 weeks in those uninfected at week 2 was higher in control arm (5.7%) compared to either intervention arms (2.9% in maternal HAART [p=0.003] and 1.7% in infant NVP arm [p<0.0001]) Estimated risk of HIV-1 transmission or death by 28 weeks was 7.0% in control arm compared to 4.1% in maternal HAART arm (p=0.03) & 2.6% in infant NVP arm (p<0.0001) Conclusion: Either maternal HAART or infant NVP for 28 weeks is effective in reducing HIV-1 transmission during breastfeeding

99. BAN study: Results

100. Is it SMART to stop after pregnancy? SMART study suggests that stopping results in increased HIV-related and unrelated clinical events regardless of CD4 Want a healthy mother What about transmission to a non-discordant partner

101. Stopping ART post-partum Controversial issue If Nadir CD4 falls within guidelines to treat � continue, but most would recommend continuing in all in resource rich settings, as treatment interruption not recommended in other settings If discontinued, stop all drugs simultaneously, unless significant differences in half-life Modifications appropriate Do not stop in HBV co-infected (reactivation risk) Contraception, contraception, contraception Adherence monitoring When stopping antiretroviral therapy, current recommendations suggest discontinuing all antiretroviral drugs simultaneously to avoid the development of drug resistance. However, if the drugs have significant differences in half-life, such a strategy may result in functional monotherapy for a period of time; if there is actively replicating virus, this could lead to development of resistance. This issue is a particular concern with the NNRTI class of drugs, both because of their long half-lives and low genetic barrier to resistance. This has clinical relevance in pregnancy, as women may interrupt ongoing therapy in early pregnancy because of nausea and vomiting or concerns about first trimester fetal exposure. Additionally, many pregnant women may not yet meet criteria for maternal treatment and are prescribed combination antiretroviral therapy solely for prophylaxis against perinatal transmission. In this situation, therapy is routinely stopped after delivery. Recent data indicate that there may be significant plasma levels of nevirapine or efavirenz for prolonged periods of time (more than 2 weeks) after stopping chronic therapy, as well as after receipt of single-dose nevirapine. Nevirapine resistance mutations have been identified postpartum in women who have received single-dose intrapartum nevirapine prophylaxis, as well as in women who have stopped nevirapine-containing combination regimens taken during pregnancy for prevention of mother-to-child transmission. In the latter study, nevirapine resistance was seen in 16% of women despite staggered stopping of the antiretroviral drugs (in which the nucleoside backbone was continued for 5 days after stopping nevirapine). Preliminary data from a South African study suggest that administration of single-dose nevirapine combined with ZDV/3TC given intrapartum and for 4 or 7 days postpartum may reduce, although not eliminate, the development of resistance compared with administration of single-dose nevirapine alone . Further research is needed to assess appropriate strategies for stopping nevirapine-containing combination regimens that are used during pregnancy for prevention of mother-to-child transmission, and to prevent development of resistance after receipt of single-dose nevirapine for prevention of intrapartum transmission. Additionally, research is needed to evaluate the effect of transient nevirapine resistance on later treatment options. When stopping antiretroviral therapy, current recommendations suggest discontinuing all antiretroviral drugs simultaneously to avoid the development of drug resistance. However, if the drugs have significant differences in half-life, such a strategy may result in functional monotherapy for a period of time; if there is actively replicating virus, this could lead to development of resistance. This issue is a particular concern with the NNRTI class of drugs, both because of their long half-lives and low genetic barrier to resistance. This has clinical relevance in pregnancy, as women may interrupt ongoing therapy in early pregnancy because of nausea and vomiting or concerns about first trimester fetal exposure. Additionally, many pregnant women may not yet meet criteria for maternal treatment and are prescribed combination antiretroviral therapy solely for prophylaxis against perinatal transmission. In this situation, therapy is routinely stopped after delivery. Recent data indicate that there may be significant plasma levels of nevirapine or efavirenz for prolonged periods of time (more than 2 weeks) after stopping chronic therapy, as well as after receipt of single-dose nevirapine. Nevirapine resistance mutations have been identified postpartum in women who have received single-dose intrapartum nevirapine prophylaxis, as well as in women who have stopped nevirapine-containing combination regimens taken during pregnancy for prevention of mother-to-child transmission. In the latter study, nevirapine resistance was seen in 16% of women despite staggered stopping of the antiretroviral drugs (in which the nucleoside backbone was continued for 5 days after stopping nevirapine). Preliminary data from a South African study suggest that administration of single-dose nevirapine combined with ZDV/3TC given intrapartum and for 4 or 7 days postpartum may reduce, although not eliminate, the development of resistance compared with administration of single-dose nevirapine alone . Further research is needed to assess appropriate strategies for stopping nevirapine-containing combination regimens that are used during pregnancy for prevention of mother-to-child transmission, and to prevent development of resistance after receipt of single-dose nevirapine for prevention of intrapartum transmission. Additionally, research is needed to evaluate the effect of transient nevirapine resistance on later treatment options.

102. PROMISE � P1077 study: Promoting maternal infant survival everywhere IMPAACT 1077HS, HAART Standard Version of the PROMISE Study: This version will be conducted in settings where the standard method of infant feeding is formula feeding and the standard of care for prevention of mother-to-child-transmission (PMTCT) for women who do not meet criteria for highly active antiretroviral therapy (HAART) for their own health involves use of HAART regimens throughout pregnancy. IMPAACT 1077BF, Breastfeeding Version of the PROMISE Study: This version will be conducted among breastfeeding populations in settings where the standard of care for PMTCT for women who do not meet criteria for HAART for their own health involves use of zidovudine or other non-HAART regimens during pregnancy. IMPAACT 1077FF, Formula Feeding Version of the PROMISE Study: This version will be conducted among formula feeding populations in settings where the standard of care for PMTCT for women who do not meet criteria for HAART for their own health involves use of zidovudine or other non-HAART regimens during pregnancy. The study will have three randomization periods: Antepartum ( randomized to HAART vs SOC ( AZT+SDNVP); Post partum ( randomized to maternal HAART or infant NVP; Maternal Health: Continue HAART or stop HAART after breast feeding interruption PROMISE has designated three study versions according to standard of care in sites were study will be conducted 1077 BF: Breastfeeding component: Sites were breastfeeding in the only infant nutritional support. Will have three randomization: (Total = 4440) Antepartum; Post partum Maternal Health 1077 FF: Formula Fed component, Sites were AP care includes AZT +SDNVP , however formula mutritional support is provided for infants. Will participate of two randomization. Total =1550 Antepartum Maternal Health 10077 HS: Standard of care includes HAART as well as formula nutritional support .Will participate of one randomization T=2000. Maternal Health. NOTE: this is the only version that is open as of today. Each randomization period will have the following # of subjects randomized: AP: HAART ( LPV/r +2 NRTIs) vs (AZT + SD NVP): 4,400 ( 3400 from BF and 1000 FF) PP: HAART ( LPV/r +2 NRTIs) to mother vs (infant NVP): 4,650 (3100 from AP component and 1550 late presenters) Maternal Health ( LPV/r +2 NRTIs) vs no HAART: 5950 (2125 on HAART AP; 2100 on HAART during BF; up to 2 IMPAACT 1077HS, HAART Standard Version of the PROMISE Study: This version will be conducted in settings where the standard method of infant feeding is formula feeding and the standard of care for prevention of mother-to-child-transmission (PMTCT) for women who do not meet criteria for highly active antiretroviral therapy (HAART) for their own health involves use of HAART regimens throughout pregnancy. IMPAACT 1077BF, Breastfeeding Version of the PROMISE Study: This version will be conducted among breastfeeding populations in settings where the standard of care for PMTCT for women who do not meet criteria for HAART for their own health involves use of zidovudine or other non-HAART regimens during pregnancy. IMPAACT 1077FF, Formula Feeding Version of the PROMISE Study: This version will be conducted among formula feeding populations in settings where the standard of care for PMTCT for women who do not meet criteria for HAART for their own health involves use of zidovudine or other non-HAART regimens during pregnancy. The study will have three randomization periods: Antepartum ( randomized to HAART vs SOC ( AZT+SDNVP); Post partum ( randomized to maternal HAART or infant NVP; Maternal Health: Continue HAART or stop HAART after breast feeding interruption PROMISE has designated three study versions according to standard of care in sites were study will be conducted 1077 BF: Breastfeeding component: Sites were breastfeeding in the only infant nutritional support. Will have three randomization: (Total = 4440) Antepartum; Post partum Maternal Health

103. Case report: Mrs BK Spontaneous vaginal delivery Baby HIV-negative Discussed continuing current ARV or switching back to EFV She preferred LPV/r as she had fewer CNS symptoms Feb 2011: all well, returned to work Jan 2011: CD4 > 700/mm3, VL<50/ml

104. Case report: Mrs BK Generally well Struggles with fatigue and occasional sleeplessness Some nausea with medications � infrequently misses doses 2008: CD4 470 (28%), and viral load <50 copies/ml

105. Conclusions Given the improvements in morbidity and mortality and the changing epidemiology of HIV more women are electing to become pregnant Preconception counseling should occur early and continuously as part of care for women Important considerations are maternal health, prevention of transmission to partners and babies, drug interactions, ARV safety and efficacy